METHODS FOR TREATING ZIKA VIRUS INFECTIONS

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This patent application claims the benefit under 35 U.S.C. §119(e) of U.S.

Provisional Patent Application No. 62/326,664, filed April 22, 2016. The foregoing application is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The invention relates generally to methods and compounds for treating Zika virus infections.

BACKGROUND OF THE INVENTION

[0003] Viruses comprising the Flaviviridae family comprise at least three distinquishable genera including pestiviruses, flaviviruses, and hepaciviruses (Calisher, et al., J. Gen. Virol., 1993, 70, 37-43). While pestiviruses cause many economically important animal diseases such as bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, hog cholera) and border disease of sheep (BDV), their importance in human disease is less well characterized (Moennig, V., et al., Adv. Vir. Res. 1992, 48, 53-98). Flaviviruses are responsible for important human diseases such as dengue fever and yellow fever while hepaciviruses cause hepatitis C virus infections in humans. Other important viral infections caused by the Flaviviridae family include West Nile virus (WNV) Janpanese encephalitis virus (JEV), tick-borne encephalitis virus, Junjin virus, Murray Valley encephalitis, St Louis enchaplitis, Omsk hemorrhagic fever virus and Zika virus. Combined, infections from the Flaviviridae virus family cause significant mortality, morbidity and economic losses throughout the world. Therefore, there is a need to develop effective treatments for Flaviviridae virus infections, particularly Zika virus infections.

SUMMARY OF THE INVENTION

[0004] In an embodiment, a method of treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound represented by the group selected from Formula I, Formula II, Formula III or Formula IV, of a pharmaceutically acceptable salt thereof, wherein Formula I, Formula II, Formula III or Formula IV are defined herein.

[0005] In an embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound selected from:

and pharmaceutically acceptable salts thereof.

[0006] In an embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound:

or a pharmaceutically acceptable salt, thereof.

[0007] In an embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound:

or a pharmaceutically acceptable salt, thereof.

[0008] In an embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound:

or a pharmaceutically acceptable salt, thereof.

[0009] In an embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administerin a therapeutically effective amount of a compound:

or a pharmaceutically acceptable salt, thereof.

[0010] In an embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administerin a therapeutically effective amount of a compound:

or a pharmaceutically acceptable salt, thereof.

[0011] In an embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of any two compounds selected from:



and pharmaceutically acceptable salts thereof.

[0012] In an embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of compounds:

or pharmaceutically acceptable salts thereof.

[0013] In an embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of or a pharmaceutically acceptable salt thereof,

and

or a pharmaceutically acceptable salt thereof.

[0014] In an embodiment, a compound of Formula I, Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt thereof, for use in treating a Zika virus infection in a human

[0015] In an embodiment, the use of a compound of Formula I, Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament useful in treating a Zika virus infection in a human.

[0016] In an embodiment, a kit comprising one or more individual dosage units of a compound selected from those described in Formula I, Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt, ester, stereoisomer, hydrate, solvate, mixture of stereoisomers, or tautomer thereof, and directions for their use in treating a Zika viral infection in a human. DETAILED DESCRIPTION OF THE INVENTION

I. DEFINITIONS

[0017] Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

[0018] When a cyclic group (e.g. cycloalkyl, carbocyclyl, bicyclic carbocyclyl, heteroaryl, heterocyclyl) is limited by a number or range of numbers, the number or numbers refer to the number of atoms making up the cyclic group, including any heteroatoms. Therefore, for example, a 4-8 membered heterocyclyl group has 4, 5, 6, 7 or 8 ring atoms.

[0019] "Alkenyl" refers to a straight or branched chain hydrocarbyl with at least one site of unsaturation, e.g., a (¾9 ² )carbon-(¾9 ² )carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH ₂ ) and allyl (-CH ₂ CH=CH ₂ ).

[0020] "Alkenylene" refers to an alkene having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Exemplary alkenylene radicals include, but are not limited to, 1,2-ethenylene

(-CH=CH-) or prop-l-enylene (-CH ₂ CH=CH-).

[0021] "Alkoxy" is RO- where R is alkyl, as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy and propoxy.

[0022] "Alkyl" refers to a saturated, straight or branched chain hydrocarbyl radical. For example, an alkyl group can have 1 to 8 carbon atoms (i.e. , (d-Cs) alkyl) or 1 to 6 carbon atoms (i.e. , (Ci-C ₆ alkyl) or 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

[0023] "Alkylene" refers to an alkyl having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Examples of alkylene radicals include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -) and butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -).

[0024] "Alkynyl" refers to a straight or branched chain hydrocarbon with at least one site of unsaturation, e.g., a (s/?)carbon-(.¾9)carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms ( C ₂ -Cs alkyne) or 2 to 6 carbon atoms ( C ₂ -C ₆ alkynyl). Examples of alkynyl groups include, but are not limited to, acetylenyl (-C≡CH) and propargyl

(-CH ₂ C≡CH) groups.

[0025] "Alkynylene" refers to an alkynyl having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but are not limited to, acetylene (-C≡C-), propargylene (-CH ₂ C≡C-), and 1-pentynylene (-CH ₂ CH ₂ CH ₂ C≡C-).

[0026] "Aryl" refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system (e.g., a fused multicyclic ring system) wherein at least one of the rings is aromatic. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocyclyl portion of the ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl and indanyl.

[0027] "Arylene" refers to an aryl as defined herein having two monovalent radical centers derived by the removal of two hydrogen atoms from two different carbon atoms of a parent aryl. t are not limited to, phenylene, e.g. ,

[0028] "Bicyclic carbocyclyl" refers to a 5-14 membered saturated or partially unsaturated bicyclic fused, bridged, or spiro ring hydrocarbon attached via a ring carbon. In a spiro bicyclic carbocyclyl, the two rings share a single common carbon atom. In a fused bicyclic carbocyclyl, the two rings share two common and adjacent carbon atoms. In a bridged bicyclic carbocyclyl, the two rings share three or more common, non-adjacent carbon atoms. Examples of bicyclic carbocyclyl groups include, but are not limited to spiro bicyclic

carbocyclyl groups wh share three or more (such as 3, 4, 5 or 6)

common atoms

[0029] "Bicyclic carbocyclylene" refers to a bicyclic carbocyclyl, as defined above, having two monovalent radical centers derived from the removal of two hydrogen atoms from the same or two different carbon atom of a parent bicyclic carbocyclyl. Examples of bicyclic carbocyclylene groups include, but are not limited to, spiro bicyclic carbocyclylene groups wherein two carbocyclyl rings share one common atom

, fuse

carbocyc lyl rings share two common atoms ed bicyclic carbocyclylene groups wherein two carbo rings share three or more (such as 3,

or 6) common atoms

[0030] "Carbocyclyloxy" is RO- where R is carbocyclyl, as defined herein.

[0031] "Bicyclic carbocyclyloxy" is RO- where R is bicyclic carbocyclyl, as defined herein.

[0032] "Carbocyclyl", and "carbocycle" refers to a hydrocarbyl group containing one saturated or partially unsaturated ring structure, attached via a ring carbon. In various embodiments, carbocyclyl refers to a saturated or a partially unsaturated C3-C12 cyclic moiety, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl.

[0033] "Carbocyclylene" (as well as "carbocyclene") refers to a carbocyclyl, as defined herein, having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent carbocyclyl. Examples of carbocyclene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene and

cyclohexylene. [0034] "Carbocyclylalkyl" refers to a hydrocarbyl group containing one saturated or partially unsaturated ring structure attached to an alkyl group, attached via a ring carbon or an alkyl carbon. In various embodiments, carbocyclylalkyl refers to a saturated or a partially unsaturated C _r -Ci2 carbocyclylalkyl moiety, examples of which include cyclopropylalkyl, cyclobutylalkyl, cyclopropylethyl, and cyclopropylpropyl.

[0035] "Carbocyclylalkylene" refers to a carbocyclylalkyl, as defined herein, having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent cycloalkylalkyl. Examples of cycloalkylene include, but are not limited to, cyclopropylmethylene and cyclopropylmethylene.

[0036] "Cycloalkyl" refers to a hydrocarbyl group containing one saturated ring structure, attached via a ring carbon. In various embodiments, cycloalkyl refers to a saturated C3-C12 cyclic moiety, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0037] "Cycloalkoxy" is RO- where R is cycloalkyl, as defined herein.

[0038] "Direct bond" refers a covalent bond between two atoms.

[0039] "Halo" or "halogen" refers to chloro (-C1), bromo (-Br), fluoro (-F) or iodo

(-1).

[0040] "Haloalkenyl" refers to alkenyl group, as defined herein, substituted with one or more halogen atoms.

[0041] "Haloalkoxy" refers to alkoxy, as defined herein, substituted with one or more halogen atoms.

[0042] "Haloalkyl" refers to an alkyl group, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. Examples of haloalkyl groups include, but are not limited to, -CF ₃ , -CHF ₂ , -CFH ₂ and -CH ₂ CF ₃ .

[0043] "Haloalkylene" refers to alkylene group, as defined herein, substituted with one or more halogen atoms.

[0044] "Heteroalkyl" refers to an alkyl group, as defined herein, in which one or more carbon atoms is replaced with an oxygen, sulfur, or nitrogen atom.

[0045] "Heteroalkylene" refers to an alkylene group, as defined herein, in which one or more carbon atoms is replaced with an oxygen, sulfur, or nitrogen atom.

[0046] "Heteroalkenyl" refers to an alkenyl group, as defined herein, in which one or more carbon atoms is replaced with an oxygen, sulfur, or nitrogen atom. [0047] "Heteroalkenylene" refers to heteroalkenyl group, as defined above, having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different atoms of a parent heteroalkenyl group.

[0048] "Heteroaryl" refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such aromatic ring. For example, heteroaryl includes monocyclic, bicyclic or tricyclic ring having up to 6 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms in the ring selected from the group consisting of oxygen, nitrogen and sulfur. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Non-limiting examples of heteroaryl include pyridyl, thienyl, furanyl, pyrimidyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, benzothienyl, indolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoindolyl, benzotriazolyl, purinyl, thianaphthenyl and pyrazinyl. Attachment of heteroaryl can occur via an aromatic ring, or, if heteroaryl is bicyclic or tricyclic and one of the rings is not aromatic or contains no heteroatoms, through a non-aromatic ring or a ring containing no heteroatoms. "Heteroaryl" is also understood to include the N-oxide derivative of any nitrogen containing heteroaryl.

[0049] "Heteroarylene" refers to a heteroaryl, as defined above, having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms or the removal of a hydrogen from one carbon atom and the removal of a hydrogen atom from one nitrogen atom of a parent heteroaryl group. Non-limiting examples of heteroar lene groups are:

[0050] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic group of 2 to 14 ring-carbon atoms and, in addition to ring-carbon atoms, 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Bi- or tricyclic heterocyclyl groups may have fused, bridged, or spiro ring connectivity. In various embodiments the heterocyclic group is attached to another moiety through carbon or through a heteroatom. Examples of heterocyclyl include without limitation azetidinyl, oxazolinyl, isoxazolinyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, 1,4-dioxanyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,

dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,

dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, chromanyl, dihydropyranoquinoxalinyl, tetrahydroquinoxalinyl, tetrahydroquinolinyl,

dihydropyranoquinolinyl and tetrahydrothienyl and N-oxides thereof. A spiro bicyclic heterocyclyl group refers to a bicyclic heterocyclyl group wherein the two rings of the bicyclic heterocyclyl group share one common atom. A fused bicyclic bicyclic heterocyclyl group refers to a bicyclic heterocyclyl group wherein the two rings of the bicyclic heterocyclyl group share two common atoms. A bridged bicyclic heterocyclyl group refers to a bicyclic heterocyclyl group wherein the two rings of the bicyclic heterocyclyl group share three or more (such as 3, 4, 5 or 6) common atoms.

[0051] "Heterocyclene" refers to a heterocyclyl, as defined herein, having two monovalent radical centers derived from the removal of two hydrogen atoms from the same or two different carbon atoms, through a carbon and a heteroatom, or through two heteroatoms of a parent heterocycle.

[0052] "Prodrug" refers to any compound that when administered to a biological system generates the drug substance, or active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound. Non-limiting examples of prodrugs include ester moieties, quaternary ammonium moieties, glycol moieties, and the like.

[0053] The term "optionally substituted" refers to a moiety wherein all substituents are hydrogen or wherein one or more of the hydrogens of the moiety are replaced by non- hydrogen substituents; that is to say the moiety that is optionally substituted is either substituted or unsubstituted.

[0054] "Leaving group" (LG) refers to a moiety of a compound that is active towards displacement or substitution in a chemical reaction. Examples of in which such as displacement or substitution occur include, but are not limited to, nucleophilic substitution bimolecular (SN2), nucleophilic substitution unimolecular (SNI), nucleophilic aromatic substitution (SNAT), and transition metal catalyzed cross-couplings. Examples of leaving groups include, but are not limited to, a halogen atom (e.g. -CI, -Br, -I) and sulfonates (e.g. mesylate (-OMs), tosylate (-OTs) or triflate (-OTf)). The skilled artisan will be aware of various chemical leaving groups and strategies for activation and will appreciate the appropriate moiety that will act as leaving groups, based on the particular chemical reaction, the functionality that the group is attached to, and the chemical reagents used to affect the displacement or substitution reaction. As a non-limiting example, in some situations, a halogen atom (e.g. -CI, -Br, or -I) serves as a leaving group in a reaction catalyzed by a transition metal (e.g. Pd catalyzed Suzuki coupling between an aryl halide and aryl boronic acid) and another reagents such as a base.

[0055] Stereoisomers: Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York.

[0056] The term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.

[0057] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers and diastereomers.

"Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0058] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate.

[0059] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. [0060] The compounds disclosed herein may have chiral centers, e.g., chiral carbon atoms. Such compounds thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds disclosed herein include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. [0061] Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. The racemic mixtures can be separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. The desired optical isomer can also be synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.

[0062] It is to be understood that for compounds disclosed herein when a bond is drawn in a non-stereochemical manner (e.g., flat) the atom to which the bond is attached includes all stereochemical possibilities. It is also to be understood that when a bond is drawn in a stereochemical manner (e.g., bold, bold-wedge, dashed or dashed-wedge) the atom to which the stereochemical bond is attached has the stereochemistry as shown unless otherwise noted.

[0063] Accordingly, in one embodiment, a compound disclosed herein is greater than 50% a single enantiomer. In another embodiment, a compound disclosed herein is at least 80% a single enantiomer. In another embodiment, a compound disclosed herein is at least 90% a single enantiomer. In another embodiment, a compound disclosed herein is at least 98% a single enantiomer. In another embodiment, a compound disclosed herein is at least 99% a single enantiomer. In another embodiment, a compound disclosed herein is greater than 50% a single diastereomer. In another embodiment, a compound disclosed herein is at least 80% a single diastereomer. In another embodiment, a compound disclosed herein is at least 90% a single diastereomer. In another embodiment, a compound disclosed herein is at least 98% a single diastereomer. In another embodiment, a compound disclosed herein is at least 99% a single diastereomer. [0064] Tautomers: The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.

[0065] Isotopes: It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( ² H or D). As a non- limiting example, a -CH ₃ group may be replaced by -CD ₃ .

[0066] Specific values listed below for radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. [0067] Protecting Groups: In certain embodiments, protecting groups include prodrug moieties and chemical protecting groups. Protecting groups may be represented by the abbreviation "PG."

[0068] "Protecting group" ("PG") refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g. Peter G. M. Wuts and Theodora W. Greene,_Protective Groups in Organic Synthesis, 4 ^th edition; John Wiley & Sons, Inc.: New Jersey, 2007. See also Kocienski, P.J. Protecting Groups, 3 edition; Georg Thieme Verlag Stuttgart: New York, 2005, in particular Chapter 1, Protecting Groups: An Overview, pages 1-48, Chapter 2, Carbonyl Protecting Groups, pages 49-118, Chapter 3, Diol Protecting Groups, pages 119-186, Chapter 4, Hydroxyl Protecting Groups, pages 187-364, Chapter 5, Thiol Protecting Groups, pages 365-392. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g. , making and breaking chemical bonds in an ordered and planned fashion.

Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity

(hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0069] In certain embodiments, protecting groups are optionally employed to prevent side reactions with the protected group during synthetic procedures. Selection of the appropriate groups to protect, when to do so, and the nature of the chemical protecting group "PG" is dependent upon the chemistry of the reaction to be protected against (e.g. , acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. PGs do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.

[0070] Salts and Hydrates: Examples of pharmaceutically acceptable salts of the compounds disclosed herein include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX ₄ ⁺ (wherein X is Ci-C ₄ alkyl). Pharmaceutically acceptable salts of a nitrogen atom or an amino group include for example salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- toluenesulfonic acids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic acids. Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na ⁺ and NX ₄ ⁺ (wherein each X is independently selected from H or a Ci-C ₄ alkyl group).

[0071] For therapeutic use, salts of active ingredients of the compounds disclosed herein will typically be pharmaceutically acceptable, i.e., they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of Formula I, II, III or IV, (such as any one of IVa-IVh) or a stereoisomer, or a mixture of stereoisomers, or another compound disclosed herein. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.

Metal salts typically are prepared by reacting the metal hydroxide with a compound disclosed herein. Examples of metal salts which are prepared in this way are salts containing Li ⁺ , Na ⁺ , and K ⁺ . A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

[0072] In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HQ, HBr, H2S04, H3PO4 or organic sulfonic acids, to basic centers, such as amines. Finally, it is to be understood that the compositions herein comprise compounds disclosed herein in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

II. COMPOUNDS OF THE PRESENT INVENTION

[0073] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying description, structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention.

[0074] Where duplicate substituents (i.e. R groups) appear, the disclosed substituent only applies to preceeding Formula I, II, III or IV. For example, R ¹ appears in both Formula I and Formula IV. The definition for R ¹ with regards to Formula I is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of Ci_ ₆ alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, Ci_6 alkoxy, F, CI, Br, I, nitro, cyano, Ci_6 haloalkyl, -N(R ¹ ) ₂ , Ci_6 acylamino, - NHS0 ₂ Ci_6 alkyl, -S0 ₂ N(R ^r ) ₂ , COR ^1" , and -S0 ₂ Ci_ ₆ alkyl; (R ^r is independently hydrogen or alkyl, which includes, but is not limited to, Ci- ₂₀ alkyl, Ci_io alkyl, or Ci_6 alkyl, R ¹ is -OR' or -N(R ^r ) ₂ ). The definition of R ¹ for Formula IV is H or F.

[0075] Provided is a method for treating a Zika infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula I:

wherein (a) R ¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 alkoxy, F, CI, Br, I, nitro, cyano, Ci_6 haloalkyl, -N(R ^r )2, Ci_ ₆ acylamino, -NHS0 ₂ Ci_ ₆ alkyl, -SC^NCR ^1' ^, COR ^1" , and -S0 ₂ Ci_ ₆ alkyl; (R ¹ is independently hydrogen or alkyl, which includes, but is not limited to, Ci _-20 alkyl, C _1-10 alkyl, or Ci_ ₆ alkyl, R ^1" is -OR' or -N(R ^r )2);

(b) R ² is hydrogen, C 1-1 ₀ alkyl, R ^3a or R ^3b and R ² together are (0¾) _η so as to form a cyclic ring that includes the adjoining N and C atoms, C(0)CR ^3a R ^3b NHR ¹ , where n is 2 to 4 and R ¹ , R ^3a , and R ^3b ; (c) R ^3a and R ^3b are (i) independently selected from hydrogen, Ci_io alkyl, cycloalkyl, -(CH ₂ ) _C (NR ³ )2, Ci_ ₆ hydroxyalkyl, -CH ₂ SH, -(CH ₂ ) ₂ S(0) _d Me, - (CH ₂ ) ₃ NHC(=NH)NH2, (lH-indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH ₂ ) _e COR ³ , aryl and aryl Ci_3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, Ci_io alkyl, Ci_6 alkoxy, halogen, nitro and cyano; (ii) R ^3a and R ^3b both are Ci_6 alkyl; (iii) R ^3a and R ^3b together are(CH2) _f so as to form a spiro ring; (iv) R ^3a is hydrogen and R ^3b and R ² together are (CH ₂ ) _n so as to form a cyclic ring that includes the adjoining N and C atoms (v) R ^3b is hydrogen and R ^3a and R ² together are (0¾) _η so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R ³ is independently hydrogen or Ci_6 alkyl and R ^3" is -OR or -N(R ³ ) ₂ ); (vi) R ^3a is H and R ^3b is H, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CH(CH ₃ ) ₂ , CH(CH ₃ )CH ₂ CH ₃ , CH ₂ Ph, CH ₂ -indol-3-yl, -CH ₂ CH ₂ SCH ₃ , CH ₂ C0 ₂ H, CH ₂ C(0)NH ₂ , CH ₂ CH ₂ COOH,

CH ₂ CH ₂ C(0)NH ₂ , CH2CH2CH2CH2NH2, -CH ₂ CH ₂ CH2NHC(NH)NH2, CH ₂ -imidazol-4-yl, CH ₂ OH, CH(OH)CH ₃ , CH ₂ ((4'-OH)-Ph), CH ₂ SH, or lower cycloalkyl; or (viii) R ^3a is CH ₃ , - CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CH(CH ₃ ) ₂ , CH(CH ₃ )CH ₂ CH ₃ , CH ₂ Ph, CH ₂ -indol-3-yl, - CH ₂ CH ₂ SCH ₃ , CH ₂ C0 ₂ H, CH ₂ C(0)NH ₂ , CH ₂ CH ₂ COOH, CH ₂ CH ₂ C(0)NH ₂ ,

CH2CH2CH2CH2NH2, -CH ₂ CH ₂ CH2NHC(NH)NH2, CH ₂ -imidazol-4-yl, CH ₂ OH,

CH(OH)CH ₃ , CH ₂ ((4'-OH)-Ph), CH ₂ SH, or lower cycloalkyl and R ^3b is H, where R ³ is independently hydrogen or alkyl, which includes, but is not limited to, Ci _-20 alkyl, Ci_io alkyl, or Ci_6 alkyl, R ^3" is -OR or -N(R ³ ) ₂ ); (d) R ⁴ is hydrogen, Ci_io alkyl, Ci_io alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, Ci_io haloalkyl, C ₃ _io cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R ⁵ is H, a lower alkyl, CN, vinyl, 0-(lower alkyl), hydroxyl lower alkyl, i.e., - (CH ₂ ) _p OH, where p is 1 -6, including hydroxyl methyl (CH ₂ OH), CH ₂ F, N ₃ , CH ₂ CN, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , alkyne (optionally substituted), or halogen, including F, CI, Br, or I, with the provisos that when X is OH, base is cytosine and R ⁶ is H, R ⁵ cannot be N ₃ and when X is OH, R ⁶ is CH ₃ or CH ₂ F and B is a purine base, R ⁵ cannot be H;

(f) R ⁶ is H, CH ₃ , CH ₂ F, CHF ₂ , CF ₃ , F, or CN;

(g) X is H, OH, F, OMe, halogen, NH ₂ , or N ₃ ; (h) Y is OH, H, Ci_ ₄ alkyl, C ₂ _ ₄ alkenyl, C ₂ _ ₄ alkynyl, vinyl, N ₃ , CN, CI, Br, F, I,

N0 ₂ , OC(0)0(Ci_ ₄ alkyl), OC(0)0(Ci_ ₄ alkyl), OC(0)0(C ₂ _ ₄ alkynyl), OC(0)0(C ₂ _ ₄ alkenyl), OCi-1 ₀ haloalkyl, O(aminoacyl), 0(Ci_io acyl), 0(Ci_ ₄ alkyl), 0(C ₂ _ ₄ alkenyl), S(Ci_ ₄ acyl), S(C alkyl), S(C ₂ _ ₄ alkynyl), S(C ₂ _ ₄ alkenyl), SO(d_ ₄ acyl), SO(d_ ₄ alkyl), SO(C ₂ _ ₄ alkynyl), SO(C ₂ _ ₄ alkenyl), S0 ₂ (d_ ₄ acyl), S0 ₂ (d_ ₄ alkyl), S0 ₂ (C ₂ _ ₄ alkynyl), S0 ₂ (C ₂ ^ alkenyl), OS(0) ₂ (Ci_ ₄ acyl), OS(0) ₂ (Ci_ ₄ alkyl), OS(0) ₂ (C ₂ ^ alkenyl), NH ₂ , NH(Ci_ ₄ alkyl), NH(C ₂ _ ₄ alkenyl), NH(C ₂ _ ₄ alkynyl), NH(C _M acyl), N(d_ ₄ alkyl) ₂ , N(C _1-18 acyl) ₂ , wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N ₃ , CN, one to three halogen (CI, Br, F, I), N0 ₂ , C(0)0(C _M alkyl), C(0)0(Ci_ ₄ alkyl), C(0)0(C ₂ _ ₄ alkynyl), C(0)0(C ₂ _ ₄ alkenyl), 0(Ci_ ₄ acyl), 0(Ci_ ₄ alkyl), 0(C ₂ ^ alkenyl), S(Ci_ ₄ acyl), S(Ci_ ₄ alkyl), S(C ₂ _ ₄ alkynyl), S(C ₂ _ ₄ alkenyl), SO(Ci_ ₄ acyl), SO(Ci_ ₄ alkyl), SO(C ₂ _ ₄ alkynyl), SO(C ₂ _ ₄ alkenyl), S0 ₂ (d_ ₄ acyl), S0 ₂ (d_ ₄ alkyl), S0 ₂ (C ₂ _ ₄ alkynyl), S0 ₂ (C ₂ ^ alkenyl), OS(0) ₂ (d_ ₄ acyl), OS(0) ₂ (Ci_ ₄ alkyl), OS(0) ₂ (C ₂ _ ₄ alkenyl), NH ₂ , NH(Ci_ ₄ alkyl), NH(C ₂ _ ₄ alkenyl), NH(C ₂ ^ alkynyl), NH(d_ ₄ acyl), N(d_ ₄ alkyl) ₂ , N(d_ ₄ acyl) ₂ ; the base is a naturally occurring or modified purine or pyrimidine base represented by the following structures: a wherein

Z is N or CR ¹² ;

R ⁷ , R ⁸ ,R ⁹ , R ¹⁰ , and R ⁿ are independently H, F, CI, Br, I, OH, OR, SH, SR, NH ₂ , NHR, NR' ₂ , lower alkyl of Ci-C ₆ , halogenated (F, CI, Br, I) lower alkyl of Ci-C ₆ , lower alkenyl of C ₂ -C ₆ , halogenated (F, CI, Br, I) lower alkenyl of C ₂ -C ₆ , lower alkynyl of C ₂ -C ₆ such as C≡CH, halogenated (F, CI, Br, I) lower alkynyl of C ₂ -C ₆ , lower alkoxy of Ci-C ₆ , halogenated (F, CI, Br, I) lower alkoxy of Ci-C ₆ , C0 ₂ H, C0 ₂ R, CONH ₂ , CONHR, CONR' ₂ , CH=CHC0 ₂ H, or CH=CHC0 ₂ R, wherein R' is an optionally substituted alkyl , which includes, but is not limited to, an optionally substituted Ci- ₂ 0 alkyl, an optionally substituted Ci_io alkyl, an optionally substituted lower alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C ₂ -C ₆ , an optionally substituted lower alkenyl of C ₂ -C ₆ , or optionally substituted acyl, which includes but is not limited to C(O) alkyl, C(0)(Ci_2o alkyl), C(0)(Ci_io alkyl), or C(0)(lower alkyl) or alternatively, in the instance of NR' ₂ , each R' comprise at least one C atom that are joined to form a heterocycle comprising at least two carbon atoms; and

R ¹² is H, halogen (including F, CI, Br, I), OH, OR, SH, SR, NH ₂ , NHR, NR ₂ , N0 ₂ lower alkyl of Ci-C ₆ , halogenated (F, CI, Br, I) lower alkyl of Ci-C ₆ , lower alkenyl of C ₂ -C ₆ , halogenated (F, CI, Br, I) lower alkenyl of C ₂ -C ₆ , lower alkynyl of C ₂ -C ₆ , halogenated (F, CI, Br, I) lower alkynyl of C ₂ -C ₆ , lower alkoxy of Ci-C ₆ , halogenated (F, CI, Br, I) lower alkoxy of Ci-C ₆ , C0 ₂ H, C0 ₂ R, CONH2, CONHR, CONR'2, CH=CHC0 ₂ H, or CH=CHC0 ₂ R; with the proviso that when base is represented by the structure c with R ¹¹ being hydrogen, R ¹² is not a: (i) -C≡C-H, (ii) -C=CH ₂ , or (iii) -N0 ₂ .

[0076] In one embodiment, the compound of Formula I is: or a pharmaceutically acceptable salt thereof.

[0077] In one embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula II:

J-Y-J

Formula II

wherein:

Y is -L-L-, -M-W-M- or Y ^y ;

J is T-P-, -P-T or -J ^m ;

W is a bond or -W ^r -;

L is -M-A-, -A-M-, or -L ⁿ ;

T is R ⁹ -Z-, -Z-R ⁹ , or -T ^p ;

R ⁹ is E-V-, or -V-E, or -R ^9q ;

each A is selected from -A ^s ;

each M is selected from -M';

each P is selected from -P ^u ;

each Z is selected from -Z ^v ;

each V is selected from -V ^w ;

each E is selected from -E ^x ;

each m is 1

each n is 0, 1, 2, 3, 4, 5, 6, 7, 9, or 10;

each p is 1, 2, 3, 4, 5, 6, 7, or 8;

each q is 0, 1, 2, or 3;

each r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; each s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 21;

each t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;

each u is 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19;

each v is 0, 1, 2, 3, 4, 5, or 6;

each w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24;

each x is 0, 1, 2, 3, 4, 5, 6, or 7;

each y is 0, 1, or 2;

wherein P is connected to M, L, or Y ^y ; A is connected to A or L; M is connected to P or J; Z is connected to P; V is connected to Z; and when W is a bond M is connected to M; each J ¹ is independently a fused bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is substituted with one or more -N(R ^L7 )C(=0)OR ^L7 , and that is optionally substituted with one or more groups independently selected from oxo, halo, -R ^L7 , -OR ^L7 , -SR ^L7 , -CF ₃ , -CCI ₃ , -OCF ₃ ,-CN, -N0 ₂ , -N(R ^L7 )C(=0)R ^L7 , -C(=0)R ^L7 , -OC(=0)R ^L7 , -C(0)OR ^L7 , -C(=0)NR ^L7 , -S(=0)R ^L7 , -S(=0) ₂ OR ^L7 , -S(=0) ₂ R ^L7 , -OS(=0) ₂ OR ^L7 ,

-S(=0) ₂ NR ^L7 , alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, and (NR ^a R ^b )carbonyl;

each R ^L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle;

R ^a and R ^b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L° is independently:

wherein: each R is independently selected from hydrogen, alkenyl, alkoxy, alkyl, halo, and haloalkyl; and

each aa is independently 1, 2, 3, or 4; each L is independently:

wherein:

each R is independently selected from hydrogen, alkenyl, alkoxy, alkyl, halo, and haloalkyl;

each R ^L3 is independently selected from cyano, nitro, SOR ⁴ , SO2R ⁴ ,

-alkylS0 ₂ R ⁴ , haloalkoxy, cyanoalkyl, NR ⁴ S0 ₂ R ⁴ , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and

each R ⁴ is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; each bb is 0, 1, 2, 3, or 4; each aa is 1, 2, 3, or 4; and the sum of bb and aa is 1, 2, 3, or 4;

} is independently:

wherein: the phenyl ring shown in L ² is optionally substituted with one or more groups independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,

arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, (NR ^a R ^b )carbonyl, cyano, nitro, SOR ⁴ , S0 ₂ R ⁴ , -alkylS0 ₂ R ⁴ , haloalkoxy, cyanoalkyl, NR ⁴ S0 ₂ R ⁴ , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo;

each R ^M is independently -H, alkyl, aryl, arylalkyl, or heterocycle;

each R ⁴ is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl;

R ^a and R ^b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and

each H ¹ is a 5 membered saturated, partially unsaturated, or aromatic ring comprising one or more heteroatoms. each L ³ is independently a fused-bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, (NR ^a R ^b )carbonyl, cyano, nitro, SOR ⁴ , S0 ₂ R ⁴ , -alkylS0 ₂ R ⁴ , haloalkoxy, cyanoalkyl, NR ⁴ S0 ₂ R ⁴ , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo;

each R ⁴ is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and R ^a and R ^b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L ⁴ is independently a fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl,

(NR ^a R ^b )carbonyl, cyano, nitro, SOR ⁴ , S0 ₂ R ⁴ , -alkylS0 ₂ R ⁴ , haloalkoxy, cyanoalkyl, NR ⁴ S0 ₂ R ⁴ , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo;

each R ⁴ is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and R ^a and R ^b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L ⁵ is independently a -CR=CR-fusedbicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,

arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, (NR ^a R ^b )carbonyl, cyano, nitro, SOR ⁴ , S0 ₂ R ⁴ , -alkylS0 ₂ R ⁴ , haloalkoxy, cyanoalkyl, NR ⁴ S0 ₂ R ⁴ , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo;

each R is independently selected from H or alkyl;

each R ⁴ is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and R ^a and R ^b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L ⁶ is independently a -CR=CR-fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,

arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, (NR ^a R ^b )carbonyl, cyano, nitro, SOR ⁴ , S0 ₂ R ⁴ , -alkylS0 ₂ R ⁴ , haloalkoxy, cyanoalkyl, NR ⁴ S0 ₂ R ⁴ , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo;

each R is independently selected from H or alkyl;

each R ⁴ is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and R ^a and R ^b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L ⁷ is independently:

wherein:

each H ^1'1 is independently a fused-bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more R ² ; each R ² is independently selected from halo, -R ^L7 , -OR ^L7 , -SR ^L7 , -N(R ^L7 ) ₂ , -CF ₃ , -CCI ₃ , -OCF ₃ ,-CN, -NO ₂ , -N(R ^L7 )C(=0)R ^L7 , -C(=0)R ^L7 , -OC(=0)R ^L7 ,

-C(0)OR ^L7 , -C(=0)NR ^L7 , -S(=0)R ^L7 , -S(=0) ₂ OR ^L7 , -S(=0) ₂ R ^L7 , -OS(=0) ₂ OR ^L7 , and -S(=0) ₂ NR ^L7 ;

each R ^L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; and each aa is independently 1, 2, 3, or 4; each L ⁹ is independently a fused-tetracyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -R ^L7 , -OR ^L7 , -SR ^L7 , -CF ₃ , -CCI ₃ , -OCF ₃ ,-CN, -N0 ₂ , -N(R

L ⁷ )C(=0)R ^L7 , -C(=0)R ^L7 , -OC(=0)R ^L7 , -C(0)OR ^L7 , -C(=0)NR ^L7 , -S(=0)R ^L7 , -S(=0) ₂ OR ^L7 , -S(=0) ₂ R ^L7 , -OS(=0) ₂ OR ^L7 , -S(=0) ₂ NR ^L7 , alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, and (NR ^a R ^b )carbonyl;

each R ^L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; each L is independently a fused-pentacyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -R ^L7 , -OR ^L7 , -SR ^L7 , -CF ₃ , -CCI ₃ , -OCF ₃ ,-CN, -N0 ₂ , -N(R

L ⁷ )C(=0)R ^L7 , -C(=0)R ^L7 , -OC(=0)R ^L7 , -C(0)OR ^L7 , -C(=0)NR ^L7 , -S(=0)R ^L7 , -S(=0) ₂ OR ^L7 _: -S(=0) ₂ R , -OS(=0) ₂ OR , -S(=0) ₂ NR , alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, and (NR ^a R ^b )carbonyl;

each R ^L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

each L ¹¹ is independently a six-ring fused saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, -R ^L7 , -OR ^L7 , -SR ^L7 , -CF ₃ , -CC1 ₃ , -OCF ₃ ,-CN, -N0 ₂ , -N(R

L ⁷ )C(=0)R ^L7 , -C(=0)R ^L7 , -OC(=0)R ^L7 , -C(0)OR ^L7 , -C(=0)NR ^L7 , -S(=0)R ^L7 , -S(=0) ₂ OR ^L7 _: -S(=0) ₂ R ^L7 , -OS(=0) ₂ OR ^L7 , -S(=0) ₂ NR ^L7 , alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, and (NR ^a R ^b )carbonyl;

each R ^L7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle;

R ^a and R ^b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

each R ⁹ is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl,

alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, -NR ^c R ^d , (NR ^c R ^d )alkenyl, (NR ^c R ^d )alkyl, and

(NR ^c R ^d )carbonyl;

R ^c and R ^d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl,

arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,

heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl,

heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR ^e R ^f )alkyl, (NR ^e R ^f )alkylcarbonyl, (NR ^e R ^f )carbonyl, (NR ^e R ^f )sulfonyl, -C(NCN)OR', and - C(NCN)NR ^X R ^Y , wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the

heterocyclylalkylcarbonyl are further optionally substituted with one -NR ^e R ^f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the

heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;

R ^x and R ^Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR ^x R ^Y )carbonyl, wherein R ^x and R ^Y are independently selected from hydrogen and alkyl; each R ⁹ is independently -N(R ^9a )-NHC(=0)0-R ^9b , wherein each R ^9a is independently arylalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSC^alkyl, cycloalkylalkylSC^alkyl, cyanoalkyl, haloalkyl, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl;

and wherein arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy;

and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR ^X R ^Y , - (NR ^x R ^Y )alkyl, oxo, and -P(0)OR ₂ , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;

and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR ^X R ^Y ,

(NR ^x R ^Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl

part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R ^9b is independently H, alkyl, aryl, haloalkyl, or arylalkyl; each R ⁹² is independently -N(R ^9a )-NHC(=0)NR ^9b ₂ ; wherein each R ^9a is independently arylalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSC^alkyl, cycloalkylalkylSC^alkyl, cyanoalkyl, haloalkyl cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,

alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl;

and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy;

and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR ^X R ^Y , - (NR ^x R ^Y )alkyl, oxo, and -P(0)OR ₂ , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;

and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR ^X R ^Y ,

(NR ^x R ^Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl

part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R ^9b is independently H, alkyl, aryl, haloalkyl, or arylalkyl; each R9 ³ is independently -N(R ^9a )-NHC(=0)R ^9b , wherein each R ^9a is independently arylalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkoxy, halocycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkoxy, alkylSC^alkyl, cycloalkylalkylSC^alkyl, cyanoalkyl, haloalkyl, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups

independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy;

and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR ^X R ^Y , - (NR ^x R ^Y )alkyl, oxo, and -P(0)OR ₂ , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;

and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR ^X R ^Y , - (NR ^x R ^Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the

heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R ^9b is independently H, alkyl, aryl, haloalkyl, or arylalkyl; each A ⁰ is independently:

wherein:

each R ^A3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, and (NR ^a R ^b )carbonyl; R ^a and R ^b are each

independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and

heterocyclylalkyl; and each

bb is independently 0, 1, 2, 3, or 4; or

each A ⁰ is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is optionally substituted with 1, 2, 3, or 4 R ^A3 groups; each A ¹ is independently:

wherein:

each R ^A1 is independently selected from cyano, nitro, SOR ⁴ , SO ₂ R ⁴ ,

-alkylS0 ₂ R ⁴ , haloalkoxy, cyanoalkyl, NR ⁴ S0 ₂ R ⁴ , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and

each R ⁴ is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; each cc is independently 1, 2, 3, or 4 each A ² is independently:

wherein:

each R ^A1 is independently selected from cyano, nitro, SOR ⁴ , SO ₂ R ⁴ ,

-alkylS0 ₂ R ⁴ , haloalkoxy, cyanoalkyl, NR ⁴ S0 ₂ R ⁴ , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo;

each R ^A3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, and (NR ^a R ^b )carbonyl; R ^a and R ^b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

each R ⁴ is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; R ^a and R ^b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bb and cc is 1, 2, 3, or 4; each A ³ is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is substituted with one or more R ^A1 groups, and which ring is optionally substituted with one or more R ^A3 groups; each A ⁴ is independently:

wherein: each H ⁵ is independently a phenyl ring or a six-membered heteroaromatic ring, which H ⁵ is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A ⁵ is independently: wherein: each H ⁶ is independently a phenyl ring or a six-membered heteroaromatic ring, which H ⁶ is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent; provided that at least one X ^A is present and each R is independently selected from H or alkyl; each A ⁶ is independently: wherein: each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, allenyl, alkynyl, or absent; provided that at least one X ^A is present and each R is independently selected from H or alkyl; each A ⁷ is independently: wherein: each H ⁷ is independently a five-membered hetero aromatic ring, which H ⁷ is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent; and each R is independently selected from H or alkyl; each A ⁸ is independently: wherein: each H ⁷ is independently a five-membered hetero aromatic ring, which H ⁷ is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ;

each H ⁸ is independently a phenyl ring, which is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A ⁹ is independently: wherein: each H ⁷ is independently a five-membered hetero aromatic ring, which H ⁷ is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A is independently: wherein: each H ⁸ is independently a phenyl ring, which is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ;

each H ⁹ is independently a six-membered heteroaromatic ring, which is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A ¹¹ is independently: wherein:

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each H is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that is optionally fused to an aryl, which H ¹⁰ is optionally substituted with one or more groups independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, and (NR ^a R ^b )carbonyl, cyano, nitro, SOR ⁴ , S0 ₂ R ⁴ , -alkylS0 ₂ R ⁴ , haloalkoxy, cyanoalkyl, NR ⁴ S0 ₂ R ⁴ , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and

each R ⁴ is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl each A is independently:

wherein:

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl;

each H ¹¹ is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that contains one or more heteroatoms that is optionally fused to an aryl, which H ¹¹ is optionally substituted with one or more groups

independently selected from oxo, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, -NR ^a R ^b , (NR ^a R ^b )alkyl, and (NR ^a R ^b )carbonyl, cyano, nitro, SOR ⁴ , S0 ₂ R ⁴ , -alkylS0 ₂ R ⁴ , haloalkoxy, cyanoalkyl, NR ⁴ S0 ₂ R ⁴ , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, and (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and

each R ⁴ is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl; and each A ¹³ is independently: wherein: each H is independently a fused aromatic bicyclic carbocycle, which is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A is independently: wherein: each H is independently a fused aromatic bicyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR,

CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A is independently: wherein: each H ¹⁴ is independently a fused unsaturated, partially unsaturated or saturated tricyclic carbocycle which is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR,

CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from

H or alkyl; each A is independently: wherein: each H ¹⁵ is independently a fused unsaturated, partially unsaturated or saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A ¹⁷ is independently: wherein: each H is independently a fused bicyclic carbocyclic ring system wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each A ¹⁸ is independently: wherein: each H is independently a fused bicyclic ring system comprising at least one heteroatom, wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR,

CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from

H or alkyl; each A is independently: wherein: each H is independently an anti-aromatic monocyclic or fused carbocyclic ring system, which carbocyclic ring system is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W ¹ is independently -X ^A - wherein:

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W ² is independently: wherein: each H is independently a fused aromatic bicyclic carbocycle, which is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W ³ is independently: wherein: each H is independently a fused bicyclic carbocyclic ring system wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W ⁴ is independently: wherein: each H ²² is independently a fused aromatic bicyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W ⁵ is independently: wherein: each Η is independently a fused bicyclic ring system comprising at least one heteroatom, wherein one ring is aromatic and another ring is partially or fully saturated, which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR,

CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from

H or alkyl; each W ⁶ is independently: wherein: each H is independently a fused unsaturated, partially unsaturated or saturated tricyclic carbocycle, which is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR,

CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from

H or alkyl; each W ⁷ is independently: wherein: each H is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W is independently: wherein: each H is independently a fused unsaturated, partially unsaturated or saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR, CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W ⁹ is independently: wherein: each H ²⁹ is independently a 5-15 carbon unsaturated, partially unsaturated or saturated bicyclic ring system that contains one or more heteroatoms; and

each X ^A is independently O, NR, SO, S0 ₂ , C(=0), NRC(=0), C(=0)NR,

CR=CR, NRC(=0)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl; each W ¹⁰ is independently -H ³⁰ =C=H ³¹ - wherein each of -H 30 and H 31 is independently a saturated 6-membered heterocyclic ring comprising one or more heteroatoms, which ring is optionally substituted with oxo; each W ¹¹ is independently -H ³² =C=H ³³ - wherein each of -H ³² and H ³³ is independently a saturated 5-membered heterocyclic ring comprising one or more heteroatoms, which ring is optionally substituted with oxo; each W ¹² is independently an anti-aromatic monocyclic or fused carbocyclic ring system, which carbocyclic ring system is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; each W ¹³ is independently a phenyl ring that is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; each W ¹⁴ is independently a 5 or 6 membered heteroaryl ring that is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; each W ¹⁵ is independently a fused unsaturated, partially unsaturated or saturated tetracyclic carbocyclic ring, which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; each W ¹⁶ is independently a fused unsaturated, partially unsaturated or saturated tetracyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; each W ¹⁷ is independently a fused unsaturated, partially unsaturated or saturated pentacyclic carbocyclic ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 : each W ¹⁸ is independently a fused unsaturated, partially unsaturated or saturated pentacyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; each W is independently a fused unsaturated, partially unsaturated or saturated hexacyclic carbocyclic ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 :

each W 20 is independently a fused unsaturated, partially unsaturated or saturated hexacyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from oxo, R ^A1 and R ^A3 ; each M° is independently a five membered heteroaryl group optionally substituted with one or more alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, (NR ^a R ^b )carbonyl and trialkylsilylalkoxyalkyl; each M ¹ is independently selected from -C(=0)NH-, -C(=0)NH-C(R ^M ) ₂ -, -NHC(=0) -, -C(R ^M ) ₂ NHC(=0)-, -NHC(=0)N R ^M -, -NHC(=0)0 -; wherein each R ^M is independently selected from H and alkyl; each M ² is independently a six-membered heteroaromatic ring, which is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ;

each M ³ is independently:

each M ⁴ is independently:

each M ⁵ is independently:

wherein the bond designated with— is fused to a ring defined for P; each M ⁶ is independently a bicyclic bridged ring system comprising 5-15 atoms wherein at least one of the atoms is a heteroatom; each M ⁷ is independently a pyrid-di-yl; each M ⁸ is independently partially saturated or a saturated five-membered ring that comprises one or more heteroatoms and that is optionally substituted with one or two oxo; each M ⁹ is independently a fused-bicyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more R ^P11; each M ¹⁰ is independently a five membered heteroaryl group substituted with at least one alkoxy, cycloalkyl, cyano, alkylsulfonyl, arylsulfonyl, NR ^h R ^h , (NR ^h R ^h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkoxy, haloalkoxyalkyloxy, cycloalkoxyalkoxy, aryloxyalkoxy, heteroaryloxyalkoxy, heterocyclyloxyalkyloxy, (NR ^h R ^h )alkoxy, cyanoalkoxy, cycloalkoxy, heterocyclyl, alkoxyalkyl, cycloalkoxyalkyl, (NR ^h R ^h )alkyl, wherein each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyloxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, and sulfonylalkyl; and wherein the five membered ring is also optionally substituted with one or more alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, and (NR ^a R ^b )carbonyl; each M ¹¹ is independently a fused-tricyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more oxo, halo, -R ^M7 , -OR M ⁷ , -SR ^M7 , -N(R ^M7 ) ₂ , -CF ₃ , -CCI3, -OCF ₃ ,-CN, -N0 ₂ , -N(R ^M7 )C(=0)R ^M7 , -C(=0)R ^M7 , - OC(=0)R ^M7 , -C(0)OR ^M7 , -C(=0)NR ^M7 , -S(=0)R ^M7 , -S(=0) ₂ OR ^M7 , -S(=0) ₂ R ^M7 , - OS(=0) ₂ OR ^M7 , or -S(=0) ₂ NR ^M7 ; each R ^M7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle; each M is independently a fused-pentacyclic, hexacyclic, or heptacyclic partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one more oxo halo, -R ^M7 , -OR ^M7 , -SR ^M7 , -N(R ^M7 ) ₂ , -CF ₃ , -CCI ₃ , -OCF ₃ ,-CN, -N0 ₂ , -N(R M ⁷ )C(=0)R ^M7 , -C(=0)R ^M7 , -OC(=0)R ^M7 , -C(0)OR ^M7 , -C(=0)NR ^M7 , -S(=0)R ^M7 ,

-S(=0) ₂ OR ^M7 , -S(=0) ₂ R ^M7 , -OS(=0) ₂ OR ^M7 , or -S(=0) ₂ NR ^M7 ;

each R ^M7 is independently -H, alkyl, aryl, arylalkyl, or heterocycle;

wherein:

X is selected from O, S, S(O), S0 ₂ , CH ₂ , CHR ^P1 °, and C(R ^P10 ) ₂ ; provided that when pn or pm is 0, X is selected from CH ₂ , CHR ^P1 °, and C(R ^{P 1 0} )2 ;

each R ^P1 ° is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;

each R ^P5 and R ^P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to

six-membered ring is optionally substituted with one or two alkyl groups; R ^Pa and R ^Pb are each independently H, alkyl, aryl, or arylalkyl; or R ^Pa and R ^Pb taken together with the atom to which they are attached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R ^1*7 and R ^P8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR ^Pa R ^Pb )alkyl; or R ^1*7 and R ^P8 , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NR ^Pz , 0, and S; wherein R ^Pz is selected from hydrogen and alkyl;

R ^P9 is selected from hydrogen and alkyl;

each P ¹ is independently:

wherein:

X is selected from O, S, S(O), S0 ₂ , CH ₂ , CHR ^P1 °, and C(R ^P10 ) ₂ ; provided that when pn is 0, X is selected from CH ₂ , CHR ^P1 °, and C(R ^P1 °) ₂ ; each R ^P1 ° is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three- to six- membered ring with an adjacent carbon atom, wherein the three- to six- membered ring is optionally substituted with one or two alkyl groups; at least one R ^{p 1 1} is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR ^h R ^h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,

heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR ^h R ^h a)lkyloxy, cyanoalkoxy,

cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NR ^hh R ^h , (NR^R^alkyl,

(NR^R^carbonyl, wherein each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R ¹ * is

independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR ^h R ^h )sulfonyl, heteroarylsulfonyl, -S(=0) ₂ R ^h , -C(=0)R ^h , -C(=0)NR ^h R ^h ; and the remaining R ^pn are independently selected from R ^P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR ^h R ^h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,

heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR ^h R ^h )alkyloxy, cyanoalkoxy,

cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;

ps is 1, 2, 3, or 4;

pn is 0, 1, or 2; each P ² is independently: wherein: each R ^P12 is independently selected from R ^P5 , R ^{pl l} ,-C(=0)OR ^h , cyano, alkylsulfonyl, arylsulfonyl, (NR ^h R ^h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR ^h R ^h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;

ps is 1, 2, 3, or 4;

pn is 0, 1, or 2; each P ³ is independently a ring of the formula:

wherein:

the ring is substituted with one or more oxo group;

each R ^P13 is independently selected from R ^P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR ^h R ^h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,

heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR ^h R ^h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;

ps is 0, 1, 2, 3, or 4;

pn is 0, 1, or 2;

each P ⁴ is independently a ring of the formula:

wherein:

the ring is optionally substituted with one or more groups R ^P14 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and - NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R ^P14 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring;

pn is 0, 1, or 2;

each R ^f is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,

-S(=0) ₂ NR ^h R ^h , -S(=0) ₂ R ^h , C(=0)R ^h , C(=0)OR ^h , -C(=0)NR ^h R ^h ; each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P ⁵ is independently a ring of the formula:

wherein:

the ring is optionally substituted with one or more groups R ^P15 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and - NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R ^P15 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring;

pn is 0, 1, or 2;

Z is O, S, S(=0), S(=0) ₂ , or NR ^f ;

each R ^f is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,

-S(=0) ₂ NR ^h R ^h , -S(=0) ₂ R ^h , C(=0)R ^h , C(=0)OR ^h , -C(=0)NR ^h R ^h ; each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P ⁶ is independently a ring of the formula:

wherein:

the ring is substituted with one or more oxo and is optionally substituted with one or more groups R ^P16 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to

six-membered ring is optionally substituted with one or two alkyl groups;

Z is O, S, S(=0), S(=0) ₂ , or NR ^f ;

pn is 0, 1, or 2; each R is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,

-S(=0) ₂ NR ^h R ^h , -S(=0) ₂ R ^h , C(=0)R ^h , C(=0)OR ^h , -C(=0)NR ^h R ^h ; each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P ⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula II through one N-link and through one C-link;

wherein the ring is optionally substituted with one or more groups independently selected from R^and R PI 1 . each P ⁸ is independently a ring of the formula:

wherein:

ps is 2, 3, 4, 5, or 6;

pn is 0, 1 or 2;

each R ^P13 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups R ^P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;

each P is independently: wherein:

X is selected from O, S, S(O), S0 ₂ , CH ₂ , CHR ^P1 °, and C(R ^P10 ) ₂ ; provided that when pn or pm is 0, X is selected from CH ₂ , CHR ^P1 °, and C(R ^{P 1 0} )2 ;

each R ^P1 ° is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;

each R ^P5 and R ^P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to

six-membered ring is optionally substituted with one or two alkyl groups;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3; each P is independently:

wherein:

X is selected from O, S, S(O), S0 ₂ , CH ₂ , CHR ^P1 °, and C(R ^P provided that when pn or pm is 0, X is selected from CH ₂ , CHR ^P1 °, and C(R ^P10 ) ₂ ; each R ^P1 ° is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;

each R ^P5 and R ^P6 is independently selected from alkoxy, alkyl, aryl halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to

six-membered ring is optionally substituted with one or two alkyl groups;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3; each P is independently:

wherein: each R is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;

pq is independently 0, 1, 2, 3, or 4;

pm is independently 0, 1, or 2;

pp is independently 1, 2, or 3;

ps is 1, 2, 3, or 4;

R ^pu is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR ^h R ^h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR ^h R ^h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NR^R ¹¹ , (NR^R^alkyl, (NR^R^carbonyl, wherein each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R ¹ * is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR ^h R ^h )sulfonyl, heteroarylsulfonyl, -S(=0) ₂ R ^h , -C(=0)R ^h , -C(=0)NR ^h R ^h ; and the remaining R ^pn are independently selected from R ^P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR ^h R ^h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR ^h R ^h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P ¹³ is independently:

wherein:

X is selected from O, S, S(O), S0 ₂ , or NR ^h ; each R ^P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;

pq is independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2 but the sum of pn and pm is greater than zero;

pp are independently 1, 2, or 3;

ps is 1, 2, 3, or 4;

each R ^pu is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR ^h R ^h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR ^h R ^h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, -NR ^hh R ^h , (NR^R^alkyl, (NR^R^carbonyl, wherein each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R ¹ * is independently aryl, arylalkyl, heterocycle,

heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR ^h R ^h )sulfonyl,

heteroarylsulfonyl, -S(=0) ₂ R ^h , -C(=0)R ^h , -C(=0)NR ^h R ^h , R ^P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR ^h R ^h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,

heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR ^h R ^h )alkyloxy, cyanoalkoxy,

cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P ¹⁴ is independently:

wherein:

the ring is substituted with one or more oxo group;

X is NR ^f ;

each R ^f is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,

-S(=0) ₂ NR ^h R ^h , -S(=0) ₂ R ^h , C(=0)R ^h , C(=0)OR ^h , -C(=0)NR ^h R ^h ; each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;

each R ^P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR ^Pa R ^Pb , wherein the alkyl can optionally form a fused three-to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;

pq is independently 0, 1, 2, 3, or 4;

pm is independently 0, 1, or 2;

ps is 1, 2, 3, or 4;

R ^pn is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR ^h R ^h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR ^h R ^h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R ^h is independently -H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or

sulfonylalkyl; and when two R ^h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; each P is:

which is substituted with one or two groups independently selected from alkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl, cyanoalkyl, and cycloalkylalkyl. each P is:

which is substituted with methylene; each P ¹⁷ is:

which is substituted with one or two groups independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkylalkenyl, and cycloalkylalkynyl.

18

each P is:

which is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl;

each P is:

wherein each R ^a is independently selected from H and halo; and each R is

independently selected from halo; each -Z°- is -C(=0)- or -C(=S ; each -Z ¹ - is independently a bond, or -C(R ^Z1 )2-; wherein each R ^Z1 is independently H, alkyl, haloalkyl, or halo; each -Z ² - is independently saturated or partially unsaturated (C3-Cs)cycloalkyl that is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; each -Z ³ - is independently saturated, partially unsaturated, or aromatic 4-8 membered heterocyclic or heteroaryl ring that is optionally substituted with one or more groups independently selected from R ^A1 and R ^A3 ; each -Z ⁴ - is independently: wherein each R is independently H, alkyl, cyano, aryl, or heteroaryl; each -Z ⁵ - is independently:

wherein each R is independently H, alkyl, cyano, aryl, or heteroaryl; or two R s together with the nitrogen to which they are attached form a 4-8 membered heterocyclic ring that is optionally substituted with one or more oxo and with one or more groups independently selected from R ^A1 and R ^A3 ; each -Z ⁶ - is independently -C(R ^Z1 )- and is doublebonded to a carbocyclic P; wherein R ^Z1 is independently H, alkyl, haloalkyl, or halo;

0 Ec Ed

each E is independently -NR R wherein

Ec Ed

Έ - and R" ^u are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl,

arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,

heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl,

heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR ^e R ^f )alkyl, (NR ^e R ^f )alkylcarbonyl, (NR ^e R ^f )carbonyl, (NR ^e R ^f )sulfonyl, -C(NCN)OR, and - C(NCN)NR ^X R ^Y , wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the

heterocyclylalkylcarbonyl are further optionally substituted with one -NR ^e R ^f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the

heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; each E 1 is independently -OC(=0)NR Ee R Ef wherein each R Ee and R Ef are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl,

alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,

cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR ^e R ^f )alkyl, (NR ^e R ^f )alkylcarbonyl, (NR ^e R ^f )carbonyl,

(NR ^e R ^f )sulfonyl, -C(NCN)OR, and - C(NCN)NR ^X R ^Y , wherein R' is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NR ^e R ^f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the

heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; or wherein R Ee and R Ef , together with the nitrogen atom to which they are attached, form a heterocycle; each E ² is independently -NR ^a R ^b , wherein R ^a is haloalkyl and R ^b is H, alkyl,

alkoxycarbonyl. or haloalkyl; each E ³ is independently -NR ^Ec R ^E3a , wherein R ^E3a is (C ₃ -C ₆ )cycloalkyloxycarbonyl; each E ⁴ is independently -OC(=0)OR ^E4a , wherein R ^E4a is cycloalkyl, aryl, or alkyl; each E ⁵ is independently -NR ^Ec S(=0) ₂ 0R ^E5a , wherein R ^E5a is is cycloalkyl, aryl or alkyl; each E ⁶ is independently -NR ^Ec S(=0) ₂ R ^E6a , wherein R ^E6a is cycloalkyl, aryl, or alkyl; each E ⁷ is independently -NR ^Ec OR ^E7a , wherein R ^E7a is cycloalkyl, aryl, alkyl, haloalkyl, cycloalkylalkyl or heteroaryl; each V° is independently H, alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl;

and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy;

and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,

-NR ^X R ^Y , -(NR ^x R ^Y )alkyl, oxo, and -P(0)OR ₂ , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;

and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,

heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR ^X R ^Y ,

(NR ^x R ^Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the

heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; each V ¹ is independently cyanoalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ² is independently haloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R are each independently selected from hydrogen, alkenyl, and alkyl; each V ³ is independently alkyl, which is substituted with one or more oxo, and which is optionally substituted with one or more groups independently selected from cycloalkyl, halo, aryl, alkenyl, and cyano; each V ⁴ is independently haloalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; wherein R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ⁵ is independently alkylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ⁶ is independently arylsulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ⁷ is independently heterocyclosulfonylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ⁸ is independently spirocycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ⁹ is independently spirocycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ¹⁰ is independently fusedbicycliccycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ¹¹ is independently fusedbicycliccycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ¹² is independently bridged-bicycliccycloalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ¹³ is independently bridged-bicyclic-cycloalkylalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ¹⁴ is independently aryloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^a R C(=0)0-; R ^a and R are each independently selected from hydrogen, alkenyl, and alkyl; each V ¹⁵ is independently arylalkoxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ¹⁶ is independently cycloalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ¹⁷ is independently cycloalkylalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ¹⁸ is independently heterocyclooxy alkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V ¹⁹ is independently heterocycloalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V 20 is independently heteroaryloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V is independently heteroarylalkyloxyalkyl, which is optionally substituted with one or more groups independently selected from cycloalkyl, alkoxy, haloalkoxy, cycloalkenyl, heterocycle, heteroaryl, hydroxy, and NR ^Va R ^Vb C(=0)0-; R ^Va and R ^Vb are each independently selected from hydrogen, alkenyl, and alkyl; each V 22 is independently cycloalkenylalkyl; each V ²³ is independently arylalkyl, wherein the aryl is substituted with one or more groups independently selected from cycloalkyl, alkenyl, cycloalkylalkyl, cyanoalkyl, cycloalkoxy, hydroxyalkoxy, -C(=0)NR ^x R ^Y , S(=0) ₂ NR ^x R ^Y , alkylsulfanyl, alkylsulfonyl, haloalkylsulfanyl, haloalkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl, arylsulfanyl, arylsulfonyl, alkoxyalkoxy, alkynyl, aryloxy, heteroaryloxy, alkylsulfonylamino;

R ^x and R ^Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR ^x R ^Y )carbonyl, wherein R ^x and R ^Y are independently selected from hydrogen and alkyl; each V 24 is independently heterocycloalkyl, wherein the heterocycle is substituted with one or more groups independently selected from cycloalkyl, alkenyl, cycloalkylalkyl, cyanoalkyl, cycloalkoxy, hydroxyalkoxy, -C(=0)NR ^x R ^Y , S(=0) ₂ NR ^x R ^Y , alkylsulfanyl, alkylsulfonyl, haloalkylsulfanyl, haloalkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl, arylsulfanyl, arylsulfonyl, alkoxyalkyoxy, alkynyl, aryloxy, heteroaryloxy,

alky If ulf onylamino ;

R ^x and R ^Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR ^x R ^Y )carbonyl, wherein R ^x and

R ^Y are independently selected from hydrogen and alkyl; each T is ndependently a spiro, branched or fused bicycloalkyl;

each T ² is ndependently aryl;

each T ³ is ndependently heteroaryl;

each T ⁴ is ndependently arylalkyl;

each T ⁵ is ndependently haloalkyl;

ndependently heteroarylalkyl; each T ⁷ is independently heterocycle; and

each T ⁸ is independently heterocycloalkyl;

or a pharmaceutically acceptable salt, or prodrug thereof.

0078] In one embodiment, the compound of Formula II is:

or a pharmaceutically acceptable salt thereof..

[0079] In one embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula III

_E la_ _y la _ _C(=0 )_p ^la _ _W ^la -P ^lb -C(=0)-V ^lb -E ^lb

Formula III

wherein

l ^a is and W ^la is optionally substituted with one or more groups independently selected from halo, alkyl, haloalkyl, or cyano;

Y ⁵ is -O-CH ₂ -, or -CH ₂ -O-;

X ⁵ is -CH ₂ -CH ₂ - or -CH=CH-;

E ^la is -N(H)(alkoxycarbonyl), -N(H)(cycloalkylcarbonyl) or

-N(H)(cycloalkyloxycarbonyl); or E ^la -V ^la taken together are R ^9a ;

E ^lb is -N(H)(alkoxycarbonyl), -N(H)(cycloalkylcarbonyl) or

-N(H)(cycloalkyloxycarbonyl); or E ^lb -V ^lb taken together are R ^9b ;

V ^la and V ^lb are each independently selected from:

P ^la is selected from:

and

R ^9a and R ^9b are each inde endently:

or a pharmaceutically acceptable salt or prodrug thereof.

[0080] In one embodiment, the compound of Formula III is:

or a pharmaceutically acceptable salt thereof.

[0081] In one embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula IV:

Formula IV

or a stereoisomer, or a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

,1 _T 2 _t 3 _t 4 _t 5 _t 6 _t 7 _t 8 _t 9

J is J , J , J , J , J , J , J , J or J ;

L is L ¹ , L ² , L ³ , L ⁴ , L ⁵ , L ⁶ , L ⁷ , L ⁸ , L ⁹ or L ¹⁰ ;

X is -0-, -CH ₂ -, -OC(O)-, -C(0)0-, -C(O)-, -S0 ₂ -, -S(0 , -N(R ¹⁶ )-, -S-, =N-0- or a bond;

A is -C(O)- , -S(0)2- , a 6-10 membered arylene, 5-10 membered heteroarylene, or 4- 10 membered heterocyclene, wherein any of said arylene, heterocyclene, or heteroarylene is optionally substituted with 1-4 Z ¹ groups;

M is a bond, d-C ₆ alkylene, -O- , or -N(R ¹⁶ )- ;

R ¹ is H or F;

R ³ , R ⁴ , and R ⁵ are each independently selected from H or Z ;

Q is Q ¹ , Q ² , Q ³ , Q ⁴ , Q ⁵ , Q ⁶ or Q ⁷ ; E is E ¹ , E ² , E ³ , E ⁴ , E ⁵ , or E ⁶ ;

G is -C0 ₂ H, -CONHSO2Z ² , tetrazolyl, -CONHP(0)(R ¹⁶ ) ₂ , -P(0)(OH)(R ¹⁶ ), and - P(0)(R ¹⁶ ) ₂ ;

© is U ¹ , ^, U ³ , U ⁴ , U ⁵ , U ⁶ or U ⁷ ;

J ¹ is halogen;

J ² is -OH and R ¹ is H;

J ³ is -NR ¹⁷ R ¹⁸ and R ¹ is H;

J ⁴ is Ci-Cs alkyl;

J ⁵ is Ci-C ₈ alkyl substituted with 1-4 Z ³ groups;

J ⁶ is C ₃ -C ₈ carbocyclyl optionally substituted with 1-4 Z ³ groups;

J ⁷ is C ₆ -Cio aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl

optionally substituted with 1-4 Z ³ groups;

J ⁸ is Ci-C ₈ alkoxy optionally substituted with 1-4 Z ³ groups and R ¹ is H;

J ⁹ is C ₃ -C ₈ carbocyclyloxy optionally substituted with 1-4 Z ³ groups and R ¹ is H;

T ¹ is C ₃ -C ₈ carbocyclylene that is attached to L and M through two adjacent carbons; T ² is C ₃ -C ₈ carcbocyclene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is substituted with 1-4 Ci-C ₈ alkyl groups;

T ³ is C ₃ -C ₈ carcbocyclene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is substituted with 1-4 halogen atoms and said carbocyclylene is optionally substituted with 1-4 Ci-C ₆ alkyl groups;

T ⁴ is C ₃ -C ₈ carbocyclene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is optionally substituted with a Ci-C ₈ alkyl group, wherein said alkyl group is optionally substituted with 1-4 Z ³ groups;

T ⁵ is 4-10 membered heterocyclene that is attached to L and M through two adjacent carbons; T ⁶ is 4-10 membered heterocyclene that is attached to L through a carbon atom and attached to M through an N atom, wherein said heterocyclene is optionally substituted with 1-4 Z ¹ groups;

T ⁷ is 4-10 membered heterocyclene that is attached to M through a carbon atom and attached to L through an N atom, wherein said heterocyclene is optionally substituted with 1-4 Z ¹ groups;

T ⁸ is 4-10 membered heterocyclene that is attached to L and M through two adjacent carbons, wherein said heterocyclene is optionally substituted with 1-4 Z ¹ groups;

T ⁹ is C5-C12 spiro bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said spiro bicyclic carbocyclylene is optionally substituted with 1-4 Z ¹ groups;

T ¹⁰ is C5-C12 fused bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said fused bicyclic carbocyclylene is optionally substituted with 1-4 Z ¹ groups;

T ¹¹ is C5-C12 bridged bicyclic carbocyclylene that is attached to L and M through two adjacent carbons, wherein said bridged bicyclic carbocyclylene is optionally substituted with 1-4 Z ¹ groups;

T ¹² is C4-C8 carbocylene that is attached to L and M through two non-adjacent

carbons, wherein said carcbocyclene is optionally substituted with 1-4 Z ¹ groups;

T ¹³ is a 5-8 membered fused, bridged, or spiro bicyclic heterocyclene that is attached to L and M through two adjacent atoms, wherein said heterocyclene is optionally substituted with 1-4 Z ¹ groups; T ¹⁴ is C ₃ -C ₈ carbocyclylene that is attached to L and M through two adjacent carbons, wherein said carbocyclylene is optionally substituted with 1-4 Z ⁴ groups; L ¹ is Ci-C ₈ alkylene or C2-C ₈ alkenylene;

L ² is Ci-C ₈ alkylene or C2-C ₈ alkenylene wherein said Ci-C ₈ alkylene is substituted with 1-4 halogens or said C2-C ₈ alkenylene is substituted with 1-4 halogens;

L ³ is Ci-C ₈ alkylene or C2-C ₈ alkenylene wherein said Ci-C ₈ alkylene is substituted with 1-4 Z ⁴ groups or said C2-C ₈ alkenylene is substituted with 1-4 Z ⁴ groups and wherein each is optionally substituted with 1-4 halogens;

L ⁴ is Ci-C ₈ alkylene or C2-C ₈ alkenylene substituted with two geminal C1-C4 alkyl groups that come together to form a spiro C ₃ -C ₈ carbocyclyl group, wherein L ⁴ is optionally substituted with 1-4 Z ¹ groups;

L ⁵ is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene that is connected to by an O, S or N atom and said heteroalkylene or heteroalkenylene is optionally substituted with 1-4 Z ³ groups;

L ⁶ is 2-8 membered heteroalkylene or 5-8 membered heteroalkenylene that is connected to by a carbon atom and said heteroalkylene or heteroalkenylene is substituted with 1-4 halogen atoms and is optionally substituted with 1-4 Z ⁴ groups;

L ⁷ is 2-8 membered heteroalkylene or 4-8 membered heteroalkenylene that is connected to by a carbon atom and said heteroalkylene or heteroalkenylene is optionally substituted with 1-4 Z ⁴ groups;

L 8 is L 8A - L 8B -L 8C wherein L 8A and L 8C are each independently selected from Ci-C ₆ alkylene, Ci-C ₆ heteroalkylene, C2-C6 alkenylene or a bond and L ^8B is a 3- to 6- membered saturated or unsaturated ring containing 0 to 3 heteroatoms selected from N, O, or S, wherein L and L connect to L at two different ring atoms and L ^8B is optionally substituted with 1-4 Z ¹ groups;

L ⁹ is C2-C8 alkynylene optionally substituted with 1-4 Z ¹ groups;

L ¹⁰ is Ci-C ₈ alkylene or C ₃ -C ₈ alkenylene substituted with two geminal Z ¹ groups that come together to form a spiro 4-8 membered heterocyclyl group, wherein L ¹⁰ is optionally substituted with 1-4 Z ¹ groups;

U ¹ is C ₆ -Ci4 membered arylene optionally substituted with 1-4 W groups;

U ² is C ₃ -C ₈ membered carbocyclylene optionally substituted with 1-4 W groups; U ³ is 4-14 membered heterocyclene optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U ⁴ is 5 or 6 membered monocyclic heteroarylene containing 1, 2 or 3 heteroatoms independently selected from N, O, or S, wherein said heteroarylene is optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U ⁵ is 8, 9 or 10 membered fused bicyclic heteroarylene containing 1, 2 or 3

heteroatom ring atoms independently selected from N, O, or S, wherein said heteroarylene is optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U ⁶ is 11-14 membered fused tricyclic heteroarylene containing 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O, or S, wherein said heteroarylene is optionally substituted with 1-4 W groups that are located on one or more ring atoms selected from C or N;

U ⁷ is 8-10 membered fused bicyclic heteroarylene containing 4 heteroatom ring atoms independently selected from N, O, or S, wherein said heteroaryl is optionally substituted with 1-2 W groups that are located on one or more ring atoms selected from C or N;

W is independently W ¹ , W ² , W ³ , W ⁴ , W ⁵ , W ⁶ or W ⁷ ;

W ¹ is oxo, halogen, -OR ⁶ , C C ₆ alkyl, -CN, -CF ₃ , -SR ⁶ , -C(0) ₂ R ⁶ , -C(0)N(R ⁶ ) ₂ , - C(0)R ⁶ , -N(R ⁶ )C(0)R ⁶ , -S0 ₂ (C C ₆ alkyl), -S(0)(C C ₆ alkyl), C ₃ -C ₈ carbocyclyl, C ₃ -C ₈ cycloalkoxy, d-C ₆ haloalkyl, -N(R ⁶ ) ₂ , -NR ⁶ (Ci-C ₆ alkyl)0(Ci-C ₆ alkyl), halo(Ci-C ₆ alkoxy), -NR ⁶ S0 ₂ R ⁶ , -S0 ₂ N(R ⁶ ) ₂ , - NHCOOR ⁶ , -NHCONHR ⁶ , C ₆ -Ci ₀ aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl or -0(4-10 membered heterocyclyl), wherein said W ¹ alkyl, carbocyclyl, cycloalkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1-4 Z ^lc groups;

each R ⁶ is independently selected from H, C ₆ -Cio aryl or Ci-C ₆ alkyl, wherein said aryl or alkyl is optionally substituted with 1 to 4 substituents independently selected from halogen atoms, Ci-C ₆ alkyl, C ₆ -Cio aryl, C ₃ -C8 carbocyclyl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, halo(Ci-C6 alkoxy), -OH, -0(Ci-C ₆ alkyl), -SH, -S(Ci-C ₆ alkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -C(0)(Ci-C ₆ alkyl), -S0 ₂ N(Ci-C ₆ alkyl) ₂ , -NHCOO(Ci-C ₆ alkyl), - NHCO(Ci-C ₆ alkyl), -NHCONH(Ci-C ₆ alkyl), -C0 ₂ (Ci-C ₆ alkyl), or - C(0)N(d-C ₆ alkyl) ₂ ;

W ² is Ci-C ₆ alkoxy substituted with a 5-14 membered heteroaryl or C ₆ -Cio aryl; wherein said heteroaryl or aryl is substituted with 1-4 Z ¹ groups;

W ³ is C ₂ -C ₆ alkynyl substituted with an C ₆ -Cio aryl, C ₃ -C8 carbocyclyl, Ci-C ₈ alkyl, Ci-C ₆ haloalkyl, 4-10 membered heterocyclyl, or 5-14 membered heteroaryl; wherein said aryl, carbocyclyl, alkyl, haloalkyl, heterocyclyl, or heteroaryl is optionally substituted with 1-4 Z ¹ groups; W ⁴ is -SF ₅ ;

W ⁵ is -0(C ₂ -C ₆ alkyl)OR ²² wherein R ²² is an C ₆ -Cio aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, and wherein said aryl, heteroaryl or heterocyclyl is optionally substituted with 1-4 Z ¹ groups;

W ⁶ is -0(C ₂ -C ₆ alkyl)NR ¹⁶ R ²² wherein R ²² is an C ₆ -C ₁₀ aryl, 5-14 membered

heteroaryl or 4-10 membered heterocyclyl, and wherein said aryl, heteroaryl or heterocyclyl is optionally substituted with 1-4 Z ¹ groups;

W ⁷ is -0(5-14 membered heteroaryl); wherein said -0(5-14 membered heteroaryl) is optionally substituted with 1-4 Z ¹ groups;

E ¹ is C ₂ -C ₆ alkenyl;

E ² is Ci-C ₆ alkyl;

E ³ is Ci-C ₆ haloalkyl;

E ⁴ is C ₂ -C6 haloalkenyl;

E ⁵ is C3-C6 carbocyclyl;

E ⁶ is Ci-C ₆ alkyl substituted with -OCH ₃ , -OCD ₃ , -OCF ₃ , or -OCF ₂ H;

Q ¹ is H, Ci-C ₈ alkyl, C3-C8 carbocyclyl, -Cio aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein when Q ¹ is not H, said Q ¹ is optionally substituted with 1-3 substituents independently selected from halogen, -OR ⁶ , -SR ⁶ , -N(R ⁶ ) ₂ , C ₆ -Cio aryl, d-C ₆ alkyl, d-C ₆ haloalkyl, d-d haloalkoxy, - CN,

-CF ₃ , -S0 ₂ (Ci-C ₆ alkyl), -S(0)(d-C ₆ alkyl), -NR ⁶ S0 ₂ Z ² ,

-S0 ₂ NR ¹⁷ R ¹⁸ , -NHCOOR ¹⁶ , -NHCOZ ² , -NHCONHR ¹⁶ , -C0 ₂ R ⁶ ,

-C(0)R ⁶ , or -CON(R ⁶ ) ₂ ;

Q ² is C5-C1 ₀ spiro bicyclic carbocyclyl optionally substituted with 1-4 Z ¹ groups; Q ³ is C5-C1 ₀ fused bicyclic carbocyclyl optionally substituted with 1-4 Z ¹ groups; Q ⁴ is C5-C1 ₀ bridged bicyclic carbocyclyl optionally substituted with 1-4 Z ¹ groups; Q ⁵ is 4-membered heterocyclyl having 1 heteroatom selected from N, O or S wherein

Q ⁵ is optionally substituted with alkyl or 1-4 Z ³ groups;

Q ⁶ is Ci-C ₈ alkyl, C ₃ -C ₈ carbocyclyl, C ₆ -Cio aryl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl, wherein Q ⁶ is substituted with 1 oxo group and with 0 to 3 substituents independently selected from halogen, -OR ⁶ , -SR ⁶ , -N(R ⁶ )2,

C ₆ -Cio aryl, d-C ₆ alkyl, Ci-C ₆ haloalkyl, Ci-C ₆ haloalkoxy, -N0 ₂ , -CN, -CF ₃ ,

-S0 ₂ (C _! -C ₆ alkyl),

-S(0)(Ci-C ₆ alkyl), -NR ⁶ S0 ₂ Z ² , -S0 ₂ NR ¹⁷ R ¹⁸ , -NHCOOR ¹⁶ ,

-NHCOZ ² , -NHCONHR ¹⁶ , -C0 ₂ R ⁶ , -C(0)R ⁶ , or -CON(R ⁶ ) ₂ ;

Q ⁷ is C3-C ₈ carbocyclyl, wherein Q ⁷ is substituted with 4-8 F atoms and each carbon of Q ⁷ is substituted with 0-2 F atoms;

each Z ¹ is independently oxo, halogen, Ci-C ₈ alkyl, C ₂ -Cs alkenyl, C ₂ -Cs alkynyl,

C ₃ -C ₈ carbocyclyl, C5-C1 ₀ bicyclic carbocyclyl, Ci-C ₈ haloalkyl, C ₆ -Cio aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, -CN, -C(0)R ¹⁶ , -

C(0)OR ¹⁶ , -C(0)NR ¹⁷ R ¹⁸ ,

-NR ¹⁷ R ¹⁸ , -NR ¹⁶ C(0)R ¹⁶ , -NR ¹⁶ C(0)NR ¹⁷ R ¹⁸ , -NR ¹⁶ S(0) ₂ R ¹⁶ ,

-NR ¹⁶ S(0) ₂ NR ¹⁷ R ¹⁸ , -NR ¹⁶ S(0) ₂ OR ¹⁶ , -OR ¹⁶ , -OC(0)R ¹⁶ ,

-OC(0)NR ¹⁷ R ¹⁸ , -SR ¹⁶ , -S(0)R ¹⁶ , -S(0) ₂ R ¹⁶ or -S(0) ₂ NR ¹⁷ R ¹⁸ wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of Z ¹ is optionally substituted with 1-4 Z ^la groups;

each Z ^la is independently oxo, halogen, C ₂ -Cs alkenyl, C ₂ -Cs alkynyl, C ₃ -C ₈

carbocyclyl, C5-C1 ₀ bicyclic carbocyclyl, Ci-C ₈ haloalkyl, C ₆ -Cio aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl,

-CN, -C(0)R ¹⁶ , -C(0)OR ¹⁶ , -C(0)NR ¹⁷ R ¹⁸ , -NR ¹⁷ R ¹⁸ , -NR ¹⁽⁵ C(0)R , -NR ¹⁽⁵ C(0)OR , -NR ¹⁽⁵ C(0)NR ^{1 /} R ^1S , -NR ¹⁽⁵ S(0) ₂ R , -NR ¹⁶ S(0) ₂ NR ¹⁷ R ¹⁸ , -NR ¹⁶ S(0) ₂ OR ¹⁶ , -OR ¹⁶ , -OC(0)R ¹⁶ ,

-OC(0)NR ¹⁷ R ¹⁸ , -SR ¹⁶ , -S(0)R ¹⁶ , -S(0) ₂ R ¹⁶ or -S(0) ₂ NR ¹⁷ R ¹⁸ wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of Z ^la is optionally substituted with 1-4 Z ^lc groups;

each R ¹⁶ is independently H, Ci-C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈

carbocyclyl, C5-C1 ₀ bicyclic carbocyclyl, C ₆ -Cio aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of R ¹⁶ is optionally substituted with 1-4 Z ^lc groups;

each Z ^lc is independently oxo, halogen, Ci-C ₈ alkyl, C ₃ -C ₈ carbocyclyl, C5-C1 ₀ bicyclic carbocyclyl, Ci-C ₈ haloalkyl, C ₆ -Cio aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, -CN, -C(0)(d-C ₈ alkyl), -C(0)0(d-C ₈ alkyl), -C(0)N(Ci-C ₈ alkyl) ₂ , -NH ₂ , -NH(C C ₈ alkyl), -N(C C ₈ alkyl) ₂ ,

-NHC(0)0(C C ₈ alkyl), -NHC(0)(C C ₈ alkyl), -NHC(0)NH(C C ₈ alkyl), - OH, -0(Ci-C ₈ alkyl), C ₃ -C ₈ cycloalkoxy, C5-C1 ₀ bicyclic carbocyclyloxy, - S(Ci-C ₈ alkyl) or

-S(0) ₂ N(Ci-C ₈ alkyl) ₂ wherein any alkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl or cycloalkoxy portion of Z ^lc is optionally substituted with 1-4 halogen atoms or Ci-C ₆ alkoxy groups;

R ¹⁷ and R ¹⁸ are each independently H, Ci-C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ carbocyclyl, C5-C1 ₀ bicyclic carbocyclyl, -C(0)R ¹⁶ ,

-C(0)OR ¹⁶ , C ₆ -Cio aryl, 5-14 membered heteroaryl or 4-10 membered heterocyclyl, wherein any alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl of R ¹⁷ or R ¹⁸ is optionally substituted with 1-4 Z ^lc groups, or R and R together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl group, wherein said 4-7 membered heterocyclyl group is optionally substituted with 1-4 Z ^lc groups; each Z ² is independently Ci-C ₈ alkyl, C ₃ -C ₈ carbocyclyl, C5-C1 ₀ bicyclic carbocyclyl, C ₆ -Cio aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, -

NR ¹⁷ R ¹⁸ or -OR ¹⁶ wherein any alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portion of Z ² is optionally substituted with 1-4 Z ^2a groups; each Z ^2a is independently oxo, halogen, Ci-C ₈ alkyl, C2-C ₈ alkynyl, C ₃ -C ₈ carbocyclyl,

C5-C1 ₀ bicyclic carbocyclyl, Ci-C ₈ haloalkyl, C ₆ -Cio aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, -(C ₂ -C ₈ alkynyl)aryl, -(C ₂ -C ₈ alkynyl)heteroaryl, -CN, -C(0)(Ci-C ₆ alkyl),

-C(0)0(Ci-C ₆ alkyl), -C(0)N(Ci-C ₆ alkyl) _2, -NH ₂ , -NH(Ci-C ₆ alkyl), -N(Ci-C ₆ alkyl) ₂ , -NHC(0)0(Ci-C ₆ alkyl), -NHC(0)(Ci-C ₆ alkyl),

-NHC(0)NH(C C ₆ alkyl), -OH, -0(C _r C ₆ alkyl), halo(C C ₆ alkoxy), C ₃ -C ₈ cycloalkoxy, -S(Ci-C ₆ alkyl), or -S0 ₂ N(Ci-C ₆ alkyl) ₂ ; wherein any alkyl, alkynyl, carbocyclyl, cycloalkoxy, aryl, heteroaryl or heterocyclyl portions of Z ^2a is optionally substituted with 1-4 halogen or Ci-C ₆ alkoxy groups; each Z ³ is independently oxo, halogen, C2-C ₈ alkenyl, C2-C ₈ alkynyl, C3-C ₈ carbocyclyl, C5-C1 ₀ bicyclic carbocyclyl, Ci-C ₈ haloalkyl, C ₆ -Cio aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, -CN, -C(0)OR ¹⁶ , -

C(0)NR ¹⁷ R ¹⁸ , -NR ¹⁷ R ¹⁸ , -NR ¹⁶ C(0)NR ¹⁷ R ¹⁸ , -OR ¹⁶ ,

-SR ¹⁶ or -SO2R ¹⁶ ; wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z ³ is optionally substituted with 1-4 halogen; and each Z ⁴ is independently oxo, C2-C ₈ alkenyl, C2-C ₈ alkynyl, C ₃ -C ₈ carbocyclyl, C5-C1 ₀ bicyclic carbocyclyl, Ci-C ₈ haloalkyl, C ₆ -Cio aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, -CN, -C(0)OR ¹⁶ , -C(0)NR ¹⁷ R ¹⁸ , -NR ¹⁷ R ¹⁸ , -NR ¹⁶ C(0)NR ¹⁷ R ¹⁸ ,

-OR ¹⁶ , -SR ¹⁶ or -S0 ₂ R ¹⁶ , wherein any alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl portions of Z ⁴ is optionally substituted with 1-4 halogen.

[0082] In one embodiment the compound of Formula IV is:

or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, A method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound selected from:

⁰

and pharmaceutically acceptable salts thereof.

[0084] In one embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound

or a pharmaceutically acceptable salt, thereof. [0085] In one embodiment, a method for treating a Zika virus infection in a human thereof com rising administering a therapeutically effective amount of a compound

or a pharmaceutically acceptable salt, thereof.

[0086] In one embodiment, a method for treating a Zika virus infection in a human in need thereof com rising administering a therapeutically effective amount of a compound

or a pharmaceutically acceptable salt, thereof.

[0087] In one embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administerin a therapeutically effective amount of a compound

or a pharmaceutically acceptable salt, thereof.

[0088] In one embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of a compound

or a pharmaceutically acceptable salt, thereof.

[0089] In one embodiment, a method for treating a Zika virus infection in a human in need thereof com rising administering a therapeutically effective amount of a compound

or a pharmaceutically acceptable salt, thereof.

[0090] In one embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of any two compounds selected from:

and pharmaceutically acceptable salts thereof.

[0091] In one embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of

or pharmaceutically acceptable salts thereof.

[0092] In one embodiment, a method for treating a Zika virus infection in a human in need thereof comprising administering a therapeutically effective amount of

or a pharmaceutically acceptable salt thereof,

and

or a pharmaceutically acceptable salt thereof.

[0093] The compound names provided herein are named using ChemBioDraw Ultra and one skilled in the art understands that the compound structure may be named or identified using other commonly recognized nomenclature systems and symbols. By way of example, a compound may be named or identified with common names, systematic or non-systematic names. The nomenclature systems and symbols that are commonly recognized in the art of chemistry including but not limited to Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). Accordingly, a compound structure

may be named or identified as (2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrah ydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino)propanoate under IUPAC and L- Alanine, N-[[P(S),2'R]-2'- deoxy-2'-fluoro-2'-methyl-P-phenyl-5'-uridylyl]-, 1-methylethyl ester under CAS; CAS Registry Number 1190307-88-0.

[0094] A compound of Formula I-IV and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. The crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). The instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula I- III and their pharmaceutically acceptable salts.

[0095] A compound of Formula I-IV and its pharmaceutically acceptable salts may also exist as an amorphous solid. As used herein, an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less. Additives, including solvents, may be used to create the amorphous forms of the instant invention. The instant invention comprises all amorphous forms of the compounds of Formula I-IV and their pharmaceutically acceptable salts.

[0096] For therapeutic use, salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a

physiologically acceptable compound. All salts, whether or not derived form a

physiologically acceptable acid or base, are within the scope of the present invention.

[0097] Finally, it is to be understood that the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

[0098] It is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds within the scope of Formula I-IV and pharmaceutically acceptable salts thereof are embraced by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

[0099] The compounds of the invention, exemplified by Formula I-IV may have chiral centers, e.g. chiral carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. The racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.

[0100] Whenever a compound described herein is substituted with more than one of the same designated group, e.g., "R" or "R ¹ ", then it will be understood that the groups may be the same or different, i.e., each group is independently selected. Wavy lines, , indicate the site of covalent bond attachments to the adjoining substructures, groups, moieties, or atoms.

[0101] Selected substituents comprising the compounds of Formula I-IV are present to a recursive degree. In this context, "recursive substituent" means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number of compounds may be present in any given embodiment. For example, R ^x comprises a R ^y substituent. R ^y can be R. R can be Z ³ . Z ³ can be Z ⁴ and Z ⁴ can be R or comprise substituents comprising R ^y . Alternatively, Z ³ can be Z ⁵ which can comprise substituents comprising R ^y . One of ordinary skill in the art of medicinal chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by way of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.

[0102] By way of example and not limitation, Z ³ and R ^y are recursive substituents in certain embodiments. Typically, each recursive substituent can independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment. More typically, each recursive substituent can independently occur 12 or fewer times in a given embodiment. Even more typically, each recursive substituent can independently occur 3 or fewer times in a given embodiment. For example, Z ³ will occur 0 to 8 times, R ^y will occur 0 to 6 times in a given embodiment. Even more typically, Z ³ will occur 0 to 6 times and R ^y will occur 0 to 4 times in a given embodiment.

[0103] Recursive substituents are an intended aspect of the invention. One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in an embodiment of the invention, the total number will be determined as set forth above.

[0104] The compounds of the present invention can be prepared by methods known to one of skill in the art. For example, the compounds of the present invention can be prepared according to the methods described in U.S. Patent No. 8,008,264 and U.S. Application Publication No. US 2012/0027752.

A. Metabolites of the Compounds of the Invention

[0105] Also falling within the scope of this invention are the in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. or ¾) compound of the invention, administering it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no anti Zika virus activity of their own.

[0106] Recipes and methods for determining stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37°C.

Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. The prodrugs of the invention typically will be stable in the digestive system but may be substantially hydrolyzed to the parental drug in the digestive lumen, liver or other metabolic organ, or within cells in general.

III. PHARMACEUTICAL FORMULATIONS

[0107] The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran,

hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10. In some embodiments, the pH of the formulations ranges from about 2 to about 5, but is ordinarily about 3 to 4.

[0108] While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients, particularly those additional therapeutic ingredients as discussed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0109] The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0110] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.

[0111] A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0112] For infections of the eye or other external tissues e.g. mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

[0113] If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.

[0114] The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so- called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

[0115] Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. Further emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 80.

[0116] The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.

[0117] Pharmaceutical formulations according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical

compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0118] Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0119] Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g.,

heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan

monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Further non-limiting examples of suspending agents include Cyclodextrin and Captisol (=Sulfobutyl ether beta- cyclodextrin; SEB-beta-CD).

[0120] Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0121] Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0122] The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

[0123] The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0124] The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight: weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

[0125] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about 1.5% w/w.

[0126] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0127] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0128] Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of Zika virus infections as described below.

[0129] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0130] Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0131] The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0132] It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0133] The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.

[0134] Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

[0135] Compounds of the invention are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

IV. ROUTES OF ADMINISTRATION

[0136] One or more compounds of the invention (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. In certain embodiments, the compounds disclosed herein are administered by intravenous injection. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.

[0137] Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg body weight per day; more typically, from about .01 to about 5 mg/kg body weight per day; most typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.

[0138] In the methods of the present invention for the treatment of a Zika virus infection, the compounds of the present invention can be administered at any time to a human who may come into contact with humans suffering from a Zika virus infection or is already suffering from a Zika virus infection. In some embodiments, the compounds of the present invention can be administered prophylactically to humans coming into contact with humans suffering from a Zika virus infection. In some embodiments, administration of the compounds of the present invention can be to humans testing positive for a Zika virus infection but not yet showing symptoms of a Zika virus infection. In some embodiments, administration of the compounds of the present invention can be to humans upon commencement of symptoms of a Zika virus infection.

[0139] Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg body weight per day; more typically, from about .01 to about 5 mg/kg body weight per day; most typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.

[0140] The effective dose of a compound of the present invention for treating the Zika virus infection can depend on whether the dose is to be used prophylactically or to treat a human already suffering from a Zika virus infection. Moreover, the dose can depend on whether the human suffering from a Zika virus infection does not yet show symptoms or is already showing symptoms of a Zika virus infection. Larger doses may be necessary for treating humans testing positive for a Zika virus infection and for humans showing symptoms of a Zika virus infection as compared to humans receiving prophylactic treatment.

[0141] Any suitable period of time for administration of the compounds of the present invention is contemplated. For example, administration can be for from 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days. The administration can also be for from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks. Longer periods of administration are also contemplated. The time for administration can depend on whether the compound is being administered prophylactically or to treat a human suffering from an a Zika virus infection. For example, a prophylactic administration can be for a period of time while the human is in regular contact with other humans suffering from an a Zika virus infection, and for a suitable period of time following the last contact with a human suffering from an a Zika virus infection. For humans already suffering from an a Zika virus infection, the period of administration can be for any length of time necessary to treat the patient and a suitable period of time following a negative test for a Zika virus infection to ensure the a Zika virus infection does not return.

V. COMBINATION THERAPY

[0142] In various methods, Compounds of Formulae I-IV (i.e. Formula I, Formula II, Formula III, and Formula IV) 1 can be concomitantly administered with at least one additional antiviral agent, for example one additional antiviral agent or two or more additional antiviral agents. Concomitant administration refers to the administration of two or more agents in any manner in which the pharmacological effects of both agents are manifested in the subject at the same time. Although concomitant administration includes simultaneous administration (e.g. via fixed-dose combinations of two or more agents), it does not require that a single pharmaceutical composition, the same type of formulation, the same dosage form, or even the same route of administration be used for administration of the agents, or that the agents be administered at the same time. Administration of Compounds of Formulae I-IV (i.e. Formula I, Formula II, Formula III, and Formula IV) and an additional antiviral agent may be concurrent, alternate, or any variation thereof, meaning that when the effective amounts of Compound 1 and the additional antiviral agent are administered during the same duration, the specific order of administration on a daily basis can be: Compounds of Formulae I-IV (i.e. Formula I, Formula II, Formula III, and Formula IV) followed by the additional antiviral agent, Compounds of Formulae I-IV (i.e. Formula I, Formula II, Formula III, and Formula IV) and the additional antiviral agent together, the additional antiviral agent followed by Compounds of Formulae I-IV (i.e. Formula I, Formula II, Formula III, and Formula IV), or any variation thereof. Additionally, it is contemplated that dosage frequencies of Compounds of Formulae I-IV (i.e. Formula I, Formula II, Formula III, and Formula IV) and the additional antiviral agent may differ. As one non-limiting example, Compounds of Formulae I-IV (i.e. Formula I, Formula II, Formula III, and Formula IV) may be administered QD while the additional antiviral agent is administered BID.

[0143] In certain embodiments, a compound of the present disclosure (e.g., a Compounds of Formulae I-IV (i.e. Formula I, Formula II, Formula III, and Formula IV)), is formulated as a tablet, which may contain one or more other compounds useful for treating VIRUSES.

[0144] In certain embodiments, such tablets are suitable for once daily dosing. VIRAL Combination Therapy

[0145] Examples of additional antiviral agents include, without limitation, the following: interferons, ribavirin, NS5A inhibitors, NS5B polymerase inhibitors, protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, toll-like receptor-7 (TLR-7) agonists, cyclophilin inhibitors, HCV internal ribosome entry site (HCV IRES) inhibitors, and pharmacokinetic enhancers.

Interferons

[0146] Examples of interferons include pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a (PEGASYS ^® ), rIFN-alpha 2b (INTRON ^® A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon alpha-nl (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha- 2b (AVI-005), PEG-Infergen, PEGylated interferon lambda (PEGylated IL-29), or belerofon, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha, infergen, rebif, pegylated IFN-beta, oral interferon alpha, feron, reaferon, intermax alpha, and r-IFN-beta.

Ribavirin

[0147] Examples of ribavirin and its analogs include ribavirin; taribavirin (viramidine); VX-497; and infergen, actimmune, and ribavirin.

NS5A Inhibitors

[0148] Examples of NS5A inhibitors include Compound 3 (described below), Compound 2 (described below), Compound A.3 (described below), Compound A.4 (described below), samatasvir, daclatasvir (BMS-790052), ABT-267, ABT-267, JNJ-47910382, MK-8742, MK- 8404, EDP-239, IDX-719, PPI-668, GSK-2336805, ACH-3102, A-831, A-689, AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052.

NS5B Polymerase Inhibitors

[0149] Examples of NS5B polymerase inhibitors include sofosbuvir (GS-7977), tegobuvir (GS-9190), GS-9669, Compound A.5 (described below), Compound A.6 (described below), Compound A.7 (described below), Compound A.8 (described below), PSI-6130 (R1656), PSI-7851, ABT-333, ABT-072, ABT-333, ABT-072, TMC647055, setrobuvir (ANA-598), IDX-21437, IDX-375, IDX-184, IDX-102, BI-207127, filibuvir (PF-868554), VX-222, valopicitabine (NM-283), BCX-4678, nesbuvir (HCV-796), BILB 1941, MK-0608, NM-107, R7128, VCH-759, GSK625433, XTL-2125, VCH-916, JTK-652, MK-3281, VBY-708, A848837, GL59728, A-63890, A-48773, A-48547, BC-2329, BMS-791325, BILB-1941, and ACH-3422.

Protease Inhibitors [0150] Protease inhibitors include NS3, NS4, and NS3/NS4 inhibitors. Examples include Compound 5 (described below), Compound A.10 (described below), Compound A.11 (described below), Compound A.12 (described below), ABT-450, simeprevir (TMC-435), boceprevir (SCH-503034), narlaprevir (SCH-900518), vaniprevir (MK-7009), MK-5172, danoprevir (ITMN-191), sovaprevir (ACH-1625), neceprevir (ACH-2684), Telaprevir (VX- 950), VX-813, VX-500, faldaprevir (BI-201335), asunaprevir (BMS-650032), BMS-605339, VBY-376, PHX-1766, YH5531, BILN-2065, and BILN-2061.

Alpha- glucosidase 1 Inhibitors

[0151] Examples of alpha-glucosidase 1 inhibitors include celgosivir (MX-3253), miglitol, and UT-231B.

Hepatoprotectants

[0152] Examples of hepatoprotectants include emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silibinin, and MitoQ ^® .

Toll-like Receptor-7 (TLR-7) Agonists [0153] Examples of TLR-7 agonists include imiquimod, 852A, GS-9524, ANA-773, ANA- 975, AZD-8848 (DSP-3025), and SM-360320.

Cyclophilin Inhibitors

[0154] Examples of cyclophilin inhibitors include DEBIO-025, SCY-635, and NIM811. HCV Internal Ribosome Entry Site (HCV IRES) Inhibitors [0155] Examples of HCV IRES inhibitors include MCI-067.

Pharmacokinetic Enhancers [0156] Examples of pharmacokinetic enhancers include GS-9350, GS-9585, B AS- 100, SPI-452, PF-4194477, TMC-41629, and roxythromycin.

Other Antiviral Agents

[0157] Other antiviral agents include GS-9525, thymosin alpha 1 (ZADAXIN ^® ), nitazoxanide, BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS- 791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide, VX-497 (merimepodib) NIM811, benzimidazole derivatives, benzo-l,2,4-thiadiazine derivatives, and phenylalanine derivatives.

Compounds

[0158] Compound 3 is an inhibitor of the HCV NS5A protein and is represented by the following chemical structure:

See US20100310512.

[0159] Compound 2 is an NS5A inhibitor and is represented by the following chemical structure:

[0160] Compound A.3 is an NS5A inhibitor and is represented by the following chemical structure:

[0161] Compound A.4 is an NS5A inhibitor and is represented by the following chemical structure:

See US20130102525 and references therein.

[0162] Compound A.5 is an NS5B Thumb II polymerase inhibitor and is represented by the following chemical structure: [0163] Compound A.6 is a nucleotide inhibitor prodrug designed to inhibit replication of viral RNA by the HCV NS5B polymerase, and is represented by the following chemical structure:

[0164] Compound A.7 is an HCV polymerase inhibitor and is represented by the following structure:

See US20130102525 and references therein.

[0165] Compound A.8 is an HCV polymerase inhibitor and is represented by the following structure:

See US20130102525 and references therein. [0166] Compound 5 is an HCV protease inhibitor and is represented by the following chemical structure:

[0167] Compound A.10 is an HCV protease inhibitor and is represented by the following chemical structure:

[0168] Compound A.11 is an HCV protease inhibitor and is represented by the following chemical structure: [0169] Compound A.12 is an HCV protease inhibitor and is represented by the following chemical structure:

See US20130102525 and references therein. [0170] In one embodiment, the additional therapeutic agent used in combination with the pharmaceutical compositions as described herein is a HCV NS3 protease inhibitor. Non- limiting examples include the following:

[0171] In another embodiment, the additional therapeutic agent used in combination with the pharmaceutical compositions as described herein is a cyclophillin inhibitor, including for example, a cyclophilin inhibitor disclosed in WO2013/185093. Non-limiting examples in addition to those listed above include the following:

and

, and stereoisomers and mixtures of stereoisomers thereof.

Combination Therapy [0172] In a specific embodiment, a compound of the present disclosure, or a

pharmaceutically acceptable salt thereof, is combined with a HCV NS5B polymerase inhibitor. In a specific embodiment, a compound of the present disclosure, or a

pharmaceutically acceptable salt thereof, is combined with a HCV NS5B polymerase inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS5B polymerase inhibitor, a HCV NS3 protease inhibitor, and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS5B polymerase inhibitor, a HCV NS4 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS5B polymerase inhibitor, a HCV NS3/NS4 protease inhibitor, and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS3 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS4 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS3/NS4 protease inhibitor and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS3 protease inhibitor, a pharmacokinetic enhancer and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS4 protease inhibitor, a pharmacokinetic enhancer, and a HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a HCV NS3/NS4 protease inhibitor, a pharmacokinetic enhancer, and a HCV NS5A inhibitor.

[0173] In a particular embodiment, a compound of the present disclosure, or a

pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from: sofosbuvir; ledipasvir; GS-5816; GS-9857; sofosbuvir and ledipasvir; sofosbuvir and GS-5816; sofosbuvir, GS-9857, and ledipasvir; tegobuvir; simeprevir; daclatasvir; interferon; pegylated interferon; ribavirin; samatasvir; setrobuvir; valopicitabine; boceprevir; narlaprevir; vaniprevir; danoprevir; sovaprevir;

neceprevir; telaprevir; faldaprevir; asunaprevir; vedroprevir; ABT-450; ABT-267; ABT-333; ACH-3422; ACH-3102; AL-335; AL-516; IDX-21437; IDX-21459; MK-3682; MK-8742;

MK-8408; MK-5172; ABT-450, ABT-267, and ritonavir; ABT-450, ABT-267, ribavirin, and ritonavir; ABT-450, ABT-267, ABT-333, ribavirin, and ritonavir; ABT-530 and ABT-493;

MK-8742 and MK-5172; MK-8408, MK-3682, and MK-5172; MK-8742, MK-3682, and

MK-5172; ACH-3422 and ACH-3102; ACH-3422, sovaprevir, and ACH-3102; and asunaprevir and daclatasvir.

[0174] In certain embodiments, a compound of the present disclosure, or a

pharmaceutically acceptable salt thereof, is co-administered with simeprevir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with MK-8742 or MK-8408. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co- administered with MK-5172. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ABT-450, ABT-267, or ABT-333. In certain embodiments, a compound of the present disclosure, or a

pharmaceutically acceptable salt thereof, is co- administered with VIEKIRA PAK ^® (a combination of ABT-450, ABT-267, and ritonavir). In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with daclatasvir. In certain embodiments, a compound of the present disclosure, or a

pharmaceutically acceptable salt thereof, is co-administered with sofosbuvir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with HARVONI ^® (sofosbuvir and ledipasvir). In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with sofosbuvir and GS-5816. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is coadministered with sofosbuvir, GS-9857, and ledipasvir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co- administered with ABT-450, ABT-267, ribavirin, and ritonavir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ABT-450, ABT-267, ribavirin, ABT-333, and ritonavir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co- administered with ABT-530 and ABT-493. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with MK-8408, MK-3682, and MK-5172. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with MK-8742 and MK-5172. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co- administered with MK-3682. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ACH-3422. In certain embodiments, a compound of the present disclosure, or a

pharmaceutically acceptable salt thereof, is co-administered with AL-335. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ACH-3422 and ACH-3102. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is coadministered with ACH-3422, sovaprevir, and ACH-3102. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is coadministered with GS-5816. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with GS-9857. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with IDX-21459. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with boceprevir. In certain embodiments, a compound of the present disclosure, or a

pharmaceutically acceptable salt thereof, is co-administered with ledipasvir. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with AL-516.

[0175] In various methods, Compound 3 is administered in an amount ranging from about 10 mg/day to about 200 mg/day. For example, the amount of Compound 3 can be about 30 mg/day, about 45 mg/day, about 60 mg/day, about 90 mg/day, about 120 mg/day, about 135 mg/day, about 150 mg/day, or about 180 mg/day. In some methods, Compound 3 is administered at about 90 mg/day. In various methods, Compound 2 is administered in an amount ranging from about 50 mg/day to about 800 mg/day. For example, the amount of Compound 2 can be about 100 mg/day, about 200 mg/day, or about 400 mg/day. In some methods, the amount of Compound A.3 is about 10 mg/day to about 200 mg/day. For example, the amount of Compound A.3 can be about 25 mg/day, about 50 mg/day, about 75 mg/day, or about 100 mg/day.

[0176] In various methods, sofosbuvir is administered in an amount ranging from about 10 mg/day to about 1000 mg/day. For example, the amount of sofosbuvir can be about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day. In some methods, sofosbuvir is administered at about 400 mg/day.

[0177] In certain methods, compound 1 is concomitantly administered with simeprevir. In certain methods, compound 1 is concomitantly administered with MK-8742 or MK-8408. In certain methods, compound 1 is concomitantly administered with MK-5172. In certain methods, compound 1 is concomitantly administered with ABT-450, ABT-267, or ABT-333. In certain methods, compound 1 is concomitantly administered with VIEKIRA PAK ^® (ABT- 450, ABT-267, and ritonavir). In certain methods, compound 1 is concomitantly administered with daclatasvir. VI. EXAMPLES

[0178] The compounds of the present invention can be prepared by a variety of means.

[0179] Published International ("PCT") Patents: WO2007/065829, WO2008/121634, WO2010/132601, WO2013075029, WO2014/008285 are hereby incorporated by reference.

[0180] Compounds were prepared according to methods known in the art. Table 1 provides the relavant art for preparing each respective compound of the invention.

A. Preparation of Compounds

B. Antiviral Activity

[0181] Another aspect of the invention relates to methods of inhibiting viral infections, comprising the step of treating a sample or subject suspected of needing such inhibition with a composition of the invention.

[0182] Within the context of the invention samples suspected of containing a virus include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of containing an organism which induces a viral infection, frequently a pathogenic organism such as a tumor virus. Samples can be contained in any medium including water and organic solvent ater mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.

[0183] If desired, the anti-virus activity of a compound of the invention after application of the composition can be observed by any method including direct and indirect methods of detecting such activity. Quantitative, qualitative, and semiquantitative methods of determining such activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.

[0184] The antiviral activity of a compound of the invention can be measured using standard screening protocols that are known. Example 6. Zika virus antiviral activity and cytotoxicity assays

[0185] Antiviral activity of Compounds 1-5 was measured against Zika virus. Zika virus antiviral assays were conducted in Vero and Huh-7 cells.

[0186] Vero E6 cells were seeded in 96-well plates at 10,000 cells per well. The next day, culture medium was replaced with the assay medium containing 3-fold serial dilutions of the compounds (ranging from 50 - 0.62 μΜ). ZIKV MR766 was added to the antiviral plates. Assay medium was added to tox plates. Cells were incubated for 7 days at 37 °C. Plates were processed by means of the ATPlite method, according to the manufacturer' s protocol (Perkin Elmer).

[0187] Huh-7 cells were seeded in 96 well plates at 6,000 cells per well. The next day, culture medium was discarded and cells were infected with ZIKV MR766. Cells were incubated for 2 hours at 37 °C and then rinsed using assay medium. Cells were further incubated in the presence of a 3-fold dilution (ranging from 50-0.076 μΜ) of the compounds at 37 °C. At day 4 post infection, supernatant was harvested and viral RNA load was determined by real-time quantitative RT=PCR (RT-qPCR).

[0188] Huh-7 cells were seeded in 96 well plates at 6,000 cells per well. The next day, culture medium was replaced with assay medium containing a serial dilution of the compound (ranging from 50 - 0.076 μΜ). Cells were incubated with compounds for 4 days at 37 °C, after which the cytotoxic/cytostatic effect of the compound was evaluated by means of the MTS/PMS method and by microscopic evaluation.

Table 2: Zika Antiviral Assays

Table 2: In Vitro Antiviral Activity of Compounds against Zika virus

[0189] All publications, patents, and patent documents cited herein above are incorporated by reference herein, as though individually incorporated by reference. [0190] The invention has been described with reference to various specific and preferred embodiments and techniques. However, one skilled in the art will understand that many variations and modifications may be made while remaining within the spirit and scope of the invention.