Amino acid phosphoramidate pronucleotides of 2′-cyano, azido and amino nucleosides for the treatment of HCV

FIELD

Provided herein are compounds, methods, and pharmaceutical compositions for use in treatment of viral infections, including hepatitis C virus infections in hosts in need thereof. In certain embodiments, 2′-cyano, azido and amino nucleosides are provided which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human.

BACKGROUND

The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide (Boyer, N. et al., J. Hepatol. 32:98-112, 2000). HCV causes a slow growing viral infection and is the major cause of cirrhosis and hepatocellular carcinoma (Di Besceglie, A. M. and Bacon, B. R., Scientific American, October: 80-85, 1999; Boyer, N. et al., J. Hepatol. 32:98-112, 2000). It is estimated there are about 130-170 million people with chronic hepatitis C virus infection, and there are about 350,000 deaths from hepatitis C-related liver diseases each year (Hepatitis C Fact Sheet, World Health Organization Fact Sheet No. 164, July 2013). Cirrhosis caused by chronic hepatitis C infection accounts for 8,000-12,000 deaths per year in the United States, and HCV infection is the leading indication for liver transplantation.

HCV infection becomes chronic in about 75% of cases, with many patients initially being asymptomatic. The first symptoms of HCV infection are often those of chronic liver disease. About 20 to 30% of patients with chronic hepatitis due to HCV develop cirrhosis, although this may take decades. Development of cirrhosis due to HCV also increases the risk of hepatocellular cancer (The Merck Manual Online, Chronic Hepatitis, available at www.merckmanuals.com/professional/hepatic_and_biliary_disorders/hepatitis/chronic_hepatitis. html, last revision March 2013).

In light of the fact that HCV infection has reached epidemic levels worldwide, and has tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat hepatitis C that have low toxicity to the host. Further, given the rising threat of other flaviviridae infections, there remains a strong need to provide new effective pharmaceutical agents that have low toxicity to the host. Therefore, there is a continuing need for effective treatments of flavivirus infections and HCV infections.

SUMMARY

Provided herein are compounds useful, for example, for the treatment of flavivirus infections such as HCV infections. The compounds are 2′-cyano, azido, and amino nucleosides. In certain embodiments, the 2′-cyano, azido, and amino nucleosides display remarkable efficacy or bioavailability, or both, for the treatment of, for example, HCV infection in a human.

In certain embodiments, the compounds provided herein are useful in the prevention and treatment of Flaviviridae infections and other related conditions such as anti-Flaviviridae antibody positive and Flaviviridae-positive conditions, chronic liver inflammation caused by HCV, cirrhosis, fibrosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-Flaviviridae antibody or Flaviviridae-antigen positive or who have been exposed to a Flaviviridae. In particular embodiments, the Flaviviridae is hepatitis C. In certain embodiments, the compounds are used to treat any virus that replicates through an RNA-dependent RNA polymerase.

A method for the treatment of a Flaviviridae infection in a host, including a human, is also provided. In certain embodiments, the method includes administering an effective amount of a compound provided herein, administered either alone or in combination or alternation with another anti-Flaviviridae agent, optionally in a pharmaceutically acceptable carrier.

In certain embodiments, provided herein are compounds according to Formula 2001:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; W is O or S; R¹is cyano, azido, or amino; R²is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₇cycloalkyl; R¹⁰is hydrogen, halogen, alkyl, cycloalkyl, or aryl; and R¹¹is alkyl, cycloalkyl, or aryl.

In certain embodiments, provided herein are compounds according to Formula I:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; R¹is cyano, azido, or amino; and R²is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₇cycloalkyl.

In certain embodiments, provided herein are compounds according to Formula 1001:

In certain embodiments, provided herein are compounds according to Formula 3001:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; W is O or S; R¹is cyano, azido, or amino; R²is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₇cycloalkyl; is hydrogen, alkyl, cycloalkyl, or aryl; R¹²is alkyl; and R¹³is hydrogen, alkyl, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, or heteroaryl.

In certain embodiments, provided herein are compounds according to Formula 4001:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; W is O or S; R¹is cyano, azido, or amino; R²is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₇cycloalkyl; R¹¹is hydrogen, alkyl, cycloalkyl, or aryl; R¹²is alkyl; and R¹³is hydrogen, alkyl, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, or heteroaryl.

In certain embodiments, provided herein are compounds according to Formula 1501:

In certain embodiments, provided herein are compounds according to Formula 2501:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; W is O or S; R¹is cyano, azido, or amino; R²is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₇cycloalkyl; R¹⁰is hydrogen, alkyl, or halo; and R¹¹is hydrogen, alkyl, cycloalkyl, or aryl.

In one aspect, the compounds provided herein are provided or administered in combination with a second therapeutic agent, such as one useful for the treatment or prevention of HCV infections. Exemplary second therapeutic agents are provided in detail elsewhere herein.

In another aspect, provided herein are pharmaceutical compositions, single unit dosage forms, and/or kits suitable for use in treating or preventing disorders such as HCV infections. In certain embodiments, each of the pharmaceutical compositions, single unit dosage forms, and/or kits comprises a therapeutically or prophylactically effective amount of a compound provided herein, e.g., of Formula 1001-1004bii, 1101, 1501-1504bii, 2001-2004b, 2005-2012, 2501-2504b, 3001-3004b, 4001-4004bii, I-XXXb, 1-48b, 101-148, 201-248, 512-545b, or 601-648c and a therapeutically or prophylactically effective amount of a second therapeutic agent such as one useful for the treatment or prevention of HCV infections.

In certain embodiments, a method of treatment of a liver disorder is provided comprising administering to an individual in need thereof a treatment effective amount of a 2′-cyano, azido, and amino nucleoside compound.

Flaviviridae which can be treated are, e.g., discussed generally in Fields Virology, Fifth Ed., Editors: Knipe, D. M., and Howley, P. M., Lippincott Williams & Wilkins Publishers, Philadelphia, Pa., Chapters 33-35, 2006. In a particular embodiment of the invention, the Flaviviridae is HCV. In an alternate embodiment, the Flaviviridae is a flavivirus or pestivirus. In certain embodiments, the Flaviviridae can be from any class of Flaviviridae. In certain embodiments, the Flaviviridae is a mammalian tick-borne virus. In certain embodiments, the Flaviviridae is a seabird tick-borne virus. In certain embodiments, the Flaviviridae is a mosquito-borne virus. In certain embodiments, the Flaviviridae is an Aroa virus. In certain embodiments, the Flaviviridae is a Dengue virus. In certain embodiments, the Flaviviridae is a Japanese encephalitis virus. In certain embodiments, the Flaviviridae is a Kokobera virus. In certain embodiments, the Flaviviridae is a Ntaya virus. In certain embodiments, the Flaviviridae is a Spondweni virus. In certain embodiments, the Flaviviridae is a Yellow fever virus. In certain embodiments, the Flaviviridae is a Entebbe virus. In certain embodiments, the Flaviviridae is a Modoc virus. In certain embodiments, the Flaviviridae is a Rio Bravo virus.

Specific flaviviruses which can be treated include, without limitation: Absettarov, Aedes, Alfuy, Alkhurma, Apoi, Aroa, Bagaza, Banzi, Bukalasa bat, Bouboui, Bussuquara, Cacipacore, Calbertado, Carey Island, Cell fusing agent, Cowbone Ridge, Culex, Dakar bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam, Kamiti River, Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban, Modoc, Mont. myotis leukoencephalitis, Murray valley encephalitis, Nakiwogo, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Quang Binh, Rio Bravo, Rocio, Royal Farm, Russian spring-summer encephalitis, Saboya, St. Louis encephalitis, Sal Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spondweni, Stratford, Tembusu, Tick-borne encephalitis, Turkish sheep encephalitis, Tyuleniy, Uganda S, Usutu, Wesselsbron, West Nile, Yaounde, Yellow fever, Yokose, and Zika.

Pestiviruses which can be treated are discussed generally in Fields Virology, Fifth Ed., Editors: Knipe, D. M., and Howley, P. M., Lippincott Williams & Wilkins Publishers, Philadelphia, Pa., Chapters 33-35, 2006. Specific pestiviruses which can be treated include, without limitation: bovine viral diarrhea virus (“BVDV”), classical swine fever virus (“CSFV,” also called hog cholera virus), and border disease virus (“BDV”).

DESCRIPTION OF EXEMPLARY EMBODIMENTS

Provided herein are compounds, compositions and methods useful for treating liver disorders such as HCV infection in a subject. Further provided are dosage forms useful for such methods.

Definitions

When referring to the compounds provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

The term “alkyl,” as used herein, unless otherwise specified, refers to a saturated straight or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group includes one to ten carbon atoms, i.e., C₁to C₁₀alkyl. In certain embodiments, the alkyl group is methyl, CF₃, CCl₃, CFCl₂, CF₂Cl, ethyl, CH₂CF₃, CF₂CF₃, propyl, isopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, or 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups, including halogenated alkyl groups. In certain embodiments, the alkyl group is a fluorinated alkyl group. Non-limiting examples of moieties with which the alkyl group can be substituted include, but not limited to, halogen (fluoro, chloro, bromo, or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.

The term “lower alkyl,” as used herein, and unless otherwise specified, refers to a saturated straight or branched hydrocarbon having one to six carbon atoms, i.e., C₁to C₆alkyl. In certain embodiments, the lower alkyl group is a primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted moieties.

The term “upper alkyl,” as used herein, and unless otherwise specified, refers to a saturated straight or branched hydrocarbon having seven to thirty carbon atoms, i.e., C₇to C₃₀alkyl. In certain embodiments, the upper alkyl group is a primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted moieties.

The term “cycloalkyl,” as used herein, unless otherwise specified, refers to a saturated cyclic hydrocarbon. In certain embodiments, the cycloalkyl group may be a saturated, and/or bridged, and/or non-bridged, and/or a fused bicyclic group. In certain embodiments, the cycloalkyl group includes three to ten carbon atoms, i.e., C₃to C₁₀cycloalkyl. In some embodiments, the cycloalkyl has from 3 to 15 (C_3-15), from 3 to 10 (C_3-10), or from 3 to 7 (C_3-7) carbon atoms. In certain embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl. The term includes both substituted and unsubstituted cycloalkyl groups, including halogenated cycloalkyl groups. In certain embodiments, the cycloalkyl group is a fluorinated cycloalkyl group. Non-limiting examples of moieties with which the cycloalkyl group can be substituted include, but not limited to, halogen (fluoro, chloro, bromo, or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary.

“Alkylene” refers to divalent saturated aliphatic hydrocarbon groups particularly having from one to eleven carbon atoms which can be straight-chained or branched. In certain embodiments, the alkylene group contains 1 to 10 carbon atoms. The term includes both substituted and unsubstituted moieties. This term is exemplified by groups such as methylene (—CH₂), ethylene (—CH₂CH₂), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂) and the like. The term includes halogenated alkylene groups. In certain embodiments, the alkylene group is a fluorinated alkylene group. Non-limiting examples of moieties with which the alkylene group can be substituted include, but not limited to, halogen (fluoro, chloro, bromo, or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, alkylaryl, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary.

“Alkenyl” refers to monovalent olefinically unsaturated hydrocarbon groups, in certain embodiment, having up to about 11 carbon atoms, from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 or from 1 to 2 sites of olefinic unsaturation. The term includes both substituted and unsubstituted moieties. Exemplary alkenyl groups include ethenyl (i.e., vinyl or —CH═CH₂), n-propenyl (—CH₂CH═CH₂), isopropenyl (—C(CH₃)═CH₂), and the like. The term includes halogenated alkenyl groups. In certain embodiments, the alkenyl group is a fluorinated alkenyl group. Non-limiting examples of moieties with which the alkenyl group can be substituted include, but not limited to, halogen (fluoro, chloro, bromo, or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary.

The term “cycloalkenyl,” as used herein, unless otherwise specified, refers to an unsaturated cyclic hydrocarbon. In certain embodiments, cycloalkenyl refers to mono- or multicyclic ring systems that include at least one double bond. In certain embodiments, the cycloalkenyl group may be a bridged, non-bridged, and/or a fused bicyclic group. In certain embodiments, the cycloalkyl group includes three to ten carbon atoms, i.e., C₃to C₁₀cycloalkyl. In some embodiments, the cycloalkenyl has from 3 to 7 (C_3-10), or from 4 to 7 (C_4-7) carbon atoms. The term includes both substituted and unsubstituted cycloalkenyl groups, including halogenated cycloalkenyl groups. In certain embodiments, the cycloalkenyl group is a fluorinated cycloalkenyl group. Non-limiting examples of moieties with which the cycloalkenyl group can be substituted include, but not limited to, halogen (fluoro, chloro, bromo, or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary.

“Alkenylene” refers to divalent olefinically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 or from 1 to 2 sites of olefinic unsaturation. This term is exemplified by groups such as ethenylene (—CH═CH—), the propenylene isomers (e.g., —CH═CHCH₂— and —C(CH₃)═CH— and —CH═C(CH₃)—) and the like. The term includes both substituted and unsubstituted alkenylene groups, including halogenated alkenylene groups. In certain embodiments, the alkenylene group is a fluorinated alkenylene group. Non-limiting examples of moieties with which the alkenylene group can be substituted include, but not limited to, halogen (fluoro, chloro, bromo, or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary.

“Alkynyl” refers to acetylenically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 or from 1 to 2 sites of alkynyl unsaturation. Non-limiting examples of alkynyl groups include acetylenic, ethynyl (—C≡CH), propargyl (—CH₂C≡CH), and the like. The term includes both substituted and unsubstituted alkynyl groups, including halogenated alkynyl groups. In certain embodiments, the alkynyl group is a fluorinated alkynyl group. Non-limiting examples of moieties with which the alkynyl group can be substituted include, but not limited to, halogen (fluoro, chloro, bromo, or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary.

The term “aryl,” as used herein, and unless otherwise specified, refers to a substituent derived from an aromatic ring. In an embodiment, an aryl group is a C₆-C₁₂aryl group. In an embodiment, an aryl group is phenyl, biphenyl, or naphthyl. The term includes both substituted and unsubstituted moieties. An aryl group can be substituted with any described moiety, including, but not limited to, one or more moieties selected from halogen (fluoro, chloro, bromo, or iodo), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

“Alkoxy” refers to the group —OR′ where R′ is alkyl or cycloalkyl. Alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

“Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy is as defined herein.

“Amino” refers to the group —NR^1′R^2′ or —NR^1′—, wherein R^1′ and R^2′ are independently selected from hydrogen, alkyl, and cycloalkyl.

“Amino alcohol” refers to the radical —NHLOH, wherein L is alkylene.

“Carboxyl” or “carboxy” refers to the radical —C(O)OH.

The term “alkylamino” or “arylamino” refers to an amino group that has one or two alkyl or aryl substituents, respectively. In certain embodiments, the alkyl substituent is upper alkyl. In certain embodiments, the alkyl substituent is lower alkyl. In another embodiment, the alkyl, upper alkyl, or lower alkyl is unsubstituted.

“Halogen” or “halo” refers to chloro, bromo, fluoro, or iodo.

“Thioalkoxy” refers to the group —SR′ where R′ is alkyl or cycloalkyl.

The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. Heterocyclyl groups are bonded to the rest of the molecule through the non-aromatic ring. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic radicals include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also be optionally substituted as described herein.

The term “alkylheterocyclo” refers to a heterocyclo group with an alkyl substituent. The term “heterocycloalkyl” refers to an alkyl group with a heterocyclo substituent.

The term “heteroaryl” refers to a monovalent monocyclic aromatic group and/or multicyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N in the ring. Heteroaryl groups are bonded to the rest of the molecule through the aromatic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzopyranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted as described herein.

The term “alkylaryl” refers to an aryl group with an alkyl substituent. The term “aralkyl” or “arylalkyl” refers to an alkyl group with an aryl substituent.

The term “alkylheterocyclyl” refers to a heterocyclyl group with an alkyl substituent. The term “heterocyclylalkyl” refers to an alkyl group with a heterocyclyl substituent.

The term “alkylheteroaryl” refers to a heteroaryl group with an alkyl substituent. The term heteroarylalkyl refers to an alkyl group with a heteroaryl substituent.

The term “protecting group” as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

“Pharmaceutically acceptable salt” refers to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, malcic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2) base addition salts formed when an acidic proton present in the parent compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion, or alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

Pharmaceutically acceptable salts further include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butyl acetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate and the like.

As used herein, the term “nucleobase” refers to the base portion of a nucleoside or nucleotide. In certain embodiments, a nucleobase is a purine or pyrimidine base, as defined herein.

The term “purine” or “pyrimidine” base refers to, but is not limited to, adenine, N⁶-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-alkylaminopurine, N⁶-thioalkyl purine, N²-alkylpurines, N²-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C⁵-alkylpyrimidines, C⁵-benzylpyrimidines, C⁵-halopyrimidines, C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine, C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine, C⁵-iodopyrimidine, C⁶-iodo-pyrimidine, C⁵—Br-vinyl pyrimidine, C⁶—Br-vinyl pyrimidine, C⁵-nitropyrimidine, C⁵-amino-pyrimidine, N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 7-deazaguanine, 7-deazaadenine, 2,6-diaminopurine, 2-amino,6-ethoxypurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.

The term “acyl” or “O-linked ester” refers to a group of the formula C(O)R¹, wherein R′ is alkyl or cycloalkyl (including lower alkyl), carboxylate reside of amino acid, aryl including phenyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally substituted with chloro, bromo, fluoro, iodo, C₁to C₄alkyl or C₁to C₄alkoxy, sulfonate esters such as alkyl or arylalkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl. Aryl groups in the esters optimally comprise a phenyl group. In particular, acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclpropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α-methoxy-α-trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl, tert-butylacetyl, trichloroacetyl, mono chloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl, 7H-dodeca-fluoroheptanoyl, 7-chlorododecafluoro-heptanoyl, 7-chloro-dodecafluoro-heptanoyl, 7H-dodecafluoroheptanoyl, 7H-do deca-fluoroheptanoyl, nona-fluoro-3,6-dioxa-heptanoyl, nonafluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl, methyl 3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxy-benzoyl, 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl, omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl-propionyl, 1-benzene-carboxyl, O-acetylmandelyl, pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl, 2,6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, perfluorocyclohexyl carboxyl, 4-methylbenzoyl, chloromethyl isoxazolyl carbonyl, perfluorocyclohexyl carboxyl, crotonyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl, 4-phenylbenzoyl.

The term “amino acid” refers to naturally occurring and synthetic α, β, γ, or δ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In certain embodiments, the amino acid is in the L-configuration. In certain embodiments, the amino acid is in the D-configuration. In certain embodiments, the amino acid can be provided as a substituent of compounds described herein, such as an alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleuccinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl substituent.

The term “amino acid derivative” refers to a group derivable from a naturally or non-naturally occurring amino acid, as described and exemplified herein. Amino acid derivatives are apparent to those of skill in the art and include, but are not limited to, ester, amino alcohol, amino aldehyde, amino lactone, and N-methyl derivatives of naturally and non-naturally occurring amino acids. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is —NR^X-G(S_C)—C(O)-Q¹, wherein Q¹is —SR^Y, —NR^YR^Y, or alkoxyl, R^Yis hydrogen or alkyl, S_Cis a side chain of a naturally occurring or non-naturally occurring amino acid, G is C₁-C₂alkyl, and R^Xis hydrogen or R^Xand S_C, together with the atoms to which they are attached, combine to form a five-membered heterocyclic ring. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is —O—C(O)-G(S_C)—NH-Q², wherein Q²is hydrogen or alkoxyl, S_Cis a side chain of a naturally occurring or non-naturally occurring amino acid and G is C₁-C₂alkyl. In certain embodiments, Q²and S_C, together with the atoms to which they are attached, combine to form a five-membered heterocyclic ring. In certain embodiments, G is C₁alkyl and S_Cis hydrogen, alkyl, arylalkyl, heterocycloalkyl, carboxylalkyl, heteroarylalkyl, aminoalkyl, hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl, sulfanylalkyl, carbamoylalkyl, alkylsulfanylalkyl, or hydroxylarylalkyl. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the amino acid derivative is in the D-configuration. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the amino acid derivative is in the L-configuration.

As used herein, the term “hydroxylalkyl” refers to an alkyl group with a hydroxyl substituent, where alkyl is as described herein.

As used herein, the term “aminoalkyl” refers to an alkyl group with an amino substituent, where alkyl and amino are as described herein.

The term “alkylaryl” refers to an aryl group with an alkyl substituent. The term “aralkyl” or “arylalkyl” refers to an alkyl group with an aryl substituent.

The term “alkylheterocyclyl” refers to a heterocyclyl group with an alkyl substituent. The term “heterocyclylalkyl” refers to an alkyl group with a heterocyclyl substituent.

The term “alkylheteroaryl” refers to a heteroaryl group with an alkyl substituent. The term “heteroarylalkyl” refers to an alkyl group with a heteroaryl substituent.

As used herein, the term “carboxylalkyl” refers to the group -alkyl-C(O)OH, where alkyl is as described herein.

As used herein, the term “aminoiminoaminoalkyl” refers to the group -alkyl-amino-C(NH)-amino, where alkyl and amino are as described herein.

As used herein, the term “aminocarbonylalkyl” refers to the group -alkyl-C(O)-amino, where alkyl and amino are as described herein.

As used herein, the term “sulfanylalkyl” refers to the group -alkyl-SH, where alkyl is as described herein.

As used herein, the term “carbamoylalkyl” refers to the group -alkyl-C(O)-amino, where alkyl and amino are as described herein.

As used herein, the term “alkylsulfanylalkyl” refers to the group -alkyl-S-alkyl, where alkyl is as described herein.

As used herein, the term “hydroxylarylalkyl” refers to the group -alkyl-aryl-OH, where alkyl and aryl are as described herein.

The term “substantially free of” or “substantially in the absence of” with respect to a nucleoside composition refers to a nucleoside composition that includes at least 85 or 90% by weight, in certain embodiments 95%, 98%, 99% or 100% by weight, of the designated diastereomer of that nucleoside. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of an undesignated diastereomer.

Similarly, the term “isolated” with respect to a nucleoside composition refers to a nucleoside composition that includes at least 85%, 90%, 95%, 98%, or 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers.

“Solvate” refers to a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

“Isotopic composition” refers to the amount of each isotope present for a given atom, and “natural isotopic composition” refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural isotopic composition.

“Isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom's natural isotopic abundance. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

“Isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

As used herein, “alkyl,” “cycloalkyl,” “alkenyl,” “cycloalkenyl,” “alkynyl,” “aryl,” “alkoxy,” “alkoxycarbonyl,” “amino,” “carboxyl,” “alkylamino,” “arylamino,” “thioalkyoxy,” “heterocyclyl,” “heteroaryl,” “alkylheterocyclyl,” “alkylheteroaryl,” “acyl,” “aralkyl,” “alkaryl,” “purine,” “pyrimidine,” “carboxyl” and “amino acid” groups optionally comprise deuterium at one or more positions where hydrogen atoms are present, and wherein the deuterium composition of the atom or atoms is other than the natural isotopic composition.

Also as used herein, “alkyl,” “cycloalkyl,” “alkenyl,” “cycloalkenyl,” “alkynyl,” “aryl,” “alkoxy,” “alkoxycarbonyl,” “carboxyl,” “alkylamino,” “arylamino,” “thioalkyoxy,” “heterocyclyl,” “heteroaryl,” “alkylheterocyclyl,” “alkylheteroaryl,” “acyl,” “aralkyl,” “alkaryl,” “purine,” “pyrimidine,” “carboxyl” and “amino acid” groups optionally comprise carbon-13 at an amount other than the natural isotopic composition.

As used herein, EC₅₀refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.

As used herein, the IC₅₀refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

The term “host,” as used herein, refers to any unicellular or multicellular organism in which the virus can replicate, including cell lines and animals, and in certain embodiments, a human. Alternatively, the host can be carrying a part of the Flaviviridae viral genome, whose replication or function can be altered by the compounds of the present invention. The term host specifically includes infected cells, cells transfected with all or part of the Flaviviridae genome and animals, in particular, primates (including chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly anticipated by the present invention (such as chimpanzees).

As used herein, the terms “subject” and “patient” are used interchangeably herein. The terms “subject” and “subjects” refer to an animal, such as a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human), and for example, a human. In certain embodiments, the subject is refractory or non-responsive to current treatments for hepatitis C infection. In another embodiment, the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat). In certain embodiments, the subject is a human.

As used herein, the terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term “therapeutic agent” includes a compound provided herein. In certain embodiments, a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof.

“Therapeutically effective amount” refers to an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. A “therapeutically effective amount” can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

“Treating” or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying the onset of the disease or disorder.

As used herein, the terms “prophylactic agent” and “prophylactic agents” as used refer to any agent(s) which can be used in the prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term “prophylactic agent” includes a compound provided herein. In certain other embodiments, the term “prophylactic agent” does not refer a compound provided herein. For example, a prophylactic agent is an agent which is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression and/or severity of a disorder.

As used herein, the phrase “prophylactically effective amount” refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence or onset of one or more symptoms associated with a disorder, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).

Compounds

Provided herein are 2′-cyano, azido and amino nucleoside compounds. In certain embodiments, they are useful for the treatment of Flaviviridae infections such as HCV infection. The 2′-cyano, azido and amino nucleoside compounds can be formed as described herein and used for the treatment of Flaviviridae infections such as HCV infection.

In certain embodiments, provided herein are compounds according to Formula 3001:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; W is O or S; R¹is cyano, azido, or amino; R²is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₇cycloalkyl; R¹¹is hydrogen, alkyl, cycloalkyl, or aryl; R¹²is alkyl; and R¹³is hydrogen, alkyl, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, or heteroaryl.

In certain embodiments, provided herein are compounds according to Formula 3001a or 3001b:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R¹, R², R¹¹, R¹², and R¹³are as defined in the context of Formula 3001.

In certain embodiments, provided herein are compounds according to Formula 3002:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R², R¹¹, R¹², and R¹³are as defined in the context of Formula 3001.

In certain embodiments, provided herein are compounds according to Formula 3002a or 3002b:

In certain embodiments, provided herein are compounds according to Formula 3003:

In certain embodiments, provided herein are compounds according to Formula 3003a or 3003b:

In certain embodiments, provided herein are compounds according to Formula 3004:

In certain embodiments, provided herein are compounds according to Formula 3004a or 3004b:

In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is O. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is S. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each R¹²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each R¹³is naphthyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each R¹¹is isopropyl and each R¹²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is phenyl or naphthyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is naphthyl.

In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is O and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is O and each R¹²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is O and each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is O and each R¹³is naphthyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is O, each is isopropyl, each R¹²is methyl, and each R¹³is phenyl or naphthyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is O, each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is O, each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is naphthyl.

In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is S and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is S and each R¹²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is S and each R¹³is phenyl or naphthyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is S, each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is phenyl or naphthyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is S, each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 3001-3004b, wherein each W is S, each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is naphthyl.

In certain embodiments, provided herein are compounds according to Formula 2001:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; W is O or S; le is cyano, azido, or amino; R²is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₇cycloalkyl; R¹⁰is hydrogen, halogen, alkyl, cycloalkyl, or aryl; and R¹¹is alkyl, cycloalkyl, or aryl.

In certain embodiments, provided herein are compounds according to Formula 2001a or 2001b:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R¹, R², R¹⁰, and R¹¹are as defined in the context of Formula 2001.

In certain embodiments, provided herein are compounds according to Formula 2002:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R², R¹⁰, and R¹¹are as defined in the context of Formula 2001.

In certain embodiments, provided herein are compounds according to Formula 2002a or 2002b:

In certain embodiments, provided herein are compounds according to Formula 2003:

In certain embodiments, provided herein are compounds according to Formula 2003a or 2003b:

In certain embodiments, provided herein are compounds according to Formula 2004:

In certain embodiments, provided herein are compounds according to Formula 2004a or 2004b:

In certain embodiments, provided herein are compounds according to Formula 2501:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; W is O or S; R¹is cyano, azido, or amino; R²is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₇cycloalkyl; R¹⁰is hydrogen, alkyl, or halo; and R¹¹is hydrogen, alkyl, cycloalkyl, or aryl.

In certain embodiments, provided herein are compounds according to Formula 2501a or 2501b:

In certain embodiments, provided herein are compounds according to Formula 2502:

In certain embodiments, provided herein are compounds according to Formula 2502a or 2502b:

In certain embodiments, provided herein are compounds according to Formula 2503:

In certain embodiments, provided herein are compounds according to Formula 2503a or 2503b:

In certain embodiments, provided herein are compounds according to Formula 2504:

In certain embodiments, provided herein are compounds according to Formula 2504a or 2504b:

In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each W is O. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each W is S. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each R¹⁰is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each R¹⁰is hydrogen and each R¹¹is isopropyl.

In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each W is O and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each W is O and each R¹⁰is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each W is O, each R¹¹is isopropyl, and each R¹⁰is hydrogen.

In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each W is S and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each W is S and each R¹⁰is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2004b and 2501-2504b, wherein each W is S, each R¹¹is isopropyl, and each R¹⁰is hydrogen.

In certain embodiments, provided herein are compounds according to Formula I:

In certain embodiments, provided herein are compounds according to Formula Ia or Ib:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, R¹, and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to Formula II:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to Formula IIa or IIb:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to Formula III:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to Formula IIIa or IIIb:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to Formula IV:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to Formula IVa or IVb:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to Formula 4001:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; W is O or S; R¹is cyano, azido, or amino; R²is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or C₃-C₇cycloalkyl; R¹¹is hydrogen, alkyl, cycloalkyl, or aryl; R¹²is alkyl; and R¹³is hydrogen, alkyl, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, or heteroaryl.

In certain embodiments, provided herein are compounds according to Formula 4001a or 4001b:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R¹, R¹¹, R¹², and R¹³are as defined in the context of Formula 4001.

In certain embodiments, provided herein are compounds according to Formula 4001ai, 4001aii, 4001bi, or 4001bii:

In certain embodiments, provided herein are compounds according to Formula 4002:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R¹¹, R¹², and R¹³are as defined in the context of Formula 4001.

In certain embodiments, provided herein are compounds according to Formula 4002a or 4002b:

In certain embodiments, provided herein are compounds according to Formula 4002ai, 4002aii, 4002bi, or 4002bii:

In certain embodiments, provided herein are compounds according to Formula 4003:

In certain embodiments, provided herein are compounds according to Formula 4003a or 4003b:

In certain embodiments, provided herein are compounds according to Formula 4003ai, 4003aii, 4003bi, or 4003bii:

In certain embodiments, provided herein are compounds according to Formula 4004:

In certain embodiments, provided herein are compounds according to Formula 4004a or 4004b:

In certain embodiments, provided herein are compounds according to Formula 4004ai, 4004aii, 4004bi, or 4004bii:

In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is O. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is S.

In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each R¹²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each R¹³is naphthyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each R¹³is phenyl or napthyl, and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each R¹³is phenyl and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each R¹³is napthyl and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each R¹³is phenyl, each R¹²is methyl, and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each R¹³is napthyl, each R¹²is methyl, and each R¹¹is isopropyl.

In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is O and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is O and each R¹²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is O and each R¹³is phenyl or napthyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is O and each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is O and each R¹³is naphthyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is O, each R¹¹is isopropyl, and each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is O, each R¹¹is isopropyl, and each R¹³is napthyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is O, each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is O, each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is napthyl.

In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is S and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is S and each R¹²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is S and each R¹³is phenyl or napthyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is S and each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is S and each R¹³is naphthyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is S, each R¹¹is isopropyl, and each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is S, each R¹¹is isopropyl, and each R¹³is napthyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is S, each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is phenyl. In certain embodiments, provided herein are compounds according to any of Formulas 4001-4004bii, wherein each W is S, each R¹¹is isopropyl, each R¹²is methyl, and each R¹³is napthyl.

In certain embodiments, provided herein are compounds according to Formula 1001:

In certain embodiments, provided herein are compounds according to Formula 1001a or 1001b:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R¹, R¹⁰, and R¹¹are as defined in the context of Formula 1001.

In certain embodiments, provided herein are compounds according to Formula 1001ai, 1001aii, 1001bi, or 1001bii:

In certain embodiments, provided herein are compounds according to Formula 1002:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base, W, R¹⁰, and R¹¹are as defined in the context of Formula 1001.

In certain embodiments, provided herein are compounds according to Formula 1002a:

In certain embodiments, provided herein are compounds according to Formula 1002ai or 1002aii:

In certain embodiments, provided herein are compounds according to Formula 1003:

In certain embodiments, provided herein are compounds according to Formula 1003a:

In certain embodiments, provided herein are compounds according to Formula 1003ai or 1003aii:

In certain embodiments, provided herein are compounds according to Formula 1004:

In certain embodiments, provided herein are compounds according to Formula 1004a:

In certain embodiments, provided herein are compounds according to Formula 1004ai or 1004aii:

In certain embodiments, provided herein are compounds according to Formula 1002b:

In certain embodiments, provided herein are compounds according to Formula 1002bi or 1002bii:

In certain embodiments, provided herein are compounds according to Formula 1003b:

In certain embodiments, provided herein are compounds according to Formula 1003bi or 1003bii:

In certain embodiments, provided herein are compounds according to Formula 1004b:

In certain embodiments, provided herein are compounds according to Formula 1004bi or 1004bii:

In certain embodiments, provided herein are compounds according to Formula 1501:

In certain embodiments, provided herein are compounds according to Formula 1501a or 1501b:

In certain embodiments, provided herein are compounds according to Formula 1501ai, 1501aii, 1501bi, or 1501bii:

In certain embodiments, provided herein are compounds according to Formula 1502:

In certain embodiments, provided herein are compounds according to Formula 1502a or 1502b:

In certain embodiments, provided herein are compounds according to Formula 1502ai, 1502aii, 1502bi, or 1502bii:

In certain embodiments, provided herein are compounds according to Formula 1503:

In certain embodiments, provided herein are compounds according to Formula 1503a or 1503b:

In certain embodiments, provided herein are compounds according to Formula 1503ai, 1503aii, 1503bi, or 1503bii:

In certain embodiments, provided herein are compounds according to Formula 1504:

In certain embodiments, provided herein are compounds according to Formula 1504a or 1504b:

In certain embodiments, provided herein are compounds according to Formula 1504ai, 1504aii, 1504bi, or 1504bii:

In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each W is O. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each W is S. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each R¹⁰is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each R¹⁰is hydrogen and each R¹¹is isopropyl.

In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each W is O and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each W is O and each R¹⁰is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each W is O, each R¹¹is isopropyl, and each R¹⁰is hydrogen.

In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each W is S and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each W is S and each R¹⁰is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii or 1501-1504bii, wherein each W is S, each R¹¹is isopropyl, and each R¹⁰is hydrogen.

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or a tautomer thereof; wherein: each R⁴is independently hydrogen, hydroxyl, hydroxylamine, alkylamino, halogen, sulfanyl, amino, or alkoxy; each R⁵is independently hydrogen, halogen, or methyl; and each R⁶is independently hydrogen, amino, or halogen.

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or a tautomer thereof; wherein: each R⁴is independently hydrogen, hydroxyl, hydroxylamine, alkylamino, halogen, sulfanyl, amino, or alkoxy; each R⁵is independently hydrogen, halogen, or methyl; each R⁶is independently hydrogen, amino, or halogen; and W is O.

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or a tautomer thereof; wherein: each R⁴is independently hydrogen, hydroxyl, hydroxylamine, alkylamino, halogen, sulfanyl, amino, or alkoxy; each R⁵is independently hydrogen, halogen, or methyl; each R⁶is independently hydrogen, amino, or halogen; and W is S.

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or a tautomer thereof; wherein: each R⁴is independently hydrogen, hydroxyl, or amino; and each R⁵is independently hydrogen, halogen, or methyl. In certain embodiments, provided herein are compounds according to any of Formulas I-IVb, 1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein each Base is independently

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or a tautomer thereof; wherein: each R⁴is independently hydrogen, hydroxyl, or amino; and each R⁵is independently halogen. In certain embodiments, provided herein are compounds according to any of Formulas I-IVb, 1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii wherein each Base is independently

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or a tautomer thereof; wherein: each R⁴is independently hydrogen, hydroxyl or amino; and each R⁵is fluoro.

In certain embodiments, provided herein are compounds according to any of Formulas I-IVb, 1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein each Base is independently adenine, thymine, Cytosine, guanine, 5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine.

In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein: each Base is independently adenine, thymine, cytosine, guanine, 5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; each W is O; and each R¹⁰is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein: each Base is independently adenine, thymine, cytosine, guanine, 5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; each W is O; and each R¹⁰is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii, 1501-1504bii, 2001-2004b, 3001-3004b, or 4001-4004bii, wherein: each Base is independently adenine, thymine, cytosine, guanine, 5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; each W is O; each R¹⁰is hydrogen; and each R¹¹is isopropyl.

In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein: each Base is independently adenine, thymine, cytosine, guanine, 5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; each W is S; and each R^Nis hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein: each Base is independently adenine, thymine, cytosine, guanine, 5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; each W is S; and each R¹¹is isopropyl. In certain embodiments, provided herein are compounds according to any of Formulas 1001-1004bii, 1501-1504bii, 2001-2004b, 2501-2504bii, 3001-3004b, or 4001-4004bii, wherein: each Base is independently adenine, thymine, cytosine, guanine, 5-fluorouracil, 2,6-diaminopurine, or 2-amino,6-ethoxypurine; each W is S; each R¹⁰is hydrogen; and each R¹¹is isopropyl.

In certain embodiments, provided herein are compounds according to any of Formulas 1005-1012:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: W and R¹are as described in the context of Formula 1001. In an embodiment, a compound according to any of Formulas 1005-1012 is provided wherein W is O. In an embodiment, a compound according to any of Formulas 1005-1012 is provided wherein W is S.

In certain embodiments, provided herein are compounds according to any of Formulas 2005-2012:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: W, R¹and R²are as described in the context of Formula 2001. In an embodiment, a compound according to any of Formulas 2005-2012 is provided wherein W is O. In an embodiment, a compound according to any of Formulas 2005-2012 is provided wherein W is S.

In certain embodiments, provided herein are compounds according to any of Formulas 2001-2012, wherein each R²is independently hydrogen, methyl, or halogen; and W is O. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2012, wherein each R²is independently hydrogen, methyl, or halogen; and W is S.

In certain embodiments, provided herein are compounds according to any of Formulas 2001-2012, wherein each R²is hydrogen and W is O. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2012, wherein each R²is hydrogen and W is S.

In certain embodiments, provided herein are compounds according to any of Formulas 2001-2012, wherein each R²is methyl and W is O. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2012, wherein each R²is methyl and W is S.

In certain embodiments, provided herein are compounds according to any of Formulas 2001-2012, wherein each R²is independently halogen and W is O. In certain embodiments, provided herein are compounds according to any of Formulas 2001-2012, wherein each R²is independently halogen and W is S.

In certain embodiments, provided herein are compounds according to any of Formulas V-XIIb:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: each R⁵is independently hydrogen, halogen, or methyl; and R¹and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to any of Formulas XIII-XIVb or XV-XVIb:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein R¹and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to any of Formulas I-XVIb or 2001-2012, wherein each R²is independently hydrogen, methyl, or halogen. In certain embodiments, provided herein are compounds according to any of Formulas I-XVIb or 2001-2012, wherein each R²is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas I-XVIb or 2001-2012, wherein each R²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas I-XVIb or 2001-2012, wherein each R²is independently halogen.

In certain embodiments, provided herein are compounds according to any of Formulas XVII-XVIIb:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein R⁵is halogen; and R¹and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to any of Formulas XVII-XVIIb, wherein each R²is independently hydrogen, methyl, or halo. In certain embodiments, provided herein are compounds according to any of Formulas XVII-XVIIb, wherein each R²is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas XVII-XVIIb, wherein each R²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas XVII-XVIIb, wherein each R²is independently halogen.

In certain embodiments, provided herein are compounds according to any of Formulas XVII-XVIIb, wherein R⁵is fluoro. In certain embodiments, provided herein are compounds according to any of Formulas XVII-XVIIb, wherein R⁵is fluoro; and each R²is independently hydrogen, methyl, or halo. In certain embodiments, provided herein are compounds according to any of Formulas XVII-XVIIb, wherein R⁵is fluoro; and each R²is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas XVII-XVIIb, wherein R⁵is fluoro; and each R²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas XVII-XVIIb, wherein R⁵is fluoro; and each R²is independently halogen.

In certain embodiments, provided herein are compounds according to any of Formulas XIX, XIXa, or XIXb:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein R¹and R²are as defined in the context of Formula I.

In certain embodiments, provided herein are compounds according to any of Formulas XIX, XIXa, or XIXb, wherein each R²is independently hydrogen, methyl, or halo. In certain embodiments, provided herein are compounds according to any of Formulas XIX, XIXa, or XIXb, wherein each R²is hydrogen. In certain embodiments, provided herein are compounds according to any of Formulas XIX, XIXa, or XIXb, wherein each R²is methyl. In certain embodiments, provided herein are compounds according to any of Formulas XIX, XIXa, or XIXb, wherein each R²is independently halogen.

In certain embodiments, provided herein are compounds according to Formula XVIII:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; and R¹is cyano, azido, or amino.

In certain embodiments, provided herein are compounds according to Formula XVIIIa or XVIIIb:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base and R²are as defined in the context of Formula XVIII.

In certain embodiments, provided herein are compounds according to Formula 1101:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; and R¹is cyano, azido, or amino.

In certain embodiments, provided herein are compounds according to Formula XXX:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; and R¹is cyano, azido, or amino.

In certain embodiments, provided herein are compounds according to Formula XXXa or XXXb:

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or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein Base and R²are as defined in the context of Formula XXX.

In certain embodiments, provided herein are compounds according to any of Formulas XVIII-XVIIIb, XXX-XXXb, or 1101, wherein each Base is independently

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or a tautomer thereof; wherein: each R⁴is independently hydroxyl or amino; and

each R⁵is independently hydrogen, halogen, or methyl. In certain embodiments, provided herein are compounds according to any of Formulas XVIII-XVIIIb, XXX-XXXb, or 1101, wherein each Base is independently

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or a tautomer thereof. In certain embodiments, provided herein are compounds according to any of Formulas XVIII-XVIIIb, XXX-XXXb, or 1101, wherein each Base is independently

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or a tautomer thereof.

In certain embodiments, provided herein are compounds according to any of Formulas 1-3b: