Phosphonate prodrugs and use thereof

Abstract

Disclosed herein are prodrugs of a nucleoside, a nucleotide, or a nucleobase, or an analog thereof, wherein said prodrug is a compound of formula I: or a pharmaceutically acceptable salt thereof, nanoparticles comprising said compound, pharmaceutical compositions comprising said compound or nanoparticle, and methods of use thereof.

Description

[0001] PHOSPHONATE PRODRUGS AND USE THEREOF

[0002] REEATED APPLICATIONS

[0003] This application claims the benefit of an priority to U.S. Provisional Patent

[0004] Application No. 63 / 540,486, filed September 26, 2023, which application is hereby incorporated by reference in its entirety.

[0005] STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0006] This invention was made with government support under Grant Nos. R01 Al 145542, R01 AI158160 and R01 Al 163042 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0007] BACKGROUND

[0008] Nucleoside compounds and their prodrug derivatives play important roles in medical applications, particularly, for the treatment of viral infections and cancers. For example, tenofovir and tenofovir alafenamide have been effectively used for the treatment and prevention of human immunodeficiency virus (HIV) infections.

[0009] There are several issues associated with the use of nucleoside compounds. They require host or viral kinase mediated conversion into their therapeutically active triphosphate forms prior to incorporation into elongating DNA or RNA, causing chain termination. Further, catalytic phosphorylation efficiency of synthetic nucleosides is slow and inefficient. Moreover, conventional nucleoside administrations have certain limitations such as variable drug pharmacokinetic profiles, short drug half-lives, poor physicochemical properties that have limited their transformation into long acting medicines, limited cellular and tissue penetration, and systemic toxicities.

[0010] Therefore, there is a high medical need to develop new drug delivery systems that improve intracellular delivery of pre-activated nucleosides.

[0011] SUMMARY

[0012] The present application provides a compound of Formula I,

[0013] R1 (I),or apharmaceutically acceptable salt thereof, wherein R1is Cio-30 aliphatic; R2is an optionally substituted aryl or a nucleobase or an analog thereof; R3is a nucleobase or an analog thereof; L1and L2are each independently bond or Ci-6 alkylene optionally substituted with 1-4 R4; L3and L4are each independently bond, Ci-6 alkylene, C3-10 carbocyclylene, C1-6 alkylene-Cs-io carbocyclylene, C2-6 alkenylene-Cs-io carbocyclylene, 3-10 membered heterocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or C2-6 alkenylene- 3-10 membered heterocyclylene, wherein the alkylene, alkenylene, carbocyclylene, and heterocyclylene are each independently optionally substituted with 1-4 R5; R4is halo; and R5is hydroxy, halo, cyano, nitro, carbenyl, halocarbenyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, or C1-6 haloalkoxyl.

[0014] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear C10-30 alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear C14-26 alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear C14 alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear C16-24 alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear Cis alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear C22 alkyl.

[0015] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R2is an optionally substituted aryl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R2is phenyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R2is a nucleobase or an analog thereof. In certain such embodiments, the nucleobase or an analog thereof is

[0016] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1is bond. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1is C1-6 alkylene. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L3is Ci-6 alkylene-Cs-io carbocyclylene, Ci-6 alkylene-3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L3is of attachment to R2, ** is the point of attachment to oxygen, and n is an integer 0-3. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L3is wherein * is the point of attachment to R2and * * is the point of attachment to oxygen. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L3is bond.

[0017] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1and L3are each bond and R2is an optionally substituted aryl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1and L3are each bond and R2is phenyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1is bond, L3is Ci-6 alkylene- C3-10 carbocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5, and R2is a nucleobase or an analog thereof. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1is bond, L3is C1-2 alkylene-Cs-6 carbocyclylene, Ci-2 alkylene-5-6 membered heterocyclylene, or 5-6 membered heterocyclylene, each of which is optionally substituted by 1-3 R5, and R2is a nucleobase or an analog thereof.

[0018] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R3is

[0019] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is bond. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is Ci-6 alkylene.

[0020] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L4is Ci-6 alkylene-Cs-io carbocyclylene, Ci-6 alkylene-3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L4is point of attachment to R3, **** is the point of attachment to oxygen, and n is an integer 0-3.

[0021] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L4is

[0022] wherein *** is the point of attachment to R3and **** is the point of attachment to oxygen. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L4is Ci-6 alkylene.

[0023] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2and L4are Ci-6 alkylene.

[0024] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is -CH2- and L4is -CH(CH3)CH2-. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is -CH2- and L4is -CH2CH2-. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is bond and L4is C1-6 alkylene-Cs-io carbocyclylene, C1-6 alkylene- 3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is bond and L4is C1-2 alkylene-Cs-6 carbocyclylene, C1-2 alkylene-5-6 membered heterocyclylene, or 5-6 membered heterocyclylene, each of which is optionally substituted by 1-3 R5. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is C1-6 alkylene and L4is 5-6 membered heterocyclylene. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is -CH2- and L4is 5-6 membered heterocyclylene.

[0025] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R5is methyl, F, hydroxy, cyano, ethynyl, methylidene, or fluoromethy lidene .

[0026] The present application provides a compound of Formula I-A,

[0027] R1 Cio-30 aliphatic; R3is a nucleobase or an analog thereof; L2is bond or Ci-6 alkylene optionally substituted by 1-4 R4; L4is bond, Ci-6 alkylene, C3-10 carbocyclylene, C1-6 alkylene-Cs-io carbocyclylene, C2-6 alkenylene-Cs-io carbocyclylene, 3-10 membered heterocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or C2-6 alkenylene-3-10 membered heterocyclylene, wherein the alkylene, alkenylene, carbocyclylene, and heterocyclylene are each independently optionally substituted with 1-4 R5; R4is halo; and R5is hydroxy, halo, cyano, nitro, C1-6 carbenyl, C1-6 halocarbenyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, or C1-6 haloalkoxyl.

[0028] In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear C10-30 alkyl. In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear C14-26 alkyl. In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear C14 alkyl. In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear C16-24 alkyl. In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear Cis alkyl. In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear C22 alkyl.

[0029] The present application provides a compound of Formula (I-B),

[0030] R1 or a pharmaceutically acceptable salt thereof, wherein R1is C10-

[0031] 30 aliphatic; R2and R3are each a nucleobase or an analog thereof; L3and L4are each independently bond, C1-6 alkylene, C3-10 carbocyclylene, C1-6 alkylene-Cs-io carbocyclylene, C2-6 alkenylene-Cs-io carbocyclylene, 3-10 membered heterocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or C2-6 alkenylene-3-10 membered heterocyclylene, wherein the alkylene, alkenylene, carbocyclylene, and heterocyclylene are each independently optionally substituted with 1-4 R5; R4is halo; and R5is hydroxy, halo, cyano, nitro, C1-6 carbenyl, C1-6 halocarbenyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, or C1-6 haloalkoxyl. The present application provides compound M5TFV, pharmaceutically acceptable salt thereof.

[0032] The present application provides compound M6TFV, pharmaceutically acceptable salt thereof.

[0033] In some embodiments, provided herein is a nanoparticle, comprising (a) a compound of formula I described above, or a pharmaceutically acceptable salt thereof, and (b) a polymer or surfactant.

[0034] In some embodiments, the polymer or surfactant is an amphiphilic block copolymer, comprising at least one block of poly(oxyethylene) and at least one block of poly(oxypropylene). An exemplary polymer or surfactant is P407.

[0035] In some embodiments, the nanoparticle described above has a diameter in the range of about 100 nm to about 1 pm.

[0036] In some embodiments, disclosed herein is a pharmaceutical composition, comprising (a) a compound of formula I described above, or a pharmaceutically acceptable salt thereof, or a nanoparticle described above, and (b) a pharmaceutically acceptable carrier.

[0037] In some embodiments, disclosed herein is a method of treating a medical condition in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, a nanoparticle disclosed herein, or a pharmaceutical composition disclosed herein.

[0038] In some embodiments, the medical condition is a cancer, a viral infection, or a blood clotting disorder. In some embodiments, the medical condition is a viral infection selected from the group consisting of an HIV infection, hepatitis B, hepatitis C, influenza A, influenza B, herpes simplex, COVID- 19 infection, and Ebola infection. In some embodiments, the compound, nanoparticle, or pharmaceutical composition is administered via injection. In some embodiments, the compound, nanoparticle, or pharmaceutical composition is administered one time in a 1 to 12 month period or longer.

[0039] The present application provides a method of treating a viral infection in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound as disclosed herein (e.g., a compond of Formula I, or a pharmaceutically acceptable salt thereof), a nanoparticle comprising (a) a compound of formula I described above, or a pharmaceutically acceptable salt thereof, and (b) a polymer or surfactant, or a pharmaceutical composition comprising (a) a compound of formula I described above, or a pharmaceutically acceptable salt thereof, or a nanoparticle described above, and (b) a pharmaceutically acceptable carrier. In certain embodiments, the viral infection is selected from the group consisting of an HIV, hepatitis B, hepatitis C, influenza A, influenza B, herpes simplex, COVID- 19, and Ebola infection.

[0040] The present application provides a method of treating cancer in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound as disclosed herein (e.g., a compond of Formula I, or a pharmaceutically acceptable salt thereof), a nanoparticle comprising (a) a compound of formula I described above, or a pharmaceutically acceptable salt thereof, and (b) a polymer or surfactant, or a pharmaceutical composition comprising (a) a compound of formula I described above, or a pharmaceutically acceptable salt thereof, or a nanoparticle described above, and (b) a pharmaceutically acceptable carrier. In certain embodiments, the cancer is selected from the group consisting of leukemia, lymphoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, bladder cancer, liver cancer, neuroblastoma, brain cancers, lung cancer, ovarian cancer, stomach cancer, skin cancer, cervical cancer, testicular cancer, kidney cancer, carcinoid tumors, and bone cancer.

[0041] The present application provides a method of treating a blood clotting disorder in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound as disclosed herein (e.g., a compond of Formula I, or a pharmaceutically acceptable salt thereof), a nanoparticle comprising (a) a compound of formula I described above, or a pharmaceutically acceptable salt thereof, and (b) a polymer or surfactant, or a pharmaceutical composition comprising (a) a compound of formula I described above, or a pharmaceutically acceptable salt thereof, or a nanoparticle described above, and (b) a pharmaceutically acceptable carrier. In certain embodiments, the blood clotting disorder is selected from the group consisting of deep vein thrombosis, pulmonary embolism, arterial thrombosis, thrombophilia, liver disease, vitamin K deficiency, and von Willebrand disease.

[0042] In certain embodiments of the foregoing methods, the compound, nanoparticle, or pharmaceutical composition is administered via injection, microarray patch, or implantable device. In certain embodiments of the foregoing methods, the compound, nanoparticle, or pharmaceutical composition is administered one time in a 1 to 12 month period or longer.

[0043] The details of one or more embodiments of the disclosure are set forth in the description below. Other features, objects, and advantages of the disclosure will be apparent from the drawings, description and from the claims.

[0044] BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 depicts the1H NMR spectrum for M5TFV.

[0046] Figure 2 depicts the1H NMR spectrum for M6TFV.

[0047] Figure 3 depicts the31P NMR spectrum for M6TFV.

[0048] Figure 4 depicts HBV load in HBV transgenic Tg05 mice following a single IM injection of NM5TFV or NM6TFV as compared to untreated mice or mice treated with nanoformulated TAF ProTide or NM4TFV diester prodrug.

[0049] DETAILED DESCRIPTION

[0050] Nucleoside, nucleotide, and nucleobase compounds play important roles in medical applications, for example, for the treatment of viral infections, cancers, and blood clotting disorders. However, there are several issues associated with the use of these compounds including, for example, variable drug pharmacokinetic profiles, short drug half-lives, poor physicochemical properties limiting their use as long acting medicines, limited cellular and tissue penetration, poor biodistribution, and systemic toxicities. In addition, frequent high doses are often needed to maintain therapeutically effective drug concentration. Therefore, there is a high medical need to develop new drug delivery systems that improve intracellular delivery of nucleoside, nucleotide, and nucleobase compounds.

[0051] As generally described herein, the present disclosure provides phosphate prodrugs of a nucleoside, a nucleotide, or a nucleobase, or an analog thereof, nanoparticles comprising said prodrug, pharmaceutical compositions comprising said prodrug, and use of the prodrugs, nanoparticles, and pharmaceutical compositions for treating medical conditions such as viral infections, cancers, and blood clotting disorders.

[0052] Definitions To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0053] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0054] The term "herein" means the entire application.

[0055] As used herein the specification, “a” or “an” may mean one or more. As used herein, when used in conjunction with the word “comprising”, the words “a” or “an” may mean one or more than one. As used herein “another” may mean at least a second or more. Still further, the terms “having”, “including”, “containing” and “comprising” are interchangeable and one of skill in the art is cognizant that these terms are open ended terms. Some embodiments of the disclosure consist of or consist essentially of one or more elements, method steps, or methods of the disclosure.

[0056] “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.

[0057] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (z.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) or a non-human animal, e.g., a mammal such as primates (e.g, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” “subject,” and “individual” are used interchangeably herein. None of these terms require the active supervision of medical personnel.

[0058] Disease, disorder, and condition are used interchangeably herein.

[0059] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or reverses or slows the progression of the disease, disorder or condition (also “therapeutic treatment”).

[0060] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject A “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit (e.g., treating, preventing, or ameliorating cancer in a subject, at a reasonable benefit / risk ratio applicable to any medical treatment) in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” encompasses an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. A “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” encompasses an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. A “prophylactic treatment” contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition.

[0061] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0062] In some embodiments, compounds described herein comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al. , Tetrahedron 33'2125 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0063] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In some embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0064] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In some embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In some embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In some embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0065] In some embodiments, compounds described herein comprise one or more isotopic substitutions. For example, H can be in any isotopic form, includingXH,2H (D or deuterium), and3H (T or tritium); C can be in any isotopic form, including12C,13C, and14C; O can be in any isotopic form, including16O and18O; F can be in any isotopic form, including18F and19F; and the like. Isotopically labelled compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labelled reagent in place of the non-labelled reagent previously employed. Suitable isotopes that may be incorporated in compounds of the present application include but are not limited to2H (also written as D for deuterium),3H (also written as T for tritium),nC,13C,14C,13N,15N,150,170,18O,18F,35S,36C1 ,82B r,75Br,76B r,77Br,123I,124I,125I, and131I.

[0066] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group is substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocyclyl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0067] It should be further understood that the terms “groups” and “radicals” are interchangeable when used herein.

[0068] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, C6, Ci-6, Ci-5, Ci-4, Ci-3, Ci-2, C2 6. C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0069] As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 30 carbon atoms (“C1-30 alkyl”). In some embodiments, an alkyl group has 10 to 30 carbon atoms (“C10-30 alkyl”). In some embodiments, an alkyl group has 14 to 30 carbon atoms (“C14-30 alkyl”). In some embodiments, an alkyl group has 14 to 26 carbon atoms (“C14-26 alkyl”). In some embodiments, an alkyl group has 16 to 24 carbon atoms (“C16-24 alkyl”). In some embodiments, an alkyl group has 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0070] As used herein, “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carboncarbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In some embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. As used herein, “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carboncarbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In some embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1- propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like.

[0071] As used herein, the term “aliphatic” refers to a saturated or partially unsaturated linear, branched, acyclic or cyclic radical that can be a hydrocarbon having only carbon and hydrogen atoms, or a radical where one or more carbon atoms are replaced by one or more heteroatoms selected from nitrogen, oxygen and sulphur. In some embodiments, 1, 2, 3, or 4 carbon atoms are replaced by a heteroatom. Exemplary aliphatic groups include alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl as defined herein. In some embodiments, an aliphatic group has 1 to 30 carbon atoms (“C1-30 aliphatic”). In some embodiments, an aliphatic group has 10 to 30 carbon atoms (“C10-30 aliphatic”). In some embodiments, an aliphatic group has 14 to 30 carbon atoms (“C14-30 aliphatic”). In some embodiments, an aliphatic group has 14 to 26 carbon atoms (“C 14-26 aliphatic”). In some embodiments, an aliphatic group has 16 to 24 carbon atoms (“C 14-30 aliphatic”).

[0072] As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“Cs-rcarbocycyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in some embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0073] The term “cycloalkyl” refers to a radical of a saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-10, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-12 cycloalkyl,” “C3-10 cycloalkyl,” “C3-8 cycloalkyl,” “C4-8 cycloalkyl,” “C4- 6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.

[0074] The term “cycloalkenyl” refers to a radical of a cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-10, 3-8, 4-8, or 4-6 carbons, having one or more carbon-carbon double bonds, referred to herein, e.g., as “C3-12 cycloalkenyl,” “C3-10 cycloalkenyl,” “C3-8 cycloalkenyl,” “C4-8 cycloalkenyl,” “C4-6 cycloalkenyl,” derived from a cycloalkene.

[0075] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0076] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (e.g., “3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” is used interchangeably.

[0077] In some embodiments, a heterocyclyl group is a 4-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-7 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1^1 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0078] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5- membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0079] Examples of saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. Where specified as being optionally substituted or substituted, substituents on a heterocyclyl (e.g., in the case of an optionally substituted heterocyclyl) is present on any substitutable position and, include, e.g., the position at which the heterocyclyl group is attached.

[0080] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g,. heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0081] As used herein, “cyano” refers to -CN.

[0082] As used herein, “nitro” refers to -NO2.

[0083] As used herein, “hydroxy” or “hydroxyl” refers to -OH.

[0084] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In some embodiments, the halo group is either fluoro or chloro.

[0085] The term “alkoxy,” as used herein, refers to an alkyl group which is attached to another moiety via an oxygen atom (-O(alkyl)). Non-limiting examples include e.g., methoxy, ethoxy, propoxy, and butoxy.

[0086] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to -OCHCF2 or -OCF3.

[0087] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. For the group C haloalkyl-O-C alkyl, the point of attachment occurs on the alkyl moiety which is halogenated.

[0088] The term “carbenyl,” as used herein refers to a radical of a compound with a neutral divalent carbon with a pair of lone electrons, i.e., a carbon that has two lone electrons and is also bonded to two other chemical groups. An exemplary carbenyl group is H2C:, also referred to herein as methylidene.

[0089] The term “halocarbenyl, as used herein refers to a “carbenyl” (as defined above) substituted with one or more halo. An exemplary halocarbenyl group is HFC:, also referred to herein as flouromethylidene.

[0090] The term “alkylene-carbocyclylene” as used herein refers to an “alkylene” (as defined herein) substituted with a “carbocyclylene” (as defined herein). For example, “C1-6 alkylene- C3-10 carbocyclylene” refers to C1-6 alkylene substituted with C3-10 carbocyclylene. Similarly, the term “alkenylene- carbocyclylene” refers to an “alkenylene” substituted with a “carbocyclylene”. For example, “C2-6 alkenylene-Cs-io carbocyclylene” refers to C2-6 alkenylene substituted with C3-10 carbocyclylene.

[0091] The term “alkylene- heterocyclylene” as used herein refers to an “alkylene” (as defined herein) substituted with a “heterocyclylene” (as defined herein). For example, “C1-6 alkylene-3-10 membered heterocyclylene” refers to C1-6 alkylene substituted with 3-10 membered heterocyclylene. Similarly, the term “alkenylene- heterocyclylene” refers to an “alkenylene” substituted with a “heterocyclylene”. For example, “C2-6 alkenylene-3-10 membered heterocyclylene” refers to C2-6 alkenylene substituted with 3-10 membered heterocyclylene.

[0092] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.

[0093] In general, the term “substituted” means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0094] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.

[0095] As used herein, “alkylene,” “alkenylene,” “alkynylene,” “carbocyclylene,” and “heterocyclylene” refer to a divalent radical of an alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl groups, respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. When a range or number of carbons is provided for a particular “carbocyclylene” group, it is understood that the range or number refers to the range or number of carbons in the divalent cyclic group. “Alkylene,” “alkenylene,” “alkynylene,” “carbocyclylene,” and “heterocyclylene,” groups are substituted or unsubstituted with one or more substituents as described herein.

[0096] “Analog,” as used herein, refers to a compound that is structurally similar to another compound (a “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. Analogs of nucleosides, nucleotides, and nucleobases include, for example, non-natural (not usually occurring in nature) nucleosides, nucleotides, and nucleobases, such as chemically or structurally modified nucleosides, nucleotides, and nucleobases.

[0097] As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below: A — Adenine; C — Cytosine; DNA — Deoxyribonucleic acid; G — Guanine; RNA — Ribonucleic acid; T — Thymine; and U — Uracil.

[0098] “Nucleoside,” as used herein, refers to a compound comprising a nucleobase and a 5- membered ring sugar (e.g., ribose or deoxyribose) or a 5-membered heterocyclyl or carbocyclyl. Nucleosides comprise bases such as A, C, G, T, U, or analogs thereof. Nucleoside analogs are modified at the base or the sugar, or both.

[0099] “Nucleotide,” as used herein, refers to a compound comprising a nucleoside and a phosphate group. Nucleotides comprise bases such as A, C, G, T, U, or analogs thereof, and comprise 1, 2, 3, 4, 5, 6, 7, 8, or more phosphates in the phosphate group. Nucleotide analogs are modified at one or more of the base, sugar, or phosphate group.

[0100] The term “base” or “nucleobase” and analogs thereof as used herein refers to a purine or pyrimidine moiety or a derivative thereof (e.g., a substituted or unsubstituted purinyl or substituted or unsubstituted pyrimidinyl) that may be a constituent of nucleic acid (z.e., DNA or RNA, or a derivative thereof). In some embodiments, the nucleobase or an analog thereof is a derivative of a naturally occurring DNA or RNA base. In some embodiments, the nucleobase or an analog thereof is a derivative of a naturally occurring DNA or RNA base, which is optionally substituted. Non-limiting examples of the nucleobase and analogs thereof include cytosine or a derivative thereof, guanine or a derivative thereof, adenine or a derivative thereof, thymine or a derivative thereof, uracil or a derivative thereof, hypoxanthine or a derivative thereof, xanthine or a derivative thereof, 7-methylguanine or a derivative thereof, deaza-adenine or a derivative thereof, deaza-guanine or a derivative thereof, deaza-hypoxanthine or a derivative thereof, 5,6-dihydrouracil or a derivative thereof, 5 -methylcytosine or a derivative thereof, or 5 -hydroxymethylcytosine or a derivative thereof. Nucleobase analogs include, for example, methylated purines or pyrimidines, acylated purines or pyrimidines, alkylated riboses or other heterocycles, e.g., diaminopurine and its derivatives, inosine and its derivatives, alkylated purines or pyrimidines, acylated purines or pyrimidines thiolated purines or pyrimidines, and the like, or the addition of a protecting group such as acetyl, difluoroacetyl, trifluoroacetyl, isobutyryl, benzoyl, 9- fluorenyhnethoxycarbonyl, phenoxy acetyl, dimethylformamidine, dibutylformamidine, N,N- diphenyl carbamate, substituted thiourea or the like. Analogs of interest include, but are not limited to, 1 -methyladenine, 2-methyladenine, N6-methyladenine, N6-isopentyladenine, 2- methylthio-N6-isopentyladenine, N,N-dimethyladenine, 8-bromoadenine, 2-thiocytosine, 3- methylcytosine, 5-methylcytosine, 5-ethylcytosine, 4-acetylcytosine, 1-methylguanine, 2- methylguanine, 7-methylguanine, 2,2-dimethylguanine, 8-bromoguanine, 8-chloroguanine, 8- aminoguanine, 8-methylguanine, 8-thioguanine, 5 -fluorouracil, 5 -bromouracil, 5- chlorouracil, 5-iodouracil, 5 -ethyluracil, 5 -propyluracil, 5 -methoxyuracil, 5- hydroxymethyluracil, 5 -(carboxyhydroxymethyl) uracil, 5-(methylaminomethyl)uracil, 5- (carboxymethylaminomethyl)-uracil, 2-thiouracil, 5-methyl-2-thiouracil, 5-(2- bromovinyl)uracil, uracil-5-oxyacetic acid, uracil-5-oxyacetic acid methyl ester, pseudouracil, 1 -methylpseudouracil, queosine, inosine, 1 -methylinosine, hypoxanthine, xanthine, 2-aminopurine, 6-hydroxyaminopurine, 6-thiopurine, and 2,6-diaminopurine.

[0101] Compounds

[0102] The present disclosure, in some embodiments, provides phosphate prodrugs of nucleosides, nucleotides, or nucleobases, and analogs thereof.

[0103] Examples of nucleosides, nucleotides, nucleobases, and analogs thereof include, but are not limited to, abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV), tenofovir alafenamide (TAF), tenofovir disoproxil fumarate, didanosine, vidarabine, BCX4430, cytarabine, gemcitabine, zalcitabine, acyclovir, valacyclovir, ganciclovir, valganciclovir, penciclovir, famciclovir, islatravir, remdesivir, ribavirin, entecavir, sofosbuvir, brivudine, GS-441524, GS-331007, GS-9148, GS-2128, ECFP (((lS,3S,5S,E)-3- (2-amino-6-oxo- l,6-dihydro-9H-purin-9-yl)-2-(fluoromethylene)-5-hydroxy- 1- (hydroxymethyl) cyclopentane- 1 -carbonitrile)), HCV-IN-31, cidofovir, adefovir, adefovir dipivoxil, laninamivir, stavudine, telbivudine, zidovudine, idoxuridine, trifluridine, ticagrelor, cangrelor, 5 -fluorouracil (5-FU), 5-bromo-2-deoxy-uridine, capecitabine, cladribine, capecitabine, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), thymidine, N(4)- Hydroxycytidine, and fludarabine.

[0104] The present application provides a compound of Formula I: (I), or a pharmaceutically acceptable salt thereof, wherein

[0105] R1is C 10-30 aliphatic;

[0106] R2is an optionally substituted aryl or a nucleobase or an analog thereof;

[0107] R3is a nucleobase or an analog thereof;

[0108] L1and L2are each independently bond or Ci-6 alkylene optionally substituted with 1-4 R4;

[0109] L3and L4are each independently bond, Ci-6 alkylene, C3-10 carbocyclylene, C1-6 alkylene-Cs-io carbocyclylene, C2-6 alkenylene-Cs-io carbocyclylene, 3-10 membered heterocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or C2-6 alkenylene-3-10 membered heterocyclylene, wherein the alkylene, alkenylene, carbocyclylene, and heterocyclylene are each independently optionally substituted with 1-4 R5;

[0110] R4is halo; and

[0111] R5is hydroxy, halo, cyano, nitro, carbenyl, halocarbenyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, or C1-6 haloalkoxyl.

[0112] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear C10-30 alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear C14-26 alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear C14 alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear C16-24 alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear Cis alkyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1is a linear C22 alkyl.

[0113] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R2is an optionally substituted aryl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R2is phenyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R2is a nucleobase or an analog thereof. In certain such embodiments, the nucleobase or an analog thereof is

[0114] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1is bond. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1is C1-6 alkylene.

[0115] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L3is C1-6 alkylene-Cs-io carbocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L3is

[0116] , wherein * is the point of attachment to R2, ** is the point of attachment to oxygen, and n is an integer 0-3. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L3is

[0117] wherein * is the point of attachment to R2and * * is the point of attachment to oxygen. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L3is bond. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1and L3are each bond and R2is an optionally substituted aryl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1and L3are each bond and R2is phenyl. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1is bond, L3is Ci-6 alkylene- C3-10 carbocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5, and R2is a nucleobase or an analog thereof. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L1is bond, L3is C1-2 alkylene-Cs-6 carbocyclylene, C1-2 alkylene-5-6 membered heterocyclylene, or 5-6 membered heterocyclylene, each of which is optionally substituted by 1-3 R5, and R2is a nucleobase or an analog thereof.

[0118] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R3is In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is bond. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is Ci-6 alkylene.

[0119] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L4is Ci-6 alkylene-Cs-io carbocyclylene, Ci-6 alkylene-3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L4is

[0120] , wherein * * * is the point of attachment to R3, **** is the point of attachment to oxygen, and n is an integer 0-3. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L4is wherein *** is the point of attachment to R3and **** is the point of attachment to oxygen. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L4is Ci-6 alkylene.

[0121] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2and L4are Ci-6 alkylene.

[0122] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is -CH2- and L4is -CH(CH3)CH2-. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is -CH2- and L4is -CH2CH2-. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is bond and L4is C1-6 alkylene-Cs-io carbocyclylene, C1-6 alkylene- 3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is bond and L4is C1-2 alkylene-Cs-6 carbocyclylene, C1-2 alkylene-5-6 membered heterocyclylene, or 5-6 membered heterocyclylene, each of which is optionally substituted by 1-3 R5. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is C1-6 alkylene and L4is 5-6 membered heterocyclylene. In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L2is -CH2- and L4is 5-6 membered heterocyclylene.

[0123] In certain embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R5is methyl, F, hydroxy, cyano, ethynyl, methylidene, or fluoromethy lidene .

[0124] The present application provides a compound of Formula I-A:

[0125] (I-A), or a pharmaceutically acceptable salt thereof, wherein

[0126] R1is C 10-30 aliphatic;

[0127] R3is a nucleobase or an analog thereof;

[0128] L2is bond or C1-6 alkylene optionally substituted by 1-4 R4;

[0129] L4is bond, C1-6 alkylene, C3-10 carbocyclylene, C1-6 alkylene-Cs-io carbocyclylene, C2-6 alkenylene-Cs-io carbocyclylene, 3-10 membered heterocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or C2-6 alkenylene-3-10 membered heterocyclylene, wherein the alkylene, alkenylene, carbocyclylene, and heterocyclylene are each independently optionally substituted with 1-4 R5;

[0130] R4is halo; and

[0131] R5is hydroxy, halo, cyano, nitro, C1-6 carbenyl, C1-6 halocarbenyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, or C1-6 haloalkoxyl.

[0132] In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear C10-30 alkyl. In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear C14-26 alkyl. In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear C14 alkyl. In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear C16-24 alkyl. In certain embodiments of the compound of formula (I -A), or a pharmaceutically acceptable salt thereof, R1is a linear Cis alkyl. In certain embodiments of the compound of formula (I-A), or a pharmaceutically acceptable salt thereof, R1is a linear C22 alkyl.

[0133] The present application provides a compound of Formula (I-B):

[0134] (I-B), or a pharmaceutically acceptable salt thereof, wherein

[0135] R1is C 10-30 aliphatic;

[0136] R2and R3are each a nucleobase or an analog thereof;

[0137] L3and L4are each independently bond, C1-6 alkylene, C3-10 carbocyclylene, C1-6 alkylene-Cs-io carbocyclylene, C 2-6 alkenylene-Cs-io carbocyclylene, 3-10 membered heterocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or C2-6 alkenylene-3-10 membered heterocyclylene, wherein the alkylene, alkenylene, carbocyclylene, and heterocyclylene are each independently optionally substituted with 1-4 R5;

[0138] R4is halo; and

[0139] R5is hydroxy, halo, cyano, nitro, C1-6 carbenyl, C1-6 halocarbenyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, or C1-6 haloalkoxyl.

[0140] The present application provides a compound selected from the group consisting of

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] pharmaceutically acceptable salts thereof.

[0151] The present application provides compound M5TFV, pharmaceutically acceptable salt thereof.

[0152] The present application provides compound M6TFV, pharmaceutically acceptable salt thereof.

[0153] In certain embodiments, compounds of the present application are produced as a single isomer at the phosphorous atom. In certain embodiments, compounds of the present application (e.g., compounds of formula I, and pharmaceutically acceptable salts thereof, such as the compounds as disclosed herein) comprise the Sp isomer substantially free of the Rp isomer. For example, in certain embodiments the present application provides a compound of formula I, or a pharmaceutically acceptable salt thereof, as the Sp isomer. In certain such embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, comprises less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the Rp isomer. In other embodiments the present application provides a compound of formula I, or a pharmaceutically acceptable salt thereof, as the Rp isomer. In certain such embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, comprises less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the Sp isomer.

[0154] The present application provides a method of preparing the compounds of formula I, and pharmaceutically acceptable salts thereof, e.g., in accordance with the synthetic protocols provided in the Examples below, without the need for chiral catalyts or chiral separations. In certain embodiments, the compounds of the present application (e.g., compounds of formula I, and pharmaceutically acceptable salts thereof, such as the compounds as disclosed herein) are produced in crystalline form.

[0155] In some embodiments, provided herein a pharmaceutically acceptable salt of the compound of formula I, such as, but not limited to, hydrochloric acid, sulphuric acid, sulphurous acid, phosphoric acid, methane sulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid salt of the compound of formula I.

[0156] In some embodiments, the pharmaceutically acceptable salt is characterized by a ratio of compound of formula I to counterion of 1: 1 or 2: 1. In some embodiments, the salt is crystalline. In some embodiments, the salt is amorphous solid.

[0157] In some embodiments, the compound of formula I is in the form of nanocrystals or other crystalline forms. In some embodiments, the compound of formula I is substantially crystalline.

[0158] In some embodiments, the compound is complexed with a hydrophobic counterion, including but not limited to pamoic acid, myristic acid, palmitic acid, stearic acid, behenic acid, napsylate, mandelic acid, tosylate, benzenesulfonate, benzoate, besylate, hydroxynaphthoate and isothionates used to form crystalline or solid salt forms.

[0159] Nanoparticles

[0160] In some embodiments, provided herein are nanoparticles, comprising (a) a compound of formula I, or a pharmaceutically acceptable salt thereof, and (b) a polymer or surfactant. In some embodiments, the compound of formula I (including crystalline or solid salt form of the compound) is encapsulated by a polymer or surfactant coating to form nanoparticles (or nanoformulations).

[0161] In some embodiments, the compound:polymer (or surfactant) ratio (by weight) is about 10: 1, about 10:6 to about 1000:6, about 20:6 to about 500:6, about 50:6 to about 200:6, or about 100:6. In some embodiments wherein two polymers (or surfactants) are used, the compound:polymer (or surfactant): polymer (or surfactant) ratio (by weight) is about 10: 1: 1; about 10: 1: 1.5; about 10:0.5: 1; about 10:0.5:0.5 to about 10:2:2; or about 10:0.5:0.5 to about 2: 1: 1.

[0162] In some embodiments, the nanoparticles are a submicron colloidal dispersion of nanocrystalline or solid salt forms of the compound stabilized by polymers (or surfactants) (e.g., polymer-coated compound crystals; a nanoformulation). In some embodiments, the compound of the nanoparticles is crystalline or a solid salt form complexed with a hydrophobic counterion. In some embodiments, the nanoparticles are crystalline. In some embodiments, the nanoparticles amorphous. As used herein, the term “crystalline” refers to an ordered state (i.e., non-amorphous), such as a substance exhibiting long-range order in three dimensions. In some embodiments, the majority (e.g., at least 50%, 60%, 70%, 80%, 90%, 95% or more) of the compound (and, optionally the hydrophobic portion of the polymer (or surfactant) are crystalline or solid salt forms complexed with a hydrophobic counterion.

[0163] In some embodiments, the nanoparticle is up to about 2 pm or about 3 pm in diameter (e.g., average diameter) or its longest dimension, particularly up to about 1 pm (e.g., about 100 nm to about 1 pm). For example, the diameter or longest dimension of the nanoparticle is about 50 nm to about 800 nm. In some embodiments, the diameter or longest dimension of the nanoparticle is about 50 nm to about 750 nm, about 50 nm to about 500 nm, about 200 nm to about 500 nm, or about 200 nm to about 400 nm. In some embodiments, the nanoparticles are rod shaped, elongated rods, irregular, or round shaped. In some embodiments, the nanoparticles of the instant disclosure are neutral. In some embodiments, the nanoparticles are positively charged. In some embodiments, the nanoparticles are negatively charged.

[0164] Any suitable method of synthesizing the nanoparticles is used to synthesize the nanoparticles disclosed herein. In some embodiments, the methods disclosed herein generate nanoparticles comprising a compound (e.g., crystalline or amorphous) coated (either partially or completely) with a polymer (or surfactant). Examples of synthesis methods include, without limitation, milling (e.g., wet milling), homogenization (e.g., high pressure homogenization), particle replication in nonwetting template (PRINT) technology, or sonication techniques, or combinations thereof. In some embodiments, the polymers (or surfactants) are firstly chemically modified with targeting ligands and then used directly or mixed with non-targeted polymers (or surfactants) in certain molar ratios to coat on the surface of drug suspensions - e.g., by using a nanoparticle synthesis process (e.g., a crystalline nanoparticle synthesis process) such as milling (e.g, wet milling), homogenization (e.g., high pressure homogenization), particle replication in nonwetting template (PRINT) technology, sonication techniques, or combinations thereof, thereby preparing targeted nanoformulations. In some embodiments, the nanoparticles are used with or without further purification, although the avoidance of further purification is desirable for quicker production of the nano particles. In some embodiments, the nanoparticles are synthesized using milling or homogenization, or both.

[0165] In some embodiments, the nanoparticles are synthesized by adding the compound to a polymer (or surfactant) solution and then generating the nanoparticles (e.g., by wet milling or high pressure homogenization). In some embodiments the compound and polymer (or surfactant) solution is agitated prior to wet milling or high pressure homogenization to form nanoparticles.

[0166] Examples of polymers (or surfactants) include, without limitation, synthetic or natural phospholipids, PEGylated lipids (e.g., PEGylated phospholipid), lipid derivatives, polysorbates, amphiphilic copolymers, amphiphilic block copolymers, polyethylene glycol)- co-poly(lactide-co-glycolide) (PEG-PLGA), their derivatives, ligand-conjugated derivatives and combinations thereof. Other surfactants and their combinations that can form stable nanosuspensions or can chemically or physically bind to the targeting ligands of HIV infectable / infected CD4+ T cells, macrophages and dendritic cells can be used in the instant disclosure. Further examples of surfactants include, without limitation: 1) nonionic surfactants (e.g., pegylated or polysaccharide-conjugated polyesters and other hydrophobic polymeric blocks such as poly(lactide-co-glycolide) (PLGA), polylactic acid (PLA), polycaprolactone (PCL), other polyesters, polypropylene oxide), poly(l,2-butylene oxide), poly(n-butylene oxide), poly(tetrahydrofurane), and poly(styrene); glyceryl esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, polypropyleneglycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers, poloxamines, cellulose, methylcellulose, hydroxylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polysaccharides, starch and their derivatives, hydroxyethylstarch, polyvinyl alcohol (PVA), polyvinylpyrrolidone, and their combination thereof); and 2) ionic surfactants (e.g., phospholipids, amphiphilic lipids, 1,2-dialkylglycero- 3-alkylphophocholines, 1, 2- distearoyl-snglecro-3-phosphocholine (DSPC), 1,2-distearoyl- sn-glycero-3- phosphoethanolamine-N[carboxy(polyethylene glycol) (DSPE-PEG), dimethylaminoethanecarbamoyl cheolesterol (DC-Chol), N-[l-(2,3-Dioleoyloxy)propyl]- N,N,N -trimethylammonium (DOTAP), alkyl pyridinium halides, quaternary ammonium compounds, lauryldimethylbenzylammonium, acyl carnitine hydrochlorides, dimethyldioctadecylammonium (DDAB), n-octylamines, oleylamines, benzalkonium, cetyltrimethylammonium, chitosan, chitosan salts, poly(ethylenimine) (PEI), poly(N- isopropyl acrylamide(PNIPAM), and poly(allylamine) (PAH), poly (dimethyldiallylammonium chloride) (PDDA), alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, alginic acid, alginic acid salts, hyaluronic acid, hyaluronic acid salts, gelatins, dioctyl sodium sulfosuccinate, sodium carboxymethylcellulose, cellulose sulfate, dextran sulfate and carboxymethylcellulose, chondroitin sulfate, heparin, synthetic poly(acrylic acid) (PAA), poly (methacrylic acid) (PMA), poly(vinyl sulfate) (PVS), poly(styrene sulfonate) (PSS), bile acids and their salts, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, derivatives thereof, and combinations thereof.

[0167] In some embodiments, the polymer (or surfactant) of the instant disclosure is charged. In some embodiments, the polymer (or surfactant) of the instant disclosure is neutral. In some embodiments, the polymer (or surfactant) is negatively charged (e.g., poloxamers, polysorbates, phospholipids, and their derivatives).

[0168] In some embodiments, the polymer (or surfactant) is an amphiphilic block copolymer or lipid derivative. In some embodiments, at least one polymer (or surfactant) of the nanoparticle is an amphiphilic block copolymer, for example, a copolymer comprising at least one block of poly(oxyethylene) and at least one block of poly(oxypropylene). In some embodiments, the polymer (or surfactant) is a triblock amphiphilic block copolymer. In some embodiments, the polymer (or surfactant) is a triblock amphiphilic block copolymer comprising a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol.

[0169] In some embodiments, the amphiphilic block copolymer is a copolymer comprising at least one block of poly(oxyethylene) and at least one block of poly(oxypropylene).

[0170] Examples of poloxamers include, without limitation, Pluronic® L31, L35, F38, L42, L43, L44, L61, L62, L63, L64, P65, F68, L72, P75, F77, L81, P84, P85, F87, F88, L92, F98, L101, P103, P104, PIOS, F108, L121, L122, L123, F127,10RS, 10R8, 12R3, 17R1, 17R2, 17R4, 17R8, 22R4, 25R1, 25R2, 2SR4, 25RS, 2SR8, 31R1, 31R2, and 31R4. In some embodiments, the polymer (or surfactant) is poloxamer 407 (Pluronic® F127, P407). In some embodiments, the polymer (or surfactant) is poloxamer 188 (P188). In some embodiments, the polymer (or surfactant) is poloxamer 338 (P338).

[0171] In some embodiments, the polymer (or surfactant) is present in the nanoparticle or surfactant solution to synthesize the nanoparticle (as described hereinabove) at a concentration ranging from about 0.0001% to about 15% by weight. In some embodiments, the concentration of the polymer (or surfactant) ranges from about 0.01% to about 15%, about 0.01% to about 10%, or about 0. 1% to about 6% by weight. In some embodiments, the nanoparticle comprises at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or higher by weight the therapeutic agent (compound of formula I or a pharmaceutically acceptable salt thereof).

[0172] Pharmaceutical Compositions

[0173] The compositions and methods of the present application may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the application and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0174] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the application. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the application. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0175] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0176] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0177] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0178] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety -nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0179] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the application, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present application with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0180] Formulations of the application suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouthwashes and the like, each containing a predetermined amount of a compound of the present application as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste. To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0181] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0182] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0183] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0184] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0185] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0186] Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0187] Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[0188] Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine. Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0189] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0190] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0191] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0192] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present application to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0193] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this application. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[0194] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0195] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0196] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the application include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0197] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0198] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0199] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0200] For use in the methods of this application, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0201] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0202] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0203] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0204] A physician having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the application. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0205] In general, a suitable daily dose of an active compound used in the compositions and methods of the application will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0206] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present application, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0207] The patient receiving this treatment is any animal in need, including primates, in particular humans.

[0208] In some embodiments, the pharmaceutical compositions provided herein are administered chronically (“chronic administration”). “Chronic administration” as used herein refers to administration of a compound, nanoparticle, or pharmaceutical composition over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or continued indefinitely, for example, for the rest of the subject’s life. In some embodiments, the compound, nanoparticle, or pharmaceutical composition is administered one time in a 1 to 12 month period. In some embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

[0209] In some embodiments, the pharmaceutical compositions provided herein are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” as used herein refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical dosage forms described herein are administered as a unit dose. Typical unit dosage forms include but are not limited to prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

[0210] In some embodiments, the pharmaceutical compositions provided herein comprise the compound of formula I as the sole active agent, or in combination with one or more additional therapeutic agents. In the treatment of any of the disorders disclosed herein, different compounds of the application may be (e.g., conjointly) administered with one or more other compounds of the application (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof). Moreover, any one or more of a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be conjointly administered with other conventional therapeutic agents in treating one or more disease conditions referred to herein.

[0211] In certain embodiments, compounds of the present application may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either simultaneously, sequentially, or by separate dosing of the individual components of the treatment. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.

[0212] In certain embodiments, conjoint administration of compounds of the present application with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the present application and the one or more additional therapeutic agent(s).

[0213] Such combination products employ the compounds of this present application within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and / or the dosage described in the publication reference.

[0214] This application includes the use of pharmaceutically acceptable salts of compounds of the application in the compositions and methods of the present application. The term “pharmaceutically acceptable salts” includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present application contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present application contain relatively basic functionalities, such as an amine, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, trifluoroacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzensulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, camphorsulfonic and the like. In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In certain embodiments, the pharmaceutically acceptable salt is a camsylate salt. In certain embodiments, contemplated salts of the compounds include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of compounds include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of compounds include, but are not limited to, Li, Na, Ca, K, Mg, Zn or other metal salts. Also included are the salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present application may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0215] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present application.

[0216] The compounds of the application, including their pharmaceutically acceptable salts, can also exist as various solvates, such as with water (also known as hydrates), methanol, ethanol, dimethylformamide, diethyl ether, acetamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0217] The compounds of the application, including their pharmaceutically acceptable salts, can also exist as various polymorphs, pseudo-polymorphs, or in amorphous state. As used herein, the term “polymorph” refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo-polymorphs, such as hydrates, solvates, or salts of the same compound. Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as x-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents. Thus, crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry.

[0218] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0219] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0220] In certain embodiments, the application comprises a method for conducting a pharmaceutical business, by determining an appropriate formulation and dosage of a compound of the application for treating or preventing any of the diseases or conditions as described herein, conducting therapeutic profiling of identified formulations for efficacy and toxicity in animals, and providing a distribution network for selling an identified preparation as having an acceptable therapeutic profile. In certain embodiments, the method further includes providing a sales group for marketing the preparation to healthcare providers.

[0221] In certain embodiments, the application relates to a method for conducting a pharmaceutical business by determining an appropriate formulation and dosage of a compound of the application for treating or preventing any of the disease or conditions as described herein, and licensing, to a third party, the rights for further development and sale of the formulation.

[0222] Methods of Use and Treatment

[0223] Disclosed herein, in some embodiments, are methods for preventing, inhibiting, or treating a viral infection, cancer, or blood clotting disorder. The methods comprise administering an effective amount of a compound, nanoparticle, or pharmaceutical composition of the instant disclosure to a subject (e.g., a human) in need thereof.

[0224] In some embodiments, provided herein is a method of treating a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound, nanoparticle, or composition disclosed herein. Examples of viral infections include, without limitation: Human Immunodeficiency Virus (HIV) infection, hepatitis B, hepatitis C, influenza (e.g., influenza A, influenza B), COVID-19 infection, Ebola infection, herpes (e.g., herpes simplex), meningitis, pneumonia, human papillomavirus infection, rotavirus infection, norovirus infection, chicken pox, mumps, measles, rubella, Zika virus infection, and viral conjunctivitis. In some embodiments, the viral infection is a retroviral or lentiviral infection, for example, an HIV infection (e.g, HIV-1 infection, HIV-2 infection). In some embodiments, provided herein is a method of treating hepatitis B infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound, nanoparticle, or composition disclosed herein. In some embodiments, provided herein is a method of treating chronic hepatitis B infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound, nanoparticle, or composition disclosed herein.

[0225] In some embodiments, provided herein is a method of treating a bacterial, fungal, mycobacterial, and / or parasitic infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound, nanoparticle, or composition disclosed herein.

[0226] In some embodiments, provided herein is a method of treating a blood clotting disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound, nanoparticle, or composition disclosed herein. For example, the compound, nanoparticle, or composition of the instant disclosure is used as an antiplatelet agent to inhibit or prevent formation of a blood clot. Exemplary blood clotting disorders include, but are not limited to, deep vein thrombosis, pulmonary embolism, arterial thrombosis, thrombophilia (e.g., antiphospholipid antibody syndrome, factor V leiden, prothrombin gene mutation, protein C deficiency, protein S deficiency, ATIII deficiency), liver disease (e.g., cirrhosis, hepatitis, acute liver failure, or acute fatty liver of pregnancy), vitamin K deficiency, and von Willebrand disease. In some embodiments, the blood clotting disorder is hereditary (inherited genetically). In some embodiments, the blood clotting disorder is acquired, for example, during or post-surgery, or is associated with cancer or pregnancy.

[0227] In some embodiments, provided herein is a method of treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound, nanoparticle, or composition disclosed herein. Exemplary cancer includes, but is not limited to, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia), lymphoma (e.g., Hodgkin lymphoma, Non-Hodgkin lymphoma), multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, bladder cancer, liver cancer, neuroblastoma, brain cancers (e.g., gliomas, meningiomas, and pituitary adenomas), lung cancer, ovarian cancer, stomach cancer, skin cancer (e.g., melanoma), cervical cancer, testicular cancer, kidney cancer, carcinoid tumors, and bone cancer.

[0228] In some embodiments, the compound, nanoparticle, or pharmaceutical composition of the instant disclosure is administered to the subject in combination with one or more additional therapeutic agent such as an antiviral agent (e.g., anti-HIV agent), anti-cancer agent, or anti-blood clotting agent. In some embodiments, the additional therapeutic agent is administered as a separate pharmaceutical composition from the compounds, nanoparticles, or compositions of the instant disclosure. In other embodiments, the additional therapeutic agent is formulated in the same pharmaceutical composition as the compositions comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, or nanoparticle comprising said compound. In some embodiments, the pharmaceutical compositions are administered at the same time. In other embodiments, the pharmaceutical compositions are administered at different times (e.g., sequentially).

[0229] In some embodiments, the compound, nanoparticle, or pharmaceutical composition of the instant disclosure is administered to the subject in combination with one or more additional antiviral agent. Exemplary antiviral agents include, but are not limited to, HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drug for treating HIV, and combinations thereof. Exemplary HIV protease inhibiting compounds include, but are not limited to, amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfmavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859, and combinations thereof. Exemplary HIV non- nucleoside inhibitors of reverse transcriptase include, but are not limited to, capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC- 083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355 BS, VRX 840773, UK-453061, and RDEA806, and combinations thereof. Exemplary HIV nucleoside inhibitors of reverse transcriptase include, but are not limited to, zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil, and combinations thereof. Exemplary HIV nucleotide inhibitors of reverse transcriptase selected include, but are not limited to, tenofovir, tenofovir disoproxil fumarate, GS-7340 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix), and CMX-157 (Chimerix), and combinations thereof. Exemplary HIV integrase inhibitors include, but are not limited to, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxy lie acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA Oi l, cabotegravir, bictegravir, and dolutegravir, and combinations thereof. Exemplary gp41 inhibitors include, but are not limited to, enfuvirtide, sifuvirtide, FB006M, and TRI- 1144, and combinations thereof. Exemplary CXCR4 inhibitor includes, but are not limited to, AMD-070. Exemplary entry inhibitor includes, but are not limited to, SP01A. Exemplary gpl20 inhibitor includes, but are not limited to, BMS-488043. Exemplary G6PD and NADH-oxidase inhibitor includes, but are not limited to, immunitin. Exemplary CCR5 inhibitors include, but are not limited to, aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004, and combinations thereof. Other drugs for treating HIV include, but are not limited to, BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV- 1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDXO10 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040), and combinations thereof.

[0230] The dosage ranges for the administration of the compounds, nanoparticles, and compositions of the disclosure, alone or in combination with one or more additional therapeutic agent, are those sufficient to produce the desired effect (e.g., curing, relieving, treating, or preventing the disclosed medical condition (e.g., viral infection, cancer, blood clotting disorder), or the symptoms of thereof (e.g., AIDS, ARC), or the predisposition towards it). In some embodiments, the pharmaceutical composition of the instant disclosure is administered to the subject at an amount from about 5 pg / kg to about 500 mg / kg. In some embodiments, the pharmaceutical composition of the instant disclosure is administered to the subject at an amount greater than about 5 pg / kg, greater than about 50 pg / kg, greater than about 0. 1 mg / kg, greater than about 0.5 mg / kg, greater than about 1 mg / kg, or greater than about 5 mg / kg. In some embodiments, the pharmaceutical composition of the instant disclosure is administered to the subject at an amount from about 0.5 mg / kg to about 100 mg / kg, about 10 mg / kg to about 100 mg / kg, or about 15 mg / kg to about 50 mg / kg. The dosage should not be so large as to cause significant adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by a clinician or physician and adjusted by the clinician or physician in the event of any counter indications.

[0231] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present disclosure to its fullest extent. The following specific examples are therefore to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0232] EXAMPLES

[0233] In order that the disclosure described herein is more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Example 1: Synthesis and characterization of M5TFV

[0234] Monophenyl tenofovir (3 g, 8.25 mmol, 1 equiv.) was dried from anhydrous benzene (30 mL), resuspended in anhydrous pyridine (25 mL) and then cooled at -10 °C under an argon atmosphere. After the addition of octadecanol (3.3 g, 12.38 mmol, 1.5 equiv) and 2 equivalents of triethylamine the reaction was heated at 65 °C for 10 minutes under an argon atmosphere and protection from light. A solution of triphenylphosphine (4.33 g, 16.51 mmol, 2 equiv.) and 2,2 ’-dithiopyridine (3.64g, 16.51 mmol, 2 equiv.) in pyridine (10 mL) was then added to the reaction mixture and heating continued for another 16h. The mixture was then concentrated to remove solvents. The residue was partitioned between dichloromethane (DCM, 200 mL) and saturated NaHCCL (150 mL). The organic phase was washed one more time with saturated NaHCCL (150 mL) then brine (150 mL) and dried over sodium sulfate. The DCM was then evaporated on a rotary evaporator followed by purification of the sample by silica column flash chromatography, eluting with 97%, 95% then 92.5% DCM in methanol. The desired compound fractions from the columns were dried on a rotary evaporator and precipitated from diethyl ether to obtain a white powder, with a chemical yield of >70% (M5TFV). Successful synthesis of the prodrug was confirmed by3H (CDCh; Figure 1) and31P NMR spectroscopy using a Bruker Avance-III HD operating at 500 MHz and a magnetic field strength of 11.7 T.

[0235] Example 2: Synthesis and characterization of M6TFV

[0236] Monophenyl tenofovir (3 g, 8.25 mmol, 1 equiv.) was dried from anhydrous benzene (30 mL), resuspended in anhydrous pyridine (25 mL) and then cooled at -10 °C under an argon atmosphere. After the addition of docosanol (4 g, 12.38 mmol, 1.5 equiv) and 2 equivalents of triethylamine the reaction was heated at 65 °C for 10 minutes under an argon atmosphere and protection from light. A solution of triphenylphosphine (4.33 g, 16.51 mmol, 2 equiv.) and 2,2 ’-dithiopyridine (3.64g, 16.51 mmol, 2 equiv.) in pyridine (10 mL) was then added to the reaction mixture and heating continued for another 16h. The mixture was then concentrated to remove solvents. The residue was partitioned between dichloromethane (DCM, 200 mL) and saturated NaHCCL (150 mL). The organic phase was washed one more time with saturated NaHCCL (150 mL) then brine (150 mL) and dried over sodium sulfate. The DCM was then evaporated on a rotary evaporator followed by purification of the sample by silica column flash chromatography, eluting with 97%, 95% then 92.5% DCM in methanol. The desired compound fractions from the columns were dried on a rotary evaporator and precipitated from diethyl ether to obtain a white powder, with a chemical yield of >70% (M6TFV). Successful synthesis of the prodrug was confirmed byJH (CDCh; Figure 2) and31P NMR (CDCh; Figure 3) spectroscopy using a Bruker Avance-III HD operating at 500 MHz and a magnetic field strength of 11.7 T.

[0237] Example 3: Nanoparticle synthesis and characterization

[0238] Solid drug nanoparticles of M5TFV, M6TFV, and tenofovir alafenamide (TAF) were manufactured by high-pressure homogenization in aqueous buffers stabilized by non-ionic surfactants to provide the nanoparticles NM5TFV, NM6TFV, and NTAF, respectively. Both NM5TFV and NM6TFV nanoformulations were prepared in a mixture of Tween 20 and PEG 3350 surfactant solutions in phosphate buffered saline at PH 7. For NTAF, a mixture of P407 and PEG 3350 were used as stabilizers. Specifically, solid drug powders were dispersed in the surfactant solutions and stirrered / agitated to form pre-suspensions. The pre-suspensions were homogenized on an Avestin EmulsiFlex-C3 high-pressure homogenizer at 15,000- 20,000 psi until the desired particle size of 250-450 nm was achieved. The homogenized solid drug nanoparticles were then evaluated for particle size, homogeneity and surface charge by dynamic light scattering using a Malvern Zetasizer Nano-ZS. The amount of TAF, M5TFV and M6TFV within the formulations after homogenization was determined from diluted formulation samples in MeOH (1,000-10,000-fold dilution) and analyzed by UPLC- ultraviolet / visible (UV / vis) spectroscopy using calibration curves with known standards. The percentage of drug entrapped within each nanosuspension was calculated using the equation: encapsulation efficiency (%) = (weight of drug in formulation / initial weight of drug added) x 100. Example 4: HBV transgenic mice efficacy study

[0239] Antiviral efficacy was tested in HBV Tg05 mice containing a stably integrated HBV transgene. The study was approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Nebraska Medical Center (UNMC, #19-034-10FC). The Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were used to prepare the data assembled in the current manuscript. Animals were housed under pathogen- free conditions and received a standard diet. C57B1 / 6 male transgenic Tg05 mice expressing 1.3 HBV of wild-type viral genome were obtained from J.-H. James Ou, University of Southern California. Mice were maintained in a pathogen-free barrier facility. Drug formulations were administered as single intramuscular injections at 168 mg / kg TFV equivalents. HBV DNA viral load in blood was measured every other week.

[0240] The synthesized prodrugs were in solid form and compatible with scalable formulation approaches for producing surfactant stabilized aqueous nanosuspenisons. Notably, a single IM injection of lipophilic NM5TFV or NM6TFV diester prodrug nanosuspensions to Tg05 mice demonstrated enhanced and sustained efficacy compared to limited anti-HBV activity for TAF ProTide or nanoformulated arylated NM4TFV diester prodrug,

[0241] Figure 4 shows suppression of HBV replication in HBV transgenic Tg05 mice (C57BL / 6). A single intramuscular injection of NM5TFV or NM6TFV (n=4 per group) suppressed HBV DNA in peripheral blood by two orders of magnitude compared to untreated, nanoformulated TAF ProTide or NM4TFV diester prodrug. Results are expressed as Mean ± SEM. NM5TFV and NM6TFV diester prodrug formulations exhibit enhanced and sustained suppression of HBV DNA replication in transgenic Tg05 mice over one month with no notable adverse events. INCORPORATION BY REFERENCE

[0242] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0243] EQUIVALENTS

[0244] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

CLAIMS(I), or a pharmaceutically acceptable salt thereof, whereinR1is C 10-30 aliphatic;R2is an optionally substituted aryl or a nucleobase or an analog thereof;R3is a nucleobase or an analog thereof;L1and L2are each independently bond or Ci-6 alkylene optionally substituted with 1-4 R4;L3and L4are each independently bond, Ci-6 alkylene, C3-10 carbocyclylene, C1-6 alkylene-Cs-io carbocyclylene, C 2-6 alkenylene-Cs-io carbocyclylene, 3-10 membered heterocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or C2-6 alkenylene-3-10 membered heterocyclylene, wherein the alkylene, alkenylene, carbocyclylene, and heterocyclylene are each independently optionally substituted with 1-4 R5;R4is halo; andR5is hydroxy, halo, cyano, nitro, carbenyl, halocarbenyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, or C1-6 haloalkoxyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is a linear C 10-30 alkyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is a linear C 14-26 alkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is a linear C14 alkyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is a linear C16-24 alkyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is a linear Cis alkyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is a linear C22 alkyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R2is an optionally substituted aryl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl.

10. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R2is a nucleobase or an analog thereof.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the nucleobase or an analog thereof is12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L1is bond.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L1is Ci-6 alkylene.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein L3is Ci-6 alkylene-Cs-io carbocyclylene, Ci-6 alkylene-3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein L3iswherein * is the point of attachment to R2, * * is the point of attachment to oxygen, and n is an integer 0-3.

16. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein L3iswherein * is the point of attachment to R2and * * is the point of attachment to oxygen.

17. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein L3is bond.

18. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein L1and L3are each bond and R2is an optionally substituted aryl.

19. The compound of any one of claims 1-7 and 18, or a pharmaceutically acceptable salt thereof, wherein L1and L3are each bond and R2is phenyl.

20. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein L1is bond, L3is Ci-6 alkylene-Cs-io carbocyclylene, Ci-6 alkylene-3- 10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5, and R2is a nucleobase or an analog thereof.

21. The compound of any one of claims 1-7 and 20, or a pharmaceutically acceptable salt thereof, wherein L1is bond, L3is C1-2 alkylene-Cs-6 carbocyclylene, C1-2 alkylene-5-6 membered heterocyclylene, or 5-6 membered heterocyclylene, each of which is optionally substituted by 1-3 R5, and R2is a nucleobase or an analog thereof.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3is23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L2is bond.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L2is Ci-6 alkylene.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein L4is Ci-6 alkylene-Cs-io carbocyclylene, Ci-6 alkylene-3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein L4iswherein *** is the point of attachment to R3, **** is the point of attachment to oxygen, and n is an integer 0-3.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein L4iswherein * * * is the point of attachment to R3and * * * * is the point of attachment to oxygen.

28. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein L4is Ci-6 alkylene.

29. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L2and L4are Ci-6 alkylene.

30. The compound of any one of claims 1-22 and 29, or a pharmaceutically acceptable salt thereof, wherein L2is -CH2- and L4is -CH(CH3)CH2-.

31. The compound of any one of claims 1-22 and 29, or a pharmaceutically acceptable salt thereof, wherein L2is -CH2- and L4is -CH2CH2-.

32. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L2is bond and L4is C1-6 alkylene-Cs-io carbocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or 3-10 membered heterocyclylene, each of which is optionally substituted by 1-4 R5.

33. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L2is bond and L4is C1-2 alkylene-Cs-6 carbocyclylene, C1-2 alkylene- 5-6 membered heterocyclylene, or 5-6 membered heterocyclylene, each of which is optionally substituted by 1-3 R5.

34. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein L2is C1-6 alkylene and L4is 5-6 membered heterocyclylene.

35. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein L2is -CH2- and L4is 5-6 membered heterocyclylene.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R5is methyl, F, hydroxy, cyano, ethynyl, methylidene, or fluoromethylidene .

37. A compound of Formula I-A:(I-A), or a pharmaceutically acceptable salt thereof, whereinR1is C 10-30 aliphatic;R3is a nucleobase or an analog thereof;L2is bond or C1-6 alkylene optionally substituted by 1-4 R4;L4is bond, C1-6 alkylene, C3-10 carbocyclylene, C1-6 alkylene-Cs-io carbocyclylene, C2-6 alkenylene-Cs-io carbocyclylene, 3-10 membered heterocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or C2-6 alkenylene-3-10 membered heterocyclylene, wherein the alkylene, alkenylene, carbocyclylene, and heterocyclylene are each independently optionally substituted with 1-4 R5;R4is halo; andR5is hydroxy, halo, cyano, nitro, C1-6 carbenyl, C1-6 halocarbenyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, or C1-6 haloalkoxyl.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R1is a linear C10-30 alkyl.

39. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R1is a linear C14-26 alkyl.

40. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R1is a linear C14 alkyl.

41. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R1is a linear C16-24 alkyl.

42. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R1is a linear Cis alkyl.

43. The compound of claim 37, or a pharmaceutically acceptable salt thereof, whereinR1is a linear C22 alkyl.

44. A compound of Formula (I-B):(I-B), or a pharmaceutically acceptable salt thereof, whereinR1is C 10-30 aliphatic;R2and R3are each a nucleobase or an analog thereof;L3and L4are each independently bond, C1-6 alkylene, C3-10 carbocyclylene, C1-6 alkylene-Cs-io carbocyclylene, C 2-6 alkenylene-Cs-io carbocyclylene, 3-10 membered heterocyclylene, C1-6 alkylene-3-10 membered heterocyclylene, or C2-6 alkenylene-3-10 membered heterocyclylene, wherein the alkylene, alkenylene, carbocyclylene, and heterocyclylene are each independently optionally substituted with 1-4 R5;R4is halo; andR5is hydroxy, halo, cyano, nitro, C1-6 carbenyl, C1-6 halocarbenyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, or C1-6 haloalkoxyl.

45. The compound of claim 1, wherein the compound is selected from the group consisting ofpharmaceutically acceptable salts thereof.

46. The compound of claim 1, wherein the compound is M5TFV,pharmaceutically acceptable salt thereof.

47. The compound of claim 1, wherein the compound is M6TFV,pharmaceutically acceptable salt thereof.

48. A nanoparticle, comprising (a) a prodrug of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, and (b) a polymer or surfactant.

49. The nanoparticle of claim 48, wherein said polymer or surfactant is an amphiphilic block copolymer.

50. The nanoparticle of claim 48, wherein said amphiphilic block copolymer comprises at least one block of poly(oxyethylene) and at least one block of poly(oxypropylene).

51. The nanoparticle of claim 48, wherein said polymer or surfactant is P407.

52. The nanoparticle of any one of claim 48-50, wherein the diameter of the nanoparticle is about 100 nm to about 1 pm.

53. A pharmaceutical composition, comprising (a) a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a nanoparticle of any one of claims 48-52, and (b) a pharmaceutically acceptable carrier.

54. A method of treating a viral infection in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, a nanoparticle of any one of claims 48-52, or a pharmaceutical composition of claim 53.

55. The method of claim 54, wherein viral infection selected from the group consisting of an HIV, hepatitis B, hepatitis C, influenza A, influenza B, herpes simplex, COVID- 19, or Ebola infection.

56. A method of treating cancer in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, a nanoparticle of any one of claims 48-52, or a pharmaceutical composition of claim 53.

57. The method of claim 56, wherein the cancer is selected from the group consisting of leukemia, lymphoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, bladder cancer, liver cancer, neuroblastoma, brain cancers, lung cancer, ovarian cancer, stomach cancer, skin cancer, cervical cancer, testicular cancer, kidney cancer, carcinoid tumors, and bone cancer.

58. A method of treating a blood clotting disorder in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, a nanoparticle of any one of claims 48-52, or a pharmaceutical composition of claim 53.

59. The method of claim 58, wherein the blood clotting disorder is selected from the group consisting of deep vein thrombosis, pulmonary embolism, arterial thrombosis, thrombophilia, liver disease, vitamin K deficiency, and von Willebrand disease.

60. The method of any one of claims 54-59, wherein the compound, nanoparticle, or pharmaceutical composition is administered via injection, microarray patch, or implantable device.

61. The method of any one of claims 54-60, wherein the compound, nanoparticle, or pharmaceutical composition is administered one time in a 1 to 12 month period or longer.

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