Phosphonate prodrugs and uses thereof

Abstract

This document discloses prodrugs of nucleosides, nucleotides, or nucleobases or their analogues, wherein the prodrug is a compound of formula I: or a pharmaceutically acceptable salt thereof, nanoparticles comprising the compound, pharmaceutical compositions comprising the compound or nanoparticles, and methods of using the prodrugs.

Description

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 540,486, filed September 26, 2023, the entire contents of which are incorporated herein by reference.

[0002] Statement on Federally Funded Research This invention was completed with government support, under grant numbers R01AI145542, R01AI158160, and R01AI163042, granted by the National Institutes of Health. The government holds certain rights to this invention. Background Technology

[0003] Nucleoside compounds and their prodrug derivatives play an important role in medical applications, especially in the treatment of viral infections and cancer. For example, tenofovir and tenofovir alafenamide have been effective in the treatment and prevention of human immunodeficiency virus (HIV) infection.

[0004] The use of nucleoside compounds presents several challenges. They require host or viral kinase-mediated conversion to their therapeutically active triphosphate form, which is then incorporated into extended DNA or RNA, leading to chain termination. Furthermore, the catalytic phosphorylation efficiency of synthetic nucleosides is slow and low. In addition, conventional nucleoside administration suffers from limitations such as variable pharmacokinetic characteristics, short half-lives, poor physicochemical properties (limiting their conversion into long-acting drugs), limited cellular and tissue penetration, and systemic toxicity.

[0005] Therefore, there is a high medical need to develop new drug delivery systems that improve the intracellular delivery of preactivated nucleosides. Summary of the Invention

[0006] This application provides compounds of formula I, (I), or a pharmaceutically acceptable salt thereof, wherein R 1 C 10-30 Aliphatic group; R 2 For optional substituted aryl or nucleobases or their analogues; R 3 It is a nucleobase or its analogue; L 1 and L 2 Each is an independent key or C 1-6 Alkylene, optionally with 1-4 R 4 Replace; L 3 and L 4 Each is independently a key, C 1-6 Alkylene, C 3-10 subcarbocyclic group, C 1-6Alkylene-C 3-10 subcarbocyclic group, C 2-6 imide-C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 1-6 alkylene-3-10-membered heterocyclic or C 2-6 Alkenyl-3-10-membered heterocyclic subgroup, wherein the alkylene, alkenyl, carbocyclic, and heterocyclic subgroups are each independently and optionally represented by 1-4 R groups. 5 Replace; R 4 It is halogen; R 5 It includes hydroxyl, halogen, cyano, nitro, carbeneyl, halogenated carbeneyl, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0007] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 10-30 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It is a linear C 14-26 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It is a linear C 14 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It is a linear C 16-24 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It is a linear C 18 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It is a linear C 22 alkyl.

[0008] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 It is an optionally substituted aryl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 2 It is phenyl. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 2 It is a nucleobase or its analogue. In some such embodiments, the nucleobase or its analogue is... .

[0009] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 1 It is a bond. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 1 It is C 1-6 Alkylene.

[0010] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 3 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 Substitution. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 3 yes , where * is related to R 2 The connection point, ** is the connection point with oxygen, and n is an integer from 0 to 3. In certain embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, L 3 yes Where * is related to R 2 The connection point, ** is the connection point with oxygen. In certain embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, L 3 It is a key.

[0011] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 1 and L 3 Each is a key, R 2 It is an optionally substituted aryl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 1 and L 3 Each is a key, R 2 It is phenyl. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 1 It is a key, L 3 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 Replace, and R 2 It is a nucleobase or an analogue thereof. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 1 It is a key, L 3 It is C 1-2Alkylene-C 5-6 Carbocyclic group, C 1-2 Alkyl-5-6-membered heterocyclic group, or 5-6-membered heterocyclic group, wherein each is optionally surrounded by 1-3 R groups. 5 Replace, and R 2 It is a nucleobase or its analogue.

[0012] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 yes In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 2 It is a bond. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 2 It is C 1-6 Alkylene.

[0013] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 4 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 Substitution. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 4 yes , where *** is related to R 3 The connection point is ****, which is the connection point with oxygen, and n is an integer between 0 and 3.

[0014] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 4 yes Among them, *** is related to R. 3 The connection point, ****, is the connection point with oxygen. In certain embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, L 4 It is C 1-6 Alkylene.

[0015] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 2 and L 4 It is C 1-6 Alkylene.

[0016] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 2 It is -CH2-, L4 It is -CH(CH3)CH2-. In certain embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, L 2 It is -CH2-, L 4 It is -CH2CH2-. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 2 It is a key, L 4 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 Substitution. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 2 It is a key, L 4 It is C 1-2 Alkylene-C 5-6 subcarbocyclic group, C 1-2 Alkyl-5-6-membered heterocyclic or 5-6-membered heterocyclic, wherein each is optionally surrounded by 1-3 R groups. 5 Substitution. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 2 It is C 1-6 Alkylene, L 4 It is a 5-6 membered heterocyclic group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 2 It is -CH2-, L 4 It is a 5-6 membered subheterocyclic group.

[0017] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 5 It is methyl, F, hydroxy, cyano, ethynyl, methyl subunit or fluoromethyl subunit.

[0018] This application provides compounds of formula IA. (IA), or a pharmaceutically acceptable salt thereof, wherein R 1 C 10-30 Aliphatic group; R 3 It is a nucleobase or its analogue; L 2 Is it a key or C? 1-6 Alkylene, optionally surrounded by 1-4 R 4 Replace; L 4 It is key, C 1-6 Alkylene, C 3-10 subcarbocyclic group, C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 2-6 imide-C 3-10Carbocyclic groups, 3-10 membered heterocyclic groups, C 1-6 alkylene-3-10-membered heterocyclic or C 2-6 Alkenyl-3-10-membered heterocyclic subgroup, wherein the alkylene, alkenyl, carbocyclic and heterocyclic subgroups are each independently and optionally surrounded by 1-4 R groups. 5 Replace; R 4 It is halogen; R 5 It is hydroxyl, halogen, cyano, nitro, C 1-6 Carbinkie, C 1-6 Halogenated carbenefit, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0019] In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 10-30 Alkyl. In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 14-26 Alkyl. In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 14 Alkyl. In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 16-24 Alkyl. In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 18 Alkyl. In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 22 alkyl.

[0020] This application provides compounds of formula (IB), (IB), or a pharmaceutically acceptable salt thereof, wherein R 1 C 10-30 Aliphatic group; R 2 and R 3 Each is a nucleobase or its analogue; L 3 and L 4 Each is an independent key, C 1-6 Alkylene, C 3-10 subcarbocyclic group, C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 2-6imide-C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 1-6 alkylene-3-10-membered heterocyclic or C 2-6 Alkenyl-3-10-membered heterocyclic subgroup, wherein the alkylene, alkenyl, carbocyclic, and heterocyclic subgroups are each independently and optionally divided by 1-4 R groups. 5 Replace; R 4 It is a halogen; and R 5 It is hydroxyl, halogen, cyano, nitro, C 1-6 Carbinkie, C 1-6 Halogenated carbenefit, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0021] This application provides compound M5TFV (M5TFV), or a pharmaceutically acceptable salt thereof.

[0022] This application provides compound M6TFV (M6TFV), or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, nanoparticles are provided herein that comprise (a) a compound of formula I described above or a pharmaceutically acceptable salt thereof, and (b) a polymer or surfactant.

[0024] In some embodiments, the polymer or surfactant is an amphiphilic block copolymer comprising at least one poly(ethylene oxide) block and at least one poly(propylene oxide) block. An exemplary polymer or surfactant is P407.

[0025] In some implementations, the diameter of the nanoparticles ranges from about 100 nm to about 1 μm.

[0026] In some embodiments, pharmaceutical compositions are disclosed herein comprising (a) a compound of formula I described above or a pharmaceutically acceptable salt thereof, or nanoparticles described above, and (b) a pharmaceutically acceptable carrier.

[0027] In some embodiments, this document discloses methods for treating a medical condition in a subject in need, wherein the methods include administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, the nanoparticles disclosed herein, or the pharmaceutical compositions disclosed herein.

[0028] In some implementations, the medical condition is cancer, a viral infection, or a blood clotting disorder. In some implementations, the medical condition is a viral infection selected from the following: HIV infection, hepatitis B, hepatitis C, influenza A, influenza B, herpes simplex, COVID-19 infection, and Ebola virus infection.

[0029] In some embodiments, the compound, nanoparticles, or pharmaceutical composition is administered by injection. In some embodiments, the compound, nanoparticles, or pharmaceutical composition is administered once every 1 to 12 months or longer.

[0030] This application provides a method for treating a subject with a viral infection, wherein the method comprises administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof), nanoparticles comprising (a) a compound of Formula I or a pharmaceutically acceptable salt thereof and (b) a polymer or surfactant, or a pharmaceutical composition comprising (a) a compound of Formula I or a pharmaceutically acceptable salt thereof or the aforementioned nanoparticles and (b) a pharmaceutically acceptable carrier. In some embodiments, the viral infection is selected from HIV, hepatitis B, hepatitis C, influenza A, influenza B, herpes simplex, COVID-19, and Ebola virus infection.

[0031] This application provides a method for treating cancer in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof), nanoparticles comprising (a) a compound of Formula I or a pharmaceutically acceptable salt thereof and (b) a polymer or surfactant, or a pharmaceutical composition comprising (a) a compound of Formula I or a pharmaceutically acceptable salt thereof or the aforementioned nanoparticles and (b) a pharmaceutically acceptable carrier. In some embodiments, the cancer is selected from leukemia, lymphoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, bladder cancer, liver cancer, neuroblastoma, brain cancer, lung cancer, ovarian cancer, gastric cancer, skin cancer, cervical cancer, testicular cancer, kidney cancer, carcinoid tumor, and bone cancer.

[0032] This application provides a method for treating a subject with blood clotting disorders, wherein the method comprises administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof), nanoparticles comprising (a) a compound of Formula I or a pharmaceutically acceptable salt thereof and (b) a polymer or surfactant, or a pharmaceutical composition comprising (a) a compound of Formula I or a pharmaceutically acceptable salt thereof or the aforementioned nanoparticles and (b) a pharmaceutically acceptable carrier. In some embodiments, the blood clotting disorder is selected from deep vein thrombosis, pulmonary embolism, arterial thrombosis, thrombotic tendency, liver disease, vitamin K deficiency, and von Willebrand disease.

[0033] In some embodiments of the above methods, the compound, nanoparticles, or pharmaceutical composition are administered via injection, microarray patch, or implantation. In some embodiments of the above methods, the compound, nanoparticles, or pharmaceutical composition are administered once every 1 to 12 months or longer.

[0034] The following description details one or more embodiments of this disclosure. Other features, objects, and advantages of this disclosure will be apparent from the drawings, specification, and claims. Attached Figure Description

[0035] Figure 1 The M5TFV was displayed. 1 H NMR spectrum.

[0036] Figure 2 The M6TFV was displayed. 1 H NMR spectrum.

[0037] Figure 3 The M6TFV was displayed. 31 P NMR spectrum.

[0038] Figure 4 The results show the HBV load in HBV transgenic Tg05 mice after a single intramuscular injection of NM5TFV or NM6TFV, compared to untreated mice or mice treated with the nanoformulation TAF ProTide or NM4TFV diester prodrug. Detailed Implementation

[0039] Nucleosides, nucleotides, and nucleobases play important roles in medical applications, such as the treatment of viral infections, cancer, and blood clotting disorders. However, the use of these compounds presents several challenges, including variable pharmacokinetic characteristics, short half-lives, poor physicochemical properties (limiting their use as long-acting drugs), limited cell and tissue penetration, poor biodistribution, and systemic toxicity. Furthermore, frequent administration of high doses is often required to maintain therapeutically effective drug concentrations. Therefore, there is a significant medical need to develop novel drug delivery systems that improve the intracellular delivery of nucleosides, nucleotides, and nucleobases.

[0040] As generally described herein, this disclosure provides phosphate prodrugs of nucleosides, nucleotides or nucleobases or their analogues, nanoparticles comprising said prodrugs, pharmaceutical compositions comprising said prodrugs, and uses of said prodrugs, nanoparticles and pharmaceutical compositions for treating medical conditions such as viral infections, cancer and blood clotting disorders.

[0041] definition To facilitate understanding of this disclosure, several terms and phrases are defined below.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Abbreviations used herein have their conventional meanings in the fields of chemistry and biology.

[0043] The term "this paper" refers to the entire application.

[0044] The terms "an" or "a" as used herein may refer to one or more. As used herein, when the words "an" or "a" are used with the word "comprising," they may refer to one or more. The term "another" as used herein may refer to at least a second or more. Furthermore, the terms "having," "comprising," "containing," and "including" are interchangeable, and those skilled in the art will recognize that these terms are open-ended. Some embodiments of this disclosure consist of, or substantially consist of, one or more elements, method steps, or methods of this disclosure.

[0045] "About" and "approximately" typically refer to the acceptable degree of error in a measured quantity under specific measurement properties or precision. An exemplary degree of error is within 20% (%) of a given value or range of values, typically within 10%, and more commonly within 5%.

[0046] The term "subject" as used herein includes, but is not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) or non-human animals, such as mammals, like 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. These terms do not require active supervision by a medical professional.

[0047] In this article, "disease", "symptoms" and "condition" can be used interchangeably.

[0048] As used herein, unless otherwise specified, the terms “treatment,” “therapeutic,” and “treatment” cover actions taken when a subject has a particular disease, symptom, or condition in order to reduce the severity of the disease, symptom, or condition, or to reverse or slow the progression of the disease, symptom, or condition (also known as “therapeutic treatment”).

[0049] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response. Those skilled in the art will understand that the effective amount of the compounds disclosed herein may vary depending on a variety of factors, such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, weight, health, and condition of the subject. A "therapeutic effective amount" of a compound refers to an amount sufficient to provide therapeutic benefit in treating a disease, condition, or illness (e.g., treating, preventing, or alleviating cancer in a subject at a reasonable benefit / risk ratio applicable to any medical treatment), or to delay or alleviate one or more symptoms associated with that disease, condition, or illness. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that provides therapeutic benefit in treating a disease, condition, or illness, whether used alone or in combination with other therapies. The term "therapeutic effective amount" includes amounts that improve overall treatment, reduce or avoid symptoms or causes of a disease or illness, or enhance the efficacy of another therapeutic agent. A "preventative effective amount" of a compound refers to an amount sufficient to prevent a disease, condition, or illness, or one or more symptoms associated with that disease, condition, or illness, or to prevent its recurrence. The preventive effective amount of a compound refers to the amount that provides a preventive benefit in preventing a disease, condition, or illness, whether used alone or in combination with other drugs. The term "preventive effective amount" includes amounts that improve overall prevention or enhance the preventive effect of another preventive agent. "Preventive treatment" encompasses actions taken before a subject begins to suffer from a specific disease, condition, or illness.

[0050] The definitions of specific functional groups and chemical terms will be described in more detail below. Chemical elements are determined based on the Periodic Table of Elements and the CAS version. Handbook of Chemistry and Physics (Handbook of Chemistry and Physics), 75 th Ed., inside cover; the definition of specific functional groups is generally based on the description therein. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactions, are described in Thomas Sorrell's work. Organic Chemistry (Organic Chemistry), University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry (March Advanced Organic Chemistry), 5 th Edition (5th Edition), John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations (Comprehensive Organic Transformation), VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis (Some modern organic synthesis methods), 3 rd Edition (3rd edition), Cambridge University Press, Cambridge, 1987.

[0051] In some embodiments, the compounds described herein contain one or more asymmetric centers and can therefore exist in various isomeric forms, such as enantiomers or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al. Enantiomers, Racemates and Resolutions (Enantiomers, racemates, and resolution) (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds(Stereochemistry of Carbon Compounds) (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions (Resolving Agents and Optical Resolving Tables) p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure also includes compounds described herein as a single isomer essentially free of other isomers, or mixtures of various isomers.

[0052] The pure enantiomers used herein are substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer excess). In other words, the "S" type compound is substantially free of the "R" type compound, and therefore, is in excess of the "R" type enantiomer. The terms "enantiomer pure" or "pure enantiomer" mean that the compound contains 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 enantiomers. In some embodiments, the weight is calculated based on the total weight of all enantiomers or stereoisomers of the compound.

[0053] In the compositions provided herein, the enantiomerically pure compound can coexist with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R compound. In some embodiments, the enantiomerically pure R compound in such compositions may, for example, contain at least about 95% by weight of R compound and at most about 5% by weight of S compound, based on the total weight of the compounds. For example, a pharmaceutical composition comprising an enantiomerically pure S compound may contain, for example, about 90% excipients and about 10% enantiomerically pure S compound. In some embodiments, the enantiomerically pure S compound in such compositions may, for example, contain at least about 95% by weight of S compound and at most about 5% by weight of R compound, based on the total weight of the compounds. In some embodiments, the active ingredient may be formulated to be virtually free of or completely free of excipients or carriers.

[0054] In some embodiments, the compounds described herein comprise one or more isotopic substitutions. For example, H can be present in any isotopic form, including 1 H, 2H (D or deuterium) and 3 H (T or tritium); C can exist in any isotopic form, including 12 C 13 C and 14 C and O can exist in any isotopic form, including 16 O and 18 O; F can exist in any isotopic form, including 18 F and 19 F; etc. Isotope-labeled compounds (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples, using a suitable isotope-labeling reagent instead of a previously used unlabeled reagent. Suitable isotopes that may be added to the compounds of this application include, but are not limited to: 2 H (also written as D, representing deuterium) 3 H (also written as T, representing tritium) 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 18 F, 35 S, 36 Cl、 82 Br、 75 Br、 76 Br、 77 Br、 123 I, 124 I, 125 I and 131 I.

[0055] The description of compounds in this disclosure is limited by the principles of chemical bonding known to those skilled in the art. Therefore, when a group is substituted by one or more of a plurality of substituents, the choice of these substitutions must conform to the principles of chemical bonding, and the resulting compound must not be inherently unstable, or known to those skilled in the art as potentially unstable under environmental conditions (e.g., aqueous, neutral, and several known physiological conditions). For example, heterocyclic groups are linked to the rest of the molecule via cyclic heteroatoms according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0056] It should also be understood that the terms “group” and “base” used in this article are interchangeable.

[0057] When listing a range of values, the purpose is to include every value within that range and its subranges. For example, "C 1-6"Alkyl" is intended to include C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 alkyl.

[0058] As used in this article, "alkyl" refers to a group with a straight-chain or branched saturated hydrocarbon group, for example, having 1 to 30 carbon atoms ("C"). 1-30 Alkyl group). In some embodiments, the alkyl group has 10 to 30 carbon atoms (“C10”). 10-30 Alkyl group). In some embodiments, the alkyl group has 14 to 30 carbon atoms (“C10”). 14-30 Alkyl group). In some embodiments, the alkyl group has 14 to 26 carbon atoms (“C14”). 14-26 Alkyl group). In some embodiments, the alkyl group has 16 to 24 carbon atoms (“C16”). 16-24 Alkyl group). In some embodiments, the alkyl group has 1 to 20 carbon atoms (“C10”). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has one carbon atom (“C1 alkyl”). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.

[0059] As used herein, “alkenyl” refers to a straight-chain or branched hydrocarbon group having 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 carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). 2-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), and octtrienyl (C8).

[0060] As used herein, “alkynyl” refers to a straight-chain or branched hydrocarbon group having 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 carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds). 2-20 The alkynyl group (“Alynyl”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C”). 2-10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2-9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments.2-8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl groups include heptynyl (C7), octynyl (C8), etc.

[0061] As used herein, the term "aliphatic" refers to a saturated or partially unsaturated linear, branched, acyclic, or cyclic group, which may be a hydrocarbon having only carbon and hydrogen atoms, or a group in which one or more carbon atoms are replaced by one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 1, 2, 3, or 4 carbon atoms are replaced by heteroatoms. Exemplary aliphatic groups as defined herein include alkyl, alkenyl, alkynyl, carbocyclic, and heterocyclic groups. In some embodiments, the aliphatic group has 1 to 30 carbon atoms ("C..."). 1-30 Aliphatic group). In some embodiments, the aliphatic group has 10 to 30 carbon atoms (“C10”). 10-30 Aliphatic group). In some embodiments, the aliphatic group has 14 to 30 carbon atoms (“C”). 14-30 Aliphatic group (“Aliphatic group”). In some embodiments, the aliphatic group has 14 to 26 carbon atoms (“C…”). 14-26 Aliphatic group). In some embodiments, the aliphatic group has 16 to 24 carbon atoms (“C16”). 14-30 Aliphatic groups).

[0062] As used in this article, "carbocyclic group" or "carbocyclic ring" refers to a non-aromatic ring system having 3 to 12 ring carbon atoms ("C"). 3-12 A group consisting of a carbocyclic group (“C”) and a non-aromatic cyclic hydrocarbon group with 0 heteroatoms. In some embodiments, the carbocyclic group has 3 to 10 cyclic carbon atoms (“C”). 3-10The carbocyclic group (“CCR”) is a carbon ring group. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 The carbocyclic group (“CCR”) is a carbon ring group. In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms (“C”). 3-7 The carbocyclic group (“CCR”) is a carbon ring group. In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 The carbocyclic group (“CCR”) is a carbon ring group. In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 The carbocyclic group (“CCR”) is a carbon ring group. In some embodiments, the carbocyclic group has 5 to 6 cyclic carbon atoms (“C”). 5-6 (Carbocyclic group"). An example C 3-6 The carbocyclic group includes, but is not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example is C... 3-8 Carbocyclic groups include, but are not limited to, the C groups mentioned above. 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include, but are not limited to, the C groups mentioned above. 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10 As shown in the examples above, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic group”) or comprises a fused, bridged, or spirocyclic ring system, such as a bicyclic system (“bicyclic carbocyclic group”), and may be saturated or may be partially unsaturated. “Carbocyclic group” also includes ring systems in which the carbocyclic ring as described above is fused with one or more aryl or heteroaryl groups, wherein the connection point is located on the carbocyclic ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the carbocyclic system.

[0063] The term "cycloalkyl" refers to a group consisting of a saturated cyclic, bicyclic, or bridged (e.g., adamantyl) hydrocarbon group with 3-12, 3-10, 3-8, 4-8, or 4-6 carbon atoms, referred to herein as "C". 3-12 cycloalkyl, C 3-10 cycloalkyl, C 3-8 cycloalkyl, C 4-8 cycloalkyl, C 4-6"Cycloalkyl" is derived from cycloalkanes. Exemplary cycloalkyls include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0064] The term "cycloalkenyl" refers to a cyclic, bicyclic, or bridged (e.g., adamantyl) hydrocarbon group derived from cycloalkenes, consisting of 3-12, 3-10, 3-8, 4-8, or 4-6 carbon atoms, having one or more carbon-carbon double bonds, e.g., referred to herein as "C". 3-12 "Cycloalkenyl", "C" 3-10 "Cycloalkenyl", "C" 3-8 "Cycloalkenyl", "C" 4-8 "Cycloalkenyl", "C" 4-6 Cycloalkenyl.

[0065] As used herein, “aryl” refers to a group in a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array), having 6–14 ring carbon atoms and 0 heteroatoms provided by the aromatic ring system (“C”). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C14”). 14 "Aryl"; for example, anthracene. "Aryl" also includes cyclic systems in which the aromatic ring as described above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or linking point is located on the aromatic ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from: acenaphthene, acenaphthylene, phenanthrene, anthracene, azulene, benzene, phenanthrene, fluorene, hexaphene, hexane, hexalene, asymmetric indole, symmetric indole, indole, naphthalene, octaphene, octalene. Ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, heptane, pyrene, pyrene-anthracene, rubidium, triphenylene, and biphenylene. In particular, aryl groups include phenyl, naphthyl, indene, and tetrahydronaphthyl.

[0066] As used herein, "heterocyclic group" or "heterocycle" refers to a group having a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (e.g., "3- to 10-membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the linking point can be a carbon atom or a nitrogen atom, provided the valence bond allows. The heterocyclic group can be monocyclic ("monocyclic heterocyclic group"), or a fused, bridged, or spirocyclic ring system, such as a bicyclic system ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A heterocyclic bicyclic system can contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the aforementioned heterocyclic ring is fused with one or more carbocyclic groups, wherein the connection point is located on the carbocyclic or heterocyclic ring; or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the connection point is located on the heterocyclic ring, and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic ring system. The terms "heterocycle," "heterocyclic group," "heterocyclic ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably.

[0067] In some embodiments, the heterocyclic group is a 4-7 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-7 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0068] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, ethylene oxide, and thiocyclopropane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxadiazolinyl, and thiocyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxopranyl, oxadiazolinyl, dithiocyclopentane, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiocyclohexane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazine, morpholino, dithiohexane, and dioxanehexane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazine. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aromatic ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with an aromatic ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0069] Examples of saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyrrolylyl, pyridoneyl, pyrrolidoneyl, piperidinyl, oxazolyl, piperazineyl, dioxacyclohexyl, dioxopentyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl, oxacyclobutyl, azacyclobutyl, and tetrahydropyrimidinyl. If specified as optional substitution or substituent, the substituent on the heterocyclic group (e.g., in the case of an optionally substituted heterocyclic group) is present at any substituted position, including, for example, positions where the heterocyclic group is attached.

[0070] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. "Hetero" can be applied to any of the above-mentioned hydrocarbon groups, such as alkyl groups (e.g., heteroalkyl groups); carbocyclic groups (e.g., heterocyclic groups); aryl groups (e.g., heteroaryl groups); and analogs having 1 to 5, particularly 1 to 3, heteroatoms.

[0071] In this article, "cyano" refers to -CN.

[0072] The term "nitro" as used in this article refers to -NO2.

[0073] The term "hydroxyl" or "hydroxyl" as used in this article refers to -OH.

[0074] As used herein, the terms "halogen" and "halogen" refer to an atom selected from fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br), and iodine (iodine, -I). In some embodiments, the halogen group is fluorine or chlorine.

[0075] As used herein, the term "alkoxy" refers to an alkyl group (-O(alkyl)) that is attached to another moiety via an oxygen atom. Non-limiting examples include, for example, methoxy, ethoxy, propoxy, and butoxy.

[0076] "Haloalkoxy" refers to a haloalkyl group that is attached to another part by an oxygen atom, such as, but not limited to, -OCHCF2 or -OCF3.

[0077] The term "haloalkyl" includes monohaloalkyl, polyhaloalkyl, and perhaloalkyl groups substituted with one or more halogen atoms, wherein the halogen is independently selected from fluorine, chlorine, bromine, and iodine. For the C1-4 haloalkyl group -O-C1-4alkyl, the linkage is located on the halogenated alkyl moiety.

[0078] As used herein, the term "carbeneji" refers to a compound group containing a neutral divalent carbon with a pair of lone electrons, that is, a carbon having two lone electrons and also bonded to two other chemical groups. An exemplary carbeneji is H₂C₂, also referred to herein as a methyl subunit.

[0079] As used herein, the term "halogenated carbene group" refers to a "carbene group" substituted with one or more halogens (as defined above). An exemplary halogenated carbene group is HFC:, also referred to herein as a fluoromethyl subunit.

[0080] As used herein, the term "alkylene-carbocyclic" refers to an "alkylene" (as defined herein) substituted with a "carbocyclic" (as defined herein). For example, "C..." 1-6 Alkylene-C 3-10 "Subcarbocyclic group" refers to the group composed of C 3-10 C substituent of carbocyclic group 1-6 Alkylene. Similarly, the term "alkenyl-carbocyclic" refers to an "alkenyl" group substituted with a "carbocyclic" group. For example, "C 2-6 imide-C 3-10 "Subcarbocyclic group" refers to the group composed of C 3-10 C substituent of carbocyclic group 2-6 Alkenyl group.

[0081] As used herein, the term "alkylene-heterocyclic" refers to an "alkylene" (as defined herein) replaced by a "heterocyclic group" (as defined herein). For example, "C 1-6 "alkylene-3-10-membered heterocyclic group" refers to a C-shaped group substituted with a 3-10-membered heterocyclic group. 1-6 Alkylene. Similarly, the term "alkenyl-heterocyclic" refers to an "alkenyl" group substituted with a "heterocyclic" group. For example, "C 2-6 "Alkenyl-3-10-membered heterocyclic group" refers to a C-shaped group substituted with a 3-10-membered heterocyclic group. 2-6 Alkenyl group.

[0082] As used herein, the terms “optional” or “optionally” mean that an event or condition described below may or may not occur, and that the description includes both the possibility that the event or condition occurs and the possibility that it does not occur. For example, “optionally substituted alkyl” means that the alkyl group may or may not be substituted.

[0083] Generally, the term "substitution" refers to the substitution of at least one hydrogen atom on a group (e.g., a carbon or nitrogen atom) by a permitted substituent, such as a substituent that, upon substitution, forms a stable compound (e.g., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents at each position may be the same or different.

[0084] Nitrogen atoms may be substituted or not substituted depending on their valence state, including primary nitrogen atoms, secondary nitrogen atoms, tertiary nitrogen atoms, and quaternary nitrogen atoms.

[0085] As used herein, “alkylene,” “alkenylene,” “ynyneene,” “carbocyclic,” and “heterocyclic” refer to divalent groups of alkyl, alkenyl, ynyne, carbocyclic, and heterocyclic groups, respectively. When a range or number of carbon atoms is provided for a particular “alkylene,” “alkenylene,” or “ynyneene” group, it should be understood that the range or number refers to the range or number of carbon atoms in a linear divalent carbon chain. When a range or number of carbon atoms is provided for a particular “carbocyclic” group, it should be understood that the range or number refers to the range or number of carbon atoms in a divalent cyclic group. “alkylene,” “alkenylene,” “ynyneene,” “carbocyclic,” and “heterocyclic” groups may be substituted or unsubstituted by one or more substituents as described herein.

[0086] As used herein, an "analog" is a compound that is structurally similar to another compound (the "reference" compound) but differs in composition. For example, one atom may be replaced by an atom of a different element, or a specific functional group may be present, or one functional group may be replaced by another, or the absolute stereochemistry of one or more chiral centers of the reference compound may differ. Therefore, an analog is a compound that is similar or comparable to the reference compound in function and appearance (but not in structure or origin). Analogs of nucleosides, nucleotides, and nucleobases include, for example, non-natural (not typically found in nature) nucleosides, nucleotides, and nucleobases, such as those with chemical or structural modifications.

[0087] Unless otherwise stated, each of the following terms used herein shall have the following definition: A—adenine; C—cytosine; DNA—deoxyribonucleic acid; G—guanine; RNA—ribonucleic acid; T—thymine; U—uracil.

[0088] As used in this article, "nucleoside" refers to a compound containing a nucleobase and a 5-membered cyclic sugar (e.g., ribose or deoxyribose) or a 5-membered heterocyclic group or carbocyclic group. Nucleosides include bases such as A, C, G, T, U, or analogs thereof. Nucleoside analogs are modified at the base or sugar or both.

[0089] As used herein, "nucleotide" refers to a compound comprising a nucleoside and a phosphate group. Nucleotides include bases such as A, C, G, T, U, or analogs thereof, and contain 1, 2, 3, 4, 5, 6, 7, 8, or more phosphate esters in the phosphate group. Nucleotide analogs are modified at one or more positions of the base, sugar, or phosphate group.

[0090] As used herein, the term "base" or "nucleobase" and its analogues refer to a purine or pyrimidine moiety or a derivative thereof (e.g., a substituted or unsubstituted purine group or a substituted or unsubstituted pyrimidine group), which can be a component of a nucleic acid (i.e., DNA or RNA, or derivatives thereof). In some embodiments, the nucleobase or its analogue is a derivative of a naturally occurring DNA or RNA base. In some embodiments, the nucleobase or its analogue is a derivative of a naturally occurring DNA or RNA base, optionally substituted. Non-limiting examples of nucleobases and their analogues include cytosine or its derivatives, guanine or its derivatives, adenine or its derivatives, thymine or its derivatives, uracil or its derivatives, hypoxanthine or its derivatives, xanthine or its derivatives, 7-methylguanine or its derivatives, deadenine adenine or its derivatives, deadenine guanine or its derivatives, deadenine hypoxanthine or its derivatives, 5,6-dihydrouracil or its derivatives, 5-methylcytosine or its derivatives, or 5-hydroxymethylcytosine or its derivatives. Nucleobase analogs include, for example, methylated purines or pyrimidines, acylated purines or pyrimidines, alkylated ribose or other heterocycles, such as diaminopurines and their derivatives, inosines and their derivatives, alkylated purines or pyrimidines, acylated purines or pyrimidines, thiolated purines or pyrimidines, etc., or with added protecting groups, such as acetyl, difluoroacetyl, trifluoroacetyl, isobutyryl, benzoyl, 9-fluorenylmethoxycarbonyl, phenoxyacetyl, dimethylformamidinium, dibutylformamidinium, N,N-diphenylcarbamate, substituted thiourea, etc. 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.

[0091] compound This disclosure provides, in some embodiments, phosphate prodrugs of nucleosides, nucleotides, or nucleobases and analogues thereof.

[0092] Examples of nucleosides, nucleotides, nucleobases, and their analogues 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, isratrovir, remdesivir, ribavirin, entecavir, sofosbuvir, brivudine, GS-441524, GS-331007, GS-9148, GS-2128, ECFP (((1S,3S,5S,E)-3-(2-amino-6-oxo-1,6-dihydro-9H-purine-9-yl)-2-(fluoromethylene)-5-hydroxy-1-(hydroxymethyl)cyclopentane-1-onitrile)), HCV-IN-31, cidofovir, adefovir, adefovir dipivoxil, lanimivir, stavudine, telbivudine, zidovudine, idoxidine, trifluorouridine, ticagrelor, canagrelor, 5-fluorouracil (5-FU), 5-bromo-2-deoxyuridine, capecitabine, cladribine, capecitabine, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), thymidine, N(4)-hydroxycytidine and fludarabine.

[0093] This application provides compounds of formula I: (I), Or its pharmaceutically acceptable salt, wherein R 1 C 10-30 Aliphatic groups; R 2 The aryl or nucleobase may be substituted by choice or an analogue thereof; R 3 It is a nucleobase or an analogue thereof; L 1 and L 2 Each is an independent key or C 1-6 Alkylene, optionally with 1-4 R 4 replace; L 3 and L 4 Each is independently a key, C 1-6 Alkylene, C 3-10 subcarbocyclic group, C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 2-6 imide-C 3-10Carbocyclic groups, 3-10 membered heterocyclic groups, C 1-6 alkylene-3-10-membered heterocyclic or C 2-6 Alkenyl-3-10-membered heterocyclic subgroup, wherein the alkylene, alkenyl, carbocyclic, and heterocyclic subgroups are each independently and optionally represented by 1-4 R groups. 5 replace; R 4 It is halogen; and R 5 It is hydroxyl, halogen, cyano, nitro, carbene, halogenated carbene, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0094] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 10-30 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It is a linear C 14-26 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It is a linear C 14 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It is a linear C 16-24 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It is a linear C 18 Alkyl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1 It is a linear C 22 alkyl.

[0095] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 It is an optionally substituted aryl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 2 It is phenyl. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, R 2 It is a nucleobase or its analogue. In some such embodiments, the nucleobase or its analogue is... .

[0096] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 1It is a bond. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 1 It is C 1-6 Alkylene.

[0097] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 3 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 Substitution. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 3 yes , where * is related to R 2 The connection point, ** is the connection point with oxygen, and n is an integer from 0 to 3. In certain embodiments of the compound of formula (I) or its pharmaceutically acceptable salt, L 3 yes Where * is related to R 2 The connection point, ** is the connection point with oxygen. In certain embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, L 3 It is a key.

[0098] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 1 and L 3 Each is a key, R 2 It is an optionally substituted aryl group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 1 and L 3 Each is a key, R 2 It is phenyl. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 1 It is a key, L 3 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 Replace, and R 2 It is a nucleobase or an analogue thereof. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 1 It is a key, L 3 It is C 1-2 Alkylene-C 5-6 Carbocyclic group, C 1-2Alkyl-5-6-membered heterocyclic group, or 5-6-membered heterocyclic group, wherein each is optionally surrounded by 1-3 R groups. 5 Replace, and R 2 It is a nucleobase or its analogue.

[0099] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 3 yes In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 2 It is a bond. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 2 It is C 1-6 Alkylene.

[0100] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 4 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 Substitution. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 4 yes , where *** is related to R 3 The connection point is ****, which is the connection point with oxygen, and n is an integer between 0 and 3.

[0101] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 4 yes Among them, *** is related to R. 3 The connection point, ****, is the connection point with oxygen. In certain embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, L 4 It is C 1-6 Alkylene.

[0102] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 2 and L 4 It is C 1-6 Alkylene.

[0103] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, L 2 It is -CH2-, L 4It is -CH(CH3)CH2-. In certain embodiments of compounds of formula (I) or their pharmaceutically acceptable salts, L 2 It is -CH2-, L 4 It is -CH2CH2-. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 2 It is a key, L 4 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 Substitution. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 2 It is a key, L 4 It is C 1-2 Alkylene-C 5-6 subcarbocyclic group, C 1-2 Alkyl-5-6-membered heterocyclic or 5-6-membered heterocyclic, wherein each is optionally surrounded by 1-3 R groups. 5 Substitution. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 2 It is C 1-6 Alkylene, L 4 It is a 5-6 membered heterocyclic group. In certain embodiments of compounds of formula (I) or pharmaceutically acceptable salts thereof, L 2 It is -CH2-, L 4 It is a 5-6 membered subheterocyclic group.

[0104] In certain embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 5 It is methyl, F, hydroxy, cyano, ethynyl, methyl subunit or fluoromethyl subunit.

[0105] This application provides compounds of formula IA. (IA), Or its pharmaceutically acceptable salt, wherein R 1 C 10-30 Aliphatic groups; R 3 It is a nucleobase or an analogue thereof; L 2 Is it a key or C? 1-6 Alkylene, optionally surrounded by 1-4 R 4 replace; L 4 It is key, C 1-6 Alkylene, C 3-10 subcarbocyclic group, C1-6 Alkylene-C 3-10 subcarbocyclic group, C 2-6 imide-C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 1-6 alkylene-3-10-membered heterocyclic or C 2-6 Alkenyl-3-10-membered heterocyclic subgroup, wherein the alkylene, alkenyl, carbocyclic and heterocyclic subgroups are each independently and optionally surrounded by 1-4 R groups. 5 replace; R 4 It is halogen; and R 5 It is hydroxyl, halogen, cyano, nitro, C 1-6 Carbinkie, C 1-6 Halogenated carbenefit, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0106] In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 10-30 Alkyl. In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 14-26 Alkyl. In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 14 Alkyl. In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 16-24 Alkyl. In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 18 Alkyl. In certain embodiments of a compound of formula (IA) or a pharmaceutically acceptable salt thereof, R 1 It is a linear C 22 alkyl.

[0107] This application provides compounds of formula (IB), (IB), Or its pharmaceutically acceptable salt, wherein R 1 C 10-30 Aliphatic groups; R 2 and R3 Each is a nucleobase or an analogue thereof; L 3 and L 4 Each is an independent key, C 1-6 Alkylene, C 3-10 subcarbocyclic group, C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 2-6 imide-C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 1-6 alkylene-3-10-membered heterocyclic or C 2-6 Alkenyl-3-10-membered heterocyclic subgroup, wherein the alkylene, alkenyl, carbocyclic, and heterocyclic subgroups are each independently and optionally divided by 1-4 R groups. 5 replace; R 4 It is halogen; and R 5 It is hydroxyl, halogen, cyano, nitro, C 1-6 Carbinkie, C 1-6 Halogenated carbenefit, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0108] This application provides compounds selected from the following: And its pharmaceutically acceptable salts.

[0109] This application provides compound M5TFV (M5TFV), or a pharmaceutically acceptable salt thereof.

[0110] This application provides compound M6TFV (M6TFV), or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the compounds of this application are produced as a single isomer at the phosphorus atom. In some embodiments, the compounds of this application (e.g., compounds of Formula I and pharmaceutically acceptable salts thereof, such as those disclosed herein) comprise a Sp isomer that is substantially free of Rp isomers. For example, in some embodiments, this application provides compounds of Formula I or pharmaceutically acceptable salts thereof as Sp isomers. In some such embodiments, compounds of Formula I or pharmaceutically acceptable salts thereof comprise 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 an Rp isomer. In other embodiments, this application provides compounds of Formula I or pharmaceutically acceptable salts thereof as Rp isomers. In some such embodiments, compounds of Formula I or pharmaceutically acceptable salts thereof comprise 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 a Sp isomer.

[0112] This application provides methods for preparing compounds of formula I and their pharmaceutically acceptable salts, for example, according to the synthetic schemes provided in the following examples, without the need for chiral catalysts or chiral separation. In some embodiments, the compounds of this application (e.g., compounds of formula I and their pharmaceutically acceptable salts, such as those disclosed herein) are produced in crystalline form.

[0113] In some embodiments, this document provides pharmaceutically acceptable salts of Formula I compounds, such as, but not limited to, hydrochlorides, sulfates, sulfites, phosphates, methanesulfonates, p-toluenesulfonates, acetates, lactates, trifluoroacetates, citrates, fumarates, maleates, tartrates, succinates, or salicylates of Formula I compounds.

[0114] In some embodiments, the pharmaceutically acceptable salt is characterized by a ratio of Formula I compound to counterion of 1:1 or 2:1. In some embodiments, the salt is crystalline. In some embodiments, the salt is an amorphous solid.

[0115] In some embodiments, the compound of Formula I is in nanocrystalline or other crystalline form. In some embodiments, the compound of Formula I is substantially crystalline.

[0116] In some embodiments, the compound is complexed with a hydrophobic counterion, including but not limited to pyruvic acid, myristic acid, palmitic acid, stearic acid, behenic acid, naphthalene sulfonate, mandelic acid, toluene sulfonate, benzene sulfonate, benzoate, benzene sulfonate, hydroxynaphthoate, and isothiocyanate, to form crystalline or solid salt forms.

[0117] Nanoparticles In some embodiments, nanoparticles are provided herein comprising: (a) a compound of formula I or a pharmaceutically acceptable salt thereof, and (b) a polymer or surfactant. In some embodiments, a compound of formula I (including crystalline or solid salt forms of the compound) is coated with a polymer or surfactant to form nanoparticles (or nanoformulations).

[0118] In some embodiments, the compound to 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, two polymers (or surfactants) are used, and 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.

[0119] In some embodiments, the nanoparticles are submicron colloidal dispersions of the compound in the form of nanocrystals or solid salts, stabilized by a polymer (or surfactant) (e.g., polymer-coated compound crystals; nanoformulations). In some embodiments, the compound of the nanoparticles is in crystalline or solid salt form complexed with a hydrophobic counterion. In some embodiments, the nanoparticles are crystalline. In some embodiments, the nanoparticles are amorphous. The term "crystalline" as used herein refers to an ordered state (i.e., a non-amorphous state), such as a substance exhibiting long-range order in three-dimensional space. In some embodiments, a majority (e.g., at least 50%, 60%, 70%, 80%, 90%, 95% or more) of the compound (with optionally the hydrophobic portion of a polymer or surfactant) is in crystalline or solid salt form complexed with a hydrophobic counterion.

[0120] In some embodiments, the diameter (e.g., average diameter) or longest dimension of the nanoparticles is at most about 2 μm or about 3 μm, particularly at most about 1 μm (e.g., about 100 nm to about 1 μm). For example, the diameter or longest dimension of the nanoparticles is about 50 nm to about 800 nm. In some embodiments, the diameter or longest dimension of the nanoparticles 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 rod-shaped, irregularly shaped, or spherical. In some embodiments, the nanoparticles of this disclosure are neutral. In some embodiments, the nanoparticles are positively charged. In some embodiments, the nanoparticles are negatively charged.

[0121] The nanoparticles disclosed herein may be synthesized using any suitable nanoparticle synthesis method. In some embodiments, the methods disclosed herein generate nanoparticles comprising a compound (e.g., crystalline or amorphous) coated (partially or completely) with a polymer (or surfactant). Examples of synthesis methods include, but are not limited to, milling (e.g., wet milling), homogenization (e.g., high-pressure homogenization), non-wetting template particle replication (PRINT) techniques, or acoustic treatment techniques, or combinations thereof. In some embodiments, the polymer (or surfactant) is first chemically modified with a targeting ligand and then used directly or mixed in a certain molar ratio with a non-targeting polymer (or surfactant) to coat the surface of a drug suspension—for example, by using nanoparticle synthesis methods (e.g., crystalline nanoparticle synthesis methods), such as milling (e.g., wet milling), homogenization (e.g., high-pressure homogenization), non-wetting template particle replication (PRINT) techniques, acoustic treatment techniques, or combinations thereof, to prepare a targeted nanoformulation. In some embodiments, the nanoparticles are used with or without further purification, but it is desirable to avoid further purification to produce nanoparticles more quickly. In some embodiments, the nanoparticles are synthesized using milling or homogenization, or both.

[0122] In some embodiments, nanoparticles are synthesized by adding a compound to a polymer (or surfactant) solution and then generating nanoparticles (e.g., by wet milling or high-pressure homogenization). In some embodiments, the compound and polymer (or surfactant) solution are stirred and then wet-milled or high-pressure homogenized to form nanoparticles.

[0123] Examples of polymers (or surfactants) include, but are not limited to, synthetic or natural phospholipids, polyethylene glycol-modified lipids (e.g., polyethylene glycol-modified phospholipids), lipid derivatives, polysorbates, amphiphilic copolymers, amphiphilic block copolymers, polyethylene glycol-co-poly(lactide-co-glycolic acid) (PEG-PLGA), their derivatives, ligand-conjugated derivatives, and combinations thereof. Other surfactants and combinations thereof may be used in this disclosure, which can form stable nanosuspensions or can chemically or physically bind targeting ligands to HIV-infectable / infected CD4+ T cells, macrophages, and dendritic cells.Other examples of surfactants include, but are not limited to: 1) nonionic surfactants (e.g., polyethylene glycolated or polysaccharide-conjugated polyesters and other hydrophobic polymer blocks, such as poly(lactide-co-glycolic acid) (PLGA), polylactic acid (PLA), polycaprolactone (PCL), other polyesters, poly(propylene oxide), poly(1,2-epoxybutane), poly(n-epoxybutane), poly(tetrahydrofuran), and poly(styrene); glycerides, polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glyceryl monostearate, polyethylene glycol, polypropylene glycol, cetyl alcohol, cetearyl stearate). Alcohols, stearyl alcohols, aralkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers, poloxamine, cellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polysaccharides, starch and its derivatives, hydroxyethyl starch, polyvinyl alcohol (PVA), polyvinylpyrrolidone and combinations thereof); and 2) ionic surfactants (e.g., phospholipids, amphiphilic lipids, 1,2-dialkylglycerol-3-alkylphosphocholine, 1,2-distearyl-sn-glycerol-3-phosphocholine (DSPC), 1,2-distearyl-sn-glycerol-3-phosphoethanolamine-N[carboxyl(polyethylene glycol))(DSPE)). -PEG), dimethylaminoethanecarbamoylcholesterol (DC-Chol), N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium (DOTAP), alkylpyridinium halides, quaternary ammonium compounds, lauryl dimethylbenzylammonium, acylcarnitine hydrochloride, dimethyl dioctadecylammonium (DDAB), n-octylamine, oleylamine, benzalkonium, hexadecyltrimethylammonium, chitosan, chitosan salts, polyethyleneimine (PEI), poly(N-isopropylacrylamide) (PNIPAM), polyallylamine (PAH), poly(dimethyldiallylamine chloride) (PDDA), alkyl Sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecyl sulfate, alkyl polyoxyethylene sulfate, alginic acid, alginate, hyaluronic acid, hyaluronic acid salts, gelatin, sodium dioctyl sulfosuccinate, sodium carboxymethyl cellulose, cellulose sulfate, dextran sulfate and carboxymethyl cellulose, chondroitin sulfate, heparin, synthetic polyacrylic acid (PAA), polymethacrylic acid (PMA), polyethylene sulfate (PVS), polystyrene sulfonate (PSS), bile acids and their salts, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid and their derivatives and combinations thereof.

[0124] In some embodiments, the polymers (or surfactants) of this disclosure are charged. In some embodiments, the polymers (or surfactants) of this disclosure are neutral. In some embodiments, the polymers (or surfactants) are negatively charged (e.g., poloxamer, polysorbates, phospholipids, and their derivatives).

[0125] In some embodiments, the polymer (or surfactant) is an amphiphilic block copolymer or a lipid derivative. In some embodiments, at least one polymer (or surfactant) of the nanoparticles is an amphiphilic block copolymer, for example, a copolymer comprising at least one poly(ethylene oxide) block and at least one poly(propylene oxide) block. 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.

[0126] In some embodiments, the amphiphilic block copolymer is a copolymer comprising at least one poly(ethylene oxide) block and at least one poly(propylene oxide) block.

[0127] Examples of poloxamer include, but are not limited to, 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, P10S, F108, L121, L122, L123, F127, 10RS, 10R8, 12R3, 17R1, 17R2, 17R4, 17R8, 22R4, 25R1, 25R2, 2SR4, 25RS, 2SR8, 31R1, 31R2, and 31R4.

[0128] 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).

[0129] In some embodiments, the polymer (or surfactant) is present in the nanoparticles or a surfactant solution to synthesize the nanoparticles (as described above), with 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%, from about 0.01% to about 10%, or from about 0.1% to about 6% by weight. In some embodiments, the nanoparticles contain at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or higher by weight of a therapeutic agent (a compound of formula I or a pharmaceutically acceptable salt thereof).

[0130] Pharmaceutical Composition The compositions and methods of this application can be used to treat individuals in need. In some 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 compound is preferably administered in the form of a pharmaceutical composition, for example, a pharmaceutical composition comprising the compound of this application and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art, including, for example, aqueous solutions (such as water or physiologically buffered saline) or other solvents or media (such as glycols, glycerols, oils (such as olive oil), or injectable organic esters). In a preferred embodiment, when such pharmaceutical compositions are used for human administration, particularly for invasive routes of administration (i.e., routes of transport or diffusion bypassing the epithelial barrier, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. For example, excipients may be selected to achieve delayed drug release or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of dosage units, such as tablets, capsules (including powdered capsules and gelatin capsules), granules, lyophilized formulations for reconstitution, powders, solutions, syrups, suppositories, injections, etc. This composition may also be present in transdermal delivery systems, such as skin patches. It may also be present in solutions suitable for topical application, such as eye drops.

[0131] Pharmaceutically acceptable carriers may contain physiologically acceptable substances, for example, substances used to stabilize compounds (such as those in this application), increase their solubility, or increase their absorption. Such physiologically acceptable substances include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents, low molecular weight proteins, or other stabilizers or excipients. For example, the choice of a pharmaceutically acceptable carrier (including physiologically acceptable substances) depends on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix, which may contain compounds such as those in this application. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers, and their preparation and administration are relatively simple.

[0132] As used in this article, "pharmaceutically acceptable" means compounds, materials, compositions, and / or dosage forms that, to a reasonable extent of medical judgment, are suitable for use in human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and have a reasonable benefit / risk ratio.

[0133] The phrase “pharmaceutically acceptable carrier” as used in this article refers to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be “acceptable,” meaning it is compatible with other components in the formulation and will not cause harm to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth gum powder; (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, and corn oil. Rice oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0134] The pharmaceutical composition (formulation) may be administered to a subject via any of a variety of routes of administration, including, for example, oral (e.g., by gavage in aqueous or non-aqueous or suspension form, tablets, capsules (including powdered capsules and gelatin capsules), boluses, powders, granules, pastes, for use on the tongue); absorption via the oral mucosa (e.g., sublingual absorption); rectally, rectally, or vaginally (e.g., suppositories, creams, or foams); parenteral administration (including intramuscular, intravenous, subcutaneous, or intrathecal administration, e.g., as a sterile solution or suspension); nasal administration; intraperitoneal administration; subcutaneous administration; transdermal administration (e.g., patches for use on the skin); and topical administration (e.g., creams, ointments, or sprays for use on the skin, or as eye drops). The compound may also be formulated as an inhalation formulation. In some embodiments, the compound may simply be dissolved or suspended in sterile water. Detailed information regarding suitable routes of administration and applicable compositions can be found, for example, in U.S. Patents 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896 and the patents referenced therein.

[0135] These formulations can be conveniently presented in unit doses and can be prepared using any method well-known in the pharmaceutical field. The amount of active ingredient that can be bound to a carrier material to form a single dosage form will vary depending on the subject receiving treatment and the specific route of administration. Generally, the amount of active ingredient that can be bound to a carrier material to form a single dosage form is the amount of the compound that produces the therapeutic effect. Generally, on a 100% basis, this amount is about 1% to about 99% of the active ingredient, preferably about 5% to about 70% of the active ingredient, and most preferably about 10% to about 30% of the active ingredient.

[0136] Methods for preparing these formulations or compositions include the following steps: combining an active compound (e.g., the compound of this application) with a carrier and optionally one or more auxiliary components. Generally, the formulation is prepared by uniformly and tightly combining the compound of this application with a liquid carrier or a finely dispersed solid carrier, or both, and then, if necessary, shaping the product.

[0137] Formulations of this application suitable for oral administration may be capsules (including powdered capsules and gelatin capsules), caches, pills, tablets, lozenges (using a flavoring matrix, typically sucrose and gum arabic or tragacanth gum), lyophilized forms, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil emulsions, or elixirs or syrups, or flavoring pastes (using an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic), and / or mouthwashes, each containing a predetermined amount of the compound of this application as an active ingredient. The composition or compound may also be administered in bolus, electuary, or paste form.

[0138] To prepare solid dosage forms (capsules (including powdered capsules and gelatin capsules), tablets, pills, sugar-coated tablets, powders, granules, etc.) for oral administration, 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 components: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicate; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain silicates, and sodium carbonate; (5) solution retardants. Agents, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrin; and (11) coloring agents. For capsules (including powdered capsules and gelatin capsules), tablets and pills, pharmaceutical compositions may also contain buffers. Similar types of solid compositions may also be used as fillers for soft-filled gelatin capsules and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0139] Tablets can be made by compression or molding, optionally with one or more excipients. Compression tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0140] Tablets and other solid dosage forms of pharmaceutical compositions, such as sugar-coated tablets, capsules (including powdered 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 formulation field. They may also be formulated to provide a slow or controlled release of the active ingredient therein, for example using varying proportions of hydroxypropyl methylcellulose to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres. They may be sterilized, for example, by filtration through a bacterial trap filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which may be dissolved immediately in sterile water or some other sterile injectable medium before use. These compositions may also optionally contain light-blocking agents and may be compositions that release the active ingredient only or preferentially in specific portions of the gastrointestinal tract and optionally in a delayed manner. Examples of usable encapsulation compositions include polymers and waxes. If suitable, the active ingredient may also be in a microencapsulated form and have one or more of the excipients described above.

[0141] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, lyophilized formulations for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters and mixtures thereof.

[0142] In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, fragrances and preservatives.

[0143] In addition to active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, and mixtures thereof.

[0144] Pharmaceutical compositions for rectal, vaginal, or urethral administration can be formulated as suppositories, which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates. The suppositories are solid at room temperature but liquid at body temperature, and thus melt and release the active compounds within the rectal or vaginal cavity.

[0145] Formulations of pharmaceutical compositions for oral application may be presented in the form of mouthwash, oral spray, or oral ointment.

[0146] Alternatively or additionally, compositions may be formulated for delivery via catheters, stents, guidewires, or other endoluminal devices. Delivery via such devices may be particularly suitable for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0147] Preparations suitable for vaginal application also include suppositories, tampons, creams, gels, pastes, foams, or sprays containing suitable carriers known in the art.

[0148] Dosage forms for topical or transdermal application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. Active compounds may be mixed under aseptic conditions with pharmaceutically acceptable carriers and any necessary preservatives, buffers, or propellants.

[0149] Ointments, pastes, creams, and gels may contain excipients in addition to active compounds, such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth gum, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0150] In addition to the active compound, powders and aerosols may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Aerosols may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0151] An additional advantage of transdermal patches is the controlled release of the compounds described herein into the body. Such dosage forms can be prepared by dissolving or dispersing the active compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds through the skin. The rate of this flux can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0152] Ophthalmic preparations, ointments, powders, solutions, etc., are also within the scope of this application. Exemplary ophthalmic preparations are described in U.S. Patent Publications 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. Liquid ophthalmic preparations may, if desired, have properties similar to, or be compatible with, tears, aqueous humor, or vitreous fluid. A preferred route of administration is topical application (e.g., topical application, such as eye drops, or application via an implant).

[0153] The phrases “parenteral administration” and “administered via a parenteral route” as used in this article refer to administration methods that differ from intravenous and local administration, and are usually administered by injection, including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0154] Pharmaceutical compositions suitable for parenteral administration contain one or more active compounds and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use. They may contain antioxidants, buffers, bacteriostatic agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0155] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of this application include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). For example, appropriate flowability can be maintained by using coating materials such as lecithin, maintaining the desired particle size in the case of dispersions, and using surfactants.

[0156] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. By adding various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenolic sorbic acid, protection against microbial activity can be ensured. The addition of isotonic agents, such as sugars and sodium chloride, to the composition may also be desirable. Furthermore, by adding substances that delay absorption, such as aluminum monostearate and gelatin, prolonged absorption of injectable drug formulations can be achieved.

[0157] In some cases, to prolong the effect of a drug, it is necessary to slow its absorption after subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate of the drug depends on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oily medium.

[0158] Injectable reservoir formulations are made by forming a microencapsulated matrix of the subject compound within a biodegradable polymer (e.g., polylactide-polyglycolic acid). The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include polyorthoesters and polyanhydrides. Reservoir injectable formulations are also prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0159] For use in the methods of this application, the active compound may be used on its own or as a pharmaceutical composition, for example, the pharmaceutical composition containing 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient and a pharmaceutically acceptable carrier.

[0160] Delivery methods can also be provided through refillable or biodegradable devices. In recent years, various sustained-release polymer devices have been developed and tested in vivo for the controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), both biodegradable and non-biodegradable, can be used to form implants for the sustained release of compounds at specific target sites.

[0161] The actual dose level of the active ingredient in a pharmaceutical composition can be altered to obtain an amount of active ingredient that effectively achieves the therapeutic response required for a particular patient, composition, and method of administration without causing toxicity to the patient.

[0162] The selected dose level will depend on a variety of factors, including the activity of the specific compound or combination of compounds or its esters, salts or amides used, the route of administration, the time of administration, the excretion rate of the specific compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound used, the age, sex, weight, condition, general health and medical history of the patient being treated, and similar factors well known in the medical field.

[0163] Physicians with general skills in the field can easily determine and prescribe an effective therapeutic dose of the required pharmaceutical composition. For example, a physician may start with a dose of the pharmaceutical composition or compound below the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. “Therapeutic effective dose” refers to the concentration of the compound sufficient to cause the desired therapeutic effect. It is generally understood that the effective dose of a compound will vary depending on the subject’s weight, sex, age, and medical history. Other factors that may affect the effective dose may include, but are not limited to, the severity of the patient’s condition, the condition being treated, the stability of the compound, and (if necessary) other types of therapeutic agents administered with the compound of this application. A larger total dose can be delivered by administering the drug multiple times. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine, 13th ed., 1814–1882, which are incorporated herein by reference).

[0164] Generally, the appropriate daily dose of the active compound used in the compositions and methods of this application refers to the amount of the lowest dose of the compound that effectively produces a therapeutic effect. Such an effective dose will typically depend on the factors mentioned above.

[0165] If desired, the effective daily dose of the active compound can be administered in one, two, three, four, five, six, or more sub-dose intervals throughout the day, optionally in unit dose form. In some embodiments of this application, the active compound can be administered two or three times daily. In a preferred embodiment, the active compound is administered once daily.

[0166] Patients receiving this treatment are any animals in need of treatment, including primates, and especially humans.

[0167] In some embodiments, the pharmaceutical compositions provided herein are for long-term administration (“long-term administration”). As used herein, “long-term administration” means administration of the compound, nanoparticles, or pharmaceutical composition over an extended period of time (e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc.) or continuously indefinitely (e.g., for the remainder of the subject's life). In some embodiments, the compound, nanoparticles, or pharmaceutical composition is administered once every 1 to 12 months. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood, for example, to provide a constant level of the compound in the blood within a therapeutic window over an extended period.

[0168] In some embodiments, the pharmaceutical compositions provided herein are presented in unit dose form to facilitate accurate administration. As used herein, the term "unit dose form" refers to physically separated units suitable for use as a unit dose in human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, and a suitable pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical dosage forms described herein are administered in unit doses. Typical unit dose forms include, but are not limited to, pre-filled, pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., of solid compositions.

[0169] In some embodiments, the pharmaceutical compositions provided herein comprise a compound of formula I as the sole active agent, or in combination with one or more other therapeutic agents. In the treatment of any condition disclosed herein, the different compounds of this application may be administered (e.g., in combination) with one or more other compounds of this application (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof). Furthermore, any one or more compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered in combination with other conventional therapeutic agents to treat one or more of the conditions mentioned herein.

[0170] In some embodiments, the compounds of this application may be used alone or in combination with another type of therapeutic agent. As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic compounds such that the previously administered therapeutic compound remains effective in the body while the second compound is being administered (e.g., both compounds are effective simultaneously in the patient, which may include synergistic effects between the two compounds). For example, the different therapeutic compounds may be administered in the same formulation or in separate formulations, and may be administered simultaneously, sequentially, or by administering the individual therapeutic components separately. In some embodiments, the different therapeutic compounds may be administered at intervals of 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week. Therefore, individuals receiving this treatment may benefit from the combined effects of the different therapeutic compounds.

[0171] In some embodiments, the combination of the compound of this application with one or more other therapeutic agents provides an improved effect compared to the individual application of the compound of formula (I) or its pharmaceutically acceptable salt or the one or more other therapeutic agents. In some such embodiments, the combination provides an synergistic effect, wherein the synergistic effect refers to the sum of the respective effects of the compound of this application and the one or more other therapeutic agents applied alone.

[0172] Such combination products utilize compounds of this application within the dosage range described herein, as well as one or more other pharmaceutically active compounds within approved dosage ranges and / or dosages described in published references.

[0173] This application includes pharmaceutically acceptable salts of the compounds of this application used in the compositions and methods of this application. The term "pharmaceutically acceptable salt" includes salts of active compounds prepared with a relatively non-toxic acid or base according to the specific substituents seen on the compounds described herein. When the compounds of this application contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds of this application contain relatively basic functional groups (e.g., amines), an acid addition salt can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, trifluoroacetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, camphorsulfonic acid, etc. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a camphorsulfonate salt. In some embodiments, the salts of the covered compounds include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In some embodiments, the covered compound salts include, but are not limited to: L-arginine, benzylamine, benzathine, betaine, calcium hydroxide, choline, dianophenate, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucosamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In some embodiments, the covered compound salts include, but are not limited to, Li, Na, Ca, K, Mg, Zn, or other metal salts. Also included are amino acid salts (such as arginine salts) and organic acid salts (such as glucuronic acid or galacturonic acid salts) (e.g., see Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds in this application may contain both basic and acidic functional groups, enabling them to be converted into base or acid addition salts.

[0174] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (e.g., solubility in polar solvents), and the salt is equivalent to the parent form of the compound for the purposes of this application.

[0175] The compounds of this application, including their pharmaceutically acceptable salts, may also exist in the form of various solvates, such as solvates with water (also called hydrates), methanol, ethanol, dimethylformamide, diethyl ether, acetamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be a crystallization solvent, which may be inherent in the preparation or crystallization solvent, or may be incidentally present in such a solvent.

[0176] The compounds of this application, including their pharmaceutically acceptable salts, may exist in various polymorphs, pseudopolymorphs, or amorphous states. As used herein, the term "polymorph" refers to different crystalline forms and other solid molecular forms of the same compound, including pseudopolymorphs such as hydrates, solvates, or salts of the same compound. Different crystalline polymorphs have different crystal structures due to variations in temperature, pressure, or the crystallization process, resulting in different molecular packing within the crystal lattice. Polymorphs differ from one another in physical properties (e.g., X-ray diffraction characteristics, stability, melting point, solubility, or dissolution rate in certain solvents). Therefore, crystalline polymorphism is an important aspect of developing suitable dosage forms in the pharmaceutical industry.

[0177] The composition may also contain wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and spices, preservatives and antioxidants.

[0178] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0179] In some embodiments, this application includes a method of conducting a pharmaceutical business, which involves determining appropriate formulations and dosages of compounds of this application to treat or prevent any of the diseases or conditions described herein, performing therapeutic characterization analyses of the determined formulations on animal efficacy and toxicity, and providing a sales distribution network for formulations determined to have acceptable therapeutic characteristics. In some embodiments, the method further includes providing a sales team for marketing the formulation to healthcare providers.

[0180] In some embodiments, this application relates to a method of conducting a pharmaceutical business, which involves determining appropriate formulations and dosages of the compounds of this application to treat or prevent any of the diseases or conditions described herein, and licensing the right to further develop and market the formulation to third parties.

[0181] Use and treatment methods In some embodiments, methods for preventing, inhibiting, or treating viral infections, cancer, or blood clotting disorders are disclosed herein. These methods involve administering an effective amount of the disclosed compound, nanoparticles, or pharmaceutical composition to a subject in need (e.g., a human).

[0182] In some embodiments, this document provides methods for treating a subject with a viral infection in need, including administering to the subject an effective amount of the compound, nanoparticles, or composition disclosed herein. Examples of viral infections include, but are not limited to: human immunodeficiency virus (HIV) infection, hepatitis B, hepatitis C, influenza (e.g., influenza A, influenza B), COVID-19 infection, Ebola virus infection, herpes (e.g., herpes simplex), meningitis, pneumonia, human papillomavirus infection, rotavirus infection, norovirus infection, chickenpox, mumps, measles, rubella, Zika virus infection, and viral conjunctivitis. In some embodiments, the viral infection is a retroviral or lentiviral infection, such as HIV infection (e.g., HIV-1 infection, HIV-2 infection). In some embodiments, this document provides methods for treating a subject with hepatitis B infection in need, including administering to the subject an effective amount of the compound, nanoparticles, or composition disclosed herein. In some embodiments, this document provides methods for treating a subject with chronic hepatitis B infection in need, including administering to the subject an effective amount of the compound, nanoparticles, or composition disclosed herein.

[0183] In some implementations, this document provides methods for treating bacterial, fungal, mycobacterial, and / or parasitic infections in subjects in need, including administering to the subject an effective amount of the compound, nanoparticles, or composition disclosed herein.

[0184] In some embodiments, this document provides methods for treating a subject with a blood clotting disorder, the method comprising administering to the subject an effective amount of the compound, nanoparticle, or composition disclosed herein. For example, the compound, nanoparticle, or composition disclosed herein is used as an antiplatelet drug to inhibit or prevent blood clot formation. Exemplary blood clotting disorders include, but are not limited to: deep vein thrombosis, pulmonary embolism, arterial thrombosis, thrombotic predisposition (e.g., antiphospholipid antibody syndrome, factor V Leiden mutation, 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 (genetically inherited). In some embodiments, the blood clotting disorder is acquired, for example, during or after surgery, or related to cancer or pregnancy.

[0185] In some implementations, this document provides methods for treating a subject with cancer in need, including administering to the subject an effective amount of a compound, nanoparticle, or composition disclosed herein. Exemplary cancers include, but are not limited to: leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia), lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma), multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, bladder cancer, liver cancer, neuroblastoma, brain cancer (e.g., glioma, meningioma, and pituitary adenoma), lung cancer, ovarian cancer, gastric cancer, skin cancer (e.g., melanoma), cervical cancer, testicular cancer, kidney cancer, carcinoid tumors, and bone cancer.

[0186] In some embodiments, the compounds, nanoparticles, or pharmaceutical compositions of this disclosure are administered to a subject together with one or more other therapeutic agents (e.g., antiviral agents, anti-HIV agents, anticancer agents, or anticoagulants). In some embodiments, the additional therapeutic agent is administered as a pharmaceutical composition different from the compounds, nanoparticles, or compositions of this disclosure. In other embodiments, the additional therapeutic agent is formulated in the same pharmaceutical composition as a composition containing a compound of formula I or a pharmaceutically acceptable salt thereof or nanoparticles containing said compound. In some embodiments, the pharmaceutical compositions are administered simultaneously. In other embodiments, the pharmaceutical compositions are administered at different times (e.g., sequentially).

[0187] In some embodiments, the compounds, nanoparticles, or pharmaceutical compositions of this disclosure are administered to a subject together with one or more other antiviral agents. Exemplary antiviral agents include, but are not limited to: HIV protease inhibitory compounds, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other medicines and combinations thereof for the treatment of HIV. Exemplary HIV protease inhibitory compounds include, but are not limited to, ampranavir, atazanavir, forosanavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tepranavir, brenavir, 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, as well as combinations thereof. Exemplary HIV non-nucleoside reverse transcriptase inhibitors include, but are not limited to: cappravirine, imivevirine, delavirine, efavirenz, nevirapine, (+) caranolide A, ectravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirine, BILR 355 BS, VRX 840773, UK-453061, and RDEA806, as well as combinations thereof. Exemplary HIV nucleoside reverse transcriptase inhibitors include, but are not limited to, zidovudine, emtricitabine, didanoxin, stavudine, zalcitabine, lamivudine, abacavir, amadoxovir, elvucitabine, allovudine, MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphorylhydrazine, fozivudine ester, apracitabine (AVX754), amadoxovir, KP-1461, and fozivudine ester, and combinations thereof. Selected exemplary HIV nucleotide reverse transcriptase inhibitors 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, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin (tyrosine kinase inhibitor), tyrphostin derivatives, quercetin, quercetin derivatives, S-1360, AR-177, L-870812, L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011, cabotevir, bicretiravir, and dolutegravir, as well as combinations thereof. Exemplary gp41 inhibitors include, but are not limited to, enfvirdi, sifvirdi, FB006M, and TRI-1144, as well as combinations thereof. Exemplary CXCR4 inhibitors include, but are not limited to, AMD-070. Exemplary entry inhibitors include, but are not limited to, SP01A. Exemplary gp120 inhibitors include, but are not limited to, BMS-488043. Exemplary G6PD and NADH oxidase inhibitors include, but are not limited to, immunoglobulins. Exemplary CCR5 inhibitors include, but are not limited to, aviloviril, maraviro, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004, and combinations thereof. Other drugs used to treat 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 (Beverimart), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDXO10 (ipilimumab), PBS119, ALG 889, and PA-1050040 (PA-040) and combinations thereof.

[0188] The dosage range of the disclosed compounds, nanoparticles, and compositions, administered alone or in combination with one or more other therapeutic agents, is a dosage range sufficient to produce the desired effect (e.g., cure, relief, treatment, or prevention of the disclosed medical condition (e.g., viral infection, cancer, blood clotting disorders) or its symptoms (e.g., AIDS, ARC), or susceptibility to it). In some embodiments, the pharmaceutical compositions of the disclosed invention are administered to a subject in an amount from about 5 µg / kg to about 500 mg / kg. In some embodiments, the pharmaceutical compositions of the disclosed invention are administered to a subject in 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 compositions of the disclosed invention are administered to a subject in an amount from about 0.5 mg / kg to about 100 mg / kg, from about 10 mg / kg to about 100 mg / kg, or from about 15 mg / kg to about 50 mg / kg. The dosage should not be too high to avoid significant adverse side effects, such as cross-reactions or allergic reactions. Generally, the dosage will vary depending on the patient's age, condition, gender, and severity of the disease, and can be determined by a clinician or physician. If any contraindications occur, the dosage will be adjusted by the clinician or physician.

[0189] Without further elaboration, it is believed that those skilled in the art will be able to make the fullest use of this disclosure based on the above description. Therefore, the following specific embodiments are merely illustrative and do not limit the rest of the disclosure in any way. Example

[0190] To provide a more complete understanding of the disclosure herein, the following examples are provided. The examples described in this application are for illustrative purposes only and should not be construed as limiting the scope of the compounds, pharmaceutical compositions, and methods provided herein.

[0191] Example 1: Synthesis and Characterization of M5TFV (M5TFV) Monophenyltenofovir (3 g, 8.25 mmol, 1 equivalent) was dried from anhydrous benzene (30 mL), resuspended in anhydrous pyridine (25 mL), and then cooled to -10°C under an argon atmosphere. After adding octadecyl alcohol (3.3 g, 12.38 mmol, 1.5 equivalent) and 2 equivalents of triethylamine, the mixture was heated at 65°C for 10 min under an argon atmosphere, protected from light. Then, a solution of triphenylphosphine (4.33 g, 16.51 mmol, 2 equivalents) and 2,2'-dithiopyridine (3.64 g, 16.51 mmol, 2 equivalents) in pyridine (10 mL) was added to the reaction mixture, and heating continued for another 16 hours. The mixture was then concentrated to remove the solvent. The residue was partitioned between dichloromethane (DCM, 200 mL) and saturated sodium bicarbonate (150 mL). The organic phase was then washed once with saturated sodium bicarbonate (150 mL), followed by brine (150 mL), and dried over sodium sulfate. Dichloromethane was then evaporated on a rotary evaporator, and the sample was purified by rapid silica column chromatography, eluting successively with 97%, 95%, and 92.5% dichloromethane / methanol. The desired compound fraction from the column was dried on a rotary evaporator and precipitated from diethyl ether to give a white powder with a chemical yield >70% (M5TFV). 1 H (CDCl3; Figure 1 )and 31 P NMR spectroscopy, using Bruker Avance-III HD, at 500 MHz and 11.7 T magnetic field strength, confirmed the successful synthesis of the prodrug.

[0192] Example 2: Synthesis and Characterization of M6TFV (M6TFV) Monophenyltenofovir (3 g, 8.25 mmol, 1 equivalent) was dried from anhydrous benzene (30 mL), resuspended in anhydrous pyridine (25 mL), and then cooled to -10°C under an argon atmosphere. After adding docosyl alcohol (4 g, 12.38 mmol, 1.5 equivalent) and 2 equivalents of triethylamine, the mixture was heated at 65°C for 10 min under an argon atmosphere, protected from light. Then, a solution of triphenylphosphine (4.33 g, 16.51 mmol, 2 equivalents) and 2,2'-dithiopyridine (3.64 g, 16.51 mmol, 2 equivalents) in pyridine (10 mL) was added to the reaction mixture, and heating continued for another 16 hours. The mixture was then concentrated to remove the solvent. The residue was partitioned between dichloromethane (DCM, 200 mL) and saturated sodium bicarbonate (150 mL). The organic phase was then washed once with saturated sodium bicarbonate (150 mL), followed by brine (150 mL), and dried over sodium sulfate. Dichloromethane was then evaporated on a rotary evaporator, and the sample was purified by rapid silica column chromatography, eluting successively with 97%, 95%, and 92.5% dichloromethane / methanol. The desired compound fraction from the column was dried on a rotary evaporator and precipitated from diethyl ether to give a white powder with a chemical yield >70% (M6TFV). 1 H (CDCl3; Figure 2 )and 31 P NMR (CDCl3; Figure 3 The successful synthesis of the prodrug was confirmed by spectroscopic analysis using Bruker Avance-III HD at 500 MHz and 11.7 T magnetic field strength.

[0193] Example 3: Synthesis and Characterization of Nanoparticles Solid drug nanoparticles of M5TFV, M6TFV, and tenofovir alafenamide (TAF) were prepared by high-pressure homogenization in an aqueous buffer stabilized with a nonionic surfactant, yielding nanoparticles NM5TFV, NM6TFV, and NTAF, respectively. The NM5TFV and NM6TFV nanoformulations were prepared in a mixture of phosphate-buffered saline solution at pH 7 and surfactant solutions of Tween 20 and PEG 3350. For NTAF, a mixture of P407 and PEG 3350 was used as a stabilizer. Specifically, the solid drug powder was dispersed in the surfactant solution and stirred / agitated to form a pre-suspension. The pre-suspension was homogenized on an Avestin EmulsiFlex-C3 high-pressure homogenizer at pressures of 15,000–20,000 psi until the desired particle size of 250–450 nm was achieved. Subsequently, the particle size, uniformity, and surface charge of the homogenized solid drug nanoparticles were evaluated by dynamic light scattering using a Malvern Zetasizer Nano-ZS. The amounts of TAF, M5TFV, and M6TFV in the homogenized formulation were determined by diluting formulation samples in MeOH (1,000–10,000-fold dilution) and analyzed by UPLC-UV / Vis spectroscopy using calibration curves with known standards. The percentage of drug encapsulated in each nanosuspension was calculated using the following formula: Encapsulation efficiency (%) = (Weight of drug in formulation / Weight of initial added drug) x 100.

[0194] Example 4: Therapeutic effect study of HBV transgenic mice Antiviral efficacy was tested in HBV Tg05 mice containing a stably integrated HBV transgene. This study was approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Nebraska Medical Center (UNMC, #19-034-10FC). Animal Research: The In Vivo Experiment Reporting (ARRIVE) guideline was used to prepare the data collected in this manuscript. Animals were housed under pathogen-free conditions and received a standard diet. Male C57Bl / 6 transgenic Tg05 mice expressing the 1.3 HBV wild-type viral genome were obtained from J.-H. James Ou, University of Southern California. Mice were maintained in a pathogen-free barrier facility. The drug formulation was administered via a single intramuscular injection at a dose of 168 mg / kg TFV equivalent. HBV DNA viral load in the blood was measured every other week.

[0195] The synthesized prodrug is in solid form, compatible with formulation methods that enable scalable preparation of surfactant-stable aqueous nanosuspensions. Notably, it is compatible with TAF ProTide or arylated NM4TFV diester prodrugs in nanoformulations. (NM4TFV) Compared to limited anti-HBV activity, a single intramuscular injection of a lipophilic NM5TFV or NM6TFV diester prodrug nanosuspension into Tg05 mice showed enhanced and sustained efficacy. Figure 4 This study demonstrated the inhibition of HBV replication in HBV transgenic Tg05 mice (C57BL / 6). A single intramuscular injection of NM5TFV or NM6TFV (n=4 per group) inhibited HBV DNA in peripheral blood by two orders of magnitude compared to untreated nanoformulations TAF ProTide or NM4TFV diester prodrugs. Results are presented as mean ± SEM. The NM5TFV and NM6TFV diester prodrug formulations exhibited enhanced and sustained inhibition of HBV DNA replication in transgenic Tg05 mice over one month, with no significant adverse events.

[0196] By incorporating references All publications and patents mentioned herein are incorporated herein by reference in their entirety, as if each publication or patent had been expressly and individually indicated as incorporated by reference. In case of any conflict, this application (including any definitions herein) shall prevail.

[0197] equivalent This disclosure may be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the above embodiments should be considered exemplary in all respects and not as limiting of the content described herein. Consequently, the scope of this disclosure is defined by the appended claims rather than the foregoing description, and all modifications that fall within the meaning and equivalence of the claims should be included therein.

Claims

1. Compounds of formula I, (I)， Or its pharmaceutically acceptable salt, wherein R 1 C 10-30 aliphatic groups; R 2 The aryl or nucleobase may be substituted by choice or an analogue thereof; R 3 It is a nucleobase or an analogue thereof; L 1 and L 2 Each is an independent key or C 1-6 Alkylene, optionally with 1-4 R 4 replace; L 3 and L 4 Each is independently a key, C 1-6 Alkylene, C 3-10 subcarbocyclic group, C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 2-6 imide-C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 1-6 alkylene-3-10-membered heterocyclic or C 2-6 Alkenyl-3-10-membered heterocyclic subgroup, wherein the alkylene, alkenyl, carbocyclic, and heterocyclic subgroups are each independently and optionally represented by 1-4 R groups. 5 replace; R 4 It is halogen; and R 5 It is hydroxyl, halogen, cyano, nitro, carbene, halogenated carbene, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 10-30 alkyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 14-26 alkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 14 alkyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 16-24 alkyl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 For linear C 18 alkyl.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 22 alkyl.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R 2 It is an aryl group that is optionally substituted.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a phenyl group.

10. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a nucleobase or its analogue.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the nucleobase or its analogue is... 。 12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L 1 It is a key.

13. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L 1 It is C 1-6 Alkylene.

14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein L 3 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 replace.

15. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein L 3 yes ， Where * is related to R 2 The connection point is **, which is the connection point with oxygen, and n is an integer between 0 and 3.

16. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein L 3 yes Where * is related to R 2 The connection point is the connection point with oxygen.

17. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein L 3 It is a key.

18. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein L 1 and L 3 Each is a key, R 2 It is an aryl group that is optionally substituted.

19. The compound according to any one of claims 1-7 and 18, or a pharmaceutically acceptable salt thereof, wherein L 1 and L 3 Each is a key, R 2 It is a phenyl group.

20. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein L 1 It is a key, L 3 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 Replace, and R 2 It is a nucleobase or its analogue.

21. The compound according to any one of claims 1-7 and 20, or a pharmaceutically acceptable salt thereof, wherein L 1 It is a key, L 3 It is C 1-2 Alkylene-C 5-6 Carbocyclic group, C 1-2 Alkyl-5-6-membered heterocyclic group, or 5-6-membered heterocyclic group, wherein each is optionally surrounded by 1-3 R groups. 5 Replace, and R 2 It is a nucleobase or its analogue.

22. The compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R 3 for 。 23. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L 2 It is a key.

24. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L 2 It is C 1-6 Alkylene.

25. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein L 4 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 replace.

26. The compound according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein L 4 for ， Among them, *** is related to R. 3 The connection point is ****, which is the connection point with oxygen, and n is an integer between 0 and 3.

27. The compound according to any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein L 4 for Among them, *** is related to R. 3 The connection point is ****, which is the connection point with oxygen.

28. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein L 4 It is C 1-6 Alkylene.

29. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L 2 and L 4 It is C 1-6 Alkylene.

30. The compound according to any one of claims 1-22 and 29, or a pharmaceutically acceptable salt thereof, wherein L 2 It is -CH2-, L 4 It is -CH(CH3)CH2-.

31. The compound according to any one of claims 1-22 and 29, or a pharmaceutically acceptable salt thereof, wherein L 2 It is -CH2-, L 4 It is -CH2CH2-.

32. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L 2 It is a key, L 4 It is C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 1-6 Alkyl-3-10-membered heterocyclic group or 3-10-membered heterocyclic group, wherein each is optionally surrounded by 1-4 R groups. 5 replace.

33. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein L 2 It is a key, L 4 It is C 1-2 Alkylene-C 5-6 subcarbocyclic group, C 1-2 Alkyl-5-6-membered heterocyclic or 5-6-membered heterocyclic, wherein each is optionally surrounded by 1-3 R groups. 5 replace.

34. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein L 2 It is C 1-6 Alkylene, L 4 It is a 5-6 member subheterocyclic group.

35. The compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein L 2 It is -CH2-, L 4 It is a 5-6 member subheterocyclic group.

36. The compound according to any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R 5 It is methyl, F, hydroxy, cyano, ethynyl, methyl subunit or fluoromethyl subunit.

37. Compounds of formula IA, (IA), Or its pharmaceutically acceptable salt, wherein R 1 C 10-30 aliphatic groups; R 3 It is a nucleobase or an analogue thereof; L 2 Is it a key or C? 1-6 Alkylene, optionally surrounded by 1-4 R 4 replace; L 4 It is key, C 1-6 Alkylene, C 3-10 subcarbocyclic group, C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 2-6 imide-C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 1-6 alkylene-3-10-membered heterocyclic or C 2-6 Alkenyl-3-10-membered heterocyclic subgroup, wherein the alkylene, alkenyl, carbocyclic and heterocyclic subgroups are each independently and optionally surrounded by 1-4 R groups. 5 replace; R 4 It is halogen; and R 5 It is hydroxyl, halogen, cyano, nitro, C 1-6 Carbinkie, C 1-6 Halogenated carbenefit, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 10-30 alkyl.

39. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 14-26 alkyl.

40. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 14 alkyl.

41. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 16-24 alkyl.

42. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 18 alkyl.

43. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a linear C 22 alkyl.

44. Compounds of formula (IB), (IB), Or its pharmaceutically acceptable salt, wherein R 1 C 10-30 aliphatic groups; R 2 and R 3 Each is a nucleobase or an analogue thereof; L 3 and L 4 Each is an independent key, C 1-6 Alkylene, C 3-10 subcarbocyclic group, C 1-6 Alkylene-C 3-10 subcarbocyclic group, C 2-6 imide-C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 1-6 alkylene-3-10-membered heterocyclic or C 2-6 Alkenyl-3-10-membered heterocyclic subgroup, wherein the alkylene, alkenyl, carbocyclic, and heterocyclic subgroups are each independently and optionally divided by 1-4 R groups. 5 replace; R 4 It is halogen; and R 5 It is hydroxyl, halogen, cyano, nitro, C 1-6 Carbinkie, C 1-6 Halogenated carbenefit, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

45. The compound according to claim 1, wherein the compound is selected from... ， ， ， ， ， ， ， ， and And its pharmaceutically acceptable salts.

46. ​​The compound according to claim 1, wherein the compound is M5TFV. (M5TFV), or a pharmaceutically acceptable salt thereof.

47. The compound according to claim 1, wherein the compound is M6TFV. (M6TFV), or a 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 nanoparticles of claim 48, wherein the polymer or surfactant is an amphiphilic block copolymer.

50. The nanoparticles of claim 48, wherein the amphiphilic block copolymer comprises at least one poly(ethylene oxide) block and at least one poly(propylene oxide) block.

51. The nanoparticles according to claim 48, wherein the polymer or surfactant is P407.

52. The nanoparticles according to any one of claims 48-50, wherein the diameter of the nanoparticles is about 100 nm to about 1 μm.

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

54. A method of treating a subject with a viral infection, wherein the method comprises administering to the 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 the viral infection is selected from HIV, hepatitis B, hepatitis C, influenza A, influenza B, herpes simplex, COVID-19, or Ebola virus infection.

56. A method of treating cancer in a subject in need, wherein the method comprises administering to the 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 leukemia, lymphoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, bladder cancer, liver cancer, neuroblastoma, brain cancer, 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 subject with blood clotting disorders, wherein the method comprises administering to the 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 deep vein thrombosis, pulmonary embolism, arterial thrombosis, thrombotic tendency, liver disease, vitamin K deficiency, and von Willebrand disease.

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

61. The method according to any one of claims 54-60, wherein the compound, nanoparticles or pharmaceutical composition is administered once every 1 to 12 months or longer.

Images