Lipid conjugates for systemic delivery, central nervous system delivery, peripheral nervous system delivery, and ocular delivery.

Abstract

This disclosure relates to compounds of formula (I), (II), (III), or (IV): This disclosure provides lipid-based lipid agents, such as JPEG2026515960000164.jpg15886 or pharmaceutically acceptable salts thereof, and related conjugates. The disclosure also relates to the use of lipid-based lipid agents and conjugates, for example, in the delivery of nucleic acids and / or in the treatment or prevention of disease.

Description

[Background technology]

[0001] Related applications This application claims priority and benefit of U.S. Patent Application No. 63 / 499,944, filed on 3 May 2023, and U.S. Patent Application No. 63 / 507,623, filed on 12 June 2023, the entire contents of those applications being incorporated herein by reference.

[0002] Oligonucleotide-based therapies are used as an effective means of regulating gene expression and have received regulatory approval from the FDA. However, one major obstacle hindering their broader clinical application is the lack of effective delivery methods for oligonucleotides to tissues outside the liver or to cell types other than hepatocytes. Therefore, there is still a need in this field for methods to efficiently and specifically deliver oligonucleotides to tissues outside the liver.

[0003] This disclosure addresses this need by designing oligonucleotide conjugates, including natural or modified lipids, that enhance oligonucleotide delivery, cellular uptake, and cellular efficacy, or other performance in extrahepatic tissues, including but not limited to the central nervous system, peripheral nervous system, eye, fat, muscle, heart, and adrenal tissue. [Overview of the project]

[0004] In some embodiments, this disclosure relates to compounds of the following formulas: (I), (II), (III), or (IV): [ka] The present invention provides a lipid ligand agent which is either or a pharmaceutically acceptable salt thereof, in which, L is the lipid portion. B is H, C1-C6 alkyl, or nucleic acid base moiety. V is -O-, -NR V -, or -C(R V) is 2-, each R V is independently H or C1-C6 alkyl optionally substituted with one or more halogens, Q is -(CR a R a ) n -NH-*, where * represents the bond to L, or Q is C6-C 10 arylene or 5- to 10-member heteroarylene, and C6-C 10 arylene or 5- to 10-member heteroarylene is optionally substituted with one or more R Q s, each R Q is independently halogen or C1-C6 alkyl optionally substituted with one or more halogens, X is H, halogen, or -OR X and R X is H, C1-C6 alkyl, or -(C1-C6 alkyl)-(C6-C 10 aryl), and C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 aryl) is optionally substituted with one or more R Xa s, or R X and R 4 together form C1-C6 alkylene, each R Xa is independently halogen, C1-C6 alkyl, or -O-(C1-C6 alkyl), and C1-C6 alkyl or -O-(C1-C6 alkyl) is optionally substituted with one or more halogens, Y is H, C1-C6 alkyl optionally substituted with one or more halogens, -P(R Y )2, -P(OR Y )(N(R Y )2), -P(=O)(OR Y )R Y , -P(=S)(OR Y )R Y , -P(=O)(SR Y )R Y , -P(=S)(SR Y )RY , -P(=O)(OR Y )2, -P(=S)(OR Y )2, -P(=O)(SR Y )2, -P(=S)(SR Y )2, or a hydroxy protecting group, Each R Y These are independently C1-C6 alkyl groups that are optionally substituted with H or one or more halogens or cyano compounds. Z is H, a C1-C6 alkyl group optionally substituted with one or more halogens, -P(R Z )2, -P(OR Z )(N(R Z )2), -P(=O)(OR Z )R Z , -P(=S)(OR Z )R Z -P(=O)(SR Z )R Z -P(=S)(SR Z )R Z , -P(=O)(OR Z )2, -P(=S)(OR Z )2, -P(=O)(SR Z )2, -P(=S)(SR Z )2, or a hydroxy protecting group, Each R Z These are independently C1-C6 alkyl groups that are optionally substituted with H or one or more halogens or cyano compounds. Alternatively, Y and Z in equation (I) or (III) can be combined to form -Si(R L” )2-O-Si(R L” )2- forms, and each R L” These are independently H or C1-C6 alkyl groups. Each R a These are independently C1-C6 alkyl groups that are optionally substituted with H, a halogen, or one or more halogens. R 1 is a C1-C6 alkyl group that is optionally substituted with H, a halogen, or one or more halogens. R 2is a C1-C6 alkyl group that is optionally substituted with H, a halogen, or one or more halogens. R 3 is a C1-C6 alkyl group that is optionally substituted with H, a halogen, or one or more halogens. R 4 is a C1-C6 alkyl group that is optionally substituted with H, a halogen, or one or more halogens, or R 4 and R X They combine to form a C1-C6 alkylene, Each R 5 is independently a C1-C6 alkyl group that is optionally substituted with H, a halogen, or one or more halogens, and n is an integer in the range of approximately 0 to approximately 10.

[0005] In some aspects, this disclosure is, (i) one or more nucleic acid agents, and (ii) Provides a conjugate comprising one or more lipid ligand units or a pharmaceutically acceptable salt thereof, wherein each lipid ligand unit is independently: [ka] During the ceremony, Variables L, B, V, Q, X, R a , n, R Y , R Z , R 1 , R 2 , R 3 , R 4 , and R 5 This is described in this specification, and When the lipid ligand unit is located at the 3' end of the nucleic acid agent, # is a binding to the rest of the conjugate, and ## is H, -P(R Y )2, -P(OR Y )(N(R Y )2), -P(=O)(OR Y )R Y , -P(=S)(OR Y )R Y, -P(=O)(SR Y )R Y , -P(=S)(SR Y )R Y , -P(=O)(OR Y )2, -P(=S)(OR Y )2, -P(=O)(SR Y )2, -P(=S)(SR Y )2, or is a hydroxy protecting group, or when the lipid-based ligand unit is at the 5'-end of the nucleic acid agent, # is H, -P(R Z )2, -P(OR Z )(N(R Z )2), -P(=O)(OR Z )R Z , -P(=S)(OR Z )R Z , -P(=O)(SR Z )R Z , -P(=S)(SR Z )R Z , -P(=O)(OR Z )2, -P(=S)(OR Z )2, -P(=O)(SR Z )2, -P(=S)(SR Z )2, or is a hydroxy protecting group, ## is a bond to the remainder of the conjugate, or # and ## are each independently a bond to the remainder of the conjugate.

[0006] In some embodiments, the present disclosure provides isotope derivatives of the lipid-based ligand agents described herein.

[0007] In some embodiments, the present disclosure provides a pharmaceutical composition comprising the lipid-based ligand agent or conjugate described herein.

[0008] In some embodiments, the present disclosure provides a method of modulating the expression of a target gene in a subject, the method comprising administering to the subject the conjugate described herein.

[0009] In certain embodiments, the Disclosure provides a method for delivering a nucleic acid agent to a subject, which includes administering a conjugate described herein to the subject.

[0010] In certain embodiments, the Disclosure provides a method for treating or preventing a disease in a subject where such treatment is needed, and such method includes administering to the subject a therapeutically effective dose of the conjugate described herein.

[0011] In some embodiments, this disclosure provides conjugates described herein for modulating the expression of a target gene in a subject.

[0012] In some embodiments, the Disclosure provides a conjugate described herein for delivering nucleic acid agents to a subject.

[0013] In some embodiments, the Disclosure provides conjugates described herein for treating or preventing diseases in subjects where such treatment is needed.

[0014] In some embodiments, this disclosure provides the use of the conjugates described herein in the manufacture of pharmaceuticals for modulating the expression of a target gene in a subject.

[0015] In some embodiments, this disclosure provides the use of the conjugates described herein in the manufacture of a pharmaceutical product for delivering nucleic acid agents to a subject.

[0016] In some embodiments, this disclosure provides the use of the conjugates described herein in the manufacture of a pharmaceutical product for treating or preventing a disease in a subject where such treatment is necessary.

[0017] In some embodiments, the disclosure provides compounds that are isotopic derivatives of lipid ligand agents described herein.

[0018] In some embodiments, this disclosure provides pharmaceutical compositions comprising the conjugates described herein.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the subject. In this specification, singular nouns also include plural nouns unless the context clearly indicates otherwise. Methods and substances similar to or equivalent to those described herein may be used in the implementation or testing of this disclosure, but preferred methods and substances are listed below. All published documents, patent applications, patents, and other references referenced herein are incorporated by reference. References cited herein are not considered prior art to the claimed invention. In case of any conflict, including definitions, this specification shall prevail. Furthermore, substances, methods, and examples are illustrative and not intended to be limiting. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0020] The features and advantages of this disclosure will become apparent from the following detailed description and claims. [Brief explanation of the drawing]

[0021] [Figure 1A] Figures 1A–1E show the knockdown of target mRNA in multiple tissues after administration of various lipid conjugates. Data are shown as the percentage of target mRNA remaining in the liver or extrahepatic tissue (i.e., white adipose tissue, brown adipose tissue, adrenal gland, or heart). [Figure 1B] Figures 1A–1E show the knockdown of target mRNA in multiple tissues after administration of various lipid conjugates. Data are shown as the percentage of target mRNA remaining in the liver or extrahepatic tissue (i.e., white adipose tissue, brown adipose tissue, adrenal gland, or heart). [Figure 1C]Figures 1A–1E show the knockdown of target mRNA in multiple tissues after administration of various lipid conjugates. Data are shown as the percentage of target mRNA remaining in the liver or extrahepatic tissue (i.e., white adipose tissue, brown adipose tissue, adrenal gland, or heart). [Figure 1D] Figures 1A–1E show the knockdown of target mRNA in multiple tissues after administration of various lipid conjugates. Data are shown as the percentage of target mRNA remaining in the liver or extrahepatic tissue (i.e., white adipose tissue, brown adipose tissue, adrenal gland, or heart). [Figure 1E] Figures 1A–1E show the knockdown of target mRNA in multiple tissues after administration of various lipid conjugates. Data are shown as the percentage of target mRNA remaining in the liver or extrahepatic tissue (i.e., white adipose tissue, brown adipose tissue, adrenal gland, or heart). [Figure 2A] Figures 2A-2G show the activity of lipid conjugates, indicated by a decrease in target mRNA in the liver and extrahepatic tissues including white fat (gonadal white adipose tissue (gWAT)), brown fat (BAT), adrenal gland, heart, quadriceps femoris (quad), and kidney tissue. [Figure 2B] Figures 2A-2G show the activity of lipid conjugates, indicated by a decrease in target mRNA in the liver and extrahepatic tissues including white fat (gonadal white adipose tissue (gWAT)), brown fat (BAT), adrenal gland, heart, quadriceps femoris (quad), and kidney tissue. [Figure 2C] Figures 2A-2G show the activity of lipid conjugates, indicated by a decrease in target mRNA in the liver and extrahepatic tissues including white fat (gonadal white adipose tissue (gWAT)), brown fat (BAT), adrenal gland, heart, quadriceps femoris (quad), and kidney tissue. [Figure 2D]Figures 2A-2G show the activity of lipid conjugates, indicated by a decrease in target mRNA in the liver and extrahepatic tissues including white fat (gonadal white adipose tissue (gWAT)), brown fat (BAT), adrenal gland, heart, quadriceps femoris (quad), and kidney tissue. [Figure 2E] Figures 2A-2G show the activity of lipid conjugates, indicated by a decrease in target mRNA in the liver and extrahepatic tissues including white fat (gonadal white adipose tissue (gWAT)), brown fat (BAT), adrenal gland, heart, quadriceps femoris (quad), and kidney tissue. [Figure 2F] Figures 2A-2G show the activity of lipid conjugates, indicated by a decrease in target mRNA in the liver and extrahepatic tissues including white fat (gonadal white adipose tissue (gWAT)), brown fat (BAT), adrenal gland, heart, quadriceps femoris (quad), and kidney tissue. [Figure 2G] Figures 2A-2G show the activity of lipid conjugates, indicated by a decrease in target mRNA in the liver and extrahepatic tissues including white fat (gonadal white adipose tissue (gWAT)), brown fat (BAT), adrenal gland, heart, quadriceps femoris (quad), and kidney tissue. [Figure 3] Figure 3 shows an example of the configuration of a linker unit, a lipid ligand unit, and a nucleic acid agent conjugate. Note that the lipid ligand unit is conjugated directly or via the linker unit, and this conjugation may be to one or both strands of the nucleic acid agent (e.g., the sense strand and / or antisense strand). [Figure 4A] Figures 4A-4F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), adrenal gland, heart, and quadriceps femoris (quad) tissue, 11 days after administration of 1 mg / kg, 2 mg / kg, and 4 mg / kg in mice. [Figure 4B]Figures 4A-4F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), adrenal gland, heart, and quadriceps femoris (quad) tissue, 11 days after administration of 1 mg / kg, 2 mg / kg, and 4 mg / kg in mice. [Figure 4C] Figures 4A-4F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), adrenal gland, heart, and quadriceps femoris (quad) tissue, 11 days after administration of 1 mg / kg, 2 mg / kg, and 4 mg / kg in mice. [Figure 4D] Figures 4A-4F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), adrenal gland, heart, and quadriceps femoris (quad) tissue, 11 days after administration of 1 mg / kg, 2 mg / kg, and 4 mg / kg in mice. [Figure 4E] Figures 4A-4F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), adrenal gland, heart, and quadriceps femoris (quad) tissue, 11 days after administration of 1 mg / kg, 2 mg / kg, and 4 mg / kg in mice. [Figure 4F] Figures 4A-4F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), adrenal gland, heart, and quadriceps femoris (quad) tissue, 11 days after administration of 1 mg / kg, 2 mg / kg, and 4 mg / kg in mice. [Figure 5A]Figures 5A-5F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (inguinal white adipose tissue (iWAT), gWAT), brown adipose tissue (BAT), heart, quadriceps femoris (quad), and kidney tissue, 10 days after administration of 2 mg / kg in mice. [Figure 5B] Figures 5A-5F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (inguinal white adipose tissue (iWAT), gWAT), brown adipose tissue (BAT), heart, quadriceps femoris (quad), and kidney tissue, 10 days after administration of 2 mg / kg in mice. [Figure 5C] Figures 5A-5F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (inguinal white adipose tissue (iWAT), gWAT), brown adipose tissue (BAT), heart, quadriceps femoris (quad), and kidney tissue, 10 days after administration of 2 mg / kg in mice. [Figure 5D] Figures 5A-5F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (inguinal white adipose tissue (iWAT), gWAT), brown adipose tissue (BAT), heart, quadriceps femoris (quad), and kidney tissue, 10 days after administration of 2 mg / kg in mice. [Figure 5E] Figures 5A-5F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (inguinal white adipose tissue (iWAT), gWAT), brown adipose tissue (BAT), heart, quadriceps femoris (quad), and kidney tissue, 10 days after administration of 2 mg / kg in mice. [Figure 5F]Figures 5A-5F show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (inguinal white adipose tissue (iWAT), gWAT), brown adipose tissue (BAT), heart, quadriceps femoris (quad), and kidney tissue, 10 days after administration of 2 mg / kg in mice. [Figure 6A] Figures 6A–6E show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), heart, and quadriceps femoris (quad) tissue, 10 days after administration of 0.5 mg / kg and 2.0 mg / kg in mice. [Figure 6B] Figures 6A–6E show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), heart, and quadriceps femoris (quad) tissue, 10 days after administration of 0.5 mg / kg and 2.0 mg / kg in mice. [Figure 6C] Figures 6A–6E show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), heart, and quadriceps femoris (quad) tissue, 10 days after administration of 0.5 mg / kg and 2.0 mg / kg in mice. [Figure 6D] Figures 6A–6E show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), heart, and quadriceps femoris (quad) tissue, 10 days after administration of 0.5 mg / kg and 2.0 mg / kg in mice. [Figure 6E] Figures 6A–6E show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver and extrahepatic tissues, including white adipose tissue (gWAT), brown adipose tissue (BAT), heart, and quadriceps femoris (quad) tissue, 10 days after administration of 0.5 mg / kg and 2.0 mg / kg in mice. [Figure 7A] Figures 7A–7J show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver, as well as in extrahepatic tissues including white fat (gWAT), brown fat (BAT), heart, and quadriceps femoris (quad) at 9 and 35 days after administration of 2 mg / kg in mice. [Figure 7B] Figures 7A–7J show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver, as well as in extrahepatic tissues including white fat (gWAT), brown fat (BAT), heart, and quadriceps femoris (quad) at 9 and 35 days after administration of 2 mg / kg in mice. [Figure 7C] Figures 7A–7J show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver, as well as in extrahepatic tissues including white fat (gWAT), brown fat (BAT), heart, and quadriceps femoris (quad) at 9 and 35 days after administration of 2 mg / kg in mice. [Figure 7D] Figures 7A–7J show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver, as well as in extrahepatic tissues including white fat (gWAT), brown fat (BAT), heart, and quadriceps femoris (quad) at 9 and 35 days after administration of 2 mg / kg in mice. [Figure 7E] Figures 7A–7J show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver, as well as in extrahepatic tissues including white fat (gWAT), brown fat (BAT), heart, and quadriceps femoris (quad) at 9 and 35 days after administration of 2 mg / kg in mice. [Figure 7F] Figures 7A–7J show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver, as well as in extrahepatic tissues including white fat (gWAT), brown fat (BAT), heart, and quadriceps femoris (quad) at 9 and 35 days after administration of 2 mg / kg in mice. [Figure 7G]Figures 7A–7J show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver, as well as in extrahepatic tissues including white fat (gWAT), brown fat (BAT), heart, and quadriceps femoris (quad) at 9 and 35 days after administration of 2 mg / kg in mice. [Figure 7H] Figures 7A–7J show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver, as well as in extrahepatic tissues including white fat (gWAT), brown fat (BAT), heart, and quadriceps femoris (quad) at 9 and 35 days after administration of 2 mg / kg in mice. [Figure 7I] Figures 7A–7J show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver, as well as in extrahepatic tissues including white fat (gWAT), brown fat (BAT), heart, and quadriceps femoris (quad) at 9 and 35 days after administration of 2 mg / kg in mice. [Figure 7J] Figures 7A–7J show the activity of the lipid conjugate, indicated by a decrease in target mRNA in the liver, as well as in extrahepatic tissues including white fat (gWAT), brown fat (BAT), heart, and quadriceps femoris (quad) at 9 and 35 days after administration of 2 mg / kg in mice. [Figure 8A] Figures 8A–8G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 8B] Figures 8A–8G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 8C] Figures 8A–8G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 8D]Figures 8A–8G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 8E] Figures 8A–8G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 8F] Figures 8A–8G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 8G] Figures 8A–8G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 9A] Figures 9A–9G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, heart, and kidneys by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 9B] Figures 9A–9G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, heart, and kidneys by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 9C] Figures 9A–9G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, heart, and kidneys by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 9D] Figures 9A–9G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, heart, and kidneys by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 9E]Figures 9A–9G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, heart, and kidneys by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 9F] Figures 9A–9G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, heart, and kidneys by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 9G] Figures 9A–9G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, heart, and kidneys by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 10A] Figures 10A–10D show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 10B] Figures 10A–10D show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 10C] Figures 10A–10D show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 10D] Figures 10A–10D show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 11A] Figures 11A–11G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 11B] Figures 11A–11G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 11C] Figures 11A–11G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 11D] Figures 11A–11G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 11E] Figures 11A–11G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 11F] Figures 11A–11G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 11G] Figures 11A–11G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, and liver induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 12A] Figures 12A–12G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 12B] Figures 12A–12G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 12C] Figures 12A–12G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 12D] Figures 12A–12G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 12E] Figures 12A–12G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 12F] Figures 12A–12G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 12G] Figures 12A–12G show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 13A] Figures 13A–13D show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 13B] Figures 13A–13D show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 13C]Figures 13A–13D show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 13D] Figures 13A–13D show the conjugated double-strand mRNA knockdown activity in the CNS, PNS, liver, and heart by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 14A] Figures 14A-14B show the mRNA knockdown activity of conjugated double-stranded mRNA in the retina and sclera / RPE layer of mice after a single intravitreal injection (ivt). [Figure 14B] Figures 14A-14B show the mRNA knockdown activity of conjugated double-stranded mRNA in the mouse retina and sclera / RPE layer after a single intravitreal injection (ivt). [Figure 15A] Figures 15A–15D show the conjugated double-strand mRNA knockdown activity in mouse CNS, PNS, and peripheral tissues induced by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 15B] Figures 15A–15D show the conjugated double-strand mRNA knockdown activity in mouse CNS, PNS, and peripheral tissues induced by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 15C] Figures 15A–15D show the conjugated double-strand mRNA knockdown activity in mouse CNS, PNS, and peripheral tissues induced by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 15D] Figures 15A–15D show the conjugated double-strand mRNA knockdown activity in mouse CNS, PNS, and peripheral tissues induced by it injection. Different numbers (#1–4) correspond to data obtained from different mice. [Figure 16A]Figures 16A–16D show the conjugated double-strand mRNA knockdown activity in mouse CNS, PNS, and peripheral tissues induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 16B] Figures 16A–16D show the conjugated double-strand mRNA knockdown activity in mouse CNS, PNS, and peripheral tissues induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 16C] Figures 16A–16D show the conjugated double-strand mRNA knockdown activity in mouse CNS, PNS, and peripheral tissues induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 16D] Figures 16A–16D show the conjugated double-strand mRNA knockdown activity in mouse CNS, PNS, and peripheral tissues induced by icv injection. Different numbers (#1–3) correspond to data obtained from different mice. [Figure 17A] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17B] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17C]Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17D] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17E] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17F] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17G] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17H] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17I] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17J] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17K] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17L]Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 17M] Figures 17A-17M show the knockdown activity of conjugated double strands in various tissues in rat spinocerebellar ducts, deep brain regions, and peripheral tissues by it injection (LSC=lumbar spinal cord, CSC=cervical spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, FC=frontal cortex, HC=hippocampus, TH=thalamus, ST=striatum, Hypo=hypothalamus, L-DRG=left dorsal root ganglion, LV=liver, HT=heart). [Figure 18A] Figures 18A-18H show the mRNA knockdown activity of conjugated double-stranded molecules containing the lipid ligand unit Q-36 in various tissues in mice, including the spinal cord-cerebellar tubule, deep brain regions, and peripheral tissues, induced by ICV injection (LSC=lumbar spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, HC=hippocampus, TH=thalamus). [Figure 18B] Figures 18A-18H show the mRNA knockdown activity of conjugated double-stranded molecules containing the lipid ligand unit Q-36 in various tissues in mice, including the spinal cord-cerebellar tubule, deep brain regions, and peripheral tissues, induced by ICV injection (LSC=lumbar spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, HC=hippocampus, TH=thalamus). [Figure 18C] Figures 18A-18H show the mRNA knockdown activity of conjugated double-stranded molecules containing the lipid ligand unit Q-36 in various tissues in mice, including the spinal cord-cerebellar tubule, deep brain regions, and peripheral tissues, induced by ICV injection (LSC=lumbar spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, HC=hippocampus, TH=thalamus). [Figure 18D]Figures 18A-18H show the mRNA knockdown activity of conjugated double-stranded molecules containing the lipid ligand unit Q-36 in various tissues in mice, including the spinal cord-cerebellar tubule, deep brain regions, and peripheral tissues, induced by ICV injection (LSC=lumbar spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, HC=hippocampus, TH=thalamus). [Figure 18E] Figures 18A-18H show the mRNA knockdown activity of conjugated double-stranded molecules containing the lipid ligand unit Q-36 in various tissues in mice, including the spinal cord-cerebellar tubule, deep brain regions, and peripheral tissues, induced by ICV injection (LSC=lumbar spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, HC=hippocampus, TH=thalamus). [Figure 18F] Figures 18A-18H show the mRNA knockdown activity of conjugated double-stranded molecules containing the lipid ligand unit Q-36 in various tissues in mice, including the spinal cord-cerebellar tubule, deep brain regions, and peripheral tissues, induced by ICV injection (LSC=lumbar spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, HC=hippocampus, TH=thalamus). [Figure 18G] Figures 18A-18H show the mRNA knockdown activity of conjugated double-stranded molecules containing the lipid ligand unit Q-36 in various tissues in mice, including the spinal cord-cerebellar tubule, deep brain regions, and peripheral tissues, induced by ICV injection (LSC=lumbar spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, HC=hippocampus, TH=thalamus). [Figure 18H] Figures 18A-18H show the mRNA knockdown activity of conjugated double-stranded molecules containing the lipid ligand unit Q-36 in various tissues in mice, including the spinal cord-cerebellar tubule, deep brain regions, and peripheral tissues, induced by ICV injection (LSC=lumbar spinal cord, BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, HC=hippocampus, TH=thalamus). [Figure 19A] Figures 19A-19B show the in vivo distribution of conjugated double strands containing the lipid ligand unit Q-36 in mice induced by icv injection, as determined by miRNAscope in situ hybridization assay (BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, HC=hippocampus, TH=thalamus). [Figure 19B] Figures 19A-19B show the in vivo distribution of conjugated double strands containing the lipid ligand unit Q-36 in mice induced by icv injection, as determined by miRNAscope in situ hybridization assay (BS=brainstem, CB=cerebellum, SSC=somatosensory cortex, HC=hippocampus, TH=thalamus). [Modes for carrying out the invention]

[0022] Oligonucleotide-based therapies require efficient and specific delivery to target disease-related tissues or cell types and regulate the expression of disease-related genes. One way to achieve specific targeting is to conjugate a targeting moiety with a nucleic acid (e.g., an oligonucleotide). The targeting moiety can help direct the nucleic acid to the target site and facilitate the internal translocation of the oligonucleotide.

[0023] This disclosure provides lipid-based ligands that can improve the targeted delivery efficiency of oligonucleotides to extrahepatic tissues (e.g., central nervous system (CNS), peripheral nervous system (PNS), eye, fat, muscle, heart, and adrenal tissue) and enhance the efficacy of target gene regulation. This disclosure also provides oligonucleotide conjugates containing lipid-based ligands. Lipid-based ligands can improve the pharmacokinetic properties, receptor-mediated endocytosis, transcytosis, capillary endothelial cell passage, and intracellular activity of oligonucleotides, among other mechanisms and pathways. This disclosure also relates, for example, to the use of lipid-based ligands and conjugates in nucleic acid delivery and / or the treatment or prevention of disease.

[0024] In some embodiments, oligonucleotide conjugates containing lipid-based ligands exhibit higher target delivery efficiency compared to oligonucleotide conjugates without lipid-based ligands.

[0025] In some embodiments, oligonucleotide conjugates containing lipid ligands show improved cellular uptake efficiency compared to oligonucleotides without lipid ligands.

[0026] In some embodiments, conjugates containing lipid-based ligands exhibit improved knockdown activity compared to oligonucleotides without lipid-based ligands.

[0027] In some embodiments, conjugates containing lipid ligands exhibit improved pharmacokinetic (PK) properties compared to oligonucleotides without lipid ligands.

[0028] In some embodiments, conjugates containing lipid ligands exhibit improved selectivity for targeting extrahepatic tissues (e.g., CNS, PNS, eye, fat, muscle, heart, and adrenal tissue) compared to oligonucleotides without lipid ligands.

[0029] In some embodiments, conjugates containing lipid-based ligands exhibit improved selectivity for targeting the CNS, PNS, or eye compared to oligonucleotides without lipid-based ligands.

[0030] In some embodiments, conjugates containing lipid ligands exhibit improved selectivity for targeting adipose tissue, muscle tissue, heart tissue, and adrenal tissue compared to oligonucleotides without lipid ligands.

[0031] Lipid-based ligand agents In some embodiments, this disclosure relates to compounds of the following formulas: (I), (II), (III), or (IV): [ka] The present invention provides a lipid ligand agent which is either or a pharmaceutically acceptable salt thereof, in which, L is the lipid portion. B is H, C1-C6 alkyl, or nucleic acid base moiety. V is -O-, -NR V -, or -C(R V )2-, Each R V These are independently C1-C6 alkyl groups that are optionally substituted with H or one or more halogens. Q is -(CR a R a ) n -NH-*, where * indicates a bond to L, or Q is C6-C 10 Arirene or 5-10 member heteroarirene, C6-C 10 Arirenes or 5-10 member heteroarirenes are one or more R Q It is optionally replaced by, Each R Q These are independently C1-C6 alkyl groups that are optionally substituted with a halogen or one or more halogens. X is H, halogen, or -OR X And, R X This is H, C1-C6 alkyl, or -(C1-C6 alkyl)-(C6-C 10 It is an aryl and C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 A aryl is one or more R(A) at will. Xa Replaced with, or R X and R 4 They combine to form a C1-C6 alkylene, Each R Xa is independently a halogen, a C1-C6 alkyl, or -O-(C1-C6 alkyl), where C1-C6 alkyl or -O-(C1-C6 alkyl) is optionally substituted with one or more halogens. Y is a C1-C6 alkyl group optionally substituted with H, one or more halogens, -P(R Y )2, -P(OR Y )(N(R Y )2), -P(=O)(OR Y )R Y , -P(=S)(OR Y)R Y -P(=O)(SR Y )R Y -P(=S)(SR Y )R Y , -P(=O)(OR Y )2, -P(=S)(OR Y )2, -P(=O)(SR Y )2, -P(=S)(SR Y )2, or a hydroxy protecting group, Each R Y These are independently C1-C6 alkyl groups that are optionally substituted with H or one or more halogens or cyano compounds. Z is H, a C1-C6 alkyl group optionally substituted with one or more halogens, -P(R Z )2, -P(OR Z )(N(R Z )2), -P(=O)(OR Z )R Z , -P(=S)(OR Z )R Z -P(=O)(SR Z )R Z -P(=S)(SR Z )R Z , -P(=O)(OR Z )2, -P(=S)(OR Z )2, -P(=O)(SR Z )2, -P(=S)(SR Z )2, or a hydroxy protecting group, Each R Z These are independently C1-C6 alkyl groups that are optionally substituted with H or one or more halogens or cyano compounds. Alternatively, Y and Z in equation (I) or (III) can be combined to form -Si(R L” )2-O-Si(R L” )2- forms, and each R L” These are independently H or C1-C6 alkyl groups. Each R a These are independently C1-C6 alkyl groups that are optionally substituted with H, a halogen, or one or more halogens. R 1is a C1-C6 alkyl group that is optionally substituted with H, a halogen, or one or more halogens. R 2 is a C1-C6 alkyl group that is optionally substituted with H, a halogen, or one or more halogens. R 3 is a C1-C6 alkyl group that is optionally substituted with H, a halogen, or one or more halogens. R 4 is a C1-C6 alkyl group that is optionally substituted with H, a halogen, or one or more halogens, or R 4 and R X They combine to form a C1-C6 alkylene, Each R 5 is independently a C1-C6 alkyl group that is optionally substituted with H, a halogen, or one or more halogens, and n is an integer in the range of approximately 0 to approximately 10.

[0032] With respect to the compounds disclosed herein, the variables L and R L , R L’ , R L” , R La B, V, R V X, R X , R Xa , Y, R Y , Z, R Z Q, R Q , R a , R 1 , R 2 , R 3 , R 4 , R 5 , and n may, where appropriate, be selected from the bases described herein, as well as any variable L, R L , R L’ , R L” , R La B, V, R V X, R X , R Xa , Y, R Y , Z, R Z Q, R Q , R a , R 1 , R 2 , R3 , R 4 , R 5 Any base described herein with respect to , and n, where appropriate, the variables L, R L , R L’ , R L” , R La B, V, R V X, R X , R Xa , Y, R Y , Z, R Z Q, R Q , R a , R 1 , R 2 , R 3 , R 4 , R 5 , and one or more of the remaining n can be combined with any of the groups described herein.

[0033] Variables L, R L , R L’ , and R La In some embodiments, L is a fatty acid, glycerolipid, glycerophospholipid, sphingolipid, sterol, prenol, or saccharolipid, any derivative thereof, or any part thereof.

[0034] In some embodiments, L is a fatty acid, a derivative thereof, or a portion thereof.

[0035] In some embodiments, L is a glycerolipid, a derivative thereof, or a portion thereof.

[0036] In some embodiments, L is a glycerophospholipid, a derivative thereof, or a portion thereof.

[0037] In some embodiments, L is a sphingolipid, a derivative thereof, or a portion thereof.

[0038] In some embodiments, L is a sterol, a derivative thereof, or a portion thereof.

[0039] In some embodiments, L is prenol, a derivative thereof, or a portion thereof.

[0040] In some embodiments, L is a saccharolipid, a derivative thereof, or a portion thereof.

[0041] In some embodiments, L is -C(=O)R L Or -C(=S)R L And, R L C2-C 200 A hydrocarbon chain or a heterohydrocarbon chain with 2 to 200 members, C2-C 200 A hydrocarbon chain or a heterohydrocarbon chain with 2 to 200 members may optionally contain one or more R L’ Replaced by, Each R L’ These are independently oxo, dihalocarbene, cyano, halogen, -OH, -O(C1-C 12 Alkyl), -O(C6-C 10 aryl), -COOH, -COO(C1-C 12 Alkyl), -CO(C1-C 30 Alkyl), -NHCO(C1-C 30 Alkyl), -CONH2, -CONH(C1-C 12 Alkyl), -CON(C1-C 12 Alkyl)2,-C(O)NHOH,-SO3H,-SO3(C1-C 12 Alkyl), -NH2, -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2,-S(C1-C 12 Alkyl), -S(C6-C 10 Ariel), -P(C6-C 10 aryl)3, -OP(=O)(O - )O-(C1-C 12 Alkylene-NMe3 + , C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10It is an aryl or a 5-10 member heteroaryl, -O(C1-C 12 Alkyl), -O(C6-C 10 Ariel), -COO(C1-C 12 Alkyl), -CO(C1-C 30 Alkyl), -NHCO(C1-C 30 Alkyl), -CONH(C1-C 12 Alkyl), -CON(C1-C 12 Alkyl)2,-SO3(C1-C 12 Alkyl), -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2,-S(C1-C 12 Alkyl), -S(C6-C 10 Ariel), -P(C6-C 10 aryl)3, -OP(=O)(O - )O-(C1-C 12 Alkylene-NMe3 + , C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 Aryls, or 5-10 member heteroaryls, can be optionally selected as one or more R La Replaced by, or Two R's L’ However, together with one or more intervening atoms, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 15 Forms aryls, or 5-15 member heteroaryls, C3-C8 cycloalkyls, 3-8 member heterocycloalkyls, C6-C 15 Aryls, or 5- to 15-membered heteroaryls, can be optionally selected as one or more R La Replaced by, and Each R La These are independently oxo, halogen, -OH, -O(C1-C 12 Alkyl), -SH, -S(C1-C 12 Alkyl), -NH2, -NH(C1-C 12 Alkyl), -N(C1-C 12Alkyl)2, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, one or more C1-C 12 3- to 8-membered heterocycloalkyl groups, C6-C, optionally substituted with alkyl groups. 10 It is an aryl, or a 5- to 10-membered heteroaryl, or Two R's La However, together with one or more intervening atoms, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 They form aryl groups or 5-10 member heteroaryl groups.

[0042] In some embodiments, L is -C(=O)R L And, R L C2-C 200 A hydrocarbon chain or a heterohydrocarbon chain with 2 to 200 members, C2-C 200 A hydrocarbon chain or a heterohydrocarbon chain with 2 to 200 members may optionally contain one or more R L’ Replaced by, Each R L’ These are independently oxo, dihalocarbene, halogen, -OH, -O(C1-C 12 Alkyl), -COOH, -COO(C1-C 12 Alkyl), -CO(C1-C 30 Alkyl), -NHCO(C1-C 30 Alkyl), -NH2, -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2, -OP(=O)(O - )O-(C1-C 12 Alkylene-NMe3 + , C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl, in which case -O(C1-C 12Alkyl), -COO(C1-C 12 Alkyl), -CO(C1-C 30 Alkyl), -NHCO(C1-C 30 Alkyl), -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2, -OP(=O)(O - )O-(C1-C 12 Alkylene-NMe3 + , C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 Aryls, or 5-10 member heteroaryls, can be optionally selected as one or more R La Replaced by, or Two R's L’ However, together with one or more intervening atoms, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 15 Forms aryls, or 5-15 member heteroaryls, C3-C8 cycloalkyls, 3-8 member heterocycloalkyls, C6-C 15 Aryls, or 5- to 15-membered heteroaryls, can be optionally selected as one or more R La Replaced by, and Each R La These are independently oxo, halogen, -OH, -O(C1-C 12 Alkyl), -NH2, -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, one or more C1-C 12 3- to 8-membered heterocycloalkyl groups, C6-C, optionally substituted with alkyl groups. 10 It is an aryl, or a 5- to 10-membered heteroaryl, or Two R's La However, together with one or more intervening atoms, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C10 They form aryl groups or 5-10 member heteroaryl groups.

[0043] In some embodiments, L is -C(=O)R L And, R L C2-C 35 A hydrocarbon chain or a 2-35 member heterohydrocarbon chain, in this case C2-C 35 A hydrocarbon chain or a 2-35 member heterohydrocarbon chain may optionally contain one or more R L’ Replaced by, Each R L’ These are independently oxo, dihalocarbene, halogen, -OH, -O(C1-C 12 Alkyl), -COOH, -COO(C1-C 12 Alkyl), -NHCO(C1-C 30 Alkyl), -NH2, -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl, in which case -O(C1-C 12 Alkyl), -COO(C1-C 12 Alkyl), -NHCO(C1-C 30 Alkyl), -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 An aryl, or a 5-10 member heteroaryl, is one or more R La It is optionally replaced by, or Two R's L’Together with one or more interfacing atoms, it forms a C3-C8 cycloalkyl or a 3-8 membered heterocycloalkyl, in which case the C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is one or more R La It is optionally replaced by, and Each R La These are independently oxo, halogen, -OH, -O(C1-C 12 Alkyl), -NH2, -NH(C1-C 12 Alkyl), or -N(C1-C 12 It is alkyl(2).

[0044] In some embodiments, L is -C(=O)R L Or C(=S)R L And, R L C2-C 30 A hydrocarbon chain or a 2-30 member heterohydrocarbon chain, in this case C2-C 30 A hydrocarbon chain or a 2-30 member heterohydrocarbon chain may have one or more R L’ It is optionally replaced by, Each R L’ These are independently oxo, dihalocarbene, cyano, halogen, -COOH, -COO(C1-C 12 Alkyl), -CONH2, -CONH(C1-C 12 Alkyl), -CON(C1-C 12 Alkyl)2,-C(O)NHOH,-SO3H,-SO3(C1-C 12 Alkyl), -OH, -O(C1-C 12 Alkyl), -O(C6-C 10 aryl), -NH2, -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2,-S(C1-C 12 Alkyl), -S(C6-C 10 Ariel), -P(C6-C 10 Ariel)3, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12Alkynyl, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl, in which case -COO(C1-C 12 Alkyl), -CONH(C1-C 12 Alkyl), -CON(C1-C 12 Alkyl)2,-SO3(C1-C 12 Alkyl), -O(C1-C 12 Alkyl), -O(C6-C 10 Arial), -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2,-S(C1-C 12 Alkyl), -S(C6-C 10 Ariel), -P(C6-C 10 Ariel)3, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 An aryl, or a 5- to 10-membered heteroaryl, contains one or more R La It is optionally replaced by, or Two R's L’ Together with one or more interfacing atoms, it forms a C3-C8 cycloalkyl or a 3-8 membered heterocycloalkyl, in which case the C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is one or more R La It is optionally replaced by, and Each R La These are independently oxo, halogen, -OH, -O(C1-C 12 Alkyl), -SH, -S(C1-C 12 Alkyl), -NH2, -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2, C1-C 12 Alkyl, C2-C 12 Alkenyl, or C2-C 12 It is alkinyl.

[0045] In some embodiments, L is -C(=O)R L And, R L C2-C 30 A hydrocarbon chain or a 2-30 member heterohydrocarbon chain, in this case C2-C 30 A hydrocarbon chain or a 2-30 member heterohydrocarbon chain may have one or more R L’ It is optionally replaced by, Each R L’ These are independently oxo, dihalocarbene, cyano, halogen, -COOH, -COO(C1-C 12 Alkyl), -CONH2, -CONH(C1-C 12 Alkyl), -CON(C1-C 12 Alkyl)2,-C(O)NHOH,-SO3H,-SO3(C1-C 12 Alkyl), -OH, -O(C1-C 12 Alkyl), -O(C6-C 10 aryl), -NH2, -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2,-S(C1-C 12 Alkyl), -S(C6-C 10 Ariel), -P(C6-C 10 Ariel)3, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 It is an aryl or a 5-10 member heteroaryl, in which case -COO(C1-C 12 Alkyl), -CONH(C1-C 12 Alkyl), -CON(C1-C 12 Alkyl)2,-SO3(C1-C 12 Alkyl), -O(C1-C 12 Alkyl), -O(C6-C 10 Arial), -NH(C1-C 12 Alkyl), -N(C1-C 12 Alkyl)2,-S(C1-C 12 Alkyl), -S(C6-C 10Ariel), -P(C6-C 10 Ariel)3, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, 3-8 member heterocycloalkyl, C6-C 10 An aryl, or a 5- to 10-membered heteroaryl, contains one or more R La It is optionally replaced by, or Two R's L’ Together with one or more interfacing atoms, it forms a C3-C8 cycloalkyl or a 3-8 membered heterocycloalkyl, in which case the C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is one or more R La It is optionally replaced by, and Each R La These are independently oxo, halogen, -OH, -O(C1-C 12 Alkyl), -SH, -S(C1-C 12 Alkyl), -NH2, -NH(C1-C 12 Alkyl), or -N(C1-C 12 It is alkyl(2).

[0046] In some embodiments, L is -C(=O)R L In some embodiments, L is -C(=S)R L That is the case.

[0047] In some embodiments, R L C2-C 150 Hydrocarbon chain, C2-C 100 Hydrocarbon chain, or C2-C 50 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0048] In some embodiments, R L C 50 -C 200 hydrocarbon chain, C 100 -C 200 hydrocarbon chain, or C 150 -C 200A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0049] In some embodiments, R L C 50 -C 150 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0050] In some embodiments, R L C2-C 150 Saturated hydrocarbon chain, C2-C 100 Saturated hydrocarbon chain, or C2-C 50 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0051] In some embodiments, R L C 50 -C 200 Saturated hydrocarbon chain, C 100 -C 200 Saturated hydrocarbon chain, or C 150 -C 200 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0052] In some embodiments, R L C 50 -C 150 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0053] In some embodiments, R L C2-C 150 Unsaturated hydrocarbon chain, C2-C 100 Unsaturated hydrocarbon chain, or C2-C 50 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0054] In some embodiments, R L C 50 -C 200 Unsaturated hydrocarbon chain, C 100 -C 200 Unsaturated hydrocarbon chains, or C 150 -C 200 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0055] In some embodiments, R L C 50 -C 150 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0056] In some embodiments, R L is a heterohydrocarbon chain of 2 to 150 members, a heterohydrocarbon chain of 2 to 100 members, or a heterohydrocarbon chain of 2 to 50 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0057] In some embodiments, R L is a heterohydrocarbon chain of 50-200 members, a heterohydrocarbon chain of 100-200 members, or a heterohydrocarbon chain of 150-200 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0058] In some embodiments, R L This is a heterohydrocarbon chain with 50 to 150 members, in which case the heterohydrocarbon chain is one or more R L’ It is optionally replaced.

[0059] In some embodiments, R L is a saturated heterohydrocarbon chain of 2 to 150 members, a saturated heterohydrocarbon chain of 2 to 100 members, or a saturated heterohydrocarbon chain of 2 to 50 members, in which case the heterohydrocarbon chain is one or more RL’ It is optionally replaced.

[0060] In some embodiments, R L This is a saturated heterohydrocarbon chain of 50-200 members, a saturated heterohydrocarbon chain of 100-200 members, or a saturated heterohydrocarbon chain of 150-200 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0061] In some embodiments, R L This is a saturated heterohydrocarbon chain with 50 to 150 members, in which case the heterohydrocarbon chain is one or more R L’ It is optionally replaced.

[0062] In some embodiments, R L This is an unsaturated heterohydrocarbon chain of 2 to 150 members, an unsaturated heterohydrocarbon chain of 2 to 100 members, or an unsaturated heterohydrocarbon chain of 2 to 50 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0063] In some embodiments, R L is a 50-200 member unsaturated heterohydrocarbon chain, a 100-200 member unsaturated heterohydrocarbon chain, or a 150-200 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0064] In some embodiments, R L This is an unsaturated heterohydrocarbon chain with 50 to 150 members, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0065] In some embodiments, R L C 15 -C 35 hydrocarbon chain, C 15 -C 34 hydrocarbon chain, C 15 -C33 hydrocarbon chain, C 15 -C 32 hydrocarbon chain, C 15 -C 31 hydrocarbon chain, C 15 -C 30 hydrocarbon chain, C 15 -C 29 hydrocarbon chain, C 15 -C 28 hydrocarbon chain, or C 15 -C 27 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0066] In some embodiments, R L C 19 -C 35 hydrocarbon chain, C 19 -C 34 hydrocarbon chain, C 19 -C 33 hydrocarbon chain, C 19 -C 32 hydrocarbon chain, C 19 -C 31 hydrocarbon chain, C 19 -C 30 hydrocarbon chain, C 19 -C 29 hydrocarbon chain, or C 19 -C 28 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0067] In some embodiments, R L C 19 -C 27 hydrocarbon chain, C 19 -C 26 hydrocarbon chain, C 19 -C 25 hydrocarbon chain, C 19 -C 24 hydrocarbon chain, C 19 -C 23 hydrocarbon chain, C 19 -C 22 hydrocarbon chain, C 19 -C 21 hydrocarbon chain, or C19 -C 20 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0068] In some embodiments, R L C 16 -C 35 hydrocarbon chain, C 17 -C 35 hydrocarbon chain, C 18 -C 35 hydrocarbon chain, C 19 -C 35 hydrocarbon chain, or C 20 -C 35 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0069] In some embodiments, R L C 21 -C 35 hydrocarbon chain, C 22 -C 35 hydrocarbon chain, C 23 -C 35 hydrocarbon chain, C 24 -C 35 hydrocarbon chain, C 25 -C 35 hydrocarbon chain, C 26 -C 35 hydrocarbon chain, C 27 -C 35 hydrocarbon chain, C 28 -C 35 hydrocarbon chain, C 29 -C 35 hydrocarbon chain, C 30 -C 35 hydrocarbon chain, C 31 -C 35 hydrocarbon chain, C 32 -C 35 hydrocarbon chain, or C 33 -C 35 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced by R. In some embodiments, L C 20 -C27 hydrocarbon chain, C 21 -C 27 hydrocarbon chain, C 22 -C 27 hydrocarbon chain, C 23 -C 27 hydrocarbon chain, C 24 -C 27 hydrocarbon chain, C 25 -C 27 hydrocarbon chain, or C 26 -C 27 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0070] In some embodiments, R L C 16 -C 34 hydrocarbon chain, C 17 -C 33 hydrocarbon chain, C 18 -C 32 hydrocarbon chain, C 19 -C 31 hydrocarbon chain, C 20 -C 30 hydrocarbon chain, C 21 -C 29 hydrocarbon chain, C 22 -C 28 hydrocarbon chain, C 23 -C 27 hydrocarbon chain, or C 24 -C 26 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0071] In some embodiments, R L C 20 -C 34 hydrocarbon chain, C 21 -C 33 hydrocarbon chain, C 22 -C 32 hydrocarbon chain, C 23 -C 31 hydrocarbon chain, C 24 -C 30 hydrocarbon chain, C 25 -C 29 hydrocarbon chain, or C26 -C 28 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0072] In some embodiments, R L C 20 -C 26 hydrocarbon chain, C 21 -C 25 hydrocarbon chain, or C 22 -C 24 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0073] In some embodiments, R L is one or more R L’ C is optionally replaced by 15 -C 34 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 19 -C 23 It is a hydrocarbon chain.

[0074] In some embodiments, R L is one or more R L’ C is optionally replaced by 15 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 16 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 17 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 18 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 19 It is a hydrocarbon chain. In some embodiments, R Lis one or more R L’ C is optionally replaced by 20 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 21 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 22 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 23 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 24 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 25 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 26 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 27 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 28 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 29 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 30 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 31 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by32 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 33 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 34 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 35 It is a hydrocarbon chain.

[0075] In some embodiments, R L C 15 -C 35 Saturated hydrocarbon chain, C 15 -C 34 Saturated hydrocarbon chain, C 15 -C 33 Saturated hydrocarbon chain, C 15 -C 32 Saturated hydrocarbon chain, C 15 -C 31 Saturated hydrocarbon chain, C 15 -C 30 Saturated hydrocarbon chain, C 15 -C 29 Saturated hydrocarbon chain, C 15 -C 28 Saturated hydrocarbon chain, or C 15 -C 27 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0076] In some embodiments, R L C 19 -C 35 Saturated hydrocarbon chain, C 19 -C 34 Saturated hydrocarbon chain, C 19 -C 33 Saturated hydrocarbon chain, C 19 -C 32 Saturated hydrocarbon chain, C 19 -C 31 Saturated hydrocarbon chain, C 19 -C 30 Saturated hydrocarbon chain, C19 -C 29 Saturated hydrocarbon chain, or C 19 -C 28 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0077] In some embodiments, R L C 19 -C 27 Saturated hydrocarbon chain, C 19 -C 26 Saturated hydrocarbon chain, C 19 -C 25 Saturated hydrocarbon chain, C 19 -C 24 Saturated hydrocarbon chain, C 19 -C 23 Saturated hydrocarbon chain, C 19 -C 22 Saturated hydrocarbon chain, C 19 -C 21 Saturated hydrocarbon chain, or C 19 -C 20 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0078] In some embodiments, R L C 16 -C 35 Saturated hydrocarbon chain, C 17 -C 35 Saturated hydrocarbon chain, C 18 -C 35 Saturated hydrocarbon chain, C 19 -C 35 Saturated hydrocarbon chain, or C 20 -C 35 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0079] In some embodiments, R L C 21 -C 35 Saturated hydrocarbon chain, C 22 -C 35 Saturated hydrocarbon chain, C 23 -C35 Saturated hydrocarbon chain, C 24 -C 35 Saturated hydrocarbon chain, C 25 -C 35 Saturated hydrocarbon chain, C 26 -C 35 Saturated hydrocarbon chain, C 27 -C 35 Saturated hydrocarbon chain, C 28 -C 35 Saturated hydrocarbon chain, C 29 -C 35 Saturated hydrocarbon chain, C 30 -C 35 Saturated hydrocarbon chain, C 31 -C 35 Saturated hydrocarbon chain, C 32 -C 35 Saturated hydrocarbon chain, or C 33 -C 35 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0080] In some embodiments, R L C 20 -C 27 Saturated hydrocarbon chain, C 21 -C 27 Saturated hydrocarbon chain, C 22 -C 27 Saturated hydrocarbon chain, C 23 -C 27 Saturated hydrocarbon chain, C 24 -C 27 Saturated hydrocarbon chain, C 25 -C 27 Saturated hydrocarbon chain, or C 26 -C 27 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0081] In some embodiments, R L C 16 -C 34 Saturated hydrocarbon chain, C 17 -C 33 Saturated hydrocarbon chain, C 18 -C 32 Saturated hydrocarbon chain, C19 -C 31 Saturated hydrocarbon chain, C 20 -C 30 Saturated hydrocarbon chain, C 21 -C 29 Saturated hydrocarbon chain, C 22 -C 28 Saturated hydrocarbon chain, C 23 -C 27 Saturated hydrocarbon chain, or C 24 -C 26 Is a saturated hydrocarbon chain, in which case the hydrocarbon chain is optionally substituted with one or more R L’ s.

[0082] In some embodiments, R L is C 20 -C 34 Saturated hydrocarbon chain, C 21 -C 33 Saturated hydrocarbon chain, C 22 -C 32 Saturated hydrocarbon chain, C 23 -C 31 Saturated hydrocarbon chain, C 24 -C 30 Saturated hydrocarbon chain, C 25 -C 29 Saturated hydrocarbon chain, or C 26 -C 28 Is a saturated hydrocarbon chain, in which case the hydrocarbon chain is optionally substituted with one or more R L’ s.

[0083] In some embodiments, R L is C 20 -C 26 Saturated hydrocarbon chain, C 21 -C 25 Saturated hydrocarbon chain, or C 22 -C 24 Is a saturated hydrocarbon chain, in which case the hydrocarbon chain is optionally substituted with one or more R L’ s.

[0084] In some embodiments, R L is optionally substituted with one or more R L’ s C 15 -C34 It is a saturated hydrocarbon chain. In some embodiments, R L is a C L’ -C 19 -C 23 saturated hydrocarbon chain optionally substituted with one or more R

[0085] In some embodiments, R L is a C L’ -C 15 saturated hydrocarbon chain optionally substituted with one or more R L In some embodiments, R L’ is a C 16 -C L saturated hydrocarbon chain optionally substituted with one or more R L’ In some embodiments, R 17 is a C L -C L’ saturated hydrocarbon chain optionally substituted with one or more R 18 In some embodiments, R L is a C L’ -C 19 saturated hydrocarbon chain optionally substituted with one or more R L In some embodiments, R L’ is a C 20 -C L saturated hydrocarbon chain optionally substituted with one or more R L’ In some embodiments, R 21 is a C L -C[[ID=5S]] L’ saturated hydrocarbon chain optionally substituted with one or more R 22 In some embodiments, R L is a C L’ -C 23 saturated hydrocarbon chain optionally substituted with one or more R L In some embodiments, R L’ is a C 24 -C L saturated hydrocarbon chain optionally substituted with one or more Ris C optionally substituted with one or more R L’ and is a saturated hydrocarbon chain. In some embodiments, R 25 is C optionally substituted with one or more R L and is a saturated hydrocarbon chain. In some embodiments, R L’ is C optionally substituted with one or more R 26 and is a saturated hydrocarbon chain. In some embodiments, R L is C optionally substituted with one or more R L’ and is a saturated hydrocarbon chain. In some embodiments, R 27 is C optionally substituted with one or more R L and is a saturated hydrocarbon chain. In some embodiments, R L’ is C optionally substituted with one or more R 28 and is a saturated hydrocarbon chain. In some embodiments, R L is C optionally substituted with one or more R L’ and is a saturated hydrocarbon chain. In some embodiments, R 29 is C optionally substituted with one or more R L and is a saturated hydrocarbon chain. In some embodiments, R L’ is C optionally substituted with one or more R 30 and is a saturated hydrocarbon chain. In some embodiments, R L is C optionally substituted with one or more R L’ and is a saturated hydrocarbon chain. In some embodiments, R 31 is C optionally substituted with one or more R L and is a saturated hydrocarbon chain. In some embodiments, R L’ is C optionally substituted with one or more R 32 and is a saturated hydrocarbon chain. In some embodiments, R L is C optionally substituted with one or more R L’ and is a saturated hydrocarbon chain. In some embodiments, R 33 is C optionally substituted with one or more R L [[ID=​​​​​​​​​​​​​​​​​​​​​​34 Unsaturated hydrocarbon chain, C 15 -C 33 Unsaturated hydrocarbon chain, C 15 -C 32 Unsaturated hydrocarbon chain, C 15 -C 31 Unsaturated hydrocarbon chain, C 15 -C 30 Unsaturated hydrocarbon chain, C 15 -C 29 Unsaturated hydrocarbon chain, C 15 -C 28 Unsaturated hydrocarbon chains, or C 15 -C 27 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0087] In some embodiments, R L C 19 -C 35 Unsaturated hydrocarbon chain, C 19 -C 34 Unsaturated hydrocarbon chain, C 19 -C 33 Unsaturated hydrocarbon chain, C 19 -C 32 Unsaturated hydrocarbon chain, C 19 -C 31 Unsaturated hydrocarbon chain, C 19 -C 30 Unsaturated hydrocarbon chain, C 19 -C 29 Unsaturated hydrocarbon chains, or C 19 -C 28 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0088] In some embodiments, R L C 19 -C 27 Unsaturated hydrocarbon chain, C 19 -C 26 Unsaturated hydrocarbon chain, C 19 -C 25 Unsaturated hydrocarbon chain, C 19 -C 24 Unsaturated hydrocarbon chain, C 19 -C23 Unsaturated hydrocarbon chain, C 19 -C 22 Unsaturated hydrocarbon chain, C 19 -C 21 Unsaturated hydrocarbon chains, or C 19 -C 20 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0089] In some embodiments, R L C 16 -C 35 Unsaturated hydrocarbon chain, C 17 -C 35 Unsaturated hydrocarbon chain, C 18 -C 35 Unsaturated hydrocarbon chain, C 19 -C 35 Unsaturated hydrocarbon chains, or C 20 -C 35 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0090] In some embodiments, R L C 21 -C 35 Unsaturated hydrocarbon chain, C 22 -C 35 Unsaturated hydrocarbon chain, C 23 -C 35 Unsaturated hydrocarbon chain, C 24 -C 35 Unsaturated hydrocarbon chain, C 25 -C 35 Unsaturated hydrocarbon chain, C 26 -C 35 Unsaturated hydrocarbon chain, C 27 -C 35 Unsaturated hydrocarbon chain, C 28 -C 35 Unsaturated hydrocarbon chain, C 29 -C 35 Unsaturated hydrocarbon chain, C 30 -C 35 Unsaturated hydrocarbon chain, C 31 -C 35 Unsaturated hydrocarbon chain, C 32 -C35 Unsaturated hydrocarbon chains, or C 33 -C 35 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0091] In some embodiments, R L C 20 -C 27 Unsaturated hydrocarbon chain, C 21 -C 27 Unsaturated hydrocarbon chain, C 22 -C 27 Unsaturated hydrocarbon chain, C 23 -C 27 Unsaturated hydrocarbon chain, C 24 -C 27 Unsaturated hydrocarbon chain, C 25 -C 27 Unsaturated hydrocarbon chains, or C 26 -C 27 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0092] In some embodiments, R L C 16 -C 34 Unsaturated hydrocarbon chain, C 17 -C 33 Unsaturated hydrocarbon chain, C 18 -C 32 Unsaturated hydrocarbon chain, C 19 -C 31 Unsaturated hydrocarbon chain, C 20 -C 30 Unsaturated hydrocarbon chain, C 21 -C 29 Unsaturated hydrocarbon chain, C 22 -C 28 Unsaturated hydrocarbon chain, C 23 -C 27 Unsaturated hydrocarbon chains, or C 24 -C 26 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0093] In some embodiments, R L C 20 -C 34 Unsaturated hydrocarbon chain, C 21 -C 33 Unsaturated hydrocarbon chain, C 22 -C 32 Unsaturated hydrocarbon chain, C 23 -C 31 Unsaturated hydrocarbon chain, C 24 -C 30 Unsaturated hydrocarbon chain, C 25 -C 29 Unsaturated hydrocarbon chains, or C 26 -C 28 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0094] In some embodiments, R L C 20 -C 26 Unsaturated hydrocarbon chain, C 21 -C 25 Unsaturated hydrocarbon chains, or C 22 -C 24 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0095] In some embodiments, R L is one or more R L’ C is optionally replaced by 15 -C 34 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 19 -C 23 It is an unsaturated hydrocarbon chain.

[0096] In some embodiments, R L is one or more R L’ C is optionally replaced by 15 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by16 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 17 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 18 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 19 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 20 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 21 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 22 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 23 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 24 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 25 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 26 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 27 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by28 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 29 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 30 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 31 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 32 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 33 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 34 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 35 It is an unsaturated hydrocarbon chain.

[0097] In some embodiments, R L is one or more R L’ It is a hydrocarbon chain that is optionally substituted.

[0098] In some embodiments, R L is one or more R L’ It is a saturated hydrocarbon chain that is optionally substituted.

[0099] In some embodiments, R L is one or more R L’ It is an unsaturated hydrocarbon chain that is optionally substituted.

[0100] In some embodiments, R LThis is a heterohydrocarbon chain with 15-35 members, 15-34 members, 15-33 members, 15-32 members, 15-31 members, 15-30 members, 15-29 members, 15-28 members, or 15-27 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0101] In some embodiments, R L This is a heterohydrocarbon chain with 19 to 35 members, 19 to 34 members, 19 to 33 members, 19 to 32 members, 19 to 31 members, 19 to 30 members, 19 to 29 members, or 19 to 28 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0102] In some embodiments, R L This is a heterohydrocarbon chain with 19 to 27 members, 19 to 26 members, 19 to 25 members, 19 to 24 members, 19 to 23 members, 19 to 22 members, 19 to 21 members, or 19 to 20 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0103] In some embodiments, R L is a heterohydrocarbon chain with 16-35 members, 17-35 members, 18-35 members, 19-35 members, or 20-35 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0104] In some embodiments, R LThis is a heterohydrocarbon chain with 21-35 members, 22-35 members, 23-35 members, 24-35 members, 25-35 members, 26-35 members, 27-35 members, 28-35 members, 29-35 members, 30-35 members, 31-35 members, 32-35 members, or 33-35 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0105] In some embodiments, R L is a heterohydrocarbon chain of 20-27 members, 21-27 members, 22-27 members, 23-27 members, 24-27 members, 25-27 members, or 26-27 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0106] In some embodiments, R L This is a heterohydrocarbon chain with 16-34 members, 17-33 members, 18-32 members, 19-31 members, 20-30 members, 21-29 members, 22-28 members, 23-27 members, or 24-26 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0107] In some embodiments, R L This is a heterohydrocarbon chain with 20-34 members, 21-33 members, 22-32 members, 23-31 members, 24-30 members, 25-29 members, or 26-28 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0108] In some embodiments, R L is a heterohydrocarbon chain with 20 to 26 members, a heterohydrocarbon chain with 21 to 25 members, or a heterohydrocarbon chain with 22 to 24 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0109] In some embodiments, R L is one or more R L’ It is a 15-34 member heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 19-23 member heterohydrocarbon chain that is optionally substituted.

[0110] In some embodiments, R L is one or more R L’ It is a 15-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 16-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 17-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is an 18-member heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 19-member heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 20-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 21-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 22-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments,L is one or more R L’ It is a 23-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 24-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 25-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 26-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 27-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 28-member heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 29-member heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 30-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 31-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 32-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 33-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 34-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 35-membered heterohydrocarbon chain that is optionally substituted.

[0111] In some embodiments, R LThis is a saturated heterohydrocarbon chain of 15-35 members, a saturated heterohydrocarbon chain of 15-34 members, a saturated heterohydrocarbon chain of 15-33 members, a saturated heterohydrocarbon chain of 15-32 members, a saturated heterohydrocarbon chain of 15-31 members, a saturated heterohydrocarbon chain of 15-30 members, a saturated heterohydrocarbon chain of 15-29 members, a saturated heterohydrocarbon chain of 15-28 members, or a saturated heterohydrocarbon chain of 15-27 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0112] In some embodiments, R L This is a saturated heterohydrocarbon chain with 19 to 35 members, a saturated heterohydrocarbon chain with 19 to 34 members, a saturated heterohydrocarbon chain with 19 to 33 members, a saturated heterohydrocarbon chain with 19 to 32 members, a saturated heterohydrocarbon chain with 19 to 31 members, a saturated heterohydrocarbon chain with 19 to 30 members, a saturated heterohydrocarbon chain with 19 to 29 members, or a saturated heterohydrocarbon chain with 19 to 28 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0113] In some embodiments, R L This is a saturated heterohydrocarbon chain with 19 to 27 members, a saturated heterohydrocarbon chain with 19 to 26 members, a saturated heterohydrocarbon chain with 19 to 25 members, a saturated heterohydrocarbon chain with 19 to 24 members, a saturated heterohydrocarbon chain with 19 to 23 members, a saturated heterohydrocarbon chain with 19 to 22 members, a saturated heterohydrocarbon chain with 19 to 21 members, or a saturated heterohydrocarbon chain with 19 to 20 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0114] In some embodiments, R L This is a saturated heterohydrocarbon chain of 16-35 members, a saturated heterohydrocarbon chain of 17-35 members, a saturated heterohydrocarbon chain of 18-35 members, a saturated heterohydrocarbon chain of 19-35 members, or a saturated heterohydrocarbon chain of 20-35 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0115] In some embodiments, R L This is a saturated heterohydrocarbon chain with 21-35 members, 22-35 members, 23-35 members, 24-35 members, 25-35 members, 26-35 members, 27-35 members, 28-35 members, 29-35 members, 30-35 members, 31-35 members, 32-35 members, or 33-35 members, in which case the heterohydrocarbon chain is one or more R L’ It is optionally replaced.

[0116] In some embodiments, R L This is a saturated heterohydrocarbon chain of 20-27 members, a saturated heterohydrocarbon chain of 21-27 members, a saturated heterohydrocarbon chain of 22-27 members, a saturated heterohydrocarbon chain of 23-27 members, a saturated heterohydrocarbon chain of 24-27 members, a saturated heterohydrocarbon chain of 25-27 members, or a saturated heterohydrocarbon chain of 26-27 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0117] In some embodiments, R L This refers to a saturated heterohydrocarbon chain with 16-34 members, 17-33 members, 18-32 members, 19-31 members, 20-30 members, 21-29 members, 22-28 members, 23-27 members, or 24-26 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0118] In some embodiments, R LThis is a saturated heterohydrocarbon chain with 20-34 members, 21-33 members, 22-32 members, 23-31 members, 24-30 members, 25-29 members, or 26-28 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0119] In some embodiments, R L This is a saturated heterohydrocarbon chain with 20-26 members, a saturated heterohydrocarbon chain with 21-25 members, or a saturated heterohydrocarbon chain with 22-24 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0120] In some embodiments, R L is one or more R L’ It is a 15-34 member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 19-23 member saturated heterohydrocarbon chain that is optionally substituted.

[0121] In some embodiments, R L is one or more R L’ It is a 15-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 16-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 17-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is an 18-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 19-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, Lis one or more R L’ It is a 20-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 21-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 22-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 23-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 24-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 25-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 26-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 27-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 28-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 29-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 30-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 31-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 32-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’It is a 33-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 34-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 35-membered saturated heterohydrocarbon chain that is optionally substituted.

[0122] In some embodiments, R L This is a 15-35 member unsaturated heterohydrocarbon chain, a 15-34 member unsaturated heterohydrocarbon chain, a 15-33 member unsaturated heterohydrocarbon chain, a 15-32 member unsaturated heterohydrocarbon chain, a 15-31 member unsaturated heterohydrocarbon chain, a 15-30 member unsaturated heterohydrocarbon chain, a 15-29 member unsaturated heterohydrocarbon chain, a 15-28 member unsaturated heterohydrocarbon chain, or a 15-27 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0123] In some embodiments, R L This is an unsaturated heterohydrocarbon chain with 19 to 35 members, 19 to 34 members, 19 to 33 members, 19 to 32 members, 19 to 31 members, 19 to 30 members, 19 to 29 members, or 19 to 28 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0124] In some embodiments, R L This is a 19-27 member unsaturated heterohydrocarbon chain, a 19-26 member unsaturated heterohydrocarbon chain, a 19-25 member unsaturated heterohydrocarbon chain, a 19-24 member unsaturated heterohydrocarbon chain, a 19-23 member unsaturated heterohydrocarbon chain, a 19-22 member unsaturated heterohydrocarbon chain, a 19-21 member unsaturated heterohydrocarbon chain, or a 19-20 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more RL’ It is optionally replaced.

[0125] In some embodiments, R L This is an unsaturated heterohydrocarbon chain with 16 to 35 members, 17 to 35 members, 18 to 35 members, 19 to 35 members, or 20 to 35 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0126] In some embodiments, R L This is a 21-35 member unsaturated heterohydrocarbon chain, a 22-35 member unsaturated heterohydrocarbon chain, a 23-35 member unsaturated heterohydrocarbon chain, a 24-35 member unsaturated heterohydrocarbon chain, a 25-35 member unsaturated heterohydrocarbon chain, a 26-35 member unsaturated heterohydrocarbon chain, a 27-35 member unsaturated heterohydrocarbon chain, a 28-35 member unsaturated heterohydrocarbon chain, a 29-35 member unsaturated heterohydrocarbon chain, a 30-35 member unsaturated heterohydrocarbon chain, a 31-35 member unsaturated heterohydrocarbon chain, a 32-35 member unsaturated heterohydrocarbon chain, or a 33-35 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain is one or more R L’ It is optionally replaced.

[0127] In some embodiments, R L This is a 20-27 member unsaturated heterohydrocarbon chain, a 21-27 member unsaturated heterohydrocarbon chain, a 22-27 member unsaturated heterohydrocarbon chain, a 23-27 member unsaturated heterohydrocarbon chain, a 24-27 member unsaturated heterohydrocarbon chain, a 25-27 member unsaturated heterohydrocarbon chain, or a 26-27 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0128] In some embodiments, R LThis is an unsaturated heterohydrocarbon chain with 16-34 members, 17-33 members, 18-32 members, 19-31 members, 20-30 members, 21-29 members, 22-28 members, 23-27 members, or 24-26 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0129] In some embodiments, R L This is a 20-34 member unsaturated heterohydrocarbon chain, a 21-33 member unsaturated heterohydrocarbon chain, a 22-32 member unsaturated heterohydrocarbon chain, a 23-31 member unsaturated heterohydrocarbon chain, a 24-30 member unsaturated heterohydrocarbon chain, a 25-29 member unsaturated heterohydrocarbon chain, or a 26-28 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0130] In some embodiments, R L is a 20-26 member unsaturated heterohydrocarbon chain, a 21-25 member unsaturated heterohydrocarbon chain, or a 22-24 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0131] In some embodiments, R L is one or more R L’ It is a 15-34 member unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 19-23 member unsaturated heterohydrocarbon chain that is optionally substituted.

[0132] In some embodiments, R L is one or more R L’ It is a 15-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, Lis one or more R L’ It is a 16-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 17-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is an 18-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 19-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 20-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 21-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 22-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 23-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 24-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 25-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 26-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 27-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 28-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more RL’ It is a 29-member unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 30-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 31-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 32-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 33-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 34-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 35-membered unsaturated heterohydrocarbon chain that is optionally substituted.

[0133] In some embodiments, R L C9-C 21 Hydrocarbon chain, C9-C 20 Hydrocarbon chain, C9-C 19 Hydrocarbon chain, C9-C 18 Hydrocarbon chain, C9-C 17 Hydrocarbon chain, C9-C 16 Hydrocarbon chain, C9-C 15 hydrocarbon chain, or C9-C 14 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0134] In some embodiments, R L C 13 -C 21 hydrocarbon chain, C 13 -C 20 hydrocarbon chain, C 13 -C 19 hydrocarbon chain, C 13 -C 18hydrocarbon chain, C 13 -C 17 hydrocarbon chain, C 13 -C 16 hydrocarbon chain, C 13 -C 15 hydrocarbon chain, or C 13 -C 14 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0135] In some embodiments, R L C 10 -C 21 hydrocarbon chain, C 11 -C 21 hydrocarbon chain, C 12 -C 21 hydrocarbon chain, or C 13 -C 21 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0136] In some embodiments, R L C 14 -C 21 hydrocarbon chain, C 15 -C 21 hydrocarbon chain, C 16 -C 21 hydrocarbon chain, C 17 -C 21 hydrocarbon chain, C 18 -C 21 hydrocarbon chain, C 19 -C 21 hydrocarbon chain, or C 20 -C 21 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0137] In some embodiments, R L C 10 -C 20 hydrocarbon chain, C 11 -C 19 hydrocarbon chain, C 12 -C 18 hydrocarbon chain, C13 -C 17 hydrocarbon chain, or C 14 -C 16 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0138] In some embodiments, R L C 14 -C 20 hydrocarbon chain, C 15 -C 19 hydrocarbon chain, or C 16 -C 18 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0139] In some embodiments, R L C 13 -C 20 hydrocarbon chain or C 14 -C 19 A hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0140] In some embodiments, R L is one or more R L’ It is a C9 hydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ C is optionally replaced by 10 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 11 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 12 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 13 It is a hydrocarbon chain. In some embodiments, R L is one or more RL’ C is optionally replaced by 14 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 15 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 16 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 17 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 18 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 19 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 20 It is a hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 21 It is a hydrocarbon chain.

[0141] In some embodiments, R L C9-C 21 Saturated hydrocarbon chain, C9-C 20 Saturated hydrocarbon chain, C9-C 19 Saturated hydrocarbon chain, C9-C 18 Saturated hydrocarbon chain, C9-C 17 Saturated hydrocarbon chain, C9-C 16 Saturated hydrocarbon chain, C9-C 15 Saturated hydrocarbon chain, or C9-C 14 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0142] In some embodiments, R L C13 -C 21 Saturated hydrocarbon chain, C 13 -C 20 Saturated hydrocarbon chain, C 13 -C 19 Saturated hydrocarbon chain, C 13 -C 18 Saturated hydrocarbon chain, C 13 -C 17 Saturated hydrocarbon chain, C 13 -C 16 Saturated hydrocarbon chain, C 13 -C 15 Saturated hydrocarbon chain, or C 13 -C 14 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0143] In some embodiments, R L C 10 -C 21 Saturated hydrocarbon chain, C 11 -C 21 Saturated hydrocarbon chain, C 12 -C 21 Saturated hydrocarbon chain, or C 13 -C 21 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0144] In some embodiments, R L C 14 -C 21 Saturated hydrocarbon chain, C 15 -C 21 Saturated hydrocarbon chain, C 16 -C 21 Saturated hydrocarbon chain, C 17 -C 21 Saturated hydrocarbon chain, C 18 -C 21 Saturated hydrocarbon chain, C 19 -C 21 Saturated hydrocarbon chain, or C 20 -C 21 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0145] In some embodiments, R L C 10 -C 20 Saturated hydrocarbon chain, C 11 -C 19 Saturated hydrocarbon chain, C 12 -C 18 Saturated hydrocarbon chain, C 13 -C 17 Saturated hydrocarbon chain, or C 14 -C 16 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0146] In some embodiments, R L C 14 -C 20 Saturated hydrocarbon chain, C 15 -C 19 Saturated hydrocarbon chain, or C 16 -C 18 A saturated hydrocarbon chain, in this case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0147] In some embodiments, R L is one or more R L’ C is optionally replaced by 13 -C 20 Saturated hydrocarbon chain or C 14 -C 19 It is a saturated hydrocarbon chain.

[0148] In some embodiments, R L is one or more R L’ It is a C9 saturated hydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ C is optionally replaced by 10 It is a saturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 11 It is a saturated hydrocarbon chain. In some embodiments, RL is one or more R L’ C is optionally replaced by 12 It is a saturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 13 It is a saturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 14 It is a saturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 15 It is a saturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 16 It is a saturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 17 It is a saturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 18 It is a saturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 19 It is a saturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 20 It is a saturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 21 It is a saturated hydrocarbon chain.

[0149] In some embodiments, R L C9-C 21 Unsaturated hydrocarbon chain, C9-C 20 Unsaturated hydrocarbon chain, C9-C 19 Unsaturated hydrocarbon chain, C9-C 18 Unsaturated hydrocarbon chain, C9-C 17Unsaturated hydrocarbon chain, C9-C 16 Unsaturated hydrocarbon chain, C9-C 15 Unsaturated hydrocarbon chain, or C9-C 14 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0150] In some embodiments, R L C 13 -C 21 Unsaturated hydrocarbon chain, C 13 -C 20 Unsaturated hydrocarbon chain, C 13 -C 19 Unsaturated hydrocarbon chain, C 13 -C 18 Unsaturated hydrocarbon chain, C 13 -C 17 Unsaturated hydrocarbon chain, C 13 -C 16 Unsaturated hydrocarbon chain, C 13 -C 15 Unsaturated hydrocarbon chains, or C 13 -C 14 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0151] In some embodiments, R L C 10 -C 21 Unsaturated hydrocarbon chain, C 11 -C 21 Unsaturated hydrocarbon chain, C 12 -C 21 Unsaturated hydrocarbon chains, or C 13 -C 21 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0152] In some embodiments, R L C 14 -C 21 Unsaturated hydrocarbon chain, C 15 -C 21 Unsaturated hydrocarbon chain, C 16 -C21 Unsaturated hydrocarbon chain, C 17 -C 21 Unsaturated hydrocarbon chain, C 18 -C 21 Unsaturated hydrocarbon chain, C 19 -C 21 Unsaturated hydrocarbon chains, or C 20 -C 21 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0153] In some embodiments, R L C 10 -C 20 Unsaturated hydrocarbon chain, C 11 -C 19 Unsaturated hydrocarbon chain, C 12 -C 18 Unsaturated hydrocarbon chain, C 13 -C 17 Unsaturated hydrocarbon chains, or C 14 -C 16 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0154] In some embodiments, R L C 14 -C 20 Unsaturated hydrocarbon chain, C 15 -C 19 Unsaturated hydrocarbon chains, or C 16 -C 18 It is an unsaturated hydrocarbon chain, in which case the hydrocarbon chain is one or more R L’ It is optionally replaced.

[0155] In some embodiments, R L is one or more R L’ C is optionally replaced by 13 -C 20 Unsaturated hydrocarbon chains or C 14 -C 19 It is an unsaturated hydrocarbon chain.

[0156] In some embodiments, RL is one or more R L’ It is a C9 unsaturated hydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ C is optionally replaced by 10 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 11 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 12 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 13 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 14 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 15 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 16 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 17 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 18 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 19 It is an unsaturated hydrocarbon chain. In some embodiments, R L is one or more R L’ C is optionally replaced by 20 It is an unsaturated hydrocarbon chain. In some embodiments, R Lis one or more R L’ C is optionally replaced by 21 It is an unsaturated hydrocarbon chain.

[0157] In some embodiments, R L is a heterohydrocarbon chain with 9 to 21 members, 9 to 20 members, 9 to 19 members, 9 to 18 members, 9 to 17 members, 9 to 16 members, 9 to 15 members, or 9 to 14 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0158] In some embodiments, R L This is a heterohydrocarbon chain with 13 to 21 members, 13 to 20 members, 13 to 19 members, 13 to 18 members, 13 to 17 members, 13 to 16 members, 13 to 15 members, or 13 to 14 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0159] In some embodiments, R L is a heterohydrocarbon chain with 10 to 21 members, an heterohydrocarbon chain with 11 to 21 members, an heterohydrocarbon chain with 12 to 21 members, or an heterohydrocarbon chain with 13 to 21 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0160] In some embodiments, R L is a heterohydrocarbon chain with 14 to 21 members, 15 to 21 members, 16 to 21 members, 17 to 21 members, 18 to 21 members, 19 to 21 members, or 20 to 21 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0161] In some embodiments, R L This is a heterohydrocarbon chain with 10-20 members, 11-19 members, 12-18 members, 13-17 members, or 14-16 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0162] In some embodiments, R L is a heterohydrocarbon chain with 14 to 20 members, a heterohydrocarbon chain with 15 to 19 members, or a heterohydrocarbon chain with 16 to 18 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0163] In some embodiments, R L is one or more RLs ’ The heterohydrocarbon chains are 13-20 member or 14-19 member, which are optionally substituted.

[0164] In some embodiments, R L is one or more R L’ It is a 9-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 10-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is an 11-member heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 12-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 13-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 14-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’It is a 15-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 16-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 17-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is an 18-member heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 19-member heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 20-membered heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 21-membered heterohydrocarbon chain that is optionally substituted.

[0165] In some embodiments, R L This is a saturated heterohydrocarbon chain with 9 to 21 members, a saturated heterohydrocarbon chain with 9 to 20 members, a saturated heterohydrocarbon chain with 9 to 19 members, a saturated heterohydrocarbon chain with 9 to 18 members, a saturated heterohydrocarbon chain with 9 to 17 members, a saturated heterohydrocarbon chain with 9 to 16 members, a saturated heterohydrocarbon chain with 9 to 15 members, or a saturated heterohydrocarbon chain with 9 to 14 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0166] In some embodiments, R L This is a saturated heterohydrocarbon chain with 13 to 21 members, a saturated heterohydrocarbon chain with 13 to 20 members, a saturated heterohydrocarbon chain with 13 to 19 members, a saturated heterohydrocarbon chain with 13 to 18 members, a saturated heterohydrocarbon chain with 13 to 17 members, a saturated heterohydrocarbon chain with 13 to 16 members, a saturated heterohydrocarbon chain with 13 to 15 members, or a saturated heterohydrocarbon chain with 13 to 14 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0167] In some embodiments, R L is a saturated heterohydrocarbon chain of 10-21 members, a saturated heterohydrocarbon chain of 11-21 members, a saturated heterohydrocarbon chain of 12-21 members, or a saturated heterohydrocarbon chain of 13-21 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0168] In some embodiments, R L This is a saturated heterohydrocarbon chain with 14 to 21 members, a saturated heterohydrocarbon chain with 15 to 21 members, a saturated heterohydrocarbon chain with 16 to 21 members, a saturated heterohydrocarbon chain with 17 to 21 members, a saturated heterohydrocarbon chain with 18 to 21 members, a saturated heterohydrocarbon chain with 19 to 21 members, or a saturated heterohydrocarbon chain with 20 to 21 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0169] In some embodiments, R L This is a saturated heterohydrocarbon chain of 10-20 members, 11-19 members, 12-18 members, 13-17 members, or 14-16 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0170] In some embodiments, R L This is a saturated heterohydrocarbon chain with 14-20 members, a saturated heterohydrocarbon chain with 15-19 members, or a saturated heterohydrocarbon chain with 16-18 members, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0171] In some embodiments, R L is one or more RLs ’ The substituted members are either 13-20 member saturated heterohydrocarbon chains or 14-19 member saturated heterohydrocarbon chains, which are optionally substituted.

[0172] In some embodiments, R L is one or more R L’ It is a 9-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 10-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is an 11-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 12-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 13-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 14-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 15-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 16-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 17-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is an 18-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 19-member saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 20-membered saturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 21-member saturated heterohydrocarbon chain that is optionally substituted.

[0173] In some embodiments, R L This is a 9-21 member unsaturated heterohydrocarbon chain, a 9-20 member unsaturated heterohydrocarbon chain, a 9-19 member unsaturated heterohydrocarbon chain, a 9-18 member unsaturated heterohydrocarbon chain, a 9-17 member unsaturated heterohydrocarbon chain, a 9-16 member unsaturated heterohydrocarbon chain, a 9-15 member unsaturated heterohydrocarbon chain, or a 9-14 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0174] In some embodiments, R L This is a 13-21 member unsaturated heterohydrocarbon chain, a 13-20 member unsaturated heterohydrocarbon chain, a 13-19 member unsaturated heterohydrocarbon chain, a 13-18 member unsaturated heterohydrocarbon chain, a 13-17 member unsaturated heterohydrocarbon chain, a 13-16 member unsaturated heterohydrocarbon chain, a 13-15 member unsaturated heterohydrocarbon chain, or a 13-14 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0175] In some embodiments, R L is a 10-21 member unsaturated heterohydrocarbon chain, an 11-21 member unsaturated heterohydrocarbon chain, a 12-21 member unsaturated heterohydrocarbon chain, or a 13-21 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0176] In some embodiments, R L This is a 14-21 member unsaturated heterohydrocarbon chain, a 15-21 member unsaturated heterohydrocarbon chain, a 16-21 member unsaturated heterohydrocarbon chain, a 17-21 member unsaturated heterohydrocarbon chain, an 18-21 member unsaturated heterohydrocarbon chain, a 19-21 member unsaturated heterohydrocarbon chain, or a 20-21 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0177] In some embodiments, R L This is a 10-20 member unsaturated heterohydrocarbon chain, an 11-19 member unsaturated heterohydrocarbon chain, a 12-18 member unsaturated heterohydrocarbon chain, a 13-17 member unsaturated heterohydrocarbon chain, or a 14-16 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0178] In some embodiments, R L This is a 14-20 member unsaturated heterohydrocarbon chain, a 15-19 member unsaturated heterohydrocarbon chain, or a 16-18 member unsaturated heterohydrocarbon chain, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0179] In some embodiments, R L is one or more RLs ’ It is a 13-20 member unsaturated heterohydrocarbon chain or a 14-19 member unsaturated heterohydrocarbon chain that is optionally substituted.

[0180] In some embodiments, R L is one or more R L’ It is a 9-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 10-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is an 11-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 12-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 13-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’It is a 14-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 15-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 16-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 17-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is an 18-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 19-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 20-membered unsaturated heterohydrocarbon chain that is optionally substituted with R. In some embodiments, L is one or more R L’ It is a 21-membered unsaturated heterohydrocarbon chain that is optionally substituted.

[0181] In some embodiments, R L is one or more R L’ It is a heterohydrocarbon chain that is optionally substituted.

[0182] In some embodiments, R L is a heterohydrocarbon chain having at least one O, in this case the heterohydrocarbon chain is one or more R L’ It is optionally replaced by R. In some embodiments, L is a heterohydrocarbon chain having at least one N, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is a heterohydrocarbon chain having at least one S, in this case the heterohydrocarbon chain has one or more R L’It is optionally replaced by R. In some embodiments, L is a heterohydrocarbon chain having at least one P, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is a heterohydrocarbon chain having at least one Se, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0183] In some embodiments, R L This is a heterohydrocarbon chain having one oxygen atom, and in this case, the heterohydrocarbon chain has one or more R atoms. L’ It is optionally replaced by R. In some embodiments, L This is a heterohydrocarbon chain having one N, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L This is a heterohydrocarbon chain having one S, and in this case, the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L This is a heterohydrocarbon chain having one P, and in this case, the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is a heterohydrocarbon chain having one Se, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0184] In some embodiments, R L is one or more R L’ It is a saturated heterohydrocarbon chain that is optionally substituted.

[0185] In some embodiments, R L is a saturated heterohydrocarbon chain having at least one O, in which case the heterohydrocarbon chain has one or more R L’It is optionally replaced by R. In some embodiments, L is a saturated heterohydrocarbon chain having at least one N, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is a saturated heterohydrocarbon chain having at least one S, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is a saturated heterohydrocarbon chain having at least one P, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is a saturated heterohydrocarbon chain having at least one Se, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0186] In some embodiments, R L is a saturated heterohydrocarbon chain having one O, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is a saturated heterohydrocarbon chain having one N, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L This is a saturated heterohydrocarbon chain having one S, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is a saturated heterohydrocarbon chain having one P, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is a saturated heterohydrocarbon chain having one Se, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0187] In some embodiments, R L is one or more R L’ It is an unsaturated heterohydrocarbon chain that is optionally substituted.

[0188] In some embodiments, R L is an unsaturated heterohydrocarbon chain having at least one O, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is an unsaturated heterohydrocarbon chain having at least one N, in this case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is an unsaturated heterohydrocarbon chain having at least one S, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is an unsaturated heterohydrocarbon chain having at least one P, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L is an unsaturated heterohydrocarbon chain having at least one Se, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0189] In some embodiments, R L This is an unsaturated heterohydrocarbon chain having one oxygen atom, in which case the heterohydrocarbon chain has one or more R atoms. L’ It is optionally replaced by R. In some embodiments, L This is an unsaturated heterohydrocarbon chain having one N, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L This is an unsaturated heterohydrocarbon chain having one S, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments,L This is an unsaturated heterohydrocarbon chain having one P, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced by R. In some embodiments, L This is an unsaturated heterohydrocarbon chain having one Se, in which case the heterohydrocarbon chain has one or more R L’ It is optionally replaced.

[0190] In some embodiments, at least one R L’ It is oxo.

[0191] In some embodiments, at least one R L’ It is a dihalocarben.

[0192] In some embodiments, at least one R L’ It is a difluorocarbene.

[0193] In some embodiments, at least one R L’ It is cyano.

[0194] In some embodiments, at least one R L’ is a halogen (for example, F, Cl, or Br).

[0195] In some embodiments, at least one R L’ is F. In some embodiments, at least two R L’ is F. In some embodiments, two R L’ It is F.

[0196] In some embodiments, at least one R L’ It is -OH.

[0197] In some embodiments, at least one R L’ is one or more R La -O(C1-C) is optionally substituted. 12 It is alkyl.

[0198] In some embodiments, at least one R L’ is one or more R La -O(C6-C) is optionally substituted. 10 It is Ariel.

[0199] In some embodiments, at least one R L’ -OH, -O(C1-C 12 Alkyl), or -O(C6-C 10 It is aryl), and in this case, -O(C1-C 12 Alkyl) or -O(C6-C 10 Aaryl is one or more R La It is optionally replaced.

[0200] In some embodiments, at least one R L’ -COOH, -COO(C1-C 12 Alkyl), -CONH2, -CONH(C1-C 12 Alkyl), -CON(C1-C 12 Alkyl)2, or -C(O)NHOH, in this case, -COO(C1-C 12 Alkyl), -CONH(C1-C 12 Alkyl), or -CON(C1-C 12 Alkyl)2 is one or more R La It is optionally replaced.

[0201] In some embodiments, at least one R L’ It is -COOH.

[0202] In some embodiments, at least one R L’ is one or more R La -COO(C1-C) is optionally substituted. 12 It is alkyl.

[0203] In some embodiments, at least one R L’ This is -COOCH3.

[0204] In some embodiments, at least one R L’ is one or more R La -CO(C1-C) is optionally substituted. 30 It is alkyl.

[0205] In some embodiments, at least one R L’ is -CO(C 21 It is alkyl.

[0206] In some embodiments, at least one R L’ is one or more R La -NHCO(C1-C) is optionally substituted. 30 It is alkyl.

[0207] In some embodiments, at least one R L’ is -NHCOC 15 H 31 That is the case.

[0208] In some embodiments, at least one R L’ is -NHCOC 21 H 43 That is the case.

[0209] In some embodiments, at least one R L’ is -NHCOC 22 H 42 That is the case.

[0210] In some embodiments, at least one R L’ This is -CONH2.

[0211] In some embodiments, at least one R L’ is one or more R La -CONH(C1-C) is optionally replaced by -CONH(C1-C 12 It is alkyl.

[0212] In some embodiments, at least one R L’ is one or more R La-CON(C1-C) is optionally replaced by -CON(C1-C 12 It is alkyl(2).

[0213] In some embodiments, at least one R L’ It is -C(O)NHOH.

[0214] In some embodiments, at least one R L’ is one or more R La -SO3H or -SO3(C1-C) are optionally substituted. 12 It is alkyl.

[0215] In some embodiments, at least one R L’ It is -SO3H.

[0216] In some embodiments, at least one R L’ is one or more R La -SO3(C1-C) is optionally substituted. 12 It is alkyl.

[0217] In some embodiments, at least one R L’ -NH2, -NH(C1-C 12 Alkyl), or -N(C1-C 12 Alkyl)2, and in this case, -NH(C1-C 12 Alkyl) or -N(C1-C 12 Alkyl)2 is one or more R La It is optionally replaced.

[0218] In some embodiments, at least one R L’ It is -NH2.

[0219] In some embodiments, at least one R L’ is one or more R La -NH(C1-C) is optionally substituted. 12 It is alkyl.

[0220] In some embodiments, at least one RL’ is one or more R La -N(C1-C) is optionally substituted. 12 It is alkyl(2).

[0221] In some embodiments, at least one R L’ is -S(C1-C 12 Alkyl) or -S(C6-C 10 aryl) and in this case, -S(C1-C 12 Alkyl) or -S(C6-C 10 Aaryl is one or more R La It is optionally replaced.

[0222] In some embodiments, at least one R L’ is one or more R La -S(C1-C) is optionally substituted. 12 It is alkyl.

[0223] In some embodiments, at least one R L’ It is -SMe.

[0224] In some embodiments, at least one R L’ is one or more R La -S(C6-C) is optionally substituted. 10 It is Ariel.

[0225] In some embodiments, at least one R L’ teeth, [ka] That is the case.

[0226] In some embodiments, at least one R L’ is one or more R La -P(C6-C) is optionally substituted. 10 It is (aryl) 3.

[0227] In some embodiments, at least one R L’It is -PPh3.

[0228] In some embodiments, at least one R L’ is one or more R La -OP(=O)(O) is arbitrarily substituted. - )O-(C1-C 12 Alkylene-NMe3 + That is the case.

[0229] In some embodiments, at least one R L’ is -OP(=O)(O - )O-(C2 alkylene)-NMe3 + That is the case.

[0230] In some embodiments, at least one R L’ is one or more R La C1-C is optionally substituted. 12 It is alkyl.

[0231] In some embodiments, at least one R L’ is one or more R La C2-C is optionally substituted. 12 It is Alkenil.

[0232] In some embodiments, at least one R L’ is one or more R La C2-C is optionally substituted. 12 It is alkinyl.

[0233] In some embodiments, at least one R L’ is one or more R La It is a C3-C8 cycloalkyl that is optionally substituted.

[0234] In some embodiments, at least one R L’ is one or more R La It is a 3- to 8-membered heterocycloalkyl group that is optionally substituted.

[0235] In some embodiments, at least one R L’ is one or more R La C6-C is optionally substituted. 10 It is Ariel.

[0236] In some embodiments, at least one R L’ is one or more R La It is a 5- to 10-member heteroaryl that is optionally substituted.

[0237] In some embodiments, at least one R L’ is one or more R La It is a tetrazolyl that is optionally substituted.

[0238] In some embodiments, two R L’ It consists of one or more intervening atoms and one or more R La This forms a C3-C8 cycloalkyl group that is optionally substituted.

[0239] In some embodiments, two R L’ It consists of one or more intervening atoms and one or more R La This forms a cyclopropyl that is optionally substituted.

[0240] In some embodiments, two R L’ It consists of one or more intervening atoms and one or more R La It forms a 3- to 8-membered heterocycloalkyl group that is optionally substituted.

[0241] In some embodiments, two R L’ It consists of one or more intervening atoms and one or more R La This forms dioxolanil which is optionally substituted. In some embodiments, two R L’ It consists of one or more intervening atoms and one or more R La This forms a dithiolanyl which is optionally substituted. In some embodiments, two R L’ It consists of one or more intervening atoms and one or more R LaIt forms azacyclobutanil which is optionally substituted.

[0242] In some embodiments, two R L’ It consists of one or more intervening atoms and one or more R La C6-C is optionally substituted. 15 Form an aryl group.

[0243] In some embodiments, two R L’ It, together with one or more intervening atoms, [ka] It forms.

[0244] In some embodiments, two R L’ It, together with one or more intervening atoms, [ka] It forms.

[0245] In some embodiments, two R L’ It, together with one or more intervening atoms, [ka] It forms.

[0246] In some embodiments, two R L’ It consists of one or more intervening atoms and one or more R La It forms a 5- to 15-membered heteroaryl that is optionally substituted.

[0247] In some embodiments, two R L’ It, together with one or more intervening atoms, [ka] It forms.

[0248] In some embodiments, two R L’ It, together with one or more intervening atoms, [ka] It forms.

[0249] In some embodiments, at least one R La It is oxo.

[0250] In some embodiments, at least one R La This is a halogen (for example, F, Cl, or Br).

[0251] In some embodiments, at least one R La is -OH or -O(C1-C 12 It is alkyl.

[0252] In some embodiments, at least one R La It is -OH.

[0253] In some embodiments, at least one R La is -O(C1-C 12 It is alkyl.

[0254] In some embodiments, at least one R La -SH or -S(C1-C 12 It is alkyl.

[0255] In some embodiments, at least one R La It is -SH.

[0256] In some embodiments, at least one R La is -S(C1-C 12 It is alkyl.

[0257] In some embodiments, at least one R La -NH2, -NH(C1-C 12 Alkyl), or -N(C1-C 12 It is alkyl 2L.

[0258] In some embodiments, at least one R La It is -NH2.

[0259] In some embodiments, at least one R La is -NH(C1-C 12 It is alkyl.

[0260] In some embodiments, at least one R La is -N(C1-C 12 It is alkyl(2).

[0261] In some embodiments, at least one R La C1-C 12 It is alkyl.

[0262] In some embodiments, at least one R La C2-C 12 It is Alkenil.

[0263] In some embodiments, at least one R La C2-C 12 It is alkinyl.

[0264] In some embodiments, at least one R La It is a C3-C8 cycloalkyl group.

[0265] In some embodiments, at least one R La is one or more C1-C 12 These are 3- to 8-membered heterocycloalkyl groups that are optionally substituted with alkyl groups.

[0266] In some embodiments, at least one R La C6-C 10 It is Ariel.

[0267] In some embodiments, at least one R La These are heteroaryl compounds with 5 to 10 members.

[0268] In some embodiments, two R La It forms a C3-C8 cycloalkyl group with one or more intervening atoms.

[0269] In some embodiments, two R La It forms a 3- to 8-membered heterocycloalkyl group with one or more intervening atoms.

[0270] In some embodiments, two R La C6-C 10 Form an aryl group.

[0271] In some embodiments, two R La It forms a 5-10 membered heteroaryl group with one or more interfacing atoms.

[0272] In some embodiments, L is selected from the structures listed in Table X. [ka] This indicates a binding site to the lipid ligand agent or the rest of the lipid ligand unit. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0273] In some embodiments, L is selected from the structures listed in Table Y. [ka] This indicates a binding site to the lipid ligand agent or the rest of the lipid ligand unit. [Table 2-1] [Table 2-2] [Table 2-3]

[0274] In some embodiments, L is selected from the structures described in Tables X and Y.

[0275] Variable B In some embodiments, B is H.

[0276] In some embodiments, B is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0277] In some embodiments, B is methyl, ethyl, or propyl.

[0278] In some embodiments, B is the nucleic acid base portion.

[0279] As used herein, the term “nucleic acid base moiety” refers to a nucleic acid base that is bonded to the rest of the compound, for example, via an atom of the nucleic acid base or its functional group.

[0280] In some embodiments, the nucleic acid base moiety is adenine (A), cytosine (C), guanine (G), thymine (T), or uracil (U).

[0281] In some embodiments, the nucleic acid base portion is [ka] And in this case, [ka] This indicates the binding site to the remaining portion of the lipid-based ligand.

[0282] In some embodiments, the nucleic acid base portion is a modified nucleic acid base.

[0283] In some embodiments, the modified nucleic acid base is 5-methylcytosine.

[0284] In some embodiments, the modified nucleic acid base is hypoxanthine, xanthine, or 7-methylguanine.

[0285] In some embodiments, the modified nucleic acid base is 5,6-dihydrouracil, 5-methylcytosine, or 5-hydroxymethylcytosine.

[0286] In some embodiments, the nucleic acid base portion is an artificial nucleic acid base.

[0287] In some embodiments, the artificial nucleic acid base is isoguanine, isocytosine, 2-amino-6-(2-thienyl)purine, or pyrrole-2-carbaldehyde.

[0288] Variables V and R V In some embodiments, V is -O-.

[0289] In some embodiments, V is -NR V - is

[0290] In some embodiments, V is -NH-.

[0291] In some embodiments, V is -C(R V )2-.

[0292] In some embodiments, V is -CH2-.

[0293] In some embodiments, at least one R V H is H.

[0294] Some implementation methods, each R V H is H.

[0295] In some embodiments, at least one R V This is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0296] In some embodiments, at least one R V These are C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0297] In some embodiments, at least one R V is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0298] Some implementation methods, each R VThis is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0299] Some implementation methods, each R V These are C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0300] Some implementation methods, each R V is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0301] Variables X, R X , R Xa , R L” , Y, R Y , Z, RZ Q, R Q , and R L In some embodiments, X is H.

[0302] In some embodiments, X is a halogen (e.g., F, Cl, Br, or I).

[0303] In some embodiments, X is F or Cl.

[0304] In some embodiments, X is F.

[0305] In some embodiments, X is -OR X That is the case.

[0306] In some embodiments, X is -OH.

[0307] In some embodiments, X is -O-(C1-C 12 It is alkyl.

[0308] In some embodiments, X is -O-(C1-C6 alkyl) (for example, C1-C6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0309] In some embodiments, X is -OCH3.

[0310] In some embodiments, X is -O-(C1-C6 alkyl)-O-(C1-C6 alkyl) (for example, C1-C6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0311] In some embodiments, X is -OCH2CH2OCH3.

[0312] In some embodiments, X is one or more R Xa -O-(C1-C6 alkyl)-(C6-C 10 It is Ariel.

[0313] In some embodiments, X is -O-(C1-C6 alkyl)-(C6-C 10 It is Ariel.

[0314] In some embodiments, X is [ka] That is the case.

[0315] In some embodiments, X is one or more R Xa It is optionally replaced by [ka] That is the case.

[0316] In some embodiments, X is optionally replaced with one or more halogens. [ka] That is the case.

[0317] In some embodiments, X is optionally substituted with one or more C1-C6 alkyl groups or -O-(C1-C6 alkyl groups). [ka] In this case, the C1-C6 alkyl or -O-(C1-C6 alkyl) is optionally substituted with one or more halogens.

[0318] In some embodiments, R X H is H.

[0319] In some embodiments, R X is one or more R Xa It is a C1-C6 alkyl group that is optionally substituted.

[0320] In some embodiments, R X It is a C1-C6 alkyl group.

[0321] In some embodiments, R X is one or more R Xa The C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) is optionally substituted.

[0322] In some embodiments, R XThis is a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I), or an -O-(C1-C6 alkyl) (e.g., C1-C6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0323] Some implementation methods, each R X These are C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0324] In some embodiments, R X These are methyl, ethyl, or propyl.

[0325] In some embodiments, R X It is methyl.

[0326] In some embodiments, R X is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0327] In some embodiments, R X is a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more -O-(C1-C6 alkyl) (e.g., C1-C6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), in which case -O-(C1-C6 alkyl) is optionally substituted with one or more halogens.

[0328] In some embodiments, R X is one or more R Xa -(C1-C6 alkyl)-(C6-C 10 It is Ariel.

[0329] In some embodiments, R X -(C1-C6 alkyl)-(C6-C) is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I). 10 The C1-C6 alkyl group is an aryl group, a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), or an O-(C1-C6 alkyl group) (e.g., the C1-C6 alkyl group is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), in which case the C1-C6 alkyl group or the O-(C1-C6 alkyl group) is optionally substituted with one or more halogens.

[0330] In some embodiments, R X is -(C1-C6 alkyl)-(C6-C 10 It is Ariel.

[0331] In some embodiments, R X and R 4 They together form C1-C6 alkylenes (e.g., methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0332] In some embodiments, R X and R 4 They combine to form methylene, ethylene, or propylene.

[0333] In some embodiments, R X and R 4 They form a methylene group together.

[0334] In some embodiments, R X and R 4 They form ethylene together.

[0335] In some embodiments, R X and R 4 They form propylene together.

[0336] In some embodiments, Y is H.

[0337] In some embodiments, Y is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0338] In some embodiments, Y is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0339] In some embodiments, Y is methyl, ethyl, or propyl.

[0340] In some embodiments, Y is -P(R Y )2, -P(OR Y )(N(R Y )2), -P(=O)(OR Y )R Y , -P(=S)(OR Y )R Y -P(=O)(SR Y )R Y -P(=S)(SR Y )R Y , -P(=O)(OR Y )2, -P(=S)(OR Y )2, -P(=O)(SR Y )2, or -P(=S)(SR Y )2.

[0341] In some embodiments, Y is -P(RY )2.

[0342] In some embodiments, Y is -PH2.

[0343] In some embodiments, Y is -P(OR Y )(N(R Y )2) is.

[0344] In some embodiments, Y is -P(OH)(NH2).

[0345] In some embodiments, Y is -P(O(C1-C6 alkyl))(N(C1-C6 alkyl)2), where C1-C6 alkyl is optionally substituted with one or more halogens or cyano compounds.

[0346] In some embodiments, Y is -P(=O)(OR Y )R Y That is the case.

[0347] In some embodiments, Y is -P(=O)(OH)(C1-C6 alkyl), where the C1-C6 alkyl is optionally substituted with one or more halogens or cyano compounds.

[0348] In some embodiments, Y is -P(=S)(OR Y )R Y That is the case.

[0349] In some embodiments, Y is -P(=S)(OH)(C1-C6 alkyl), where the C1-C6 alkyl is optionally substituted with one or more halogens or cyano compounds.

[0350] In some embodiments, Y is -P(=O)(SR Y )R Y That is the case.

[0351] In some embodiments, Y is -P(=O)(SH)(C1-C6 alkyl), where the C1-C6 alkyl is optionally substituted with one or more halogens or cyano compounds.

[0352] In some embodiments, Y is -P(=S)(SR Y )R Y That is the case.

[0353] In some embodiments, Y is -P(=S)(SH)(C1-C6 alkyl), where the C1-C6 alkyl is optionally substituted with one or more halogens or cyano compounds.

[0354] In some embodiments, Y is -P(=O)(OR Y )2.

[0355] In some embodiments, Y is -P(=O)(OH)2.

[0356] In some embodiments, Y is -P(=S)(OR Y )2.

[0357] In some embodiments, Y is -P(=S)(OH)2.

[0358] In some embodiments, Y is -P(=O)(SR Y )2.

[0359] In some embodiments, Y is -P(=O)(SH)².

[0360] In some embodiments, Y is -P(=S)(SR Y )2.

[0361] In some embodiments, Y is -P(=S)(SH)².

[0362] In some embodiments, Y is a hydroxy protecting group.

[0363] In some embodiments, Y is a silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl).

[0364] In some embodiments, Y is triphenylmethyl (Tr) or 4,4'-dimethoxytrityl (DMTr).

[0365] In some embodiments, Y is an optionally substituted acyl (e.g., an optionally substituted acetyl) or benzyl.

[0366] In some embodiments, at least one R Y H is H.

[0367] Some implementation methods, each R Y H is H.

[0368] In some embodiments, at least one R Y is a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or cyanosides.

[0369] Some implementation methods, each R Y is a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or cyanosides.

[0370] In some embodiments, at least one R Y H is H, and at least one R Yis a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens or cyanosides.

[0371] In some embodiments, if X is an -OH group, Y is not an H group or a hydroxyl protecting group.

[0372] In some embodiments, if X is -OH, Y is a C1-C6 alkyl, -P(R) which is optionally substituted with one or more halogens. Y )2, -P(OR Y )(N(R Y )2), -P(=O)(OR Y )R Y , -P(=S)(OR Y )R Y -P(=O)(SR Y )R Y -P(=S)(SR Y )R Y , -P(=O)(OR Y )2, -P(=S)(OR Y )2, -P(=O)(SR Y )2, or -P(=S)(SR Y )2.

[0373] In some embodiments, if Y is H or a hydroxy protecting group, then X is not -OH.

[0374] In some embodiments, if Y is H or a hydroxy protecting group, then X is H, a halogen, or -OR X And R X This is C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 It is an aryl, and in this case, C1-C6 alkyl or -(C1-C6 alkyl)-(C6-C 10 Aaryl is one or more R Xa It is optionally replaced.

[0375] In some embodiments, Z is H.

[0376] In some embodiments, Z is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0377] In some embodiments, Z is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0378] In some embodiments, Z is methyl, ethyl, or propyl.

[0379] In some embodiments, Z is -P(R Z )2, -P(OR Z )(N(R Z )2), -P(=O)(OR Z )R Z , -P(=S)(OR Z )R Z -P(=O)(SR Z )R Z -P(=S)(SR Z )R Z , -P(=O)(OR Z )2, -P(=S)(OR Z )2, -P(=O)(SR Z )2, -P(=S)(SR Z )2.

[0380] In some embodiments, Z is -P(R Z )2.

[0381] In some embodiments, Z is -PH2.

[0382] In some embodiments, Z is -P(OR Z )(N(R Z )2) is.

[0383] In some embodiments, Z is -P(OH)(NH2).

[0384] In some embodiments, Z is -P(O(C1-C6 alkyl))(N(C1-C6 alkyl)2), where C1-C6 alkyl is optionally substituted with one or more halogens or cyano compounds.

[0385] In some embodiments, Z is -P(=O)(OR Z )R Z That is the case.

[0386] In some embodiments, Z is -P(=O)(OH)(C1-C6 alkyl), where the C1-C6 alkyl is optionally substituted with one or more halogens or cyano compounds.

[0387] In some embodiments, Z is -P(=S)(OR Z )R Z That is the case.

[0388] In some embodiments, Z is -P(=S)(OH)(C1-C6 alkyl), where the C1-C6 alkyl is optionally substituted with one or more halogens or cyano compounds.

[0389] In some embodiments, Z is -P(=O)(SR Z )R Z That is the case.

[0390] In some embodiments, Z is -P(=O)(SH)(C1-C6 alkyl), where the C1-C6 alkyl is optionally substituted with one or more halogens or cyano compounds.

[0391] In some embodiments, Z is -P(=S)(SR Z )R Z That is the case.

[0392] In some embodiments, Z is -P(=S)(SH)(C1-C6 alkyl), where the C1-C6 alkyl is optionally substituted with one or more halogens or cyano compounds.

[0393] In some embodiments, Z is -P(=O)(OR Z )2.

[0394] In some embodiments, Z is -P(=O)(OH)2.

[0395] In some embodiments, Z is -P(=S)(OR Z )2.

[0396] In some embodiments, Z is -P(=S)(OH)2.

[0397] In some embodiments, Z is -P(=O)(SR Z )2.

[0398] In some embodiments, Z is -P(=O)(SH)².

[0399] In some embodiments, Z is -P(=S)(SR Z )2.

[0400] In some embodiments, Z is -P(=S)(SH)².

[0401] In some embodiments, Z is a hydroxy protecting group.

[0402] In some embodiments, Z is a silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl).

[0403] In some embodiments, Z is triphenylmethyl (Tr) or 4,4'-dimethoxytrityl (DMTr).

[0404] In some embodiments, Z is a substituted acyl (e.g., an optionally substituted acetyl) or a benzyl.

[0405] In some embodiments, at least one R Z H is H.

[0406] Some implementation methods, each R Z H is H.

[0407] In some embodiments, at least one R Z is a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or cyanosides.

[0408] Some implementation methods, each R Z is a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or cyanosides.

[0409] In some embodiments, at least one R Z H is H, and at least one R Z is a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I) or cyanosides.

[0410] In some embodiments, Y and Z in formula (I) together are -Si(R L” )2-O-Si(R L” ) forms 2-.

[0411] In some embodiments, Y and Z in formula (I) together form -Si(C1-C6 alkyl)2-O-Si(C1-C6 alkyl)2-.

[0412] In some embodiments, Y and Z in formula (I) together form -Si(iPr)2-O-Si(iPr)2-.

[0413] In some embodiments, Y and Z in formula (III) together are -Si(R L” )2-O-Si(R L” ) forms 2-.

[0414] In some embodiments, Y and Z in formula (III) together form -Si(C1-C6 alkyl)2-O-Si(C1-C6 alkyl)2-.

[0415] In some embodiments, Y and Z in formula (III) together form -Si(iPr)2-O-Si(iPr)2-.

[0416] In some embodiments, Y and Z in formulas (I), (III), (I'), (III'), (V'), (IA), (III-A), (VA), (VII-A), (IX-A), (XI-A), (I'-A), (III'-A), (V'-A), (VII'-A), (IX'-A), (XI'-A), (IB), (III-B), (VB), (I'-B), (III'-B) or (V'-B) are together -Si(R L” )2-O-Si(R L” )2- forms, and in this case each R L” These are independently H or C1-C6 alkyl groups.

[0417] In some embodiments, Y and Z of formulas (I), (III), (I'), (III'), (V'), (IA), (III-A), (VA), (VII-A), (IX-A), (XI-A), (I'-A), (III'-A), (V'-A), (VII'-A), (IX'-A), (XI'-A), (IB), (III-B), (VB), (I'-B), (III'-B), or (V'-B) together form -Si(C1-C6alkyl)2-O-Si(C1-C6alkyl)2-.

[0418] In some embodiments, Y and Z in formulas (I), (III), (I'), (III'), (V'), (IA), (III-A), (VA), (VII-A), (IX-A), (XI-A), (I'-A), (III'-A), (V'-A), (VII'-A), (IX'-A), (XI'-A), (IB), (III-B), (VB), (I'-B), (III'-B), or (V'-B) together form -Si(iPr)2-O-Si(iPr)2-.

[0419] In some embodiments, Q is -(CR a R a ) n The expression is -NH-*, where * indicates a bond to L.

[0420] In some embodiments, Q is -(CR a R a ) 1-5 It is -NH-*.

[0421] In some embodiments, Q is -(CR a R a )5-NH-*. In some embodiments, Q is -(CR a R a )4-NH-*. In some embodiments, Q is -(CR a R a )3-NH-*. In some embodiments, Q is -(CR a R a )2-NH-*. In some embodiments, Q is -(CR a R aIt is )-NH-*.

[0422] In some embodiments, Q is -(CH2) 1-5 It is -NH-*.

[0423] In some embodiments, Q is -(CH2)5-NH-*. In some embodiments, Q is -(CH2)4-NH-*. In some embodiments, Q is -(CH2)3-NH-*. In some embodiments, Q is -(CH2)2-NH-*. In some embodiments, Q is -(CH2)-NH-*.

[0424] In some embodiments, Q is -NH-*.

[0425] In some embodiments, Q is one or more R Q C6-C is optionally substituted. 10 It is arrine.

[0426] In some embodiments, Q is C6-C 10 It is arrine.

[0427] In some embodiments, Q is one or more R Q These are 5-10 member heteroarylenes that are optionally substituted.

[0428] In some embodiments, Q is a 5- to 10-membered heteroarylene.

[0429] In some embodiments, Z is one or more R Q It is a triazolylene that is optionally substituted.

[0430] In some embodiments, Q is triazolylene.

[0431] In some embodiments, Q is [ka] In the formula, * indicates a bond to L, [ka] This indicates the binding site to the remaining portion of the lipid-based ligand.

[0432] In some embodiments, Q is [ka] In the formula, * indicates a bond to L, [ka] This indicates the binding site to the remaining portion of the lipid-based ligand.

[0433] In some embodiments, at least one R Q is a halogen (e.g., F, Cl, Br, or I) or a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0434] In some embodiments, at least one R Q This is a halogen (e.g., F, Cl, Br, or I).

[0435] In some embodiments, at least one R Q It is either F or Cl.

[0436] In some embodiments, at least one R Q This is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0437] In some embodiments, at least one R QThese are C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0438] In some embodiments, at least one R Q is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0439] In some embodiments, at least one R L” H is H.

[0440] In some embodiments, at least one R L” It is a C1-C6 alkyl group.

[0441] In some embodiments, at least one R L” This is methyl, ethyl, or propyl (e.g., iPr).

[0442] Some implementation methods, each R L” H is independent of H.

[0443] Some implementation methods, each R L” These are independently C1-C6 alkyl groups.

[0444] Some implementation methods, each R L” These are independently methyl, ethyl, or propyl (e.g., iPr).

[0445] Variable R a , R 1 , R 2 , R 3 , R 4 , R 5 , and n Some implementation methods, each R a H is H.

[0446] In some embodiments, at least one R a is a halogen (e.g., F, Cl, Br, or I) or a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0447] In some embodiments, at least one R a This is a halogen (e.g., F, Cl, Br, or I).

[0448] In some embodiments, at least one R a It is either F or Cl.

[0449] In some embodiments, at least one R a This is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0450] In some embodiments, at least one R a These are C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0451] In some embodiments, at least one R a is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0452] In some embodiments, R 1 H is H.

[0453] In some embodiments, R1 This is a halogen (e.g., F, Cl, Br, or I).

[0454] In some embodiments, R 1 It is either F or Cl.

[0455] In some embodiments, R 1 This is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0456] In some embodiments, R 1 These are C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0457] In some embodiments, R 1 is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0458] In some embodiments, R 2 H is H.

[0459] In some embodiments, R 2 This is a halogen (e.g., F, Cl, Br, or I).

[0460] In some embodiments, R 2 It is either F or Cl.

[0461] In some embodiments, R 2This is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0462] In some embodiments, R 2 These are C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0463] In some embodiments, R 2 is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0464] In some embodiments, R 3 H is H.

[0465] In some embodiments, R 3 This is a halogen (e.g., F, Cl, Br, or I).

[0466] In some embodiments, R 3 It is either F or Cl.

[0467] In some embodiments, R 3 This is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0468] In some embodiments, R 3 These are C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0469] In some embodiments, R 3 is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0470] In some embodiments, R 4 H is H.

[0471] In some embodiments, R 4 This is a halogen (e.g., F, Cl, Br, or I).

[0472] In some embodiments, R 4 It is either F or Cl.

[0473] In some embodiments, R 4 This is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0474] In some embodiments, R 4 These are C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0475] In some embodiments, R 4 is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0476] In some embodiments, R 4 and R XThey together form C1-C6 alkylenes (e.g., methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0477] In some embodiments, R 4 and R X They combine to form methylene, ethylene, or propylene.

[0478] In some embodiments, R 4 and R X They form a methylene group together.

[0479] In some embodiments, R 4 and R X They form ethylene together.

[0480] In some embodiments, R 4 and R X They form propylene together.

[0481] Some implementation methods, each R 5 H is H.

[0482] In some embodiments, at least one R 5 is a halogen (e.g., F, Cl, Br, or I) or a C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0483] In some embodiments, at least one R 5 This is a halogen (e.g., F, Cl, Br, or I).

[0484] In some embodiments, at least one R 5 It is either F or Cl.

[0485] In some embodiments, at least one R 5This is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) that is optionally substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0486] In some embodiments, at least one R 5 These are C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0487] In some embodiments, at least one R 5 is a C1-C6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0488] In some embodiments, R a , R 1 , R 2 , R 3 , R 4 , and R 5 Each of these is H.

[0489] In some embodiments, n is an integer in the range of about 1 to about 10.

[0490] In some embodiments, n is an integer in the range of about 2 to about 10.

[0491] In some embodiments, n is an integer in the range of about 3 to about 10, about 4 to about 10, about 5 to about 10, or about 6 to about 10.

[0492] In some embodiments, n is an integer in the range of approximately 1 to approximately 8, approximately 1 to approximately 7, approximately 1 to approximately 6, approximately 1 to approximately 5, approximately 1 to approximately 4, or approximately 1 to approximately 3.

[0493] In some embodiments, n is an integer in the range of about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, or about 2 to about 3.

[0494] In some embodiments, n is 0.

[0495] In some embodiments, n is 1.

[0496] In some embodiments, n is 2.

[0497] In some embodiments, n is 3.

[0498] In some embodiments, n is 4.

[0499] In some embodiments, n is 5.

[0500] In some embodiments, n is 6.

[0501] In some embodiments, n is 7.

[0502] In some embodiments, n is 8.

[0503] In some embodiments, n is 9.

[0504] In some embodiments, n is 10.

[0505] Exemplary Embodiments of Lipid-Based Ligand Agents In some embodiments, the lipid ligand is of formula (I'), (II'), (III'), (IV'), (V'), or (VI'). [ka]

[0506] In some embodiments, the lipid ligand is of formula (IA), (II-A), (III-A), (IV-A), (VA), (VI-A), (VII-A), (VIII-A), (IX-A), (XA), (XI-A), or (XII-A). [ka]

[0507] In some embodiments, the lipid ligand is of formula (I'-A), (II'-A), (III'-A), (IV'-A), (V'-A), (VI'-A), (VII'-A), (VIII'-A), (IX'-A), (X'-A), (XI'-A), or (XII'-A). [ka]

[0508] In some embodiments, the lipid ligand is of formula (IB), (II-B), (III-B), (IV-B), (VB), or (VI-B). [ka]

[0509] In some embodiments, the lipid ligand is of formula (I'-B), (II'-B), (III'-B), (IV'-B), (V'-B), or (VI'-B). [ka]

[0510] In some embodiments, the lipid ligand agent is of the formula (IC), (II-C), (III-C), (IV-C), (VC), (VI-C), (VII-C), (VIII-C), (IX-C), (XC), (XI-C), or (XII-C). [ka]

[0511] In some embodiments, the lipid ligand is of formula (I'-C), (II'-C), (III'-C), (IV'-C), (V'-C), (VI'-C), (VII'-C), (VIII'-C), (IX'-c), (X'-C), (XI'-C), or (XII'-C). [ka]

[0512] In some embodiments, the lipid ligand agent is as follows: [ka] or a pharmaceutically acceptable salt thereof, in the formula, [ka] This indicates a single bond or a double bond. Y is -P(R Y )2, -P(OR Y )(N(R Y )2), -P(=O)(OR Y )R Y , -P(=S)(OR Y )R Y -P(=O)(SR Y )R Y -P(=S)(SR Y )R Y , -P(=O)(OR Y )2, -P(=S)(OR Y )2, -P(=O)(SR Y )2, -P(=S)(SR Y )2, or a hydroxy protecting group (e.g., silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl), triphenylmethyl (Tr), 4,4'-dimethoxytrityl (DMTr), substituted acyl (e.g., optionally substituted acetyl), or benzyl), Each RY These are independently C1-C6 alkyl groups that are optionally substituted with H or one or more halogens or cyano compounds. Z is -P(R Z )2, -P(OR Z )(N(R Z )2), -P(=O)(OR Z )R Z , -P(=S)(OR Z )R Z -P(=O)(SR Z )R Z -P(=S)(SR Z )R Z , -P(=O)(OR Z )2, -P(=S)(OR Z )2, -P(=O)(SR Z )2, -P(=S)(SR Z )2, or a hydroxy protecting group (e.g., silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl), triphenylmethyl (Tr), 4,4'-dimethoxytrityl (DMTr), substituted acyl (e.g., optionally substituted acetyl), or benzyl), Each R Z These are C1-C6 alkyl groups that are independently and optionally substituted with H, or one or more halogens or cyano compounds.

[0513] In some embodiments, the lipid ligand is selected from the compounds listed in Table L and their pharmaceutically acceptable salts.

[0514] In some embodiments, the lipid ligand is selected from the compounds listed in Table L. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7]

[0515] In some embodiments, the lipid ligand is selected from the compounds listed in Table M and their pharmaceutically acceptable salts.

[0516] In some embodiments, the lipid ligand is selected from the compounds listed in Table M. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8]

[0517] In some embodiments, the lipid ligand is selected from the compounds listed in Table P and their pharmaceutically acceptable salts.

[0518] In some embodiments, the lipid ligand is selected from the compounds listed in Table P. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0519] In some embodiments, the lipid ligand is selected from the compounds listed in Tables M and P, and their pharmaceutically acceptable salts.

[0520] In some embodiments, the lipid ligand is selected from the compounds listed in Tables M and P. In some embodiments, the disclosure provides isotopic derivatives (e.g., isotope-labeled compounds) of the lipid ligands disclosed herein.

[0521] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples herein, by substituting non-isotopic labeling reagents with isotopic labeling reagents.

[0522] In some embodiments, the isotopic derivative is a deuterium-labeled derivative.

[0523] As used herein, the term “isotope derivative” refers to a derivative of a chemical structure in which one or more atoms are isotope-enriched or labeled. For example, an isotope derivative of an agent is isotope-enriched or labeled with respect to one or more isotopes compared to the corresponding agent. In some embodiments, the isotope derivative is, 2 H,13 C, 14 C, 15 N, 18 O, 29 Si, 32 P, and 34 The isotopic derivative is enriched with respect to or labeled with respect to one or more atoms selected from S. In some embodiments, the isotopic derivative is a deuterium-labeled derivative (i.e., with respect to one or more atoms). 2 (Enriched with H). In some embodiments, the derivative is 2 It is an H-labeled derivative. In some embodiments, the derivative is 13 C-labeled derivative or 14 It is a 1C-labeled derivative. In some embodiments, the derivative is 18 It is an F-labeled derivative. In some embodiments, the derivative is 123 I-labeled derivative, 124 I-labeled derivative, 125 I-labeled derivative, 129 I-labeled derivative, 131 I-labeled derivative, 135 I-labeled derivatives, or any combination thereof. In some embodiments, the derivatives are 31 P-labeled derivative or 32 It is a P-labeled derivative. In some embodiments, the derivative is 33 S-labeled derivative, 34 S-labeled derivative, 35 S-labeled derivative, 36 These are S-labeled derivatives, or any combination thereof.

[0524] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by substituting non-isotopic labeling reagents with isotopic labeling reagents.

[0525] Furthermore, it is understood that isotope substitution may result in certain therapeutic benefits stemming from increased metabolic stability, such as an extension of the in vivo half-life or a reduction in the required dose.

[0526] To avoid any doubt, in this specification, when a base is conditioned by “as described herein,” it should be understood that the base includes the broadest definition that first appears, as well as all specific definitions for that base.

[0527] It will be understood that the compounds disclosed herein may be presented in a particular configuration. Such a particular configuration is not to be construed as limiting the disclosure to one or more isomers, tautomers, regioisomers, or stereoisomers, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration is intended to encompass and refer to the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof, respectively, but such presentation is also intended to refer to a particular configuration of the compound.

[0528] It will be understood that the compounds disclosed herein may also be presented without a specific configuration (e.g., without a specific stereochemistry). Such presentations are intended to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, presentations of compounds herein without a specific configuration are intended to refer to any of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0529] As used herein, the term “isomer” means a compound having the same molecular formula but differing in the bonding order of its atoms or the arrangement of its atoms in space. Compounds having the same molecular formula but differing in the bonding nature or order of their atoms, or in the arrangement of their atoms in space, are called “isomers.” Isomers that differ in the arrangement of their atoms in space are called “stereoisomers.” Stereoisomers that are not mirror images of each other are called “diastereomers,” and stereoisomers that are mirror images that cannot be superimposed on each other are called “enantiomers.” If a compound has a chiral center, for example, if it is bonded to four different groups, there may be a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of their chiral center, described by the Cahn and Prelog R and S sequencing rules, or by the way the molecule rotates its plane of polarization and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0530] The compounds of this disclosure may have one or more chiral centers, and therefore such compounds can be produced as individual (R) stereoisomers or (S) stereoisomers, or as mixtures thereof. Unless otherwise indicated, the descriptions or nomenclature of specific compounds in this specification and the claims are intended to include both individual enantiomers and their racemates or other mixtures. Methods for determining stereochemistry and separating stereoisomers are known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition J. March, John Wiley and Sons, New York, 2001), and include, for example, synthesis from optically active starting materials or by resolution of racemates. Some of the compounds of this disclosure may have geometric isomer centers (E and Z isomers). It should be understood that this disclosure encompasses all optical isomers, diastereomers, and geometric isomers, as defined herein, that are biologically active, as well as mixtures thereof.

[0531] As used herein, the term “chiral center” refers to a carbon atom bonded to four non-identical substituents.

[0532] As used herein, the term “chiral isomer” means a compound having at least one chiral center. Compounds having multiple chiral centers may exist as individual diastereomers or as a mixture of diastereomers called a “diastereomer mixture.” When a single chiral center is present, the stereoisomers are characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold, and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0533] As used herein, the term “geometric isomer” means a diastereomer whose existence is due to the impediment to rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, according to the Cahn-Ingold-Prelog rule, where the group is on the same side or opposite side of the double bond within the molecule.

[0534] It should be understood that the compounds of this disclosure may be illustrated as different chiral or geometric isomers. Where a compound exists in chiral or geometric isomeric form, it should be understood that all isomeric forms are intended to be included within the scope of this disclosure, that the naming of the compound does not exclude any isomeric form, and that not all isomers may have the same level of activity.

[0535] It should be understood that the structures and other compounds discussed in this disclosure include all of their atropic isomers. It should also be understood that not all atropic isomers may possess the same level of activity.

[0536] As used herein, the term “atropic isomer” refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. The existence of atropic isomers arises from rotational limitations caused by the obstruction of rotation of the larger group around a central bond. Such atropic isomers typically exist as a mixture, but as a result of recent advances in chromatography techniques, in limited cases it is possible to separate a mixture of two atropic isomers.

[0537] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to another. This conversion involves formal transfer of hydrogen atoms, accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of sets of tautomers in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Of the various possible types of tautomerism, two are generally observed. Keto-enol tautomerism involves a simultaneous shift of electrons and hydrogen atoms. Ring-chain tautomerism occurs when an aldehyde group (-CHO) in a sugar chain molecule reacts with one of the hydroxyl groups (-OH) in the same molecule, resulting in a cyclic (ring-shaped) form, as shown in glucose.

[0538] It should be understood that the compounds of this disclosure may be illustrated as different tautomers. If a compound has tautomers, all tautomers are intended to be included within the scope of this disclosure, and the nomenclature of the compounds does not exclude any tautomers. It should be understood that certain tautomers may have higher levels of activity than others.

[0539] Compounds of any formula described herein are understood to include, where applicable, the compound itself, as well as their salts and solvates. Salts may be formed, for example, between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chlorides, bromides, iodides, sulfates, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfons, trifluoroacetates, glutamates, glucurons, glutarates, malates, maleates, succinates, fumarates, tartrates, tosylates, salicylates, lactates, naphthalenesulfons, and acetates (e.g., trifluoroacetates).

[0540] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for the formation of a pharmaceutically acceptable salt. Similarly, salts may also be formed between a cation and a negatively charged group on a substituted compound disclosed herein (e.g., a carboxylate salt). Suitable cations include sodium, potassium, magnesium, calcium ions, and ammonium cations, such as tetramethylammonium or diethylammonium ions. The substituted compounds disclosed herein also include their salts containing a quaternary nitrogen atom.

[0541] It should be understood that the compounds of this disclosure, for example, salts of the compounds, may exist in either a hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvate and acetone solvate.

[0542] As used herein, “solvate” means a solvated form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds, in their crystalline solid state, tend to capture solvent molecules in a fixed molar ratio, thereby forming solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with one molecule of another substance, where the water retains its molecular state as H2O.

[0543] As used herein, the term “analog” refers to a compound that is structurally similar to another compound but has a slightly different composition (for example, one atom being substituted with an atom of a different element, or the presence of a particular functional group, or one functional group being substituted with another). Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but not in structure or origin.

[0544] As used herein, the term “derivative” refers to a compound having a common core structure and being substituted with one of the various groups described herein.

[0545] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of one atom or group of atoms with another broadly similar atom or group of atoms. The purpose of bioisostere substitution is to create a novel compound having similar biological properties to the parent compound. Bioisostere substitution may be physicochemical or topological. Examples of carboxylic acid bioisosteres, but not limited to, include acylsulfonamides, tetrazoles, sulfonates, and phosphates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0546] Furthermore, it should be understood that any one of the formulas disclosed herein may exist in both solvated and non-solvated forms, such as hydrated forms. Preferred pharmaceutically acceptable solvates are hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure encompasses all such solvated forms having biological activity as defined herein.

[0547] Furthermore, it should be understood that any particular compound of any of the formulas disclosed herein may exhibit polymorphism, and that this disclosure encompasses all such forms, or mixtures thereof, that have biological activity as defined herein. It is generally known that crystalline materials can be analyzed using conventional techniques, such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0548] Any compound of any of the formulas disclosed herein may exist in many different tautomers, and any reference to any compound of any of the formulas includes all such forms. To avoid any doubt, a compound may exist in one of several tautomers, and even if only one is specifically described or shown, all the others are encompassed in the formulas disclosed herein. Examples of tautomers include, for example, the keto-, enol-, and enolate- forms, such as the following pairs of tautomers: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acinitro. [ka]

[0549] Any compound of any of the formulas disclosed herein that contains an amine functional group may also form an N-oxide. References herein to any compound of any of the formulas containing an amine functional group also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience. More specifically, N-oxides can be prepared by the procedure of LWDeady (Syn.Comm. 1977, 7, 509-514), in which the amine compound is reacted with metachloroperoxybenzoic acid (mCPBA) in an inert solvent, such as dichloromethane.

[0550] Any compound of any of the formulas disclosed herein may be administered in the form of a prodrug, which is broken down in the body of a human or animal to release the compound disclosed herein. Prodrugs may be used to alter the physical and / or pharmacokinetic properties of the compound disclosed herein. Prodrugs can be formed when the compound disclosed herein contains a suitable group or substituent to which a characterizing group can be added.

[0551] Accordingly, this disclosure includes any one compound of the formulas disclosed herein as defined above, when made available by organic synthesis and when made available by cleavage of its prodrug in the body of a human or animal. Accordingly, this disclosure includes any one compound of the formulas disclosed herein produced by organic synthesis and also includes compounds produced in the body of a human or animal by metabolism of precursor compounds, i.e., any one compound of the formulas disclosed herein may be a synthetically produced compound or a metabolically produced compound.

[0552] A suitable pharmaceutically acceptable prodrug of any one of the compounds of the formulas disclosed herein is based on reasonable medical judgment that it is free from undesirable pharmacological activity and excessive toxicity and is suitable for administration to the human or animal body. Various forms of prodrugs are described in the following literature, for example: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al. al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0553] The in vivo effect of any one compound of the formulas disclosed herein may be partially exerted by one or more metabolites formed in the human or animal body after administration of any one compound of the formulas disclosed herein. As previously stated herein, the in vivo effect of any one compound of the formulas disclosed herein may also be exerted by the metabolism of a precursor compound (prodrug).

[0554] This disclosure appropriately excludes any individual compounds that do not possess the biological activity defined herein.

[0555] Conjugate containing lipid ligand units As used herein, the term “conjugate” refers to a compound or complex containing a nucleic acid agent covalently bound to a ligand. In some embodiments, the conjugate further comprises lipid ligand units as described herein.

[0556] In some aspects, this disclosure is, (i) one or more nucleic acid agents, and (iii) Provides a conjugate comprising one or more lipid ligand units or a pharmaceutically acceptable salt thereof, wherein each lipid ligand unit is independently: [ka] During the ceremony, Variables L, B, V, Q, X, R a , n, R Y , R Z , R 1 , R 2 , R 3 , R 4 , and R 5 This is described in this specification, and When the lipid ligand unit is located at the 3' end of the nucleic acid agent, # is a binding to the rest of the conjugate, and ## is H, -P(R Y )2, -P(OR Y)(N(R Y )2), -P(=O)(OR Y )R Y , -P(=S)(OR Y )R Y -P(=O)(SR Y )R Y -P(=S)(SR Y )R Y , -P(=O)(OR Y )2, -P(=S)(OR Y )2, -P(=O)(SR Y )2, -P(=S)(SR Y )2, or a hydroxy protecting group, When the lipid ligand unit is located at the 5' end of the nucleic acid agent, # is H, -P(R Z )2, -P(OR Z )(N(R Z )2), -P(=O)(OR Z )R Z , -P(=S)(OR Z )R Z -P(=O)(SR Z )R Z -P(=S)(SR Z )R Z , -P(=O)(OR Z )2, -P(=S)(OR Z )2, -P(=O)(SR Z )2, -P(=S)(SR Z )2, or a hydroxy protecting group, ## is the binding to the rest of the conjugate, or # and ## are independent bindings to the rest of the conjugate.

[0557] It is understood that one or more lipid ligand units can independently bind to one or more nucleic acid agents at terminal or internal positions. Furthermore, if a nucleic acid agent contains multiple chains (e.g., sense and antisense chains), it is understood that one or more lipid ligand units can bind to the same or different chains of the nucleic acid agent.

[0558] In some embodiments, # is H, -P(R Z )2, -P(OR Z )(N(R Z )2), -P(=O)(OR Z )R Z , -P(=S)(OR Z )R Z -P(=O)(SR Z )R Z -P(=S)(SR Z )R Z , -P(=O)(OR Z )2, -P(=S)(OR Z )2, -P(=O)(SR Z )2, -P(=S)(SR Z )2, or a hydroxy protecting group, and ## is a bond to the rest of the conjugate.

[0559] In some embodiments, # is a conjugate to the rest of the conjugate, and ## is H, -P(R Y )2, -P(OR Y )(N(R Y )2), -P(=O)(OR Y )R Y , -P(=S)(OR Y )R Y -P(=O)(SR Y )R Y -P(=S)(SR Y )R Y , -P(=O)(OR Y )2, -P(=S)(OR Y )2, -P(=O)(SR Y )2, -P(=S)(SR Y )2, or a hydroxy protecting group.

[0560] In some embodiments, # and ## are independently bindings to the rest of the conjugate.

[0561] In some embodiments, the conjugate further includes one or more linker units.

[0562] In some embodiments, the conjugate comprises double-stranded RNA (e.g., double-stranded siRNA) and one or more lipid ligand units.

[0563] In some embodiments, one or more lipid ligand units are directly bound to a nucleic acid agent (e.g., siRNA).

[0564] In some embodiments, one or more lipid ligand units are bound to a nucleic acid agent (e.g., siRNA) via one or more linker units.

[0565] In some embodiments, the conjugate is (Nucleic acid agent) - [(Linker unit)] 0-1 -(Lipid system ligand units)] 1-3 ,or [(Lipid ligand unit)-(Linker unit)] 0-1 ] 1-3 -(Nucleic acid agent)-[(Linker unit)] 0-1 -(Lipid system ligand units)] 1-3 , including, In this case, when the linker unit and the lipid ligand unit are bound to the nucleic acid agent (e.g., siRNA), they are independently bound to either a terminal position (e.g., a nucleotide at the 3' or 5' end) or an internal position (e.g., a nucleotide that is not at the 3' or 5' end) of the nucleic acid agent (e.g., siRNA).

[0566] In some embodiments, the conjugate includes: [ka] [ka] In this case, the nucleic acid agent may be optionally further bound to one or more linker units and one or more lipid ligand units at one or more positions within the nucleic acid agent, according to the binding described herein.

[0567] One or more bindings to the nucleic acid agent can independently occur at one or more internal positions of the nucleic acid agent, for example, on the sense strand and / or antisense strand (e.g., [ka] ), 3'-terminal position (for example, [ka] ), or at the 5'-terminal position (for example, [ka] It is understood that this is possible.

[0568] In some embodiments, the conjugate is selected from the conjugates shown in Figure 3.

[0569] In some embodiments, at least one lipid ligand unit in the conjugate is: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0570] In some embodiments, at least one lipid ligand unit in the conjugate is selected from the structures listed in Table C. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] Table 6-5 Table 6-6 Table 6-7 Table 6-8 Table 6-9 Table 6-10 Table 6-11 Table 6-12 Table 6-13 Table 6-14 Table 6-15 Table 6-16 Table 6-17 Table 6-18 Table 6-19 Table 6-20 Table 6-21 [Table 6-22]

[0571] In some embodiments, at least one lipid ligand unit in the conjugate is selected from the structures listed in Table N. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12] [Table 7-13] [Table 7-14] [Table 7-15] [Table 7-16] [Table 7-17] [Table 7-18] [Table 7-19] [Table 7-20]

[0572] In some embodiments, at least one lipid ligand unit in the conjugate is selected from the structures listed in Table Q. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9]

[0573] Lipid ligand units As used herein, “lipid ligand unit” refers to a portion of a lipid ligand agent in which the 5', 2', and / or 3' positions are bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0574] In some embodiments, the lipid ligand unit corresponds to a lipid ligand agent whose 5' position is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0575] In some embodiments, the lipid ligand unit corresponds to a lipid ligand agent whose 3' position is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0576] In some embodiments, the lipid ligand unit corresponds to a lipid ligand agent in which the 2' position is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent.

[0577] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (I), (II), (III), or (IV), where, The 3' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0578] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (I), (II), (III), or (IV), where, The 2' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0579] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (I'), (II'), (III'), or (IV'), where, The 3' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0580] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (I'), (II'), (III'), or (IV'), where, The 2' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0581] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (IA), (II-A), (III-A), (IV-A), (VA), (VI-A), (VII-A), (VIII-A), (IX-A), (XA), (XI-A), or (XII-A), where, The 3' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0582] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (IA), (II-A), (III-A), (IV-A), (VA), (VI-A), (VII-A), (VIII-A), (IX-A), (XA), (XI-A), or (XII-A), where, The 2' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0583] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (I'-A), (II'-A), (III'-A), (IV'-A), (V'-A), (VI'-A), (VII'-A), (VIII'-A), (IX'-A), (X'-A), (XI'-A), or (XII'-A), where, The 3' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0584] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (I'-A), (II'-A), (III'-A), (IV'-A), (V'-A), (VI'-A), (VII'-A), (VIII'-A), (IX'-A), (X'-A), (XI'-A), or (XII'-A), where, The 2' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0585] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (IB), (II-B), (III-B), (IV-B), (VB), or (VI-B), where, The 3' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0586] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (IB), (II-B), (III-B), (IV-B), (VB), or (VI-B), where, The 2' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0587] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (I'-B), (II'-B), (III'-B), (IV'-B), (V'-B), or (VI'-B), where, The 3' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0588] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (I'-B), (II'-B), (III'-B), (IV'-B), (V'-B), or (VI'-B), where, The 2' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0589] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (IC), (II-C), (III-C), (IV-C), (VC), (VI-C), (VII-C), (VIII-C), (IX-C), (XC), (XI-C), or (XII-C), where, The 3' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0590] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (IC), (II-C), (III-C), (IV-C), (VC), (VI-C), (VII-C), (VIII-C), (IX-C), (XC), (XI-C), or (XII-C), where, The 2' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0591] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (I'-C), (II'-C), (III'-C), (IV'-C), (V'-C), (VI'-C), (VII'-C), (VIII'-C), (IX'-C), (X'-C), (XI'-C), or (XII'-C), where, The 3' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0592] In some embodiments, at least one lipid ligand unit corresponds to a lipid ligand agent of formula (I'-C), (II'-C), (III'-C), (IV'-C), (V'-C), (VI'-C), (VII'-C), (VIII'-C), (IX'-C), (X'-C), (XI'-C), or (XII'-C), where, The 2' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0593] In some embodiments, at least one lipid ligand unit is selected from Table C, in which case, The 3' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0594] In some embodiments, at least one lipid ligand unit is selected from Table C, in which case, The 2' position of the lipid ligand unit is bound to the nucleic acid agent at the 5' end, 3' end, or internal position of the nucleic acid agent, and / or The 5' position of the lipid ligand unit is bound to the nucleic acid agent at its 5' end, 3' end, or internal position.

[0595] Linker unit As used herein, "linker unit" refers to a lipid ligand unit and a portion having a bond to a nucleic acid agent.

[0596] In some embodiments, the linker unit is a ribose derivative.

[0597] In some embodiments, the linker unit is a 1'-alkyl-modified ribose derivative, as described, for example, in PCT application PCT / US2022 / 039517 (incorporated herein by reference).

[0598] In some embodiments, the linker unit is a 2'-alkyl or 3'-alkyl modified ribose derivative, as described, for example, in PCT application PCT / US2022 / 044377 (incorporated herein by reference).

[0599] In some embodiments, the linker unit is a polyhydroxylated cyclopentane derivative, as described, for example, in PCT application PCT / US2022 / 045748 (incorporated herein by reference).

[0600] Nucleic acid agents In some embodiments, the nucleic acid agent includes an oligonucleotide.

[0601] In some embodiments, the nucleic acid agent (e.g., an oligonucleotide) comprises one or more phosphate groups, or one or more phosphate group analogs.

[0602] In some embodiments, the linker unit is bonded to the nucleic acid agent (e.g., an oligonucleotide) via a phosphate group in the nucleic acid agent or a phosphate group analog.

[0603] In some embodiments, the oligonucleotide has a length of 1 to 40 nucleotides, 10 to 40 nucleotides, 12 to 35 nucleotides, 15 to 30 nucleotides, 18 to 25 nucleotides, or 20 to 23 nucleotides. In some embodiments, the oligonucleotide has a length of 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides. In some embodiments, the oligonucleotide has a length of 20, 21, 22, or 23 nucleotides.

[0604] In some embodiments, the nucleic acid agent includes RNA, DNA, or a mixture thereof.

[0605] In some embodiments, the nucleic acid agent includes RNA.

[0606] In some embodiments, the oligonucleotide is siRNA (e.g., single-stranded siRNA (e.g., hairpin single-stranded siRNA) or double-stranded siRNA), microRNA, antimicroRNA, microRNA mimetic, antagomir, dsRNA, ssRNA, aptamer, immunostimulatory oligonucleotide, decoy oligonucleotide, splicing-modified oligonucleotide, triple-stranded oligonucleotide, G-quadrivalent oligonucleotide, or antisense oligonucleotide.

[0607] In some embodiments, the nucleic acid agent comprises double-stranded RNA (dsRNA), in which case the double-stranded RNA comprises a sense strand and an antisense strand as described herein.

[0608] In some embodiments, the nucleic acid agent comprises a double-stranded siRNA (ds-siRNA), in which case the double-stranded siRNA comprises a sense strand and an antisense strand as described herein.

[0609] The sense chain is also known as the passenger chain, and the terms "sense chain" and "passenger chain" are used interchangeably herein.

[0610] The antisense chain is also known as the guide chain, and the terms "antisense chain" and "guide chain" are used interchangeably herein.

[0611] In some embodiments, the oligonucleotide is iRNA.

[0612] The term "iRNA" refers to RNA agents that can downregulate the expression of target genes (e.g., siRNA), such as endogenous or pathogenic target RNAs. While not intended to be theoretical, iRNAs can act through one or more of numerous mechanisms, including post-transcriptional cleavage of target mRNA (referred to in this art as RNAi), or pre-transcriptional or pre-translational mechanisms. iRNAs may be single-stranded or multi-stranded; for example, they may be double-stranded iRNAs. If an iRNA is single-stranded, it may contain 5' modifications, such as one or more phosphate groups or one or more phosphate group analogs. In some embodiments, iRNAs are double-stranded. In some embodiments, one or both strands of a double-stranded iRNA may be modified, such as a 5' modification.

[0613] The iRNA agent contains a region sufficiently homologous to the target gene and is of sufficient length in terms of nucleotides, thereby allowing the iRNA or a fragment to mediate the downregulation of the target gene. The iRNA agent is a region that is at least partially, and in some embodiments, fully complementary to the target RNA, or contains such a region. Complete complementarity between the iRNA and the target is not required, but the match may be sufficient for the iRNA or its cleavage product to induce sequence-specific silencing of the target RNA, such as mRNA, by RNAi cleavage.

[0614] Nucleotides in iRNA can be modified (for example, one or more nucleotides may contain a 2'-F group or a 2'-OCH3 group, or may be nucleotide substitutes). Single-stranded or double-stranded regions of iRNA may be modified or contain nucleotide substitutes, such as regions that do not form a hairpin pair, such as regions that link two complementary regions. Modifications stabilize one or more 3' or 5' ends of iRNA, for example, in terms of stability against exonucleases. Examples of modifications include C3 (or C6, C7, C12) aminolinkers, thiol linkers, carboxyl linkers, non-nucleotide spacers (C3, C6, C9, C12, non-basic, triethylene glycol, hexaethylene glycol), and certain biotin or fluorescein reagents that become phosphoramidites with another DMT-protected hydroxyl group, enabling multiple couplings during RNA synthesis. Other modifications include, for example, the use of modifications at the 2'OH group of ribose sugar, for example, the use of deoxyribonucleotides such as deoxythymidine instead of ribonucleotides, and for example, modifications of phosphate groups such as phosphothioate modifications. In some embodiments, different chains contain different modifications.

[0615] In some embodiments, the iRNA is selected such that it contains single-stranded or unpaired regions at one or both ends of the molecule. Double-stranded iRNA may have overhangs, for example, one or two 5' or 3' overhangs (e.g., 3' overhangs of at least 2-3 nucleotides). In some embodiments, the iRNA has overhangs at each end, such as 3' overhangs of 1, 2, or 3 nucleotides. The overhangs may result from one strand being longer than the other, or from two strands of equal length being twisted together.

[0616] In some embodiments, the double-stranded region between iRNA strands is 6 to 30 nucleotides long. In some embodiments, the double-stranded region is 15 to 30 nucleotides long, most preferably 18, 19, 20, 21, 22, and 23 nucleotides long. In some embodiments, the double-stranded region is 6 to 20 nucleotides long, most preferably 6, 7, 8, 9, 10, 11, and 12 nucleotides long.

[0617] The oligonucleotides may be those described in U.S. Patent Publications 2009 / 0239814, 2012 / 0136042, 2013 / 0158824, or 2009 / 0247608. Each of these documents is incorporated herein by reference.

[0618] In some embodiments, the oligonucleotide is siRNA.

[0619] In some embodiments, the oligonucleotide is a single-stranded siRNA.

[0620] In some embodiments, the oligonucleotide is a double-stranded siRNA, such as the double-stranded siRNA described herein.

[0621] As used herein, "single-stranded siRNA" is an siRNA consisting of a single strand and containing a double-stranded region formed by pairing within the strand, which may be, for example, a hairpin structure or a panhandle structure, or may contain such structures. The single-stranded siRNA may also be antisense against a target molecule.

[0622] The single-stranded iRNA may be long enough to enter RISC and participate in RISC-mediated target mRNA cleavage. The single-stranded siRNA is at least 14 nucleotides long, and in some embodiments, at least 15, 20, 25, 29, 35, 40, or 50 nucleotides long. In some embodiments, the single-stranded siRNA is less than 200, 100, 80, 60, 50, 40, or 30 nucleotides long.

[0623] In some embodiments, single-stranded siRNA has a length of 10–40 nucleotides, 12–35 nucleotides, 15–30 nucleotides, 18–25 nucleotides, or 20–23 nucleotides. In some embodiments, single-stranded siRNA has a length of 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides. In some embodiments, single-stranded siRNA has a length of 20, 21, 22, or 23 nucleotides.

[0624] A hairpin siRNA has a double-stranded region of at least 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotide pairs, or an equal amount. The double-stranded region may be 200, 100, or 50 nucleotides or less in length. In some embodiments, the double-stranded region ranges in length from 15 to 30, 17 to 23, 19 to 23, and 19 to 21 nucleotide pairs. The hairpin may have a single-stranded overhang or an unpaired terminal region. In some embodiments, the overhang is 2 to 3 nucleotides in length. In some embodiments, the overhang is on the sense side of the hairpin, and in some embodiments, it is on the antisense side of the hairpin.

[0625] In some embodiments, the oligonucleotide is a double-stranded siRNA.

[0626] As used herein, “double-stranded siRNA agent” is an siRNA agent comprising two or more strands, in some examples two strands, in which a double-stranded structure region may be formed by inter-strand hybridization.

[0627] In some embodiments, the sense strand of a double-stranded siRNA may be at least 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 29, 40, or 60 nucleotides long, or equal to that length. The sense strand may be 200, 100, or 50 nucleotides or less long. The range may be 17-25, 19-23, 19-21, 21-23, or 20-22 nucleotides long.

[0628] In some embodiments, the sense strand has a length of 10–40 nucleotides, 12–35 nucleotides, 15–30 nucleotides, 18–25 nucleotides, or 20–23 nucleotides. In some embodiments, the sense strand has a length of 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides. In some embodiments, the sense strand has a length of 20, 21, 22, or 23 nucleotides.

[0629] In some embodiments, the sense strand has a length of 18, 19, 20, 21, or 22 nucleotides.

[0630] In some embodiments, the antisense strand of the double-stranded siRNA may be at least 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 29, 40, or 60 nucleotides long, or equal to that length. The sense strand may be 200, 100, or 50 nucleotides or less long. The range may be 17-25, 19-23, 19-21, 21-23, or 20-22 nucleotides long.

[0631] In some embodiments, the antisense chain has a length of 10–40 nucleotides, 12–35 nucleotides, 15–30 nucleotides, 18–25 nucleotides, or 20–23 nucleotides. In some embodiments, the antisense chain has a length of 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides. In some embodiments, the antisense chain has a length of 20, 21, 22, or 23 nucleotides.

[0632] In some embodiments, the antisense chain has a length of 20, 21, 22, 23, or 24 nucleotides.

[0633] In some embodiments, the sense strand has a length of 18, 19, 20, 21, or 22 nucleotides, and the antisense strand has a length of 20, 21, 22, 23, or 24 nucleotides.

[0634] In some embodiments, the sense strand has a length of 18 nucleotides, and the antisense strand has a length of 20 nucleotides.

[0635] In some embodiments, the sense strand has a length of 19 nucleotides, and the antisense strand has a length of 21 nucleotides.

[0636] In some embodiments, the sense strand has a length of 20 nucleotides, and the antisense strand has a length of 22 nucleotides.

[0637] In some embodiments, the sense strand has a length of 21 nucleotides, and the antisense strand has a length of 23 nucleotides.

[0638] In some embodiments, the sense strand has a length of 22 nucleotides, and the antisense strand has a length of 24 nucleotides.

[0639] The double-stranded portion of a double-stranded siRNA may be at least 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 29, 40, or 60 nucleotide pairs long, or equal to such length. The double-stranded portion may be 200, 100, or 50 nucleotide pairs or less long. The range may be 15-30, 17-23, 19-23, and 19-21 nucleotide pairs long.

[0640] In some embodiments, the siRNA is large enough to be cleaved by endogenous molecules such as Dicer to produce even smaller siRNAs, such as siRNA agents.

[0641] The sense and antisense strands may be selected such that the double-stranded siRNA contains single-stranded or unpaired regions at one or both ends of the molecule. Thus, the double-stranded siRNA may contain sense and antisense strands paired to include overhangs, e.g., one or two 5' or 3' overhangs, or a 3' overhang of 1-3 nucleotides. The overhangs may result from one strand being longer than the other, or from two strands of equal length being twisted. Some embodiments have at least one 3' overhang. In some embodiments, both ends of the siRNA molecule have 3' overhangs. In some embodiments, the overhang is 2 nucleotides.

[0642] In some embodiments, the length of the double-stranded region is, for example, 15–30, or 18, 19, 20, 21, 22, and 23 nucleotides in the ssiRNA range considered above. The ssiRNA may be similar in length and structure to products naturally obtained by dicer treatment from longer dsiRNAs. Embodiments in which the two strands of the ssiRNA are joined, for example, covalently, are also included. Hairpin structures or other single-stranded structures that provide the required double-stranded region and 3' overhang are also anticipated.

[0643] The siRNAs described herein, including double-stranded and single-stranded siRNAs, can mediate the silencing of target RNA, such as mRNA, or transcripts of protein-coding genes. For convenience, such mRNA is also referred to herein as the silencing mRNA. Such genes are also called target genes. Generally, the silencing RNA is an endogenous gene or a pathogen gene. In addition, RNA other than mRNA, such as tRNA or viral RNA, can also be targeted.

[0644] As used herein, the phrase "RNAi-mediated" refers to the ability to silence target RNA in a sequence-specific manner. While we do not wish to be bound by theory, silencing is thought to be achieved through the RNAi mechanism or process, and the use of guide RNA, such as a 21-23 nucleotide ssiRNA.

[0645] In some embodiments, the siRNA is "sufficiently complementary" to the target RNA, e.g., the target mRNA, thereby silencing the production of the protein encoded by the target mRNA. In other embodiments, the siRNA is "exactly complementary" to the target RNA, e.g., the target RNA and the siRNA anneal to form a hybrid made up solely of Watson-Crick base pairs in the exactly complementary region. A "sufficiently complementary" target RNA may contain an internal region that is exactly complementary to the target RNA (e.g., an internal region of at least 10 nucleotides). In even more embodiments, the siRNA specifically recognizes a single-nucleotide difference. In this case, the siRNA mediates RNAi only if exact complementarity exists in the single-nucleotide difference region (e.g., a region of up to 7 nucleotides within a single-nucleotide difference).

[0646] MicroRNAs: MicroRNAs (miRNAs) are highly conserved small RNA molecules that are transcribed from DNA in plant and animal genomes but are not translated into proteins. Processed miRNAs are single-stranded, approximately 17-25 nucleotide (nt)RNA molecules that are incorporated into the RNA-induced silencing complex (RISC) and have been identified as important regulators of development, cell proliferation, apoptosis, and differentiation. miRNAs are thought to play a role in regulating gene expression by binding to the 3'-untranslated region of specific mRNAs. RISCs mediate downregulation of gene expression through translation inhibition, transcript cleavage, or both. RISCs are also involved in transcriptional silencing in the nuclei of a wide range of eukaryotes.

[0647] The number of miRNA sequences identified to date is large and increasing. Examples can be found, for instance, in “miRBase: microRNA sequences, targets and gene nomenclature” Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright A J. NAR, 2006, 34, Database Issue, D140-D144; and “The microRNA Registry” Griffiths-Jones S. NAR, 2004, 32, Database Issue, D109-D111.

[0648] Antisense Oligonucleotides: In some embodiments, the nucleic acid is an antisense oligonucleotide directed to a target polynucleotide. The term “antisense oligonucleotide,” or simply “antisense,” means that it contains an oligonucleotide complementary to the targeted polynucleotide sequence. An antisense oligonucleotide is a single strand of DNA or RNA that is complementary to a selected sequence, e.g., the target gene mRNA. Antisense oligonucleotides are thought to inhibit gene expression by binding to complementary mRNA. Binding to the target mRNA can inhibit gene expression by either inhibiting its translation by binding to the complementary mRNA strand, or by leading to the degradation of the target mRNA. Antisense DNA can be used to target specific complementary (coding or non-coding) RNA. If binding occurs, this DNA / RNA hybrid can be degraded by the enzyme RNase H. In some embodiments, the antisense oligonucleotide contains about 10 to about 50 nucleotides, more preferably about 15 to about 30 nucleotides. The term also includes antisense oligonucleotides that may not be exactly complementary to the desired target gene. Therefore, examples in which non-target-specific activity is present in the antisense, or in which the antisense sequence contains one or more mismatches with the target sequence, are most preferred for specific applications and are also expected.

[0649] Antisense oligonucleotides have been demonstrated to be effective and targeted inhibitors of protein synthesis, and as a result, can be used to specifically inhibit protein synthesis by target genes. The efficacy of antisense oligonucleotides in inhibiting protein synthesis is well established. For example, the synthesis of polygalacturonase and muscarinic acetylcholine receptor type 2 is inhibited by antisense oligonucleotides directed to their respective mRNA sequences (U.S. Patents 5,739,119 and 5,759,829; each patent incorporated by reference). Furthermore, examples of antisense inhibition have been demonstrated in nuclear protein cyclins, multidrug resistance genes (MDG1), ICAM-1, E-selectin, STK-1, striatal GABAA receptors, and human EGF (Jaskulski et al., Science. 1988 Jun. 10; 240(4858): 1544-6; Vasanthakumar and Ahmed, Cancer Commun. 1989; 1(4): 225-32; Peris et al., Brain Res Mol Brain Res. 1998 Jun. 15; 57(2): 310-20; U.S. Patents 5,801,154, 5,789,573, 5,718,709 and 5,610,288. Each reference is incorporated by reference). Furthermore, antisense constructs have been reported that can inhibit various abnormal cell proliferations, such as cancer, and can be used in their treatment (U.S. Patents 5,747,470, 5,591,317, and 5,783,683; each patent incorporated by reference).

[0650] Methods for constructing antisense oligonucleotides are well known in the art and can be readily adapted to construct antisense oligonucleotides targeting any polynucleotide sequence. Selection of antisense oligonucleotide sequences specific to a given target sequence is based on analysis of the selected target sequence, as well as determination of its secondary structure, Tm, binding energy, and relative stability. Antisense oligonucleotides may be selected based on their relative non-formation of dimers, hairpins, or other secondary structures that reduce or hinder specific binding to the target mRNA in host cells. Highly preferred target regions of mRNA include the AUG translation start codon region or its vicinity, and sequences substantially complementary to the 5' region of the mRNA. These secondary structure analyses and target site selections can be performed, for example, using OLIGO primer analysis software (Molecular Biology Insights) V.4 and / or BLASTN 2.0.5 algorithm software (Altschul et al., Nucleic Acids Res. 1997, 25(17):3389-402).

[0651] Antagomil: Antagomils are RNA-like oligonucleotides with various modifications for pharmacological properties such as RNAse defense and enhanced tissue and cellular uptake. They differ from ordinary RNA, for example, by complete 2'-O-methylation of sugars, a phosphorothioate backbone, and a cholesterol moiety at the 3' terminus. Antagomils can be used to efficiently silence endogenous miRNAs by forming a double helix containing the antagomil and endogenous miRNA, thereby preventing miRNA-induced gene silencing. An example of antagomil-mediated miRNA silencing is the silencing of miR-122 described in Krutzfeldt et al, Nature, 2005, 438:685-689. That literature is expressly incorporated herein by reference in its entirety. Antagomil RNA can be synthesized using standard solid-phase oligonucleotide synthesis protocols. See U.S. Patent Application Publications 2007 / 0123482 and 2007 / 0213292 (each document is incorporated herein by reference).

[0652] Antagomyl may comprise ligand-conjugate monomer subunits and monomers for oligonucleotide synthesis. Exemplary monomers are described in U.S. Patent Application Publication 2005 / 0107325 (which is incorporated by reference in its entirety). Antagomyl may have a ZXY structure, for example, as described in WO2004 / 080406. Antagomyl may be complexed with amphiphilic moieties. Examples of amphiphilic moieties for use with oligonucleotide agents are described in WO2004 / 080406 (which is incorporated by reference in its entirety).

[0653] Aptamers: Aptamers are nucleic acid or peptide molecules that bind to specific target molecules with high affinity and specificity (Tuerk and Gold, Science 249:505 (1990); Ellington and Szostak, Nature 346:818 (1990). Each reference is incorporated by reference in its entirety). Successful construction of DNA or RNA aptamers that bind to a wide variety of substances, from large proteins to small organic molecules, has been achieved. See Eaton, Curr. Opin. Chem. Biol. 1:10-16 (1997), Famulok, Curr. Opin. Struct. Biol. 9:324-9 (1999), and Hermann and Patel, Science 287:820-5 (2000). Each reference is incorporated by reference in its entirety. Aptamers may be RNA-based or DNA-based and may contain a riboswitch. Riboswitches are parts of mRNA molecules that can directly bind to small target molecules, thereby influencing gene activity. Therefore, mRNA containing riboswitches is directly involved in regulating its own activity depending on the presence or absence of its target molecule. Generally, aptamers are manipulated by repeated rounds of in vitro selection or by similar SELEX (systematic evolution of ligands by exponential enrichment) to bind to a variety of molecular targets, such as small molecules, proteins, nucleic acids, and even cells, tissues, and organisms. Aptamers may be produced by any known method, including synthesis, recombination, and purification methods, and may be used alone or in combination with other aptamers specific to the same target. Furthermore, as will be further detailed herein, the term “aptamer” specifically includes “secondary aptamers” containing consensus sequences obtained by comparing two or more known aptamers for a given target.

[0654] Ribozymes: In another embodiment, nucleic acid-lipid particles are associated with ribozymes. Ribozymes are RNA molecular complexes having a specific catalytic domain that possesses endonuclease activity (Kim and Cech, Proc Natl Acad Sci USA. 1987 December; 84(24): 8788-92; Forster and Symons, Cell. 1987 Apr. 24; 49(2): 211-20). For example, many ribozymes accelerate phosphoester transfer reactions with a high degree of specificity, often cleaving only one of several phosphoesters in an oligonucleotide substrate (Cech et al., Cell. 1981 December; 27(3 Pt 2): 487-96; Michel and Westhof, J Mol Biol. 1990 Dec. 5; 216(3): 585-610; Reinhold-Hurek and Shub, Nature. 1992 May 14; 357(6374): 173-6). This specificity stems from the requirement that the substrate binds to the internal guide sequence (IGS) of the ribozyme via specific base-pairing interactions, after which the chemical reaction takes place.

[0655] Currently, at least six basic types of naturally occurring enzyme RNAs have been identified. Each can catalyze the hydrolysis of RNA phosphodiester bonds in trans under physiological conditions (and thus cleave other RNA molecules). Generally, enzyme nucleic acids act by first binding to target RNA. Such binding occurs via the target-binding portion of the enzyme nucleic acid, which is held in close proximity to the enzyme portion of the molecule and acts to cleave the target RNA. Thus, the enzyme nucleic acid first recognizes the target RNA via complementary base pairing, then binds to it, and once bound to the correct site, acts enzymatically to cleave the target RNA. By strategically cleaving such target RNA, the synthesis of the encoded protein is prevented. After binding to and cleaving its RNA target, the enzyme nucleic acid can be released from the RNA, search for another target, and repeatedly bind to and cleave new targets.

[0656] Enzymatic nucleic acid molecules can be formed from, for example, hammerhead, hairpin, δ-type hepatitis virus, group I intron or RNaseP RNA (associated with an RNA guide sequence), or Neurospora crassa VS RNA motifs. Specific examples of hammerhead motifs are described in Rossi et al. Nucleic Acids Res. 1992 Sep. 11; 20(17): 4559-65. Examples of hairpin motifs are described in Hampel et al. (Eur. Pat. Appl. Publ. No. EP 0360257), Hampel and Tritz, Biochemistry 1989 Jun. 13; 28(12): 4929-33; Hampel et al., Nucleic Acids Res. 1990 Jan. 25; 18(2): 299-304, and U.S. Patent No. 5,631,359. Examples of δ hepatitis virus motifs are described in Perrotta and Been, Biochemistry. 1992 Dec. 1;31(47):11843-52. Examples of RNaseP motifs are described in Guerrier-Takada et al., Cell. 1983 December;35(3 Pt 2):849-57. Neurospora crassa VS RNA ribozyme motifs are described in Collins (Saville and Collins, Cell. 1990 May 18;61(4):685-96; Saville and Collins, Proc Natl Acad Sci USA. 1991 Oct. 1;88(19):8826-30; Collins and Olive, Biochemistry. 1993 Mar. 23;32(11):2795-9). Examples of group I introns are described in U.S. Patent No. 4,987,071. A key characteristic of the enzyme nucleic acid molecule used is that it has a specific substrate-binding site complementary to one or more regions of the DNA or RNA of the target gene, and that it has a nucleotide sequence within or around the substrate-binding site that confers RNA cleavage activity to the molecule. Therefore, ribozyme constructs are not limited to the specific motifs mentioned herein.

[0657] Methods for constructing ribozymes targeting arbitrary polynucleotide sequences are known in the art. Ribozymes may be designed as described in international patent application publications WO93 / 23569 and WO94 / 02595, and may be synthesized and validated in vivo and in vitro as described herein. These documents are specifically incorporated herein by reference.

[0658] Ribozyme activity can be optimized by altering the length of the ribozyme binding arm, or by chemically synthesizing the ribozyme with modifications to prevent degradation by serum ribonucleases (see, for example, International Patent Publications WO92 / 07065, WO93 / 15187, and WO91 / 03162, European Patent Publication 92110298.4, U.S. Patent No. 5,334,711, and International Patent Publication WO94 / 13688, which describe various chemical modifications that can be made to the sugar portion of the enzyme RNA molecule), by modifications to improve efficacy in cells, and by removing stem II bases to shorten RNA synthesis time and reduce chemical requirements.

[0659] Immunostimulatory Oligonucleotides Nucleic acids associated with lipid particles can be immunostimulant and, when administered to a target, can induce an immune response. These targets may be mammals or other patients. Examples of ISSes include certain palindromes that result in hairpin secondary structures (Yamamoto S., et al. (1992) J.Immunol. 148:4072-4076; this document is incorporated by reference in its entirety), or CpG motifs, as well as other known ISS mechanisms (e.g., multi-G domains; see WO96 / 11266; this document is incorporated by reference in its entirety).

[0660] The immune response may be an innate immune response or an adaptive immune response. The immune system can be further divided into the innate immune system and the acquired adaptive immune system in vertebrates. The latter can be further divided into humoral and cellular components. In some embodiments, the immune response may be mucosal.

[0661] In some embodiments, immunostimulant nucleic acids are immunostimulant only when administered in combination with lipid particles, and not immunostimulant when administered in a “free form.” Such oligonucleotides are considered immunostimulant.

[0662] Immunostimulatory nucleic acids are considered non-sequence-specific if they specifically bind to target polynucleotides to induce an immune response and do not require a reduction in their expression. Therefore, certain immunostimulatory nucleic acids may contain sequences corresponding to spontaneously occurring gene or mRNA regions, but can still be considered non-sequence-specific.

[0663] In some embodiments, the immunostimulatory nucleic acid or oligonucleotide contains at least one CpG dinucleotide. The oligonucleotide or CpG dinucleotide may or may not be methylated. In another embodiment, the immunostimulatory nucleic acid contains at least one CpG dinucleotide having methylated cytosine. In some embodiments, the nucleic acid contains one CpG dinucleotide, in which case the cytosine in the CpG dinucleotide is methylated. In another embodiment, the nucleic acid contains at least two CpG dinucleotides, in which case at least one cytosine in the CpG dinucleotide is methylated. In a further embodiment, each cytosine in the CpG dinucleotides present in the sequence is methylated. In another embodiment, the nucleic acid contains multiple CpG dinucleotides, in which case at least one of the CpG dinucleotides contains methylated cytosine.

[0664] Addition between lipid ligand units, linker units, and nucleic acid agents. In some embodiments, the addition between the lipid ligand unit and the linker unit is a binding.

[0665] In some embodiments, the addition between the lipid ligand unit and the linker unit is a portion (e.g., a portion containing a cleavable group).

[0666] In some embodiments, the addition between the lipid ligand unit and the linker unit includes -C(=O)- attached to the linker unit.

[0667] In some embodiments, the addition between the lipid ligand unit and the nucleic acid agent is a binding.

[0668] In some embodiments, the addition between the lipid ligand unit and the nucleic acid agent is a partial (e.g., a partial containing a cleavable group).

[0669] In some embodiments, the addition between the linker unit and the nucleic acid agent is a bond.

[0670] In some embodiments, the addition between the linker unit and the nucleic acid agent is a portion (e.g., a portion containing a cleavable group).

[0671] The addition between the lipid ligand unit, the linker unit, and the nucleic acid agent may be a cleavable or incleavable group.Suitable groups include, for example, -NR-, -C(=O)-, -C(=O)NH-, -S(=O)-, -S(=O)2-, -S(=O)2NH-, or a series of atoms, for example, but not limited to alkylene, alkenylene, alkynylene, arylalkylene, arylalkenylene, arylalkynylene, heteroarylalkylene, heteroarylalkenylene, heteroarylalkynylene, heterocyclylalkylene, heterocyclylalkenylene, heterocyclylalkynylene, arylene, heteroarylene, heterocyclylene, cyclo Alkylene, cycloalkenylene, alkylarylalkylene, alkylarylalkenylene, alkylarylalkylynylene, alkenylarylalkylene, alkenylarylalkenylene, alkenylarylalkylynylene, alkenylarylalkylynylene, alkenylarylalkylynylene, alkenylarylalkylynylene, alkenyl heteroarylalkylene, alkenyl heteroarylalkenylene Kenyl heteroarylalkylene, alkynyl heteroarylalkylene, alkynyl heteroarylalkenylene, alkynyl heteroarylalkylene, alkyl heterocyclylalkylene, alkyl heterocyclylalkenylene, alkylhererocyclylalkylene, alkenyl heterocyclylalkylene, alkenyl heterocyclylalkenylene, alkenyl heterocyclylalkylene, alkynyl heterocyclylalkylene, alkynyl heterocyclylalkenylene, alkynyl heterocyclylalkylene, alkylally Examples include ylenes, alkenyl arylenes, alkynyl arylenes, alkyl heteroarylenes, alkenyl heteroarylenes, or alkynyl herreroarylenes, each of which may be substituted or unsubstituted, and one or more methylene groups may be interrupted or terminated by -O-, -S-, -S(=O)-, -S(=O)2-, -NR-, -C(=O)-, substituted or unsubstituted aryls, substituted or unsubstituted heteroaryls, or substituted or unsubstituted heterocycles, in which case R is hydrogen, acyl, aliphatic, or substituted aliphatic.

[0672] A cleavable group is a group that is sufficiently stable outside the cell but is cleaved upon entering the target cell, releasing both of its constituent parts together. In a preferred embodiment, the cleavable group is cleaved at a rate at least 10 times, preferably at least 100 times faster, in the target cell or under a first reference condition (for example, a condition that can be selected to mimic or represent intracellular conditions) than in the target blood or under a second reference condition (for example, a condition that can be selected to mimic or represent conditions found in blood or serum).

[0673] Cleavable groups are susceptible to the influence of cleavage agents, such as pH, redox potential, or the presence of degradable molecules. Generally, cleavage agents are more frequently, or at higher levels or with greater activity, inside cells than in serum or blood. Examples of such degrading agents include redox agents that are selected for or do not have substrate specificity, such as oxidases or reductases or reducing agents present in cells, such as mercaptans, which can degrade redox-cleavable groups by reduction; esterases; endosomes; or agents that can create an acidic environment, such as agents that result in a pH of 5 or less; and enzymes that can hydrolyze or degrade acid-cleavable groups by acting as general acids, peptidases (which may be substrate-specific), and phosphatases.

[0674] For example, cleavable groups such as disulfide bonds may be pH-sensitive. The pH of human serum is 7.4, while the average intracellular pH is slightly lower, ranging from approximately 7.1 to 7.3. Endosomes have a more acidic pH ranging from 5.5 to 6.0, and lysosomes have an even more acidic pH of approximately 5.0. Some linkers have cleavable groups that are cleaved at a favorable pH, thereby releasing cationic lipids from intracellular ligands or into desired compartments of the cell.

[0675] The conjugate may contain a cleavable group that can be cleaved by a specific enzyme. The type of cleavable group incorporated into the conjugate may depend on the target cell. For example, a liver-targeting ligand may be attached to a cationic lipid via a chemical moiety containing an ester group. Hepatocytes are rich in esterases, and the group is cleaved more efficiently in hepatocytes than in cell types that are not rich in esterases. Other cell types rich in esterases include lung, renal cortex, and testicular cells.

[0676] For example, when targeting peptidase-rich cell types such as hepatocytes or synovial cells, coupling groups containing peptide bonds may be used.

[0677] In general, the suitability of a candidate cleavable group can be evaluated by testing the ability (or conditions) under which a degrading agent cleaves the candidate group. It is also desirable to test the candidate cleavable group for resistance to cleavage in blood or in contact with other non-target tissues. Thus, relative sensitivity to cleavage may be determined between first and second conditions, in which case the first condition is selected to show cleavage in target cells, and the second condition is selected to show cleavage in other tissues or biological fluids, for example, in blood or serum. Evaluation may be carried out in a cell-free system, in cells, in cell culture, in organ or tissue culture, or in a whole animal. It may be useful to perform an initial evaluation in cell-free or culture conditions and then confirm it by further evaluation in a whole animal. In a preferred embodiment, a useful candidate compound is cleaved at least about 2, 4, 10, or 100 times faster in cells (or in vitro conditions selected to mimic intracellular conditions) compared with blood or serum (or in vitro conditions selected to mimic extracellular conditions).

[0678] Redox-cleavable groups. One type of cleavable group is a redox-cleavable group that is cleaved by reduction or oxidation. An example of a reductively cleavable group is a disulfide bond group (-SS-). Methods described herein may be attempted to determine whether a candidate cleavable group is a suitable “reductively cleavable group” or, for example, suitable for use with a particular iRNA moiety and a particular targeting agent. For example, a candidate can be evaluated by incubation with dithiothreitol (DTT) or another reducing agent using reagents known in the art that mimic the rate of cleavage observed in cells, e.g., in target cells. Candidates may also be evaluated under conditions selected to mimic blood or serum conditions. In a preferred embodiment, the candidate compound is cleaved by up to 10% in blood. In a preferred embodiment, a useful candidate compound is degraded at least about 2, 4, 10, or 100 times faster in cells (or under in vitro conditions selected to mimic intracellular conditions) compared to blood (or under in vitro conditions selected to mimic extracellular conditions). The cleavage rate of candidate compounds can be determined using standard enzyme kinetic assays under conditions selected to mimic intracellular media and compared to conditions selected to mimic extracellular media.

[0679] Phosphate-based cleavable groups. Phosphate-based cleavable groups are cleaved by agents that decompose or hydrolyze the phosphate group. Examples of agents that cleave phosphate groups in cells include enzymes such as phosphatases in cells. In some embodiments, the phosphate-based binding group is -OP(=O)(OR k )-O-, -OP(=S)(OR k )-O-, -OP(=S)(SR k )-O-, -SP(=O)(OR k )-O-, -OP(=O)(OR k )-S-, -SP(=O)(OR k )-S-, -OP(=S)(OR k )-s-, -SP(=S)(OR k )-O-, -OP(=O)(Rk )-O-, -OP(=S)(R k )-O-, -SP(=O)(R k )-O-, -SP(=S)(R k )-O-, -SP(=O)(R k )-S-, or -OP(=S)(R k In some embodiments, the phosphate-based binding group is -OP(=O)(OH)-O-, -OP(=S)(OH)-O-, -OP(=S)(SH)-O-, -SP(=O)(OH)-O-, -OP(=O)(OH)-S-, -SP(=O)(OH)-S-, -OP(=S)(OH)-S-, -SP(=S)(OH)-O-, -OP(=O)(H)-O-, -OP(=S)(H)-O-, -SP(=O)(H)-O-, -SP(=O)(H)-O-, -SP(=O)(H)-S-, or -OP(=S)(H)-S-. In some embodiments, the phosphate-based binding group is -OP(=O)(OH)-O-.

[0680] Acid-cleavable groups. Acid-cleavable groups are binding groups that are cleaved under acidic conditions. In preferred embodiments, acid-cleavable groups are cleaved in an acidic environment with a pH of about 6.5 or less (e.g., about 6.0, 5.5, 5.0 or less), or by agents such as enzymes that can act as common acids. Within cells, certain low-pH organelles, such as endosomes and lysosomes, can provide a cleavage environment for acid-cleavable binding groups. Examples of acid-cleavable groups, but not limited to, include hydrazones, esters, and amino acid esters. Acid-cleavable groups may have the general formula -C=NN-, C(O)O, or -OC(O). In preferred embodiments, the carbon bonded to the oxygen of the ester (alkoxy group) is an aryl group, a substituted alkyl group, or a tertiary alkyl group, such as dimethylpentyl or t-butyl. These candidates can be evaluated using methods similar to those described above.

[0681] Esteric cleavable groups. These esteric cleavable groups are cleaved in cells by enzymes such as esterases and amidases. Examples of esteric cleavable groups include, but are not limited to, esters of alkylene, alkenylene, and alkynylene groups. The cleavable binding group of an ester has the general formula -C(O)O- or -OC(O)-. These candidates can be evaluated using methods similar to those described above.

[0682] Cleavable groups of peptides. Cleavable groups of peptides are cleaved in cells by enzymes such as peptidases and proteases. Cleavable groups of peptides are peptide bonds formed between amino acids, creating oligopeptides (e.g., dipeptides, tripeptides, etc.) and polypeptides. Cleavable groups of peptides do not include amide groups (-C(O)NH-). Amide groups can be formed between any alkylene, alkenylene, or alkylene. Peptide bonds are a special type of amide bond formed between amino acids, creating peptides and proteins. Cleavable groups of peptides are generally limited to peptide bonds (i.e., amide bonds) formed between amino acids to create peptides and proteins, and do not include the entire amide functional group. The cleavable bonding group of peptides has the general formula -NHCHR A C(O)NHCHR B It contains C(O)-, in the formula, R A and R BThese are the R groups of two adjacent amino acids. These candidates can be evaluated using methods similar to those described above. As used herein, "carbohydrate" refers to a compound that is either a carbohydrate itself, which is composed of one or more monosaccharide units having at least six carbon atoms (which may be linear, branched, or cyclic), with each carbon atom bonded to an oxygen, nitrogen, or sulfur atom, or a compound that has a carbohydrate portion as part thereof, which is composed of one or more monosaccharide units having at least six carbon atoms (which may be linear, branched, or cyclic), with each carbon atom bonded to an oxygen, nitrogen, or sulfur atom. Typical carbohydrates include sugars (monosaccharides, disaccharides, trisaccharides, and oligosaccharides containing about 4 to 9 monosaccharide units), as well as polysaccharides such as starch, glycogen, cellulose, and polysaccharide gums. Specific monosaccharides include sugars with C5 or more (preferably C5 to C8). Disaccharides and trisaccharides include sugars having 2 or 3 monosaccharide units (preferably C5 to C8).

[0683] Synthesis method In some embodiments, this disclosure provides methods for producing the compounds described herein (e.g., lipid ligands).

[0684] In some embodiments, this disclosure provides compounds that can be obtained or are obtained by methods for producing the compounds described herein (e.g., lipid ligands).

[0685] In some embodiments, the Disclosure provides intermediates described herein that are suitable for use in methods for producing compounds described herein (e.g., lipid ligands).

[0686] The compounds of this disclosure can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the attached examples.

[0687] In the descriptions of the synthesis methods described herein, and in any synthesis methods optionally mentioned for preparing the starting materials, it should be understood that all proposed reaction conditions, including the selection of solvent, reaction atmosphere, reaction temperature, experimental duration, and work-up procedure, can be selected by those skilled in the art.

[0688] Those skilled in organic synthesis understand that the functional groups present in various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0689] It will be understood that in the processes defined herein, during the synthesis of the compounds of this disclosure, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesirable reactions. An experienced chemist will understand when such protection is necessary and how to position and subsequently remove such protecting groups. For examples of protecting groups, see one of the many general texts on the subject, e.g., 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any conventional method described in the literature or known to an experienced chemist, suitable for the removal of the protecting group in question, and such method should be selected so as to remove the protecting group while minimizing interference with other groups in the molecule. Thus, if the reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect the groups in some of the reactions described herein.

[0690] For example, suitable protecting groups for amino groups or alkylamino groups include, for instance, acyl groups, such as alkanoyl groups like acetyl; alkoxycarbonyl groups, such as methoxycarbonyl groups, ethoxycarbonyl groups, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups; or aroyl groups, such as benzoyl groups. Suitable protecting groups for hydroxyl or alkylhydroxyl groups may be, for example, acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl ether (MEM), dimethoxytrityl (DMT), methoxymethyl ether (MOM), methoxytrityl (MMT), p-methoxybenzyl ether (PMB), p-methoxyphenyl ether (PMP), pivaloyl (Piv), tetrahydropyranyl (THP), tetrahydrofuran (THF), trityl (triphenylmethyl, Tr), silyl ethers (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), methyl ethers, or ethoxyethyl ethers (EE). Suitable protecting groups for 1,2-diols may be, for example, acetals. A suitable protecting group for 1,3-diols may be, for example, tetraisopropyl disiloxanylidene (TIPDS).

[0691] The deprotection conditions for the above protecting groups inevitably change depending on the choice of protecting group. For example, acyl groups such as alkanoyl or alkoxycarbonyl groups, or aroyl groups, can be removed by hydrolysis with an appropriate base such as an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butoxycarbonyl groups can be removed by treatment with an appropriate acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid. Arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed by hydrogenation with a catalyst such as palladium carbon, or by treatment with a Lewis acid such as boron tris(trifluoroacetic acid). Another suitable protecting group for primary amino groups is the phthaloyl group, which can be removed by treatment with an alkylamine, such as dimethylaminopropylamine, or hydrazine.

[0692] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups like acetyl, alloyl groups like benzoyl, or arylmethyl groups like benzyl. The deprotection conditions for the above protecting groups inevitably change depending on the choice of protecting group. For example, acyl groups such as alkanoyl or alloyl groups can be removed by hydrolysis using a suitable base such as an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation on a catalyst such as palladium-carbon.

[0693] Suitable protecting groups for carboxyl groups include, for example, esterifying groups, such as methyl or ethyl groups which can be removed by hydrolysis with a base such as sodium hydroxide, or tert-butyl groups which can be removed by treatment with an acid, such as an organic acid such as trifluoroacetic acid, or benzyl groups which can be removed by hydrogenation with a catalyst such as palladium carbon.

[0694] The reaction of the compounds is preferable to be carried out in the presence of a suitable solvent, and the suitable solvent is preferably inert under the respective reaction conditions. Examples of suitable solvents, but are not limited to, include: hydrocarbons, e.g., hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons, e.g., trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols, e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers, e.g., diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane. These include glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglym); ketones, such as acetone, methyl isobutyl ketone (MIBK), or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the above solvents, or mixtures with water.

[0695] The reaction temperature is preferably between approximately -100°C and 300°C, depending on the reaction process and conditions used.

[0696] Reaction times generally range from a few minutes to several days, depending on the reactivity of each compound and the reaction conditions. A suitable reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperatures mentioned above, suitable reaction times generally range from 10 minutes to 48 hours.

[0697] Furthermore, by utilizing the procedures described herein, in addition to ordinary skills in the art, the additional compounds disclosed herein can be readily prepared. Those skilled in the art will readily understand that these compounds can be prepared using known variations of the conditions and processes of the following preparation procedures.

[0698] As will be understood by those skilled in the art of organic synthesis, the compounds of this disclosure are readily available through a variety of synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize what kinds of reagents and reaction conditions to use to obtain the compounds of this disclosure, and how they are applied and adapted whenever necessary or useful in any particular case. Furthermore, some of the compounds of this disclosure can be readily synthesized by reacting other compounds of this disclosure under suitable conditions, for example, by converting certain functional groups present in the compounds of this disclosure or their suitable precursors to others by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions, which are known to those skilled in the art. Similarly, those skilled in the art can apply synthetic protecting (or safeguarding) groups whenever necessary or useful. Suitable safeguarding groups and methods for introducing and removing them are known to those skilled in the art of chemical synthesis, and are described in detail, for example, PGMWuts, TW Greene, “Greene's Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0699] The general route for the preparation of the compounds of this application is described in schemes A and B of this specification. Scheme A [ka] Scheme B [ka]

[0700] Compounds (e.g., nucleic acid agents, lipid ligands, and conjugates) were prepared by solid-phase synthesis according to standard synthesis protocols, or by post-synthesis conjugation.

[0701] In short, oligonucleotide synthesis was performed on a solid support, and each nucleoside phosphoramidite was incorporated from the 3'-terminus to the 5'-terminus to prepare single-chain oligonucleotides. ETT or BTT was used as an activator for the coupling reaction. Iodine in water / pyridine / THF was used to oxidize the phosphate tryster (P(III)) to obtain the phosphate backbone, and DDTT was used to prepare the phosphorothioate bond. The oligonucleotides were cleaved from the solid support using an aqueous ammonium solution, and the protecting groups were removed overall. The crude oligonucleotide product was then concentrated and purified by strong anion exchange or reverse-phase HPLC. The purified fractions were combined and concentrated.

[0702] In some cases, the oligonucleotide single chain was subsequently conjugated with a targeted ligand (e.g., a natural lipid or modified lipid) via post-synthesis conjugation to obtain a conjugate. The conjugation reaction was carried out using standard conjugation methods. The crude conjugate product was further purified by strong anion exchange or reverse-phase HPLC. The purified fractions were combined and concentrated.

[0703] Next, the synthesized single-stranded molecules were dialyzed against water using a MidiTrap G-25 column or an Amicon MWCO filter, concentrated, and their OD (Oxygen-Digital) amounts were measured. Based on equimolar amounts, the sense and antisense strands were annealed at 95°C for 5 minutes and cooled to room temperature to obtain conjugated double-stranded molecules with a purity of over 90%. The double-stranded solution was freeze-dried to obtain the desired conjugate. Its amount was calculated based on the molar amount of single-stranded molecules consumed during annealing.

[0704] Biological assays Once compounds (e.g., lipid-based lipid agents) or conjugates designed, selected, prepared, and / or optimized by the methods described above have been generated, they may be characterized using various assays known to those skilled in the art to determine whether they have biological activity. For example, compounds or conjugates may be characterized by conventional assays, including, but not limited to, those described below, to determine whether they have desirable activity, such as target-binding activity, and / or specificity and / or stability.

[0705] Furthermore, high-throughput screening can be used to expedite analysis using such assays. As a result, it may be possible to rapidly screen for the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263. High-throughput assays may be one or more different assay techniques, including, but are not limited to, those described below.

[0706] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds or conjugates of this disclosure. These in vitro or in vivo biological assays include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell survival assays, and the assays described herein.

[0707] In some embodiments, biological assays are described in the examples herein.

[0708] In some embodiments, the Disclosure provides a pharmaceutical composition comprising one of the compounds or conjugates of the Disclosure as an active ingredient.

[0709] As used herein, the term “composition” shall encompass any product containing a specific amount of a specific component, as well as any product obtained directly or indirectly from a specific combination of a specific component.

[0710] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (if water-soluble) or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. Suitable carriers for intravenous administration include physiological saline, bacteriostatic water for injection, Cremophor EL® (BASF, Parsippany, New Jersey), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid enough to pass easily through an injection needle. The composition must be stable under manufacturing and storage conditions and protected from microbial contamination, such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by using a surfactant. The action of microorganisms can be inhibited by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Often, the composition preferably contains isotonic agents, such as sugars, polyhydric alcohols like mannitol and sorbitol, and sodium chloride. Sustained absorption of the injectable composition can be achieved by including absorption-delaying agents, such as aluminum monostearate or gelatin, in the composition.

[0711] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound in a suitable solvent, along with one or a combination of the components listed above as needed, and then sterilizing by filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and other necessary components from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods are vacuum drying and freeze-drying, thereby obtaining powders of the active ingredient and any additional desired components from those solutions that have been previously sterilized and filtered.

[0712] The formulations of the present disclosure may be in the form of aqueous solutions comprising an aqueous vehicle. The components of the aqueous vehicle may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonic agents, viscosity / suspensioning agents, buffering agents, and pH adjusters, as well as mixtures thereof.

[0713] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, as well as mixtures thereof, selected from the group.

[0714] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0715] Any suitable preservative can be used. Examples of preservatives include, for example, quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, melthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, as well as mixtures thereof, selected from the group.

[0716] The aqueous vehicle may also contain an isotonic agent to adjust its tonicity (osmotic pressure). The isotonic agent can be selected from the group consisting of glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, as well as mixtures thereof.

[0717] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, hydrochloric acid, and mixtures thereof, with sodium hydroxide and / or hydrochloric acid being preferred. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Therefore, depending on the formulation, it is not always necessary to use both an acid and a base, and the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0718] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffer (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffer (e.g., boric acid or its salts including disodium tetraborate), citrate buffer (e.g., citric acid or its salts including sodium citrate), ε-aminocaproic acid, and mixtures thereof.

[0719] In a further aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of the disclosure as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0720] The compositions of this disclosure may be in forms suitable for oral use (e.g., as tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as fine powders or liquid aerosols), administration by blowing (e.g., as fine powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0721] The compositions of this disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients known in the art. Accordingly, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings and / or preservatives.

[0722] An effective amount of the compounds of this disclosure for therapeutic use is sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with, an inflammasome-associated condition as referred to herein.

[0723] An effective amount of the compounds of this disclosure for therapeutic use is sufficient to treat, slow the progression of, and / or reduce the symptoms associated with, the inflammasome-associated conditions referred to herein.

[0724] The therapeutic or prophylactic doses of compounds of formula (I), (II), (III), or (IV) will inevitably vary according to known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0725] How to use In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in a subject, the method including administering the conjugate of the Disclosure to the subject.

[0726] In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in a cell or tissue of interest, the method including administering the conjugate of the Disclosure to the subject.

[0727] In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in a subject central nervous system tissue, peripheral nervous system tissue, eye tissue, white adipose tissue, brown adipose tissue, cardiac tissue, muscle tissue (e.g., quadriceps femoris tissue), adrenal gland tissue, and / or renal tissue, the method comprising administering the conjugate of the Disclosure to the subject.

[0728] In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in a subject white adipose tissue, brown adipose tissue, cardiac tissue, muscle tissue (e.g., quadriceps femoris tissue), adrenal tissue, and / or renal tissue, the method comprising administering the conjugate of the Disclosure to the subject.

[0729] In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in a subject white adipose tissue, brown adipose tissue, cardiac tissue, muscle tissue (e.g., quadriceps femoris tissue), adrenal tissue, and / or renal tissue, the method comprising administering the conjugate of the Disclosure to the subject, wherein the conjugate is C2-C 35 Hydrocarbon chains or 2- to 35-membered heterohydrocarbon chains (e.g., R L C2-C 35 It contains a lipid portion that includes a hydrocarbon chain or a heterohydrocarbon chain with 2 to 35 members.

[0730] In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in a subject white adipose tissue, brown adipose tissue, cardiac tissue, muscle tissue (e.g., quadriceps femoris tissue), adrenal tissue, and / or renal tissue, the method comprising administering the conjugate of the Disclosure to the subject, wherein the conjugate is C 20 -C 35 Hydrocarbon chains or 20-35 member heterohydrocarbon chains (e.g., R L C 20 -C 35 It contains a lipid portion that includes a hydrocarbon chain or a heterohydrocarbon chain with 20 to 35 members.

[0731] In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in white adipose tissue, brown adipose tissue, cardiac tissue, muscle tissue (e.g., quadriceps femoris tissue), adrenal tissue, and / or renal tissue, the method comprising administering the conjugate of the Disclosure to the subject, wherein the conjugate comprises L selected from the structures described in Table X.

[0732] In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in a subject central nervous system tissue, peripheral nervous system tissue, and / or ocular tissue, the method including administering the conjugate of the Disclosure to the subject.

[0733] In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in a subject central nervous system tissue, peripheral nervous system tissue, and / or ocular tissue, the method comprising administering the conjugate of the Disclosure to the subject, wherein the conjugate is C2-C 30 Hydrocarbon chains or 2- to 30-membered heterohydrocarbon chains (e.g., R L C2-C 30It contains a lipid portion that includes a hydrocarbon chain or a heterohydrocarbon chain with 2 to 30 members.

[0734] In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in a subject central nervous system tissue, peripheral nervous system tissue, and / or ocular tissue, the method comprising administering the conjugate of the Disclosure to the subject, in which case the conjugate is C 14 -C 20 Hydrocarbon chains or 14- to 20-membered heterohydrocarbon chains (e.g., R L C 14 -C 20 It contains a lipid portion that includes a hydrocarbon chain or a heterohydrocarbon chain with 14 to 20 members.

[0735] In certain embodiments, the Disclosure provides a method for modulating (e.g., reducing or eliminating) the expression of a target gene in a subject central nervous system tissue, peripheral nervous system tissue, and / or ocular tissue, the method comprising administering the conjugate of the Disclosure to the subject, wherein the conjugate comprises L selected from the structures described in Table Y.

[0736] In certain aspects, the Disclosure provides a method for delivering a nucleic acid agent to a subject, which includes administering the conjugate of the Disclosure to the subject.

[0737] In certain aspects, the Disclosure provides a method for treating or preventing a disease in a subject where such treatment is needed, and such method includes administering a therapeutically effective dose of the conjugate of the Disclosure to such subject.

[0738] In certain embodiments, the Disclosure provides a conjugate of the Disclosure for regulating (e.g., reducing or eliminating) the expression of a target gene in a subject.

[0739] In some embodiments, the Disclosure provides a conjugate of the Disclosure for modulating (e.g., reducing or eliminating) the expression of a target gene in a cell or tissue of interest.

[0740] In some embodiments, the Disclosure provides conjugates of the Disclosure for regulating (e.g., reducing or eliminating) the expression of target genes in the central nervous system tissue, peripheral nervous system tissue, eye tissue, white adipose tissue, brown adipose tissue, cardiac tissue, muscle tissue (e.g., quadriceps femoris tissue), adrenal tissue, and / or renal tissue.

[0741] In some embodiments, the Disclosure provides conjugates of the Disclosure for modulating (e.g., reducing or eliminating) the expression of target genes in the white adipose tissue, brown adipose tissue, cardiac tissue, muscle tissue (e.g., quadriceps femoris tissue), adrenal tissue, and / or renal tissue.

[0742] In certain embodiments, the Disclosure provides conjugates of the Disclosure for regulating (e.g., reducing or eliminating) the expression of a target gene in the central nervous system tissue, peripheral nervous system tissue, and / or ocular tissue.

[0743] In certain embodiments, the Disclosure provides a conjugate of the Disclosure for delivering nucleic acid agents to a subject.

[0744] In certain aspects, the Disclosure provides a conjugate of the Disclosure for treating or preventing a disease in a subject where such treatment is needed.

[0745] In some embodiments, the Disclosure provides the use of the conjugates of the Disclosure in the manufacture of a pharmaceutical product to modulate (e.g., reduce or eliminate) the expression of a target gene in a subject.

[0746] In some embodiments, the Disclosure provides the use of the conjugates of the Disclosure in the manufacture of a pharmaceutical product for modulating (e.g., reducing or eliminating) the expression of a target gene in a target cell or tissue.

[0747] In some embodiments, the Disclosure provides the use of the conjugates of the Disclosure in the manufacture of pharmaceuticals to modulate (e.g., reduce or eliminate) the expression of a target gene in the white adipose tissue, brown adipose tissue, cardiac tissue, muscle tissue (e.g., quadriceps femoris tissue), adrenal tissue, and / or renal tissue.

[0748] In certain embodiments, the Disclosure provides the use of the conjugates of the Disclosure in the manufacture of pharmaceuticals to modulate (e.g., reduce or eliminate) the expression of a target gene in the central nervous system tissue, peripheral nervous system tissue, and / or ocular tissue.

[0749] In some embodiments, the Disclosure provides the use of the Conjugate of the Disclosure in the manufacture of a pharmaceutical product for delivering nucleic acid agents to a subject.

[0750] In certain aspects, the Disclosure provides the use of the Conjugate of the Disclosure in the manufacture of a pharmaceutical product for treating or preventing a disease in a subject where such treatment is needed.

[0751] In some embodiments, the subject is a cell.

[0752] In some embodiments, the subject is an organization.

[0753] In some embodiments, the tissues covered are central nervous system tissue, peripheral nervous system tissue, eye tissue, white adipose tissue, brown adipose tissue, cardiac tissue, muscle tissue (e.g., quadriceps femoris tissue), adrenal gland tissue, and / or kidney tissue.

[0754] In some embodiments, the tissues to be studied are white adipose tissue, brown adipose tissue, cardiac tissue, muscle tissue (e.g., quadriceps femoris tissue), adrenal tissue, and / or kidney tissue.

[0755] In some embodiments, the subject is central nervous system tissue, peripheral nervous system tissue, and / or ocular tissue.

[0756] In some embodiments, the subject is a human.

[0757] In some embodiments, the target genes are Factor VII, Eg5, PCSK9, TPX2, apoB, SAA, TTR, HBV, HCV, RSV, PDGF beta gene, Erb-B gene, Src gene, CRK gene, GRB2 gene, RAS gene, MEKK gene, JNK gene, RAF gene, Erk1 / 2 gene, PCNA(p21) gene, MYB gene, JUN gene, FOS gene, BCL-2 gene, cyclin D gene, VEGF gene The mutations include genes, EGFR gene, cyclin A gene, cyclin E gene, WNT-1 gene, beta-catenin gene, c-MET gene, PKC gene, NFKB gene, STAT3 gene, survivor gene, Her2 / Neu gene, topoisomerase I gene, topoisomerase II alpha gene, p73 gene, p21 (WAF1 / CIP1) gene, p27 (KIP1) gene, PPM1D gene, RAS gene, caveolin I gene, MIB I gene, MTAI gene, M68 gene, mutations in tumor suppressor genes, p53 tumor suppressor gene, LDHA, or any combination thereof.

[0758] In some embodiments, the disease is characterized by the undesirable expression of a target gene.

[0759] In some embodiments, administration results in a decrease or elimination of the expression of the target gene in the subject.

[0760] In some embodiments, the disease is a viral infection, such as HCV, HBV, HPV, HSV, or HIV infection.

[0761] In some embodiments, the disease is cancer.

[0762] In some embodiments, cancer includes cholangiocarcinoma, bladder cancer, transitional cell carcinoma, urothelial carcinoma, brain tumor, glioma, astrocytoma, breast cancer, metaplastic carcinoma, cervical cancer, cervical squamous cell carcinoma, rectal cancer, colorectal cancer, colon cancer, hereditary nonpolyposis colorectal cancer, colorectal adenocarcinoma, gastrointestinal stromal tumor (GIST), endometrial cancer, endometrial stromal sarcoma, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, ocular melanoma, uveal melanoma, gallbladder cancer, gallbladder adenocarcinoma, renal cell carcinoma, clear cell renal cell carcinoma, Wilms' tumor, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CLL). MML), liver cancer, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, lung cancer, non-small cell lung cancer (NSCLC), mesothelioma, B-cell lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, T-cell lymphoma, progenitor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma, multiple myeloma, nasopharyngeal cancer (NPC), neuroblastoma, oropharyngeal cancer, oral squamous cell carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, pseudopapillary tumor, acinar cell carcinoma, prostate cancer, prostatic adenoma, skin cancer, melanoma, malignant melanoma, cutaneous melanoma, small intestine cancer, stomach cancer, gastric carcinoma, gastrointestinal stromal tumor (GIST), uterine cancer, or uterine sarcoma.

[0763] In some embodiments, the disease is a proliferative, inflammatory, autoimmune, nervous system, ocular, respiratory, metabolic, cutaneous, auditory, cardiac, muscular, adrenal, central nervous system, peripheral nervous system, liver, kidney, white adipose tissue, brown adipose tissue, and / or infectious disease.

[0764] In some embodiments, the disease is a disease of the central nervous system, peripheral nervous system, eye, heart, muscle, adrenal gland, kidney, white adipose tissue, and / or brown adipose tissue.

[0765] In some embodiments, the disease is a proliferative, inflammatory, autoimmune, nervous system, ocular, respiratory system, metabolic, cutaneous, auditory, cardiac, muscular, adrenal, liver, kidney, white adipose tissue, brown adipose tissue, and / or infectious disease.

[0766] In some embodiments, the disease is a disease of the heart, muscle, adrenal gland, kidney, white adipose tissue, and / or brown adipose tissue.

[0767] In some embodiments, the disease is proliferative, inflammatory, autoimmune, nervous system, ocular, respiratory, metabolic, cutaneous, auditory, central nervous system, peripheral nervous system, liver, kidney, or infectious disease.

[0768] In some embodiments, the disease is a disease of the central nervous system, the peripheral nervous system, or the eye tissue.

[0769] definition Unless otherwise stated, the following terms used in this specification and in the claims have the meanings set forth below.

[0770] While we do not intend to limit ourselves by this statement, and various options for the variables are described herein, this disclosure is intended to encompass implementable embodiments having combinations of options. This disclosure may be construed as excluding unimplementable embodiments caused by particular combinations of options.

[0771] As used herein, “hydrocarbon chain” means a linear or branched portion consisting of hydrogen and carbon, unless one or more substitutions are otherwise specified. In some embodiments, the hydrocarbon chain is a saturated hydrocarbon chain (e.g., alkyl). In some embodiments, the hydrocarbon chain is an unsaturated hydrocarbon chain (e.g., containing one or more double bonds and / or one or more triple bonds (e.g., alkenyl or alkynyl)). In some embodiments, the hydrocarbon chain has two substituents (e.g., two R L’ ) together with one or more interfacing atoms form a ring portion (e.g., a C3-C8 cycloalkyl or a 3-8 membered heterocycloalkyl), in which case the substituent includes at least one ring atom. When the ring portion is located inside the hydrocarbon chain, the hydrocarbon chain (e.g., C2-C 35The carbon atoms in the ring are counted via the shortest path through the ring (for example, [ka] It contains two carbon atoms of a hydrocarbon chain, in this case each [ka] (The symbol indicates the bonding point to the rest of the hydrocarbon chain). When the ring portion is located at the end of the hydrocarbon chain, the hydrocarbon chain (e.g., C2~C) 35 The carbon atoms of ) are counted via the longest path within the ring (for example, [ka] This includes two carbon atoms of a hydrocarbon chain, in this case, [ka] (The symbol indicates the bonding point to the rest of the hydrocarbon chain.)

[0772] As used herein, “heterohydrocarbon chain” means a linear or branched portion consisting of hydrogen, carbon, and one or more heteroatoms (such as O, N, S, P, or Se), for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 or 1-7 or 1-8 or 1-9 or 1-10 or 1-11 or 1-12 or 1-13 or 1-14 heteroatoms, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 heteroatoms, unless otherwise specified. A “X-membered” heterohydrocarbon chain means a heterohydrocarbon chain in which the total number of carbon atoms and heteroatoms on the longest path of the chain is “X” (e.g., a 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35-membered heterohydrocarbon chain), unless one or more substitutions are otherwise specified. In some embodiments, the heterohydrocarbon chain is a saturated heterohydrocarbon chain. In some embodiments, the heterohydrocarbon chain is an unsaturated heterohydrocarbon chain (e.g., containing one or more double bonds and / or one or more triple bonds). In some embodiments, the heterohydrocarbon chain has two substituents (e.g., two R L’ ) together with one or more interfacing atoms form a ring portion (e.g., a C3-C8 cycloalkyl or a 3-8 membered heterocycloalkyl), in which case the substituent includes at least one ring atom. When the ring portion is located inside a heterohydrocarbon chain, the atoms of the heterohydrocarbon chain (e.g., a 2-35 membered chain) are counted via the shortest path through the ring (e.g., [ka] It contains two atoms of a heterohydrocarbon chain, in this case each [ka] (This indicates the bonding point to the rest of the heterohydrocarbon chain). When the ring portion is located at the end of the heterohydrocarbon chain, the atoms of the heterohydrocarbon chain (e.g., 2-35 members) are counted via the longest path within the ring (e.g., [ka] This includes two atoms of a heterohydrocarbon chain, in this case, [ka] (The symbol indicates the bonding point to the rest of the heterohydrocarbon chain.)

[0773] As used herein, “alkyl,” “C1, C2, C3, C4, C5, or C6 alkyl,” or “C1-C6 alkyl” is intended to include “linear saturated aliphatic hydrocarbon groups of C1, C2, C3, C4, C5, or C6, and branched saturated aliphatic hydrocarbon groups of C3, C4, C5, or C6.” For example, C1-C6 alkyl is intended to include alkyl groups of C1, C2, C3, C4, C5, and C6. Examples of alkyls include, but are not limited to, moieties having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, linear or branched alkyls have 6 or fewer carbon atoms (e.g., C1-C6 for linear and C3-C6 for branched), and in other embodiments, linear or branched alkyls have 4 or fewer carbon atoms.

[0774] As used herein, the term “optionally substituted alkyl” refers to an unsubstituted alkyl or an alkyl in which substituents are specified to substitute for one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon skeleton. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0775] As used herein, the term "alkylene" refers to a divalent group obtained by removing a hydrogen radical from an alkyl group.

[0776] As used herein, the term “alkenyl” includes unsaturated aliphatic groups that are similar to the alkyls described above in length and substitution possibilities, but contain at least one double bond. For example, the term “alkenyl” includes linear alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In some embodiments, linear or branched alkenyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0777] As used herein, the term “optionally substituted alkenyl” refers to an unsubstituted alkenyl, or an alkenyl in which substituents are specified to substitute for one or more hydrogen atoms on carbon atoms of one or more hydrocarbon skeletons. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0778] As used herein, the term “alkynyl” includes unsaturated aliphatic groups that are similar to the alkyls described above in length and substitution possibilities, but contain at least one triple bond. For example, “alkynyl” includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl) and branched alkynyl groups. In some embodiments, linear or branched alkynyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3-C6” includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to contain a divalent unsaturated aliphatic hydrocarbon group of C2, C3, C4, C5, or C6 in a chain (straight or branched). For example, a C2-C6 alkenylene linker is intended to contain an alkenylene linker group of C2, C3, C4, C5, or C6.

[0779] As used herein, the term “optionally substituted alkynyl” refers to an unsubstituted alkynyl, or an alkynyl in which substituents are specified to substitute for one or more hydrogen atoms on carbon atoms of one or more hydrocarbon skeletons. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0780] Other optionally substituted moieties (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moieties) include both an unsubstituted moiety and a moiety having one or more of the specified substituents. For example, substituted heterocycloalkyls include those substituted with one or more alkyl groups such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0781] As used herein, the term "cycloalkyl" refers to a group of 3 to 30 carbon atoms (e.g., C3-C3-C3). 12 , C3-C 10This refers to monocyclic or polycyclic (e.g., fused ring, bridging ring, or spirocycle) systems of saturated or partially unsaturated hydrocarbons having C3-C8 rings. Examples of cycloalkyls, though not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyls, only one of the rings in the cycloalkyl must be non-aromatic.

[0782] As used herein, the term "heterocycloalkyl" means, unless otherwise specified, one or more heteroatoms (e.g., O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1, 1-2, 1-3, 1-4, 1-5, or 1-6 heteroatoms, e.g., saturated or partially unsaturated 3-8 member monocyclic, 7-12 member bicyclic (fused, bridging, or spiro-ring), or 11-14 member tricyclic ring systems (fused, bridging, or spiro-ring) having 1, 2, 3, 4, 5, or 6 heteroatoms.Examples of heterocycloalkyl groups, though not limited to these, include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxyranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, and 1,4-dia Zepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]yl, 7 'H-Spiro[cyclohexane-1,5'-Flo[3,4-b]pyridine]-yl, 3'H-Spiro[cyclohexane-1,1'-Flo[3,4-c]pyridine]-yl, 3-Azabicyclo[3.1.0]hexanyl, 3-Azabicyclo[3.1.0]hexane-3-yl, 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-Hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8 Examples include tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxazaspiro[3.4]octanyl, 2-oxazaspiro[3.4]octan-6-yl, and 5,6-dihydro-4H-cyclopenta[b]thiophenyl.In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl must be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0783] As used herein, the term "aryl" includes aromatic groups, including "conjugated" groups, or polycyclic systems having one or more aromatic rings, and does not contain heteroatoms in the ring structure. The term aryl includes both monovalent and divalent groups. Examples of aryl groups, but not limited to, include phenyl, biphenyl, and naphthyl. Phenyl is a convenient example of an aryl group.

[0784] As used herein, the term “heteroaryl” is intended to include a carbon atom and one or more heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur, such as one or one-two or one-three or one-four or one-five or one-six heteroatoms, or a stab...

Claims

1. Compounds of formula (I), (II), (III), or (IV): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, L is the lipid portion, B is H, C １ -C ６ It is an alkyl or nucleic acid base portion, V is -O-, -NR Ｖ -, or -C(R Ｖ ) ２ - and Each R Ｖ C is independently and optionally substituted with H or one or more halogens. １ -C ６ It is alkyl, Q is -(CR ａ R ａ ), ｎ -NH-*, where * represents a bond to L, or Q is C ６ -C １０ arylene or 5- to 10-membered heteroarylene, and the C ６ -C １０ arylene or 5- to 10-membered heteroarylene is optionally substituted with one or more R Ｑ s. Each R Ｑ C is independently substituted with a halogen, or one or more halogens optionally. １ -C ６ It is alkyl, X is H, halogen, or - OR Ｘ And, R Ｘ H, C １ -C ６ Alkyl, or -(C １ -C ６ (Alkyl)-(C ６ -C １０ It is aryl, and the C １ -C ６ Alkyl or -(C １ -C ６ (Alkyl)-(C ６ -C １０ A aryl is one or more R(R) at will. Ｘａ Replaced by, or R Ｘ and R ４ They are together C １ -C ６ Forming alkylenes, Each R Ｘａ These are independently halogen, C １ -C ６ Alkyl, or -O-(C １ -C ６ Alkyl) and the above C １ -C ６ Alkyl, or -O-(C １ -C ６ Alkyl) is optionally substituted with one or more halogens, Y is optionally substituted with H and one or more halogens. １ -C ６ Alkyl, -P(R) Ｙ ) ２ , -P(OR Ｙ ) (N(R Ｙ ) ２ ), -P(=O)(OR Ｙ ) R Ｙ , -P(=S)(OR Ｙ ) R Ｙ , -P(=O)(SR Ｙ ) R Ｙ , -P(=S)(SR Ｙ ) R Ｙ , -P(=O)(OR Ｙ ) ２ , -P(=S)(OR Ｙ ) ２ , -P(=O)(SR Ｙ ) ２ , -P(=S)(SR Ｙ ) ２ , or a hydroxy protecting group, Each R Ｙ C is independently and optionally substituted with H, or one or more halogens or cyanosides. １ -C ６ It is alkyl, Z is H, C optionally substituted with one or more halogens １ -C ６ alkyl, -P(R Ｚ ), -P(OR ２ ), -P(OR Ｚ )(N(R Ｚ ), -P(=O)(OR ２ ), -P(=O)(OR Ｚ ), -P(=S)(OR Ｚ ), -P(=S)(OR Ｚ ), -P(=O)(SR Ｚ ), -P(=S)(SR Ｚ ), -P(=O)(SR Ｚ ), -P(=S)(SR Ｚ ), -P(=O)(OR Ｚ ), -P(=S)(OR Ｚ ), -P(=O)(SR ２ ), -P(=S)(SR Ｚ ), -P(=O)(SR ２ ), -P(=S)(SR Ｚ ), -P(=S)(SR ２ ), -P(=S)(SR Ｚ ), or a hydroxy protecting group, ２ and Each R Ｚ is independently H, or C optionally substituted with one or more halogens or cyano １ -C ６ alkyl, Alternatively, Y and Z in equation (I) or (III) together become -Si(R Ｌ” ) ２ -O-Si(R Ｌ” ) ２ - forms, each R Ｌ” H or C １ -C ６ It is alkyl, Each R ａ C is independently substituted with H, a halogen, or one or more halogens as an option. １ -C ６ It is alkyl, R １ C is optionally substituted with H, a halogen, or one or more halogens. １ -C ６ It is alkyl, R ２ C is optionally substituted with H, a halogen, or one or more halogens. １ -C ６ It is alkyl, R ３ C is optionally substituted with H, a halogen, or one or more halogens. １ -C ６ It is alkyl, R ４ C is optionally substituted with H, a halogen, or one or more halogens. １ -C ６ Alkyl, or R ４ and R Ｘ They came together, C １ -C ６ Forming alkylenes, Each R ５ C is independently substituted with H, a halogen, or one or more halogens as an option. １ -C ６ It is alkyl, and n is an integer in the range of approximately 0 to approximately 10, and is a compound.

2. A conjugate, or a pharmaceutically acceptable salt thereof, (i) one or more nucleic acid agents, and (ii) comprising one or more lipid ligand units, each lipid ligand unit independently being: 【Chemistry 2】 During the ceremony, Variables L, B, V, Q, X, R ａ ,n,R Ｙ , R Ｚ , R １ , R ２ , R ３ , R ４ , and R ５ This is described in claim 1, and When the lipid ligand unit is located at the 3'-terminus of the nucleic acid agent, # is a coupling to the rest of the aforementioned conjugate, and ## is H, -P(R Ｙ ) ２ , -P(OR Ｙ ) (N(R Ｙ ) ２ ), -P(=O)(OR Ｙ ) R Ｙ , -P(=S)(OR Ｙ ) R Ｙ , -P(=O)(SR Ｙ ) R Ｙ , -P(=S)(SR Ｙ ) R Ｙ , -P(=O)(OR Ｙ ) ２ , -P(=S)(OR Ｙ ) ２ , -P(=O)(SR Ｙ ) ２ , -P(=S)(SR Ｙ ) ２ , or a hydroxy protecting group, or When the lipid ligand unit is located at the 5'-terminus of the nucleic acid agent, # is H, -P(R Ｚ ) ２ , -P(OR Ｚ ) (N(R Ｚ ) ２ ), -P(=O)(OR Ｚ ) R Ｚ , -P(=S)(OR Ｚ ) R Ｚ , -P(=O)(SR Ｚ ) R Ｚ , -P(=S)(SR Ｚ ) R Ｚ , -P(=O)(OR Ｚ ) ２ , -P(=S)(OR Ｚ ) ２ , -P(=O)(SR Ｚ ) ２ , -P(=S)(SR Ｚ ) ２ , or a hydroxy protecting group, ## is the binding to the rest of the aforementioned conjugate, or # and ## are conjugates, respectively, that are linked to the rest of the aforementioned conjugate.

3. L is -C(=O)R Ｌ or -C(=S)R Ｌ And in the formula, R Ｌ C ２ -C ２００ A hydrocarbon chain or a heterohydrocarbon chain with 2 to 200 members, and the C ２ -C ２００ A hydrocarbon chain or a heterohydrocarbon chain with 2 to 200 members may optionally contain one or more R Ｌ’ Replaced by, Each R Ｌ’ These are independently oxo, dihalocarbene, cyano, halogen, -OH, -O(C) １ -C １２ Alkyl), -O (C ６ -C １０ aryl), -COOH, -COO(C １ -C １２ Alkyl), -CO(C １ -C ３０ Alkyl), -NHCO(C １ -C ３０ Alkyl), -CONH ２ , -CONH(C １ -C １２ Alkyl), -CON(C １ -C １２ Alkyl) ２ , -C(O)NHOH, -SO ３ H, -SO ３ (C １ -C １２ Alkyl), -NH ２ ,-NH(C １ -C １２ Alkyl), -N(C １ -C １２ Alkyl) ２ , -S(C １ -C １２ Alkyl), -S (C ６ -C １０ Aryl), -P(C ６ -C １０ Ariel) ３ , -OP(=O)(O － ) O - ( C １ -C １２ Alkylene)-NMe ３ ＋ , C １ -C １２ Alkyl, C ２ -C １２ Alkenil, C ２ -C １２ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 member heterocycloalkyl, C ６ -C １０ The aryl or 5- to 10-membered heteroaryl, and the -O(C １ -C １２ Alkyl), -O (C ６ -C １０ Ayl), - COO (C １ -C １２ Alkyl), -CO(C １ -C ３０ Alkyl), -NHCO(C １ -C ３０ Alkyl), -CONH(C １ -C １２ Alkyl), -CON(C １ -C １２ Alkyl) ２ , -SO ３ (C １ -C １２ Alkyl), -NH(C １ -C １２ Alkyl), -N(C １ -C １２ Alkyl) ２ , -S(C １ -C １２ Alkyl), -S (C ６ -C １０ Aryl), -P(C ６ -C １０ Ariel) ３ , -OP(=O)(O － ) O - ( C １ -C １２ Alkylene)-NMe ３ ＋ , C １ -C １２ Alkyl, C ２ -C １２ Alkenil, C ２ -C １２ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 member heterocycloalkyl, C ６ -C １０ Aryls, or 5- to 10-membered heteroaryls, can be optionally selected as one or more R Ｌａ Replaced by, or Two R's Ｌ’ However, along with one or more intervening atoms, C ３ -C ８ Cycloalkyl, 3-8 member heterocycloalkyl, C ６ -C １５ Forming an aryl or a 5-15 member heteroaryl, the C ３ -C ８ Cycloalkyl, 3-8 member heterocycloalkyl, C ６ -C １５ Aryls, or 5- to 15-membered heteroaryls, are optionally selected as one or more R Ｌａ Replaced by, and Each R Ｌａ These are independently oxo, halogen, -OH, -O(C) １ -C １２ Alkyl), -SH, -S(C １ -C １２ Alkyl), -NH ２ ,-NH(C １ -C １２ Alkyl), -N(C １ -C １２ Alkyl) ２ , C １ -C １２ Alkyl, C ２ -C １２ Alkenil, C ２ -C １２ Alkinyl, C ３ -C ８ Cycloalkyl, one or more C １ -C １２ 3- to 8-membered heterocycloalkyl groups, C, which are optionally substituted with alkyl groups. ６ -C １０ It is an aryl, or a 5- to 10-membered heteroaryl, or Two R's Ｌａ However, along with one or more intervening atoms, C ３ -C ８ Cycloalkyl, 3-8 member heterocycloalkyl, C ６ -C １０ A compound or conjugate according to any one of claims 1 or 2, which forms an aryl or a 5- to 10-membered heteroaryl.

4. R Ｌ However, one or more R Ｌ’ C is optionally replaced by ２ -C ３５ A compound or conjugate according to any one of claims 1 to 3, which is a hydrocarbon chain.

5. R Ｌ However, one or more R Ｌ’ The compound or conjugate according to any one of claims 1 to 4, wherein the compound is a 2- to 35-membered heterohydrocarbon chain that is optionally substituted.

6. At least one R Ｌ’ The compound or conjugate according to any one of claims 1 to 5, wherein the compound is an oxo.

7. At least one R Ｌ’ The compound or conjugate according to any one of claims 1 to 6, wherein the compound is a dihalocarbene.

8. At least one R Ｌ’ The compound or conjugate according to any one of claims 1 to 7, wherein the compound is cyano.

9. At least one R Ｌ’ The compound or conjugate according to any one of claims 1 to 8, wherein the compound is a halogen.

10. At least one R Ｌ’ However, -OH, -O(C) １ -C １２ Alkyl), or -O (C ６ -C １０ It is aryl, and the -O(C １ -C １２ Alkyl) or -O(C ６ -C １０ A aryl is one or more R Ｌａ A compound or conjugate according to any one of claims 1 to 9, which is optionally substituted by the compound or conjugate described in any one of claims 1 to 9.

11. At least one R Ｌ’ However, -COOH, -COO(C １ -C １２ Alkyl), -CO(C １ -C ３０ Alkyl), -CONH ２ , -CONH(C １ -C １２ Alkyl), -CON(C １ -C １２ Alkyl) ２ , or -C(O)NHOH, and the -COO(C １ -C １２ Alkyl), -CO(C １ -C ３０ Alkyl), -CONH(C １ -C １２ Alkyl), or -CON(C １ -C １２ Alkyl) ２ is one or more R Ｌａ A compound or conjugate according to any one of claims 1 to 10, which is optionally substituted by the compound or conjugate according to any one of claims 1 to 10.

12. At least one R Ｌ’ However, one or more R Ｌａ NHCO(C) is optionally substituted. １ -C ３０ A compound or conjugate according to any one of claims 1 to 11, wherein the compound is alkyl.

13. At least one R Ｌ’ However, -SO ３ H, or one or more R Ｌａ It is optionally replaced by -SO ３ (C １ -C １２ A compound or conjugate according to any one of claims 1 to 12, wherein the compound is alkyl.

14. At least one R Ｌ’ However, -NH ２ ,-NH(C １ -C １２ Alkyl), or -N(C １ -C １２ Alkyl) ２ And the above-NH(C １ -C １２ Alkyl) or -N(C １ -C １２ Alkyl) ２ is one or more R Ｌａ A compound or conjugate according to any one of claims 1 to 13, which is optionally substituted by the compound or conjugate according to any one of claims 1 to 13.

15. At least one R Ｌ’ However, -S(C １ -C １２ Alkyl) or -S (C ６ -C １０ It is aryl, and the -S(C １ -C １２ Alkyl) or -S (C ６ -C １０ A aryl is one or more R Ｌａ A compound or conjugate according to any one of claims 1 to 14, which is optionally substituted by the compound or conjugate according to any one of claims 1 to 14.

16. At least one R Ｌ’ However, -P(C ６ -C １０ Ariel) ３ or -OP (=O) (O － ) O - ( C １ -C １２ Alkylene)-NMe ３ ＋ And the above-P(C) ６ -C １０ Ariel) ３ or -OP (=O) (O － ) O - ( C １ -C １２ Alkylene)-NMe ３ ＋ is one or more R Ｌａ A compound or conjugate according to any one of claims 1 to 15, which is optionally substituted by the compound or conjugate according to any one of claims 1 to 15.

17. At least one R Ｌ’ However, one or more R Ｌａ C is optionally replaced by １ -C １２ A compound or conjugate according to any one of claims 1 to 16, wherein the compound is alkyl.

18. At least one R Ｌ’ However, one or more R Ｌａ C is optionally replaced by ２ -C １２ The compound or conjugate according to any one of claims 1 to 17, wherein the compound is an alkenyl.

19. At least one R Ｌ’ However, one or more R Ｌａ C is optionally replaced by ２ -C １２ The compound or conjugate according to any one of claims 1 to 18, wherein the compound is an alkynyl.

20. At least one R Ｌ’ However, one or more R Ｌａ C is optionally replaced by ３ -C ８ A compound or conjugate according to any one of claims 1 to 19, wherein the compound is a cycloalkyl compound.

21. At least one R Ｌ’ However, one or more R Ｌａ The compound or conjugate according to any one of claims 1 to 20, wherein the compound is a 3- to 8-membered heterocycloalkyl group that is optionally substituted.

22. At least one R Ｌ’ However, one or more R Ｌａ C is optionally replaced by ６ -C １０ A compound or conjugate according to any one of claims 1 to 21, wherein the compound is an aryl compound.

23. At least one R Ｌ’ However, one or more R Ｌａ The compound or conjugate according to any one of claims 1 to 22, wherein the compound is a 5- to 10-membered heteroaryl that is optionally substituted.

24. Two R's Ｌ’ However, together with one or more intervening atoms, one or more R Ｌａ C is optionally replaced by ３ -C ８ A compound or conjugate according to any one of claims 1 to 23, which forms a cycloalkyl group.

25. Two R's Ｌ’ However, together with one or more intervening atoms, one or more R Ｌａ The compound or conjugate according to any one of claims 1 to 24, which forms a 3- to 8-membered heterocycloalkyl group that is optionally substituted.

26. Two R's Ｌ’ However, together with one or more intervening atoms, one or more R Ｌａ C is optionally replaced by ６ -C １５ A compound or conjugate according to any one of claims 1 to 25, which forms an aryl group.

27. Two R's Ｌ’ However, together with one or more intervening atoms, one or more R Ｌａ The compound or conjugate according to any one of claims 1 to 26, which forms a 5- to 15-membered heteroaryl that is optionally substituted.

28. The compound or conjugate according to any one of claims 1 to 27, wherein L is selected from the structures described in Tables X and Y.

29. The compound is a compound of formula (I'), (II'), (III'), (IV'), (V'), or (VI'): 【Transformation 3】 The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

30. The compound is a compound of formula (I-A), (II-A), (III-A), (IV-A), (V-A), (VI-A), (VII-A), (VIII-A), (IX-A), (X-A), (XI-A), or (XII-A): 【Chemistry 4】 The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

31. The compound is a compound of the formula (I'-A), (II'-A), (III'-A), (IV'-A), (V'-A), (VI'-A), (VII'-A), (VIII'-A), (IX'-A), (X'-A), (XI'-A), or (XII'-A): 【Transformation 5】 The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.

32. The compound is a compound of formula (I-B), (II-B), (III-B), (IV-B), (V-B), or (VI-B): 【Transformation 6】 The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof.

33. The compound is a compound of the formula (I'-B), (II'-B), (III'-B), (IV'-B), (V'-B), or (VI'-B): 【Transformation 7】 The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

34. Y is a hydroxy protecting group, and Z is a hydroxy protecting group, or In equations (I), (III), (I'), (III'), (V'), (I-A), (III-A), (V-A), (VII-A), (IX-A), (XI-A), (I'-A), (III'-A), (V'-A), (VII'-A), (IX'-A), (XI'-A), (I-B), (III-B), (V-B), (I'-B), (III'-B), or (V'-B), Y and Z together are -Si(R Ｌ’’ ) ２ -O-Si(R Ｌ’’ ) ２ - forms, each R Ｌ” H or C １ -C ６ A compound according to any one of claims 1 to 33, wherein it is alkyl.

35. The aforementioned compound, 【Transformation 8】 or a pharmaceutically acceptable salt thereof, in the formula, Y is -P(R Ｙ ) ２ , -P(OR Ｙ ) (N(R Ｙ ) ２ ), -P(=O)(OR Ｙ ) R Ｙ , -P(=S)(OR Ｙ ) R Ｙ , -P(=O)(SR Ｙ ) R Ｙ , -P(=S)(SR Ｙ ) R Ｙ , -P(=O)(OR Ｙ ) ２ , -P(=S)(OR Ｙ ) ２ , -P(=O)(SR Ｙ ) ２ , -P(=S)(SR Ｙ ) ２ , or a hydroxy protecting group (e.g., silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl), triphenylmethyl (Tr), 4,4'-dimethoxytrityl (DMTr), substituted acyl (e.g., optionally substituted acetyl), or benzyl), Each R Ｙ C is independently and optionally substituted with H, or one or more halogens or cyanosides. １ -C ６ It is alkyl, Z is -P(R Ｚ ) ２ , -P(OR Ｚ ) (N(R Ｚ ) ２ ), -P(=O)(OR Ｚ ) R Ｚ , -P(=S)(OR Ｚ ) R Ｚ , -P(=O)(SR Ｚ ) R Ｚ , -P(=S)(SR Ｚ ) R Ｚ , -P(=O)(OR Ｚ ) ２ , -P(=S)(OR Ｚ ) ２ , -P(=O)(SR Ｚ ) ２ , -P(=S)(SR Ｚ ) ２ , or hydroxy protecting groups (e.g., silyl (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl), triphenylmethyl (Tr), 4,4'-dimethoxytrityl (DMTr), substituted acyl (e.g., optionally substituted acetyl), or benzyl), and Each R Ｚ C is independently and optionally substituted with H, or one or more halogens or cyanosides. １ -C ６ A compound according to any one of claims 1 to 34, wherein it is alkyl.

36. The compound according to any one of claims 1 to 35, wherein the compound is selected from the compounds listed in Table L and their pharmaceutically acceptable salts.

37. The compound according to any one of claims 1 to 36, wherein the compound is selected from the compounds listed in Tables M and P, and their pharmaceutically acceptable salts.

38. A compound that is an isotopic derivative of the compound described in any one of claims 1 to 37.

39. The aforementioned conjugate, (Nucleic acid agent) - [(Linker unit) ０－１ - (lipid ligand unit) １－３ ,or [(Lipid ligand unit) - (Linker unit)] ０－１ ] １－３ - (Nucleic acid agent) - [(Linker unit) ０－１ - (lipid ligand unit) １－３ , including, During the ceremony, When the linker unit and the lipid ligand unit are bound to the nucleic acid agent (e.g., siRNA), they are independently bound to the terminal position (e.g., the 3' or 5' terminal nucleotide) or the internal position (e.g., a nucleotide other than the 3' or 5' terminal) of the nucleic acid agent (e.g., siRNA), and The conjugate according to any one of claims 1 to 38, wherein each linker unit is independent of other linker units, and each lipid ligand unit is independent of other lipid ligand units.

40. At least one lipid ligand unit in the conjugate, 【Chemistry 9】 The conjugate according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.

41. The conjugate according to any one of claims 1 to 40, wherein at least one lipid ligand unit in the conjugate is selected from the structures listed in Table C.

42. The conjugate according to any one of claims 1 to 41, wherein at least one lipid ligand unit in the conjugate is selected from the structures described in Tables N and Q.

43. The conjugate according to any one of claims 1 to 42, wherein the nucleic acid agent comprises an oligonucleotide.

44. The conjugate according to any one of claims 1 to 43, wherein the nucleic acid agent comprises one or more phosphate groups or analogs of one or more phosphate groups.

45. The conjugate according to any one of claims 1 to 44, wherein the linker unit is bound to the nucleic acid agent via a phosphate group in the nucleic acid agent or a phosphate group analog.

46. The conjugate according to any one of claims 1 to 45, wherein the nucleic acid agent comprises RNA.

47. The conjugate according to any one of claims 1 to 46, wherein the oligonucleotide is siRNA, microRNA, antimicroRNA, microRNA mimetic, antimiR, antagomir, dsRNA, ssRNA, aptamer, immunostimulatory oligonucleotide, decoy oligonucleotide, splicing-modified oligonucleotide, triple-stranded oligonucleotide, G-quadrilateral oligonucleotide, or antisense oligonucleotide.

48. A pharmaceutical composition comprising a compound or conjugate according to any one of claims 1 to 47.

49. A method for regulating the expression of a target gene in a subject, comprising administering a conjugate according to any one of claims 1 to 48 to the subject.

50. A method for delivering a nucleic acid agent to a target, comprising administering a conjugate according to any one of claims 1 to 49 to the target.

51. A method for treating or preventing a disease in a subject in need, comprising administering a therapeutically effective amount of the conjugate described in any one of claims 1 to 50 to the subject.

52. A conjugate according to any one of claims 1 to 51 for regulating the expression of a target gene in a subject.

53. A conjugate according to any one of claims 1 to 52 for delivering a nucleic acid agent to a target.

54. A conjugate according to any one of claims 1 to 53 for treating or preventing a disease in a subject where such treatment is necessary.

55. Use of the conjugate according to any one of claims 1 to 54 in the manufacture of a pharmaceutical product for regulating the expression of a target gene in a subject.

56. Use of a conjugate according to any one of claims 1 to 55 in the manufacture of a pharmaceutical product for delivering a nucleic acid agent to a target.

57. Use of the conjugate according to any one of claims 1 to 56 in the manufacture of a pharmaceutical product for treating or preventing a disease in a subject where such use is necessary.

58. The method, conjugate, or use according to any one of claims 1 to 57, wherein the subject is a human.

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