WO2024119098A1 - Systèmes et formulations de distribution de nanoparticules lipidiques (lnp) - Google Patents

Systèmes et formulations de distribution de nanoparticules lipidiques (lnp) Download PDF

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WO2024119098A1
WO2024119098A1 PCT/US2023/082118 US2023082118W WO2024119098A1 WO 2024119098 A1 WO2024119098 A1 WO 2024119098A1 US 2023082118 W US2023082118 W US 2023082118W WO 2024119098 A1 WO2024119098 A1 WO 2024119098A1
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PCT/US2023/082118
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Li LAI
Charitha GURUGE
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Prime Medicine, Inc.
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
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    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
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    • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the Sequence Listing XML file that has been electronically filed contains the information of the nucleotide and/or amino acid sequences disclosed in the patent application using the symbols and format in accordance with the requirements of 37 C.F.R. ⁇ 1.832 through 1.834. [0003]
  • the Sequence Listing XML filed herewith serves as the electronic copy required by ⁇ 1.834(b)(1). [0004]
  • the Sequence Listing XML is identified as follows: “272059-538159_Sequence- listing.xml” (13,923 bytes in size), which was created on November 28, 2023.
  • FIELD OF THE INVENTION [0005]
  • the present disclosure describes compounds, compositions, lipid nanoparticles, and methods for delivering constructs and polynucleotides.
  • LNP lipid nanoparticle
  • the LNP compositions comprise a lipid that comprises a compound described herein.
  • the compound described herein is a biodegradable ionizable lipid.
  • the present disclosure provides compounds of Formula I: I wherein A is N, CH, or phenyl; and wherein each R i , R ii , and R iii is independently: , Q is independently –O–, –CH 2 –, –C(O)–, –C(O)O–, –OC(O)–, – OC(O)CH2CH(OH)–, –CH2-OC(O)–, or –NHC(O)–; subscript “a” is independently an integer between 1 and 5; D is independently N or O, wherein when D is N, R 1 and R 2 are each independently H, C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl , or together with the N- atom they are connected to form nsubstituted C3-C6 heterocycloal
  • the compound of Formula I is a compound of Formula II: [0010] In some embodiments, the compound of Formula I is a compound of Formula II-A: R 3 1 R 4 [0011] In some embodiments, the compound of Formula I is a compound of Formula III: [0012] In some embodiments, the compound of Formula I is a compound of Formula IV: [0013] In one aspect, the present disclosure provides compounds of Formula II: wherein, A is N or CH; Q is independently –O–, –CH 2 –, –C(O)–, –C(O)O–, –OC(O)–, –OC(O)CH 2 CH(OH)–, –CH2-OC(O)–, or –NHC(O)–; subscript “a” is independently an integer between 1 and 5; D is independently N or O, wherein when D is N, R and R are each independently H, C 1 -C 6 alkyl, hydroxy- substituted C 1 -C 6 alkyl;
  • the present disclosure provides compounds of Formula II-A: R 3 R 4 wherein, A is N or CH; Q is independently –O–, –CH2–, –C(O)–, –C(O)O–, –OC(O)–, –OC(O)CH2CH(OH)–, –CH 2 -OC(O)–, or –NHC(O)–; subscript “a” is independently an integer between 1 and 5; D is independently N or O, wherein when D is N, R 1 and R 2 are each independently H, C1-C6 alkyl, hydroxy- substituted C1-C6 alkyl or together with the N-atom they are connected to form a su ed C3-C6 heterocycloalkyl or substituted or unsubstituted C 5 -C 6 heteroaryl; R a and R b are each independently H or C1-C6 alkyl; when D is O, one of R or R is absent and the other is H or
  • the present disclosure provides compounds of Formula III: wherein, A is N or CH; Q is independently –O–, –CH 2 –, –C(O)–, –C(O)O–, –OC(O)–, –OC(O)CH 2 CH(OH)–, –CH2-OC(O)–, or –NHC(O)–; subscript “a” is independently an integer between 1 and 5; D is independently N or O, wherein when D is N, R 1 and R 2 are each independently H, C1-C6 alkyl, hydroxy- substituted C1-C6 alkyl or together with the N-atom they are connected to form a su d C 3 -C 6 heterocycloalkyl or substituted or unsubstituted C5-C6 heteroaryl; R a and R b are each independently H or C 1 -C 6 alkyl; when D is O, one of R 1 or R 2 is absent and the other is H or C1-C6
  • lipid nanoparticle (LNP) composition comprising a biodegradable ionizable lipid that comprises a compound as described herein.
  • LNP lipid nanoparticle
  • the present disclosure provides a lipid nanoparticle (LNP) composition comprising: a biodegradable ionizable lipid that comprises a compound as described herein; a phospholipid; a polyethylene glycol-lipid; and a sterol.
  • Another aspect of the present disclosure provides a pharmaceutical composition comprising the LNP composition described herein.
  • Another aspect of the present disclosure provides a method for delivering polynucleotides into a cell comprising: introducing into the cell at least one lipid nanoparticle comprising a biodegradable ionizable lipid that comprises any one of the compounds described herein and one or more polynucleotides.
  • Another aspect of the present disclosure provides a method for delivering a prime editing system into a cell comprising: introducing into the cell at least one lipid nanoparticle comprising a biodegradable ionizable lipid that comprises any one of the compounds described herein and one or more components of a prime editing system.
  • FIG.1 shows in vivo prime editing efficiency of Pcsk9 PE3 when delivered in LNPs comprising Compound 3 or Compound 8 to WT mice (1 mg/kg).
  • FIG.2 shows in vivo prime editing efficiency of Pcsk9 PE2 when delivered in LNPs comprising Compound 3 or Compound 14 to WT mice (1 mg/kg).
  • FIG.3 shows in vivo prime editing efficiency of Pcsk9 PE2 when delivered in LNPs comprising Compound 187, Compound 188, Compound 4, or Compound 16 to WT mice (0.3 mg/kg).
  • DETAILED DESCRIPTION [0028] Provided herein are compounds of Formulas I, II, III, and IV. Compositions, lipid nanoparticles, and pharmaceutical compositions provided herein can comprise the compounds described herein. Methods for delivering said compositions and lipid nanoparticles are also provided herein. [0029] The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this disclosure is not limited to the particular embodiments described herein and as such can vary.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
  • the term “about” meaning within an acceptable error range for the particular value should be assumed.
  • the term “between” means the range of numbers including the first and the last number in a range.
  • the term “substantially” as used herein may refer to a value approaching 100% of a given value. In some embodiments, the term may refer to an amount that may be at least about 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 99.99% of a total amount. In some embodiments, the term may refer to an amount that may be about 100% of a total amount.
  • hydroxyl refers to an –OH moiety.
  • aliphatic encompasses the terms alkyl, alkenyl, and alkynyl, each of which being optionally substituted as set forth below.
  • an "alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-15 (e.g., carbon atoms. An alkyl group can be straight or branched.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecanyl, n- tridecanyl, n-tetradecanyl, n-pentadecanyl, or 2-ethylhexyl.
  • an alkyl group can be substituted (i.e., optionally substituted) with one or more substituents independently selected from halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroaryl
  • an alkyl group can be substituted with one or more substituents independently selected from carboxy (such as HOOC-alkyl, alkoxycarbonyl, and alkylcarbonyloxy), cyano, hydroxy, alkoxy, acyl, aralkyl, aryl, heteroaryl, sulfonylaminoalkyl (such as alkyl-SO2-amino), amino, amido, cycloaliphatic, or halo.
  • carboxy such as HOOC-alkyl, alkoxycarbonyl, and alkylcarbonyloxy
  • cyano hydroxy, alkoxy, acyl, aralkyl, aryl, heteroaryl
  • sulfonylaminoalkyl such as alkyl-SO2-amino
  • an alkyl group can be substituted with one or more substituents independently selected from halo, oxo, hydroxy, cyano, halo, alkoxy (e.g., C1-6 alkoxy), –C(O)-C 1-6 alkoxy and –C(O)-C 1-6 alkyl.
  • an alkyl group can be substituted with one or more substituents independently selected from halo, alkoxy, and hydroxy.
  • an alkyl group can be substituted with –OH (“hydroxy- substituted alkyl”).
  • an "alkenyl” group refers to an aliphatic hydrocarbon group that contains 2-20 carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
  • an alkenyl group can be substituted (i.e., optionally substituted) with one or more substituents independently selected from halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroary
  • an alkenyl group can be substituted with one or more substituents independently selected from cyano, alkoxy, acyl, hydroxy, aryl, aralkyl, alkoxyaryl, sulfonylamino (such as alkyl-SO2-amino), amino, amido, cycloaliphatic, or halo.
  • an alkenyl group can be substituted with one or more substituents as set forth herein for alkyl groups.
  • an alkenyl group can be substituted with –OH (“hydroxy- substituted alkenyl”).
  • an "alkynyl” group refers to an aliphatic hydrocarbon group that contains 4-15 (e.g., 4-12, 4-10, 4-9, or 4-8) carbon atoms and has at least one triple bond.
  • An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, ethynyl, propargyl, and butynyl.
  • an alkynyl group can be substituted (i.e., optionally substituted) with one or more substituents independently selected from aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SO 2 -, aliphaticamino-SO 2 -, or cycloaliphatic-SO 2 -], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alky
  • an alkynyl group can be substituted with one or more substituents independently selected from cyano, alkoxy, acyl, hydroxy, aryl, aralkyl, alkoxyaryl, sulfonylamino (such as alkyl-SO 2 -amino), amino, amido, cycloaliphatic, or halo.
  • an alkynyl group can be substituted with one or more substituents as set forth herein for alkyl groups and/or alkenyl groups.
  • heterocycloalkyl refers to a 3-10 membered mono- or bicyclic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof).
  • heterocycloalkyl group examples include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa
  • a monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, that would be categorized as heteroaryls.
  • a "heterocycloalkenyl” group refers to a mono- or bicyclic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S).
  • Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature.
  • a heterocycloalkyl or heterocycloalkenyl group has 1-3 heteroatoms independently selected from N, O, or S.
  • a heterocycloalkyl or heterocycloalkenyl group can be substituted (i.e., optionally substituted) with one or more substituents independently selected from phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycl
  • a heterocycloalkyl or heterocycloalkenyl group can be substituted with one or more substituents as set forth herein for aryl groups, aralkyl groups, cycloalkyl groups, and/or cycloalkenyl groups.
  • a "heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic.
  • a heteroaryl group includes a benzofused ring system having 2 to 3 rings.
  • a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophene- yl, quinolinyl, or isoquinolinyl).
  • heterocycloaliphatic moieties e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophene- yl, quinolinyl, or isoquinolinyl.
  • heteroaryl examples include azetidinyl, pyridyl, 1H- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,
  • monocyclic heteroaryls include furyl, thiophene-yl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.
  • Monocyclic heteroaryls are numbered according to standard chemical nomenclature.
  • bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.
  • a heteroaryl group has 1-3 heteroatoms independently selected from N, O, or S.
  • a heteroaryl group can be substituted (i.e., optionally substituted) with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bi
  • a heteroaryl can be unsubstituted.
  • a heteroaryl group can be substituted with one or more substituents independently selected from halo [e.g., mono- and di-halo]; carboxy [e.g., alkoxycarbonyl]; cyano; amino [e.g., (alkylsulfonyl)amino and (dialkyl)amino]; amido [e.g., aminocarbonyl, (alkylcarbonyl)amino, (((alkyl)amino)alkyl)aminocarbonyl, ((heteroaryl)amino)carbonyl, (heterocycloaliphatic)carbonyl, and (alkylcarbonyl)amino]; cyanoalkyl; alkoxy; sulfamoyl [e.g., aminosulfonyl]; sulfonyl [e.g., al
  • a heteroaryl group can be substituted with one or more substituents as set forth herein for aryl groups, aralkyl groups, cycloalkyl groups, cycloalkenyl groups, heterocycloalkyl groups, and/or heterocycloalkenyl groups.
  • a "carbonyl” refers to –C(O)–.
  • the term "substituted,” whether preceded by the term “optionally” or not, refers generally to the replacement of hydrogen atoms in a given structure with the radical of a specified substituent.
  • an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
  • a ring substituent such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom.
  • the term “isomerically pure” refers to an isomeric form of a compound that is substantially free from other isomeric forms of the compound (e.g., substantially free from other stereoisomers (e.g., enantiomers, diastereomers, geometric (or conformational) isomers, etc.), constitutional isomers, isotopomers, etc.).
  • an “isomerically pure” compound having at least one asymmetric center of a particular configuration i.e., R or S configuration
  • is substantially free from other isomeric forms of the compound having a different configuration at the at least one asymmetric center i.e., R or S configuration
  • An “isomerically pure” compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, of a single isomer of the compound based on the total weight of all isomers of the compound that are present.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • the term "pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • the term “pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, cam
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm.
  • lipid refers to a group of organic compounds that include, but are not limited to, esters of fatty acids and are generally characterized by being poorly soluble in water, but soluble in many organic solvents.
  • a “lipid nanoparticle” may refer to particles having at least one dimension in the nanometers range (e.g., 1-1,000 nm) and include the compounds described herein.
  • lipid nanoparticles can be included in compositions that are used to deliver at least one polynucleotide and/or construct according to this disclosure.
  • the lipid nanoparticles of the disclosure comprise at least one polynucleotide and/or one or more components of a prime editing system.
  • the lipid nanoparticles can include one or more additional lipid components.
  • the at least one polynucleotide and/or construct may be encapsulated in the lipid portion of the lipid nanoparticle or an aqueous space enveloped by some or all of the lipid portion of the lipid nanoparticle.
  • the lipid nanoparticles can have a mean diameter of from about 30 nm to about 150 nm, from about 40 nm to about 150 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, from about 70 nm to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 n
  • biodegradable refers to materials that, when introduced into cells, are broken down by cellular machinery (e.g., enzymatic degradation) or by hydrolysis into components that cells can either reuse or dispose of without significant toxic effect(s) on the cells.
  • components generated by breakdown of a biodegradable material do not induce inflammation and/or other adverse effects in vivo.
  • biodegradable materials are enzymatically broken down. Alternatively or additionally, in some embodiments, biodegradable materials are readily broken down and eliminated.
  • “ionizable lipids” are positively charged at acidic pH and neutral at physiological pH.
  • a “cell” can generally refer to a biological cell.
  • a cell can be the basic structural, functional and/or biological unit of a living organism.
  • a cell can originate from any organism having one or more cells. Some non-limiting examples include: a prokaryotic cell, eukaryotic cell, a bacterial cell, an archaeal cell, a cell of a single-cell eukaryotic organism, a protozoa cell, a cell from a plant, an animal cell, a cell from an invertebrate animal (e.g.
  • a cell from a vertebrate animal e.g., fish, amphibian, reptile, bird, mammal
  • a cell from a mammal e.g., a pig, a cow, a goat, a sheep, a rodent, a rat, a mouse, a non-human primate, a human, etc.
  • a cell may not originate from a natural organism (e.g., a cell can be synthetically made, sometimes termed an artificial cell).
  • the cell is a human cell.
  • a cell may be of or derived from different tissues, organs, and/or cell types.
  • the cell is a primary cell.
  • the term primary cell means a cell isolated from an organism, e.g., a mammal, which is grown in tissue culture (i.e., in vitro) for the first time before subdivision and transfer to a subculture.
  • mammalian primary cells can be modified through introduction of one or more polynucleotides, polypeptides, and/or prime editing compositions (e.g., through transfection, transduction, electroporation and the like) and further passaged.
  • a cell is not isolated from an organism but forms part of a tissue or organ of an organism, e.g., a mammal.
  • the cell is a stem cell.
  • the cell is a human stem cell.
  • construct refers to refers to a polynucleotide or a portion of a polynucleotide, comprising one or more nucleic acid sequences encoding one or more transcriptional products and/or proteins.
  • a construct may be a recombinant nucleic acid molecule or a part thereof.
  • the one or more nucleic acid sequences of a construct are operably linked to one or more regulatory sequences, for example, transcriptional initiation regulatory sequences.
  • a construct is a vector, a plasmid, or a portion thereof.
  • a construct comprises DNA.
  • a construct comprises RNA.
  • a construct is double stranded.
  • a construct is single stranded.
  • a construct comprises an expression cassette.
  • An expression cassette means a polynucleotide comprising a nucleic acid sequence that encodes one or more transcriptional products and is operably linked to at least one transcriptional regulatory sequence, e.g., a promoter.
  • polynucleotide or “nucleic acid molecule” can be any polymeric form of nucleotides, including DNA, RNA, a hybridization thereof, or RNA-DNA chimeric molecules.
  • a polynucleotide can be a cDNA, genomic DNA, mRNA, tRNA, rRNA, microRNA, antisense DNA or RNA, plasmid DNA, microRNA inhibitors, mRNA- interfering complementary RNA (micRNA), multivalent RNA, etc.
  • a polynucleotide is double stranded, e.g., a double-stranded DNA in a gene.
  • a polynucleotide is single-stranded or substantially single-stranded, e.g., single-stranded DNA or an mRNA. In some embodiments, a polynucleotide is a cell-free nucleic acid molecule. In some embodiments, a polynucleotide circulates in blood. In some embodiments, a polynucleotide is a cellular nucleic acid molecule. In some embodiments, a polynucleotide is a cellular nucleic acid molecule in a cell circulating in blood. [0086] Polynucleotides can have any three-dimensional structure.
  • polynucleotides a gene or gene fragment (for example, a probe, primer, EST or SAGE tag), an exon, an intron, intergenic DNA (including, without limitation, heterochromatic DNA), messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), a ribozyme, cDNA, a recombinant polynucleotide, a branched polynucleotide, a plasmid, a vector, isolated DNA, isolated RNA, sgRNA, guide RNA, a nucleic acid probe, a primer, an snRNA, a long non-coding RNA, a snoRNA, a siRNA, a miRNA, a tRNA-derived small RNA (tsRNA), an antisense RNA, an shRNA, or a small rDNA-derived RNA (srRNA).
  • a gene or gene fragment for example, a probe, primer, EST or SAGE tag
  • a polynucleotide comprises deoxyribonucleotides, ribonucleotides or analogs thereof.
  • a polynucleotide comprises modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polynucleotide.
  • the sequence of nucleotides can be interrupted by non-nucleotide components.
  • a polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component.
  • a polynucleotide is composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide is RNA.
  • the polynucleotide may comprise one or more other nucleotide bases, such as inosine (I), which is read by the translation machinery as guanine (G).
  • a polynucleotide may be modified.
  • the terms “modified” or “modification” refers to chemical modification with respect to the A, C, G, T and U nucleotides.
  • modifications may be on the nucleoside base and/or sugar portion of the nucleosides that comprise the polynucleotide.
  • the modification may be on the internucleoside linkage (e.g., phosphate backbone).
  • multiple modifications are included in the modified nucleic acid molecule.
  • a single modification is included in the modified nucleic acid molecule.
  • protein and “polypeptide” can be used interchangeably to refer to a polymer of two or more amino acids joined by covalent bonds (e.g., an amide bond) that can adopt a three-dimensional conformation.
  • a protein or polypeptide comprises at least 10 amino acids, 15 amino acids, 20 amino acids, 30 amino acids or 50 amino acids joined by covalent bonds (e.g., amide bonds).
  • a protein comprises at least two amide bonds.
  • a protein comprises multiple amide bonds.
  • a protein comprises an enzyme, enzyme precursor proteins, regulatory protein, structural protein, receptor, nucleic acid binding protein, a biomarker, a member of a specific binding pair (e.g., a ligand or aptamer), or an antibody.
  • a protein may be a full-length protein (e.g., a fully processed protein having certain biological function).
  • a protein may be a variant or a fragment of a full-length protein.
  • a variant of a protein or enzyme for example a variant reverse transcriptase, comprises a polypeptide having an amino acid sequence that is about 60% identical, about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 96% identical, about 97% identical, about 98% identical, about 99% identical, about 99.5% identical, or about 99.9% identical to the amino acid sequence of a reference protein.
  • a protein comprises one or more protein domains or subdomains.
  • polypeptide domain when used in the context of a protein or polypeptide, refers to a polypeptide chain that has one or more biological functions, e.g., a catalytic function, a protein-protein binding function, or a protein-DNA function.
  • a protein comprises multiple protein domains.
  • a protein comprises multiple protein domains that are naturally occurring.
  • a protein comprises multiple protein domains from different naturally occurring proteins.
  • a protein that comprises amino acid sequences from different origins or naturally occurring proteins may be referred to as a fusion, or chimeric protein.
  • a protein or polypeptide includes naturally occurring amino acids (e.g., one of the twenty amino acids commonly found in peptides synthesized in nature, and known by the one letter abbreviations A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y and V).
  • a protein or polypeptides includes non-naturally occurring amino acids (e.g., amino acids which is not one of the twenty amino acids commonly found in peptides synthesized in nature, including synthetic amino acids, amino acid analogs, and amino acid mimetics).
  • a protein or polypeptide is modified.
  • a protein comprises an isolated polypeptide.
  • isolated means free or removed to varying degrees from components which normally accompany it as found in the natural state or environment. For example, a polypeptide naturally present in a living animal is not isolated, and the same polypeptide partially or completely separated from the coexisting materials of its natural state is isolated.
  • a protein is present within a cell, a tissue, an organ, or a virus particle.
  • a protein is present within a cell or a part of a cell (e.g., a bacteria cell, a plant cell, or an animal cell).
  • the cell is in a tissue, in a subject, or in a cell culture.
  • the cell is a microorganism (e.g., a bacterium, fungus, protozoan, or virus).
  • a protein is present in a mixture of analytes (e.g., a lysate).
  • the protein is present in a lysate from a plurality of cells or from a lysate of a single cell.
  • encode refers to a polynucleotide which is said to “encode” another polynucleotide, a polypeptide, or an amino acid if, in its native state or when manipulated by methods well known to those skilled in the art, it can be used as a polynucleotide synthesis template, e.g., transcribed into an RNA, reverse transcribed into a DNA or cDNA, and/or translated to produce an amino acid, or a polypeptide or fragment thereof.
  • a polynucleotide comprising three contiguous nucleotides form a codon that encodes a specific amino acid.
  • a polynucleotide comprises one or more codons that encode a polypeptide.
  • a polynucleotide comprising one or more codons comprises a mutation in a codon compared to a wild-type reference polynucleotide.
  • the mutation in the codon encodes an amino acid substitution in a polypeptide encoded by the polynucleotide as compared to a wild-type reference polypeptide.
  • the LNP compositions comprise a biodegradable ionizable lipid that comprises a compound described herein. In some embodiments, the LNP compositions comprise a biodegradable ionizable lipid that comprises a compound described here, a phospholipid, a polyethylene glycol-lipid; and a cholesterol. [0098] A. Compounds [0099] The present disclosure provides lipid nanoparticle (LNP) compositions. In some embodiments, the LNP compositions comprise a biodegradable ionizable lipid that comprises a compound described herein.
  • the present disclosure provides compounds of Formula I: I wherein A is N, CH, or phenyl; and wherein each R i , R ii , and R iii is independently: , Q is independently –O–, –CH 2 –, –C(O)–, –C(O)O–, –OC(O)–, – OC(O)CH2CH(OH)–, –CH2-OC(O)–, or –NHC(O)–; subscript “a” is independently an integer between 1 and 5; D is independently N or O, wherein when D is N, R and R are each independently H, C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl , or together with the N- atom they are connected to form nsubstituted C3-C6 heterocycloalkyl or substituted or unsubstituted C 5 -C 6 heteroaryl; R a and R
  • Compounds including the group having at least one of R i , R ii , and R iii represented by may be particularly suited for forming lipid ic acid molecules, such as guide RNA molecules comprising more than 100, 120 or 150 nucleotides.
  • the compound of Formula I includes at least one of a disulfide bond, an ester group, a carbmate group or an alkenyl group.
  • the compound of Formula I includes at least two such groups, at least three such groups, at least four such groups, at least 5 such groups or at least 6 such groups.
  • the compound of Formula I is a compound of Formula II: .
  • the compound of Formula I is a compound of Formula II-A: R 3 1 R 4 [00105] In some embodimen ts, the compound of Formula I is a compound of Formula III: [00106] In some embodiments, the compound of Formula I is a compound of Formula IV: [00107] (i) Compounds of Formula II, Formula II-A, and Formula III [00108] In one aspect, the present disclosure provides compounds of Formula II: wherein, A is N or CH; Q is independently –O–, –CH2–, –C(O)–, –C(O)O–, –OC(O)–, –OC(O)CH2CH(OH)–, –CH 2 -OC(O)–, or –NHC(O)–; subscript “a” is independently an integer between 1 and 5; D is independently N or O, wherein when D is N, R 1 and R 2 are each independently H, C1-C6 alkyl, hydroxy- substituted C1-
  • the present disclosure provides compounds of Formula II-A: wherein, A is N or CH; Q is independently –O–, –CH 2 –, –C(O)–, –C(O)O–, –OC(O)–, –OC(O)CH 2 CH(OH)–, –CH2-OC(O)–, or –NHC(O)–; subscript “a” is independently an integer between 1 and 5; D is independently N or O, wherein when D is N, R 1 and R 2 are each independently H, C1-C6 alkyl, hydroxy- substituted C1-C6 alkyl or together with the N-atom they are connected to form a substituted or unsubstituted C 3 -C 6 heterocycloalkyl or substituted or unsubstituted C5-C6 heteroaryl; when D is O, one of R 1 or R 2 is absent and the other is H or C 1 -C 6 alkyl; subscript “g” is independently 0
  • the present disclosure provides compounds of Formula III: wherein, A is N or CH; Q is independently –O–, –CH2–, –C(O)–, –C(O)O–, –OC(O)–, –OC(O)CH2CH(OH)–, –CH 2 -OC(O)–, or –NHC(O)–; subscript “a” is independently an integer between 1 and 5; D is independently N or O, wherein when D is N, R 1 and R 2 are each independently H, C1-C6 alkyl, hydroxy- substituted C1-C6 alkyl or together with the N-atom they are connected to form a su d C 3 -C 6 heterocycloalkyl or substituted or unsubstituted C5-C6 heteroaryl; R a and R b are each independently H or C 1 -C 6 alkyl; when D is O, one of R 1 or R 2 is absent and the other is H or C1-C
  • each G 1 is independently –CH 2 – or –C(O)–; each subscript “b” is independently an integer between 0 and 10; each X 1 is absent, or independently –O–, –C(O)O– or –OC(O)–; each subscript “c” is independently an integer between 0 and 10; each subscript “d” is independently 0 or 1; each Y 1 is independently –O–, –CH2–, –CH(C1-6 alkyl)–, or – CH(C1-6 alkyl)-CH2-O–; each Y 2 is independently absent or –O–, –CH2–, or –CH(C1-6 alkyl)–; each subscript “e” is independently 0, 1, or 2; each subscript “f” is independently 0 or 1; each E is independently –S– or –S-S—; each G 2 is independently –CH– or –N–; each L 1 and L 2 is independently –O– or –CH 2 –
  • the compound of Formula II, Formula II-A, or Formula III includes at least one of a disulfide bond, an ester group, a carbmate group or an alkenyl group.
  • the compound of Formula I, II, II-A, or III includes at least two such groups, at least three such groups or at least four such groups, at least 5 such groups or at least 6 such groups.
  • each of R 3 , R 4 and R 5 is present and each includes at least one such group, suitably at least 2 such groups.
  • A is CH. In some embodiments, A is N.
  • Q is independently –O–, –CH 2 –, –C(O)–, –C(O)O–, – OC(O)–, –OC(O)CH2CH(OH)–, –CH2-OC(O)–, or –NHC(O)–.
  • Q is – O–.
  • Q is –CH 2 –.
  • Q is –C(O)–.
  • Q is –C(O)O–.
  • Q is –OC(O)–.
  • Q is –OC(O)CH 2 CH(OH)–.
  • Q is –CH 2 -OC(O)–. In some embodiments, Q is –NHC(O)–. [00114] In some embodiments, subscript “a” is independently an integer between 1 and 5, that is 1, 2, 3, 4, or 5. [00115] In some embodiments, R 1 and R 2 are each independently C1-C6 alkyl. In some embodiments, R 1 and R 2 are each independently methyl or ethyl. In some embodiments, R 1 and R 2 are each independently methyl. In some embodiments, R 1 and R 2 are each independently ethyl.
  • R 1 and R 2 together with the N-atom they are connected to form a substituted or unsubstitued C 3 -C 6 heterocycloalkyl.
  • the C 3 -C 6 heterocycloalkyl is a pyrrolidinyl or piperazinyl.
  • the C3-C6 heterocycloalkyl is substituted with a C 1 -C 6 alkyl.
  • the C 1 -C 6 alkyl is methyl, ethyl, propyl, or isopropyl.
  • the C3-C6 heterocycloalkyl is unsubstituted.
  • R 1 and R 2 together with the N-atom they are connected to form a substituted or unsubstituted C5-C6 heteroaryl.
  • the C5-C6 heteroaryl is imidazolyl.
  • R 1 is C 1 -C 6 alkyl and R 2 is hydroxy-substituted C 1 -C 6 alkyl.
  • the C 1 -C 6 alkyl is methyl, ethyl, propyl, or isopropyl and the hydroxy- substituted C 1 -C 6 alkyl is –CH 2 -OH, –CH 2 -CH 2 -OH, –CH 2 -CH 2 -CH 2 -OH, –C(CH 3 ) 2 OH, or – CH2CH2CH2CH2-OH.
  • subscript “g” is 0. In some embodiments, subscript “g” is 1.
  • each R 3 , R 4 and R 5 is independently Formula A.1, Formula A.2, or Formula A.3:
  • Formula A.1 comprises the following structure: wherein each G 1 is independently –CH 2 – or –C(O)–; each subscript “b” is independently an integer between 0 and 10; each X 1 is absent, or independently –O–, –C(O)O– or –OC(O)–; each subscript “c” is independently an integer between 0 and 10; each subscript “d” is independently 0 or 1; each Y is independently –O–, –CH 2 –, –CH(C 1 - 6 alkyl)–, or – CH(C1-6 alkyl)-CH2-O—; each Y 2 is independently absent or –O–, –CH 2 –, or –CH(C 1 - 6 alkyl)–; each subscript “e” is independently
  • each G 1 is –CH2–. In some embodiments, each G 1 is –C(O)–.
  • each subscript “b” is independently an integer between 0 and 10. In some embodiments, each subscript “b” is independently 0. In some embodiments, each subscript “b” is independently 1. In some embodiments, each subscript “b” is independently 2. In some embodiments, each subscript “b” is independently 3. In some embodiments, each subscript “b” is independently 4. In some embodiments, each subscript “b” is independently 5. In some embodiments, each subscript “b” is independently 6. In some embodiments, each subscript “b” is independently 7. In some embodiments, each subscript “b” is independently 8.
  • each subscript “b” is independently 9. In some embodiments, each subscript “b” is independently 10. [00125] In some embodiments, each X 1 is absent. In some embodiments, each X 1 is independently –O–, –C(O)O– or –OC(O)–. In some embodiments, each X 1 is–O–. In some embodiments, each X 1 is –C(O)O–. In some embodiments, each X 1 is –OC(O)–. [00126] In some embodiments, each subscript “c” is independently an integer between 0 and 10. In some embodiments, each subscript “c” is independently 0. In some embodiments, each subscript “c” is independently 1.
  • each subscript “c” is independently 2. In some embodiments, each subscript “c” is independently 3. In some embodiments, each subscript “c” is independently 4. In some embodiments, each subscript “c” is independently 5. In some embodiments, each subscript “c” is independently 6. In some embodiments, each subscript “c” is independently 7. In some embodiments, each subscript “c” is independently 8. In some embodiments, each subscript “c” is independently 9. In some embodiments, each subscript “c” is independently 10. [00127] In some embodiments, each subscript “d” is independently 0 or 1. In some embodiments, each subscript “d” is independently 0. In some embodiments, each subscript “d” is independently 1.
  • each Y is independently –O–, –CH 2 –, –CH(C 1 - 6 alkyl)–, or – CH(C1-6 alkyl)-CH2-O–.
  • each Y 1 is –O–.
  • each Y 1 is –CH 2 –.
  • each Y 1 is –CH(C 1 - 6 alkyl)–.
  • each Y 1 is –CH(CH3)–.
  • each Y 1 is –CH(CH2CH3)–.
  • each Y 1 is –CH(C1-6 alkyl)-CH2-O–.
  • each Y 1 is –CH(CH3)-CH2-O–. In some embodiments, each Y 1 is –CH(CH 3 )–. In some embodiments, each Y 1 is – CH(CH2CH3)-CH2-O)–. [00129] In some embodiments, each Y 2 is absent. In some embodiments each Y 2 is independently –O–, –CH2–, or –CH(C1-6 alkyl)–. In some embodiments each Y 2 is –O–. In some embodiments each Y 2 is –CH 2 –. In some embodiments each Y 2 is –CH(C 1 - 6 alkyl)–. In some embodiments, each Y 2 is –CH(CH3)–.
  • each Y 1 is –CH(CH3)–. In some embodiments, each Y 2 is –CH(CH 2 CH 3 )–. [00130] In some embodiments, each subscript “e” is independently 0, 1, or 2. In some embodiments, each subscript “e” is independently 0. In some embodiments, each subscript “e” is independently 1. In some embodiments, each subscript “e” is independently 2. [00131] In some embodiments, each subscript “f” is independently 0 or 1. In some embodiments, each subscript “f” is independently 0. In some embodiments, each subscript “f” is independently 1. [00132] In some embodiments, each E is independently –S– or –S-S–. In some embodiments, each E is –S–.
  • each E is –S-S–.
  • each R 6 is a C 3 -C 15 alkyl or a C 4 -C 20 alkenyl. In some embodiments, each R 6 is a C3-C15 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 14 alkyl, C 15 alkyl, C 16 alkyl, C 17 alkyl, C 18 alkyl, C 19 alkyl, or C20 alkyl.
  • R 6 is a pentyl, hexyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, or n-pentadecanyl.
  • each R 6 is a C4-C20 alkenyl.
  • each R 6 is a C 4 alkenyl, C 5 alkenyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 14 alkenyl, C 15 alkenyl, C 16 alkenyl, C 17 alkenyl, C 18 alkenyl, C 19 alkenyl, or C 20 alkenyl.
  • each R 6 is a C 4 -C 20 alkenyl with one double bond. In some embodiments, each R 6 is a C 4 -C 20 alkenyl with two double bonds.
  • each R 6 is a C6-C20 alkenyl with three double bonds. In some embodiments, each R 6 is a C 8 -C 20 alkenyl with four double bonds. In some embodiments, each R 6 is a C 10 - C20 alkenyl with five double bonds. In some embodiments, each R 6 is a non-2-eneyl or dodeca-5,7-dienyl. [00135] In some embodiments, each R is a C 4 -C 15 alkynyl.
  • each R is a C4 alkynyl, C5 alkynyl, C6 alkynyl, C7 alkynyl, C8 alkynyl, C9 alkynyl, C10 alkynyl, C11 alkynyl, C 12 alkynyl, C 14 alkynyl, or C 15 alkynyl.
  • each R 6 is a C 4 -C 15 alkynyl with one triple bond.
  • each R 6 is a C4-C15 alkynyl with two triple bonds.
  • each R 6 is a C6-C15 alkynyl with three triple bonds.
  • each R 6 is a oct-3-ynyl or a non-4-ynyl.
  • G 1 is –C(O)–
  • subscript “b” is 1
  • X 1 is absent
  • subscript “c” and “d” are 0,
  • subscript “e” is 2
  • subscript “f” is 1
  • E is –S-S–
  • R 6 is a C3-C15 alkyl.
  • G 1 is –CH 2 –; subscript “b” is 1, X 1 is – C(O)O–, subscript “c” is 1, subscript “d” is 0, subscript “e” is 2, subscript “f” is 1, E is –S-S– , and R 6 is a C 3 -C 15 alkyl.
  • G 1 is –CH2–; subscript “b” is 1, X 1 is – C(O)O–, subscript “c” is 2, subscript “d” is 1, Y 1 is –O–, Y 2 is – CH 2 –, subscript “e” and “f” are each 0, and R 6 is a C3-C15 alkyl.
  • each G 1 is –CH2–; each subscript “b” is 5; each X 1 is absent, each subscript “c” and “d” are 1, each Y 1 is –CH2–, each Y 2 is –O–; each subscript “e” and “f” is 0, and each R 6 is a C4-C20 alkenyl.
  • each G 1 is –CH 2 –; each subscript “b” is 1; each X 1 is –C(O)O–, each subscript “c” “d” and “e” is 0, each subscript “f” is 1, each E is –S- S, and each R 6 is a C 3 -C 15 alkyl.
  • each G 1 is –CH2–; each subscript “b” is 1, each subscript “c” “d” “e” and “f” is 0, each X 1 is absent, and each R 6 is a C 4 -C 20 alkenyl.
  • each G 1 is –C(O)–; each subscript “b” is 1, each subscript “c” “d” “e” and “f” is 0, each X 1 is absent, and each R 6 is a C 4 -C 20 alkenyl.
  • each G 1 is –C(O)–; each subscript “b” is 2, each X 1 is absent, each subscript “c” “d” and “e” is 0, each subscript “f” is 1, each E is –S-S– and each R 6 is a C 3 -C 15 alkyl.
  • each G 1 is –CH 2 –; each subscript “b” is 7; each X 1 is absent, each subscript “c” is 0; each subscript “d” is 1; each Y 1 is –CH(C1-6 alkyl)- CH 2 -O–, each Y 2 is –CH(C 1 - 6 alkyl)–; each subscript “e” is 0; each subscript “f” is 0, and each R 6 is a C3-C15 alkyl.
  • each G 1 is –CH2–; each subscript “b” is 0, 1, or 2; each X 1 is –O–, each subscript “c” is 1; each subscript “d” is 1; (i) each Y 1 is –CH 2 – and each Y 2 is –O– or (ii) each Y 1 is –O– and each Y 2 is – CH2–; each subscript “e” is 0; each subscript “f” is 0, and each R 6 is a C3-C15 alkenyl.
  • each G 1 is –CH2–; each subscript “b” is 0; each X 1 is –O–, each subscript “c” is 1; each subscript “d” is 1; (i) each Y 1 is –CH2– and each Y 2 is –O– or (ii) each Y 1 is –O– and each Y 2 is – CH2–; each subscript “e” is 0; each subscript “f” is 0, and each R 6 is a C3-C15 alkenyl.
  • each G 1 is –CH 2 –; each subscript “b” is 2; each X 1 is –O–, each subscript “c” is 1; each subscript “d” is 1; (i) each Y 1 is –CH 2 – and each Y 2 is –O– or (ii) each Y 1 is –O– and each Y 2 is – CH 2 –; each subscript “e” is 0; each subscript “f” is 0, and each R 6 is a C3-C15 alkenyl. [00148] 2.
  • R 3 is Formula A.2.
  • R 4 is Formula A.2.
  • R 5 is Formula A.2.
  • Formula A.2 comprises the following structure: Formula A.2 wherein each G 1 is independently –CH 2 – or –C(O)–; each subscript “b” is independently an integer between 0 and 10; each X 1 is absent, or independently –O–, –C(O)O– or –OC(O)–; each subscript “c” is independently an integer between 0 and 10; each subscript “d” is independently 0 or 1; each Y 1 is independently –O–, –CH 2 –, –CH(C 1 - 6 alkyl)–, or – CH(C1-6 alkyl)-CH2-O—; each Y 2 is independently absent or –O–, –CH 2 –, or –CH(C 1 - 6 alkyl)–; each subscript “e” is independently 0, 1, or 2; each subscript “f” is independently 0 or 1; each E is independently –S– or –S-S–;
  • each G 1 is –CH2–. In some embodiments, each G 1 is –C(O)–.
  • each subscript “b” is independently an integer between 0 and 10. In some embodiments, each subscript “b” is independently 0. In some embodiments, each subscript “b” is independently 1. In some embodiments, each subscript “b” is independently 2. In some embodiments, each subscript “b” is independently 3. In some embodiments, each subscript “b” is independently 4. In some embodiments, each subscript “b” is independently 5. In some embodiments, each subscript “b” is independently 6. In some embodiments, each subscript “b” is independently 7. In some embodiments, each subscript “b” is independently 8.
  • each subscript “b” is independently 9. In some embodiments, each subscript “b” is independently 10. [00153] In some embodiments, each X 1 is absent. In some embodiments, each X 1 is independently –O–, –C(O)O– or –OC(O)–. In some embodiments, each X 1 is–O–. In some embodiments, each X 1 is –C(O)O–. In some embodiments, each X 1 is –OC(O)–. [00154] In some embodiments, each subscript “c” is independently an integer between 0 and 5. In some embodiments, each subscript “c” is independently 0. In some embodiments, each subscript “c” is independently 1.
  • each subscript “c” is independently 2. In some embodiments, each subscript c is independently 3. In some embodiments, each subscript “c” is independently 4. In some embodiments, each subscript “c” is independently 5. In some embodiments, each subscript “c” is independently 6. In some embodiments, each subscript “c” is independently 7. In some embodiments, each subscript “c” is independently 8. In some embodiments, each subscript “c” is independently 9. In some embodiments, each subscript “c” is independently 10. [00155] In some embodiments, each subscript “d” is independently 0 or 1. In some embodiments, each subscript “d” is independently 0. In some embodiments, each subscript “d” is independently 1.
  • each Y 1 is independently –O–, –CH 2 –,–CH(C 1 - 6 alkyl)–, or – CH(C1-6 alkyl)-CH2-O–. In some embodiments, each Y 1 is –O–. In some embodiments, each Y 1 is –CH 2 –. In some embodiments, each Y 1 is –CH(C 1 - 6 alkyl)–. In some embodiments, each Y 1 is –CH(CH3)–. In some embodiments, each Y 1 is –CH(CH2CH3)–. In some embodiments, each Y 1 is –CH(C 1 - 6 alkyl)-CH 2 -O–.
  • each Y 1 is –CH(CH 3 )-CH 2 -O–. In some embodiments, each Y 1 is –CH(CH3)–. In some embodiments, each Y 1 is – CH(CH2CH3)-CH2-O)–. [00157] In some embodiments, each Y 2 is absent. In some embodiments each Y 2 is independently –O–, –CH2–, or –CH(C1-6 alkyl)–. In some embodiments each Y 2 is –O–. In some embodiments each Y 2 is –CH2–. In some embodiments each Y 2 is –CH(C1-6 alkyl)–. In some embodiments, each Y 2 is –CH(CH3)–.
  • each Y 1 is –CH(CH3)–. In some embodiments, each Y 2 is –CH(CH 2 CH 3 )– [00158] In some embodiments, each subscript “e” is independently 0, 1, or 2. In some embodiments, each subscript “e” is independently 0. In some embodiments, each subscript “e” is independently 1. In some embodiments, each subscript “e” is independently 2. [00159] In some embodiments, each subscript “f” is independently 0 or 1. In some embodiments, each subscript “f” is independently 0. In some embodiments, each subscript “f” is independently 1. [00160] In some embodiments, each E is independently –S– or –S-S–. In some embodiments, each E is –S–.
  • each E is –S-S–.
  • each G 2 is independently –CH– or –N–. In some embodiments, each G 2 is –CH–. In some embodiments, each G 2 is –N–. [00162] In some embodiments, each L 1 and L 2 is independently –O– or –CH 2 –. In some embodiments, each L 1 and L 2 is –O–. In some embodiments, each L 1 and L 2 is –CH2–. In some embodiments, each L is –O–. In some embodiments, each L is –CH 2 –. In some embodiments, each L 2 is –O–. In some embodiments, each L 2 is –CH2–.
  • each R 7 and R 8 is a C 3 -C 15 alkyl or a C 4 -C 20 alkenyl. In some embodiments, each R 7 and R 8 is a C3-C15 alkyl. In some embodiments, each R 7 and R 8 is a C3-C15 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 alkyl, C12 alkyl, C 14 alkyl, C 15 alkyl, C 16 alkyl, C 17 alkyl, C 18 alkyl, C 19 alkyl, or C 20 alkyl.
  • each R 7 and R 8 is a pentyl, hexyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n- dodecanyl, n-tridecanyl, n-tetradecanyl, or n-pentadecanyl.
  • each R 7 is a pentyl, hexyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n- tetradecanyl, or n-pentadecanyl.
  • each R 8 is a pentyl, hexyl, n-octyl, n- nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, or n-pentadecanyl.
  • each R 7 and R 8 is independently a C 4 -C 20 alkenyl.
  • each R 7 and R 8 is independently a C4 alkenyl, C5 alkenyl, C6 alkenyl, C7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 14 alkenyl, C 15 alkenyl, C16 alkenyl, C17 alkenyl, C18 alkenyl, C19 alkenyl, or C20 alkenyl.
  • each R 7 and R 8 is independently a C4-C20 alkenyl with one double bond.
  • each R 7 and R 8 is independently a C4-C20 alkenyl with two double bonds.
  • each R 7 and R 8 is independently a C6-C20 alkenyl with three double bonds. In some embodiments, each R 7 and R 8 is independently a C8-C20 alkenyl with four double bonds. In some embodiments, each R 7 and R 8 is independently a C10-C20 alkenyl with five double bonds. In some embodiments, each R 7 and R 8 is a non-2-eneyl or dodeca-5,7- dienyl. [00165] In some embodiments, each R 7 and R 8 is a C 4 -C 15 alkynyl.
  • each R 7 and R 8 is a C4 alkynyl, C5 alkynyl, C6 alkynyl, C7 alkynyl, C8 alkynyl, C9 alkynyl, C 10 alkynyl, C 11 alkynyl, C 12 alkynyl, C 14 alkynyl, or C 15 alkynyl.
  • each R 7 and R 8 is a C4-C15 alkynyl with one triple bond.
  • each R 7 and R 8 is a C 6 -C 15 alkynyl with two triple bonds.
  • each R 7 and R 8 is a C 8 - C 15 alkynyl with three triple bonds.
  • each R 7 and R 8 is a oct-3-ynyl or a non-4-ynyl.
  • each G 1 is –CH 2 –; each subscript “b” is 4-6; each X 1 is absent, each subscript “c” is 1; each subscript “d” is 1; each Y 1 is –CH2–, each Y 2 is –O–; each subscript “e” is 1-2; each subscript “f” is 0, each G 2 is –CH–, L 1 and L 2 are each –CH2–, and each R 7 and R 8 is independently a C3-C15 alkyl.
  • each G 1 is –CH 2 –; each subscript “b” is 4-6; each X 1 is absent, each subscript c is 1; each subscript d is 1; each Y is –CH 2 –, each Y is –O–; each subscript e is 1; each subscript “f” is 0, each G 2 is –CH–, L 1 and L 2 are each –CH2–, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each G 1 is –CH 2 –; each subscript “b” is 4-6; each X 1 is absent, each subscript “c” is 1; each subscript “d” is 1; each Y 1 is –CH2–, each Y 2 is –O–; each subscript “e” is 2; each subscript “f” is 0, each G 2 is –CH– , L 1 and L 2 are each –CH 2 –, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each G 1 is –CH2–; each subscript “b” is 5; each X 1 is absent, each subscript “c” is 1; each subscript “d” is 1; each Y 1 is –CH 2 –, each Y 2 is –O–; each subscript “e” is 0, 1, or 2, each subscript “f” is 0; each G 2 is –CH–, L 1 and L 2 are each –CH 2 –, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each G 1 is –CH2–; each subscript “b” is 5; each X 1 is absent, each subscript “c” is 1; each subscript “d” is 1; each Y 1 is –CH 2 –, each Y 2 is –O–; each subscript “e” is 0, each subscript “f” is 0; each G 2 is –CH–, L 1 and L 2 are each –CH2–, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each G 1 is –CH 2 –; each subscript “b” is 5; each X 1 is absent, each subscript “c” is 1; each subscript “d” is 1; each Y 1 is –CH2–, each Y 2 is –O–; each subscript “e” is 1, each subscript “f” is 0; each G 2 is –CH–, L 1 and L 2 are each –CH2–, and each R 7 and R 8 is independently a C3-C15 alkyl.
  • each G 1 is –CH2–; each subscript “b” is 5; each X 1 is absent, each subscript “c” is 1; each subscript “d” is 1; each Y 1 is –CH2–, each Y 2 is –O–; each subscript “e” is 2, each subscript “f” is 0; each G 2 is –CH–, L 1 and L 2 are each –CH2–, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each G 1 is –CH2–; each subscript “b” is 1-8; each X 1 is absent, each subscript “c” is 0, each subscript “d” is 1; each Y 1 is –O–, each Y 2 is absent or–CH2–; each subscript “e” is 0, 1, or 2, each subscript “f” is 0; each G 2 is –CH– or – N–; L 1 and L 2 are each –CH 2 – or –O–, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each subscript “b” is 1, 2, 3, 4, 5, 6, 7, or 8; and each G 1 is –CH 2 –; each X 1 is absent, each subscript “c” is 0, each subscript “d” is 1; each Y 1 is –O–, each Y 2 is absent or–CH 2 –; each subscript “e” is 0, 1, or 2, each subscript “f” is 0; each G 2 is –CH– or –N–; L 1 and L 2 are each –CH 2 – or –O–, and each R 7 and R 8 is independently a C 3 - C 15 alkyl [00169]
  • each G 1 is –CH2–; each subscript “b” is 1; each X 1 is –C(O)O–, each subscript “c” is 2, each subscript “d” is 1; each Y 1 is –O–, each Y 2 is absent or –CH 2 – ; each subscript “e” is 1, each subscript “f” is 0; each G 2 is –CH–; L 1 and L 2 are each –CH2– or –O–, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each G 1 is –CH2–; each subscript “b” is 1; each X 1 is –C(O)O–, each subscript “c” is 2, each subscript “d” is 1; each Y 1 is –O–, each Y 2 is absent or –CH 2 – ; each subscript “e” is 2, each subscript “f” is 0; each G 2 is –CH–; L 1 and L 2 are each –CH2– or –O–, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each G 1 is –CH2–; each subscript “b” is 5-8; each X 1 is absent, each subscript “c” is 0, each subscript “d” is 1; each Y 1 is – CH 2 –, each Y 2 is –O– ; each subscript “e” is 0, 1, or 2, each subscript “f” is 0; each G 2 is –CH– or –N–; L 1 and L 2 are each –CH2– or –O–, and each R 7 and R 8 is independently a C3-C15 alkyl.
  • each subscript “b” is 5, 6, 7, or 8; and each G 1 is –CH2–; each X 1 is absent, each subscript “c” is 0, each subscript “d” is 1; each Y 1 is – CH2–, each Y 2 is – O– ; each subscript “e” is 0, 1, or 2, each subscript “f” is 0; each G 2 is –CH– or –N–; L 1 and L 2 are each –CH2– or –O–, and each R 7 and R 8 is independently a C3-C15 alkyl.
  • each G 1 is –CH 2 –; each subscript “b” is 5-8; each X 1 is absent, each subscript “c” is 0, each subscript “d” is 1; each Y 1 is –CH(C1-6 alkyl)– or –CH(C 1 - 6 alkyl)-CH 2 -O–, each Y 2 is –O– or absent ; each subscript “e” is 0, 1, or 2, each subscript “f” is 0; each G 2 is –CH–, L 1 and L 2 are each –CH2–, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each subscript “b” is 5, 6, 7, or 8; and each G 1 is –CH2–; each X 1 is absent, each subscript “c” is 0, each subscript “d” is 1; each Y 1 is –CH(C 1 - 6 alkyl)– or –CH(C 1 - 6 alkyl)-CH 2 -O–, each Y 2 is –O– or absent ; each subscript “e” is 0, 1, or 2, each subscript “f” is 0; each G 2 is –CH–, L 1 and L 2 are each – CH 2 –, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each G 1 is –CH 2 –; each subscript “b” is 0, 1, or 2; each X 1 is –O–, each subscript “c” is 1; each subscript “d” is 1; (i) each Y 1 is –CH2– and each Y 2 is –O– or (ii) each Y 1 is –O– and each Y 2 is – CH 2 –; each subscript “e” is 0; each subscript “f” is 0, ach G 2 is –CH–, L 1 and L 2 are each –CH2–, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each subscript “b” is 0, 1, or 2; and each G is –CH 2 –; each X is –O–, each subscript c is 1; each subscript d is 1; each Y 1 is –CH2–; each Y 2 is –O–; each subscript “e” is 0; each subscript “f” is 0, ach G 2 is – CH–, L 1 and L 2 are each –CH 2 –, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • each subscript “b” is 0, 1, or 2; and each G 1 is –CH2–; each X 1 is –O–, each subscript “c” is 1; each subscript “d” is 1; each Y 1 is –O–; each Y 2 is – CH2–; each subscript “e” is 0; each subscript “f” is 0, ach G 2 is –CH–, L 1 and L 2 are each –CH 2 –, and each R 7 and R 8 is independently a C3-C15 alkyl. [00173] 3.
  • R 3 is Formula A.3.
  • R 4 is Formula A.3.
  • R 5 is Formula A.3.
  • Formula A.3 comprises the following structure: G 1 X 1 E Y 1 Y 2 L 2 R7 wherein each G 1 is independently –CH2– or –C(O)–; each subscript “b” is independently an integer between 0 and 10; each X 1 is absent, or independently –O–, –C(O)O– or –OC(O)–; each subscript “c” is independently an integer between 0 and 10; each subscript “d” is independently 0 or 1; each Y 1 is independently –O–, –CH 2 –, –CH(C 1 - 6 alkyl)–, or – CH(C1-6 alkyl)-CH2-O–; each Y 2 is independently absent or –O–, –CH 2 –, or –CH(C 1 - 6 alkyl)–; each subscript “e” is independently 0, 1, or 2; each subscript “f” is independently 0 or 1; each E is independently 0 or 1; each E
  • each G is –CH 2 –. In some embodiments, each G is –C(O)–.
  • each subscript “b” is independently an integer between 0 and 10, i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each subscript “b” is independently 0. In some embodiments, each subscript “b” is independently 1. In some embodiments, each subscript “b” is independently 2. In some embodiments, each subscript “b” is independently 3. In some embodiments, each subscript “b” is independently 4. In some embodiments, each subscript “b” is independently 5. In some embodiments, each subscript “b” is independently 6. In some embodiments, each subscript “b” is independently 7.
  • each subscript “b” is independently 8. In some embodiments, each subscript “b” is independently 9. In some embodiments, each subscript “b” is independently 10. [00178] In some embodiments, each X 1 is absent. In some embodiments, each X 1 is independently –O–, –C(O)O– or –OC(O)–. In some embodiments, each X 1 is–O–. In some embodiments, each X 1 is –C(O)O–. In some embodiments, each X 1 is –OC(O)–. [00179] In some embodiments, each subscript “c” is independently an integer between 0 and 5. In some embodiments, each subscript “c” is independently 0.
  • each subscript “c” is independently 1. In some embodiments, each subscript “c” is independently 2. In some embodiments, each subscript “c” is independently 3. In some embodiments, each subscript “c” is independently 4. In some embodiments, each subscript “c” is independently 5. In some embodiments, each subscript “c” is independently 6. In some embodiments, each subscript “c” is independently 7. In some embodiments, each subscript “c” is independently 8. In some embodiments, each subscript “c” is independently 9. In some embodiments, each subscript “c” is independently 10. [00180] In some embodiments, each subscript “d” is independently 0 or 1. In some embodiments, each subscript “d” is independently 0. In some embodiments, each subscript “d” is independently 1.
  • each Y 1 is independently –O–, –CH2–, –CH(C1-6 alkyl)–, or – CH(C 1 - 6 alkyl)-CH 2 -O–. In some embodiments, each Y 1 is –O–. In some embodiments, each Y 1 is –CH 2 –. In some embodiments, each Y 1 is –CH(C 1 - 6 alkyl)–. In some embodiments, each Y 1 is –CH(CH 3 )–. In some embodiments, each Y 1 is –CH(CH 2 CH 3 )–. In some embodiments, each Y 1 is –CH(C 1 - 6 alkyl)-CH 2 -O–.
  • each Y 1 is –CH(CH 3 )-CH 2 -O–. In some embodiments, each Y 1 is –CH(CH3)–. In some embodiments, each Y 1 is – CH(CH 2 CH 3 )-CH 2 -O)–. [00182] In some embodiments, each Y 2 is absent. In some embodiments each Y 2 is independently –O–, –CH 2 –, or –CH(C 1 - 6 alkyl)–. In some embodiments each Y 2 is –O–. In some embodiments each Y is –CH 2 –. In some embodiments each Y is –CH(C 1 - 6 alkyl)–.
  • each Y 2 is –CH(CH3)–. In some embodiments, each Y 1 is –CH(CH3)–. In some embodiments, each Y 2 is –CH(CH 2 CH 3 )– [00183] In some embodiments, each subscript “e” is independently 0, 1, or 2. In some embodiments, each subscript “e” is independently 0. In some embodiments, each subscript “e” is independently 1. In some embodiments, each subscript “e” is independently 2. [00184] In some embodiments, each subscript “f” is independently 0 or 1. In some embodiments, each subscript “f” is independently 0. In some embodiments, each subscript “f” is independently 1.
  • each E is independently –S– or –S-S–. In some embodiments, each E is –S–. In some embodiments, each E is –S-S–. [00186] In some embodiments, each G 2 is independently –CH– or –N–. In some embodiments, each G 2 is –CH–. In some embodiments, each G 2 is –N–. [00187] In some embodiments, each L 1 and L 2 is independently –O– or –CH 2 –. In some embodiments, each L 1 and L 2 is –O–. In some embodiments, each L 1 and L 2 is –CH2–. In some embodiments, each L 1 is –O–.
  • each L 1 is –CH2–. In some embodiments, each L 2 is –O–. In some embodiments, each L 2 is –CH2–. [00188] In some embodiments, each R 7 and R 8 is a C3-C15 alkyl or a C4-C20 alkenyl. In some embodiments, each R 7 and R 8 is a C3-C15 alkyl.
  • each R 7 and R 8 is a C3-C15 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 alkyl, C12 alkyl, C 14 alkyl, C 15 alkyl, C 16 alkyl, C 17 alkyl, C 18 alkyl, C 19 alkyl, or C 20 alkyl.
  • each R 7 and R 8 is a pentyl, hexyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n- dodecanyl, n-tridecanyl, n-tetradecanyl, or n-pentadecanyl.
  • each R 7 is a pentyl, hexyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n- tetradecanyl, or n-pentadecanyl.
  • each R 8 is a pentyl, hexyl, n-octyl, n- nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, or n-pentadecanyl.
  • each R 7 and R 8 is independently a C 4 -C 20 alkenyl.
  • each R 7 and R 8 is independently a C 4 alkenyl, C 5 alkenyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 14 alkenyl, C 15 alkenyl, C 16 alkenyl, C 17 alkenyl, C 18 alkenyl, C 19 alkenyl, or C 20 alkenyl.
  • each R 7 and R 8 is independently a C4-C20 alkenyl with one double bond.
  • each R 7 and R 8 is independently a C 4 -C 20 alkenyl with two double bonds.
  • each R 7 and R 8 is independently a C6-C20 alkenyl with three double bonds. In some embodiments, each R 7 and R 8 is independently a C 8 -C 20 alkenyl with four double bonds. In some embodiments, each R and R is independently a C 10 -C 20 alkenyl with five double bonds. In some embodiments, each R 7 and R 8 is a non-2-eneyl or dodeca-5,7- dienyl. [00190] In some embodiments, each R 7 and R 8 is a C4-C15 alkynyl.
  • each R 7 and R 8 is a C4 alkynyl, C5 alkynyl, C6 alkynyl, C7 alkynyl, C8 alkynyl, C9 alkynyl, C 10 alkynyl, C 11 alkynyl, C 12 alkynyl, C 14 alkynyl, or C 15 alkynyl.
  • each R 7 and R 8 is a C4-C15 alkynyl with one triple bond.
  • each R 7 and R 8 is a C 6 -C 15 alkynyl with two triple bonds.
  • each R 7 and R 8 is a C 8 - C15 alkynyl with three triple bonds.
  • each R 7 and R 8 is a oct-3-ynyl or a non-4-ynyl.
  • each G 1 is –CH2–; each subscript “b” is 1; each X 1 is –C(O)O–, each subscript “c” is 2; each subscript “f” is 1, each E is –S-S–, each subscript “e” is 2, each subscript “d” is 1; each Y 1 is –O– and each Y 2 is absent, each G 2 is – CH–, L 1 and L 2 are each –CH 2 –, and each R 7 and R 8 is independently a C 3 -C 15 alkyl.
  • subscript “g” is 1, and R 4 and R 5 are each Formula A.1. In some embodiments, in Formula II, subscript “g” is 1, and R 4 and R 5 are each Formula A.2. In some embodiments, in Formula II, subscript “g” is 1, and R 4 and R 5 are each Formula A.3. [00193] In some embodiments, in Formula II, subscript “g” is 1, and R 4 or R 5 is Formula A.1 and the other is Formula A.2. In some embodiments, in Formula II, subscript “g” is 1, and R 4 or R 5 is Formula A.1 and the other is Formula A.3.
  • subscript “g” is 1, and R 4 or R 5 is Formula A.2 and the other is Formula A.3. [00194] In some embodiments, in Formula II, subscript “g” is 0 and R 3 and R 4 are each Formula A.1. In some embodiments, in Formula II, subscript “g” is 0 and R 3 and R 4 are each Formula A.2. In some embodiments, in Formula II, subscript “g” is 0 and R 3 and R 4 are each Formula A.3. [00195] In some embodiments, in Formula II, subscript “g” is 0 and R 3 or R 4 is Formula A.1 and the other is Formula A.2.
  • subscript “g” is 0 and R 3 or R 4 is Formula A.1 and the other is Formula A.3. In some embodiments, in Formula II, subscript “g” is 0 and R 3 or R 4 is Formula A.2 and the other is Formula A.3. [00196] In some embodiments, in Formula II-A, subscript “g” is 1, and R 4 and R 5 are each Formula A.1. In some embodiments, in Formula II-A, subscript “g” is 1, and R 4 and R 5 are each Formula A.2. In some embodiments, in Formula II-A, subscript “g” is 1, and R 4 and R 5 are each Formula A.3.
  • subscript g is 1, and R or R is Formula A.1 and the other is Formula A.2.
  • subscript “g” is 1, and R 4 or R 5 is Formula A.1 and the other is Formula A.3.
  • subscript “g” is 1, and R 4 or R 5 is Formula A.2 and the other is Formula A.3.
  • subscript “g” is 0 and R 3 and R 4 are each Formula A.1.
  • subscript “g” is 0 and R 3 and R 4 are each Formula A.2.
  • subscript “g” is 0 and R 3 and R 4 are each Formula A.3.
  • subscript “g” is 0 and R 3 or R 4 is Formula A.1 and the other is Formula A.2.
  • subscript “g” is 0 and R 3 or R 4 is Formula A.1 and the other is Formula A.3.
  • subscript “g” is 0 and R 3 or R 4 is Formula A.2 and the other is Formula A.3.
  • Formula A.1, Formula A.2, and/or Formula A.3 is: ,
  • the compound of Formula II-A is a compound of Formula II- A1 or Formula II-A2: R 3 or [00202] In some embodiments, the compound of Formula II-A is a compound of Formula II- A1: R 3 1 R 4 [00203] In some embodimen ts, the compound of Formula II-A is a compound of Formula II- A2: [00204] In some embodiments, the compound of Formula II or Formula II-A is a compound of Formula II-1a or II-1b: or [00205] In some embodiments, the compound of Formula III is a compound of Formula III- 1a: [00206] In some embodiments, the compound of Formula II or Formula II-A is a compound of Formula II-2a, II-2b, II-2c, or II-2d: or .
  • the compound of Formula III is a compound Formula III-2a or III-2b: r , wherein R c is H or C1-C6 alkyl.
  • the compound of Formula II or Formula II-A is a compound of Formula II-3a or II-3b: or 5 [00209] In some embodiments, the compound of Formula III is a compound of Formula III- 3a: [00210] In some embodiments, the compound of Formula II or Formula II-A is of Formula II-4a, II-4b, II-4c, or II-4d: , [00211] In some embodiments, the compound of Formula III is a compound of Formula III- 4a or III-4b: [00212] In some embodiments, the compound of Formula II or Formula II-A is a compound of Formula II-5a or II-5b: R 5 [00213] In some embodiments, the compound of Formula III is a compound of Formula III- 5a: [00214] In some embodiments, the compound of Formula II or Formula II-A is a compound of Formula II-6a, Formula II-6b, Formula II-6c, Formula II-6d, Formula II-6e, or Formula II- 6f: , or or R 3 R
  • A is N
  • Q is -CH2-
  • a is 2
  • D is N
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or together with the N-atom they are connected to form an unsubstituted or Me-substituted C 3 -C 6 heterocycloalkyl.
  • R 3 is according to Formula A.1, wherein f is 1 and E is S-S.
  • R 6 is a C 3-15 -alkyl group.
  • G 1 is -CH2-, b is 1, X 1 is -C(O)O-, c is 2, d is 0, and e is 0, or G 1 is C(O), b is 2, X 1 is absent, c is 0, d is 0 and e is 0.
  • g is 1, R 4 and R 5 are each according to Formula A.2, wherein G 1 is -CH2-, X 1 is absent, d is 1, Y 1 is -CH2-, Y 2 is -O-, f is 0, G 2 is - CH-, and L 1 and L 2 are each –CH 2 –.
  • R 3 is according to Formula A.1, wherein d is 1, Y 1 is -O- and Y 2 is absent or is -CH 2 -.
  • R 6 is a C 3-15 -alkyl group.
  • G 1 is -CH2-, b is 1, X 1 is -C(O)O-, c is 2, e is 0, and f is 0.
  • R 4 and R 5 are each according to Formula A.2, wherein G 1 is -CH2-, X 1 is absent, d is 1, Y 1 is -CH2-, Y 2 is -O-, f is 0, G 2 is -CH-, and L 1 and L 2 are each –CH2–.
  • A is N
  • D is N
  • R 1 and R 2 are each independently C 1 -C 6 alkyl, or together with the N-atom they are connected to form an unsubstituted or Me-substituted C3-C6 heterocycloalkyl, wherein either (a) Q is - CH 2 - or -C(O)- and a is 3, (b) Q is -CH 2 - and a is 1, or(c) Q is -C(O)O-, and a is 2.
  • the hydrocarbon chains can be generated by coupling the di-acids of Formula (SD) with various alcohols.
  • Reductive amination of compound of Formula (SE) with various head groups can generate the key intermediate of Formula (SF).
  • the compounds of Formula (SG) can be generated by treating the intermediate of Formula (SF) with compounds of Formula (SG-1) under basic conditions.
  • the compounds of Formula (SH) can be generated by treating the infermediate of Formula (SF) with compounds of Formula (SH-1) under Michael addition conditions.
  • Substituents R 2 and R 6 as shown in Scheme 1 correspond to substituents R 2 and R 6 as defined in the present disclosure.
  • Substituents A 1 and A 2 correspond to additional groups or moieties present substituent R 3 , as defined in the present disclosure.
  • Scheme 2 ording to Scheme 2.
  • compounds of Formula (SN) and Formula (SQ) can be prepared by coupling a compound of Formula (SI) with acids of Formula (SJ), followed by TBS deprotection to generate a compound of Formula (SL).
  • the key intermediate of Formula (SM) can be generated by the oxidation of a compound of Formula (SL).
  • the compounds of Formula (SN) can be generated by treating the intermediate of Formula (SM) with compounds of Formula (SN-1) under reductive amination conditions.
  • the compounds of Formula (SQ) can be generated through the reductive amination of benzylamine (compound of Formula (SQ-1)) with the intermediate of Formula (SM) to generate the compound of Formula (SO), followed by de-benzylation with hydrogen/Pd on carbon to generate the compound of Formula (SP).
  • Treatment of the compound of Formula (SP) with amino carboxylic acid compounds of Formula (SQ-1) and catalazyed by HATU/DIPEA can generate the compound of Formula (SQ).
  • Substituent R 2 and subscripts “a” “b” “c” and “d” as shown in Scheme 2 correspond to substituents/subscripts as defined in the present disclosure.
  • Substituents A 3 represent additional groups or moieties present in Formula A.1, Formula A.2, or Formula A.3, as defined in the present disclosure.
  • Scheme 3 [00230]
  • compounds of Formula II, Formula II-A, or Formula III can also be prepared according to Scheme 3.
  • compounds of Formula (SU) having symmetrical or hybrid tails can be prepared by treating a compound of Formula (SR) with 4- (dimethylamino)butanoic acid with EDC/DMAP to afford a compound of Formula (SS).
  • each A is –N– or phenyl. In some embodiments, each A is – N–. In some embodiments, each A is phenyl. [00241] In some embodiments, each G 3 is independently –C(O)–, –CH2–, or –CH2-CH2- C(O)–. In some embodiments, each G 3 is independently –C(O)–. In some embodiments, each G 3 is independently–CH2–. In some embodiments, each G 3 is independently –CH2-CH2- C(O)–. [00242] In some embodiments, each X 2 is absent or independently –NH– or –O–. In some embodiments, each X 2 is absent.
  • each X 2 is independently –NH–. In some embodiments, each X 2 is independently –O–. [00243] In some embodiments, A is phenyl, each G 3 is –C(O)– and each X 2 is –NH–. In some embodiments, A is phenyl, each G 3 is –C(O)– and each X 2 is –O–. [00244] In some embodiments, A is –N–, each G 3 is –CH2-CH2-C(O)– and each X 2 is –NH–. In some embodiments, A is –N–, each G 3 is –CH2– and each X 2 is –O–.
  • each subscript “n” is independently an integer between 0 and 3. In some embodiments, each subscript “n” is independently 0. In some embodiments, each subscript “n” is independently 1. In some embodiments, each subscript “n” is independently 2. In some embodiments, each subscript “n” is independently 3. [00246] In some embodiments, each L 3 is independently –CH 2 – or –O-C(O)–. In some embodiments, each L 3 is independently –CH2–. In some embodiments, each L 3 is independently –O-C(O)–.
  • each L is independently –N– or –CH–. In some embodiments, each L 4 is independently –N–. In some embodiments, each L 4 is independently –CH–. [00248] In some embodiments, each L 3 is independently –CH2– and each L 4 is independently –N–. In some embodiments, each L 3 is independently –O-C(O)– and each L 4 is independently –N–.
  • each R 9 is independently H, a C8-C20 alkyl; a C8-C20 alkenyl; a hydroxyl-substituted C 8 -C 20 alkyl; a hydroxyl-substituted C 8 -C 20 alkenyl; , or Formula B.1.
  • each R 9 is diments, each R 9 is independently a C 8 -C 20 alkyl.
  • each R 9 is independently a C8-C20 alkenyl.
  • each R 9 is independently a hydroxyl-substituted C8-C20 alkyl.
  • each R 9 is independently a hydroxyl-substituted C8-C20 alkenyl. In some embodiments, each R 9 is independently . In some embodiments, each R 9 is independently [00250] In some embodiments, each R 9 is a C8-C20 alkyl. In some embodiments, each R 9 is a C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 14 alkyl, C 15 alkyl, C 16 alkyl, C 17 alkyl, C 18 alkyl, C19 alkyl, or C20 alkyl.
  • R 9 is a pentyl, hexyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, or n-pentadecanyl.
  • each R 9 is a C8-C20 alkenyl.
  • each R 9 is a C8 alkenyl, C9 alkenyl, C10 alkenyl, C11 alkenyl, C12 alkenyl, C14 alkenyl, C15 alkenyl, C16 alkenyl, C 17 alkenyl, C 18 alkenyl, C 19 alkenyl, or C 20 alkenyl.
  • each R 9 is a C8-C20 alkenyl with one double bond.
  • each R 9 is a C8-C20 alkenyl with two double bonds.
  • each R 9 is a C 8 -C 20 alkenyl with three double bonds.
  • each R 9 is a C8-C20 alkenyl with four double bonds. In some embodiments, each R 9 is a C 10 -C 20 alkenyl with five double bonds. In some embodiments, each R 9 is a non-2-eneyl, dodeca-5,7-dienyl, arach. [00252] In some embodiments, each R 9 is independent , where the subscript is 6, 7, 8, 9, 10, 11, or 12. [00253] In some embodiments, each R 9 is independently Formula B.1. [00254] 4.
  • each subscript “m” is independently 0, 1, or 2; each X 3 is absent or independently –S– or –S-S–, each subscript “o” is 0 or 1; each Y 3 is independently –CH2– or –O–; each Y 4 is independently –CH2–, –O–, –CH(CH3)S–, or –NR 10 – ; and each R 10 is independently a branched or unbranched C6-C15 alkyl.
  • each subscript “m” is independently 0, 1, or 2. In some embodiments, each subscript “m” is independently 0. In some embodiments, each subscript “m” is independently 1. In some embodiments, each subscript “m” is independently 2.
  • each X 3 is absent or independently –S– or –S-S–. In some embodiments, each X 3 is absent. In some embodiments, each X 3 is independently –S–. In some embodiments, each X 3 is independently –S-S–. [00257] In some embodiments, each subscript “o” is 0 or 1. In some embodiments, each subscript “o” is 0. In some embodiments, each subscript “o” is 1. [00258] In some embodiments, each Y 3 is independently –CH2– or –O–. In some embodiments, each Y 3 is independently –CH2–. In some embodiments, each Y 3 is independently –O–.
  • each Y 4 is independently –CH2–, –O–, –CH(CH3)S–, or – NR 10 –. In some embodiments, each Y 4 is independently –CH2–. In some embodiments, each Y 4 is independently –O–. In some embodiments, each Y 4 is independently –CH(CH 3 )S–. In some embodiments, each Y 4 is independently –NR 10 –. [00260] In some embodiments, each R 10 is independently a branched or unbranched C 6 -C 15 alkyl.
  • each R 10 is a branched C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C 11 alkyl, C 12 alkyl, C 14 alkyl, or C 15 alkyl.
  • each R 10 is an unbranched C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 alkyl, C12 alkyl, C14 alkyl, or C 15 alkyl
  • R 10 is a pentyl, hexyl, n-octyl, n-nonyl, n-decanyl, n- undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, or n-pentadecanyl [00261]
  • each R is Formula B.1, wherein in Formula B.1., each subscript “m” is 2, each X 3 is –S-S–, each subscript “o” is 0, and each R 10 is an unbranched C 6 -C 15 alkyl.
  • each R 9 is Formula B.1, wherein in Formula B.1., each subscript “m” is 1, each X 3 is absent, each subscript “o” is 1, each Y 3 is –O–, each Y 4 is– CH 2 –, and each R 10 is an unbranched C 6 -C 15 alkyl.
  • each R 9 is Formula B.1, wherein in Formula B.1., each subscript “m” is 1, each X 3 is absent, each subscript “o” is 1, each Y 3 is –O–, each Y 4 is– CH(CH3)S–, and each R 10 is an unbranched C6-C15 alkyl.
  • each L 3 is –O-C(O)– and each L 4 is –CH–, and attached to each L 4 , one R 9 is H and the othe .
  • the compound of Formula IV is a compound of Formula IV- A-1: R 10 H O N N 1 0
  • the compound of Formula IV is a compound of Formula IV- A-2: R 10 O O N n R 10 10
  • the compound of Formula IV is a compound of Formula IV- A-3: R 10 R 10
  • the compound of Formula IV is a compound of Formula IV- B-1: [00270]
  • the compound of Formula IV is a compound of Formula IV- B-2: Formula IV-B-2.
  • the compound of Formula IV is a compound of Formula IV- B-3: [00272] In some embodiments, the compound of Formula IV is a compound of Formula IV- B-4: [00273] (iv) General Synthetic Shemes of Formula IV [00274] Compounds of Formula IV of the present disclosure can be synthesized according to the following general synthetic schemes.
  • Scheme 7 [00276] Compounds of Formula IV, such as compounds of Formula IV-A-1 and Formula IV-A-2, can be prepared according to Scheme 7.
  • the compound of Formula (S-DD) can be obtained by the treatment of the acetyl chloride compound of Formula (S-BB) with mono- Cbz protected diamino compound of Formula (S-CC) under the condition of TEA/DCM.
  • the Cbz protected compound of Formula (S-DD) can be treated with H2/Pd/C to obtain the free amino compound of Formula (S-EE).
  • compounds of Formula IV such as Compound 300, a mixture of compound of Formula (S-EE) with epoxide of Formula (S-FF) is heated without solvent.
  • Scheme 8 [00278] Compounds of Formula IV, such as compounds of Formula IV-A-3, can be prepared according to Scheme 8.
  • a Cbz-protected amino alcohol (compound of Formula (S-HH)) can be mixed with a compound of Formula (S-GG) under the condition NaH/THF to produce a Cbz-protected compound of Formula (S-II).
  • the amino compound of Formula (S-JJ) can be obtained by deprotection under TFA.
  • compounds of Formula IV such as Compound 301
  • a mixture of compound of Formula (S-JJ) with epoxide of Formula (S-KK) is heated without solvent.
  • Scheme 9 d IV-A-3, can be prepared according to Scheme 9.
  • a mono-protected amino compound Formula (S-LL) with acrylate ester Formula (S-MM) under Michael addition condition can produce intermediates of Formula (S-NN).
  • Compound of Formula (S- OO) can be obtained by deprotection.
  • Compounds of Formula (S-PP) can be generated by coupling the compound of Formula (S-OO) with 1,3,5-phenyltricarboxylic acid catalyzed by HATU/DIPEA.
  • Substituent X 2 and subscript “n” are equivalent to the substituents and subscripts as described herein.
  • Substituent A 4 represents additional groups or moieties of substituent R 9 described herein and P represents a protecting group.
  • Scheme 10: -2 can be prepared according to Scheme 10.
  • the di-alkylated compound of Formula (S-SS) can be obtained by reductive amination of aldehyde of Formula (S-QQ) with mono-protected amino compound of Formula (S-RR) catalyzed by NaHB(OAc) 3 . Deprotection can afford a compound of Formula (S-TT).
  • the desired compounds can be obtained by coupling tri- carboxylic acids with a compound of Formula (S-TT) catalyzed by HATU/DIPEA.
  • Substituent X 2 and subscript “n” are equivalent to the substituents and subscripts as described herein.
  • Substituent A 3 represents additional groups or moieties of substituent R 9 described herein.
  • Scheme 11 [00284] Compounds of Formula IV, such as compounds of Formula IV-B-3 and IV-B-4, can be prepared according to Scheme 11.
  • the compound of of Formula (S-XX) can be obtained by the treatment of mono-protected alcohol of Formula (S-WW) with 4-nitro-phenylchloro formate. Treatment with a secondary amine can afford the compound of Formula (S-YY).
  • the compounds of Formula IV (Formula S-AAA) can be obtained by coupling tri-carboxylic acids with the compound of Formula (S-YY), catalyzed by HATU/DIPEA.
  • Scheme 12 [00286] Compounds of Formula IV can also be prepared according to Scheme 12.
  • the compound of Formula (S-BBB) can be obtained by coupling of mono-protected amino compounds with tri-carboxylic acids catalyzed by HATU/DIPEA. After deprotection, the compounds of Formula (S-DDD) can be obtained by heating a mixture of the free amino compound and epoxide of Formula (S-CCC).
  • Substituent X 2 and subscript “n” are equivalent to the substituents and subscripts as described herein.
  • Substituent A 3 represents additional groups or moieties of substituent R 9 described herein.
  • he compound of Formula (S-FFF) can be obtained by the treatment of acrylate ester with mono- protected amino compound of Formula (S-EEE) under Michael addition conditions. Deprotection can provide the compound of Formula (S-GGG).
  • the desired compounds of Formula (S-HHH) can be obtained by coupling tri-carboxylic acids with the compound of Formula (S-GGG) catalyzed by HATU/DIPEA.
  • Substituent X 2 and subscript “n” are equivalent to the substituents and subscripts as described herein.
  • Substituent A 3 represents additional groups or moieties of substituent R 9 described herein.
  • the LNP compositions comprise a biodegradable ionizable lipid that comprises a compound described herein.
  • a biodegradable ionizable lipid may include an amine-containing group on the head group.
  • a biodegradable ionizable lipid may include an amine-containing group on the core.
  • a biodegradable ionizable lipid may include an ester, disulfide, and/or hydroxyl group on the tail group.
  • a biodegradable ionizable lipid is or comprises a compound described herein (e.g., a compound of Formulae I, II, III, or IV).
  • a lipid nanoparticle (LNP) composition comprises: a biodegradable ionizable lipid that comprises a compound described herein; a phospholipid; a polyethylene glycol-lipid; and a sterol.
  • a LNP composition comprises a phospholipid.
  • a phospholipid includes, but is not limited to, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl serine, phosphatidic acid, 2- lysophosphatidyl choline, and sphingomyelin.
  • a fatty acid moiety includes but is not limited to lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, alphalinolenic acid, erucic acid, phytanic acid, arachidic acid, arachidonic acid, eicosapentaenoic acid, behenic acid, docosapentaenoic acid, and docosahexaenoic acid.
  • Non-natural species including natural species with modifications and substitutions including branching, oxidation, cyclization, and alkynes are also contemplated.
  • a phospholipid may be functionalized with or cross-linked to one or more alkynes (e.g., an alkenyl group in which one or more double bonds is replaced with a triple bond).
  • alkynes e.g., an alkenyl group in which one or more double bonds is replaced with a triple bond.
  • Other phospholipids include, but are not limited to, 1,2-distearoyl-snglycero-3- phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2- dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycerophosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3- phosphocholine (DPPC), 1,2-diunde
  • the phospholipid is 1,2-distearoyl-snglycero-3- phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2- dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dimyristoyl-sn-glycerophosphocholine (DMPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1- hexadecyl snglycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn- glycero-3- phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl- sn-glycero-3-phosphocholine, 1,2- didocosa
  • the phospholipid is 1,2-distearoyl-snglycero-3- phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2- dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-di-O-octadecenyl-sn-glycero-3- phosphocholine (18:0 Diether PC), 1-hexadecyl snglycero-3-phosphocholine (C16 Lyso PC), or 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3- phosphocholine, 1,2-diphytanoyl-sn-glycero-3- phosphoethanolamine (ME 16.0 PE).
  • DSPC 1,2-distearoyl-snglycero-3- phosphocholine
  • the phospholipid is DOPE. In some embodiments, the phospholipid is DSPC. [00302] In some embodiments, the LNP composition comprises a phospholipid at about 5 mol% to about 45 mol%, about 10 mol% to about 45 mol%, or about 10 mol% to about 40 mol%. [00303] (vi). Polyethylene glycol-lipid [00304] In some embodiments, a LNP composition comprises a polyethylene glycol-lipid (PEG-lipids). In some embodiments, PEG lipids include PEG conjugated to saturated or unsaturated C 6 -C 20 alkyl chains.
  • polyethylene glycol (PEG) lipids include PEG-modified lipids such as PEG-modified phosphatidylethanolamines, PEG- modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG- modified diacylglycerols, and PEG-modified dialkylglycerols.
  • PEG-modified lipids such as PEG-modified phosphatidylethanolamines, PEG- modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG- modified diacylglycerols, and PEG-modified dialkylglycerols.
  • polyethylene glycol lipids include DMG-PEG, DLPE-PEGs, DMPE-PEGS, DPPC-PEGS, and DSPE-PEGs.
  • the polyethylene glycol lipid’s name is followed by XXX, intended to signify the
  • the polyethylene glycol lipid is DMG-PEGXXX
  • the XXX represents molecular weight, such as molecular weight of the polyethylene glycol moiety, e.g. DMG- PEG1000, DMG-PEG2000, DMG-PEG3000, or DMG-PEG5000.
  • the PEG lipid is a PEG conjugated to saturated or unsaturated C6-C20 alkyl chains (e.g., C14 alkyl chains).
  • the PEG lipid is a DMG- PEGXXX (e.g., DMG-PEG2000).
  • the PEG lipid is DMG-PEG2000, DSG-PEG2000, C 14 PEG2000, or C 18 PEG2000.
  • the LNP composition comprises a PEG lipid at about 0.5 mol% to about 3 mol% or about 0.5 mol% to about 2 mol%.
  • a LNP composition comprises a sterol.
  • Sterols are known in the art and typically refer to compounds having a perhydrocyclopentanophenanthrene ring system with one or more OH substituents.
  • sterols include, but are not limited to, cholesterol, campesterol, ergosterol, sitosterol, and the like.
  • the sterol is cholesterol.
  • a cholesterol is modified.
  • a cholesterol is an oxidized cholesterol.
  • a cholesterol is esterified cholesterol.
  • the sterol is a cholesterol-based lipid such as PEGylated cholesterol, DC-Choi (N,N-dimethyl-N-ethylcarboxamidocholesterol), 1,4-bis(3-N- oleylamino-propyl)piperazine, or combinations thereof.
  • Exemplary sterols include, but are not limited to, 25-hydroxycholesterol (25-OH), 20 ⁇ -hydroxycholesterol (20 ⁇ -OH), 27- hydroxycholesterol, 6-keto-5 ⁇ - hydroxycholesterol, 7-ketocholesterol, 7 ⁇ - hydroxycholesterol, 7 ⁇ -hydroxycholesterol, 7 ⁇ -25- dihydroxycholesterol, beta-sitosterol, stigmasterol, brassicasterol, campesterol, or combinations thereof.
  • the sterol is cholesterol, beta-sitosterol, 25- hydroxycholesterol (25-OH), 20 ⁇ -hydroxycholesterol (20 ⁇ -OH), or 27-hydroxycholesterol.
  • the sterol is cholesterol.
  • the LNP composition comprises a sterol at about 15 mol% to about 50 mol%, about 20 mol% to about 50 mol%, about 25 mol% to about 45 mol%, or about 30 mol% to about 50 mol%.
  • a lipid nanoparticle (LNP) composition comprises a biodegradable ionizable lipid as disclosed herein at about 35 mol% to about 60 mol% or at about 40 mol% to about 55 mol%.
  • a lipid nanoparticle (LNP) composition comprises a biodegradable ionizable lipid at about 35 mol% to about 60 mol%, a phospholipid at about 5 mol% to about 45mol%, a PEG lipid at about 0.5 mol% to about 3 mol%, and a sterol at about 15 mol% to about 50 mol%.
  • a lipid nanoparticle (LNP) composition comprises a biodegradable ionizable lipid at about 40 mol% to about 55 mol%, a phospholipid at about 10 mol% to about 40 mol%, a PEG lipid at about 0.5 mol% to about 2 mol%, and a sterol at about 30 mol% to about 50 mol%.
  • the LNP composition further comprises at least one polynucleotide.
  • the at least one polynucleotide present in the compositions described herein can be a DNA, cDNA, and RNA of all types.
  • the at least one polynucleotide is a double stranded DNA, single-stranded DNA, complexed DNA, encapsulated DNA, naked RNA, encapsulated RNA, messenger RNA (mRNA), tRNA, short interfering RNA (siRNA), double stranded RNA (dsRNA), micro-RNA (miRNA), antisense RNA (asRNA), or combinations thereof.
  • the at least one polynucleotide can also be a DNA construct, such as expression vectors, expression vectors encoding a desired gene product, and the like.
  • the at least one polynucleotide is an mRNA.
  • the at least one polynucleotide is or encodes one or more components of a prime editing system.
  • Prime Editing System [00319]
  • the LNP composition further comprises one or more components of a prime editing system.
  • the term “prime editing system” or “prime editing composition” refers to compositions involved in the methods of prime editing.
  • a prime editing system may include a prime editor, e.g., a prime editor fusion protein, and one or more prime editing guide RNAs (PEgRNAs).
  • PEgRNAs prime editing guide RNAs
  • a prime editing system may further comprise additional elements.
  • a prime editing system may comprise a prime editor, a PEgRNA, and a second strand nick guide RNA (ngRNA).
  • Prime editing system may include one or more prime editors and one or more PEgRNAs.
  • a prime editing system may include (i) one or more polynucleotides encoding one or more prime editor polypeptides and (ii) one or more PEgRNAs, or one or more polynucleotides encoding one or more PEgRNAs.
  • Prime editing refers to programmable editing of a target DNA using a prime editor complexed with a PEgRNA to incorporate an intended nucleotide edit into the target DNA through target-primed DNA synthesis.
  • a target DNA may comprise a double stranded DNA molecule having two complementary strands.
  • the prime editing process may search specific targets and edit the endogeneous sequence of a target DNA, e.g., a target gene.
  • the spacer sequence of a PEgRNA comprises complementarity to a target strand of the target gene, and can anneal with the target strand.
  • the PEgRNA may form a complex with a prime editor, which may generate a nick in the target gene on the edit strand which is the complementary strand of the target strand.
  • the prime editing complex may then use a free 3’ end formed at the nick site of the edit strand to initiate DNA synthesis, where a primer binding site (PBS) of the PEgRNA complexes with the free 3’ end, and a single stranded DNA is synthesized using an editing template of the PEgRNA as a template.
  • the editing template may comprise one or more nucleotide edits compared to the endogenous target gene sequence. Accordingly, the newly-synthesized single stranded DNA also comprises the nucleotide edit(s) encoded by the editing template.
  • a prime editor refers to the polypeptide or polypeptide components involved in prime editing.
  • a prime editor includes a polypeptide domain having DNA binding activity and a polypeptide domain having DNA polymerase activity.
  • the polypeptide domain having DNA binding activity is a polypeptide domain having programmable DNA binding activity.
  • the prime editor further comprises a polypeptide domain having nuclease activity.
  • the polypeptide domain having DNA binding activity comprises a nuclease domain or nuclease activity. In some embodiments, the polypeptide domain having nuclease activity comprises a nickase, or a fully active nuclease. As used herein, the term “nickase” refers to a nuclease capable of cleaving only one strand of a double-stranded DNA target. In some embodiments, the prime editor comprises a polypeptide domain that is an inactive nuclease.
  • the polypeptide domain having programmable DNA binding activity comprises a nucleic acid guided DNA binding domain, for example, a CRISPR-Cas protein, for example, a Cas9 nickase, a Cpf1 nickase, or another CRISPR-Cas nuclease.
  • the polypeptide domain having DNA polymerase activity comprises a template-dependent DNA polymerase, for example, a DNA-dependent DNA polymerase or an RNA-dependent DNA polymerase.
  • the DNA polymerase is a reverse transcriptase.
  • the prime editor comprises additional polypeptides or polypeptide domains involved in prime editing, for example, a polypeptide domain having 5’ endonuclease activity, e.g., a 5' endogenous DNA flap endonucleases (e.g., FEN1), for helping to drive the prime editing process towards the edited product formation.
  • the prime editor further comprises an RNA-protein recruitment polypeptide, for example, a MS2 coat protein.
  • polypeptide domains of a prime editor may be fused or linked by a peptide linker to form a fusion protein.
  • a prime editor comprises one or more polypeptide domains provided in trans as separate proteins, which are capable of being associated to each other through non-peptide linkages or through aptamers or recruitment sequences.
  • a prime editor may comprise a DNA binding domain and a reverse transcriptase domain associated with each other by an RNA-protein recruitment aptamer, e.g., a MS2 aptamer, which may be linked to a PEgRNA.
  • Prime editor polypeptide components may be encoded by one or more polynucleotides in whole or in part.
  • a single polynucleotide, construct, or vector encodes the prime editor fusion protein.
  • multiple polynucleotides, constructs, or vectors each encode a polypeptide domain or portion of a domain of a prime editor, or a portion of a prime editor fusion protein.
  • a prime editor may comprise an N-terminal portion fused to an intein-N and a C-terminal portion fused to an intein-C, each of which is individually encoded by a vector.
  • a prime editor polypeptide is fused to one or more nuclear localization signals.
  • a prime editor polypeptide is fused to a polypeptide permeant domain to promote uptake by the cell.
  • the permeant domain is a peptide, a peptidomimetic, or a non-peptide carrier.
  • a prime editor polypeptide is produced in vitro or by host cells.
  • a prime editor polypeptide is prepared by in vitro synthesis.
  • Various commercial synthetic apparatuses can be used.
  • a prime editor polypeptide is isolated and purified in accordance with recombinant synthesis methods, for example, by expression in a host cell and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique.
  • PEgRNA refers to a guide polynucleotide that comprises one or more intended nucleotide edits for incorporation into the target double stranded DNA.
  • the PEgRNA associates with and directs a prime editor to incorporate the one or more intended nucleotide edits into the target gene via prime editing.
  • a PEgRNA comprises a spacer that is complementary or substantially complementary to a search target sequence on a target strand of the target gene.
  • the PEgRNA comprises a gRNA core that associates with a DNA binding domain, e.g., a CRISPR-Cas protein domain, of a prime editor.
  • a PEgRNA comprises an extension arm that comprises an editing template and a primer binding site (PBS).
  • the editing template comprises comprises one or more intended nucleotide edits to be incorporated in the target DNA by prime editing.
  • the editing template comprises substantial or partial complementarity to the editing target sequence except at the position of the intended nucleotide edits to be incorporated into the target gene.
  • a PEgRNA consists of RNA.
  • a PEgRNA is a chimeric or hybrid PEgRNA that comprises an RNA portion (e.g., including the spacer and the gRNA core) and a DNA portion (e.g., the extension arm comprising the editing template that includes a strand of DNA).
  • a PEgRNA comprises a single polynucleotide molecule that comprises a spacer, a gRNA core, and an extension arm.
  • a PEgRNA comprises multiple polynucleotide molecules, for example, two polynucleotide molecules.
  • the prime editing system comprises a PEgRNA, a prime editor, and further comprises a second strand nick guide polynucleotide, e.g., a nick guide RNA (ngRNA).
  • a ngRNA comprises a spacer (referred to as a ngRNA spacer or ng spacer) and a gRNA core, wherein the ng spacer comprises a region of complementarity to the edit strand, and wherein the gRNA core can interact with a Cas, e.g., Cas9, of a prime editor.
  • a prime editing system comprises a first prime editing guide RNA (PEgRNA), a second PEgRNA, and one or more prime editors (a dual prime editing system).
  • dual prime editing involves two different PEgRNAs each complexed with a prime editor.
  • the prime editor is the same for each of the PEgRNA-prime editor complexes.
  • the prime editor is different for each of the PEgRNA-prime editor complexes.
  • the first PEgRNA and the second PEgRNA each comprises a spacer, a gRNA core, and an extension arm comprising a PBS and an editing template.
  • each of the two PEgRNAs comprises a spacer comprising a region of complementarity to a distinct search target sequence of the double stranded target DNA, wherein the two distinct search target sequences are on the two complementary strands of the double stranded target DNA.
  • the two PEgRNAs each can direct a prime editor to initiate the prime editing process on the two complementary strands of the double stranded target DNA.
  • the editing template of the first PEgRNA and the editing template of the second PEgRNA comprises a region of complementarity to each other.
  • the editing template of the first PEgRNA and the editing template of the second PEgRNA each comprises a region of complementarity to a distinct sequence of the double stranded target DNA.
  • a prime editing system comprises (i) a prime editor or one or more polynucleotides encoding the prime editor, and (ii) a PEgRNA or one or more polynucleotides encoding the PEgRNA.
  • a prime editing system comprises (i) a prime editor or one or more polynucleotides encoding the prime editor, (ii) a PEgRNA or one or more polynucleotides encoding the PEgRNA, and (iii) a ngRNA or one or more polynucleotides the ngRNA.
  • a prime editing system is a dual prime editing system that comprises (i) a prime editor or one or more polynucleotides encoding the prime editor, (ii) a first PEgRNA or one or more polynucleotides encoding the PEgRNA, and (iii) a second PEgRNA or one or more polynucleotides encoding the second PEgRNA.
  • the one or more polynucleotides encoding the prime editor, the PEgRNA, the ngRNA, the first PEgRNA, and/or the second PEgRNA is a part of, or encoded by, an expression cassette, a construct, or a vector.
  • the vector is a non-viral vector.
  • the one or more polynucleotides is operably linked to a regulatory element, e.g., a transcriptional control element, such as a promoter.
  • a transcriptional control element such as a promoter.
  • the polynucleotide is operably linked to multiple control elements.
  • any of a number of suitable transcription and translation control elements including constitutive and inducible promoters, transcription enhancer elements, transcription terminators, etc. may be used in the expression vector (e.g., U6 promoter, H1 promoter).
  • Prime editing system components may be encoded individually by separate polynucleotides, or two or more prime editing system components may be encoded by a single polynucleotide.
  • a prime editor polypeptide and one or more PEgRNA(s) or ngRNA are encoded by a single polynucleotide.
  • the polynucleotide encodes a prime editor fusion protein comprising a DNA binding domain and a DNA polymerase domain.
  • the polynucleotide encodes a DNA polymerase domain of a prime editor.
  • the polynucleotide encodes a DNA binding domain of a prime editor.
  • the polynucleotide encodes a portion of a prime editor protein, for example, a N-terminal portion of a prime editor fusion protein connected to an intein-N.
  • the polynucleotide encodes a portion of a prime editor protein, for example, a C-terminal portion of a prime editor fusion protein connected to an intein-C. In some embodiments, the polynucleotide encodes a PEgRNA. In some embodiments, the polynucleotide encodes two or more components of a prime editing composition, for example, a prime editor fusion protein and a PEgRNA. [00333] In some embodiments, a prime editing system comprises one or more polynucleotides that encode prime editor components and/or the first PEgRNA and/or the second PEgRNA.
  • a prime editing system comprises a polynucleotide encoding a fusion protein comprising a DNA binding domain and a DNA polymerase domain. In some embodiments, a prime editing system comprises (i) a polynucleotide encoding a fusion protein comprising a DNA binding domain and a DNA polymerase domain, (ii) a first PEgRNA or a polynucleotide encoding the first PEgRNA, and (iii) a second PEgRNA or a polynucleotide encoding the second PEgRNA.
  • a prime editing system comprises (i) a polynucleotide encoding a DNA binding domain of a prime editor, e.g., a Cas9 nickase, (ii) a polynucleotide encoding a DNA polymerase domain of a prime editor, e.g., a reverse transcriptase, (iii) a first PEgRNA or a polynucleotide encoding the first PEgRNA, and (iv) a second PEgRNA or a polynucleotide encoding the second PEgRNA. [00334] (x).
  • compositions comprising any of the compounds, compositions and/or nanoparticles described herein, and one or more pharmaceutically acceptable excipient.
  • the compounds and LNP compositions described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • the present disclosure provides a pharmaceutical composition comprising a compound described herein, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • a pharmaceutical composition comprising a LNP composition described herein, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle [00337]
  • a pharmaceutical composition comprises any of the compounds described herein, at least one polynucleotide, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprises any of the compounds described herein, one or more components of a prime editing system, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprises any of the compositions described herein and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprises any of the lipid nanoparticles described herein and one or more pharmaceutically acceptable excipients.
  • pharmaceutical composition refers to a composition formulated for pharmaceutical use.
  • the pharmaceutical composition comprises additional agents, e.g., for specific delivery, increasing half-life, or other therapeutic compounds.
  • a pharmaceutically-acceptable excipient comprises any vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the compound from one site (e.g., the delivery site) of the body, to another site (e.g., organ, tissue or portion of the body).
  • a pharmaceutically acceptable carrier is “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to a tissue and/or subject (e.g., physiologically compatible, sterile, physiologic pH, etc.).
  • a pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.
  • the pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as twin 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
  • Preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • Formulations of the pharmaceutical compositions described herein can be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient(s) into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable excipient includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • the pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents also may be added.
  • the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • compositions described herein also may be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches also may be used.
  • the pharmaceutical compositions described herein may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds or LNP compositions described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions described herein can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions described herein may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions described herein may be formulated in an ointment such as petrolatum.
  • the pharmaceutical compositions described herein also may be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzy
  • the oral compositions also can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation also may be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may be used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • the dosage form also may comprise buffering agents.
  • Solid compositions of a similar type also may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • Solid dosage forms optionally may contain opacifying agents.
  • solid dosage forms also can be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions include polymeric substances and waxes.
  • Solid compositions of a similar type also may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the LNP composition may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms also may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms also may comprise buffering agents. They may optionally contain opacifying agents and also can be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes.
  • (xi). Delivery Also disclosed herein are methods for delivering polynucleotides or prime editing system(s) into a target cell by utilizing the LNP compositions described herein.
  • the LNP compositions described herein are used to deliver a prime editing system, a DNA plasmid encoding prime editor components, a DNA plasmid encoding a PEgRNA and optionally an ngRNA, a DNA plasmid encoding a PEgRNA pair, a DNA plasmid encoding a prime editor fusion protein, or one or more DNA plasmids encoding one or more of a prime editor fusion protein, a PEgRNA, an ngRNA, or a PEgRNA pair.
  • the LNP compositions described herein are used to deliver an mRNA encoding prime editor components, an mRNA encoding prime editor fusion protein, a PEgRNA and optionally ngRNA, or a PEgRNA pair.
  • the LNP compositions described herein are used to deliver a prime editor protein, a prime editor fusion protein, a PEgRNA and optionally ngRNA, or a PEgRNA pair.
  • a method for delivering polynucleotides into a cell comprising: introducing into the cell at least one lipid nanoparticle comprising a biodegradable ionizable lipid that comprises any of the compounds described herein and one or more polynucleotides.
  • the polynucleotides are DNA or mRNA.
  • a method for delivering a prime editing system into a cell comprising: introducing into the cell at least one lipid nanoparticle comprising a biodegradable ionizable lipid that comprises any of the compounds described herein and one or more components of a prime editing system.
  • the one or more components of a prime editing system comprises a construct encoding prime editor components.
  • the construct is a DNA plasmid encoding prime editor components.
  • the one or more components of a prime editing system comprises a construct encoding a prime editing guide RNA (PEgRNA), and optionally a nick guide RNA (ngRNA).
  • the one or more components of a prime editing system comprises a construct encoding a PEgRNA pair, wherein the PEgRNA comprises a first PEgRNA and/or a second PEgRNA.
  • the construct is a DNA plasmid encoding a prime editing guide RNA (PEgRNA), and optionally a nick guide RNA (ngRNA).
  • the construct is a DNA plasmid encoding a PEgRNA pair, wherein the PEgRNA comprises a first PEgRNA and/or a second PEgRNA.
  • the prime editor components comprise a prime editing guide RNA (PEgRNA), and optionally a nick guide RNA (ngRNA).
  • the prime editor components comprise a PEgRNA pair, wherein the PEgRNA comprises a first PEgRNA and/or a second PEgRNA.
  • the one or more components of a prime editing system comprises a construct encoding a prime editor fusion protein.
  • the construct is a DNA plasmid encoding a prime editor fusion protein.
  • the one or more components of a prime editing system comprises one or more constructs encoding one or more of a prime editor fusion protein, PEgRNA, ngRNA, or a PEgRNA pair.
  • the one or more constructs are one or more DNA plasmids encoding one or more of a prime editor fusion protein, PEgRNA, ngRNA, or a PEgRNA pair.
  • the one or more components of a prime editing system comprises an mRNA encoding prime editor components.
  • the one or more components of a prime editing system comprises an mRNA encoding a prime editor fusion protein.
  • the prime editor components comprise a prime editing guide RNA (PEgRNA), and optionally a nick guide RNA (ngRNA).
  • the prime editor components comprise a PEgRNA pair, wherein the PEgRNA comprises a first PEgRNA and/or a second PEgRNA.
  • the one or more components of a prime editing system comprises a PEgRNA, and optionally an ngRNA.
  • the one or more components of a prime editing system comprises a PEgRNA pair. In some embodiments, the one or more components of a prime editing system comprises a prime editor protein, a prime editor fusion protein, a PEgRNA, a ngRNA, or a PEgRNA pair.
  • the LNP composition is formulated to deliver at least one polynucleotide or one or more components of the prime editing system to target cells.
  • the target cells are or comprise liver cells, bone marrow cells, lung cells, eye cells, muscle cells, or cells in the central nervous system.
  • the first and second lipid nanoparticles are the same.
  • the first and second lipid nanoparticles are different.
  • the first and second lipid nanoparticles are introduced into the cell simultaneously.
  • the first and second lipid nanoparticles are introduced into the cell sequentially.
  • Delivery to the cells can be in vitro, via ex vivo administration, or via in vivo administration.
  • the target cells are or comprise human cells, mammalian cells, liver cells (e.g., hepatocytes), bone marrow cells (e.g., bone marrow monocytes), lung cells, eye cells, muscle cells, or cells in the central nervous system. [00379] III.
  • EDCI 1-(3-dimethylaminopropy)-3-ethylcarbodiimide
  • DMAP N,N- dimethylpyridin-4-amine
  • DMF dimethylformamide
  • DMP Dess-Martin periodinane
  • DIEA N,N-diisopropylethylamine
  • DCM dichloromethane
  • TBAF tetrabutylammonium fluoride
  • TEA triethylamine
  • THF tetrahydrofuran
  • TBS t-butyldimethylsilyl
  • MsCl methane sulfonyl chloride
  • PPTS 4-methylbenzenesulfonic acid pyridine
  • TBAI tetrabutylammoniumiodide
  • IPA isopropanol
  • TBSCl tert-butyldimethylsilyl chloride
  • DM 2-methylbenzenesulfonic acid pyridine
  • Example 1 Synthesis of Compound 3 – (bis(2-butyloctyl) 10-(N-(3- (dimethylamino)propyl)-3-(pentyldisulfaneyl) propanamido)nonadecanedioate) [00389]
  • General procedure for preparation of Compound 3-3 [00390] To a solution of 9-bromononanoic acid (3-1, 50 g, 210.85 mmol), DIEA (32.70 g, 253.02 mmol, 44.07 mL), DMAP (5.15 g, 42.17 mmol) and 2-butyloctan-1-ol (3-2, 43.22 g, 231.94 mmol) in DCM (500 mL), EDCI (48.50 g, 253.02 mmol) was added at 0 o C and the mixture was stirred at 20 o C for 12 h under N2.
  • the mixture was quenched with sat.NH4Cl (1000 mL) at 25°C and extracted with DCM (500 mL ⁇ 2), the combined organic layers were washed with brine (300 mL ⁇ 5), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the residual oil was dissolved in DCM (1000 mL) was added HCl (12 M, 200 mL) at 20°C. The mixture was stirred at 20 °C for 10 min. Then the mixture was poured into H 2 O (500 mL), The aqueous phase was extracted with DCM (200 mL ⁇ 2).
  • the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , eluted with petroleum ether: ethyl acetate from 100:0 to 5:1) to afford compound 7-3 (3.2 g, yield 82.47%) as colorless oil.
  • reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, eluted with petroleum ether: ethyl acetate from 100:0 to 5:1) to afford compound 7-4 (2.60 g, yield 83.99%) as light-yellow oil.
  • the reaction mixture was quenched by addition H 2 O 5 mL at 5 °C, and then diluted with H 2 O 10 mL and extracted with EtOAc 45 mL (15 mL ⁇ 3). The combined organic layers were washed with brine 30 mL (10 mL ⁇ 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product.
  • the crude product was added HCl (12 M) 10 ml in DCM (10 mL) and stirred at 25 o C for 30 min.
  • reaction mixture was diluted with H 2 O 10 mL and extracted with DCM 20 mL (10 mL ⁇ 2). The combined organic layers were washed with brine 20 mL (10 mL ⁇ 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Welch Xltimate C4100*30*10um; mobile phase: [water(TFA)-ACN]; gradient: 55%-100% B over 10 min) to get TFA salt. The product was then dissolved in DCM (10 mL), and saturated aqueous Na 2 CO 3 was added to adjust pH to 7.
  • reaction mixture was diluted with H2O 10 mL and extracted with DCM 20 mL (10 mL ⁇ 2). The combined organic layers were washed with brine 20 mL (10 mL ⁇ 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Welch Xltimate C4100*30*10um; mobile phase: [water(FA)-ACN]; gradient:40%-80% B over 6 min) to give Compound 5 (45.9 mg, yield 10.14%) as light yellow oil.
  • Example 6 Synthesis of Compound 6 (bis(2-butyloctyl) 10-(N-(4- (dimethylamino)butyl)-3-pentyldisulfaneyl) propanamido) nonadecanedioate) [00443] A mixture of Compound 6-2 (205.34 mg, 1.77 mmol), Compound 6-1 (600 mg, 883.52 umol) in MeOH (8 mL) was degassed and purged with N 2 for 3 times, and then NaBH3CN (138.80 mg, 2.21 mmol) was added, the mixture was stirred at 50 °C for 12 h under N 2 atmosphere.
  • reaction mixture was diluted with H2O 10 mL and extracted with DCM 20 mL (10 mL ⁇ 2). The combined organic layers were washed with brine 20 mL (10 mL ⁇ 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC(column: Welch Xltimate C4100*30*10um; mobile phase: [water(FA)-ACN]; gradient: 40%-80% B over 6 min) to give Compound 9 (156.9 mg, yield 28.98%) as light yellow oil.
  • Mobile phase A was 0.04% trifluoroacetic acid in water
  • mobile phase B was 0.02% trifluoroacetic acid in acetonitrile.
  • the column used for chromatography was a Luna LC- C18 50*2 mm (5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100- 2000.
  • DAD diode array
  • ELSD evaporative light scattering
  • Example 10 Synthesis of Compound 10 (bis(3-hexylnonyl) 10-(3- (pentyldisulfaneyl)-N-(3-(pyrrolidin-1- yl)propyl)propanamido)nonadecanedioateedioate) yn es s o ompoun [00456]
  • General procedure for the preparation of Compound 10-3 [00457] A mixture of Compound 10-1 (300 mg, 393.05 ⁇ mol), Compound 10-2 (75.59 mg, 589.57 ⁇ mol), NaBH3CN (49.40 mg, 786.10 umol) in MeOH (5 ml) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50 °C for 12 hr under N 2 atmosphere.
  • the reaction mixture was diluted with H2O 10 mL and extracted with DCM 20 mL (10 mL ⁇ 2). The combined organic layers were washed with brine 20 mL (10 mL ⁇ 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Welch Xltimate C4100*30mm*10um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 55%-100% B over 8.0 min) to give the TFA salt. The product was then dissolved in DCM (10 mL), and saturated aqueous Na 2 CO 3 was added to adjust pH to 7.
  • the reaction mixture was diluted with H 2 O 10 mL and extracted with DCM 20 mL (10 mL ⁇ 2). The combined organic layers were washed with brine 20 mL (10 mL ⁇ 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Welch Xltimate C4100*30mm*10um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 55%-100% B over 8.0 min) to give the TFA salt. The product was then dissolved in DCM (10 mL), and saturated aqueous Na 2 CO 3 was added to adjust pH to 7.
  • the reaction was diluted with H 2 O (20 mL) and extracted with EtOAc (10 mL ⁇ 3). The combined organic layers were washed with brine (20 mL ⁇ 3), dried over anhydride Na2SO4, filtered, and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (Welch Xltimate C4100*30mm*10um;mobile phase: [H 2 O (0.04%TFA)-ACN];gradient:40%-90% B over 8.0 min) to give the TFA salt.
  • the product was then dissolved in DCM (20 mL), and saturated aqueous Na 2 CO 3 was added to adjust pH to 7.
  • the reaction was diluted with H2O (20 mL) and extracted with DCM (20 mL ⁇ 3). The combined organic layers were washed with brine (20 mL ⁇ 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (Welch Xltimate C4 100*30mm*10um;mobile phase: [H2O (0.04%HCl)-ACN];gradient:40%-90% B over 8.0 min) to give the HCl salt.
  • the product was then dissolved in DCM (20 mL), and saturated aqueous Na 2 CO 3 was added to adjust pH to 7.
  • Example 20 Synthesis of Compound 21(di(tridecan-7-yl) 10-((3- (dimethylamino)propyl)(3-(2-(nonanoyloxy)ethoxy)-3- oxopropyl)amino)nonadecanedioate) [00491] To a solution of Compound 21-1 (280 mg, 352.94 ⁇ mol) and 2-(acryloyloxy)ethyl nonanoate (21-2, 289.51 mg, 1.13 mmol) in i-PrOH (3 mL), DIEA (136.85 mg, 1.06 mmol) was added at 20 °C under N2.
  • Example 25 Synthesis of Compound 26 (bis(2-hexyloctyl) 10-(N-(3-(4- methylpiperazin-1-yl)propyl)-3-(pentyldisulfaneyl)propanamido) nonadecanedioate) [00515] To a solution of Compound 26-1 (0.3 g, 408.05 ⁇ mol) and 3-(4-methylpiperazin-1- yl)propan-1-amine (26-2, 96.25 mg, 612.07 ⁇ mol) in MeOH (6 mL), NaBH 3 CN (51.28 mg, 816.09 ⁇ mol) was added at 20 o C.
  • the reaction mixture was quenched by H2O (5 mL) and extracted with DCM (3 ⁇ 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC(Welch Xltimate C4100*30mm*10um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:50%-80% B over 6.0 min) to give the TFA salt.
  • the product was then dissolved in DCM (5 mL), and saturated aqueous Na2CO3 was added to adjust pH to 7.
  • Example 27 Synthesis of Compound 193 (bis(2-hexyloctyl) 10-(N-(4- (diethylamino)butyl)-3-(pentyldisulfaneyl)propanamido)nonadecanedioate) [ ] ompoun - was synt es ze rom ompoun , rst steps.
  • the residue was purified by prep-HPLC (column: Welch Xltimate C4100 ⁇ 30 mm ⁇ 10 um; mobile phase: [H 2 O (0.1% TFA) - ACN];gradient:50% - 90% B over 8.0 min) to give the TFA salt.
  • the product was then dissolved in DCM (3 mL), and saturated aqueous Na 2 CO 3 was added to adjust pH to 7.
  • Example 29 Synthesis of Compound 31 (bis(2-hexyloctyl) 10-((3-(2- (octyldisulfaneyl)ethoxy)-3-oxopropyl)(3-(pyrrolidin-1- yl)propyl)amino)nonadecanedioate) ⁇ mol), Compound 31-1 (0.2 g, 236.01 ⁇ mol), DIEA (152.51 mg, 1.18 mmol) in i-PrOH (4 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 110 °C for 16 h under N2 atmosphere.
  • Example 30 Synthesis of Compound 32 (bis(2-hexyloctyl) 10-((3-(2- (decyldisulfaneyl) ethoxy)-3-oxopropyl)(3-(pyrrolidin-1- yl)propyl)amino)nonadecanedioate)
  • Compound 32-1 0.2 g, 236.01 ⁇ mol
  • DIEA (152.51 mg, 1.18 mmol) in i-PrOH (4 mL) at 20 °C, and then the mixture was stirred at 110 °C for 12 hr.
  • the residue was purified by prep-HPLC (Welch Xltimate C4100 ⁇ 30 mm ⁇ 10 um; mobile phase: [H2O (0.1 % TFA) - ACN];gradient:50 % - 90 % B over 8.0 min) to give the TFA salt.
  • the product was then dissolved in DCM (3 mL), and saturated aqueous Na2CO3 was added to adjust pH to 7.
  • Example 39 Synthesis of Compound 190 (hexyl (7,31-dibutyl-10,28- dioxo-9,11,27,29-tetraoxaheptatriacontan-19-yl)(3-(dimethylamino)propyl) carbamate) [00587] To a solution of Compound 190-1 (260 mg, 0.34 mmol) and Compound 190-2 (271 mg, 1.01 mmol) in DCM (3 mL), TEA (103 mg, 1.01 mmol) was added at 20 °C. The mixture was stirred at 20 °C for 3 h. LC-MS showed Reactant 1 was consumed completely and ⁇ 20% desired compound was detected.
  • the reaction mixture was quenched by addition of water (2000 mL) and extracted with ethyl acetate (3 ⁇ 1500 mL). The combined organic phase was washed with brine (1500 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 159-3 (110 g, yield 92%) as colorless oil.
  • Example 43 Synthesis of Compound 160-A O Cl N O OH N NaCN, TBAI O 160-3 O ° O ° O [00627]
  • tetrabutylammoniumiodide (1.11 g, 3.00 mmol) and sodium cyanide (7.35 g, 30.00 mmol) in dimethyl sulfoxide (50 mL)
  • 160-1 5 g, 30 mmol
  • dimethyl sulfoxide 10 mL
  • 164-1 (2.3 g, 7.97 mmol) in dichloromethane (30 mL) were added 164-2 (1.14 g, 8.77 mmol), 1-(3-dimethylaminopropy)-3-ethylcarbodiimide (1.53 g, 7.97 mmol), N,N-diisopropylethylamine (3.09 g, 23.91 mmol) and N,N-dimethylpyridin-4-amine (194.79 mg, 1.59 mmol). Then the resulting mixture was stirred at 20 °C for 12 hrs.
  • Example 48 Synthesis of Compound 196 g, he mixture was stirred at 25 C for 16 h. LC-MS showed Reactant was consumed completely and the desired compound was detected. The aqueous phase was extracted with DCM (3 ⁇ 100 mL). The combined organic phase was washed with brine (2 ⁇ 100 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 196- 3 (5.13 g, 44.54 mmol) as yellow oil.
  • Example 53 Synthesis of Compound 213 . , . DIEA (816.74 mg, 6.32 mmol), EDCI (908.60 mg, 4.74 mmol) and DMAP (77.20 mg, 631.96 ⁇ mol) at 25 o C under N2 atmosphere. The mixture was stirred at 25 o C for 1 h. Then the solution of compound 213-2 (1.5 g, 4.74 mmol) in DCM (5 mL) was added. The resulting mixture was stirred at 25 o C for 12 hrs. LC-MS showed ⁇ 40% of desired compound was detected. Then the mixture was concentrated under reduce pressure.
  • Example 57 Synthesis of Compound 214 added HATU (575.23 mg, 1.51 mmol ) and DIEA (195.52 mg, 1.51 mmol ) and 214-1 (500 mg, 1.51 mmol) at 25 o C under N2 atmosphere. The mixture was stirred at 25 o C for 12 hrs. LCMS showed ⁇ 50% of desired compound was detected. Then the mixture was concentrated under reduce pressure.
  • Example 58 Synthesis of Compound 235 [00715] To a stirred solution of compound 235-1 (5 g, 21.93 mmol) and compound 235-2 (5.7 g, 32.90 mmol) in dichloromethane (100 mL) were added N, N'- Dicyclohexylcarbodiimide (5 g, 24.12 mmol) and 4-Dimethylaminopyridine (1.3 g, 10.97 mmol). Reaction mixture was stirred at room temperature for 16h. After completion of reaction (monitored by TLC), solvent was evaporated under reduced pressure, diluted with water, and extracted with dichloromethane.
  • reaction mixture was diluted with dichloromethane and washed with water and brine solution. Organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtained crude which was purified through combi- flash column chromatography using 30% EtOAc in Hexane as an eluent to afford 1- (heptadecan-9-yl) 8-(3-hydroxy-2-(((8-oxo-8-(pentadecan-7-yloxy) octanoyl) oxy) methyl) propyl) octanedioate 235-5 as a colorless oil (2.3 g, 21%).
  • reaction mixture was diluted with dichloromethane, washed with water and brine solution. Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through combi-flash column chromatography using 0-5% MeOH in DCM as an eluent to afford O'1,O1-(2-((N-(4-(dimethylamino)butyl)octanamido)methyl)propane-1,3- diyl)8,8'-di(pentadecan-7-yl) di(octanedioate) as a brown oil (40 mg, 34%).
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash chromatography (0-80% EtOAc: Hexane) to obtained desired product 237-5 as colorless oil (3 g) yield 31.75%.
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash column chromatography (0-30% EtOAc: Hexane) to obtained desired product 237-7 as colorless oil (0.9 g) yield 39.30%.
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered, and concentrated to yield the crude product which was purified by Combi-flash column chromatography (0-30% EtOAc: Hexane) to obtain desired product 237-8 as pale- yellow oil (2 g), yield 73.91%.
  • reaction mixture was diluted with DCM, washed with water and brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash column chromatography (0-50% EtOAc: Hexane) to obtain desired product 238-5 as colorless oil (5.5 g) yield 32.56%.
  • reaction mixture was diluted with DCM, washed with water and brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash column chromatography (0-30% EtOAc: Hexane) to obtain desired product 238-6 as pale-yellow oil (2.6 g), yield 80.94%.
  • reaction mixture was diluted with dichloromethane, washed with water and brine. Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using (30% EtOAc: Hexane) as an eluent to afford 1-(heptadecan-9-yl) 8-(3-hydroxy-2-(((8-oxo-8- (pentadecan-7-yloxy) octanoyl) oxy) methyl) propyl) octanedioate 239-5 as a colourless oil (2.3 g, 21%).
  • reaction mixture was diluted with dichloromethane, washed with water and brine solution. Combined organic layer was collected and dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through combi- flash column chromatography using 0-5% MeOH in DCM as an eluent to afford O'1,O1-(2- ((N-(4-(dimethylamino)butyl)nonanamido)methyl)propane-1,3-diyl)8,8'-di(pentadecan-7-yl) di(octanedioate) as a brown oil (30 mg, 25%).
  • Example 62 Synthesis of Compound 240 [00760] Synthesis of Compound 240-3 [00761] To a stirred solution of compound 240-1 (10 g, 58.07 mmol) in DCM (120 mL) was added DCC (13.18 mL, 63.88 mmol) and DMAP (3.54 g, 29.03 mmol) followed by addition of compound 240-2 (14.16 g, 81.31 mmol) at 0° C under nitrogen atmosphere. Stirred the reaction mixture at room temperature for 16h. Reaction was periodically monitored by TLC. After completion of reaction, the reaction mixture was diluted with DCM, washed with sodium bicarbonate, water and brine solution.
  • reaction mixture was diluted with DCM, washed with water and brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by combi-flash column chromatography (5-40% EtOAc: Hexane) to obtain desired product (240-5) as colorless oil (2.5 g), yield 18.80%.
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered, and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash chromatography (0-80% EtOAc: Hexane) to obtained desired product 241-5 as colorless oil (3.5 g) yield 37.04%.
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered, and concentrated to yield the crude product which was purified by Combi-flash chromatography (0-30% EtOAc: Hexane) to obtained desired product 241-7 as colorless oil (2.5 g), yield 46.8%.
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered, and concentrated to yield the crude product which was purified by Combi-flash column chromatography (0-30% EtOAc: Hexane) to obtain desired product 241-8 as pale- yellow oil (2 g), yield 73.91%.
  • reaction mixture was diluted with dichloromethane, washed with water and brine solution dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using 30% EtOAc in hexane an eluent to afford 1-(heptadecan-9-yl) 8-(3- hydroxy-2-(((8-oxo-8-(pentadecan-7-yloxy) octanoyl) oxy) methyl) propyl) octanedioate 243-5 as a colourless oil (2.3 g, 21%).
  • reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through combi- flash column chromatography using 20% EtOAc in hexane as an eluent to afford O'1, O1-(2- (bromomethyl) propane-1,3-diyl) 8,8'-di(pentadecan-7-yl) di(octanedioate) 243-6 as a colorless oil (2.3 g, 92%).
  • reaction mixture was filtered through celite.
  • celite was washed with DCM.
  • the combined filtrates were dried over sodium sulphate and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash column chromatography (0-50% EtOAc: Hexane) to obtain desired product 246-3 as off white solid (25 g), yield 40.29%.
  • reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using 30% EtOAc: Hexane as an eluent to afford 1-(heptadecan-9-yl) 8-(3- hydroxy-2-(((8-oxo-8-(pentadecan-7-yloxy) octanoyl) oxy) methyl) propyl) octanedioate 247-5 as a colorless oil (2.3 g, 21%).
  • reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using 20% EtOAc in hexane as an eluent to afford O1, O1-(2-(bromomethyl) propane-1,3- diyl) 8,8'-di(pentadecan-7-yl) di(octanedioate) 247-6 as a colorless oil (2.3 g, 92%).
  • reaction mixture was diluted with DCM, washed with water and brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash chromatography (0-30% EtOAc: Hexane) to obtain desired product 234-6 as pale-yellow oil (2.6 g) yield 80.94%.
  • reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water(FA)-ACN];B%: 15%-40%,10min) to afford crude 167-3 (1.1 g, yield 26.21%) as colorless oil.
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash column chromatography (0-80% EtOAc: Hexane) to obtained desired product 264-5 as colourless oil (3.9 g), yield 35.89%.
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash column chromatography (0- 30% EtOAc: Hexane) to obtained desired product 264-7 as colourless oil (1 g), yield 43.67%.
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash column chromatography (0-30% EtOAc: Hexane) to obtain desired product 264- 8 as pale-yellow oil (0.7 g), yield 64.67%.
  • Example 76 Synthesis of Compound 265.
  • Synthesis of Compound 265-3 [00905] To a stirred solution of compound 265-1 (25 g, 97.65 mmol) in DCM (250 mL) were added DCC 22.12 g, 107.42 mmol), DMAP (5.95 g, 48.82 mmol) and compound 265-2 (23.78 g, 136.7 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 16h. Progress of reaction was periodically monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite. The celite was washed with DCM.
  • reaction mixture was diluted with DCM, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash column chromatography (0-30% EtOAc: Hexane) to obtain desired product 265-6 as pale-yellow oil (2.1 g), yield 64%.
  • reaction mixture was diluted with dichloromethane, washed with water and brine solution. Combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi- flash column chromatography using (0-50% EtOAc: hexane) as an eluent to afford O'1, O1- (2-(hydroxymethyl) propane-1,3-diyl) 8,8'-di(tridecan-7-yl) di(octanedioate) 266-5 as a colourless oil (3.0 g, 23%).
  • reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using 0-50% EtOAc in hexane as an eluent to afford O'1,O1-(2-(bromomethyl)propane-1,3-diyl) 8,8'-di(tridecan-7-yl) di(octanedioate) 266- 6 as a colourless oil (2.2 g, 69%).
  • reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using 0-5% MeOH in DCM as an eluent to afford O'1,O1-(2-((N-(4- (diethylamino)butyl)octanamido)methyl)propane-1,3-diyl) 8,8'-di(tridecan-7-yl) di(octanedioate) Compound 266 as a light-yellow oil (30 mg, 26%).
  • Example 78 Synthesis of Compound 268. [00927] To a stirred solution of compound 268-1 (25 g, 97.65 mmol) in DCM (250 mL) were added DCC (22.12 g, 107.42 mmol), DMAP (5.95 g, 48.82 mmol) and compound 268-2 (23.78 g, 136.7 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 16h. After completion of reaction (monitored by TLC), reaction mixture was filtered through celite and washed with DCM.
  • reaction mixture was diluted with DCM, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using 30% EtOAc in hexane as an eluent to afford 1-(heptadecan-9-yl) 8-(3-hydroxy-2-((oleoyloxy)methyl) propyl) octanedioate (268-7) as a colourless oil (2 g, 53%).
  • reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude product which was purified through Combi-flash column chromatography using 20% EtOAc in hexane as an eluent to afford 1-(3-bromo-2-((oleoyloxy)methyl) propyl) 8-(heptadecan-9-yl) octanedioate (268-8) as a colourless oil (1.8 g, 82%).
  • Example 79 Synthesis of Compound 269. [00940] To a stirred solution of compound 269-1 (25 g, 97.65 mmol) in DCM (250 mL) were added DCC 22.12 g, 107.42 mmol), DMAP (5.95 g, 48.82 mmol) and compound 269-2 (23.78 g, 136.7 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 16h. After completion of reaction (monitored by TLC), reaction mixture was filtered through celite and celite was washed with DCM.
  • reaction mixture was diluted with DCM, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using 30% EtOAc in hexane as an eluent to afford 1-(heptadecan-9-yl) 8-(3-hydroxy-2-((oleoyloxy)methyl) propyl) octanedioate (269-7) as a colourless oil (2 g, 53%).
  • reaction mixture was diluted with DCM, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using 20% EtOAc in hexane as an eluent to afford 1-(3-bromo-2-((oleoyloxy)methyl) propyl) 8-(heptadecan-9-yl) octanedioate (269-8) as a colourless oil (1.8 g, 82%).
  • Example 80 Synthesis of Compound 270.
  • [00952] Synthesis of Compound 270-3
  • 4- Dimethylaminopyridine 3.01 g, 25.00 mmol
  • compound 270-2 13.05 g, 75.00 mmol
  • Reaction mixture was stirred at room temperature for 16h. After completion of reaction (monitored by TLC), reaction mixture was filtered through celite and was washed with dichloromethane.
  • reaction mixture was diluted with dichloromethane, washed with water and brine solution. Combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi- flash column chromatography using (0-50% EtOAc: Hexane) as an eluent to afford O'1, O1- (2-(hydroxymethyl) propane-1,3-diyl) 8,8'-di(tridecan-7-yl) di(octanedioate) 270-5 as a colourless oil (3.0 g, 23%).
  • reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using 0-50% EtOAc in hexane as an eluent to afford O'1,O1-(2-(bromomethyl)propane-1,3-diyl) 8,8'-di(tridecan-7-yl) di(octanedioate) 270- 6 as a colourless oil (2.2 g, 69%).
  • reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtained crude which was purified through Combi-flash column chromatography using 0-5% MeOH in DCM as an eluent to afford O'1,O1-(2-((N-(4- (pyrrolidin-1-yl)butyl)nonanamido)methyl)propane-1,3-diyl) 8,8'-di(tridecan-7-yl) di(octanedioate) Compound 270 as a light-yellow oil (40 mg, 35%).
  • Example 81 Synthesis of Compound 271.
  • [00963] Synthesis of Compound 271-10 [00964] To a stirred solution of compound 271-8 (5.3 g, 18.76 mmol) in DCM (200 mL) were added EDC.HCl (7.16 g, 37.52 mmol), DMAP (457 mg, 3.75 mmol), DIPEA (9.30 mL, 56.29 mmol) and compound 271-9 (1.99 g, 18.76 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16h. Reaction was periodically monitored by TLC.
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash column chromatography (0-80% EtOAc: hexane) to obtained desired product 271-10 as colourless oil (3.2 g), yield 46.02%.
  • reaction mixture was diluted with DCM, washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to yield the crude product which was purified by Combi-flash column chromatography (0-30% EtOAc: hexane) to obtain desired product 271-12 as pale-yellow oil (550 mg), yield 67.46%.
  • Example 82 Synthesis of Compound 272.
  • Synthesis of Compound 272-3 [00975] To a stirred solution of compound 272-1 (25 g, 97.65 mmol) in DCM (250 mL) were added DCC 22.12 g, 107.42 mmol), DMAP (5.95 g, 48.82 mmol) and compound 272-2 (23.78 g, 136.7 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 16h. Reaction was periodically monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite. The celite was washed with DCM.

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Abstract

La présente divulgation concerne des compositions, des nanoparticules (telles que des nanoparticules lipidiques) et/ou des compositions de nanoparticules lipidiques et leurs procédés d'utilisation.
PCT/US2023/082118 2022-12-02 2023-12-01 Systèmes et formulations de distribution de nanoparticules lipidiques (lnp) WO2024119098A1 (fr)

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WO2017049245A2 (fr) * 2015-09-17 2017-03-23 Modernatx, Inc. Composés et compositions pour l'administration intracellulaire d'agents thérapeutiques
WO2018078053A1 (fr) * 2016-10-26 2018-05-03 Curevac Ag Vaccins à arnm à nanoparticules lipidiques
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US20160376224A1 (en) * 2015-06-29 2016-12-29 Acuitas Therapeutics, Inc. Lipids and lipid nanoparticle formulations for delivery of nucleic acids
WO2017049245A2 (fr) * 2015-09-17 2017-03-23 Modernatx, Inc. Composés et compositions pour l'administration intracellulaire d'agents thérapeutiques
WO2018078053A1 (fr) * 2016-10-26 2018-05-03 Curevac Ag Vaccins à arnm à nanoparticules lipidiques
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