Oligonucleotide compositions and methods thereof

Abstract

Among other things, the present disclosure provides oligonucleotides, compositions and methods thereof. In some embodiments, oligonucleotides comprise various chemical modifications including 5' - end groups that comprise phosphonate groups. In some embodiments, provided technologies are useful for treating various conditions, disorders or diseases.

Description

Attorney Docket No.: 2010581-1441 OLIGONUCLEOTIDE COMPOSITIONS AND METHODS THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No.63 / 625,263, filed January 25, 2024, the entirety of which is incorporated herein by reference. BACKGROUND

[0002] Oligonucleotides are useful in various applications, e.g., therapeutic, diagnostic, and / or research applications. For example, oligonucleotides targeting various genes can be useful for treatment of conditions, disorders or diseases related to such target genes. SUMMARY

[0003] Various chemical modifications have been reported to improve properties and activities of oligonucleotides. For example, 5’-end −P(O)(OH)2 group which may exist in a salt form as −P(O)(O−)2, in some cases together with another chemical moiety, has been incorporated at 5’-end of various oligonucleotides to improve properties and / or activities of the oligonucleotides, e.g., as RNAi agents. Among other things, the present disclosure provides groups (e.g., those that are or comprise various optionally substituted heteroaryl or heterocyclic rings (e.g., −Cy5E−, −CyIL−, etc.)) that can be optionally utilized with acidic groups (e.g., phosphate, sulfonate, carbonate, etc.) and derivatives thereof (e.g., esters, amides, etc. and combinations thereof (e.g., −P(O)(OEt)2, −P(O)(OEt)(NHMe), −S(O)2OEt, −C(O)OEt, etc.)) in oligonucleotides. In some embodiments, such oligonucleotide can provide improved properties, activities, manufacturing efficiency, lowered cost, etc. when compared to reference oligonucleotides. For example, in some embodiments, such oligonucleotides can provide comparable of higher activities but with improved manufacturing efficiency and / or cost. Provided oligonucleotides are useful for various purposes. In some embodiments, oligonucleotides are useful as RNAi agents. In some embodiments, oligonucleotides are useful as ssRNAi agents. In some embodiments, oligonucleotide are useful as dsRNAi agents.

[0004] In some embodiments, provided structures can be utilized as end groups for oligonucleotides, e.g., 5’-end groups. In some embodiments, provided structures can replace traditional 5’-end groups, e.g., phosphate, vinyl phosphate, etc., present in RNAi reagents.

[0005] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide), wherein the compound comprises a moiety of formula O-E: R5E−Cy5E−, O-E wherein: Page 1 of 448 12513573v1Attorney Docket No.: 2010581-1441 R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R520-5 heteroatomsindependently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −RRC11, −ORRC11, −C(O)ORRC11, or −N(RRC11)2; each of RRC11is independently R’; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10Page 2 of 448 12513573v1Attorney Docket No.: 2010581-1441 aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0006] In some embodiments, such a compound is an oligonucleotide. In some embodiments, a moiety of formula O-E is a 5’-end group of an oligonucleotide. In some embodiments, it is a 5’-end group in an RNAi agent. In some embodiments, it is a 5’-end group of a ssRNAi oligonucleotide. In some embodiments, it is a 5’-end group of a strand of a double strand oligonucleotide agent. In some embodiments, it is a 5’-end group of a sense strand (e.g., of a dsRNAi agent). In some embodiments, it is a 5’-end group of an antisense strand (e.g., of a dsRNAi agent).

[0007] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide), wherein the compound comprises a moiety of formula O-E, wherein: R5Eis R’, −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R52is −LR52−R521; R53is −LR53−R531; R54is −LR54−R541; each of LR5E, LR51, LR52, LR53and LR54is independently L; each of R511, R521, R531, R541, RL51, RL52, RL53and RL54is independently R’; (RRC)c;substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −RRC11, −ORRC11, −C(O)ORRC11, or −N(RRC11)2; each of RRC11is independently R’; Page 3 of 448 12513573v1Attorney Docket No.: 2010581-1441 each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10aliphatic and C1-10heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0008] In some embodiments, provided structures can be utilized in internucleotidic linkages, e.g., between the first and second nucleosides at a 5’-end.

[0009] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide), wherein the compound comprises a moiety of formula IL: −CyIL−P(WIL)(RIL)−LIL−, IL wherein: –CyIL– is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; WILis O or S; oreach of LIL, LIL1, LIL2, LIL3and LIL4is independently L; Page 4 of 448 12513573v1Attorney Docket No.: 2010581-1441 each of RIL11, RIL21, RIL31and RIL41is independently R’; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10aliphatic and C1-10heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0010] In some embodiments, RILis −RIL1, −ORIL1, −SRIL1, −N(RIL1)(RIL2), or −N=C[N(RIL1)(RIL2)][N(RIL3)(RIL4)].

[0011] In some embodiments, a moiety of formula IL is an internucleotidic linkage in an oligonucleotide. In some embodiments, it is an internucleotidic linkage linking the first two nucleosides at the 5’-end.

[0012] In some embodiments, provided compounds are oligonucleotides useful for biological purposes. In some embodiments, provided compounds are oligonucleotides useful as therapeutics. In some embodiments, provided compounds are oligonucleotides useful as RNAi agents. In some embodiments, provided compounds are oligonucleotides useful as ssRNAi agents. In some embodiments, provided compounds are oligonucleotides useful in dsRNAi agents. In some embodiments, the present disclosure provides agents comprising a first and a second oligonucleotides, wherein a first oligonucleotide is or comprises a compound as described herein. In some embodiments, a first oligonucleotide is a guide strand. In some embodiments, a first oligonucleotide is a passenger strand.

[0013] Among other things, provided technologies (e.g., compounds, oligonucleotides, agents, compositions, methods, etc.) are useful for reducing levels of nucleic acids or products thereof. In some embodiments, a nucleic acid is or comprises RNA. In some embodiments, a nucleic acid is or comprises Page 5 of 448 12513573v1Attorney Docket No.: 2010581-1441 mRNA. In some embodiments, a product is a polypeptide encoded thereby. In some embodiments, a nucleic acid or a product thereof is associated with a condition, disorder or disease. In some embodiments, provided technologies are useful for preventing or treating conditions, disorders or diseases associated with target nucleic acids or products thereof. In some embodiments, a nucleic acid is targeted via base sequence complementarity. In some embodiments, reduction of level of a target nucleic acid or a product thereof reduces severity of or removes a symptom of a condition, disorder or disease. In some embodiments, reduction of level of a target nucleic acid or a product thereof slows down or prevents progression of a condition, disorder or disease.

[0014] In some embodiments, the present disclosure provides technologies for manufacturing provided compounds, oligonucleotide, agents, compositions, etc. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0015] Technologies of the present disclosure may be understood more readily by reference to the following detailed description of certain embodiments. Definitions

[0016] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0017] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional / second one or more; (v) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included.

[0018] Unless otherwise specified, description of oligonucleotides and elements thereof (e.g., base sequence, sugar modifications, internucleotidic linkages, linkage phosphorus stereochemistry, patterns thereof, etc.) is from 5’ to 3’. As those skilled in the art will appreciate, in some embodiments, oligonucleotides may be provided and / or utilized as salt forms, particularly pharmaceutically acceptable Page 6 of 448 12513573v1Attorney Docket No.: 2010581-1441 salt forms, e.g., sodium salts. As those skilled in the art will also appreciate, in some embodiments, individual oligonucleotides within a composition may be considered to be of the same constitution and / or structure even though, within such composition (e.g., a liquid composition), particular such oligonucleotides might be in different salt form(s) (and may be dissolved and the oligonucleotide chain may exist as an anion form when, e.g., in a liquid composition) at a particular moment in time. For example, those skilled in the art will appreciate that, at a given pH, individual internucleotidic linkages along an oligonucleotide chain may be in an acid (H) form, or in one of a plurality of possible salt forms (e.g., a sodium salt, or a salt of a different cation, depending on which ions might be present in the preparation or composition), and will understand that, so long as their acid forms (e.g., replacing all cations, if any, with H+) are of the same constitution and / or structure, such individual oligonucleotides may properly be considered to be of the same constitution and / or structure.

[0019] Aliphatic: As used herein, “aliphatic” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or combinations thereof. In some embodiments, aliphatic groups contain 1-50 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-9 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0020] Alkenyl: As used herein, the term “alkenyl” refers to an aliphatic group, as defined herein, having one or more double bonds.

[0021] Alkyl: As used herein, the term “alkyl” is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, alkyl has 1-100 carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-C20for straight chain, C2-C20for branched chain), and alternatively, about 1-10. In some embodiments, cycloalkyl rings have from about 3-10 carbon atoms in their ring structure where such rings are monocyclic, bicyclic, or polycyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, an alkyl group may be a lower alkyl group, Page 7 of 448 12513573v1Attorney Docket No.: 2010581-1441 wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C1-C4for straight chain lower alkyls).

[0022] Alkynyl: As used herein, the term “alkynyl” refers to an aliphatic group, as defined herein, having one or more triple bonds.

[0023] Aryl: The term “aryl", as used herein, used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic. In some embodiments, an aryl group is a monocyclic, bicyclic or polycyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, an aryl group is a biaryl group. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0024] Chiral control: As used herein, “chiral control” refers to control of the stereochemical designation of the chiral linkage phosphorus in a chiral internucleotidic linkage within an oligonucleotide. As used herein, a chiral internucleotidic linkage is an internucleotidic linkage whose linkage phosphorus is chiral. In some embodiments, a control is achieved through a chiral element that is absent from the sugar and base moieties of an oligonucleotide, for example, in some embodiments, a control is achieved through use of one or more chiral auxiliaries during oligonucleotide preparation, which chiral auxiliaries often are part of chiral phosphoramidites used during oligonucleotide preparation. In contrast to chiral control, a person having ordinary skill in the art will appreciate that conventional oligonucleotide synthesis which does not use chiral auxiliaries cannot control stereochemistry at a chiral internucleotidic linkage if such conventional oligonucleotide synthesis is used to form the chiral internucleotidic linkage. In some embodiments, the stereochemical designation of each chiral linkage phosphorus in each chiral internucleotidic linkage within an oligonucleotide is controlled.

[0025] Chirally controlled oligonucleotide composition: The terms “chirally controlled oligonucleotide composition”, “chirally controlled nucleic acid composition”, and the like, as used herein, refers to a composition that comprises a plurality of oligonucleotides (or nucleic acids) which share a common base sequence, wherein the plurality of oligonucleotides (or nucleic acids) share the same linkage phosphorus stereochemistry at one or more chiral internucleotidic linkages (chirally controlled or stereodefined internucleotidic linkages, whose chiral linkage phosphorus is Rp or Sp in the composition (“stereodefined”), not a random Rp and Sp mixture as non-chirally controlled internucleotidic linkages). Page 8 of 448 12513573v1Attorney Docket No.: 2010581-1441 In some embodiments, a chirally controlled oligonucleotide composition comprises a plurality of oligonucleotides (or nucleic acids) that share: 1) a common base sequence, 2) a common pattern of backbone linkages, and 3) a common pattern of backbone phosphorus modifications, wherein the plurality of oligonucleotides (or nucleic acids) share the same linkage phosphorus stereochemistry at one or more chiral internucleotidic linkages (chirally controlled or stereodefined internucleotidic linkages, whose chiral linkage phosphorus is Rp or Sp in the composition (“stereodefined”), not a random Rp and Sp mixture as non-chirally controlled internucleotidic linkages). Level of the plurality of oligonucleotides (or nucleic acids) in a chirally controlled oligonucleotide composition is pre-determined / controlled or enriched (e.g., through chirally controlled oligonucleotide preparation to stereoselectively form one or more chiral internucleotidic linkages) compared to a random level in a non-chirally controlled oligonucleotide composition. In some embodiments, about 1%-100%, (e.g., about 5%-100%, 10%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a chirally controlled oligonucleotide composition are oligonucleotides of the plurality. In some embodiments, about 1%-100%, (e.g., about 5%-100%, 10%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%- 100%, 80-100%, 90-100%, 95-100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a chirally controlled oligonucleotide composition that share the common base sequence, the common pattern of backbone linkages, and the common pattern of backbone phosphorus modifications are oligonucleotides of the plurality. In some embodiments, a level is about 1%-100%, (e.g., about 5%- 100%, 10%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a composition, or of all oligonucleotides in a composition that share a common base sequence (e.g., of a plurality of oligonucleotide or an oligonucleotide type), or of all oligonucleotides in a composition that share a common base sequence, a common pattern of backbone linkages, and a common pattern of backbone phosphorus modifications, or of all oligonucleotides in a composition that share a common base sequence, a common patter of base modifications, a common pattern of sugar modifications, a common pattern of internucleotidic linkage types, and / or a common pattern of internucleotidic linkage modifications. In some embodiments, the plurality of oligonucleotides share the same stereochemistry at about 1-50 (e.g., about 1- Page 9 of 448 12513573v1Attorney Docket No.: 2010581-1441 10, 1-20, 5-10, 5-20, 10-15, 10-20, 10-25, 10-30, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) chiral internucleotidic linkages. In some embodiments, the plurality of oligonucleotides share the same stereochemistry at about 1%-100% (e.g., about 5%-100%, 10%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%) of chiral internucleotidic linkages. In some embodiments, oligonucleotides (or nucleic acids) of a plurality share the same pattern of sugar and / or nucleobase modifications, in any. In some embodiments, oligonucleotides (or nucleic acids) of a plurality are various forms of the same oligonucleotide (e.g., acid and / or various salts of the same oligonucleotide). In some embodiments, oligonucleotides (or nucleic acids) of a plurality are of the same constitution. In some embodiments, level of the oligonucleotides (or nucleic acids) of the plurality is about 1%-100%, (e.g., about 5%-100%, 10%- 100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95- 100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides (or nucleic acids) in a composition that share the same constitution as the oligonucleotides (or nucleic acids) of the plurality. In some embodiments, each chiral internucleotidic linkage is a chiral controlled internucleotidic linkage, and the composition is a completely chirally controlled oligonucleotide composition. In some embodiments, oligonucleotides (or nucleic acids) of a plurality are structurally identical. In some embodiments, a chirally controlled internucleotidic linkage has a diastereopurity of about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5%, typically about or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5%. In some embodiments, a chirally controlled internucleotidic linkage has a diastereopurity of about or at least about 95%. In some embodiments, a chirally controlled internucleotidic linkage has a diastereopurity of about or at least about 96%. In some embodiments, a chirally controlled internucleotidic linkage has a diastereopurity of about or at least about 97%. In some embodiments, a chirally controlled internucleotidic linkage has a diastereopurity of about or at least about 98%. In some embodiments, a chirally controlled internucleotidic linkage has a diastereopurity of about or at least about 99%. In some embodiments, a percentage of a level is or is about or at least about (DS)nc, wherein DS is a diastereopurity as described in the present disclosure (e.g., about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% or more) and nc is the number of chiral linkage phosphorus as described in the present disclosure (e.g., 1-50, 1-40, 1-30, 1-25, 1-20, 5-50, 5-40, 5- 30, 5-25, 5-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more). Page 10 of 448 12513573v1Attorney Docket No.: 2010581-1441 In some embodiments, a percentage of a level is or is at least (DS)nc, wherein DS is a diastereopurity as described in the present disclosure (e.g., about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% or more) and nc is the number of chirally controlled internucleotidic linkages as described in the present disclosure (e.g., 1-50, 1-40, 1-30, 1-25, 1-20, 5-50, 5-40, 5-30, 5-25, 5-20, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more). In some embodiments, a percentage of a level is or is at least (DS)nc, wherein DS is about 95%-100%. For example, when DS is 99% and nc is 10, the percentage is or is at least 90% ((99%)10≈ 0.90 = 90%). In some embodiments, level of a plurality of oligonucleotides in a composition is represented as the product of the diastereopurity of each chiral linkage phosphorus. In some embodiments, level of a plurality of oligonucleotides in a composition is represented as the product of the diastereopurity of each chirally controlled internucleotidic linkage in the oligonucleotides. In some embodiments, diastereopurity of an internucleotidic linkage connecting two nucleosides in an oligonucleotide (or nucleic acid) is represented by the diastereopurity of an internucleotidic linkage of a dimer connecting the same two nucleosides, wherein the dimer is prepared using comparable conditions, in some instances, identical synthetic cycle conditions (e.g., for the linkage between Nx and Ny in an oligonucleotide ….NxNy….., the dimer is NxNy). In some embodiments, not all chiral internucleotidic linkages are chiral controlled internucleotidic linkages, and the composition is a partially chirally controlled oligonucleotide composition. In some embodiments, a non-chirally controlled internucleotidic linkage has a diastereopurity of less than about 80%, 75%, 70%, 65%, 60%, 55%, or of about 50%, as typically observed in stereorandom oligonucleotide compositions (e.g., as appreciated by those skilled in the art, from traditional oligonucleotide synthesis, e.g., the phosphoramidite method). In some embodiments, oligonucleotides (or nucleic acids) of a plurality are of the same type. In some embodiments, a chirally controlled oligonucleotide composition comprises non-random or controlled levels of individual oligonucleotide or nucleic acids types. For instance, in some embodiments a chirally controlled oligonucleotide composition comprises one and no more than one oligonucleotide type. In some embodiments, a chirally controlled oligonucleotide composition comprises more than one oligonucleotide type. In some embodiments, a chirally controlled oligonucleotide composition comprises multiple oligonucleotide types. In some embodiments, a chirally controlled oligonucleotide composition is a composition of oligonucleotides of an oligonucleotide type, which composition comprises a non-random or controlled level of a plurality of oligonucleotides of the oligonucleotide type.

[0026] Comparable: The term “comparable” is used herein to describe two (or more) sets of conditions or circumstances that are sufficiently similar to one another to permit comparison of results obtained or phenomena observed. In some embodiments, comparable sets of conditions or circumstances are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will appreciate that sets of conditions are comparable to one another when Page 11 of 448 12513573v1Attorney Docket No.: 2010581-1441 characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under the different sets of conditions or circumstances are caused by or indicative of the variation in those features that are varied.

[0027] Cycloaliphatic: The term “cycloaliphatic,” “carbocycle,” “carbocyclyl,” “carbocyclic radical,” and “carbocyclic ring,” are used interchangeably, and as used herein, refer to saturated or partially unsaturated, but non-aromatic, cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having, unless otherwise specified, from 3 to 30 ring members. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, a cycloaliphatic group has 3–6 carbons. In some embodiments, a cycloaliphatic group is saturated and is cycloalkyl. The term “cycloaliphatic” may also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl. In some embodiments, a cycloaliphatic group is bicyclic. In some embodiments, a cycloaliphatic group is tricyclic. In some embodiments, a cycloaliphatic group is polycyclic. In some embodiments, “cycloaliphatic” refers to C3-C6 monocyclic hydrocarbon, or C8-C10 bicyclic or polycyclic hydrocarbon, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, or a C9-C16 polycyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.

[0028] Heteroaliphatic: The term “heteroaliphatic”, as used herein, is given its ordinary meaning in the art and refers to aliphatic groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). In some embodiments, one or more units selected from C, CH, CH2, and CH3 are independently replaced by one or more heteroatoms (including oxidized and / or substituted forms thereof). In some embodiments, a heteroaliphatic group is heteroalkyl. In some embodiments, a heteroaliphatic group is heteroalkenyl.

[0029] Heteroalkyl: The term “heteroalkyl”, as used herein, is given its ordinary meaning in the art and refers to alkyl groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol)-, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[0030] Heteroaryl: The terms “heteroaryl” and “heteroar–”, as used herein, used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to monocyclic, bicyclic or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic Page 12 of 448 12513573v1Attorney Docket No.: 2010581-1441 and at least one aromatic ring atom is a heteroatom. In some embodiments, a heteroaryl group is a group having 5 to 10 ring atoms (i.e., monocyclic, bicyclic or polycyclic), in some embodiments 5, 6, 9, or 10 ring atoms. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, a heteroaryl group has 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In some embodiments, a heteroaryl is a heterobiaryl group, such as bipyridyl and the like. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be monocyclic, bicyclic or polycyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0031] Heteroatom: The term “heteroatom", as used herein, means an atom that is not carbon or hydrogen. In some embodiments, a heteroatom is boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon; charged forms of nitrogen (e.g., quaternized forms, forms as in iminium groups, etc.), phosphorus, sulfur, oxygen; etc.). In some embodiments, a heteroatom is silicon, phosphorus, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is silicon, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is oxygen, sulfur or nitrogen.

[0032] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring", as used herein, are used interchangeably and refer to a monocyclic, bicyclic or polycyclic ring moiety (e.g., 3-30 membered) that is saturated or partially unsaturated and has one or more heteroatom ring atoms. In some embodiments, a heterocyclyl group is a stable 5– to 7–membered monocyclic or 7– to 10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms Page 13 of 448 12513573v1Attorney Docket No.: 2010581-1441 selected from oxygen, sulfur and nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic, bicyclic or polycyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0033] Internucleotidic linkage: As used herein, the phrase “internucleotidic linkage” refers generally to a linkage linking nucleoside units of an oligonucleotide or a nucleic acid. In some embodiments, an internucleotidic linkage is a phosphodiester linkage, as extensively found in naturally occurring DNA and RNA molecules (natural phosphate linkage (−OP(=O)(OH)O−), which as appreciated by those skilled in the art may exist as a salt form). In some embodiments, an internucleotidic linkage is a modified internucleotidic linkage (not a natural phosphate linkage). In some embodiments, an internucleotidic linkage is a “modified internucleotidic linkage” wherein at least one oxygen atom or −OH of a phosphodiester linkage is replaced by a different organic or inorganic moiety. In some embodiments, such an organic or inorganic moiety is selected from =S, =Se, =NR’, –SR’, –SeR’, –N(R’)2, B(R’)3, –S–, –Se–, and –N(R’)–, wherein each R’ is independently as defined and described in the present disclosure. In some embodiments, an internucleotidic linkage is a phosphotriester linkage, phosphorothioate linkage (or phosphorothioate diester linkage, −OP(=O)(SH)O−, which as appreciated by those skilled in the art may exist as a salt form), or phosphorothioate triester linkage. In some embodiments, a modified internucleotidic linkage is a phosphorothioate linkage. In some embodiments, an internucleotidic linkage is one of, e.g., PNA (peptide nucleic acid) or PMO (phosphorodiamidate Morpholino oligomer) linkage. In some embodiments, a modified internucleotidic linkage is a non-negatively charged internucleotidic linkage. In some embodiments, a modified internucleotidic linkage is a neutral internucleotidic linkage (e.g., n001 in certain provided oligonucleotides). It is understood by a person of ordinary skill in the art that an internucleotidic linkage may exist as an anion or cation at a given pH due to the existence of acid or base moieties in the linkage.

[0034] Linkage phosphorus: as defined herein, the phrase “linkage phosphorus” is used to indicate that Page 14 of 448 12513573v1Attorney Docket No.: 2010581-1441 the particular phosphorus atom being referred to is the phosphorus atom present in the internucleotidic linkage, which phosphorus atom corresponds to the phosphorus atom of a phosphodiester internucleotidic linkage as occurs in naturally occurring DNA and RNA. In some embodiments, a linkage phosphorus atom is in a modified internucleotidic linkage, wherein each oxygen atom of a phosphodiester linkage is optionally and independently replaced by an organic or inorganic moiety. In some embodiments, a linkage phosphorus atom is chiral (e.g., as in phosphorothioate internucleotidic linkages). In some embodiments, a linkage phosphorus atom is achiral (e.g., as in natural phosphate linkages).

[0035] Modified nucleobase: The terms "modified nucleobase", "modified base" and the like refer to a chemical moiety which is chemically distinct from a nucleobase, but which is capable of performing at least one function of a nucleobase. In some embodiments, a modified nucleobase is a nucleobase which comprises a modification. In some embodiments, a modified nucleobase is capable of at least one function of a nucleobase, e.g., forming a moiety in a polymer capable of base-pairing to a nucleic acid comprising an at least complementary sequence of bases. In some embodiments, a modified nucleobase is substituted A, T, C, G, or U, or a substituted tautomer of A, T, C, G, or U. In some embodiments, a modified nucleobase in the context of oligonucleotides refer to a nucleobase that is not A, T, C, G or U.

[0036] Modified nucleoside: The term "modified nucleoside" refers to a moiety derived from or chemically similar to a natural nucleoside, but which comprises a chemical modification which differentiates it from a natural nucleoside. Non-limiting examples of modified nucleosides include those which comprise a modification at the base and / or the sugar. Non-limiting examples of modified nucleosides include those with a 2’ modification at a sugar. Non-limiting examples of modified nucleosides also include abasic nucleosides (which lack a nucleobase). In some embodiments, a modified nucleoside is capable of at least one function of a nucleoside, e.g., forming a moiety in a polymer capable of base-pairing to a nucleic acid comprising an at least complementary sequence of bases.

[0037] Modified nucleotide: The term “modified nucleotide” includes any chemical moiety which differs structurally from a natural nucleotide but is capable of performing at least one function of a natural nucleotide. In some embodiments, a modified nucleotide comprises a modification at a sugar, base and / or internucleotidic linkage. In some embodiments, a modified nucleotide comprises a modified sugar, modified nucleobase and / or modified internucleotidic linkage. In some embodiments, a modified nucleotide is capable of at least one function of a nucleotide, e.g., forming a subunit in a polymer capable of base-pairing to a nucleic acid comprising an at least complementary sequence of bases.

[0038] Modified sugar: The term “modified sugar” refers to a moiety that can replace a sugar. A modified sugar mimics the spatial arrangement, electronic properties, or some other physicochemical property of a sugar. In some embodiments, as described in the present disclosure, a modified sugar is substituted ribose or deoxyribose. In some embodiments, a modified sugar comprises a 2’-modification. Page 15 of 448 12513573v1Attorney Docket No.: 2010581-1441 Examples of useful 2’-modification are widely utilized in the art and described herein. In some embodiments, a 2’-modification is 2’-F. In some embodiments, a 2’-modification is 2’-OR, wherein R is optionally substituted C1-10aliphatic. In some embodiments, a 2’-modification is 2’-OMe. In some embodiments, a 2’-modification is 2’-MOE. In some embodiments, a modified sugar is a bicyclic sugar (e.g., a sugar used in LNA, BNA, etc.). In some embodiments, in the context of oligonucleotides, a modified sugar is a sugar that is not ribose or deoxyribose as typically found in natural RNA or DNA.

[0039] Nucleic acid: The term “nucleic acid”, as used herein, includes any nucleotides and polymers thereof. The term “polynucleotide”, as used herein, refers to a polymeric form of nucleotides of any length, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) or a combination thereof. These terms refer to the primary structure of the molecules and, thus, include double- and single-stranded DNA, and double- and single-stranded RNA. These terms include, as equivalents, analogs of either RNA or DNA comprising modified nucleotides and / or modified polynucleotides, such as, though not limited to, methylated, protected and / or capped nucleotides or polynucleotides. The terms encompass poly- or oligo-ribonucleotides (RNA) and poly- or oligo-deoxyribonucleotides (DNA); RNA or DNA derived from N-glycosides or C-glycosides of nucleobases and / or modified nucleobases; nucleic acids derived from sugars and / or modified sugars; and nucleic acids derived from phosphate bridges and / or modified internucleotidic linkages. The term encompasses nucleic acids containing any combinations of nucleobases, modified nucleobases, sugars, modified sugars, phosphate bridges or modified internucleotidic linkages. Examples include, and are not limited to, nucleic acids containing ribose moieties, nucleic acids containing deoxy-ribose moieties, nucleic acids containing both ribose and deoxyribose moieties, nucleic acids containing ribose and modified ribose moieties. Unless otherwise specified, the prefix poly- refers to a nucleic acid containing 2 to about 10,000 nucleotide monomer units and wherein the prefix oligo- refers to a nucleic acid containing 2 to about 200 nucleotide monomer units.

[0040] Nucleobase: The term “nucleobase” refers to the parts of nucleic acids that are involved in the hydrogen-bonding that binds one nucleic acid strand to another complementary strand in a sequence specific manner. The most common naturally-occurring nucleobases are adenine (A), guanine (G), uracil (U), cytosine (C), and thymine (T). In some embodiments, a naturally-occurring nucleobases are modified adenine, guanine, uracil, cytosine, or thymine. In some embodiments, a naturally-occurring nucleobases are methylated adenine, guanine, uracil, cytosine, or thymine. In some embodiments, a nucleobase comprises a heteroaryl ring wherein a ring atom is nitrogen, and when in a nucleoside, the nitrogen is bonded to a sugar moiety. In some embodiments, a nucleobase comprises a heterocyclic ring wherein a ring atom is nitrogen, and when in a nucleoside, the nitrogen is bonded to a sugar moiety. In some embodiments, a nucleobase is a “modified nucleobase,” a nucleobase other than adenine (A), guanine (G), uracil (U), cytosine (C), and thymine (T). In some embodiments, a modified nucleobase is substituted A, Page 16 of 448 12513573v1Attorney Docket No.: 2010581-1441 T, C, G or U. In some embodiments, a modified nucleobase is a substituted tautomer of A, T, C, G, or U. In some embodiments, a modified nucleobases is methylated adenine, guanine, uracil, cytosine, or thymine. In some embodiments, a modified nucleobase mimics the spatial arrangement, electronic properties, or some other physicochemical property of the nucleobase and retains the property of hydrogen-bonding that binds one nucleic acid strand to another in a sequence specific manner. In some embodiments, a modified nucleobase can pair with all of the five naturally occurring bases (uracil, thymine, adenine, cytosine, or guanine) without substantially affecting the melting behavior, recognition by intracellular enzymes or activity of the oligonucleotide duplex. As used herein, the term “nucleobase” also encompasses structural analogs used in lieu of natural or naturally-occurring nucleotides, such as modified nucleobases and nucleobase analogs. In some embodiments, a nucleobase is optionally substituted A, T, C, G, or U, or an optionally substituted tautomer of A, T, C, G, or U. In some embodiments, a “nucleobase” refers to a nucleobase unit in an oligonucleotide or a nucleic acid (e.g., A, T, C, G or U as in an oligonucleotide or a nucleic acid).

[0041] Nucleoside: The term “nucleoside” refers to a moiety wherein a nucleobase or a modified nucleobase is covalently bound to a sugar or a modified sugar. In some embodiments, a nucleoside is a natural nucleoside, e.g., adenosine, deoxyadenosine, guanosine, deoxyguanosine, thymidine, uridine, cytidine, or deoxycytidine. In some embodiments, a nucleoside is a modified nucleoside, e.g., a substituted natural nucleoside selected from adenosine, deoxyadenosine, guanosine, deoxyguanosine, thymidine, uridine, cytidine, and deoxycytidine. In some embodiments, a nucleoside is a modified nucleoside, e.g., a substituted tautomer of a natural nucleoside selected from adenosine, deoxyadenosine, guanosine, deoxyguanosine, thymidine, uridine, cytidine, and deoxycytidine. In some embodiments, a “nucleoside” refers to a nucleoside unit in an oligonucleotide or a nucleic acid.

[0042] Nucleotide: The term “nucleotide” as used herein refers to a monomeric unit of a polynucleotide that consists of a nucleobase, a sugar, and one or more internucleotidic linkages (e.g., phosphate linkages in natural DNA and RNA). The naturally occurring bases [guanine, (G), adenine, (A), cytosine, (C), thymine, (T), and uracil (U)] are derivatives of purine or pyrimidine, though it should be understood that naturally and non-naturally occurring base analogs are also included. The naturally occurring sugar is the pentose (five-carbon sugar) deoxyribose (which forms DNA) or ribose (which forms RNA), though it should be understood that naturally and non-naturally occurring sugar analogs are also included. Nucleotides are linked via internucleotidic linkages to form nucleic acids, or polynucleotides. Many internucleotidic linkages are known in the art (such as, though not limited to, phosphate, phosphorothioates, boranophosphates and the like). Artificial nucleic acids include PNAs (peptide nucleic acids), phosphotriesters, phosphorothionates, H-phosphonates, phosphoramidates, boranophosphates, methylphosphonates, phosphonoacetates, thiophosphonoacetates and other variants of the phosphate Page 17 of 448 12513573v1Attorney Docket No.: 2010581-1441 backbone of native nucleic acids, such as those described herein. In some embodiments, a natural nucleotide comprises a naturally occurring base, sugar and internucleotidic linkage. As used herein, the term “nucleotide” also encompasses structural analogs used in lieu of natural or naturally-occurring nucleotides, such as modified nucleotides and nucleotide analogs. In some embodiments, a “nucleotide” refers to a nucleotide unit in an oligonucleotide or a nucleic acid.

[0043] Oligonucleotide: The term "oligonucleotide" refers to a polymer or oligomer of nucleotides, and may contain any combination of natural and non-natural nucleobases, sugars, and internucleotidic linkages.

[0044] Oligonucleotides can be single-stranded or double-stranded. A single-stranded oligonucleotide can have double-stranded regions (formed by two portions of the single-stranded oligonucleotide) and a double-stranded oligonucleotide, which comprises two oligonucleotide chains, can have single-stranded regions for example, at regions where the two oligonucleotide chains are not complementary to each other. Example oligonucleotides include, but are not limited to structural genes, genes including control and termination regions, self-replicating systems such as viral or plasmid DNA, single-stranded and double- stranded RNAi agents and other RNA interference reagents (RNAi agents or iRNA agents), shRNA, antisense oligonucleotides, ribozymes, microRNAs, microRNA mimics, supermirs, aptamers, antimirs, antagomirs, Ul adaptors, triplex-forming oligonucleotides, G-quadruplex oligonucleotides, RNA activators, immuno-stimulatory oligonucleotides, and decoy oligonucleotides.

[0045] Oligonucleotides of the present disclosure can be of various lengths. In particular embodiments, oligonucleotides can range from about 2 to about 200 nucleosides in length. In various related embodiments, oligonucleotides, single-stranded, double-stranded, or triple-stranded, can range in length from about 4 to about 10 nucleosides, from about 10 to about 50 nucleosides, from about 20 to about 50 nucleosides, from about 15 to about 30 nucleosides, from about 20 to about 30 nucleosides in length. In some embodiments, an oligonucleotide is from about 9 to about 39 nucleosides in length. In some embodiments, an oligonucleotide is from about 25 to about 70 nucleosides in length. In some embodiments, an oligonucleotide is from about 26 to about 70 nucleosides in length. In some embodiments, an oligonucleotide is from about 27 to about 70 nucleosides in length. In some embodiments, an oligonucleotide is from about 28 to about 70 nucleosides in length. In some embodiments, an oligonucleotide is from about 29 to about 70 nucleosides in length. In some embodiments, an oligonucleotide is from about 30 to about 70 nucleosides in length. In some embodiments, an oligonucleotide is from about 31 to about 70 nucleosides in length. In some embodiments, an oligonucleotide is from about 32 to about 70 nucleosides in length. In some embodiments, an oligonucleotide is from about 25 to about 60 nucleosides in length. In some embodiments, an oligonucleotide is from about 25 to about 50 nucleosides in length. In some embodiments, an Page 18 of 448 12513573v1Attorney Docket No.: 2010581-1441 oligonucleotide is from about 25 to about 40 nucleosides in length. In some embodiments, an oligonucleotide is from about 30 to about 40 nucleosides in length. In some embodiments, the oligonucleotide is at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleosides in length. In some embodiments, an oligonucleotide is at least 4 nucleosides in length. In some embodiments, an oligonucleotide is at least 5 nucleosides in length. In some embodiments, an oligonucleotide is at least 6 nucleosides in length. In some embodiments, an oligonucleotide is at least 7 nucleosides in length. In some embodiments, an oligonucleotide is at least 8 nucleosides in length. In some embodiments, an oligonucleotide is at least 9 nucleosides in length. In some embodiments, an oligonucleotide is at least 10 nucleosides in length. In some embodiments, an oligonucleotide is at least 11 nucleosides in length. In some embodiments, an oligonucleotide is at least 12 nucleosides in length. In some embodiments, an oligonucleotide is at least 15 nucleosides in length. In some embodiments, an oligonucleotide is at least 15 nucleosides in length. In some embodiments, an oligonucleotide is at least 16 nucleosides in length. In some embodiments, an oligonucleotide is at least 17 nucleosides in length. In some embodiments, an oligonucleotide is at least 18 nucleosides in length. In some embodiments, an oligonucleotide is at least 19 nucleosides in length. In some embodiments, an oligonucleotide is at least 20 nucleosides in length. In some embodiments, an oligonucleotide is at least 25 nucleosides in length. In some embodiments, an oligonucleotide is at least 26 nucleosides in length. In some embodiments, an oligonucleotide is at least 27 nucleosides in length. In some embodiments, an oligonucleotide is at least 28 nucleosides in length. In some embodiments, an oligonucleotide is at least 29 nucleosides in length. In some embodiments, an oligonucleotide is at least 30 nucleosides in length. In some embodiments, an oligonucleotide is at least 31 nucleosides in length. In some embodiments, an oligonucleotide is at least 32 nucleosides in length. In some embodiments, an oligonucleotide is at least 33 nucleosides in length. In some embodiments, an oligonucleotide is at least 34 nucleosides in length. In some embodiments, an oligonucleotide is at least 35 nucleosides in length. In some embodiments, an oligonucleotide is at least 36 nucleosides in length. In some embodiments, an oligonucleotide is at least 37 nucleosides in length. In some embodiments, an oligonucleotide is at least 38 nucleosides in length. In some embodiments, an oligonucleotide is at least 39 nucleosides in length. In some embodiments, an oligonucleotide is at least 40 nucleosides in length. In some embodiments, an oligonucleotide is 25 nucleosides in length. In some embodiments, an oligonucleotide is 26 nucleosides in length. In some embodiments, an oligonucleotide is 27 nucleosides in length. In some embodiments, an oligonucleotide is 28 nucleosides in length. In some embodiments, an oligonucleotide is 29 nucleosides in length. In some embodiments, an oligonucleotide is 30 nucleosides in length. In some embodiments, an oligonucleotide is 31 nucleosides in length. In some embodiments, an oligonucleotide is 32 nucleosides in length. In some embodiments, an oligonucleotide is 33 nucleosides in length. In some embodiments, an oligonucleotide is 34 nucleosides in length. In some Page 19 of 448 12513573v1Attorney Docket No.: 2010581-1441 embodiments, an oligonucleotide is 35 nucleosides in length. In some embodiments, an oligonucleotide is 36 nucleosides in length. In some embodiments, an oligonucleotide is 37 nucleosides in length. In some embodiments, an oligonucleotide is 38 nucleosides in length. In some embodiments, an oligonucleotide is 39 nucleosides in length. In some embodiments, an oligonucleotide is 40 nucleosides in length. In some embodiments, each nucleoside counted in an oligonucleotide length independently comprises a nucleobase comprising a ring having at least one nitrogen ring atom. In some embodiments, each nucleoside counted in an oligonucleotide length independently comprises A, T, C, G, or U, or optionally substituted A, T, C, G, or U, or an optionally substituted tautomer of A, T, C, G or U.

[0046] Optionally Substituted: As described herein, compounds of the disclosure may contain optionally substituted, substituted and / or unsubstituted moieties. In general, the term “substituted,” means that one or more hydrogens of the designated moiety are independently replaced with a substituent. Unless otherwise indicated, an “optionally substituted” group may independently have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with two or more substituents, the substituents may be either the same or different at every position. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. Various substituents are described below.

[0047] Monovalent substituents are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; −O(CH2)0- 4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4Ph, which may be substituted with R°; −(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)N(R°)2; −N(R°)C(S)N(R°)2; –(CH2)0–4N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; −N(R°)N(R°)C(O)N(R°)2; −N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; −(CH2)0–4C(O)OSi(R°)3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR°, −SC(S)SR°; −(CH2)0–4SC(O)R°; –(CH2)0–4C(O)N(R°)2; –C(S)N(R°)2; –C(S)SR°; −SC(S)SR°, -(CH2)0–4OC(O)N(R°)2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; −C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; −S(O)2N(R°)2; -(CH2)0–4S(O)R°; –N(R°)S(O)2N(R°)2; –N(R°)S(O)2R°; –N(OR°)R°; −C(NH)N(R°)2; – Si(R°)3; –OSi(R°)3; −P(R°)2; −P(OR°)2; −OP(R°)2; −OP(OR°)2; −N(R°)P(R°)2; −B(R°)2; −OB(R°)2; −P(O)(R°)2; −OP(O)(R°)2; −N(R°)P(O)(R°)2; –(C1-4 straight or branched alkylene)O–N(R°)2; or –(C1-4 straight or branched alkylene)C(O)O–N(R°)2; wherein each R° may be independently substituted as defined below and is independently hydrogen, C1-10 (e.g., C1-6, C1-4, etc.) aliphatic, C1-10 (e.g., C1-6, C1-4, etc.) heteroaliphatic having 1-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, C6-10(e.g., C6, C10, etc.) aryl, 5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having Page 20 of 448 12513573v1Attorney Docket No.: 2010581-1441 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, −CH2−(C6-10(e.g., C6, C10, etc.) aryl), −O(CH2)0-1(C6-10(e.g., C6, C10, etc.) aryl), −CH2−(5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), −O(CH2)0-1(5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), a 3-10 (e.g., 3-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, or partially unsaturated ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-10 (e.g., 3-6, 5- 6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated or aromatic ring (for aromatic ring, 5-10 (e.g., 5-9, 5-6, 5, 6, 9, 10, etc.) membered) having, in addition to the intervening atom(s), 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined below.

[0048] Monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0– 2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; –O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, – – – – – – – isunsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Divalent substituents on a saturated carbon atom of R° are independently =O or =S.

[0049] Divalent substituents are independently the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, −O(C(R*2))2–3O−, or −S(C(R*2))2–3S−, wherein each independent occurrence of R*is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group are independently −O(CR*2)2–3O−, wherein each independent occurrence of R*is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6- membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0050] Substituents on the aliphatic group of R*are independently halogen, –R^, -(haloR^), –OH, −OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is Page 21 of 448 12513573v1Attorney Docket No.: 2010581-1441 unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0051] Substituents on a substitutable nitrogen are independently –R†, −NR†2, −C(O)R†, –C(O)OR†, – C(O)C(O)R†, –C(O)CH2C(O)R†, –S(O)2R†, –S(O)2NR†2, −C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12 (e.g., 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0052] Substituents on the aliphatic group of R†are independently halogen, −R^, -(haloR^), −OH, – OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3-6 (e.g., 3-5, 5-6, etc.)-membered saturated, partially unsaturated, or aromatic ring (for aromatic ring, 5- or 6-membered) having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0053] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0054] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, an active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray Page 22 of 448 12513573v1Attorney Docket No.: 2010581-1441 applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0055] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0056] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: 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 acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0057] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salt include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, Page 23 of 448 12513573v1Attorney Docket No.: 2010581-1441 bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, a provided compound comprises one or more acidic groups, e.g., an oligonucleotide, and a pharmaceutically acceptable salt is an alkali, alkaline earth metal, or ammonium (e.g., an ammonium salt of N(R)3, wherein each R is independently defined and described in the present disclosure) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, a pharmaceutically acceptable salt is a sodium salt. In some embodiments, a pharmaceutically acceptable salt is a potassium salt. In some embodiments, a pharmaceutically acceptable salt is a calcium salt. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. In some embodiments, a provided compound comprises more than one acid groups, for example, an oligonucleotide may comprise two or more acidic groups (e.g., in natural phosphate linkages and / or modified internucleotidic linkages). In some embodiments, a pharmaceutically acceptable salt, or generally a salt, of such a compound comprises two or more cations, which can be the same or different. In some embodiments, in a pharmaceutically acceptable salt (or generally, a salt), all ionizable hydrogen (e.g., in an aqueous solution with a pKa no more than about 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2; in some embodiments, no more than about 7; in some embodiments, no more than about 6; in some embodiments, no more than about 5; in some embodiments, no more than about 4; in some embodiments, no more than about 3) in the acidic groups are replaced with cations. In some embodiments, each phosphorothioate and phosphate group independently exists in its salt form (e.g., if sodium salt, −O−P(O)(SNa)−O− and −O−P(O)(ONa)−O−, respectively). In some embodiments, each phosphorothioate and phosphate internucleotidic linkage independently exists in its salt form (e.g., if sodium salt, −O−P(O)(SNa)−O− and −O−P(O)(ONa)−O−, respectively). In some embodiments, a pharmaceutically acceptable salt is a sodium salt of an oligonucleotide. In some embodiments, a pharmaceutically acceptable salt is a sodium salt of an oligonucleotide, wherein each acidic phosphate and modified phosphate group (e.g., phosphorothioate, phosphate, etc.), if any, exists as a salt form (all sodium salt).

[0058] Predetermined: By predetermined (or pre-determined) is meant deliberately selected or non- random or controlled, for example as opposed to randomly occurring, random, or achieved without control. Page 24 of 448 12513573v1Attorney Docket No.: 2010581-1441 Those of ordinary skill in the art, reading the present specification, will appreciate that the present disclosure provides technologies that permit selection of particular chemistry and / or stereochemistry features to be incorporated into oligonucleotide compositions, and further permits controlled preparation of oligonucleotide compositions having such chemistry and / or stereochemistry features. Such provided compositions are “predetermined” as described herein. Compositions that may contain certain oligonucleotides because they happen to have been generated through a process that are not controlled to intentionally generate the particular chemistry and / or stereochemistry features are not “predetermined” compositions. In some embodiments, a predetermined composition is one that can be intentionally reproduced (e.g., through repetition of a controlled process). In some embodiments, a predetermined level of a plurality of oligonucleotides in a composition means that the absolute amount, and / or the relative amount (ratio, percentage, etc.) of the plurality of oligonucleotides in the composition is controlled. In some embodiments, a predetermined level of a plurality of oligonucleotides in a composition is achieved through chirally controlled oligonucleotide preparation.

[0059] Protecting group: The term “protecting group,” as used herein, is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Also included are those protecting groups specially adapted for nucleoside and nucleotide chemistry described in Current Protocols in Nucleic Acid Chemistry, edited by Serge L. Beaucage et al.06 / 2012, the entirety of Chapter 2 is incorporated herein by reference. Suitable amino–protecting groups include methyl carbamate, ethyl carbamante, 9–fluorenylmethyl carbamate (Fmoc), 9–(2–sulfo)fluorenylmethyl carbamate, 9–(2,7– dibromo)fluoroenylmethyl carbamate, 2,7–di–t–butyl–[9–(10,10–dioxo–10,10,10,10– tetrahydrothioxanthyl)]methyl carbamate (DBD–Tmoc), 4–methoxyphenacyl carbamate (Phenoc), 2,2,2– trichloroethyl carbamate (Troc), 2–trimethylsilylethyl carbamate (Teoc), 2–phenylethyl carbamate (hZ), 1– (1–adamantyl)–1–methylethyl carbamate (Adpoc), 1,1–dimethyl–2–haloethyl carbamate, 1,1–dimethyl– 2,2–dibromoethyl carbamate (DB–t–BOC), 1,1–dimethyl–2,2,2–trichloroethyl carbamate (TCBOC), 1– methyl–1–(4–biphenylyl)ethyl carbamate (Bpoc), 1–(3,5–di–t–butylphenyl)–1–methylethyl carbamate (t– Bumeoc), 2–(2’– and 4’–pyridyl)ethyl carbamate (Pyoc), 2–(N,N–dicyclohexylcarboxamido)ethyl carbamate, t–butyl carbamate (BOC), 1–adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1–isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4–nitrocinnamyl carbamate (Noc), 8–quinolyl carbamate, N–hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p–methoxybenzyl carbamate (Moz), p–nitobenzyl carbamate, p–bromobenzyl carbamate, p–chlorobenzyl carbamate, 2,4–dichlorobenzyl carbamate, 4–methylsulfinylbenzyl carbamate (Msz), 9– anthrylmethyl carbamate, diphenylmethyl carbamate, 2–methylthioethyl carbamate, 2–methylsulfonylethyl carbamate, 2–(p–toluenesulfonyl)ethyl carbamate, [2–(1,3–dithianyl)]methyl carbamate (Dmoc), 4– Page 25 of 448 12513573v1Attorney Docket No.: 2010581-1441 methylthiophenyl carbamate (Mtpc), 2,4–dimethylthiophenyl carbamate (Bmpc), 2–phosphonioethyl carbamate (Peoc), 2–triphenylphosphonioisopropyl carbamate (Ppoc), 1,1–dimethyl–2–cyanoethyl carbamate, m–chloro–p–acyloxybenzyl carbamate, p–(dihydroxyboryl)benzyl carbamate, 5– benzisoxazolylmethyl carbamate, 2–(trifluoromethyl)–6–chromonylmethyl carbamate (Tcroc), m– nitrophenyl carbamate, 3,5–dimethoxybenzyl carbamate, o–nitrobenzyl carbamate, 3,4–dimethoxy–6– nitrobenzyl carbamate, phenyl(o–nitrophenyl)methyl carbamate, phenothiazinyl–(10)–carbonyl derivative, N’–p–toluenesulfonylaminocarbonyl derivative, N’–phenylaminothiocarbonyl derivative, t–amyl carbamate, S–benzyl thiocarbamate, p–cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p–decyloxybenzyl carbamate, 2,2– dimethoxycarbonylvinyl carbamate, o–(N,N–dimethylcarboxamido)benzyl carbamate, 1,1–dimethyl–3– (N,N–dimethylcarboxamido)propyl carbamate, 1,1–dimethylpropynyl carbamate, di(2–pyridyl)methyl carbamate, 2–furanylmethyl carbamate, 2–iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p–(p’–methoxyphenylazo)benzyl carbamate, 1–methylcyclobutyl carbamate, 1– methylcyclohexyl carbamate, 1–methyl–1–cyclopropylmethyl carbamate, 1–methyl–1–(3,5– dimethoxyphenyl)ethyl carbamate, 1–methyl–1–(p–phenylazophenyl)ethyl carbamate, 1–methyl–1– phenylethyl carbamate, 1–methyl–1–(4–pyridyl)ethyl carbamate, phenyl carbamate, p–(phenylazo)benzyl carbamate, 2,4,6–tri–t–butylphenyl carbamate, 4–(trimethylammonium)benzyl carbamate, 2,4,6– trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3–phenylpropanamide, picolinamide, 3–pyridylcarboxamide, N– benzoylphenylalanyl derivative, benzamide, p–phenylbenzamide, o–nitophenylacetamide, o– nitrophenoxyacetamide, acetoacetamide, (N’–dithiobenzyloxycarbonylamino)acetamide, 3–(p– hydroxyphenyl)propanamide, 3–(o–nitrophenyl)propanamide, 2–methyl–2–(o– nitrophenoxy)propanamide, 2–methyl–2–(o–phenylazophenoxy)propanamide, 4–chlorobutanamide, 3– methyl–3–nitrobutanamide, o–nitrocinnamide, N–acetylmethionine derivative, o–nitrobenzamide, o– (benzoyloxymethyl)benzamide, 4,5–diphenyl–3–oxazolin–2–one, N–phthalimide, N–dithiasuccinimide (Dts), N–2,3–diphenylmaleimide, N–2,5–dimethylpyrrole, N–1,1,4,4–tetramethyldisilylazacyclopentane adduct (STABASE), 5–substituted 1,3–dimethyl–1,3,5–triazacyclohexan–2–one, 5–substituted 1,3– dibenzyl–1,3,5–triazacyclohexan–2–one, 1–substituted 3,5–dinitro–4–pyridone, N–methylamine, N– allylamine, N–[2–(trimethylsilyl)ethoxy]methylamine (SEM), N–3–acetoxypropylamine, N–(1– isopropyl–4–nitro–2–oxo–3–pyroolin–3–yl)amine, quaternary ammonium salts, N–benzylamine, N–di(4– methoxyphenyl)methylamine, N–5–dibenzosuberylamine, N–triphenylmethylamine (Tr), N–[(4– methoxyphenyl)diphenylmethyl]amine (MMTr), N–9–phenylfluorenylamine (PhF), N–2,7–dichloro–9– fluorenylmethyleneamine, N–ferrocenylmethylamino (Fcm), N–2–picolylamino N’–oxide, N–1,1– dimethylthiomethyleneamine, N–benzylideneamine, N–p–methoxybenzylideneamine, N– Page 26 of 448 12513573v1Attorney Docket No.: 2010581-1441 diphenylmethyleneamine, N–[(2–pyridyl)mesityl]methyleneamine, N–(N’,N’– dimethylaminomethylene)amine, N,N’–isopropylidenediamine, N–p–nitrobenzylideneamine, N– salicylideneamine, N–5–chlorosalicylideneamine, N–(5–chloro–2– hydroxyphenyl)phenylmethyleneamine, N–cyclohexylideneamine, N–(5,5–dimethyl–3–oxo–1– cyclohexenyl)amine, N–borane derivative, N–diphenylborinic acid derivative, N– [phenyl(pentacarbonylchromium– or tungsten)carbonyl]amine, N–copper chelate, N–zinc chelate, N– nitroamine, N–nitrosoamine, amine N–oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o–nitrobenzenesulfenamide (Nps), 2,4– dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2–nitro–4–methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3–nitropyridinesulfenamide (Npys), p–toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,–trimethyl–4–methoxybenzenesulfonamide (Mtr), 2,4,6– trimethoxybenzenesulfonamide (Mtb), 2,6–dimethyl–4–methoxybenzenesulfonamide (Pme), 2,3,5,6– tetramethyl–4–methoxybenzenesulfonamide (Mte), 4–methoxybenzenesulfonamide (Mbs), 2,4,6– trimethylbenzenesulfonamide (Mts), 2,6–dimethoxy–4–methylbenzenesulfonamide (iMds), 2,2,5,7,8– pentamethylchroman–6–sulfonamide (Pmc), methanesulfonamide (Ms), β– trimethylsilylethanesulfonamide (SES), 9–anthracenesulfonamide, 4–(4’,8’– dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0060] Suitably protected carboxylic acids further include, but are not limited to, silyl–, alkyl–, alkenyl–, aryl–, and arylalkyl–protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t–butyldimethylsilyl, t–butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p–methoxybenzyl, 3,4–dimethoxybenzyl, trityl, t–butyl, tetrahydropyran–2–yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p–methoxybenzyl (MPM), 3,4–dimethoxybenzyl, O– nitrobenzyl, p–nitrobenzyl, p–halobenzyl, 2,6–dichlorobenzyl, p–cyanobenzyl), and 2– and 4–picolyl.

[0061] Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t–butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p–methoxybenzyloxymethyl (PMBM), (4–methoxyphenoxy)methyl (p–AOM), guaiacolmethyl (GUM), t–butoxymethyl, 4–pentenyloxymethyl (POM), siloxymethyl, 2– methoxyethoxymethyl (MEM), 2,2,2–trichloroethoxymethyl, bis(2–chloroethoxy)methyl, 2– (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3–bromotetrahydropyranyl, tetrahydrothiopyranyl, 1–methoxycyclohexyl, 4–methoxytetrahydropyranyl (MTHP), 4– Page 27 of 448 12513573v1Attorney Docket No.: 2010581-1441 methoxytetrahydrothiopyranyl, 4–methoxytetrahydrothiopyranyl S,S–dioxide, 1–[(2–chloro–4– methyl)phenyl]–4–methoxypiperidin–4–yl (CTMP), 1,4–dioxan–2–yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a–octahydro–7,8,8–trimethyl–4,7–methanobenzofuran–2–yl, 1– ethoxyethyl, 1–(2–chloroethoxy)ethyl, 1–methyl–1–methoxyethyl, 1–methyl–1–benzyloxyethyl, 1– methyl–1–benzyloxy–2–fluoroethyl, 2,2,2–trichloroethyl, 2–trimethylsilylethyl, 2–(phenylselenyl)ethyl, t– butyl, allyl, p–chlorophenyl, p–methoxyphenyl, 2,4–dinitrophenyl, benzyl, p–methoxybenzyl, 3,4– dimethoxybenzyl, o–nitrobenzyl, p–nitrobenzyl, p–halobenzyl, 2,6–dichlorobenzyl, p–cyanobenzyl, p– phenylbenzyl, 2–picolyl, 4–picolyl, 3–methyl–2–picolyl N–oxido, diphenylmethyl, p,p’– dinitrobenzhydryl, 5–dibenzosuberyl, triphenylmethyl, α–naphthyldiphenylmethyl, p– methoxyphenyldiphenylmethyl, di(p–methoxyphenyl)phenylmethyl, tri(p–methoxyphenyl)methyl, 4–(4’– bromophenacyloxyphenyl)diphenylmethyl, 4,4’,4’’–tris(4,5–dichlorophthalimidophenyl)methyl, 4,4’,4’’– tris(levulinoyloxyphenyl)methyl, 4,4’,4’’–tris(benzoyloxyphenyl)methyl, 3–(imidazol–1–yl)bis(4’,4’’– dimethoxyphenyl)methyl, 1,1–bis(4–methoxyphenyl)–1’–pyrenylmethyl, 9–anthryl, 9–(9– phenyl)xanthenyl, 9–(9–phenyl–10–oxo)anthryl, 1,3–benzodithiolan–2–yl, benzisothiazolyl S,S–dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t–butyldimethylsilyl (TBDMS), t–butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri–p–xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t– butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p– chlorophenoxyacetate, 3–phenylpropionate, 4–oxopentanoate (levulinate), 4,4–(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4–methoxycrotonate, benzoate, p– phenylbenzoate, 2,4,6–trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9–fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2–trichloroethyl carbonate (Troc), 2– (trimethylsilyl)ethyl carbonate (TMSEC), 2–(phenylsulfonyl) ethyl carbonate (Psec), 2– (triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p–nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p–methoxybenzyl carbonate, alkyl 3,4–dimethoxybenzyl carbonate, alkyl o–nitrobenzyl carbonate, alkyl p–nitrobenzyl carbonate, alkyl S– benzyl thiocarbonate, 4–ethoxy–1–napththyl carbonate, methyl dithiocarbonate, 2–iodobenzoate, 4– azidobutyrate, 4–nitro–4–methylpentanoate, o–(dibromomethyl)benzoate, 2–formylbenzenesulfonate, 2– (methylthiomethoxy)ethyl, 4–(methylthiomethoxy)butyrate, 2–(methylthiomethoxymethyl)benzoate, 2,6– dichloro–4–methylphenoxyacetate, 2,6–dichloro–4–(1,1,3,3–tetramethylbutyl)phenoxyacetate, 2,4– bis(1,1–dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)–2– methyl–2–butenoate, o–(methoxycarbonyl)benzoate, α–naphthoate, nitrate, alkyl N,N,N’,N’– tetramethylphosphorodiamidate, alkyl N–phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4– Page 28 of 448 12513573v1Attorney Docket No.: 2010581-1441 dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). For protecting 1,2– or 1,3–diols, the protecting groups include methylene acetal, ethylidene acetal, 1–t– butylethylidene ketal, 1–phenylethylidene ketal, (4–methoxyphenyl)ethylidene acetal, 2,2,2– trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p–methoxybenzylidene acetal, 2,4–dimethoxybenzylidene ketal, 3,4– dimethoxybenzylidene acetal, 2–nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1–methoxyethylidene ortho ester, 1–ethoxyethylidine ortho ester, 1,2–dimethoxyethylidene ortho ester, α–methoxybenzylidene ortho ester, 1–(N,N– dimethylamino)ethylidene derivative, α–(N,N’–dimethylamino)benzylidene derivative, 2– oxacyclopentylidene ortho ester, di–t–butylsilylene group (DTBS), 1,3–(1,1,3,3– tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra–t–butoxydisiloxane–1,3–diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[0062] In some embodiments, a hydroxyl protecting group is acetyl, t-butyl, tbutoxymethyl, methoxymethyl, tetrahydropyranyl, 1 -ethoxyethyl, 1 -(2-chloroethoxy)ethyl, 2- trimethylsilylethyl, p- chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6- dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4,4'-dimethoxytrityl, trimethylsilyl, triethylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifiuoroacetyl, pivaloyl, 9- fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl, (DMTr) and 4,4',4''-trimethoxytrityl (TMTr), 2- cyanoethyl (CE or Cne), 2-(trimethylsilyl)ethyl (TSE), 2-(2-nitrophenyl)ethyl, 2-(4-cyanophenyl)ethyl 2- (4-nitrophenyl)ethyl (NPE), 2-(4-nitrophenylsulfonyl)ethyl, 3,5-dichlorophenyl, 2,4-dimethylphenyl, 2- nitrophenyl, 4-nitrophenyl, 2,4,6-trimethylphenyl, 2-(2-nitrophenyl)ethyl, butylthiocarbonyl, 4,4',4''- tris(benzoyloxy)trityl, diphenylcarbamoyl, levulinyl, 2-(dibromomethyl)benzoyl (Dbmb), 2- (isopropylthiomethoxymethyl)benzoyl (Ptmt), 9-phenylxanthen-9-yl (pixyl) or 9-(p- methoxyphenyl)xanthine-9-y1 (MOX). In some embodiments, each of the hydroxyl protecting groups is, independently selected from acetyl, benzyl, t- butyldimethylsilyl, t-butyldiphenylsilyl and 4,4'- dimethoxytrityl. In some embodiments, the hydroxyl protecting group is selected from the group consisting of trityl, monomethoxytrityl and 4,4'-dimethoxytrityl group. In some embodiments, a phosphorous linkage protecting group is a group attached to the phosphorous linkage (e.g., an internucleotidic linkage) throughout oligonucleotide synthesis. In some embodiments, a protecting group is attached to a sulfur atom of an phosphorothioate group. In some embodiments, a protecting group is attached to an oxygen atom of an internucleotide phosphorothioate linkage. In some embodiments, a protecting group is attached to an oxygen atom of the internucleotide phosphate linkage. In some embodiments a protecting group is 2- cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, Page 29 of 448 12513573v1Attorney Docket No.: 2010581-1441 2-(p-nitrophenyl)ethyl (NPE or Npe), 2-phenylethyl, 3-(N-tert-butylcarboxamido)-1-propyl, 4-oxopentyl, 4-methylthio-l-butyl, 2-cyano-1,1-dimethylethyl, 4-N-methylaminobutyl, 3-(2-pyridyl)-1-propyl, 2-[N- methyl-N-(2-pyridyl)]aminoethyl, 2-(N-formyl,N-methyl)aminoethyl, or 4-[N-methyl-N-(2,2,2- trifluoroacetyl)amino]butyl.

[0063] Subject: As used herein, the term “subject” or “test subject” refers to any organism to which a compound (e.g., an oligonucleotide) or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.) and plants. In some embodiments, a subject is a human. In some embodiments, a subject may be suffering from and / or susceptible to a disease, disorder and / or condition.

[0064] Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. A base sequence which is substantially identical or complementary to a second sequence is not fully identical or complementary to the second sequence, but is mostly or nearly identical or complementary to the second sequence. In some embodiments, an oligonucleotide with a substantially complementary sequence to another oligonucleotide or nucleic acid forms duplex with the oligonucleotide or nucleic acid in a similar fashion as an oligonucleotide with a fully complementary sequence. In addition, one of ordinary skill in the biological and / or chemical arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and / or chemical phenomena.

[0065] Sugar: The term “sugar” refers to a monosaccharide or polysaccharide in closed and / or open form. In some embodiments, sugars are monosaccharides. In some embodiments, sugars are polysaccharides. Sugars include, but are not limited to, ribose, deoxyribose, pentofuranose, pentopyranose, and hexopyranose moieties. As used herein, the term “sugar” also encompasses structural analogs used in lieu of conventional sugar molecules, such as glycol, polymer of which forms the backbone of the nucleic acid analog, glycol nucleic acid (“GNA”), etc. As used herein, the term “sugar” also encompasses structural analogs used in lieu of natural or naturally-occurring nucleotides, such as modified sugars and nucleotide sugars. In some embodiments, a sugar is a RNA or DNA sugar (ribose or deoxyribose). In some embodiments, a sugar is a modified ribose or deoxyribose sugar, e.g., 2’-modified, 5’-modified, etc. As described herein, in some embodiments, when used in oligonucleotides and / or nucleic acids, modified sugars may provide one or more desired properties, activities, etc. In some embodiments, a sugar is optionally substituted ribose or deoxyribose. In some embodiments, a “sugar” refers to a sugar unit in an oligonucleotide or a nucleic acid. Page 30 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0066] Susceptible to: An individual who is “susceptible to” a disease, disorder and / or condition is one who has a higher risk of developing the disease, disorder and / or condition than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition is predisposed to have that disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not have been diagnosed with the disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may exhibit symptoms of the disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not exhibit symptoms of the disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0067] Therapeutic agent: As used herein, the term “therapeutic agent” in general refers to any agent that elicits a desired effect (e.g., a desired biological, clinical, or pharmacological effect) when administered to a subject. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, an appropriate population is a population of subjects suffering from and / or susceptible to a disease, disorder or condition. In some embodiments, an appropriate population is a population of model organisms. In some embodiments, an appropriate population may be defined by one or more criterion such as age group, gender, genetic background, preexisting clinical conditions, prior exposure to therapy. In some embodiments, a therapeutic agent is a substance that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms or features of a disease, disorder, and / or condition in a subject when administered to the subject in an effective amount. In some embodiments, a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans. In some embodiments, a therapeutic agent is a provided compound, e.g., a provided oligonucleotide.

[0068] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired Page 31 of 448 12513573v1Attorney Docket No.: 2010581-1441 biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0069] Treat: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0070] Unsaturated: The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0071] As those skilled in the art will appreciate, methods and compositions described herein relating to provided compounds (e.g., oligonucleotides) generally also apply to pharmaceutically acceptable salts of such compounds. Description of Certain Embodiments

[0072] Certain embodiments are described below as examples.

[0073] Oligonucleotides are useful tools for a wide variety of applications. For example, RNAi oligonucleotides are useful in therapeutic, diagnostic, and research applications, including the treatment of a variety of conditions, disorders, and diseases. The use of naturally occurring nucleic acids (e.g., unmodified DNA or RNA) is limited, for example, by their susceptibility to endo- and exo-nucleases. As such, various synthetic counterparts have been developed to circumvent these shortcomings and / or to further improve various properties and activities. These include synthetic oligonucleotides that contain chemical modifications, e.g., base modifications, sugar modifications, backbone modifications, etc., which, among other things, render these molecules less susceptible to degradation and improve other properties and / or activities. From a structural point of view, modifications to internucleotidic linkages can introduce chirality and / or alter charge, and certain properties may be affected by configurations of linkage phosphorus atoms of oligonucleotides. For example, binding affinity, sequence specific binding to complementary RNA, stability against nucleases, cleavage of target nucleic acids, delivery, pharmacokinetics, etc., can be affected by, inter alia, chirality and / or charge of backbone linkage atoms. Page 32 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0074] Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as chemical modifications (e.g., modifications of sugar, base, and / or internucleotidic linkages) or patterns thereof, conjugation to lipids or other moieties, and / or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages), and / or patterns thereof], can have significant impact on properties and activities (e.g., stability, specificity, selectivity, activities to reduce levels of products (transcripts and / or protein) of target genes, etc.). In some embodiments, oligonucleotide properties can be adjusted by optimizing chemical modifications (modifications of base, sugar, and / or internucleotidic linkage moieties), patterns of chemical modifications, stereochemistry and / or patterns of stereochemistry.

[0075] In some embodiments, the present disclosure recognizes that oligonucleotide compositions comprising oligonucleotides with controlled structural elements, e.g., controlled chemical modifications and / or controlled backbone stereochemistry patterns, provide unexpected properties and activities, including but not limited to those described herein. In some embodiments, provided compositions comprising oligonucleotides having chemical modifications (e.g., base modifications, sugar modification, internucleotidic linkage modifications, etc.) or patterns thereof have improved properties and activities. Non-limiting examples of such improved properties include: directing a decrease in the expression and / or level of a target gene or its gene product; and / or directing RNA interference; and / or directing RNase H- mediated knockdown.

[0076] In some embodiments, the present disclosure provides technologies (e.g., oligonucleotides, compositions, methods, etc.) for RNAi. In some embodiments, an oligonucleotide is a RNAi agent (e.g., a RNAi oligonucleotide). In some embodiments, the present disclosure provides technologies (e.g., oligonucleotides, compositions, methods, etc.) for single-stranded RNAi. In some embodiments, an oligonucleotide is a ssRNAi agent (e.g., a ssRNAi oligonucleotide).

[0077] In some embodiments, the present disclosure provides technologies for modifying and / or improving a RNAi agent, e.g., by replacing a 5’-end structure with a 5’-end structure as described herein. In some embodiments, a ssRNAi agent is a ssRNAi agent described in WO 2018 / 223056. In some embodiments, the present disclosure provides technologies (e.g., oligonucleotides, compositions, methods, etc.) for double-stranded RNAi. In some embodiments, an oligonucleotide is a dsRNAi agent (e.g., a dsRNAi oligonucleotide). In some embodiments, a dsRNAi agent is a dsRNAi agent described in WO 2021 / 234459, WO 2023 / 049218, WO 2023 / 091644, WO 2024 / 148329, WO 2024 / 086633, WO 2024 / 092105, WO 2023 / 138689, WO 2024 / 188164, WO 2024 / 120412, WO 2024 / 240058, WO 2024 / 226789, WO 2023 / 003922, WO 2024 / 077148, WO 2024 / 059165, WO 2024 / 138105, WO 2024 / 249240, WO 2024 / 138111, WO 2024 / 138105, WO 2024 / 137729, WO 2024 / 123646, or WO 2023 / 250368. In some embodiments, a RNAi agent is a RNAi agent (e.g., a RNAi oligonucleotide) Page 33 of 448 12513573v1Attorney Docket No.: 2010581-1441 described in WO 2022 / 011214, WO 2023 / 220744, WO 2024 / 173520, WO 2023 / 245060, WO 2024 / 182580, WO 2024 / 192379, WO 2024 / 197017, WO 2024 / 196753, WO 2024 / 044542, WO 2024 / 086633, or WO 2024 / 102961. In some embodiments, a RNAi agent or a strand thereof has the same structure as such a reported oligonucleotide agent thereof except that R5E−Cy5E− as described herein replaces the corresponding structure in the reported oligonucleotide agent thereof. In some embodiments, a RNAi agent or a strand thereof has the same structure as such a reported oligonucleotide agent thereof except that R5E−Cy5E−SU(−BA)− replaces the corresponding structure (e.g., the 5’-end nucleoside) in the reported oligonucleotide agent thereof. In some embodiments, a strand is or comprises a guide strand.

[0078] In some embodiments, RNA interference is reportedly a post-transcriptional, targeted gene- silencing technique that uses an RNAi agent to target a RNA, e.g., a gene transcript such as a messenger RNA (mRNA), comprising a sequence complementary to the RNAi agent, for cleavage mediated by the RISC (RNA-induced silencing complex) pathway. In nature, a type of RNAi reportedly occurs when a Type III endonuclease known as Dicer (Sharp et al., 2001. Genes Dev. 15:485) cleaves a long dsRNA (double-stranded RNA) (e.g., a foreign dsRNA introduced into a mammalian cell) into shorter fragments called siRNAs. For example, siRNAs (small interfering RNAs or short inhibitory RNAs) can comprise about 21 to 23 nucleotides long and comprise about 19 base pair duplexes and may comprise two base 3' overhangs (Bernstein, et al., 2001. Nature 409:363). The siRNAs are reportedly then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., 2001. Cell 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleaves the target to induce silencing (Elbashir, et al., 2001. Genes Dev.15:188). Cleavage of the target RNA reportedly takes place in the middle of the region complementary to the antisense strand of the siRNA duplex. The use of the RNAi agent to a target transcript reportedly results in a decrease of gene activity, level and / or expression, e.g., a "knock-down" or "knock-out" of the target gene or target sequence. Artificial siRNAs are useful both as therapeutics and for experimental use.

[0079] In some embodiments, RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can direct a decrease in the expression, level and / or activity of a target gene, e.g., a target gene, or a product thereof. In some embodiments, provided RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can direct a decrease in the expression and / or level of a target gene or its gene product. In some embodiments, provided RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can direct a decrease in levels of target products. In some embodiments, provided RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can reduce levels of transcripts of target genes. In some embodiments, provided RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can reduce levels of mRNA of target genes. In Page 34 of 448 12513573v1Attorney Docket No.: 2010581-1441 some embodiments, provided RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can reduce levels of proteins encoded by target genes. In some embodiments, provided RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can direct a decrease in the expression and / or level of a target gene or its gene product via RNA interference. In some embodiments, provided RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can direct a decrease in the expression and / or level of a target gene or its gene product via a biochemical mechanism which does not involve RNA interference or RISC (including, but not limited to, RNaseH-mediated knockdown or steric hindrance of gene expression). In some embodiments, provided RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can direct a decrease in the expression and / or level of a target gene or its gene product via RNA interference and / or RNase H-mediated knockdown. In some embodiments, provided RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can direct a decrease in the expression and / or level of a target gene or its gene product by sterically blocking translation after binding to a target gene mRNA, and / or by altering or interfering with mRNA splicing and / or exon inclusion or exclusion. In some embodiments, provided RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) comprise one or more structural elements described herein or known in the art in accordance with the present disclosure, e.g., base sequences; modifications; stereochemistry; patterns of internucleotidic linkages; GC contents; long GC stretches; patterns of backbone linkages; patterns of backbone chiral centers; patterns of backbone phosphorus modifications; additional chemical moieties, including but not limited to, one or more targeting moieties, lipid moieties, and / or carbohydrate moieties, etc.; seed regions; post-seed regions; 5’-end structures; 5’-end regions; 5' nucleotide moieties; 3’-end regions; 3’-terminal dinucleotides; 3’-end caps; etc. In some embodiments, a seed region of an oligonucleotide is or comprises the second to eighth, second to seventh, second to sixth, third to eighth, third to seventh, third to seven, or fourth to eighth or fourth to seventh nucleotides, counting from the 5’ end; and the post-seed region of the oligonucleotide is the region immediately 3’ to the seed region, and interposed between the seed region and the 3’ end region. In some embodiments, a provided composition comprises a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide). In some embodiments, a provided composition comprises one or more lipid moieties, one or more carbohydrate moieties (unless otherwise specified, other than sugar moieties of nucleoside units that form oligonucleotide chain with internucleotidic linkages), and / or one or more targeting components. In some embodiments, RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can direct a decrease in the expression, level and / or activity of a target gene or a product thereof by sterically blocking translation after binding to a target gene mRNA, and / or by altering or interfering with mRNA splicing. Regardless, however, the present disclosure is not limited to any particular mechanism. In some embodiments, the present disclosure provides RNAi oligonucleotides (e.g., Page 35 of 448 12513573v1Attorney Docket No.: 2010581-1441 ssRNAi oligonucleotides, dsRNAi oligonucleotides), compositions, methods, etc., capable of operating via double-stranded RNA interference, single-stranded RNA interference, RNase H-mediated knock-down, steric hindrance of translation, or a combination of two or more such mechanisms.

[0080] In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) comprises a structural element or a portion thereof described herein, e.g., in Table 1. In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) comprises a base sequence (or a portion thereof) described herein, wherein each T can be independently substituted with U and vice versa, a chemical modification or a pattern of chemical modifications (or a portion thereof), and / or a format or a portion thereof described herein. In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) has a base sequence which comprises the base sequence (or a portion thereof) wherein each T can be independently substituted with U, pattern of chemical modifications (or a portion thereof), and / or a format of an oligonucleotide disclosed herein, e.g., in Table 1, or otherwise disclosed herein. In some embodiments, such oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides), reduce expression, level and / or activity of a gene, e.g., a gene, or a gene product thereof.

[0081] Among other things, RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) may hybridize to their target nucleic acids (e.g., pre- mRNA, mature mRNA, etc.). For example, in some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) can hybridize to a nucleic acid derived from a DNA strand (either strand of the gene). In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) can hybridize to a transcript. In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) can hybridize to a target nucleic acid in any stage of RNA processing, including but not limited to a pre-mRNA or a mature mRNA. In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) can hybridize to any element of a target nucleic acid or its complement, including but not limited to: a promoter region, an enhancer region, a transcriptional stop region, a translational start signal, a translation stop signal, a coding region, a non-coding region, an exon, an intron, an intron / exon or exon / intron junction, the 5' UTR, or the 3' UTR. In some embodiments, RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can hybridize to their targets with no more than 2 mismatches. In some embodiments, RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can hybridize to their targets with no more than one mismatch. In some embodiments, RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) can hybridize to their targets with no mismatches (e.g., when all C-G and / or A-T / U base paring).

[0082] In some embodiments, an oligonucleotide can hybridize to two or more variants of transcripts. In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) Page 36 of 448 12513573v1Attorney Docket No.: 2010581-1441 can hybridize to two or more or all variants of a transcript. In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) can hybridize to two or more or all variants of a transcript derived from the sense strand.

[0083] In some embodiments, a suitable RNAi agent can be selected by any processes known in the art or conceivable by one of ordinary skill in the art in accordance with the present disclosure. For example, the selection criteria can include one or more of the following steps: initial analysis of the target gene sequence and design of RNAi agents; this design can take into consideration sequence similarity across species (human, cynomolgus, mouse, etc.) and dissimilarity to other (non-target) genes; screening of RNAi agents in vitro (e.g., at 10 nM in cells expressing the target transcript); determination of EC50 or IC50 in cells; determination of viability of cells treated with RNAi agents, wherein it is desired, in some embodiments, that the RNAi agent to the target not inhibit the viability of these cells; testing with human PBMC (peripheral blood mononuclear cells), e.g., to test levels of TNF-alpha to estimate immunogenicity, wherein immunostimulatory sequences are usually less desired; testing in human whole blood assay, wherein fresh human blood is treated with an RNAi agent and cytokine / chemokine levels are determined [e.g., TNF-alpha (tumor necrosis factor-alpha) and / or MCP1 (monocyte chemotactic protein 1)], wherein immunostimulatory sequences are usually less desired; determination of gene knockdown in vivo using cells or tumors in test animals; and optimization of specific modifications of the RNAi agents.

[0084] As appreciated by those skilled in the art, oligonucleotides can be of various lengths to provide desired properties and / or activities for various uses. Many technologies for assessing, selecting and / or optimizing ds oligonucleotide length are available in the art and can be utilized in accordance with the present disclosure. In some embodiments, RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) are of suitable lengths to hybridize with their targets and reduce levels of their targets and / or an encoded product thereof. In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) is long enough to recognize a target nucleic acid (e.g., a target mRNA). In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) is sufficiently long to distinguish between a target nucleic acid and other nucleic acids (e.g., a nucleic acid having a base sequence which is not a target sequence) to reduce off-target effects. In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) is sufficiently short to reduce complexity of manufacture or production and to reduce cost of products.

[0085] In some embodiments, the base sequence of a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) is about 10-500 nucleobases in length. In some embodiments, a base sequence is about 10-500 nucleobases in length. In some embodiments, a base sequence is about 10- 50 nucleobases in length. In some embodiments, a base sequence is about 15-50 nucleobases in length. In some embodiments, a base sequence is from about 15 to about 30 nucleobases in length. In some Page 37 of 448 12513573v1Attorney Docket No.: 2010581-1441 embodiments, a base sequence is from about 10 to about 25 nucleobases in length. In some embodiments, a base sequence is from about 15 to about 22 nucleobases in length. In some embodiments, a base sequence is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases in length. In some embodiments, a base sequence is about 18 nucleobases in length. In some embodiments, a base sequence is about 19 nucleobases in length. In some embodiments, a base sequence is about 20 nucleobases in length. In some embodiments, a base sequence is about 21 nucleobases in length. In some embodiments, a base sequence is about 22 nucleobases in length. In some embodiments, a base sequence is about 23 nucleobases in length. In some embodiments, a base sequence is about 24 nucleobases in length. In some embodiments, a base sequence is about 25 nucleobases in length. In some embodiments, each nucleobase is optionally substituted A, T, C, G, U, or an optionally substituted tautomer of A, T, C, G, or U.

[0086] In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) comprises a base sequence described herein or a portion (e.g., a span of 5-50, 5-40, 5-30, 5-20, or 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 20 or at least 10, at least 15, contiguous nucleobases) thereof with 0-5 (e.g., 0, 1, 2, 3, 4 or 5) mismatches, wherein each T can be independently substituted with U and vice versa. In some embodiments, a RNAi oligonucleotide (e.g., ssRNAi oligonucleotide, dsRNAi oligonucleotide) comprises a base sequence described herein, or a portion thereof, wherein a portion is a span of at least 10 contiguous nucleobases, or a span of at least 15 contiguous nucleobases with 1-5 mismatches. In some embodiments, RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) comprise a base sequence described herein, or a portion thereof, wherein a portion is a span of at least 10 contiguous nucleobases, or a span of at least 10 contiguous nucleobases with 1-5 mismatches, wherein each T can be independently substituted with U and vice versa. In some embodiments, base sequences of RNAi oligonucleotides (e.g., ssRNAi oligonucleotides, dsRNAi oligonucleotides) comprise or consist of 10-50 (e.g., about or at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45; in some embodiments, at least 15; in some embodiments, at least 16; in some embodiments, at least 17; in some embodiments, at least 18; in some embodiments, at least 19; in some embodiments, at least 20; in some embodiments, at least 21; in some embodiments, at least 22; in some embodiments, at least 23; in some embodiments, at least 24; in some embodiments, at least 25) contiguous bases of a base sequence that is identical to or complementary to a base sequence of a gene or a transcript (e.g., mRNA) thereof.

[0087] Base sequences of ssRNAi oligonucleotides and / or the guide strand of dsRNAi oligonucleotides, as appreciated by those skilled in the art, typically have sufficient length and complementarity to their targets, e.g., RNA transcripts (e.g., pre-mRNA, mature mRNA, etc.) to mediate target-specific knockdown. In some embodiments, the base sequence of a ssRNAi oligonucleotide or a dsRNAi oligonucleotide guide strand has a sufficient length and identity to a transcript target to mediate Page 38 of 448 12513573v1Attorney Docket No.: 2010581-1441 target-specific knockdown. In some embodiments, a ssRNAi oligonucleotide or a dsRNAi oligonucleotide guide strand is complementary to a portion of a transcript (a transcript target sequence). In some embodiments, the base sequence of a ssRNAi oligonucleotide or a dsRNAi oligonucleotide has 90% or more identity with the base sequence of an oligonucleotide disclosed in Table 1, wherein each T can be independently substituted with U and vice versa. In some embodiments, the base sequence a ssRNAi oligonucleotide or a dsRNAi oligonucleotide has 95% or more identity with the base sequence of an oligonucleotide disclosed in Table 1, wherein each T can be independently substituted with U and vice versa. In some embodiments, the base sequence of a ssRNAi oligonucleotide or a dsRNAi oligonucleotide comprises a continuous span of 15 or more bases of an oligonucleotide disclosed in Table 1, wherein each T can be independently substituted with U and vice versa, except that one or more bases within the span are abasic (e.g., a nucleobase is absent from a nucleotide). In some embodiments, the base sequence of a ssRNAi oligonucleotide or a dsRNAi oligonucleotide comprises a continuous span of 19 or more bases of an oligonucleotide disclosed herein, except that one or more bases within the span are abasic (e.g., a nucleobase is absent from a nucleotide). In some embodiments, the base sequence of a ssRNAi oligonucleotide or a dsRNAi oligonucleotide comprises a continuous span of 19 or more bases of an oligonucleotide disclosed herein, wherein each T can be independently substituted with U and vice versa, except for a difference in the 1 or 2 bases at the 5’ end and / or 3’ end of the base sequences.

[0088] In certain embodiments, oligonucleotides of provided technologies comprise useful chemical modifications and / or patterns thereof (e.g., presence and / or absence of certain modifications), nucleobase modifications and / or patterns thereof (e.g., presence and / or absence of certain modifications), internucleotidic linkages modifications and / or stereochemistry and / or patterns thereof [e.g., types, modifications, and / or configuration (Rp or Sp) of chiral linkage phosphorus, etc.], etc., which, when combined with one or more other structural elements described herein (e.g., R5E−Cy5E−, −CyIL−P(WIL)(RIL)−LIL−) can provide high activities and / or various desired properties, e.g., as agents to reduce expression, activity, and / or level of a gene or gene product thereof. In some embodiments, oligonucleotides comprise useful 5’-modifications as described herein that can provide reduced expression, activity, and / or level of a gene or a gene product thereof. In some embodiments, provided oligonucleotides provide high stability, high activity, high manufacture efficiency, lower manufacture cost, e.g., when compared to oligonucleotides having an alternative 5’-group (e.g., phosphate, vinyl phosphonate, etc.).

[0089] Among other things, the present disclosure provides oligonucleotides comprising chemical modifications that may provide improved properties and / or activities as compared to reference oligonucleotides and compositions (e.g., those described herein or reported in the art). For example, in some embodiments, oligonucleotides comprising one or more chemical modifications as described herein may provide improved stability, pharmacokinetic properties, pharmacodynamic properties and / or improved Page 39 of 448 12513573v1Attorney Docket No.: 2010581-1441 activities (e.g., improved reduction of expression, activity, and / or level of a gene or gene product thereof). Various oligonucleotides and compositions are described herein. For example, in some embodiments, the present disclosure provides oligonucleotides and compositions thereof, including chirally controlled oligonucleotide compositions thereof, wherein the oligonucleotides comprise R5E−Cy5E− or −CyIL−P(WIL)(RIL)−LIL−. In some embodiments, oligonucleotides comprise several (e.g., 1, 2, 3, 4, or 5 or more; in some embodiments, 3 or more) nucleosides independently comprising sugar modifications (e.g., 2’-OR modifications wherein R is optionally substituted C1-6alkyl (e.g., 2’-OMe, 2’-MOE, etc.,), 2’-F modifications, etc.)) at their 5’- and 3’-ends. In some embodiments, the first several (e.g., 1, 2, 3, 4, or 5 or more; in some embodiments, 3 or more) nucleosides and / or the last several (e.g., 1, 2, 3, 4, or 5 or more; in some embodiments, 3 or more) nucleosides independently comprise sugar modifications. In some embodiments, the first 3 or more and the last 3 or more nucleosides independently comprise sugar modifications. In some embodiments, all nucleosides in the oligonucleotide independently comprise sugar modifications. In some embodiments, one or more internucleotidic linkages bonded to such nucleosides are non-negatively charged internucleotidic linkage such as phosphoryl guanidine internucleotidic linkages like n001.

[0090] Among other things, the present disclosure encompass the recognition that traditional technologies for incorporating certain R5Egroups, e.g., −P(O)(OH)2, into compounds, e.g., utilization of protected groups such as −P(O)(OMe)2, −P(O)(OEt)2, etc., often utilize deprotection conditions that can reduce efficiency and / or increase cost of manufacturing. For example, when −P(O)(OMe)2, −P(O)(OEt)2, etc., are utilized to incorporate −P(O)(OH)2 into oligonucleotides, removal of the methyl or ethyl groups may require extra steps and / or harsher reaction conditions which can lead to lower manufacturing efficiency, lower oligonucleotide yields and / or purity, and / or increased cost compared to manufacturing of reference oligonucleotides without −P(O)(OH)2 (e.g., otherwise identical oligonucleotides without −P(O)(OH)2).

[0091] In some embodiments, the present disclosure provides technologies for incorporating various R5Egroups, e.g., −P(O)(OH)2, into compounds, e.g., oligonucleotides which technologies can provide higher yield, higher purity, higher efficiency, lower operation complexity, milder reaction condition, shorter preparation time, and / or lower cost, etc. when compared to using, e.g., −P(O)(OMe)2, or −P(O)(OEt)2. In some embodiments, the present disclosure provides protected groups which can be deprotected under oligonucleotide synthesis conditions, e.g., during cleavage and / or deprotection, utilized for oligonucleotides without −P(O)(OH)2groups or whose 5’-ends have −OH groups as typically present in oligonucleotides. In some embodiments, provided technologies are useful for preparing stereorandom oligonucleotide compositions. In some embodiments, provided technologies are useful for stereoselective oligonucleotide synthesis. In some embodiments, a stereoselective oligonucleotide synthesis stereoselectively and independently prepares one stereochemical configuration of each of one or more or Page 40 of 448 12513573v1Attorney Docket No.: 2010581-1441 all chiral linkage phosphorus in an oligonucleotide over the other. In some embodiments, provided technologies are useful for preparing chirally controlled oligonucleotide compositions. In some embodiments, a chiral auxiliary is utilized during stereoselective oligonucleotide synthesis. Certain useful stereoselective oligonucleotide synthesis technologies including chiral auxiliaries, cycles, conditions, etc. are described in US 10167309, US 11643657, US 11718638, US 11608355 and US 20230089442, the entirety of each of which is independently incorporated herein by reference.

[0092] For example, in some embodiments, provided technologies utilizes −P(O)(ORPG)2as described herein for prepare compounds including oligonucleotides. In some embodiments, −P(O)(ORPG)2 are converted into −P(O)(OH)2 during manufacturing or after administration to a subject.

[0093] In some embodiments, the present disclosure provides technologies comprising −P(O)(ORPG)2 wherein each RPGis a group that is labile to oligonucleotide synthesis conditions, e.g., during cleavage, deprotection and / or chiral auxiliary removal, utilized for reference oligonucleotides without −P(O)(OH)2 groups. In some embodiments, each RPGis a group that can be removed under oligonucleotide synthesis conditions for reference oligonucleotides without −P(O)(OH)2 groups. In some embodiments, −P(O)(ORPG)2 is a protected −P(O)(OH)2 group that is converted to −P(O)(OH)2 which may exist in a salt form, e.g., under oligonucleotide synthesis conditions. In some embodiments, as exemplified herein the P atom is bonded to a carbon atom.

[0094] In some embodiments, RPGcomprises 1) an alpha carbon atom bonded to the oxygen to which it is attached, wherein the alpha carbon atom is bonded to a hydrogen, and 2) a beta carbon atom, wherein the beta carbon atom is bonded to a group RPG11that can facilitate removal of RPG(e.g., compared to ethyl), such as an electron-withdrawing group. In some embodiments, RPG11is an electron-withdrawing group (e.g., as described in US 20230089442). In some embodiments, RPG11is Rsas described herein. In some embodiments, RPG11is −CN. In some embodiments, RPG11is −Ls−Rs11wherein each Lsand Rs11is independently as described herein. In some embodiments, RPGis −CH2−Rs, wherein the −CH2− is independently optionally substituted and Rsis as described herein. In some embodiments, the −CH2− is optionally mono-substituted. In some embodiments, RPGis RP1as described herein. In some embodiments, RPGis RP2as described herein. In some embodiments, RPGis −O−CH2CH2CN.

[0095] In some embodiments, RPGis −CH2−O(CO)RPG12, wherein RPG12is trisubstituted methyl and the −CH2− is optionally substituted. In some embodiments, RPGis −CH2−O(CO)RPG12, wherein RPG12is −C(Rs11)3wherein each Rs11is independently as described herein. In some embodiments, RPGis RPG12, wherein RPG12is trisubstituted methyl. In some embodiments, RPG12is −C(Rs11)3wherein each Rs11is independently as described herein. In some embodiments, the carbon of the trisubstituted methyl or −C(Rs11)3is bonded to three carbon atoms. In some embodiments, RPG12is optionally substituted t-butyl. In some embodiments, RPG12is t-butyl. In some embodiments, RPGis RP1or RP2as described herein. In Page 41 of 448 12513573v1Attorney Docket No.: 2010581-1441 some embodiments, −ORPGis −O−CH2−O−C(O)−RP, wherein RPis optionally substituted tert-butyl. In some embodiments, −ORPGis −O−CH2−O−C(O)−tBu.

[0096] In some embodiments, −P(O)(ORPG)2has the structure of −P(O)(RP1)(RP2) as described herein (e.g., in formula I), wherein each of R1and RP2is independently as described herein.

[0097] In some embodiments, RPGis labile under a basic condition. In some embodiments, RPGis labile under an acidic condition. In some embodiments, −P(O)(ORPG)2is converted into −P(O)(OH)2under an acidic condition. In some embodiments, −P(O)(ORPG)2is converted into −P(O)(OH)2under a basic condition. In some embodiments, a condition is utilized in oligonucleotide synthesis for a reference oligonucleotide which does not have a −P(O)(OH)2 group but is otherwise identical. In some embodiments, a condition is a cleavage and / or deprotection condition in oligonucleotide synthesis. In some embodiments, a condition is a chiral auxiliary removal, cleavage and / or deprotection condition in oligonucleotide synthesis.

[0098] As those skilled in the art appreciate, acidic and / or basic groups, e.g., −P(O)(OH)2, may exist in various forms including various salt forms. In some embodiments, an acidic and / or basic group, e.g., −P(O)(OH)2, is in a salt form. In some embodiments, an acidic and / or basic group, e.g., −P(O)(OH)2, is in a pharmaceutically acceptable salt form.

[0099] In some embodiments, as described below, the present disclosure provides technologies, e.g., compounds (e.g., nucleosides, phosphoramidites, oligonucleotides, reaction reagents, etc.), methods, etc., that are useful for, among other things, oligonucleotide synthesis. Oligonucleotides

[0100] Among other things, the present disclosure provides oligonucleotides of various designs, which may comprise various nucleobases and patterns thereof, sugars and patterns thereof, internucleotidic linkages and patterns thereof, and / or chemical moieties and patterns thereof as described in the present disclosure. In some embodiments, provided oligonucleotides can direct a decrease in the expression and / or level of a target gene or its gene product. In some embodiments, provided oligonucleotides can direct a decrease in levels of target products. In some embodiments, provided oligonucleotide can reduce levels of transcripts of target genes. In some embodiments, provided oligonucleotide can reduce levels of mRNA of target genes. In some embodiments, provided oligonucleotide can reduce levels of proteins encoded by target genes. In some embodiments, provided oligonucleotides can direct a decrease in the expression and / or level of a target gene or its gene product via RNA interference. In some embodiments, provided oligonucleotides can direct a decrease in the expression and / or level of a target gene or its gene product via a biochemical mechanism which does not involve RNA interference or RISC (e.g., RNase H-mediated knockdown or steric hindrance of gene expression, etc.). In some embodiments, provided oligonucleotides Page 42 of 448 12513573v1Attorney Docket No.: 2010581-1441 can direct a decrease in the expression and / or level of a target gene or its gene product via RNA interference. In some embodiments, provided oligonucleotides can direct a decrease in the expression and / or level of a target gene or its gene product via RNase H-mediated knockdown. In some embodiments, provided oligonucleotides can direct a decrease in the expression and / or level of a target gene or its gene product by sterically blocking translation after binding to a target gene mRNA, and / or by altering or interfering with mRNA splicing and / or exon inclusion or exclusion.

[0101] In some embodiments, a provided composition comprises an oligonucleotide. In some embodiments, a provided composition comprises one or more lipid moieties, one or more carbohydrate moieties (unless otherwise specified, other than sugar moieties of nucleoside units that form oligonucleotide chain with internucleotidic linkages), and / or one or more targeting components.

[0102] In some embodiments, provided technologies are useful for preparing or delivering oligonucleotides comprising one or more various chemical moieties (e.g., 5’-end modifications) which may exist in various salt forms. In some embodiments, the present disclosure provides oligonucleotides comprising one or more 5’-end modifications (e.g., R5E, R5E−Cy5E−, etc.) as described herein. In some embodiments, oligonucleotides comprising one or more 5’-end modifications as described herein are administered to a subject for preventing or treating conditions, disorders or diseases.

[0103] For example, in some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide) comprising a moiety of formula O-E: R5E−Cy5E−, O-E wherein each variable is independently as described herein. In some embodiments, a moiety of formula O-E is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0104] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, etc.) of formula O-E-a or a salt thereof: R5E−Cy5E−ROL, O-E-a wherein: ROLis −LOL−ROL1; LOLis L; ROL1is R’ or a nucleic acid moiety; and each of R5E, −Cy5E−, L and R’ is independently as described herein.

[0105] In some embodiments, the present disclosure provides a compound (e.g., a compound of formula O-E, an oligonucleotide, etc.), wherein the compound comprises a moiety of formula O: R5E−Cy5E−SU(−BA)−, Page 43 of 448 12513573v1Attorney Docket No.: 2010581-1441 O wherein: each of R5Eand −Cy5E− is independently as described herein; SU is a sugar ; LSUis L; s is 0-5;Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; BA is hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; and each of L, R’ and R is independently as described herein.

[0106] In some embodiments, a moiety of formula O is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0107] In some embodiments, the present disclosure provides a compound of formula O’ or a salt thereof: R5E−Cy5E−SU(−BA)−ROL, O’ wherein each of R5E, −Cy5E−, SU, BA, and ROLis independently as described herein.

[0108] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide), wherein the compound comprises a moiety of formula IL: −CyIL−P(WIL)(RIL)−LIL−, IL wherein each of −CyIL−, WIL, RILand LILis independently as described herein. In some embodiments, a moiety of formula IL is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0109] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, Page 44 of 448 12513573v1Attorney Docket No.: 2010581-1441 a compound of formula O-E, a compound of formula IL, etc.), wherein the compound comprises a moiety of formula O-II: R5E−L5E−SU(−BA)−CyIL−P(WIL)(RIL)−LIL−, O-II wherein: L5Eis −Cy5E− or −O−; and each of R5E, −Cy5E−, SU, BA, −CyIL−, WIL, RILand LILis independently as described herein. In some embodiments, a moiety of formula O-II is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0110] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound is a compound of formula O-II-a or a salt thereof: R5E−L5E−SU(−BA)−CyIL−P(WIL)(RIL)−LIL−ROL, 5E 5wherein each of R , LE, as described herein.

[0111] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound comprises a moiety of formula O-III: R5E−L5E−SU(−BA)−LIL−P(WIL)(RIL)−CyIL−, O-III wherein each of R5E, L5E, SU, BA, LIL, WIL, RILand −CyIL− is independently as described herein. In some embodiments, a moiety of formula O-III is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0112] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound is a compound of formula O-III-a or a salt thereof: R5E−L5E−SU(−BA)−LIL−P(WIL)(RIL)−CyIL−ROL, O-III-a wherein each of R5E, L5E, SU, BA, LIL, WIL, RIL, −CyIL− and ROLis independently as described herein.

[0113] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound comprises a moiety of formula O-II-b: R5E−L5E−SU(−BA)−CyIL−P(WIL)(RIL)−LIL−SU2(−BA2)−, O-II-b Page 45 of 448 12513573v1Attorney Docket No.: 2010581-1441 wherein: each of SU and SU2is independently a sugar moiety or ; LSUis L; s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; each of BA and BA2is independently hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; and each of R5E, L5E, LIL, WIL, RIL, −CyIL−, L, R’ and R is independently as described herein.

[0114] In some embodiments, a moiety of formula O-II-b is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0115] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound is a compound of formula O-II-c or a salt thereof: R5E−L5E−SU(−BA)−CyIL−P(WIL)(RIL)−LIL−SU2(−BA2)−ROL, O-II-c wherein each of R5E, L5E, SU, BA, LIL, WIL, RIL, −CyIL−, SU2, BA2and ROLis independently as described herein.

[0116] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound comprises a moiety of formula O-III-b: R5E−L5E−SU(−BA)−LIL−P(WIL)(RIL)−CyIL−SU2(−BA2)−, O-III-b wherein each of R5E, L5E, SU, BA, LIL, WIL, RIL, −CyIL−, SU2and BA2is independently as described herein. In some embodiments, a moiety of formula O-III-b is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form. Page 46 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0117] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound is a compound of formula O-III-c or a salt thereof: R5E−L5E−SU(−BA)−LIL−P(WIL)(RIL)−CyIL−SU2(−BA2)−ROL, O-III-c wherein each of R5E, L5E, SU, BA, LIL, WIL, RIL, −CyIL−, SU2, BA2and ROLis independently as described herein.

[0118] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, etc.), wherein the compound comprises a moiety of formula O-I: , wherein:LSC5is a covalent bond or optionally substituted −CH2−; R2sis −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −L2s−R2a, −L2s−OR2a, −L2s−SR2a, −L2s−N(R2a)2, −O−L2s−OR2a, −O−L2s−SR2a, or −O−L2s−N(R2a)2, or R2sis L2sconnecting C2 with C1, C2, C3, C4 or C5; each L2sis independently L; each R2ais independently R’; and each of R5E, −Cy5E−, BA, L and R’ is independently as described herein.

[0119] In some embodiments, a moiety of formula O-I is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0120] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, etc.), wherein the compound comprises a moiety of formula O-I’: ,wherein: LSC5is a covalent bond or optionally substituted −CH2−; R2sis −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −L2s−R2a, −L2s−OR2a, −L2s−SR2a, −L2s−N(R2a)2, −O−L2s−OR2a, −O−L2s−SR2a, or −O−L2s−N(R2a)2, or R2sis L2sconnecting C2 with C1, C2, C3, C4 or C5; each L2sis independently L; Page 47 of 448 12513573v1Attorney Docket No.: 2010581-1441 each R2ais independently R’; and each of R5E, −Cy5E−, BA, L and R’ is independently as described herein.

[0121] In some embodiments, a moiety of formula O-I’ is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0122] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound is a compound of formula O-I-a or a salt thereof: ,wherein each variable is independently as described herein.

[0123] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound is a compound of formula O-I-a’ or a salt thereof: ,wherein each variable is independently as described herein.

[0124] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound is a compound of formula O-I-a-a or a salt thereof: ,wherein each variable is independently as described herein.

[0125] In some embodiments, the present disclosure provides a compound (e.g., an oligonucleotide, a compound of formula O-E, a compound of formula IL, etc.), wherein the compound is a compound of formula O-I-a-a’ or a salt thereof: Page 48 of 448 12513573v1Attorney Docket No.: 2010581-1441 ,wherein each variable is independently

[0126] In some embodiments, the present disclosure provides a compound comprising a moiety of formula O-II-c-1: ,wherein: each of LSC5and LSC52is independently a covalent bond or optionally substituted −CH2−; each of R2sand R2s2is independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −L2s−R2a, −L2s−OR2a, −L2s−SR2a, −L2s−N(R2a)2, −O−L2s−OR2a, −O−L2s−SR2a, or −O−L2s−N(R2a)2, or is L2sconnecting C2 with C1, C2, C3, or C4 of the same ring; each L2sis independently L; each R2ais independently R’; and each of R5E, Cy5E, LSC5, BA, CyIL, WIL, RIL, LIL, BA2, L and R’ is independently as described herein.

[0127] In some embodiments, a moiety of formula O-II-c-1 is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0128] In some embodiments, the present disclosure provides a compound comprising a moiety of formula O-II-c-1’: ,Page 49 of 448 12513573v1Attorney Docket No.: 2010581-1441 O-II-c-1’ wherein: each of LSC5and LSC52is independently a covalent bond or optionally substituted −CH2−; each of R2sand R2s2is independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −L2s−R2a, −L2s−OR2a, −L2s−SR2a, −L2s−N(R2a)2, −O−L2s−OR2a, −O−L2s−SR2a, or −O−L2s−N(R2a)2, or is L2sconnecting C2 with C1, C2, C3, or C4 of the same ring; each L2sis independently L; each R2ais independently R’; and each of R5E, Cy5E, LSC5, BA, CyIL, WIL, RIL, LIL, BA2, L and R’ is independently as described herein.

[0129] In some embodiments, a moiety of formula O-II-c-1’ is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0130] In some embodiments, the present disclosure provides a compound is of formula O-II-c-2 or a salt thereof: ,wherein each variable is independently as described herein.

[0131] In some embodiments, the present disclosure provides a compound is of formula O-II-c-2’ or a salt thereof: ,wherein each variable is independently as described herein. Page 50 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0132] In some embodiments, the present disclosure provides a compound is of formula O-II-c-2-a or a salt thereof: ,wherein each variable is independently as described herein.

[0133] In some embodiments, the present disclosure provides a compound is of formula O-II-c-2-a’ or a salt thereof: ,wherein each variable is independently as described herein.

[0134] In some embodiments, the present disclosure provides a compound comprising a moiety of formula O-II-d-1: ,wherein each variable is independently as described herein. In some embodiments, a moiety of formula O-II-d-1 is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0135] In some embodiments, the present disclosure provides a compound comprising a moiety of Page 51 of 448 12513573v1Attorney Docket No.: 2010581-1441 formula O-II-d-1’: ,wherein each variable is independently as described herein. In some embodiments, a moiety of formula O-II-d-1’ is in a salt form. In some embodiments, it is in a pharmaceutically acceptable salt form.

[0136] In some embodiments, the present disclosure provides a compound is of formula O-II-d-2 or a salt thereof: ,wherein each variable is independently as described herein.

[0137] In some embodiments, the present disclosure provides a compound is of formula O-II-d-2’ or a salt thereof: ,wherein each variable is independently as described herein.

[0138] In some embodiments, the present disclosure provides a compound is of formula O-II-d-2-a or a salt thereof: Page 52 of 448 12513573v1Attorney Docket No.: 2010581-1441 ,wherein each variable is as

[0139] In some embodiments, the present disclosure provides a compound is of formula O-II-d-2-a’ or a salt thereof: ,wherein each variable is independently as described herein.

[0140] As those skilled in the art appreciate, oligonucleotides may comprise various sugars, nucleobases, internucleotidic linkages as described herein. In some embodiments, an oligonucleotide comprises a PS linkage. In some embodiments, an oligonucleotide comprises a PN linkage. In some embodiments, an oligonucleotide comprises a PO linkage. In some embodiments, an oligonucleotide comprises a PS linkage and a PN linkage. In some embodiments, an oligonucleotide comprises a PS linkage and a PO linkage. In some embodiments, an oligonucleotide comprises a PO linkage, a PS linkage and a PN linkage. In some embodiments, the number of PS internucleotidic linkages in an oligonucleotide is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more. In some embodiments, the number of PN internucleotidic linkages in an oligonucleotide is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more. In some embodiments, the number of PO internucleotidic linkages in an oligonucleotide is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more. In some embodiments, each PS linkage is a phosphorothioate internucleotidic linkage. In some embodiments, each PN linkage is independently a non-negatively charged internucleotidic linkage. In some embodiments, each PN linkage is independently a neutral internucleotidic linkage. In some embodiments, each PN linkage is independently a phosphoryl Page 53 of 448 12513573v1Attorney Docket No.: 2010581-1441 guanidine internucleotidic linkage. In some embodiments, each PN linkage is independently n001.

[0141] In some embodiments, each PS internucleotidic linkage is independently chirally controlled. In some embodiments, each PN internucleotidic linkage is independently chirally controlled. In some embodiments, each chiral linkage phosphorus is independently chirally controlled.

[0142] In some embodiments, an oligonucleotide has a length of about 10-200 (e.g., about 10-20, 10- 30, 10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-120, 10-150, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-120, 20-150, 20-200, 25-30, 25-40, 25-50, 25-60, 25-70, 25-80, 25-90, 25-100, 25-120, 25-150, 25-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-120, 30-150, 30-200, 10, 20, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 60, etc.) nucleobases. In some embodiments, the base sequence of an oligonucleotide is about 10-60 nucleobases in length. In some embodiments, a base sequence is about 15-50 nucleobases in length. In some embodiments, a base sequence is from about 15 to about 35 nucleobases in length. In some embodiments, an oligonucleotide is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 or more nucleobases in length. In some embodiments, each nucleobase counted in the length is independently optionally substituted or protected A, T, C, G, U or a tautomer thereof.

[0143] In some embodiments, oligonucleotides are provided as salt forms. In some embodiments, oligonucleotides are provided as salts comprising negatively-charged internucleotidic linkages (e.g., phosphorothioate internucleotidic linkages, natural phosphate linkages, etc.) existing as their salt forms. In some embodiments, oligonucleotides are provided as pharmaceutically acceptable salts. In some embodiments, oligonucleotides are provided as metal salts. In some embodiments, oligonucleotides are provided as sodium salts. In some embodiments, oligonucleotides are provided as ammonium salts. In some embodiments, oligonucleotides are provided as metal salts, e.g., sodium salts, wherein each negatively-charged internucleotidic linkage is independently in a salt form (e.g., for sodium salts, −O−P(O)(SNa)−O− for a phosphorothioate internucleotidic linkage, −O−P(O)(ONa)−O− for a natural phosphate linkage, etc.).

[0144] In some embodiments, oligonucleotides are chiral controlled, comprising one or more chirally controlled internucleotidic linkages. In some embodiments, provided oligonucleotides are stereochemically pure. In some embodiments, provided oligonucleotides or compositions thereof are substantially pure of other stereoisomers. In some embodiments, the present disclosure provides chirally controlled oligonucleotide compositions.

[0145] As described herein, oligonucleotides of the present disclosure can be provided in high purity (e.g., 50%-100%). In some embodiments, oligonucleotides of the present disclosure are of high stereochemical purity (e.g., 50%-100%). In some embodiments, oligonucleotides in provided compositions Page 54 of 448 12513573v1Attorney Docket No.: 2010581-1441 are of high stereochemical purity (e.g., high percentage (e.g., 50%-100%) of a stereoisomer compared to the other stereoisomers of the same oligonucleotide). In some embodiments, a percentage is at least or about 50%. In some embodiments, a percentage is at least or about 60%. In some embodiments, a percentage is at least or about 70%. In some embodiments, a percentage is at least or about 75%. In some embodiments, a percentage is at least or about 80%. In some embodiments, a percentage is at least or about 85%. In some embodiments, a percentage is at least or about 90%. In some embodiments, a percentage is at least or about 95%.

[0146] In some embodiments, oligonucleotides of the present disclosure are at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% stereochemically pure at linkage phosphorus of chiral internucleotidic linkages. In some embodiments, oligonucleotides of the present disclosure are prepared stereoselectively and are substantially free of stereoisomers. In some embodiments, in provided compositions comprising a plurality of oligonucleotides which share the same base sequence of the same pattern of chiral linkage phosphorus stereochemistry (e.g., comprising one or more of Rp and / or Sp, wherein each chiral linkage phosphorus is independently Rp or Sp), at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of all oligonucleotides in the composition that share the same base sequence as oligonucleotides of the plurality share the same pattern of chiral linkage phosphorus stereochemistry or are oligonucleotides of the plurality. In some embodiments, in provided compositions comprising a plurality of oligonucleotides which share the same base sequence of the same pattern of chiral linkage phosphorus stereochemistry, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of all oligonucleotides in the composition that share the same constitution as oligonucleotides of the plurality share the same pattern of chiral linkage phosphorus stereochemistry or are oligonucleotides of the plurality. In some embodiments, diastereomeric excess of each chiral phosphorus is independently about or at least about 90%. In some embodiments, diastereomeric excess of each chiral phosphorus is independently about or at least about 95%. In some embodiments, diastereomeric excess of each chiral phosphorus is independently about or at least about 97%. In some embodiments, diastereomeric excess of each chiral phosphorus is independently about or at least about 98%. In some embodiments, diastereomeric purity is about or at least about (DS)nc, wherein DS is about 90-100%, and nc is the number of chiral linkage phosphorus. In some embodiments, DS is about 90% or more. In some embodiments, DS is about 95% or more. In some embodiments, DS is about 96% or more. In some embodiments, DS is about 97% or more. In some embodiments, DS is about 98% or more. In some embodiments, DS is about 99% or more. In some embodiments, diastereomeric purity is represented as the product of the diastereopurity of each chiral linkage phosphorus.

[0147] In some embodiments, the present disclosure provides an agent comprising a first oligonucleotide and a second oligonucleotide, wherein the first and second oligonucleotides comprise base sequences complementary to each other and are capable of forming a duplex. In some embodiments, an Page 55 of 448 12513573v1Attorney Docket No.: 2010581-1441 agent is a dsRNAi agent. In some embodiments, a first oligonucleotide is a guide strand. In some embodiments, a first oligonucleotide is a passenger strand. In some embodiments, a first oligonucleotide comprises R5E−Cy5E− as described herein. In some embodiments, a first oligonucleotide comprises −CyIL−P(WIL)(RIL)−LIL− as described herein. In some embodiments, a second oligonucleotide comprises R5E−Cy5E− as described herein. In some embodiments, a second oligonucleotide comprises −CyIL−P(WIL)(RIL)−LIL− as described herein. In some embodiments, a first oligonucleotide is of 21 nucleobases in length. In some embodiments, a first oligonucleotide is of 23 nucleobases in length. In some embodiments, a second oligonucleotide is of 21 nucleobases in length. In some embodiments, a second oligonucleotide is of 23 nucleobases in length.

[0148] In some embodiments, the present disclosure provides dsRNA agent comprising a first oligonucleotide and a second oligonucleotide, wherein the first oligonucleotide is or comprises an oligonucleotide comprising R5E−Cy5E− or −CyIL−P(WIL)(RIL)−LIL− as described herein. In some embodiments, a first oligonucleotide is or comprises a guide strand. In some embodiments, a first oligonucleotide is or comprises a passenger strand.

[0149] Certain oligonucleotides and / or compositions are described in Table 1 below. Table 1. Example Oligonucleotides / Compositions / Base Sequences ID Description Base Sequence SSR- RNA1{p.[c5m](U)[Ssp].[fl2r](U)[Rsp].m(A)[n001S].[fl2r](U)p.m(A)p.[fl2r]( UUAUAGAG A G A G A G G G G G G G GPage 56 of 448 12513573v1Attorney Docket No.: 2010581-1441 2r](C)[Ssp].m(A)[Ssp].[fl2r](G)[Ssp].m(C)[Ssp].[fl2r](A)[n070S].m(C)[Ssp].[ CACAGUU fl2r](A)[Ssp].m(G)[Ssp].m(U)[Ssp].m(U)}$$$$V2.0 SSR- RNA1 [Rm5d5m](U)[R ][fl2r](C)[S ]m(U)[n071S][fl2r](A) m(C) [fl UCUACUUG G G G G G G G G A G G G G G G G G G G G G G G GPage 57 of 448 12513573v1Attorney Docket No.: 2010581-1441 0106516 (U)p.m(U)[n001S].[fl2r](G)p.m(U)p.[fl2r](G)p.m(U)p.m(U)p.m(A)[Ssp].[fl2r] UGUUACAG (C)[Ssp].m(A)[Ssp].[fl2r](G)[Ssp].m(C)[Ssp].[fl2r](A)[n001S].m(C)[Ssp].[fl2r CACAGUU ](A)[Ss ]m(G)[Ss ]m(U)[Ss ]m(U)}$$$$V20 G G G G G G GU C G G G G G G G G G G G G G GPage 58 of 448 12513573v1Attorney Docket No.: 2010581-1441 SSR- RNA1{p.[Rm5d5m](U)[Rsp].[fl2r](C)[Ssp].m(U)[n001S].[fl2r](A)p.m(C)p.[fl UCUACUUG 01061892r](U)p.m(U)p.[fl2r](G)p.m(U)p.[fl2r](G)[n001S].m(U)p.m(U)p.m(A)[Ssp].[fl UGUUACAG 2r](C)[Ss ]m(A)[Ss ][fl2r](G)[Ss ]m(C)[Ss ][fl2r](A)[Ss ]m(C)[Ss ][fl2 CACAGUU G G G G G G G G G G G G G G G G G G G G G G G GPage 59 of 448 12513573v1Attorney Docket No.: 2010581-1441 2r](C)[Ssp].m(A)[Ssp].[fl2r](G)[Ssp].m(C)[Ssp].[fl2r](A)[Ssp].m(C)[Ssp].[fl2 CACAGUU r](A)[Ssp].m(G)[Ssp].m(U)[Ssp].m(U)}$$$$V2.0 SSR- RNA1 [Rm5d5m](U)[R ][fl2r](C)[S ]m(U)[n001S][fl2r](A) m(C) [fl UCUACUUG G G G G G G G G G G G G G G G G G G G G G G GPage 60 of 448 12513573v1Attorney Docket No.: 2010581-1441 SSR- RNA1{m(U)[Ssp].[fl2r](C)[Rsp].m(C)[n001S].[fl2r](U)p.m(U)p.[fl2r](C)p.m( UCCUUCCCU 0105217 C)p.m(C)p.m(U)p.m(G)[n001R].[fl2r](A)p.m(A)p.m(G)p.[fl2r](G)p.m(U)p.[fl GAAGGUUC 2r](U) m(C) m(C) m(U) m(C) m(C)[Ss ]m(U)[Ss ]m(U)}$$$$V20 CUCCUU G A G A G A G A G A G A G A G A G A G A G A C G UPage 61 of 448 12513573v1Attorney Docket No.: 2010581-1441 0101599 r](U)p.[fl2r](C)p.[fl2r](U)p.m(U)p.m(G)p.m(C)p.m(U)p.m(C)p.m(U)p.m(A)p. UCUUGCUC m(U)p.m(A)[Ssp].m(A)}|CHEM1{[GalNAc3C12oyl]}|CHEM2{[nC6o]}$CH UAUAA EM2RNA11:R1-1:R1CHEM2CHEM11:R2-1:R1$$$V20 G A G A G A G A G A G A G A G A G A G APage 62 of 448 12513573v1Attorney Docket No.: 2010581-1441 1:R1|CHEM1,CHEM2,1:R2-1:R1$$$V2.0HELM Description and Base Sequence, due to their length, may be divided into multiple lines in Table 1 (e.g., Table 1A and Table 1B). Unless otherwise specified, all oligonucleotides in Table 1 are single- stranded. As appreciated by those skilled in the art, nucleoside units are unmodified and contain unmodified nucleobases and 2’-deoxy sugars unless otherwise indicated (e.g., with m, [fl2r], etc.); linkages, unless otherwise indicated, are natural phosphate linkages; and acidic / basic groups may independently exist in their salt forms. If a sugar is not specified, the sugar is a natural DNA sugar; and if an internucleotidic linkage is not specified, the internucleotidic linkage is a natural phosphate linkage. A natural DNA sugar may also be indicated with “d” as in d(G), d(A), d(C), d(T), etc., and a natural phosphate linkage may be indicated with “p” in Table 1. Oligonucleotides in Table 1 (e.g., Table 1A and Table 1B) are described using the Hierarchical Editing Language for Macromolecules (HELM), which is described in, e.g., Zhang, T. et al. J Chem Inf Model.2012 Oct 22;52(10):2796-806 and Milton, J. et al. J Chem Inf Model.2017 Jun 26;57(6):1233-1239, which are incorporated herein by reference. As described in Zhang et al., 2012 and Milton et al., 2017, connections between oligonucleotides, linker moieties, GalNAc moieties, etc. may be indicated in HELM, for example, as the following: CHEM1,RNA1,1:R1-1:R1, wherein CHEM1 is, e.g., a first linker or moiety, RNA1 is an oligonucleotide, and 1:R1-1:R1 indicates that CHEM1 is linked via a first attachment point to a first attachment point on a first monomer of RNA1, as described herein (see, e.g., below). Various moieties and modifications (e.g., internucleotidic linkages, sugars, nucleobases, etc.) are described in the present disclosure including the below: m: 2’-OMe; m5: methyl at 5-position of C (nucleobase is 5-methylcytosine); f or [fl2r]: 2’-F; r: 2’-OH; p: phosphodiester (phosphate). It can a linkage or be an end group (or a component thereof), e.g., a linkage between a linker and an oligonucleotide chain, an internucleotidic linkage (a natural phosphate linkage), etc.; [Rsp]: Phosphorothioate in the Rp configuration; [Ssp]: Phosphorothioate in the Sp configuration; ;Page 63 of 448 12513573v1Attorney Docket No.: 2010581-1441 [n001R]: n001 in Rp configuration; [n001S]: n001 in Sp configuration; ; ;[tz] , wherein the carbon atom is bonded to, e.g., [sa] and the nitrogen atom is bonded to a(e.g., the 5’ position carbon atom of [d5m](U));[azir]: , wherein the carbon atom is bonded to a phosphorus atom (e.g., the phosphorus atom in, atom is bonded to a carbon atom in a sugar (e.g., the 5’ position carbon atom of [d5m](U)); Page 64 of 448 12513573v1Attorney Docket No.: 2010581-1441 , wherein the carbon atom is bonded to a phosphorus atom (e.g., the phosphorus atom atom is bonded to a carbon atom in a sugar (e.g., the 5’ position carbon atom of[1m41tz] , wherein the −CH2− is bonded to a phosphorus atom (e.g., the phosphorus atom in carbon atom is bonded to a carbon atom in a sugar (e.g., the 4’ position carbonatom of [dd5m](U)); [pyrl] , wherein the carbon atom is bonded to a phosphorus atom (e.g., the phosphorus atomnitrogen atom is bonded to a carbon atom in a sugar (e.g., the 5’ position carbon atom of [d5m](U)); , wherein the carbon atom is bonded to a phosphorus atom (e.g., the phosphorus atomatom is bonded to a carbon atom in a sugar (e.g., the 5’ position carbon atom of [d5m](U)); ;Page 65 of 448 12513573v1Attorney Docket No.: 2010581-1441 ;Page 66 of 448 12513573v1Attorney Docket No.: 2010581-1441 N N O;L001, nC6o or [nC6o]: −NH−(CH2)6− linker (C6 linker, C6 amine linker or C6 amino linker), connected to Mod (e.g., Mod001) through −NH− (e.g., forming an amide group –C(O)−NH−), and, in various cases, the 5’-end of the oligonucleotide chain through a phosphate linkage (O or PO); Mod001, GalNAc3C12oyl or [GalNAc3C12oyl]: ;Page 67 of 448 12513573v1Attorney Docket No.: 2010581-1441 Phosphoramidites

[0150] Various phosphoramidites can be utilized for oligonucleotide preparation, e.g., those described in US 10167309, US 11643657, US 11718638, US 11608355, US 20230089442, etc. In some embodiments, the present disclosure provides phosphoramidites comprising −P(OR1)N(R2)(R3) as described herein. In some embodiments, a phosphoramidite comprises −P(OR1)N(R2)(R3) which is bonded to a sugar moiety of a nucleoside. In some embodiments, a phosphoramidite comprise R5Eas described herein. In some embodiments, a phosphoramidite comprises R5E−Cy5E− wherein each of R5Eand Cy5Eis independently as described herein. In some embodiments, a phosphoramidite comprises −P(OR1)N(R2)(R3) which is bonded to a moiety, e.g., an optionally substituted triazole ring, that is bonded to a sugar moiety of a nucleoside. In some embodiments, a sugar is a natural sugar. In some embodiments, a sugar is a modified sugar. In some embodiments, a nucleobase in a phosphoramidite is an optionally substituted natural nucleobase. In some embodiments, a nucleobase in a phosphoramidite is optionally protected A, T, C, G, U, or 5mC (e.g., for oligonucleotide synthesis). In some embodiments, a phosphoramidite is abasic.

[0151] In some embodiments, the present disclosure provides a compound having the structure of Formula P or a salt thereof: R5E−Cy5E−SU(−BA)−OP(OR1)N(R2)(R3) P wherein: each of R1, R2, and R3is independently R’, or two or three of R1, R2, and R3are taken together with their intervening atoms to ; Ring A is an optionallyring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; t is 0-5; each Rsis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −Ls−Rs11, −Ls−ORs11, −Ls−SRs11, −Ls−N(Rs11)2, −O−Ls−ORs11, −O−Ls−SRs11, −O−Ls−N(Rs11)2, −C(Rs11)3 or −Ls−Si(Rs11)3; each Rs11is independently R’; each Lsis independently L; and each of R5E, Cy5E, SU, BA, L and R’ is independently as described herein.

[0152] In some embodiments, such a compound is utilized as a phosphoramidite for oligonucleotide synthesis. In some embodiments, L5Eis an optionally substituted triazole ring.

[0153] In some embodiments, the provided technology provides a compound of formula P-I or a salt Page 68 of 448 12513573v1Attorney Docket No.: 2010581-1441 thereof: , wherein each variable is independently

[0154] In some embodiments, the a compound of formula P-II or a salt thereof: , wherein each variable is independently

[0155] In some embodiments, the provided technology provides a compound of formula P-IA or a salt thereof: ,wherein each variable is independently as described herein.

[0156] In some embodiments, the provided technology provides a compound of formula P-IIA or a salt thereof: Page 69 of 448 12513573v1Attorney Docket No.: 2010581-1441 ,wherein each variable is independently as

[0157] In some embodiments, −P(OR1)N(R2)(R3) is −P(OCH2CH2CN)N[CH(CH3)2]2. In some embodiments, −P(OR1)N(R2)(R3) is wherein each variable is independently as described herein. In somecomprises a chiral auxiliary.

[0158] In some embodiments, such a compound is utilized as a phosphoramidite for oligonucleotide synthesis. Nucleosides

[0159] Various nucleosides can be utilized for oligonucleotide preparation, e.g., those described in US 10167309, US 11643657, US 11718638, US 11608355, US 20230089442, etc. In some embodiments, the present disclosure provides nucleosides comprising −P(O)(ORPG)2 as described herein. In some embodiments, a nucleoside comprises −P(O)(ORPG)2 which is bonded to the sugar moiety of the nucleoside. In some embodiments, a phosphoramidite comprises −P(O)(ORPG)2 which is bonded to a moiety, e.g., an optionally substituted triazole ring, that is bonded to the sugar moiety of the nucleoside. In some embodiments, a sugar is a natural sugar. In some embodiments, a sugar is a modified sugar. In some embodiments, a nucleobase is an optionally substituted natural nucleobase. In some embodiments, a nucleobase is optionally protected A, T, C, G, U, or 5mC (e.g., for oligonucleotide synthesis). In some embodiments, a nucleoside is abasic.

[0160] In some embodiments, the provided technology provides a compound of formula (RPGO)2P(O)−L5E−SU(−BA)−OH wherein each other variable is independently as described herein. In some embodiments, such a compound is utilized as a nucleoside, e.g., for phosphoramidite preparation.

[0161] In some embodiments, the present disclosure provides a nucleoside comprising R5Eas described herein. In some embodiments, the present disclosure provides a nucleoside comprising R5E−Cy5E−, wherein each of R5Eand Cy5Eis independently as described herein.

[0162] In some embodiments, the provided technology provides a compound of formula N or a salt thereof: R5E−Cy5E−SU(−BA)−OH Page 70 of 448 12513573v1Attorney Docket No.: 2010581-1441 N wherein each variable is independently as described herein. In some embodiments, such a compound is utilized as a nucleoside, e.g., for phosphoramidite preparation.

[0163] In some embodiments, the provided technology provides a compound of formula N-II or a salt thereof: , wherein each variable is independently

[0164] In some embodiments, the a compound of formula N-IIA or a salt thereof: ,wherein each variable is independently as described herein.

[0165] In some embodiments, such a compound is utilized as a nucleoside, e.g., for phosphoramidite preparation.

[0166] In some embodiments, provided nucleosides can react with phosphorus-containing agents, e.g., compounds of formula V or salts thereof to provide phosphoramidites.

[0167] In some embodiments, the present disclosure provides a compound, wherein the compound is a compound of formula III or a salt thereof: N3−SU(BA)−OH, III wherein each of SU and BA is independently of any one of the preceding claims.

[0168] In some embodiments, the provided technology provides a compound (e.g., a compound of formula III or a salt thereof), wherein the compound is a compound of formula III’ or a salt thereof: ,Page 71 of 448 12513573v1Attorney Docket No.: 2010581-1441 wherein each variable is independently as described herein. In some embodiments, such a compound is utilized as a nucleoside, e.g., for phosphoramidite preparation. In some embodiments, such a compound is utilized to prepare for, e.g., a compound of formula II or a salt thereof.

[0169] In some embodiments, the provided technology provides a compound (e.g., a compound of formula III or a salt thereof), wherein the compound is a compound of formula III’A or a salt thereof: ,wherein each variable is independently as described herein. In some embodiments, such a compound is utilized as a nucleoside, e.g., for phosphoramidite preparation. In some embodiments, such a compound is utilized to prepare for, e.g., a compound of formula II or a salt thereof. Example Embodiments for Certain Variables

[0170] Certain embodiments of certain variables utilized in various formulae are described below. Those skilled in the art appreciate that an embodiment for a variable, e.g., R, L, etc., can also be applicable to other variables that can be such a variable, e.g., R, L, etc., respectively. R5E

[0171] In some embodiments, R5Eis R’. In some embodiments, R5Eis −H. In some embodiments, −LR5E−P(W5E)(L51R51)(L52R52). In some embodiments, R5Eis −P(O)(OC2H5)2. In some embodiments, R5Eis −CH2P(O)(OC2H5)2. In some embodiments, R5Eis −CH(CH3)P(O)(OC2H5)2. In some embodiments, R5Eis −P(O)(OCH3)2. In some embodiments, R5Eis −P(O)(OCH2CH2CN)2. In some embodiments, R5Eis −P(O)(OCH2OC(O)tBu)2. In some embodiments, R5Eis −P(O)(OCH2SC(O)tBu)2. In some embodiments, R5Eis −P(O)(OH)2. In some embodiments, R5Eis −P(O)(OC2H5)(NHCH3). In some embodiments, R5Eis −P(S)(OC2H5)(NHCH3). In some embodiments, R5Eis −P(S)(OC2H5)2. In some embodiments, R5Eis −COOH. In some embodiments, R5Eis −LR5E−S(O)2L53R53. In some embodiments, R5Eis −S(O)2(NHCH3). In some embodiments, R5Eis −S(O)2(OCH2CH(CH3)2. In some embodiments, R5Eis −LR5E−C(O)L54R54. In some In some embodiments, R5Eis −C(O)L54R54. In some embodiments, R5E(L52R52). In some embodiments, R5Eis −B(L51R51)(L52R52). In some (OR51)(OR52). In some embodiments, R5Eis −B(OR51)(OR52). In some embodiments,and are taken together with their intervening atoms to form an optionally substituted ring as described herein. Page 72 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0172] For example, in some embodiments, R5E,, orPage 73 of 448 12513573v1Attorney Docket No.: 2010581-1441 ,,Page 74 of 448 12513573v1Attorney Docket No.: 2010581-1441 ,Page 75 of 448 12513573v1Attorney Docket No.: 2010581-1441 , anPage 76 of 448 12513573v1Attorney Docket No.: 2010581-1441Page 77 of 448 12513573v1Attorney Docket No.: 2010581-1441 tert-butyl. In some embodiments, a compound does not , wherein each variable is independently as described herein. In some not, wherein each variable is independently as described herein.

[0176] In some embodiments, W5Eis O. In some embodiments, W5Eis S. LR5E

[0177] In some embodiments, LR5Eis a covalent bond. In some embodiments, LR5Eis optionally substituted −CH2−. In some embodiments, LR5Eis −CH(CH3)−. In some embodiments, LR5Eis −CH2−.

[0178] In some embodiments, LR5Ecomprises one or more C=C double bond. In some In Inis or comprise optionally substituted (E)−CH=CH−. In some embodiments, LR5Eis or comprise optionally substituted (Z)−CH=CH−. In some embodiments, LR5Eis or comprise −CH=CH−. In some embodiments, LR5Eis or comprise (E)−CH=CH−. In some embodiments, LR5Eis or comprise (Z)−CH=CH−. L51

[0179] In some embodiments, L51is a covalent bond. In some embodiments, L51is −O−. In some embodiments, L51is −S−. In some embodiments, L51is −N(RL51)−. In some embodiments, L51and L52are the same. In some embodiments, L51and L52are different. L52Page 78 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0180] In some embodiments, L52is a covalent bond. In some embodiments, L52is −O−. In some embodiments, L52is −S−. In some embodiments, L52is −N(RL52)−. In some embodiments, −L52R52is −O−RPG. L53

[0181] In some embodiments, L53is a covalent bond. In some embodiments, L53is −O−. In some embodiments, L53is −S−. In some embodiments, L53is −N(RL53)−. In some embodiments, −L53R53is −O−RPG. L54

[0182] In some embodiments, L54is a covalent bond. In some embodiments, L54is −O−. In some embodiments, L54is −S−. In some embodiments, L54is −N(RL54)−. In some embodiments, −L54R54is −O−RPG. R51

[0183] In some embodiments, R51is −R511. In some embodiments, R51is −H. In some embodiments, R51is optionally substituted C1-6 aliphatic. In some embodiments, R51is optionally substituted C1-6 alkyl. In some embodiments, R51is methyl. In some embodiments, R51is ethyl. In some embodiments, R51is −CH2CH2−CN. In some embodiments, R51is −LR51−R511, wherein LR51is −CH2−O−C(O)−, wherein −C(O)− is bonded to R511, and the −CH2− is optionally substituted. In some embodiments, R51is −LR51−R511, wherein LR51is −CH2−S−C(O)−, wherein −C(O)− is bonded to R511, and the −CH2− is optionally substituted. In some embodiments, −L51R51is −O−RPG. In some embodiments, −L51R51is −O−CH2−S−C(O)−tBu. In some embodiments, −L51R51is −O−CH2−O−C(O)−tBu. In some embodiments, −L51R51is −O−CH2CH2CN. R52

[0184] In some embodiments, R52is −R521. In some embodiments, R52is −H. In some embodiments, R52is optionally substituted C1-6 aliphatic. In some embodiments, R52is optionally substituted C1-6 alkyl. In some embodiments, R52is methyl. In some embodiments, R52is ethyl. In some embodiments, R52is −CH2CH2−CN. In some embodiments, R52is −LR52−R521, wherein LR52is −CH2−O−C(O)−, wherein −C(O)− is bonded to R521, and the −CH2− is optionally substituted. In some embodiments, R52is −LR52−R521, wherein LR52is −CH2−S−C(O)−, wherein −C(O)− is bonded to R521, and the −CH2− is optionally substituted. In some embodiments, −L52R52is −O−RPG. In some embodiments, −L52R52is −O−CH2−S−C(O)−tBu. In some embodiments, −L52R52is −O−CH2−O−C(O)−tBu. In some embodiments, −L52R52is −O−CH2CH2CN.

[0185] In some embodiments, −L51R51and −L52R52are the same. In some embodiments, −L51R51and −L52R52are different. R53Page 79 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0186] In some embodiments, R53is −R531. In some embodiments, R53is −H. In some embodiments, R53is optionally substituted C1-6aliphatic. In some embodiments, R53is optionally substituted C1-6alkyl. In some embodiments, R53is methyl. In some embodiments, R53is ethyl. In some embodiments, R53is −CH2CH2−CN. In some embodiments, R53is −LR53−R531, wherein LR53is −CH2−O−C(O)−, wherein −C(O)− is bonded to R531, and the −CH2− is optionally substituted. In some embodiments, R53is −LR53−R531, wherein LR53is −CH2−S−C(O)−, wherein −C(O)− is bonded to R531, and the −CH2− is optionally substituted. In some embodiments, −L53R53is −O−RPG. In some embodiments, −L53R53is −O−CH2−S−C(O)−tBu. In some embodiments, −L53R53is −O−CH2−O−C(O)−tBu. In some embodiments, −L53R53is −O−CH2CH2CN. R54

[0187] In some embodiments, R54is −R541. In some embodiments, R54is −H. In some embodiments, R54is optionally substituted C1-6 aliphatic. In some embodiments, R54is optionally substituted C1-6 alkyl. In some embodiments, R54is methyl. In some embodiments, R54is ethyl. In some embodiments, R54is −CH2CH2−CN. In some embodiments, R54is −LR54−R541, wherein LR54is −CH2−O−C(O)−, wherein −C(O)− is bonded to R541, and the −CH2− is optionally substituted. In some embodiments, R54is −LR54−R541, wherein LR54is −CH2−S−C(O)−, wherein −C(O)− is bonded to R541, and the −CH2− is optionally substituted. In some embodiments, −L54R54is −O−RPG. R511

[0188] In some embodiments, R511is R as described herein. In some embodiments, R511is optionally substituted C1-6 aliphatic. In some embodiments, R511is optionally substituted tert-butyl. In some embodiments, R511is tert-butyl. In some embodiments, −L51R51is −O−RPG. R521

[0189] In some embodiments, R521is R as described herein. In some embodiments, R521is optionally substituted C1-6 aliphatic. In some embodiments, R521is optionally substituted tert-butyl. In some embodiments, R521is tert-butyl. R531

[0190] In some embodiments, R531is R as described herein. In some embodiments, R531is optionally substituted C1-6aliphatic. In some embodiments, R531is optionally substituted tert-butyl. In some embodiments, R531is tert-butyl. R541

[0191] In some embodiments, R541is R as described herein. In some embodiments, R541is optionally substituted C1-6aliphatic. In some embodiments, R541is optionally substituted tert-butyl. In some embodiments, R541is tert-butyl. RL51Page 80 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0192] In some embodiments, RL51is R as described herein. In some embodiments, RL51is −H. RL52

[0193] In some embodiments, RL52is R as described herein. In some embodiments, RL52is −H. In some embodiments, R52is −R521. RL53

[0194] In some embodiments, RL53is R as described herein. In some embodiments, RL53is −H. In some embodiments, R53is −R531. In some embodiments, R53is −H. In some embodiments, R53is optionally substituted C1-6 aliphatic. In some embodiments, R53is optionally substituted C1-6 alkyl. In some embodiments, R53is methyl. In some embodiments, R53is ethyl. In some embodiments, R53is CH2CH(CH3)2. In some embodiments, R53is −CH2CH2−CN. In some embodiments, R53is −LR53−R531, wherein LR53is −CH2−O−C(O)−, wherein −C(O)− is bonded to R531, and the −CH2− is optionally substituted. In some embodiments, R53is −LR53−R531, wherein LR53is −CH2−S−C(O)−, wherein −C(O)− is bonded to R531, and the −CH2− is optionally substituted. In some embodiments, −L53R53is −O−RPG. RL54

[0195] In some embodiments, RL54is R as described herein. In some embodiments, RL54is −H. LR51

[0196] In some embodiments, LR51is a covalent bond. In some embodiments, LR51is −CH2−O−(CO)−. In some embodiments, LR51is −CH2−S−(CO)−. In some embodiments, −C(O)− is bonded to L51. In some embodiments, LR51and LR52are the same. In some embodiments, LR51and LR52are different. LR52

[0197] In some embodiments, LR52is a covalent bond. In some embodiments, LR52is −CH2−O−(CO)−. In some embodiments, LR52is −CH2−S−(CO)−. In some embodiments, −C(O)− is bonded to L52. LR53

[0198] In some embodiments, LR53is a covalent bond. In some embodiments, LR53is −CH2−O−(CO)−. In some embodiments, LR53is −CH2−S−(CO)−. In some embodiments, −C(O)− is bonded to L53. LR54

[0199] In some embodiments, LR54is a covalent bond. In some embodiments, LR54is −CH2−O−(CO)−. In some embodiments, LR54is −CH2−S−(CO)−. In some embodiments, −C(O)− is bonded to L54. L5E

[0200] In some embodiments, L5Eis a covalent bond. In some embodiments, L5Eis −O−. In some Page 81 of 448 12513573v1Attorney Docket No.: 2010581-1441 embodiments, L5Eis Cy5E. Ring C

[0201] In some embodiments, Ring C is an optionally substituted bivalent 3-10 (e.g., 3-8, 3-6, 3-5, 4- 6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having 0-5 (e.g., 0, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur. In some embodiments, Ring C is an optionally substituted bivalent 3-10 (e.g., 3-8, 3-6, 3-5, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having 0-5 (e.g., 0, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0202] In some embodiments, Ring C is monocyclic. In some embodiments, Ring C is an optionally substituted 5-6 membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring C is an optionally substituted 5-membered aromatic ring having 1-4 heteroatoms each of which is nitrogen. In some embodiments, Ring C is optionally substituted . In some embodiments, Ring C is . In some embodiments, Ring C isoptionally . In some embodiments, Ring C . In someembodiments, Ring C is optionally . In some embodiments, Ring C is. In some embodiments, Ring C is optionally . In someembodiments, Ring C is . In some embodiments, Ring C is optionally substituted . In some embodiments, Ring C . In some embodiments, Ring C is optionally. In some embodiments, Ring C . In some embodiments, Ring C isoptionally . In some embodiments, Ring C . In some embodiments,Ring C is optionally . In some embodiments, Ring C .Page 82 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0203] In some embodiments, Ring C is an optionally substituted 3-7 membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring C is an optionally substituted 3-6 membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring C is 3-membered. In some embodiments, Ring C is 4-membered. In some embodiments, Ring C is 5-membered. In some embodiments, Ring C is 6-membered.

[0204] In some embodiments, Ring C is optionally . In some embodiments,Ring C . In some embodiments, Ring C is optionally . In someembodiments, Ring C . In some embodiments, Ring C is optionally substitutedoptionally .

[0205] In somepartially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring C is 5-membered. In some embodiments, Ring C is 6-membered. In some embodiments, Ring C is 7-membered.

[0206] In some embodiments, Ring C is optionally . In some embodiments,Ring .

[0207] In some embodiments, Ring C is optionally In some embodiments,Page 83 of 448 12513573v1Attorney Docket No.: 2010581-1441 Ring . rings as described herein can also be utilized for Ring C.

[0209] In some embodiments, c is 1-5. In some embodiments, c is 2-5. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, c is 3. In some embodiments, c is 4. In some embodiments, c is 5. In some embodiments, c is 0. RRC

[0210] In some embodiments, an occurrence of RRCis −H. In some embodiments, an occurrence of RRCis C1-6 aliphatic. In some embodiments, an occurrence of RRCis C1-6 alkyl. In some embodiments, an occurrence of RRCis methyl. In some embodiments, an occurrence of RRCis optionally substituted phenyl. In some embodiments, an occurrence of RRCis phenyl. In some embodiments, an occurrence of RRCis −C(O)ORRC11. In some embodiments, RRC11is −H. In some embodiments, an occurrence of RRCis −N(RRC11)2. In some embodiments, an occurrence of RRCis −NH2. Cy5E

[0211] In some embodiments, –Cy5E– is a covalent bond (i.e., is absent). In some embodiments, −Cy5E− is a covalent bond, and LR5Ecomprises a cyclic structure, . In someembodiments, LR5Eis or . In some embodiments, LR5E.(RRC)c

[0212] In some embodiments, –Cy5E– . In some embodiments, , wherein Ring C is optionally substituted. InRing C is substituted. Inembodiments, Ring C is unsubstituted.

[0213] In some embodiments, −Cy5E− is optionally . In some embodiments,. In some embodiments, −Cy5E− is optionally . In somePage 84 of 448 12513573v1Attorney Docket No.: 2010581-1441 embodiments, −Cy5E− . In some embodiments, −Cy5E− is optionally substituted. In some is . In some embodiments, −Cy5E− isoptionally . In some embodiments, −Cy5E− . In someembodiments, −Cy5E− is optionally . In some embodiments, −Cy5E− .In some embodiments, −Cy5E− is optionally . In some embodiments, −Cy5E− is−Cy5E− is optionally . In some embodiments,some embodiments, −Cy5E− is optionally . In someembodiments, −Cy5E− is . In some embodiments, −Cy5E− is optionally .In some embodiments, −Cy5E− . In some embodiments, −Cy5E− is optionally substituted. In some embodiments, −Cy5E− isoptionally . In some embodiments, −Cy5E− . In some embodiments,−Cy5E− is optionally . In some embodiments, −Cy5E− . In someembodiments, −Cy5E− is optionally . In some embodiments, −Cy5E− isPage 85 of 448 12513573v1Attorney Docket No.: 2010581-1441 .In some embodiments, −Cy5E−is optionally . In some embodiments,some embodiments, −Cy5E− is optionally In someto R5E. In some,SU and SU2Page 86 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0216] In some embodiments, SU is a sugar moiety as described herein. In some embodiments, SU is . In some embodiments, SU is , wherein LSUis optionallysubstituted −CH2−. In some embodiments, SU is , wherein LSUis −CH2−. In some.

[0217] For example, in some , wherein each of R1s, R2s, R2s’,R2sRSU,, wherein each of R2sand R4sis independently RSU. In some embodiments, SU is , wherein R2sRSU. In some , wherein each of R1s, R2s,R2s’, R2s’’, R3s, R3s’, R4s and R5s is independently RSU. In some embodiments, SU ,wherein each of R1s, R2s, R2s’, R2s’’, R3s, R3s’, and R4sis independently RSU, andPage 87 of 448 12513573v1Attorney Docket No.: 2010581-1441substituted –CH2− or −N(R’)−. In some embodiments, SU , wherein R2s is RSU.

[0218] As described herein some embodiments, R2sis2sembodiments, R is −F. In some embodiments, R2sis −OR wherein R is optionally substituted C1-6 alkyl. In some embodiments, R2sis −OMe. In some embodiments, R2sis −MOE.

[0219] In some embodiments, SU is −CH2−CH(−)−CH2−, wherein one −CH2− is bonded to −Cy5E− and the other is bonded to BA.

[0220] In some embodiments, SU is a UNA sugar. In some embodiments, SU is a GNA sugar. In some embodiments, SU is a LNA sugar. In some embodiments, SU is a homo DNA sugar.

[0221] In some embodiments, SU is a sugar conjugated with an additional moiety, e.g., a lipid moiety.

[0222] Embodiments described for SU are also applicable to SU2. In some embodiments, SU and SU2are the same. In some embodiments, SU and SU2are different. LSU

[0223] In some embodiments, LSUis an optionally substituted is optionally substituted −CH2−. In some embodiments, LSUis −CH2−. In some embodiments, LSUis bonded to −Cy5E−. In some embodiments, LSUis a covalent bond. Ring S

[0224] In some embodiments, Ring S is a ring in a sugar as described herein. In some embodiments, Ring S is an optionally substituted 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, Ring S is an optionally substituted 3-10 membered ring having 0-5 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring S is an optionally substituted 3-10 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring S is an optionally substituted 3-10 membered ring having one heteroatom which is oxygen. In some embodiments, Ring S is an optionally substituted monocyclic 5-membered ring. In some embodiments, Ring S is an optionally substituted monocyclic 6-membered ring. In some embodiments, Ring S is an optionally substituted monocyclic 7-membered ring. In some embodiments, Ring S is an optionally substituted bicyclic 7-membered ring.

[0225] For example, in some embodiments, Ring S is optionally , wherein BA is bonded at position 1 and LSUis bonded at position 4. In someoptionally Page 88 of 448 12513573v1Attorney Docket No.: 2010581-1441 substituted , wherein BA is bonded at position a and LSUis bonded at position b. s

[0226] In some embodiments, s is 0-5. In some embodiments, s is 1-5. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, s is 5. RSU

[0227] In some embodiments, RSUis −H. In some embodiments, RSUis −F. In some embodiments, RSUis In some embodiments, RSUis −ORSU11. In some embodiments, RSUis −OMe. In some embodiments, RSUis −OCH2CH2OCH3. In some embodiments, two RSUgroup are R and are taken together to form a ring as described herein. In some embodiments, two RSU, e.g., bonded to the carbon atoms at positions 2 and 4, form optionally substituted −O−CH2−, wherein −O− is bonded to the carbon atom at position 2. In some embodiments, −O−CH2− is unsubstituted. RSU11

[0228] In some embodiments, RSU11is optionally substituted C1-6 aliphatic. In some embodiments, RSU11is optionally substituted C1-6 alkyl. In some embodiments, RSU11is methyl. In some embodiments, RSU11is −CH2CH2OCH3. R1s

[0229] In some embodiments, R1sis −H. In some embodiments, R1sis RSU. R2s

[0230] In some embodiments, Rs2is −H. In some embodiments, R2sis −F.

[0231] In some embodiments, R2sis −Cl. In some embodiments, R2sis −Br. In some embodiments, R2sis −I. In some embodiments, R2sis −CN. In some embodiments, R2sis −N3. In some embodiments, R2sis −NO. In some embodiments, R2sis −NO2.

[0232] In some embodiments, R2sis −L2s−R2a. In some embodiments, Rs2is R2a. In some embodiments, Rs2is R. In some embodiments, R2sis −O−L2s’−R2a, wherein L2s’is a covalent bond, or a bivalent, optionally substituted group selected from C1-10aliphatic and C1-10heteroaliphatic group having 1-4 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L2s’are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L2s’is a covalent bond. In some embodiments, L2s’is an optionally substituted bivalent C1-10aliphatic group. In some embodiments, L2s’is a bivalent C1-10aliphatic group. In some embodiments, L2s’is an optionally substituted bivalent linear C1-Page 89 of 448 12513573v1Attorney Docket No.: 2010581-144110aliphatic group. In some embodiments, L2s’is a bivalent linear C1-10aliphatic group. In some embodiments, L2s’is an optionally substituted C1-10alkylene group. In some embodiments, L2s’is a C1-10alkylene group. In some embodiments, L2s’is optionally substituted −(CH2)1-10−. In some embodiments, L2s’is −(CH2)1-10−. In some embodiments, L2s’is an optionally substituted bivalent C1-10heteroaliphatic group having 1-4 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, one or more methylene units are independently replaced as described herein. For example, in some embodiments, R2sis −O(CH2)0-10R2a, wherein each −CH2− is optionally substituted. In some embodiments, R2ais optionally substituted C1-10 aliphatic. In some embodiments, R2ais optionally substituted C1-10 alkyl. In some embodiments, R2ais optionally substituted linear C1-10 alkyl. In some embodiments, R2ais C1-10 alkyl. In some embodiments, R2ais C1-10 linear alkyl. In some embodiments, R2sis −O(CH2)0-15CH3. In some embodiments, R2sis −O(CH2)15CH3.

[0233] In some embodiments, R2sis −L2s−OR2a. In some embodiments, R2sis −OR2a. In some embodiments, R2sis −OMe.

[0234] In some embodiments, R2sis −L2s−SR2a. In some embodiments, R2sis −SR2a.

[0235] In some embodiments, R2sis −L2s−N(R2a)2. In some embodiments, R2sis −N(R2a)2.

[0236] In some embodiments, R2sis −O−L2s−OR2a. In some embodiments, R2sis −O−L2s−SR2a. In some embodiments, R2sis or −O−L2s−N(R2a)2. In some embodiments, L2sis an optionally substituted bivalent C2-10 aliphatic group. In some embodiments, L2sis a bivalent C2-10 aliphatic group. In some embodiments, L2sis a bivalent linear C2-10 aliphatic group. In some embodiments, L2sis a bivalent linear C2-10 alkylene group. In some embodiments, R2sis −OCH2CH2OCH3.

[0237] In some embodiments, R2sis L2sconnecting C2 with C1, C2, C3, C4 or C5 wherein Lsis L as described herein. For example, in some embodiments, L is (C2)−O−(unsubstituted methylene)−. In some embodiments, L is (C2)−O−(substituted methylene)−. In some embodiments, L is (C2)−O−(substituted methylene)−, wherein the methylene group is substituted with methyl. In some embodiments, L is (C2)−O−(substituted methylene)−, wherein the methylene group is substituted with ethyl. In some embodiments, the carbon atom of the methylene group is R. In some embodiments, the carbon atom of the methylene group is S.

[0238] In some embodiments, C2 and C4 are connected through −O−CH2−, wherein the −CH2− is optionally substituted. In some embodiments, C2 and C4 are connected through −O−CH2−. In some embodiments, C2 and C4 are connected through −O−CH(CH3)−. In some embodiments, C2 and C4 are connected through −O−CH(CH2OMe)−. In some embodiments, the configuration of the chiral carbon in L2sis R. In some embodiments, the configuration of the chiral carbon in L2sis S. In some embodiments, the −O− is bonded to C2. In some embodiments, a sugar is a LNA sugar.

[0239] In some embodiments, a sugar is conjugated with an additional moiety, e.g., a lipid moiety. Page 90 of 448 12513573v1Attorney Docket No.: 2010581-1441 In some embodiments, a lipid moiety is conjugated at R2s. L2s

[0240] In some embodiments, L2sis a covalent bond. In some embodiments, L2sis an optionally substituted bivalent C1-10aliphatic group wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L2sis an optionally substituted bivalent C1-5aliphatic group wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L2sis an optionally substituted bivalent C1-5 aliphatic group wherein one or more methylene units of L are optionally and independently replaced by −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L2sis an optionally substituted bivalent C1-10 aliphatic group. In some embodiments, L2sis an optionally substituted bivalent C2-10 aliphatic group. In some embodiments, L2sis a bivalent C2-10 aliphatic group. In some embodiments, L2sis a bivalent linear C2-10 aliphatic group. In some embodiments, L2sis a bivalent linear C1-10 alkylene group. In some embodiments, L2sis a bivalent linear C2-10 alkylene group. In some embodiments, L2sis optionally substituted −O−CH2−. R2a

[0241] As defined herein, R2ais R’ as described herein. In some embodiments, R2ais R as described herein. In some embodiments, R2ais −H. In some embodiments, R2ais C1-6 aliphatic. In some embodiments, R2ais C1-6 alkyl. In some embodiments, R2ais methyl.

[0242] In some embodiments, two or more R2aare R’ and are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur. In some embodiments, two R2aattached to the same atom are R’ and are taken together with the atom to which they are attached to form an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, 3-20, 5-9, etc.) membered ring having, in addition to the intervening atom(s), 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur. In some embodiments, a formed ring is as described herein. R2s’

[0243] In some embodiments, R2s’is R as described herein. In some embodiments, R2s’is −H. In some embodiments, R2s’is −F. In some embodiments, R2s’is −ORs11wherein Rs11is optionally substituted C1-6aliphatic. Page 91 of 448 12513573v1Attorney Docket No.: 2010581-1441 R2s'’

[0244] In some embodiments, R2s”is R as described herein. In some embodiments, R2s”is −H. In some embodiments, R2s”is −F. In some embodiments, R2s”is −ORs11wherein Rs11is optionally substituted C1-6aliphatic. R3s

[0245] In some embodiments, R3sis −H. In some embodiments, R3sis RSU. R3s’

[0246] In some embodiments, R3sis −H. In some embodiments, R3sis RSU. R4s

[0247] In some embodiments, R4sis −H. In some embodiments, R4sis RSU. R5s

[0248] In some embodiments, an occurrence of R5sis −H. In some embodiments, R5sis RSU. In some embodiments, an occurrence of R5sis optionally substituted C1-6 aliphatic. In some embodiments, an occurrence of R5sis methyl. In some embodiments, both R5sare −H. XS

[0249] In some embodiments, Xsis −O−. In some embodiments, Xsis −S−. In some embodiments, Xsis optionally substituted −CH2−. In some embodiments, Xsis −CH2−. CyIL

[0250] In some embodiments, –CyIL– is an optionally substituted bivalent 3-10 (e.g., 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, the ring has 1-5 heteroatoms independently selected nitrogen, oxygen and sulfur. In some embodiments, the ring has 1-5 heteroatoms each of which is nitrogen. In some embodiments, −CyIL− is an optionally substituted 3- membered ring. In some embodiments, −CyIL− is an optionally substituted 4-membered ring. In some embodiments, −CyIL− is an optionally substituted 5-membered ring. In some embodiments, −CyIL− is an optionally substituted 6-membered ring. In some embodiments, −CyIL− is an optionally substituted saturated ring. In some embodiments, −CyIL− is an optionally substituted partially unsaturated ring. In some embodiments, −CyIL− is an optionally substituted saturated ring. In some embodiments, −CyIL− is bonded to a 3’ position of a sugar.

[0251] In some embodiments, −CyIL− is optionally . In some embodiments,−CyIL− is . In some embodiments, the nitrogen atom is bonded to a sugar. In some Page 92 of 448 12513573v1Attorney Docket No.: 2010581-1441 embodiments, the carbon atom is bonded to a sugar.

[0252] Other suitable rings as described herein can also be utilized for CyIL. WIL

[0253] In some embodiments, WILis O. In some embodiments, WILis S. RIL

[0254] In some embodiments,is −RIL1. In some embodiments, RILis −ORIL1. In some embodiments, RILis −SRIL1. In some embodiments, RILis −N(RIL1)(RIL2). In some embodiments, RILis −N=C[N(RIL1)(RIL2)][N(RIL3)(RIL4)]. In some In some embodiments, RILis OH. In some embodiments, RILis SH.RIL1

[0255] In some embodiments, RIL11is −H. In some embodiments, RIL11is optionally substituted C1-6 aliphatic. In some embodiments, RIL1and RIL2are both R’ and are taken together with the nitrogen atom to which they are bond to form an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, RIL1and RIL2are both R’ and are taken together with the nitrogen atom to which they are bond to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having, in addition to the intervening atom(s), 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, the formed ring is saturated. In some embodiments, the formed ring is partially unsaturated. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. RIL2

[0256] In some embodiments, RIL21is −H. In some embodiments, RIL21is optionally substituted C1-6 aliphatic. In some embodiments, RIL1and RIL2are both R’ and are taken together with the nitrogen atom to which they are bond to form an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, RIL1and RIL2are both R’ and are taken together with the nitrogen atom to which they are bond to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring Page 93 of 448 12513573v1Attorney Docket No.: 2010581-1441 having, in addition to the intervening atom(s), 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, RIL2and RIL3are both R’ and are taken together with the nitrogen atom to which they are bond to form an optionally substituted 3- 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1- 10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, RIL2and RIL3are both R’ and are taken together with the nitrogen atom to which they are bond to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having, in addition to the intervening atom(s), 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1- 4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, the formed ring is saturated. In some embodiments, the formed ring is partially unsaturated. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6- membered. RIL3

[0257] In some embodiments, RIL31is −H. In some embodiments, RIL31is optionally substituted C1-6 aliphatic. In some embodiments, RIL3and RIL4are both R’ and are taken together with the nitrogen atom to which they are bond to form an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, RIL2and RIL3are both R’ and are taken together with the nitrogen atom to which they are bond to form an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3- 10, 5-10, 3-7, 3-6, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, RIL2and RIL3are both R’ and are taken together with the nitrogen atom to which they are bond to form an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having, in addition to the intervening atom(s), 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, the formed ring is saturated. In some embodiments, the formed ring is partially unsaturated. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. RIL4Page 94 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0258] In some embodiments, RIL41is −H. In some embodiments, RIL41is optionally substituted C1-6aliphatic. In some embodiments, RIL3and RIL4are both R’ and are taken together with the nitrogen atom to which they are bond to form an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, the formed ring is saturated. In some embodiments, the formed ring is partially unsaturated. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6- membered. LIL

[0259] In some embodiments, LILis a covalent bond. In some embodiments, LILis optionally substituted −CH2−. In some embodiments, LILis −CH2−. In some embodiments, LILis −O−. In some embodiments, LILis bonded to a 3’ position of a sugar. LIL1

[0260] In some embodiments, LIL1is a covalent bond. In some embodiments, LIL1is a bivalent, optionally substituted C1-10 aliphatic wherein one or more methylene units of LIL1are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, LIL1is a bivalent, optionally substituted C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of LIL1are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, the heteroaliphatic group comprises −N=C[−N(−)(−)][−N(−)(−)].LIL2is a covalent bond. In some embodiments, it is L as described herein and is not a covalent bond. LIL3

[0262] In some embodiments, LIL3is a covalent bond. In some embodiments, it is L as described herein and is not a covalent bond. LIL4

[0263] In some embodiments, LIL4is a covalent bond. In some embodiments, it is L as described herein and is not a covalent bond. Page 95 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0264] In some embodiments, −CyIL−P(WIL)(RIL)−LIL− is or In someembodiments, it is or some embodiments, it is or In someembodiments, it is or some embodiments, it is or . Insome embodiments, it is or some embodiments, it is or . Insome embodiments, it is or .

[0265] In some embodiments, −CyIL−P(WIL)(RIL)− is orembodiments, it is or some embodiments, it is or In somePage 96 of 448 12513573v1Attorney Docket No.: 2010581-1441 embodiments, it is or some embodiments, it is or . Insome embodiments, it is or some embodiments, it is or . Insome embodiments, it is or . ROL

[0266] In some embodiments, ROLis −R’. In some embodiments, ROLis −H. In some embodiments, ROLis −OH. In some embodiments, ROLis −OH. In some embodiments, ROLis a nucleic acid moiety (e.g., H−ROLis a nucleic acid). In some embodiments, ROLis an oligonucleotide moiety (e.g., H−ROLis a nucleic acid). In some embodiments, the nucleic acid or oligonucleotide is attached to a solid support. LOL

[0267] In some embodiments, LOLis a covalent bond. In some embodiments, LOLis −O−. ROL1

[0268] In some embodiments, ROL1is −R’. In some embodiments, ROL1is −H. In some embodiments, ROL1is a nucleic acid moiety (e.g., H−ROLis a nucleic acid). In some embodiments, ROL1is an oligonucleotide moiety (e.g., H−ROLis a nucleic acid). In some embodiments, the nucleic acid or oligonucleotide is attached to a solid support.

[0269] In some embodiments, ROLor ROL1is a moiety of an oligonucleotide. In some embodiments, length of an oligonucleotide is about or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 50, 60, 70, 80 or 90 nucleobases in length. In some embodiments, each nucleobase in the length is independently optionally substituted or protected A, T, C or G. In some embodiments, an oligonucleotide comprises a PS internucleotidic linkage. In some embodiments, the number of PS internucleotidic linkages in an oligonucleotide is about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some embodiments, an oligonucleotide comprises a phosphorothioate internucleotidic linkage. In some embodiments, the Page 97 of 448 12513573v1Attorney Docket No.: 2010581-1441 number of phosphorothioate internucleotidic linkages in an oligonucleotide is about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some embodiments, an oligonucleotide comprises a PO internucleotidic linkage. In some embodiments, the number of PO internucleotidic linkages in an oligonucleotide is about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some embodiments, an oligonucleotide comprises a natural phosphate linkage internucleotidic linkage. In some embodiments, the number of natural phosphate linkages in an oligonucleotide is about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some embodiments, an oligonucleotide comprises a PN internucleotidic linkage. In some embodiments, the number of PN internucleotidic linkages in an oligonucleotide is about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some embodiments, a PN internucleotidic linkage is a phosphoryl guanidine internucleotidic linkage. In some embodiments, each PN internucleotidic linkage is independently a phosphoryl guanidine internucleotidic linkage. In some embodiments, a PN internucleotidic linkage is n001. In some embodiments, each PN internucleotidic linkage is n001. In some embodiments, a chiral linkage phosphorus in a PS internucleotidic linkage is chirally controlled. In some embodiments, a phosphorothioate internucleotidic linkage is chirally controlled. In some embodiments, each phosphorothioate internucleotidic linkage is independently chirally controlled. In some embodiments, a chiral linkage phosphorus in a PN internucleotidic linkage is chirally controlled. In some embodiments, a n001 is chirally controlled. In some embodiments, each n001 is independently chirally controlled. In some embodiments, each linkage phosphorus is independently chirally controlled. RP1

[0270] In some embodiments, RP1is −O−CH2CH2CN. In some embodiments, RP1is −O−CH2−O−C(O)−RP, wherein RPis optionally substituted tert-butyl. In some embodiments, RP1is −O−CH2−O−C(O)−tBu.RP2is −O−CH2CH2CN. In some embodiments, RP2is −O−CH2−O−C(O)−RP, wherein RPis optionally substituted tert-butyl. In some embodiments, RP2is −O−CH2−O−C(O)−tBu.

[0272] In some embodiments, RP1and RP2are the same. In some embodiments, RP1and RP2are different. In some embodiments, each of RP1and RP2is −O−CH2CH2CN. In some embodiments, each of RP1and RP2is independently −O−CH2−O−C(O)−RP, wherein RPis optionally substituted tert-butyl. In some embodiments, each of RP1and RP2is −O−CH2−O−C(O)−tBu. RP

[0273] In some embodiments, RPis substituted tert-butyl. In some embodiments, RPis tert-butyl. Page 98 of 448 12513573v1Attorney Docket No.: 2010581-1441 BA

[0274] In some embodiments, BA is hydrogen.

[0275] In some embodiments, BA is an optionally substituted 3-20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, BA is an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, BA is an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from nitrogen and oxygen. In some embodiments, BA is an optionally substituted ring having at least one nitrogen atom. In some embodiments, BA is an optionally substituted 5-15 membered ring. In some embodiments, BA is an optionally substituted 5-10 membered ring. In some embodiments, BA is an optionally substituted 5-9 membered ring. In some embodiments, BA is an optionally substituted 9-membered ring. In some embodiments, BA is an optionally substituted 10-membered ring. In some embodiments, an optionally substituted 5-membered ring. In some embodiments, BA is an optionally substituted 6-membered ring. In some embodiments, BA is an optionally substituted monocyclic ring. In some embodiments, BA is an optionally substituted bicyclic ring. In some embodiments, BA is bonded to C1 of a sugar at a nitrogen atom.

[0276] In some embodiments, BA is an optionally substituted group, wherein the group isprotected nucleobase. In some embodiments, BA is an optionally protected nucleobase selected from A, T, C, G, U and 5mU. In some embodiments, protection is suitable for oligonucleotide synthesis.

[0277] In some embodiments, BA is an optionally substituted or protected nucleobase. Various nucleobases are as described herein and can be utilized as BA. L

[0278] Certain embodiments for L are described below. Various variables, e.g., L2s, Ls, etc., can be L, and embodiments for L can also be applied to such variables that can be L.

[0279] In some embodiments, L is a covalent bond. In some embodiments, L is a bivalent, optionally substituted C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic group Page 99 of 448 12513573v1Attorney Docket No.: 2010581-1441 wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L is a bivalent, optionally substituted C1-6aliphatic group wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L is a bivalent, optionally substituted C1-5aliphatic group wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, each methylene unit are replaced. In some embodiments, at least one methylene unit is not replaced. In some embodiments, L comprises at least one chain carbon atom. In some embodiments, L is −O−. In some embodiments, L is −S−. In some embodiments, L is −N(R’)−. In some embodiments, L is −C(O)−.

[0280] In some embodiments, no methylene unit is replaced. In some embodiments, L is a bivalent, optionally substituted C1-10 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic group. In some embodiments, L is optionally substituted C1-6 aliphatic group. In some embodiments, L is bivalent, optionally substituted C1-10 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) alkylene. In some embodiments, L is optionally substituted C1-6 alkylene. In some embodiments, L is linear. In some embodiments, L is branched. In some embodiments, L is substituted. In some embodiments, L is not substituted.

[0281] In some embodiments, L is a bivalent, optionally substituted C1-10 heteroaliphatic (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L is a bivalent, optionally substituted C1-6 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−. In some embodiments, L is linear. In some embodiments, L is branched. In some embodiments, L is substituted. In some embodiments, L is not substituted.

[0282] In some embodiments, a methylene unit is replaced by −Cy− as described herein. Cy Page 100 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0283] As used herein, −Cy− is an optionally substituted bivalent 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, −Cy− is an optionally substituted bivalent 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, −Cy− is monocyclic. In some embodiments, −Cy− is bicyclic. In some embodiments, −Cy− is polycyclic. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 5-8, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur and 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, etc.) carbon atoms. In some embodiments, a monocyclic ring unit is an optionally substituted saturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted partially unsaturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted aromatic ring. In some embodiments, a monocyclic ring unit is an optionally substituted phenyl ring. In some embodiments, a monocyclic ring unit is an optionally substituted 5-membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6- membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. Each monocyclic ring unit is independently optionally substituted. In some embodiments, a monocyclic ring unit is unsaturated. In some embodiments, a monocyclic ring unit is saturated. In some embodiments, −Cy− is an optionally substituted saturated ring. In some embodiments, −Cy− is an optionally substituted partially unsaturated ring. In some embodiments, −Cy− is an optionally substituted aromatic ring.

[0284] In some embodiments, −Cy− is an optionally substituted bivalent 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered monocyclic cycloaliphatic ring. In some embodiments, −Cy− is an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered monocyclic cycloalkyl ring. In some embodiments, −Cy− is an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered monocyclic heteroaliphatic ring having 1-5 heteroatoms. In some embodiments, −Cy− is an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) membered monocyclic heteroalkyl ring having 1-5 heteroatoms. In some embodiments, −Cy− is an optionally substituted bivalent 5-15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered bicyclic or polycyclic cycloaliphatic group. In some embodiments, −Cy− is an optionally substituted bivalent 5-15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered Page 101 of 448 12513573v1Attorney Docket No.: 2010581-1441 bicyclic or polycyclic cycloalkyl group. In some embodiments, −Cy− is an optionally substituted 5-15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered bicyclic or polycyclic heteroaliphatic ring having 1-5 heteroatoms. In some embodiments, −Cy− is an optionally substituted 5-15 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered bicyclic or polycyclic heterocyclyl ring having 1-5 heteroatoms. In some embodiments, a cycloaliphatic, cycloalkyl, heteroaliphatic or heteroalkyl ring is 3-membered. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6- membered. In some embodiments, it is 7-membered. In some embodiments, it is 8-membered. In some embodiments, it is 9-membered. In some embodiments, it is 10-membered. In some embodiments, it is 11-membered. In some embodiments, it is 12-membered. In some embodiments, −Cy− is optionally substituted phenylene. In some embodiments, −Cy− is an optionally substituted bivalent 10-membered bicyclic aryl ring. In some embodiments, −Cy− is an optionally substituted 5-membered heteroaryl ring having 1-4 heteroatoms. In some embodiments, −Cy− is an optionally substituted 6-membered heteroaryl ring having 1-4 heteroatoms. In some embodiments, −Cy− is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-5 heteroatoms. In some embodiments, −Cy− is an optionally substituted 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms. In some embodiments, a heteroaliphatic, heterocyclyl or heteroaryl ring contains no more than 1 heteroatom. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur.

[0285] In some embodiments, −Cy− is an optionally substituted 4-7 membered ring having 0-3 heteroatoms. In some embodiments, −Cy− is an optionally substituted 6-membered aryl ring. In some embodiments, an aryl ring is substituted. In some embodiments, it is substituted with one or more halogen. In some embodiments, it is substituted with one or more −F. In some embodiments, it is not is is. In some embodiments, it is optionally . In some embodiments, it is. In some embodiments, −Cy− is an optionally substituted 5-membered heteroaryl ring havingIn some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur. In some embodiments, −Cy− is optionally Page 102 of 448 12513573v1Attorney Docket No.: 2010581-1441 substituted . In some embodiments, −Cy− is .

[0286] R1is R’ as is not −H. In some embodiments, R1is R as described herein. In some embodiments, R1is optionally substituted C1-6 aliphatic. In some embodiments, R1is optionally substituted methyl. In some embodiments, R1is optionally substituted ethyl. In some embodiments, R1is optionally substituted ethyl, wherein the methylene unit boned to the oxygen is optionally monosubstituted, and the methyl is substituted with an electron-withdrawing group, e.g., −CN. Certain electron-withdrawing groups are described in US 10167309, US 11643657, US 11718638, US 11608355 or US 20230089442, the electron-withdrawing groups of each of which are incorporated herein by reference. In some embodiments, R1is −OCH2CH2CN. R2

[0287] In some embodiments, R2is R’ as described herein and is not −H. In some embodiments, R2is R as described herein. In some embodiments, R2is not −H. In some embodiments, R2is optionally substituted C1-10aliphatic. In some embodiments, R2is optionally substituted C1-10alkyl. In some embodiments, R2is C1-6aliphatic. In some embodiments, R2is C1-6alkyl. In some embodiments, R2is isopropyl. R3

[0288] In some embodiments, R3is R’ as described herein and is not −H. In some embodiments, R3is R as described herein. In some embodiments, R3is not −H. In some embodiments, R3is optionally substituted C1-10aliphatic. In some embodiments, R3is optionally substituted C1-10alkyl. In some embodiments, R3is C1-6aliphatic. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is isopropyl.

[0289] In some embodiments, R2and R3are the same. In some embodiments, they are different.

[0290] In some embodiments, −P(OR1)N(R2)(R3) is −P(OCH2CH2CN)N[CH(CH3)2]2.

[0291] In some embodiments, two or three of R1, R2, and R3are taken together with their intervening atoms to form wherein each variable is independently as described herein. In some embodiments,together with their intervening atoms to form a ring as described herein. In some embodiments, R2and R3are taken together with their intervening atoms to from a ring as described herein. In some embodiments, R1, R2and R3are taken together with their intervening atoms to form a ring as described herein. Ring A

[0292] As defined herein, Ring A is an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, Page 103 of 448 12513573v1Attorney Docket No.: 2010581-1441 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having, in addition to the intervening atoms, 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, Ring A is an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, Ring A has no additional heteroatoms. In some embodiments, Ring has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional heteroatoms.

[0293] In some embodiments, Ring A is not substituted (as appreciated by those skilled in the art, not including Rs). In some embodiments, Ring A is substituted (as appreciated by those skilled in the art, not including Rs).

[0294] In some embodiments, Ring A is monocyclic. In some embodiments, Ring A is bicyclic. In some embodiments, Ring A is polycyclic. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 4-6, 5-6, 5-8, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur and 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, etc.) carbon atoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 4-10 (e.g., 4, 5, 6, 7, 8, 9, 10, 5-7, 5-6) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur and 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, etc.) carbon atoms. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-10 membered. In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-7 membered. In some embodiments, each monocyclic ring unit is independently an optionally substituted 4-6 membered. In some embodiments, each monocyclic ring unit is independently an optionally substituted 5-6 membered. In some embodiments, each monocyclic ring unit is independently an optionally substituted 5-membered. In some embodiments, a monocyclic ring unit is an optionally substituted saturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted partially unsaturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted aromatic ring. In some embodiments, a monocyclic ring unit is an optionally substituted phenyl ring. In some embodiments, a monocyclic ring unit is an optionally substituted 5-membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6-membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. Each monocyclic ring unit is independently optionally substituted. In some embodiments, a monocyclic ring unit is Page 104 of 448 12513573v1Attorney Docket No.: 2010581-1441 unsaturated. In some embodiments, a monocyclic ring unit is saturated.

[0295] In some embodiments, a monocyclic ring unit comprising the nitrogen atom to which R2and R3are bond is an optionally substituted saturated 4-10 (e.g., 4-8, 4-6, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having 0-2 heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit comprising the nitrogen atom to which R2and R3are bond is an optionally substituted saturated 4-10 (e.g., 4-8, 4-6, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having no heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen and sulfur. In some embodiments, it is 4-membered. In some embodiments, it is 5- membered. In some embodiments, it is 6-membered. In some embodiments, it is 7-membered. In some embodiments, it is 8-membered.

[0296] In some embodiments, Ring A is an optionally substituted saturated ring. In some embodiments, Ring A is an optionally substituted partially unsaturated ring. In some embodiments, Ring A is an optionally substituted aromatic ring.

[0297] In some embodiments, Ring A is an optionally substituted monocyclic 3-10 (e.g., 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is an optionally substituted bicyclic or polycyclic 6-20 (e.g., 6-15, 6-10, 8-20, 8-15, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10-membered. In some embodiments, Ring A is 3-9 membered. In some embodiments, Ring A is 3-7 membered. In some embodiments, Ring A is 4-10 membered. In some embodiments, Ring A is 4-7 membered. In some embodiments, Ring A is 5-10 membered. In some embodiments, Ring A is 5-7 membered. In some embodiments, Ring A is 3- membered. In some embodiments, Ring A is 4-membered. In some embodiments, Ring A is 5- membered. In some embodiments, Ring A is 6-membered. In some embodiments, Ring A is 7- membered. In some embodiments, Ring A is 8-membered. In some embodiments, Ring A is 9- membered. In some embodiments, Ring A is 10-membered. In some embodiments, Ring A is 11- membered. In some embodiments, Ring A is 12-membered. In some embodiments, Ring A is monocyclic. In some embodiments, Ring A is bicyclic. In some embodiments, Ring A is an optionally substituted bicyclic 7-12 membered ring. In some embodiments, Ring A is an optionally substituted bicyclic 8-10 membered ring. In some embodiments, Ring A is an optionally substituted bicyclic 7- membered ring. In some embodiments, Ring A is an optionally substituted bicyclic 8-membered ring. In some embodiments, Ring A is an optionally substituted bicyclic 9-membered ring. In some Page 105 of 448 12513573v1Attorney Docket No.: 2010581-1441 embodiments, Ring A is an optionally substituted bicyclic 10-membered ring. In some embodiments, Ring A is polycyclic. In some embodiments, Ring A has no additional heteroatoms. In some embodiments, Ring A has 0-6, e.g., 0, 1-6, 1-5, 1-3, or 1, 2, 3, 4, 5, or 6 additional heteroatoms. In some embodiments, Ring A comprises one or more aromatic ring. In some embodiments, Ring A is bicyclic or polycyclic, and each monocyclic ring unit is independently 3-10 (e.g., 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4-8, 4- 7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered, saturated, partially unsaturated or aromatic and having 0-5 (e.g., 0, 1-5, 1-3, 1, 2, 3, 4, or 5) heteroatoms. In some embodiments, a monocyclic ring unit is saturated. In some embodiments, a monocyclic ring unit is partially unsaturated. In some embodiments, a monocyclic ring unit is aromatic. In some embodiments, a monocyclic ring unit is heteroaromatic. Those skilled in the art appreciate that intervening atom(s), e.g., of groups taken together to form a ring, are typically atoms on the shortest path connecting such groups if multiple paths exist.

[0298] In some embodiments, a monocyclic ring unit comprising the phosphorus, nitrogen and oxygen atoms is saturated. In some embodiments, a monocyclic ring unit comprising the phosphorus, nitrogen and oxygen atoms is partially saturated. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it is 7- membered. In some embodiments, it has one or more additional heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, the phosphorus, nitrogen and oxygen atoms are the only heteroatoms in that monocyclic ring unit.

[0299] In some embodiments, a monocyclic ring unit comprising the nitrogen atom to which R2and R3are bond is an optionally substituted partially unsaturated 4-10 (e.g., 4-8, 4-6, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having 0-2 heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit comprising the nitrogen atom to which R2and R3are bond is an optionally substituted partially unsaturated 4-10 (e.g., 4-8, 4-6, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having no heteroatoms in addition to the nitrogen atom independently selected from nitrogen, oxygen and sulfur. In some embodiments, it is 4-membered. In some embodiments, it is 5-membered. In some embodiments, it is 6-membered. In some embodiments, it is 7- membered. In some embodiments, it is 8-membered.

[0300] In some embodiments, Ring A comprises optionally , wherein each Lais independently a covalent bond or a bivalent C1-5aliphatic group whereinmethylene units of each Laare optionally and independently replaced by −O−, −S−, or −NH. In some embodiments, Ring A Page 106 of 448 12513573v1Attorney Docket No.: 2010581-1441 is optionally substituted , wherein each Lais independently a covalent bond or a bivalent C1-5aliphatic group more methylene units of each Laare optionally and independently replacedby −O−, −S−, or −NH. In some embodiments, Ring A comprises optionally , wherein each Lais independently a covalent bond or a bivalent C1-5 aliphatic group wherein amethylene units of each L are optionally and independently replaced by −O−, −S−, or In some embodiments, Ring A is optionally , wherein each Lais independently a covalent bond or a bivalent C1-5 aliphatic group wherein one methylene units of each Laare optionally andindependently replaced by −O−, −S−, or −NH. In some embodiments, Lais a covalent bond. In some embodiments, Lais not a covalent bond. In some embodiments, Lais −CH2−. In some embodiments, Lais –(CH2)2−. In some embodiments, Lais –(CH2)3−. In some embodiments, Lais –(CH2)4−. In some embodiments, Lais –(CH2)5−. In some embodiments, a methylene unit is replaced with −O−. In some embodiments, a methylene unit is replaced with −S−. In some embodiments, a methylene unit is replaced with −NH−.

[0301] In some embodiments, Ring A is optionally . In some embodiments,Ring A is optionally . In some embodiments, Ring A is optionally substituted.In some embodiments, an occurrence of Rsis bonded to a carbon atom bonded to the oxygen of −P(OR1)N(R2)(R3). In some embodiments, −P(OR1)N(R2)(R3) , wherein each of Rs1andRs2is independently Rsas described herein. In some embodiments, −P(OR1)N(R2)(R3) .

[0303] In some embodiments, one of Rs1and Rs2is −H. In some embodiments,Page 107 of 448 12513573v1Attorney Docket No.: 2010581-1441 independently not −H. In some embodiments, Rs1is R as described herein. In some embodiments, Rs1is not hydrogen. In some embodiments, Rs1is hydrogen. In some embodiments, Rs1is hydrogen and Rs2is not hydrogen. In some embodiments, Rs1is optionally substituted C1-6aliphatic. In some embodiments, Rs1is methyl. In some embodiments, Rs1is optionally substituted phenyl. In some embodiments, Rs1is phenyl. In some embodiments, Rs2is R as described herein. In some embodiments, Rs2is not hydrogen. In some embodiments, Rs2is hydrogen. In some embodiments, Rs2is optionally substituted C1-6aliphatic. In some embodiments, wherein Rs2is methyl. In some embodiments, Rs2is optionally substituted phenyl. In some embodiments, wherein Rs2is phenyl.

[0304] In some embodiments, −P(OR1)N(R2)(R3) wherein each variable isindependently as described herein. In some is of such a structure thatis a chiral auxiliary, e.g., described in US 10167309, US 11643657, US 11718638, US20230089442, the chiral auxiliaries of each of which are incorporated herein by reference. For example, in some embodiments, it is . In some embodiments, it is. In some embodiments, it . In some embodiments, it isIn some embodiments, it . In some embodiments, it isIn some embodiments, it . Insome some embodiments, it . In some embodiments, it. In some embodiments, it . In somePage 108 of 448 12513573v1Attorney Docket No.: 2010581-1441 embodiments, it . t

[0305] In some embodiments, t is 0. In some embodiments, t is 1-5. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 5. Rs

[0306] In some embodiments, Rsis −F. In some embodiments, Rsis −Cl. In some embodiments, Rsis −Br. In some embodiments, Rsis −I. In some embodiments, Rsis −CN. In some embodiments, Rsis −N3. In some embodiments, Rsis −NO. In some embodiments, Rsis −NO2.

[0307] In some embodiments, Rsis −Ls−Rs11wherein each of Lsand Rs11is independently as described herein. In some embodiments, Rsis Rs11as described herein.

[0308] In some embodiments, Rsis R’ as described herein. For example, in some embodiments, R’ is −C(O)R wherein R is as described herein. In some embodiments, R’ is −CO2R wherein R is as described herein. In some embodiments, R’ is −S(O)2R wherein R is as described herein. In some embodiments, R is C1-6aliphatic. In some embodiments, R is C1-6alkyl. In some embodiments, R is optionally substituted phenyl. In some embodiments, Rsis −S(O)2R wherein R is optionally substituted C1-6 aliphatic. In some embodiments, Rsis −S(O)2Me. In some embodiments, Rsis −S(O)2t-Bu. In some embodiments, Rsis −S(O)2R wherein R is optionally substituted phenyl. In some embodiments, Rsis −S(O)2Ph.

[0309] In some embodiments, Rsis R as described herein. For example, in some embodiments, R is not −H. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted C1-6 alkyl. In some embodiments, R is methyl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl.

[0310] In some embodiments, Rsis −Ls−ORs11wherein each of Lsand Rs11is independently as described herein. In some embodiments, Rsis −ORs11wherein Rs11is as described herein. In some embodiments, Rsis −CH2ORs11wherein Rs11is as described herein.

[0311] In some embodiments, Rsis −Ls−SRs11wherein each of Lsand Rs11is independently as described herein. In some embodiments, Rsis −SRs11wherein Rs11is as described herein. In some embodiments, Rsis −CH2SRs11wherein Rs11is as described herein.

[0312] In some embodiments, Rsis −Ls−N(Rs11)2 wherein each of Lsand Rs11is independently as described herein. In some embodiments, Rsis −N(Rs11)2 wherein each of Lsand Rs11is independently as described herein. In some embodiments, Rsis −CH2N(Rs11)2 wherein each of Lsand Rs11is independently Page 109 of 448 12513573v1Attorney Docket No.: 2010581-1441 as described herein.

[0313] In some embodiments, Rsis −C(Rs11)3wherein each Rs11is independently as described herein. In some embodiments, Rsis −CH(Rs11)2wherein each Rs11is independently as described herein. In some embodiments, two or more Rs11are taken together with the carbon atom to which they are attached to form an optionally substituted 3-20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having 0-10 (e.g., 0, 1-10, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, Rsis optionally .

[0314] In some embodiments, Rsis −Ls−Sis11R is independently as described herein. In some embodiments, each Rs11is independently R’ as described herein and is not −H. In some embodiments, each Rs11is independently R as described herein and is not −H. In some embodiments, at least one Rs11is optionally substituted C1-10aliphatic. In some embodiments, at least one Rs11is optionally substituted C1-10alkyl. In some embodiments, at least one Rs11is methyl. In some embodiments, at least one Rs11is optionally substituted phenyl. In some embodiments, at least one Rs11is phenyl. In some embodiments, each Rs11is independently an optionally substituted group selected from C1-10aliphatic and 6-10 membered aryl. In some embodiments, each Rs11is independently an optionally substituted group selected from C1-10alkyl and 6-10 membered aryl. In some embodiments, each Rs11is independently an optionally substituted group selected from C1-6alkyl and 6-10 phenyl. In some embodiments, Rs11is −SiPh2Me. Rs11

[0315] As used herein, Rs11is R’ as described herein. For example, in some embodiments, R’ is R as described herein. In some embodiments, R’ is −C(O)R wherein R is as described herein. In some embodiments, R’ is −CO2R wherein R is as described herein. In some embodiments, R’ is −S(O)2R wherein R is as described herein. Rs11is −H. In some embodiments, Rs11is not −H. In some embodiments, two or more Rs11on the same atom are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. Certain embodiments of rings are described herein. Ls

[0316] As used herein, Lsis L as described herein. For example, in some embodiments, L is a covalent bond. In some embodiments, L is optionally substituted −CH2−. In some embodiments, L is Page 110 of 448 12513573v1Attorney Docket No.: 2010581-1441 −CH2−. In some embodiments, L is monosubstituted −CH2−. R’

[0317] Certain embodiments for R’ are described below. Various variables, e.g., R2a, R1, R2, R3, Rs, Rs11, etc., can be R’, and embodiments for R’ can also be applied to such variables that can be R’.

[0318] In some embodiments, R’ is R as described herein. In some embodiments, R’ is −H. In some embodiments, R’ is not −H.

[0319] In some embodiments, R’ is −C(O)R wherein R is as described herein. In some embodiments, R’ is −CO2R wherein R is as described herein. In some embodiments, R’ is −S(O)2R wherein R is as described herein. In some embodiments, as described herein, R is not −H.

[0320] In some embodiments, two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1- 10, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, two or more R’ on the same atom are taken together with the atom to which they are attached to form an optionally substituted 3-20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1-10, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, two R’ on the same atom are taken together with the atom to which they are attached to form an optionally substituted 3-20 (e.g., 3-15, 3-10, 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered ring having, in addition to the intervening atom(s), 0-10 (e.g., 0, 1-10, 1-5, 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

[0321] In some embodiments, each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ on the same atom are taken together with the atom to which they are attached to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. Ring

[0322] Compounds of the present disclosure may contain various rings. In some embodiments, a variable, e.g., R or a variable that can be R, can be of a ring as described herein. In some embodiments, two variables, e.g., two R’ groups, may be taken together with their intervening atom(s) to form a ring as described herein. In some embodiments, a ring is monovalent. In some embodiments, a ring is bivalent. In some embodiments, a ring structure can be polyvalent. Rings are optionally substituted. In some embodiments, a ring is unsubstituted. In some embodiments, a ring is substituted. Page 111 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0323] Certain embodiments and features of rings are described below as examples.

[0324] In some embodiments, a ring is an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring is an optionally substituted 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 3-15, 3-14, 3-10, 5-10, 3-7, 3-6, etc.) membered ring having 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-10, 0-5, 1-5, etc.) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, a ring is monocyclic. In some embodiments, a ring is bicyclic. In some embodiments, a ring is polycyclic.

[0325] In some embodiments, each monocyclic ring unit is independently an optionally substituted 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 3-8, 3-7, 3-6, 5-8, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, 1-2, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur and 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-5, 1-4, etc.) carbon atoms. In some embodiments, a monocyclic ring unit is an optionally substituted saturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted partially unsaturated ring. In some embodiments, a monocyclic ring unit is an optionally substituted aromatic ring. In some embodiments, a monocyclic ring unit is an optionally substituted phenyl ring. In some embodiments, a monocyclic ring unit is an optionally substituted 5- membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is an optionally substituted 6-membered heteroaromatic having 1-4 (e.g., 1, 2, 3, 4, 1-3, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. Each monocyclic ring unit is independently optionally substituted. In some embodiments, a monocyclic ring unit is unsaturated. In some embodiments, a monocyclic ring unit is saturated.

[0326] In some embodiments, a ring is an optionally substituted saturated ring. In some embodiments, a ring is an optionally substituted partially unsaturated ring. In some embodiments, a ring is an optionally substituted aromatic ring.

[0327] In some embodiments, a ring is an optionally substituted 3-10 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a ring is 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10-membered. In some embodiments, a ring is 3-9 membered. In some embodiments, a ring is 3-7 membered. In some embodiments, a ring is 4-10 membered. In some embodiments, a ring is 4-7 membered. In some embodiments, a ring is 5-10 membered. In some embodiments, a ring is 5-7 membered. In some embodiments, a ring is 3-membered. Page 112 of 448 12513573v1Attorney Docket No.: 2010581-1441 In some embodiments, a ring is 4-membered. In some embodiments, a ring is 5-membered. In some embodiments, a ring is 6-membered. In some embodiments, a ring is 7-membered. In some embodiments, a ring is 8-membered. In some embodiments, a ring is 9-membered. In some embodiments, a ring is 10-membered. In some embodiments, a ring is monocyclic. In some embodiments, a ring is bicyclic. In some embodiments, a ring is polycyclic. In some embodiments, a ring has no heteroatoms. In some embodiments, a ring has 1-6, e.g., 1-5, 1-3, or 1, 2, 3, 4, 5, or 6 heteroatoms. In some embodiments, a ring formed by two or more groups taken together with their intervening atom(s) has no heteroatoms in addition to the intervening atom(s). In some embodiments, a ring formed by two or more groups taken together with their intervening atom(s) has 1-6, e.g., 1-5, 1-3, or 1, 2, 3, 4, 5, or 6 heteroatoms in addition to the intervening atom(s). In some embodiments, a ring is saturated. In some embodiments, a ring is partially unsaturated. In some embodiments, a ring comprises one or more aromatic ring. In some embodiments, a ring is bicyclic or polycyclic, and each monocyclic ring unit is independently 3-10 (e.g., 3-9, 3-8, 3-7, 3-6, 4-10, 4-9, 4-8, 4-7, 4-6, 5-10, 5-9, 5-8, 5-7, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10) membered, saturated, partially unsaturated or aromatic and having 0-5 (e.g., 0, 1- 5, 1-3, 1, 2, 3, 4, or 5) heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen and sulfur. In some embodiments, a monocyclic ring unit is saturated. In some embodiments, a monocyclic ring unit is partially unsaturated. In some embodiments, a monocyclic ring unit is aromatic. In some embodiments, a monocyclic ring unit is heteroaromatic. Those skilled in the art appreciate that intervening atom(s), e.g., of groups taken together to form a ring, are typically atoms on the shortest path connecting such groups if multiple paths exist.

[0328] In some embodiments, a ring has one or more heteroatoms. In some embodiments, a ring comprises a nitrogen atom. In some embodiments, a ring comprises an oxygen atom. In some embodiments, a ring comprises a sulfur atom. R

[0001] Various variables in the present disclosure can independently be R. Certain embodiments for R are described below as examples. Those skilled in the art reading the present disclosure appreciate that embodiments that are described for a variable that can be R and fall within the definition of R can be embodiments for R as well. Those skilled in the art reading the present disclosure further appreciate that embodiments for R, e.g., those described for R, those described for a variable that can be R and within the definition of R, etc., can be embodiments for a variable that can be R.

[0002] In some embodiments, R is −H. In some embodiments, R is not −H. In some embodiments, R is optionally substituted C1-10(e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) aliphatic. In some embodiments, R is optionally substituted C1-8aliphatic. In some embodiments, R is optionally substituted C1-6aliphatic. In some embodiments, R is optionally substituted C1-10(e.g., C1-6, C2-8, C1, C2, Page 113 of 448 12513573v1Attorney Docket No.: 2010581-1441 C3, C4, C5, C6, C7, C8, C9, C10, etc.) alkyl. In some embodiments, R is optionally substituted C1-8alkyl. In some embodiments, R is optionally substituted C1-6aliphatic. In some embodiments, R is optionally substituted C1-6alkyl. In some embodiments, R is optionally substituted −CH2−C3-6cycloaliphatic. In some embodiments, R is optionally substituted −CH2−C3-6cycloaliphatic. In some embodiments, R is optionally substituted −CH2−C3-6 cycloalkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is isopropyl. In some embodiments, R is −CF3. In some embodiments, R is −CH2CF3. In some embodiments, R is butyl. In some embodiments, R is t-butyl.

[0003] In some embodiments, R is optionally substituted 3-10 membered (e.g., 3-9, 3-8, 3-7, 3-6, 5- 7, 4, 5, 6, 7, 8, 9, 10, etc.) cycloaliphatic. In some embodiments, R is optionally substituted C3-10 cycloalkyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl.

[0004] In some embodiments, R is optionally substituted C1-10 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) heteroaliphatic having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, R is optionally substituted C1-6 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) heteroaliphatic having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, R is optionally substituted C1-10 (e.g., C1- 6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) heteroaliphatic having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted C1-6 (e.g., C1-6, C2-8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) heteroaliphatic having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted C1-6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur C1-6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted C1-6 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur C1-6 heteroaliphatic having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is heteroalkyl.

[0005] In some embodiments, R is optionally substituted 3-15 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 3-10, 3-7, 4-10, 4-6, etc.) membered heterocyclic ring having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, R is optionally substituted 3-15 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 3-10, 3-7, 4- 10, 4-6, etc.) membered heterocyclic ring having 1-5 (e.g., 1-4, 1-3, 1-2, 1, 2, 3, 4, 5, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally Page 114 of 448 12513573v1Attorney Docket No.: 2010581-1441 substituted 3-10 (e.g., 3-9, 3-8, 3-7, 3-6, 5-7, 4, 5, 6, 7, 8, 9, 10, etc.) membered heterocyclyl having 1-4 (e.g., 1, 2, 3, 4, 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 3-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 3- membered heterocyclyl having one heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 4-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 5-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6-membered heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 8-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 9-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 10-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, there is one carbon atom in a heterocyclyl ring. In some embodiments, there are two or more (e.g., 2-14, 2-9, 2-6, 2-4, 3-10, 3-5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, etc.) carbon atoms in a heterocyclyl ring.

[0006] In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted naphthyl. In some embodiments, R is optionally substituted 1-naphthyl. In some embodiments, R is optionally substituted 2-naphthyl. In some embodiments, R is naphthyl.

[0007] In some embodiments, R is optionally substituted 5-14 (e.g., 5, 6, 9, 10, 14, etc.) membered heteroaryl having 1-6 (e.g., 1-5, 1-4, 1, 2, 3, 4, 5, 6, etc.) heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. In some embodiments, R is optionally substituted 5-14 (e.g., 5, 6, 9, 10, 14, etc.) membered heteroaryl having 1-6 (e.g., 1-5, 1-4, 1, 2, 3, 4, 5, 6, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted 5-10 (e.g., 5, 6, 9, 10, etc.) membered heteroaryl having 1-6 (e.g., 1-5, 1-4, 1, 2, 3, 4, 5, 6, etc.) heteroatoms independently selected from oxygen, nitrogen and sulfur. In some embodiments, R is optionally substituted 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, a heteroaryl ring is monocyclic and is 5-membered. In some embodiments, a heteroaryl ring is monocyclic and is 6-membered. In some embodiments, a heteroaryl ring is bicyclic and is 9-membered. In some embodiments, a heteroaryl ring is bicyclic and is Page 115 of 448 12513573v1Attorney Docket No.: 2010581-1441 10-membered. In some embodiments, a heteroaryl ring is tricyclic and is 14-membered. In some embodiments, R is optionally substituted 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 5- membered heteroaryl having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted 6- membered heteroaryl having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 8-10 membered aromatic ring having 1-6 heteroatoms nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 9-membered aromatic ring having 1-6 heteroatoms nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 10-membered aromatic ring having 1-6 heteroatoms nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 9-membered aromatic ring having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, R is optionally substituted bicyclic 10- membered aromatic ring having 1 heteroatom nitrogen, oxygen and sulfur. In some embodiments, at least one heteroatom is nitrogen. In some embodiments, at least one heteroatom is oxygen. In some embodiments, at least one heteroatom is sulfur. In some embodiments, each heteroatom is the same. In some embodiments, at least one heteroatom is different from another heteroatom.

[0008] In some embodiments, a provided compound, e.g., an oligonucleotide, comprises , ,Page 116 of 448 12513573v1Attorney Docket No.: 2010581-1441 ,Page 117 of 448 12513573v1Attorney Docket No.: 2010581-1441Page 118 of 448 12513573v1Attorney Docket No.: 2010581-1441 NH OPage 119 of 448 12513573v1Attorney Docket No.: 2010581-1441. In some embodiments, the presentsome embodiments, an oligonucleotide comprises such a nucleoside. In some embodiments, R5E−Cy5E−SU(−BA)− is Page 120 of 448 12513573v1Attorney Docket No.: 2010581-1441 OPage 121 of 448 12513573v1Attorney Docket No.: 2010581-1441 NH OPage 122 of 448 12513573v1Attorney Docket No.: 2010581-1441a structure.

[0010] As described herein, various groups may be optionally substituted. Substituents are routinely utilized in chemistry including in development of various therapeutics. Many substituents can be utilized in accordance with the present disclosure. In some embodiments, an optionally substituted group is unsubstituted. In some embodiments, an optionally substituted group is substituted. Substituents are Page 123 of 448 12513573v1Attorney Docket No.: 2010581-1441 preferably those that result in the formation of compounds for a desired property, activity, use, etc., as described herein. In some embodiments, compounds are stable for therapeutic use as described herein. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a substituent is a hydrocarbon group. In some embodiments, a substituent comprises a heteroatom. In some embodiments, a substituent comprises multiple heteroatoms. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, sulfur, phosphorus and silicon. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, halogen, nitrogen, oxygen, and sulfur. In some embodiments, each atom in a substituent is independently selected from hydrogen, carbon, fluorine, chlorine, bromine, iodine, nitrogen, oxygen, and sulfur. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in a substituent is about or no more than about 1; in some embodiments, it is no more than about 2; in some embodiments, it is no more than about 3; in some embodiments, it is no more than about 4; in some embodiments, it is no more than about 5; in some embodiments, it is no more than about 6; in some embodiments, it is no more than about 7; in some embodiments, it is no more than about 8; in some embodiments, it is no more than about 9; in some embodiments, it is no more than about 10; in some embodiments, it is no more than about 11; in some embodiments, it is no more than about 12; in some embodiments, it is no more than about 13; in some embodiments, it is no more than about 14; in some embodiments, it is no more than about 15; in some embodiments, it is no more than about 20. In some embodiments, the total number of carbon and non- halogen heteroatom(s) in each substituent is independently no more than about 20. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 15. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 10. In some embodiments, the total number of carbon and non-halogen heteroatom(s) in each substituent is independently no more than about 6. Nucleobases

[0329] Various nucleobases may be utilized in phosphoramidites, nucleosides, oligonucleotides, etc., in accordance with the present disclosure. In some embodiments, a nucleobase is a natural nucleobase, the most commonly occurring ones being A, T, C, G and U. In some embodiments, a nucleobase is a modified nucleobase in that it is not A, T, C, G or U. In some embodiments, a nucleobase is optionally substituted A, T, C, G or U, or a substituted tautomer of A T, C, G or U. In some embodiments, a nucleobase is optionally substituted A, T, C, G or U, e.g., 5mC, 5-hydroxymethyl C, etc. In some embodiments, a nucleobase is alkyl-substituted A, T, C, G or U. In some embodiments, a nucleobase is A. In some Page 124 of 448 12513573v1Attorney Docket No.: 2010581-1441 embodiments, a nucleobase is T. In some embodiments, a nucleobase is C. In some embodiments, a nucleobase is G. In some embodiments, a nucleobase is U. In some embodiments, a nucleobase is 5mC. In some embodiments, a nucleobase is substituted A, T, C, G or U. In some embodiments, a nucleobase is a substituted tautomer of A, T, C, G or U. In some embodiments, substitution protects certain functional groups in nucleobases to minimize undesired reactions during oligonucleotide synthesis. Suitable technologies for nucleobase protection in oligonucleotide synthesis are widely known in the art and may be utilized in accordance with the present disclosure. In some embodiments, BA is a nucleobase as described herein. In some embodiments, BA2is a nucleobase as described herein.

[0330] In some embodiments, a nucleobase is a natural nucleobase or a modified nucleobase derived from a natural nucleobase. Examples include uracil, thymine, adenine, cytosine, and guanine optionally having their respective amino groups protected by acyl protecting groups, 2-fluorouracil, 2-fluorocytosine, 5-bromouracil, 5-iodouracil, 2,6-diaminopurine, azacytosine, pyrimidine analogs such as pseudoisocytosine and pseudouracil and other modified nucleobases such as 8-substituted purines, xanthine, or hypoxanthine (the latter two being the natural degradation products). Certain examples of modified nucleobases are disclosed in Chiu and Rana, RNA, 2003, 9, 1034-1048, Limbach et al. Nucleic Acids Research, 1994, 22, 2183-2196 and Revankar and Rao, Comprehensive Natural Products Chemistry, vol.7, 313. In some embodiments, a modified nucleobase is substituted uracil, thymine, adenine, cytosine, or guanine. In some embodiments, a modified nucleobase is a functional replacement, e.g., in terms of hydrogen bonding and / or base pairing, of uracil, thymine, adenine, cytosine, or guanine. In some embodiments, a nucleobase is optionally substituted uracil, thymine, adenine, cytosine, 5-methylcytosine, or guanine. In some embodiments, a nucleobase is uracil, thymine, adenine, cytosine, 5-methylcytosine, or guanine.

[0331] In some embodiments, a modified base is optionally substituted adenine, cytosine, guanine, thymine, or uracil, or a tautomer thereof. In some embodiments, a modified nucleobase is a modified adenine, cytosine, guanine, thymine or uracil, modified by one or more modifications by which: a nucleobase is modified by one or more optionally substituted groups independently selected from acyl, halogen, amino, azide, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, heteroaryl, carboxyl, hydroxyl, biotin, avidin, streptavidin, substituted silyl, and combinations thereof; one or more atoms of a nucleobase are independently replaced with a different atom selected from carbon, nitrogen and sulfur; one or more double bonds in a nucleobase are independently hydrogenated; or one or more aryl or heteroaryl rings are independently inserted into a nucleobase.

[0332] In some embodiments, a modified nucleobase is a modified nucleobase reported in, e.g., Page 125 of 448 12513573v1Attorney Docket No.: 2010581-1441 WO2017 / 210647. In some embodiments, modified nucleobases are expanded-size nucleobases in which one or more aryl and / or heteroaryl rings, such as phenyl rings, have been added. Certain examples of modified nucleobases, including nucleobase replacements, are described in the Glen Research catalog (Glen Research, Sterling, Virginia); Krueger AT et al., Acc. Chem. Res., 2007, 40, 141-150; Kool, ET, Acc. Chem. Res., 2002, 35, 936-943; Benner S.A., et al., Nat. Rev. Genet., 2005, 6, 553-543; Romesberg, F.E., et al., Curr. Opin. Chem. Biol., 2003, 7, 723-733; or Hirao, I., Curr. Opin. Chem. Biol., 2006, 10, 622-627. In some embodiments, an expanded-size nucleobase is an expanded-size nucleobase described in, e.g., WO2017 / 210647. In some embodiments, modified nucleobases are moieties such as corrin- or porphyrin- derived rings. Certain porphyrin-derived base replacements have been described in, e.g., Morales-Rojas, H and Kool, ET, Org. Lett., 2002, 4, 4377-4380. In some embodiments, a porphyrin-derived ring is a porphyrin-derived ring described in, e.g., WO2017 / 219647. In some embodiments, a modified nucleobase is a modified nucleobase described in, e.g., WO2017 / 219647. In some embodiments, a modified nucleobase is fluorescent. Examples of such fluorescent modified nucleobases include phenanthrene, pyrene, stillbene, isoxanthine, isozanthopterin, terphenyl, terthiophene, benzoterthiophene, coumarin, lumazine, tethered stillbene, benzo-uracil, naphtho-uracil, etc., and those described in e.g., WO2017 / 210647. In some embodiments, a nucleobase or modified nucleobase is selected from: C5- propyne T, C5-propyne C, C5-Thiazole, phenoxazine, 2-thio-thymine, 5-triazolylphenyl-thymine, diaminopurine, and N2-aminopropylguanine.

[0333] In some embodiments, a modified nucleobase is selected from 5-substituted pyrimidines, 6- azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and O-6 substituted purines. In certain embodiments, modified nucleobases are selected from 2- aminopropyladenine, 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N- methylguanine, 6-N- methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5- propynyl (−C≡C-CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5- ribosyluracil (pseudouracil), 4- thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7- methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3- deazaguanine, 3-deazaadenine, 6-N- benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N- benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. In some embodiments, modified nucleobases are tricyclic pyrimidines, such as l,3-diazaphenoxazine-2-one, l,3-diazaphenothiazine-2-one or 9-(2-aminoethoxy)-l,3-diazaphenoxazine-2- one (G-clamp). In some embodiments, modified nucleobases are those in which the purine or pyrimidine base is replaced with other heterocycles, for example, 7-deaza- adenine, 7-deazaguanosine, 2-aminopyridine or 2- pyridone. In some embodiments, modified nucleobases Page 126 of 448 12513573v1Attorney Docket No.: 2010581-1441 are those disclosed in US 3687808, The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J.I., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y.S., Chapter 15, Antisense Research and Applications, Crooke, S.T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; or in Chapters 6 and 15, Antisense Drug Technology, Crooke S.T., Ed., CRC Press, 2008, 163-166 and 442-443.

[0334] In some embodiments, modified nucleobases and methods thereof are those described in US 20030158403, US 3687808, US 4845205, US 5130302, US 5134066, US 5 175273, US 5367066, US 5432272, US 5434257, US 5457187, US 5459255, US 5484908, US 5502177, US 5525711, US 5552540, US 5587469, US 5594 121, US 5596091, US 5614617, US 5645985, US 5681941, US 5750692, US 5763588, US 5830653, or US 6005096.

[0335] In some embodiments, a modified nucleobase is substituted. In some embodiments, a modified nucleobase is substituted such that it contains, e.g., heteroatoms, alkyl groups, or linking moieties connected to fluorescent moieties, biotin or avidin moieties, or other protein or peptides. In some embodiments, a modified nucleobase is a “universal base” that is not a nucleobase in the most classical sense, but that functions similarly to a nucleobase. One example of a universal base is 3-nitropyrrole.

[0336] In some embodiments, nucleosides that can be utilized in provided technologies comprise modified nucleobases and / or modified sugars, e.g., 4-acetylcytidine; 5-(carboxyhydroxylmethyl)uridine; 2’-O-methylcytidine; 5-carboxymethylaminomethyl-2-thiouridine; 5-carboxymethylaminomethyluridine; dihydrouridine; 2’-O-methylpseudouridine; beta,D-galactosylqueosine; 2’-O-methylguanosine; N6- isopentenyladenosine; 1-methyladenosine; 1-methylpseudouridine; 1-methylguanosine; l-methylinosine; 2,2-dimethylguanosine; 2-methyladenosine; 2-methylguanosine; N7-methylguanosine; 3-methyl-cytidine; 5-methylcytidine; 5-hydroxymethylcytidine; 5-formylcytosine; 5-carboxylcytosine; N6-methyladenosine; 7-methylguanosine; 5-methylaminoethyluridine; 5-methoxyaminomethyl-2-thiouridine; beta,D- mannosylqueosine; 5-methoxycarbonylmethyluridine; 5-methoxyuridine; 2-methylthio-N6- isopentenyladenosine; N-((9-beta,D-ribofuranosyl-2-methylthiopurine-6-yl)carbamoyl)threonine; N-((9- beta,D-ribofuranosylpurine-6-yl)-N-methylcarbamoyl)threonine; uridine-5-oxyacetic acid methylester; uridine-5-oxyacetic acid (v); pseudouridine; queosine; 2-thiocytidine; 5-methyl-2-thiouridine; 2- thiouridine; 4-thiouridine; 5-methyluridine; 2’-O-methyl-5-methyluridine; and 2’-O-methyluridine.

[0337] In some embodiments, a nucleobase, e.g., a modified nucleobase comprises one or more biomolecule binding moieties such as e.g., antibodies, antibody fragments, biotin, avidin, streptavidin, receptor ligands, or chelating moieties. In other embodiments, a nucleobase is 5-bromouracil, 5-iodouracil, or 2,6-diaminopurine. In some embodiments, a nucleobase comprises substitution with a fluorescent or biomolecule binding moiety. In some embodiments, a substituent is a fluorescent moiety. In some embodiments, a substituent is biotin or avidin. Page 127 of 448 12513573v1Attorney Docket No.: 2010581-1441

[0338] Certain examples of nucleobases and related methods are described in US 3687808, 4845205, US 513030, US 5134066, US 5175273, US 5367066, US 5432272, US 5457187, US 5457191, US 5459255, US 5484908, US 5502177, US 5525711, US 5552540, US 5587469, US 5594121, US 5596091, US 5614617, US 5681941, US 5750692, US 6015886, US 6147200, US 6166197, US 6222025, US 6235887, US 6380368, US 6528640, US 6639062, US 6617438, US 7045610, US 7427672, US or US 7495088.

[0339] In some embodiments, an oligonucleotide comprises a nucleobase, sugar, nucleoside, and / or internucleotidic linkage which is described in any of: Gryaznov, S; Chen, J.-K. J. Am. Chem. Soc. 1994, 116, 3143; Hendrix et al.1997 Chem. Eur. J.3: 110; Hyrup et al.1996 Bioorg. Med. Chem.4: 5; Jepsen et al. 2004 Oligo. 14: 130-146; Jones et al. J. Org. Chem. 1993, 58, 2983; Koizumi et al. 2003 Nuc. Acids Res.12: 3267-3273; Koshkin et al.1998 Tetrahedron 54: 3607-3630; Kumar et al.1998 Bioo. Med. Chem. Let.8: 2219-2222; Lauritsen et al.2002 Chem. Comm.5: 530-531; Lauritsen et al.2003 Bioo. Med. Chem. Lett.13: 253-256; Mesmaeker et al. Angew. Chem., Int. Ed. Engl.1994, 33, 226; Morita et al.2001 Nucl. Acids Res. Supp.1: 241-242; Morita et al.2002 Bioo. Med. Chem. Lett.12: 73-76; Morita et al.2003 Bioo. Med. Chem. Lett. 2211-2226; Nielsen et al. 1997 Chem. Soc. Rev. 73; Nielsen et al.1997 J. Chem. Soc. Perkins Transl. 1: 3423-3433; Obika et al. 1997 Tetrahedron Lett. 38 (50): 8735–8; Obika et al. 1998 Tetrahedron Lett. 39: 5401-5404; Pallan et al. 2012 Chem. Comm. 48: 8195-8197; Petersen et al. 2003 TRENDS Biotech. 21: 74-81; Rajwanshi et al. 1999 Chem. Commun. 1395-1396; Schultz et al. 1996 Nucleic Acids Res. 24: 2966; Seth et al. 2009 J. Med. Chem. 52: 10-13; Seth et al. 2010 J. Med. Chem. 53: 8309-8318; Seth et al.2010 J. Org. Chem.75: 1569-1581; Seth et al.2012 Bioo. Med. Chem. Lett.22: 296-299; Seth et al. 2012 Mol. Ther-Nuc. Acids. 1, e47; Seth, Punit P; Siwkowski, Andrew; Allerson, Charles R; Vasquez, Guillermo; Lee, Sam; Prakash, Thazha P; Kinberger, Garth; Migawa, Michael T; Gaus, Hans; Bhat, Balkrishen; et al. From Nucleic Acids Symposium Series (2008), 52(1), 553-554; Singh et al.1998 Chem. Comm. 1247-1248; Singh et al.1998 J. Org. Chem. 63: 10035-39; Singh et al.1998 J. Org. Chem. 63: 6078-6079; Sorensen 2003 Chem. Comm. 2130-2131; Ts'o et al. Ann. N. Y. Acad. Sci. 1988, 507, 220; Van Aerschot et al. 1995 Angew. Chem. Int. Ed. Engl. 34: 1338; Vasseur et al. J. Am. Chem. Soc.1992, 114, 4006; WO 2007090071; or WO 2016 / 079181.

[0340] In some embodiments, an oligonucleotide comprises a modified nucleobase, nucleoside or nucleotide which is described in any of: Feldman et al.2017 J. Am. Chem. Soc.139: 11427-11433, Feldman et al.2017 Proc. Natl. Acad. Sci. USA 114: E6478-E6479, Hwang et al.2009 Nucl. Acids Res.37: 4757- 4763, Hwang et al. 2008 J. Am. Chem. Soc. 130: 14872-14882, Lavergne et al. 2012 Chem. Eur. J. 18: 1231-1239, Lavergne et al. 2013 J. Am. Chem. Soc. 135: 5408-5419, Ledbetter et al.2018 J. Am. Chem. Soc.140: 758-765, Malyshev et al.2009 J. Am. Chem. Soc.131: 14620-14621, Seo et al.2009 Chem. Bio. Chem. 10: 2394-2400, e.g., d3FB, d2Py analogs, d2Py, d3MPy, d4MPy, d5MPy, d34DMPy, d35DMPy, d45DMPy, d5FM, d5PrM, d5SICS, dFEMO, dMMO2, dNaM, dNM01, dTPT3, nucleotides with 2’-azido, Page 128 of 448 12513573v1Attorney Docket No.: 2010581-1441 2’-chloro, 2’-amino or arabinose sugars, isocarbostiryl-, napthyl- and azaindole-nucleotides, and modifications and derivatives and functionalized versions thereof, e.g., those in which the sugar comprises a 2’-modification and / or other modification, and dMMO2 derivatives with meta-chlorine, -bromine, - iodine, -methyl, or -propinyl substituents.

[0341] In some embodiments, a nucleobase comprises at least one optionally substituted ring which comprises a heteroatom ring atom. In some embodiments, a nucleobase comprises at least one optionally substituted ring which comprises a nitrogen ring atom. In some embodiments, such a ring is aromatic. In some embodiments, a nucleobase is bonded to a sugar through a heteroatom. In some embodiments, a nucleobase is bonded to a sugar through a nitrogen atom. In some embodiments, a nucleobase is bonded to a sugar through a ring nitrogen atom.

[0342] In some embodiments, an oligonucleotide comprises a nucleobase or modified nucleobase as described in US 10167309, US 11643657, US 11718638, US 11608355 and US 20230089442.

[0343] In some embodiments, a nucleobase is an optionally substituted purine base residue. In some embodiments, a nucleobase is a protected purine base residue. In some embodiments, a nucleobase is an optionally substituted adenine residue. In some embodiments, a nucleobase is a protected adenine residue. In some embodiments, a nucleobase is an optionally substituted guanine residue. In some embodiments, a nucleobase is a protected guanine residue. In some embodiments, a nucleobase is an optionally substituted cytosine residue. In some embodiments, a nucleobase is a protected cytosine residue. In some embodiments, a nucleobase is an optionally substituted thymine residue. In some embodiments, a nucleobase is a protected thymine residue. In some embodiments, a nucleobase is an optionally substituted uracil residue. In some embodiments, a nucleobase is a protected uracil residue. In some embodiments, a nucleobase is an optionally substituted 5-methylcytosine residue. In some embodiments, a nucleobase is a protected 5-methylcytosine residue.

[0344] In some embodiments, a provided oligonucleotide comprises a modified nucleobase described in, e.g., US 5552540, US 6222025, US 6528640, US 4845205, US 5681941, US 5750692, US 6015886, US 5614617, US 6147200, US 5457187, US 6639062, US 7427672, US 5459255, US 5484908, US 7045610, US 3687808, US 5502177, US 55257116235887, US 5175273, US 6617438, US 5594121, US 6380368, US 5367066, US 5587469, US 6166197, US 5432272, US 7495088, US 5134066, or US 5596091. In some embodiments, a nucleobase is described in WO 2020 / 154344, WO 2020 / 154343, WO 2020 / 154342, WO 2020 / 165077, WO 2020 / 201406, WO 2020 / 216637, or WO 2020 / 252376, and can be utilized in accordance with the present disclosure.

[0345] In some embodiments, a nucleobase is a protected base residue as used in oligonucleotide preparation. In some embodiments, a nucleobase is a base residue illustrated in US 2011 / 0294124, US 2015 / 0211006, US 2015 / 0197540, WO 2015 / 107425, WO 2017 / 192679, WO 2018 / 022473, WO Page 129 of 448 12513573v1Attorney Docket No.: 2010581-1441 2018 / 098264, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, WO 2019 / 032612, or WO 2020 / 191252. Sugars

[0346] Various sugars, including modified sugars, can be utilized in accordance with the present disclosure in, e.g., phosphoramidites, nucleosides, oligonucleotides, etc. In some embodiments, SU is a sugar as described herein. In some embodiments, SU2is a sugar as described herein.

[0347] The most common naturally occurring nucleosides comprise ribose sugars (e.g., in RNA) or deoxyribose sugars (e.g., in DNA) linked to the nucleobases adenosine (A), cytosine (C), guanine (G), thymine (T) or uracil (U). In some embodiments, a sugar, e.g., in a phosphoramidite, a nucleoside, an oligonucleotide, etc., is a natural DNA sugar (in DNA nucleic acids or oligonucleotides, having the structure , wherein a nucleobase is attached to the 1’ position, and the 3’ and 5’ positions arelinkages (as appreciated by those skilled in the art, if at the 5’-end of oligonucleotide, the 5’ position may be connected to a 5’-end group, and if at the 3’-end of an oligonucleotide, the 3’ position may be connected to a 3’-end group (e.g., −OH)). In some embodiments, a sugar is a natural RNA sugar (in RNA nucleic acids or oligonucleotides, having the structure of , wherein a nucleobase is attached to the 1’ position, and the 3’ and 5’ positions arelinkages (as appreciated by those skilled in the art, if at the 5’-end of an oligonucleotide, the 5’ position may be connected to a 5’-end group (e.g., −OH), and if at the 3’-end of an oligonucleotide, the 3’ position may be connected to a 3’-end group (e.g., −OH)). In some embodiments, a sugar is a modified sugar in that it is not a natural DNA sugar or a natural RNA sugar. Among other things, modified sugars may provide improved stability. In some embodiments, modified sugars can be utilized to alter and / or optimize one or more hybridization characteristics. In some embodiments, modified sugars can be utilized to alter and / or optimize target nucleic acid recognition. In some embodiments, modified sugars can be utilized to optimize Tm. In some embodiments, modified sugars can be utilized to improve oligonucleotide activities.

[0348] Sugars can be bonded to internucleotidic linkages at various positions. For example, internucleotidic linkages can be bonded to the 2’, 3’, 4’ or 5’ positions of sugars. In some embodiments, Page 130 of 448 12513573v1Attorney Docket No.: 2010581-1441 as most commonly in natural nucleic acids, an internucleotidic linkage connects with one sugar at the 5’ position and another sugar at the 3’ position unless otherwise indicated.

[0349] In some embodiments, a sugar is an optionally substituted natural DNA or RNA sugar. In some embodiments, a sugar is optionally . In some embodiments, the 2’ position isoptionally substituted. In some embodiments, a sugar . In some embodiments, a sugar has, wherein each of R1s, R2s, R3s, R4s, and R5sis sugar modification (e.g., those described in USUS 20180216108, US 20180216107, US 9598458, WO 2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO 2017 / 192679, WO 2017 / 210647, WO 2018 / 098264, WO 2018 / 022473, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 032612, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, WO 2019 / 032612, WO 2020 / 191252, WO 2021 / 071858, or WO 2022 / 099159, the substituents, sugar modifications, descriptions of R1s, R2s, R3s, R4s, and R5s, and modified sugars of each of which are independently incorporated herein by reference). In some embodiments, each of R1s, R2s, R3s, R4s, and R5sis independently Rs, wherein each Rsis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −Ls−R’, −Ls−OR’, −Ls−SR’, −Ls−N(R’)2, −O−Ls−OR’, −O−Ls−SR’, or −O−Ls−N(R’)2, wherein each R’ is independently as described herein, and each Lsis independently a covalent bond or optionally substituted bivalent C1-6aliphatic or heteroaliphatic having 1- 4 heteroatoms; or two Rsare taken together to form a bridge −Ls−. In some embodiments, R’ is optionally substituted C1-10aliphatic. In some embodiments, a sugar has the . In someembodiments, a sugar has the In some embodiments, a sugar has the structuresome embodiments, a sugar has the In some embodiments,Page 131 of 448 12513573v1Attorney Docket No.: 2010581-1441 a sugar has the some embodiments, a sugar has the. In some embodiments, a sugar has the . In some embodiments, a sugar has thestructure . In some embodiments, a sugar has the . In some substituted C1-6 aliphatic. In some is optionallystituted 6 some embodiments, R5subsis optionally substituted some embodiments, R5sis methyl. In some embodiments, a sugar has the structure . In some embodiments, asugar has the structure . In some embodiments, a sugar has the structure Insome embodiments, a sugar has the structure . In some embodiments, a 2’-modified sugarhas the structure of , wherein R2sis a 2’-modification. In some embodiments, a sugar has the, wherein R2sis −H, halogen, or −OR, wherein R is optionally substituted C1-6R2sis −H. In some embodiments, R2sis −F. In some embodiments, R2sis −OMe. In some embodiments, a modified nucleoside is mA, mT, mC, m5mC, mG, mU, etc., in which R2sis −OMe. In some embodiments, R2sis −OCH2CH2OMe. In some embodiments, R2sis −OCH2CH2OH. In some embodiments, a 2’-F modified sugar has the structure . In some embodiments, a 2’-OMe modified sugar has the structure . In some embodiments, a 2’-MOE modified sugarPage 132 of 448 12513573v1Attorney Docket No.: 2010581-1441 has the ..

[0350] In some embodiments, a sugar has the structure of , wherein R2sand R4sare taken together to form −Ls−, wherein Lsis a covalent bond or optionally substituted bivalent C1-6 aliphatic or heteroaliphatic having 1-4 heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen or sulfur). In some embodiments, Lsis optionally substituted C2−O−CH2−C4. In some embodiments, Lsis C2−O−CH2−C4. In some embodiments, Lsis C2−O−(R)-CH(CH2CH3)−C4. In some embodiments, Lsis C2−O−(S)-CH(CH2CH3)−C4.

[0351] In some embodiments, a sugar has the , wherein each variableis independently as described herein. In some embodiments, a sugar has the structure , wherein each variable is independently as described herein. In some embodiments, R5sembodiments, a sugar has the , wherein each variable is independently as described herein. In someIn some embodiments, R3sis −H. In some embodiments, a sugar . In some embodiments, a sugar .

[0352] In some embodiments, a sugar is optionally , wherein Xsis −S−, −Se−, or optionally substituted −CH2−. In some embodiments, thesubstituted. In some embodiments, a sugar is . In some embodiments, a sugar has the structure ofPage 133 of 448 12513573v1Attorney Docket No.: 2010581-1441 a US2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO 2017 / 192679, WO 2017 / 210647, WO 2018 / 098264, WO 2018 / 022473, WO 2018 / 223056, WO 2018 / 223073, WO 2018 / 223081, WO 2018 / 237194, WO 2019 / 032607, WO 2019 / 032612, WO 2019 / 055951, WO 2019 / 075357, WO 2019 / 200185, WO 2019 / 217784, WO 2019 / 032612, WO 2020 / 191252, WO 2021 / 071858, and / or WO 2022 / 099159, the substituents, descriptions of R1s, R2s, R3s, R4s, and R5s, and modified sugars of each of which are independently incorporated herein by reference). In some embodiments, each of R1s, R2s, R3s, R4s, and R5sis independently Rs, wherein each Rsis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −Ls−R’, −Ls−OR’, −Ls−SR’, −Ls−N(R’)2, −O−Ls−OR’, −O−Ls−SR’, or −O−Ls−N(R’)2, wherein each R’ is independently as described herein, and each Lsis independently a covalent bond or optionally substituted bivalent C1-6aliphatic or heteroaliphatic having 1-4 heteroatoms; or two Rsare taken together to form a bridge −Ls−. In some embodiments, R’ is optionally substituted C1-10aliphatic. In some embodiments, a . thePage 134 of 448 12513573v1Attorney Docket No.: 2010581-1441 some embodiments, R5sis optionally substituted C1-6aliphatic. C1-6alkyl. In some embodiments, R5sis optionallyR5sis methyl. In some embodiments, a sugar has the structure 2’-embodiments, R2sis −F. In some embodiments, R2sis −OMe. In some embodiments, R2sis −OCH2CH2OMe. In some embodiments, R2sis −OCH2CH2OH. In some embodiments, a modified sugar has the structure . In some embodiments, a modified sugar has the structure of. In some embodiments, a modified sugar having the structure . Insome embodiments, a modified sugar having the structure . In some embodiments, Xsis −S−. In some embodiments, Xsis optionally substitutedembodiments, Xsis −CH2−. In some embodiments, a modified sugar having the structure . In some embodiments, aPage 135 of 448 12513573v1Attorney Docket No.: 2010581-1441 modified sugar having the structure .

[0353] or, wherein each R2sis independently −H, −F, −OH or −ORak, wherein Rakis optionally and each of the other variables is independently as described herein. In someembodiments, each of R1s, R3s, R4s, and R5sis independently −H. In some embodiments, each of R1s, R3sand R4s, and one of R5s, are independently −H, and the other R5sis independently C1-6aliphatic. In some embodiments, an occurrence of R5sis C1-6aliphatic, e.g., methyl. In some embodiments, R2sis −H. In some embodiments, R2sis −F. In some embodiments, R2sis --ORak. In some embodiments, R2sis −OMe. In some embodiments, R2sis −OCH2CH2CH3. In some embodiments, at least one occurrence of R2sis −H. In some embodiments, at least one occurrence of R2sis not −H. In some embodiments, Xsis −O−. In some embodiments, Xsis −S−. In some embodiments, Xsis optionally substituted −CH2−. In some embodiments, Xsis −CH2−.

[0354] In some embodiments, a sugar has the , wherein R2sand R4sare taken together to form −Ls−, wherein Lsis a covalent bondbivalent C1-6 aliphatic or heteroaliphatic having 1-4 heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen or sulfur). In some embodiments, Lsis optionally substituted C2−O−CH2−C4. In some embodiments, Lsis C2−O−CH2−C4. In some embodiments, Lsis C2−O−(R)- CH(CH2CH3)−C4. In some embodiments, Lsis C2−O−(S)-CH(CH2CH3)−C4. In some embodiments, Xsis −S−. In some embodiments, Xsis optionally substituted −CH2−. In some embodiments, Xsis −CH2−. In some embodiments, Xsis −Se−.

[0355] In some embodiments, a sugar has the , wherein each variablePage 136 of 448 12513573v1Attorney Docket No.: 2010581-1441 is independently as described herein. In some embodiments, a sugar has the structure , wherein each variable is independently as described herein. In some embodiments,embodiments, a sugar has the , wherein each variable is independently as described herein. In some In some embodiments, R3sis −H. In some sembodiments, X is −S−. In some substituted −CH2−. In some embodiments, Xsis −CH2−.

[0356] In some embodiments, a nucleoside comprising a modified sugar has the structure of or a salt form thereof, wherein BAsis −H or an optionally substituted or protected BA), and R2sis as2sdescribed herein. In some embodiments, R is −OH, halogen, or optionally substituted C1-C6 alkoxy. In some embodiments, BAsis −H. In some embodiments, BAsis an optionally substituted or protected nucleobase. In some embodiments, BAsis BA. In some embodiments, R2sis −F. In some embodiments, a nucleoside comprising a modified sugar has the structure of or a salt form thereof, wherein each variable is independently as described herein. In someR2sis −H, −OH, halogen, or optionally substituted C1-C6 alkoxy. In some embodiments, R2sis −H. In some embodiments, R2sis −F. In some embodiments, a nucleoside comprising a modified sugar has the structure of , wherein each variable is as described herein. In some embodiments, anucleoside comprising a modified sugar has the structure or a salt form thereof, whereineach variable is independently as described herein. In some R2sis −H, −OH, halogen, or optionally substituted C1-C6 alkoxy. In some embodiments, R2sis −H. In some embodiments, R2sis −F. Page 137 of 448 12513573v1Attorney Docket No.: 2010581-1441 In some embodiments, a nucleoside comprising a modified sugar has the or a salt form thereof, wherein R2s’is Rs, and each of Rs, R2sand BAsis In some embodiments, each of R2sand R2s’is independently −H, −OH, halogen, orC1- C6 alkoxy. In some embodiments, R2sis −H. In some embodiments, R2sis −OH. In some embodiments, R2sis halogen. In some embodiments, R2sis −F. In some embodiments, R2sis optionally substituted C1-C6 alkoxy. In some embodiments, R2s’is −H. In some embodiments, R2s’is −OH. In some embodiments, R2s’is halogen. In some embodiments, R2s’is −F. In some embodiments, R2s’is optionally substituted C1-C6 alkoxy. In some embodiments, BAsis −H. In some embodiments, BAsis an optionally substituted or protected nucleobase. In some embodiments, BAsis BA. In some embodiments, nucleobases such as BA are optionally substituted or protected for oligonucleotide synthesis. Certain such nucleosides including sugars and nucleobases and uses thereof are described in WO 2020 / 154342. In some embodiments, an oligonucleotide comprises arabinoside, 2’-deoxy-2’-fluoro-arabinoside, 2’-OR arabinoside, adeoxycytidine, DNA-abasic, RNA-abasic, or 2’-OR abasic, wherein R is not hydrogen (e.g., optionally substituted C1-6 aliphatic). In some embodiments, 2’-OR is 2’-OMe. In some ...

Claims

Attorney Docket No.: 2010581-1441 CLAIMS 1. A compound, wherein the compound is a compound of formula P or a salt thereof: R5E−Cy5E−SU(−BA)−OP(OR1)N(R2)(R3) P wherein: R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511;0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −RRC11, −ORRC11, −C(O)ORRC11, or −N(RRC11)2; independently R’;SU is a sugar moiety or ; LSUis L; s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, Page 407 of 448 12513573v1Attorney Docket No.: 2010581-1441 −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; BA is hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each of R1, R2, and R3is independently R’, or two or three of R1, R2, and R3are taken together with their intervening atoms to form ; Ring A is an optionally ring having, in addition to the interveningatoms, 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; t is 0-5; each Rsis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −Ls−Rs11, −Ls−ORs11, −Ls−SRs11, −Ls−N(Rs11)2, −O−Ls−ORs11, −O−Ls−SRs11, −O−Ls−N(Rs11)2, −C(Rs11)3 or −Ls−Si(Rs11)3; each Rs11is independently R’; each Lsis independently L; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. Page 408 of 448 12513573v1Attorney Docket No.: 2010581-1441 2. The compound of claim 1, wherein −P(OR1)N(R2)(R3) is −P(OCH2CH2CN)N[CH(CH3)2]2.

3. The compound of claim 1, wherein two or three of R1, R2, and R3are taken together with their intervening atoms to form .

4. The compound 1-3, wherein Ring A is or comprises optionally substituted.

5. The compound of claim 1, , wherein each of Rs1and Rs2is independently Rs.

6. The compound of claim 1, wherein −P(OR1)N(R2)(R3) .

7. The compound of any one of claims 3-6, wherein anLsis optionally substituted −CH2−.

8. The compound of any one of claims 3-7, wherein an occurrence of Rsis −Ls−Si(Rs11)3.

9. The compound of any one of claims 3-7, wherein Rsis −Ls−Rs11.

10. The compound of claim 9, wherein Rs11is −S(O)2R wherein R is optionally substituted C1-6 aliphatic.

11. The compound of claim 1, wherein −P(OR1)N(R2)(R3) ,.

12. The compound of claim 1, wherein −P(OR1)N(R2)(R3) or.wherein the compound comprises a moiety of formula O: R5E−Cy5E−SU(−BA)−, O Page 409 of 448 12513573v1Attorney Docket No.: 2010581-1441 wherein: R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R52is −LR52−R521; R53is −LR53−R531; R54is −LR54−R541; each of LR5E, LR51, LR52, LR53and LR54is independently L; each of R511, R521, R531, R541, RL51, RL52, RL53and RL54is independently R’; –Cy5E– is a covalent ; Ring C is an optionally 3-10 membered ring having 0-5 heteroatomsindependently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; each of RRC11is independently R’; SU is a sugar ; LSUis L;s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; Page 410 of 448 12513573v1Attorney Docket No.: 2010581-1441 BA is hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

14. A compound, wherein the compound is a compound of formula O’ or a salt thereof: R5E−Cy5E−SU(−BA)−ROL, O’ wherein: R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R52is −LR52−R521; R53is −LR53−R531; Page 411 of 448 12513573v1Attorney Docket No.: 2010581-1441 R54is −LR54−R541; each of LR5E, LR51, LR52, LR53and LR54is independently L; each of R511, R521, R531, R541, RL51, RL52, RL53and RL54is independently R’; –Cy5E– is a covalent ; Ring C is an optionally 3-10 membered ring having 0-5 heteroatoms independently selected fromphosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; each of RRC11is independently R’; SU is a sugar ; LSUis L;s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; BA is hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; ROLis −LOL−ROL1; LOLis L; ROL1is R’ or a nucleic acid moiety; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; Page 412 of 448 12513573v1Attorney Docket No.: 2010581-1441 –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

15. A compound, wherein the compound comprises a moiety of formula IL: −CyIL−P(WIL)(RIL)−LIL−, IL wherein: –CyIL– is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; WILis O or S; RILis −RIL1, −ORIL1, −SRIL1, −N(RIL1)(RIL2), −N=C(RIL1)(RIL2), or −N=C[N(RIL1)(RIL2)][N(RIL3)(RIL4)]; RIL1is −LIL1−RIL11; RIL2is −LIL2−RIL21; RIL3is −LIL3−RIL31;LIL3and LIL4is independently L; each of RIL11, RIL21, RIL31and RIL41is independently R’; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10aliphatic and C1-10heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; Page 413 of 448 12513573v1Attorney Docket No.: 2010581-1441 each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

16. A compound, wherein the compound comprises a moiety of formula O-E: R5E−Cy5E−, O-E wherein: R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R52is −LR52−R521;0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −RRC11, −ORRC11, Page 414 of 448 12513573v1Attorney Docket No.: 2010581-1441 −C(O)ORRC11, or −N(RRC11)2; each of RRC11is independently R’; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10aliphatic and C1-10heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

17. A compound, wherein the compound is a compound of formula O-E-a or a salt thereof: R5E−Cy5E−ROL, O-E-a wherein: R5Eis R’, −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511;each of LR5E, LR51, LR52, LR53and LR54is independently L; Page 415 of 448 12513573v1Attorney Docket No.: 2010581-1441 each of R511, R521, R531, R541, RL51, RL52, RL53and RL54is independently R’; ; substituted bivalent 3-10 membered ring having 0-5 heteroatomsnitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −RRC11, −ORRC11, −C(O)ORRC11, or −N(RRC11)2; each of RRC11is independently R’; ROLis −LOL−ROL1; LOLis L; ROL1is R’ or a nucleic acid moiety; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10aliphatic and C1-10heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

18. A compound, wherein the compound comprises a moiety of formula O-II: R5E−L5E−SU(−BA)−CyIL−P(WIL)(RIL)−LIL−, O-II wherein: Page 416 of 448 12513573v1Attorney Docket No.: 2010581-1441 R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R520-5 heteroatomsindependently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; each of RRC11is independently R’; SU is a sugar ; LSUis L;s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; Page 417 of 448 12513573v1Attorney Docket No.: 2010581-1441 BA is hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; –CyIL– is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; WILis O or S; RILis −RIL1, −ORIL1, −SRIL1, −N(RIL1)(RIL2), −N(RIL1)(RIL2), or −N=C[N(RIL1)(RIL2)][N(RIL3)(RIL4)]; RIL1is −LIL1−RIL11; RIL2is −LIL2−RIL21; RIL3is −LIL3−RIL31; RIL4is −LIL4−RIL41; each of LIL, LIL1, LIL2, LIL3and LIL4is independently L; each of RIL11, RIL21, RIL31and RIL41is independently L; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

19. A compound, wherein the compound is a compound of formula O-II-a or a salt thereof: R5E−L5E−SU(−BA)−CyIL−P(WIL)(RIL)−LIL−ROL, O-II-a Page 418 of 448 12513573v1Attorney Docket No.: 2010581-1441 wherein: R5Eis R’, −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R520-5 heteroatomsindependently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; each of RRC11is independently R’; SU is a sugar ; LSUis L;s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; Page 419 of 448 12513573v1Attorney Docket No.: 2010581-1441 BA is hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; –CyIL– is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; WILis O or S; RILis −RIL1, −ORIL1, −SRIL1, −N(RIL1)(RIL2), −N(RIL1)(RIL2), or −N=C[N(RIL1)(RIL2)][N(RIL3)(RIL4)]; RIL1is −LIL1−RIL11; RIL2is −LIL2−RIL21; RIL3is −LIL3−RIL31; RIL4is −LIL4−RIL41; each of LIL, LIL1, LIL2, LIL3and LIL4is independently L; each of RIL11, RIL21, RIL31and RIL41is independently L; ROLis −LOL−ROL1; LOLis L; ROL1is R’ or a nucleic acid moiety; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur. Page 420 of 448 12513573v1Attorney Docket No.: 2010581-1441 20. A compound, wherein the compound comprises a moiety of formula O-III: R5E−L5E−SU(−BA)−LIL−P(WIL)(RIL)−CyIL−, O-III wherein: R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R52is −LR52−R521; R53is −LR53−R531; R54is −LR54−R541; each of LR5E, LR51, LR52, LR53and LR54is independently L; each of R511, R521, R531, R541, RL51, RL52, RL53and RL54is independently R’; L5Eis −Cy5E− or −O−; –Cy5E– is a covalent ; Ring C is an optionally3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; each of RRC11is independently R’; SU is a sugar moiety or ; LSUis L; s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, Page 421 of 448 12513573v1Attorney Docket No.: 2010581-1441 −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; BA is hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; –CyIL– is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; WILis O or S; RILis −RIL1, −ORIL1, −SRIL1, −N(RIL1)(RIL2), −N(RIL1)(RIL2), or −N=C[N(RIL1)(RIL2)][N(RIL3)(RIL4)]; RIL1is −LIL1−RIL11; RIL2is −LIL2−RIL21; RIL3is −LIL3−RIL31; RIL4is −LIL4−RIL41; each of LIL, LIL1, LIL2, LIL3and LIL4is independently L; each of RIL11, RIL21, RIL31and RIL41is independently L; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, Page 422 of 448 12513573v1Attorney Docket No.: 2010581-1441 phosphorus and sulfur.

21. A compound, wherein the compound is a compound of formula O-III-a or a salt thereof: R5E−L5E−SU(−BA)−LIL−P(WIL)(RIL)−CyIL−ROL, O-III-a wherein: R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511;0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; each of RRC11is independently R’; SU is a sugar ; LSUis L;s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; Page 423 of 448 12513573v1Attorney Docket No.: 2010581-1441 each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; BA is hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; –CyIL– is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; WILis O or S; orRIL3is −LIL3−RIL31; RIL4is −LIL4−RIL41; each of LIL, LIL1, LIL2, LIL3and LIL4is independently L; each of RIL11, RIL21, RIL31and RIL41is independently R’; ROLis −LOL−ROL1; LOLis L; ROL1is R’ or a nucleic acid moiety; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10Page 424 of 448 12513573v1Attorney Docket No.: 2010581-1441 aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

22. A compound, wherein the compound comprises a moiety of formula O-II-b: R5E−L5E−SU(−BA)−CyIL−P(WIL)(RIL)−LIL−SU2(−BA2)−, O-II-b wherein: R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R52is −LR52−R521; R53is −LR53−R531; R54is −LR54−R541; each of LR5E, LR51, LR52, LR53and LR54is independently L; each of R511, R521, R531, R541, RL51, RL52, RL53and RL54is independently R’; L5Eis −Cy5E− or −O−; –Cy5E– is a covalent ; Ring C is an optionally3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; each of RRC11is independently R’; each of SU and SU2is independently a sugar moiety ;Page 425 of 448 12513573v1Attorney Docket No.: 2010581-1441 LSUis L; s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; each of BA and BA2is independently hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; –CyIL– is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; WILis O or S; orRIL3is −LIL3−RIL31; RIL4is −LIL4−RIL41; each of LIL, LIL1, LIL2, LIL3and LIL4is independently L; each of RIL11, RIL21, RIL31and RIL41is independently R’; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and Page 426 of 448 12513573v1Attorney Docket No.: 2010581-1441 each R is independently hydrogen, or an optionally substituted group selected from C1-10aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

23. A compound, wherein the compound is a compound of formula O-II-c or a salt thereof: R5E−L5E−SU(−BA)−CyIL−P(WIL)(RIL)−LIL−SU2(−BA2)−ROL, O-II-c wherein: R5Eis R’, −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R52is −LR52−R521;0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; each of RRC11is independently R’; each of SU and SU2is independently a sugar moiety ;Page 427 of 448 12513573v1Attorney Docket No.: 2010581-1441 LSUis L; s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; each of BA and BA2is independently hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; –CyIL– is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; WILis O or S; RILis −RIL1, −ORIL1, −SRIL1, −N(RIL1)(RIL2), or −N=C[N(RIL1)(RIL2)][N(RIL3)(RIL4)];RIL3is −LIL3−RIL31; RIL4is −LIL4−RIL41; each of LIL, LIL1, LIL2, LIL3and LIL4is independently L; each of RIL11, RIL21, RIL31and RIL41is independently R’; ROLis −LOL−ROL1; LOLis L; ROL1is R’ or a nucleic acid moiety; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to Page 428 of 448 12513573v1Attorney Docket No.: 2010581-1441 the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

24. A compound, wherein the compound comprises a moiety of formula O-III-b: R5E−L5E−SU(−BA)−LIL−P(WIL)(RIL)−CyIL−SU2(−BA2)−, O-III-b wherein: R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R52is −LR52−R521; R53is −LR53−R531; R54is −LR54−R541; each of LR5E, LR51, LR52, LR53and LR54is independently L; each of R511, R521, R531, R541, RL51, RL52, RL53and RL54is independently R’; L5Eis −Cy5E− or −O−; –Cy5E– is a covalent ; Ring C is an optionally3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; Page 429 of 448 12513573v1Attorney Docket No.: 2010581-1441 each of RRC11is independently R’; each of SU and SU2is independently a sugar moiety or ; LSUis L; s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; each of BA and BA2is independently hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; –CyIL– is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; WILis O or S; orRIL4is −LIL4−RIL41; each of LIL, LIL1, LIL2, LIL3and LIL4is independently L; each of RIL11, RIL21, RIL31and RIL41is independently R’; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; Page 430 of 448 12513573v1Attorney Docket No.: 2010581-1441 each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

25. A compound, wherein the compound is a compound of formula O-III-c or a salt thereof: R5E−L5E−SU(−BA)−LIL−P(WIL)(RIL)−CyIL−SU2(−BA2)−ROL,wherein: R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511;0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; c is 0-5; Page 431 of 448 12513573v1Attorney Docket No.: 2010581-1441 each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; each of RRC11is independently R’; each of SU and SU2is independently a sugar moiety or ; LSUis L; s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, or −O−LSU11−N(RSU11)2, each LSU11is independently L; each RSU11is independently R’; each of BA and BA2is independently hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; –CyIL– is an optionally substituted bivalent 3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; WILis O or S; ];RIL3is −LIL3−RIL31; RIL4is −LIL4−RIL41; each of LIL, LIL1, LIL2, LIL3and LIL4is independently L; each of RIL11, RIL21, RIL31and RIL41is independently R’; ROLis −LOL−ROL1; LOLis L; ROL1is R’ or a nucleic acid moiety; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and Page 432 of 448 12513573v1Attorney Docket No.: 2010581-1441 independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

26. The compound of any one of claims 22-25, wherein SU2is .

27. The compound of claim 26, wherein LSUis optionally substituted −CH2− or a covalent bond.

28. The compound of any one of claims 22-25, orsugar. 28, where2in BA is an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

30. The compound of any one of claims 22-28, wherein BA2is an optionally substituted group, a31. The compound of any one of claims 15-30, wherein –CyIL– is an optionally substituted bivalent 3-10 (e.g., 3-6, 5-10, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered ring having 0-5 (e.g., 1, 2, 3, 4, 5, 1-5, 1-4, Page 433 of 448 12513573v1Attorney Docket No.: 2010581-1441 1-2, etc.) heteroatoms independently selected from nitrogen, oxygen and sulfur.

32. The compound of any one of claims 15-30, wherein −CyIL− is optionally substituted . compound of any one of claims 15-32, wherein WILis O.compound of any one of claims 15-32, wherein WILis S.

35. The compound of any one of claims 15-32, wherein −P(WIL)(RIL)− is −P(O)(OH)−.

36. The of one of claims 15- wherein −P − is −P −. .N wherein: R5Eis R’, −LR5E−B(L51R51)(L52R52), −LR5E−P(W5E)(L51R51)(L52R52), −LR5E−S(O)2L53R53, or −LR5E−C(O)L54R54; W5Eis O or S; L51is a covalent bond, −O−, −S−, or −N(RL51)−; L52is a covalent bond, −O−, −S−, or −N(RL52)−; L53is a covalent bond, −O−, −S−, or −N(RL53)−; L54is a covalent bond, −O−, −S−, or −N(RL54)−; R51is −LR51−R511; R52is −LR52−R521; R53is −LR53−R531; R54is −LR54−R541; each of LR5E, LR51, LR52, LR53and LR54is independently L; each of R511, R521, R531, R541, RL51, RL52, RL53and RL54is independently R’; –Cy5E– is a covalent ; Ring C is an optionally3-10 membered ring having 0-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus, boron and sulfur; Page 434 of 448 12513573v1Attorney Docket No.: 2010581-1441 c is 0-5; each RRCis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, or −RRC11, −ORRC11, −N(RRC11)2; each of RRC11is independently R’; SU is a sugar ; LSUis L;s is 0-5; Ring S is an optionally substituted 3-10 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each RSUis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −LSU11−RSU11, −LSU11−ORSU11, −LSU11−SRSU11, −LSU11−N(RSU11)2, −O−LSU11−ORSU11, −O−LSU11−SRSU11, orBA is hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; each L is independently a covalent bond, or a bivalent, optionally substituted group selected from C1-10 aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered Page 435 of 448 12513573v1Attorney Docket No.: 2010581-1441 heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

40. The compound of any one Embodiments 1-14 and 18-39, wherein SU .R1s2,45. The compound of any one of claims 1-42, wherein R5Eis −LR5E−B(L51R51)(L52R52).

46. The compound of any one of claims 1-42, wherein R5Eis −LR5E−S(O)2L53R53.

47. The compound of any one of claims 1-42, wherein R5Eis −LR5E−C(O)L54R54.

48. The compound of any one of the preceding claims, wherein Ring C is monocyclic.

49. The compound of any one of the preceding claims, wherein Ring C is an optionally substituted 5- 6 membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

50. The compound of any one of the preceding claims, wherein Ring C is optionally substituted orPage 436 of 448 12513573v1Attorney Docket No.: 2010581-1441 51. The compound of any one of claims 1-48, wherein Ring C is an optionally substituted 3-7 membered saturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. , ,N3−SU(BA)−OH, III wherein each of SU and BA is independently of any one of the preceding claims.

55. A compound, wherein the compound is a compound of formula III’ or a salt thereof: , wherein:BA is hydrogen, or an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; or BA is an optionally substituted or protected nucleobase; R2sis −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −L2s−R2a, −L2s−OR2a, −L2s−SR2a, −L2s−N(R2a)2, Page 437 of 448 12513573v1Attorney Docket No.: 2010581-1441 −O−L2s−OR2a, −O−L2s−SR2a, or −O−L2s−N(R2a)2, or R2sis L2sconnecting C2 with C1, C2, C3, C4 or C5; each L2sis independently L; each R2ais independently R’; each L is independently a bivalent, optionally substituted group selected from C1-10aliphatic and C1-10 heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; –Cy– is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

56. The compound of any one of the preceding claims, wherein BA is an optionally substituted 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

57. The compound of any one of the preceding claims, wherein BA is an optionally substituted group, wherein the , or a tautomer thereof.

58. The compound of any one of the preceding claims, wherein the compound is an oligonucleotide, wherein the length of the oligonucleotide is about or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 50, 60, 70, 80 or 90 nucleobases in length.

59. The compound of any one of the preceding claims, wherein the oligonucleotide comprises a phosphorothioate internucleotidic linkage, a natural phosphate linkage, a phosphoryl guanidine Page 438 of 448 12513573v1Attorney Docket No.: 2010581-1441 internucleotidic linkage or a MsPA internucleotidic linkage.

60. The compound of any one of the preceding claims, wherein each chiral linkage phosphorus is independently chirally controlled.

61. The compound of any one of the preceding claims, wherein each chirally controlled linkage phosphorus independently has a diastereopurity of about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5%.

62. The compound of any one of claims 13-61, wherein the compound is a RNAi agent.

63. The compound of any one of the preceding claims, wherein the compound is in a pharmaceutically acceptable salt form.

64. The compound of any one of the preceding claims, wherein the compound is in a sodium salt form.

65. A compound, wherein the compound is a compound of formula IV or a salt thereof: R5E−≡, IV wherein R5Eis of any one of the preceding claims.

66. A compound, wherein the compound is a compound of formula IV’ or a salt thereof: ,wherein: each of RP1and RP2is −O−CH2CH2CN or −O−CH2−O−C(O)−RP, wherein RPis optionally substituted tert-butyl.

67. The compound of claim 65, wherein RP1and RP2are −O−CH2CH2CN.

68. The compound of claim 65, wherein RP1and RP2are −O−CH2−O−C(O)−tBu.

69. The compound of any one of the preceding claims, wherein the purity of the compound is about or more than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

70. A method for preparing an oligonucleotide,of an oligonucleotide into −P(O)(OH)2 (e.g., a salt form thereof).

71. A method for preparing an oligonucleotide, comprising coupling a compound of any one of claims 1-64, wherein the compound is a compound of formula P or a salt thereof, to an oligonucleotide or Page 439 of 448 12513573v1Attorney Docket No.: 2010581-1441 nucleoside.

72. A method for preparing an oligonucleotide, comprising reacting a compound of any one of claims 1-64, wherein the compound is a compound of formula P or a salt thereof, with a compound comprising a −OH group.

73. The method of claim 72, wherein the −OH group is 5’-OH of an oligonucleotide.

74. The method of any one of claims 70-73, wherein the oligonucleotide preparation comprises utilized a solid support.

75. The method of any one of claims 70-74, comprising reacting a compound of any one of claims 1- 64, wherein the compound is a compound of formula P or a salt thereof, with an oligonucleotide on a solid support.

76. The method of any one of claims 70-74, comprising preparing a compound of any one of claims 13-64, wherein the compound is a compound of formula O-E or IL or a salt thereof.

77. The method of any one of claims 70-74, comprising into −P(O)(OH)2 (e.g., a salt form thereof).

78. The method of claim 77, wherein RP1and RP2are −OCH2CH2CN, and the conversion is performed in the presence of a base.

79. The method of claim 77, wherein RP1and RP2are −OCH2OC(O)tBu.

80. The method of any one of claims 70-79, wherein the conversion occurs during cleavage and deprotection that removes base protection groups and / or chiral auxiliaries and / or cleaves the oligonucleotide from a solid support.

81. The method of any one of claims 70-80, wherein the oligonucleotide prepared is a compound of any one of claims 13-64, wherein the compound is a compound of formula O-E or IL or a salt thereof.

82. A method for preparing a compound of any one of claims 1-64, wherein the compound is a compound of formula P or a salt thereof, comprising reacting a compound of any one of claims 39-64, wherein the compound is a compound of formula N or a salt thereof, with a compound of formula V or a salt thereof: ,wherein: LG is a leaving group; Page 440 of 448 12513573v1Attorney Docket No.: 2010581-1441 each of R1, R2, and R3is independently R’, or two or three of R1, R2, and R3are taken together with their intervening atoms to form ; Ring A is an optionally ring having, in addition to the intervening atoms, 0-10 heteroatomssilicon, nitrogen, oxygen, phosphorus and sulfur; t is 0-5; each Rsis independently −F, −Cl, −Br, −I, −CN, −N3, −NO, −NO2, −Ls−Rs11, −Ls−ORs11, −Ls−SRs11, −Ls−N(Rs11)2, −O−Ls−ORs11, −O−Ls−SRs11, −O−Ls−N(Rs11)2, −C(Rs11)3or −Ls−Si(Rs11)3; each Rs11is independently R’; each Lsis independently L; each L is independently a bivalent, optionally substituted group selected from C1-10aliphatic and C1-10heteroaliphatic group having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, wherein one or more methylene units of L are optionally and independently replaced by −Cy−, −O−, −S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −SC(O)−, or −C(O)O−; −Cy− is an optionally substituted bivalent 3-20 membered ring having 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −S(O)2R, or two or more R’ are taken together with their intervening atom(s) to form an optionally substituted 3-20 membered ring having, in addition to the intervening atom(s), 0-10 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-10 aliphatic, C1-10 heteroaliphatic having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, C6-14 aryl, a 5-14 membered heteroaryl ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur, and a 3-15 membered heterocyclic ring having 1-5 heteroatoms independently selected from silicon, nitrogen, oxygen, phosphorus and sulfur.

83. The method of claim 82, wherein LG is −Cl.

84. The method of any one of claims 82-83, wherein the reaction is performed in the presence of a base.

85. The method of any one of claims 70-81, comprising a method of any one of claims 82-84.

86. A method for preparing a compound of any one of claims 39-64, wherein the compound is a compound of formula N or a salt thereof, comprising reacting a compound of any one of claims 54-64, wherein the compound is a compound of formula III’ or a salt thereof, with a compound of any one of Page 441 of 448 12513573v1Attorney Docket No.: 2010581-1441 claims 65-69.

87. The method of claim 86, wherein the reaction is in the presence of a base.

88. The method of any one of claims 86-87, wherein the reaction is in the presence of a copper salt.

89. The method of any one of claims 70-85, comprising a method of any one of claims 86-88.

90. A method for preparing a compound of any one of claims 65-69, comprising oxidizing a compound of formula VI or a salt thereof: ,wherein: each of RP1and RP2is −O−CH2CH2CN or −O−CH2−O−C(O)−RP, wherein RPis optionally substituted tert-butyl.

91. The method of any one of claims 70-89, comprising a method of claim 90.

92. A method for preparing a compound of formula VI or a salt thereof: ,comprising reacting ≡−MgBr with a compound of formula VII or a salt thereof: ,wherein: LG is a leaving group; and each of RP1and RP2is −O−CH2CH2CN or −O−CH2−O−C(O)−RP, wherein RPis optionally substituted tert-butyl.

93. The method of any one of claims 70-91, comprising a method of claim 92.

94. A method for preparing a compound of formula VII or a salt thereof: ,wherein LG is −Cl, comprising reacting HO−CH2CH2−CN with PCl3in the presence of a base. Page 442 of 448 12513573v1Attorney Docket No.: 2010581-1441 95. The method of any one of claims 70-93, comprising a method of claim 94.

96. A method for preparing a compound of any one of claims 65-69, wherein each of RP1and RP2is −O−CH2−O−C(O)−RP, wherein RPis optionally substituted tert-butyl, comprising reacting a compound of formula IX or a salt thereof: ,with a compound having the structure of or a thereof: LG−CH2−O−C(O)−RP, X wherein: RPis optionally substituted tert-butyl; LG is a leaving group; each of RP3and RP4is independently −O−RSP, wherein RSPis an optionally substituted optionally substituted C1-6 aliphatic.

97. The method of any one of claims 70-89, comprising a method of claim 96.

98. A method for preparing a compound of formula IX or a salt thereof: ,comprising reacting ≡−MgBr with a compound of formula XI or a salt thereof: ,wherein: LG is a leaving group each of RP3and RP4is independently −O−RSP, wherein each RSPis independently optionally substituted C1-6 aliphatic.

99. The method of any one of claims 70-89 and 96-97, comprising a method of claim 98.

100. A method for preparing a compound of any one of claims 54-64, wherein the compound is a compound of formula III or a salt thereof, comprising reacting a compound of formula XII or a salt Page 443 of 448 12513573v1Attorney Docket No.: 2010581-1441 thereof: , wherein LG is a leaving group, with an101. A method for preparing a 54-64, wherein the compound is a compound of formula III or a salt thereof, comprising reacting a compound of formula XII’ or a salt thereof: ,wherein LG is a leaving group, with an azide.

102. The method of any one of claims 70-99, comprising a method of any one of claims 100-101.

103. A method for preparing a compound of formula XII or a salt thereof: , wherein LG is −I, comprising reacting aXIII or a salt thereof: ,with I2; or a method for preparing a compound of formula XII’ or a salt thereof: ,Page 444 of 448 12513573v1Attorney Docket No.: 2010581-1441 wherein LG is −I, comprising reacting a compound of formula XIII’ or a salt thereof: ,with I2.

104. The method of any one of claims 70-102, comprising a method of claim 103.

105. An agent, comprising: a first oligonucleotide; and a second oligonucleotide; wherein: the first and second oligonucleotides comprise base sequences complementary to each other and are capable of forming a duplex; and the first oligonucleotide is or comprises a compound of any one of claims 13-64.

106. The agent of claim 105, wherein the agent is a dsRNAi agent.

107. The agent of claim 106, wherein the first oligonucleotide is a guide strand.

108. The agent of claim 106, wherein the first oligonucleotide is a passenger strand.

109. The agent of any one of claims 105-108, wherein each chiral linkage phosphorus is independently chirally controlled.

110. A pharmaceutical composition, comprising a compound or agent of any one of the preceding claims and a pharmaceutically acceptable carrier.

111. A chirally controlled composition of a compound or agent of any one of the preceding claims.

112. A composition comprising a compound or agent of any one of the preceding claims, wherein diastereopurity of a chiral linkage phosphorus is DS, wherein DS is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5%; or a composition comprising a compound or agent of any one of the preceding claims, wherein diastereopurity of each chiral linkage phosphorus is independently DS, wherein DS is about or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5%; or a composition comprising a compound or agent of any one of the preceding claims, wherein diastereopurity of the compound or agent is about or at least about (DS)nc, wherein DS is about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5%, and nc is the number of chirally controlled linkage phosphorus.

113. A method for preparing a compound of any one of claims 13-64, an agent of any one of claims Page 445 of 448 12513573v1Attorney Docket No.: 2010581-1441 105-109 and a composition of any one of claims 110-112, comprising a method of any one of claims 70- 104.

114. A method for reducing level of a target nucleic acid or a product thereof in a system, comprising administering to the system a compound of any one of claims 13-64, an agent of any one of claims 105- 109 and a composition of any one of claims 110-112, wherein the compound or agent, or the compound or agent in the composition, comprises a base sequence that is complementary to the base sequence of the target nucleic acid or a portion thereof.

115. A method for reducing level of a target nucleic acid or a product thereof in a system, comprising administering to the system a compound of any one of claims 13-64, an agent of any one of claims 105- 109 and a composition of any one of claims 110-112, wherein the compound or agent, or the compound or agent in the composition, can hybridize to the target nucleic acid or a portion thereof.

116. A method for treating a condition, disorder or disease, comprising administering or delivering to a subject suffering therefrom an effective amount of a compound of any one of claims 13-64, an agent of any one of claims 105-109 and a composition of any one of claims 110-112, wherein the condition, disorder or disease is associated with level of a target nucleic acid or a product thereof, wherein the compound or agent, or the compound or agent in the composition, comprises a base sequence that is complementary to the base sequence of the target nucleic acid or a portion thereof; or a method for treating a condition, disorder or disease, comprising administering or delivering to a subject suffering therefrom an effective amount of a compound of any one of claims 13-64, an agent of any one of claims 105-109 and a composition of any one of claims 110-112, wherein the condition, disorder or disease is associated with level of a target nucleic acid or a product thereof, wherein the compound or agent, or the compound or agent in the composition, can hybridize to the target nucleic acid or a portion thereof; or a method for preventing a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto an effective amount of a compound of any one of claims 13-64, an agent of any one of claims 105-109 and a composition of any one of claims 110-112, wherein the condition, disorder or disease is associated with level of a target nucleic acid or a product thereof, wherein the compound or agent, or the compound or agent in the composition, comprises a base sequence that is complementary to the base sequence of the target nucleic acid or a portion thereof; or a method for preventing a condition, disorder or disease, comprising administering or delivering to a subject susceptible thereto an effective amount of a compound of any one of claims 13-64, an agent of any one of claims 105-109 and a composition of any one of claims 110-112, wherein the condition, disorder or disease is associated with level of a target nucleic acid or a product thereof, wherein the compound or agent, or the compound or agent in the composition, can hybridize to the target nucleic acid Page 446 of 448 12513573v1Attorney Docket No.: 2010581-1441 or a portion thereof.

117. A compound or composition of any one of the preceding claims, for use in the prevention or treatment of a condition, disease or disorder, or for manufacturing a medicament for the prevention or treatment of a condition, disease or disorder.

118. Use of a compound or composition of any one of the preceding claims, for the prevention or treatment of a condition, disease or disorder, or for manufacturing a medicament for the prevention or treatment of a condition, disease or disorder.

119. A compound, method, agent, use, or composition of any one of Embodiments 1-739. Page 447 of 448 12513573v1