Stereoselective techniques for chiral compounds

Abstract

In particular, the present disclosure provides techniques for the stereoselective preparation of chiral compounds. In some embodiments, the prepared chiral compounds are useful for the chirality-controlled preparation of oligonucleotides. In some embodiments, such oligonucleotides target transcripts associated with various conditions, disorders, or diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 309,467, filed February 11, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Chiral compounds are useful for many purposes, including stereoselective synthesis. For example, chiral compounds can be used, among other things, as chiral auxiliaries in the stereoselective synthesis of oligonucleotides. These compounds are also useful, among other things, as biologically active agents, including therapeutic agents, in many cases. Summary of the Invention [Means for solving the problem]

[0003] Summary of the Invention In particular, stereopure and stereoenriched chiral compounds are important reagents for stereoselective oligonucleotide synthesis. In some embodiments, the present disclosure provides techniques (e.g., compounds, methods, etc.) for the stereoselective preparation of chiral compounds. In some embodiments, the provided techniques are particularly useful because they offer higher selectivity, shorter synthetic routes, higher overall yields, milder reaction conditions, lower production costs, and / or easier scalability compared to reference techniques, e.g., reported existing techniques. For example, in some embodiments, the provided techniques utilize more stable intermediates compared to existing techniques (e.g., ketones, which are more stable compared to aldehydes).

[0004] In some embodiments, the present disclosure provides techniques for preparing chiral compounds, such as chiral phosphoramidites or salts thereof. In some embodiments, the present disclosure provides techniques for preparing cis-cyclic phosphoramidites (e.g., -LR) where the phosphorus atom is chiral and is the ring atom. 1(relative to) In some embodiments, the provided techniques can deliver increased cis cyclic phosphoramidite levels relative to the corresponding P epimer. In some embodiments, the present disclosure provides techniques for epimerization of P chiral centers. For example, in some embodiments, the present disclosure provides techniques for epimerization of cis cyclic phosphoramidites at the chiral phosphorus atom.

[0005] In some embodiments, the present disclosure provides techniques for preparing oligonucleotides comprising a PN bond. In some embodiments, the oligonucleotide comprises a sulfonyl PN bond. In some embodiments, the provided techniques utilize reduced and / or equivalent amounts of azide reagent. In some embodiments, the provided techniques reduce costs and / or improve safety.

[0006] In some embodiments, the present disclosure provides a compound of formula P: [ka] or a salt thereof, comprising: Formula INT-1: [ka] or a salt thereof to provide a compound of formula P or a salt thereof; wherein each variable is independently as described herein.

[0007] In some embodiments, the present disclosure provides a compound of formula Pa: [ka] or a salt thereof, comprising: Formula INT-1-a: [ka] or a salt thereof to provide a compound of formula Pa or a salt thereof; wherein each variable is independently as described herein.

[0008] In some embodiments, the provided techniques do not require cryogenic conditions and can be carried out on a larger scale with easier operating conditions. In some embodiments, the provided techniques have provided chiral compounds with higher stereoselectivity. In some embodiments, the provided techniques have provided chiral compounds with higher stereopurity. In some embodiments, the provided techniques have provided chiral compounds with higher chemical purity. [Brief explanation of the drawings]

[0009] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 is an NMR spectrum showing the isomerization of OMeU-L-DPSE cis isomer 8-3 to trans isomer 8-4. [Figure 2] FIG. 1 is an NMR spectrum showing the isomerization of OMeU-L-PSM cis isomer 8-11 to trans isomer 8-12. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description of Some Embodiments 1.Definition As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thFurther, general principles of organic chemistry are specified in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0011] As used herein, unless otherwise clear from the 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 or not used in conjunction with "limited to"), and "include" (whether or not used in conjunction with "not limited to") may be understood to encompass the itemized elements or steps, whether presented by themselves or presented with one or more additional elements 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 allow for standard variations as understood by one of ordinary skill in the art; and (vi) when ranges are given, the endpoints are included.

[0012] Unless otherwise specified, descriptions of oligonucleotides and their elements (e.g., base sequence, sugar modifications, internucleotide linkages, stereochemistry of the linking phosphorus, etc.) are in 5' to 3' order. Unless otherwise specified, the oligonucleotides described herein may be provided and / or utilized in salt form, particularly pharmaceutically acceptable salt form. As one of skill in the art will appreciate, oligonucleotides may be in various forms, e.g., acid, base, or salt form. In some embodiments, individual oligonucleotides within a composition may be considered to be of the same constitution and / or structure even within such a composition (e.g., a liquid composition), and a particular such oligonucleotide may be in a different salt form at a particular moment (and may be dissolved or may exist as an anionic form when the oligonucleotide chain is, for example, in a liquid composition). For example, one of skill in the art will appreciate that at a given pH, individual internucleotide bonds along an oligonucleotide chain may be in the acid (H) form or one of the possible salt forms (e.g., sodium salts or salts of different cations depending on the ions that may be present in the preparation or composition), and may be in their acid form (e.g., all cations, if present, may be H). + It will be understood that so long as the nucleotides (replaced by ) are of the same composition and / or structure, such individual oligonucleotides may be considered to be of the same composition and / or structure, as appropriate.

[0013] Aliphatic: As used herein, "aliphatic" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is fully saturated or contains one or more units of unsaturation, or a combination thereof. Unless otherwise specified, aliphatic groups contain 1-100 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, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof.

[0014] Alkyl: As used herein, the term "alkyl" has its ordinary meaning in the art and can 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, an 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-C for a straight chain). 20 , C2 to C for branched chains 20), or about 1-10. In some embodiments, cycloalkyl rings have from about 3-10 carbon atoms in their ring structure, and such rings are monocyclic, bicyclic, or polycyclic, or have about 5, 6, or 7 carbons in the ring structure. In some embodiments, alkyl groups can be lower alkyl groups, where the lower alkyl group has 1-4 carbon atoms (e.g., C1-C4 for a straight chain lower alkyl).

[0015] Alkenyl: As used herein, the term "alkenyl" refers to an alkyl group, as defined herein, having one or more double bonds.

[0016] Alkynyl: As used herein, the term "alkynyl" refers to an alkyl group, as defined herein, having one or more triple bonds.

[0017] Aryl: The term "aryl," used alone or as part of a larger moiety of "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or polycyclic ring system having a total of 5 to 30 ring members, wherein at least one ring in these systems is aromatic. In some embodiments, an aryl group is a monocyclic, bicyclic, or polycyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in these systems is aromatic, and wherein each ring in these systems contains 3 to 7 ring members. 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, including, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl, and the like, which may bear one or more substituents. As used herein, also included within the scope of the term "aryl" are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl. In some embodiments, the aryl group has its radical or point of attachment on the aromatic ring.

[0018] Chiral control: As used herein, "chiral control" refers to the ability to control the stereochemical designation of the chiral bridging phosphorus in a chiral internucleotide bridge within an oligonucleotide. In some embodiments, control is achieved through chiral elements not present in the sugar and base portions of the oligonucleotide; for example, in some embodiments, control is achieved by using one or more chiral auxiliaries during preparation of the oligonucleotide, as exemplified in the present disclosure. In contrast to chiral control, those skilled in the art understand that conventional oligonucleotide synthesis without the use of chiral auxiliaries is unable to control the stereochemistry at the chiral internucleotide linkage when such conventional oligonucleotide synthesis is used to form the chiral internucleotide linkage. In some embodiments, the stereochemical designation of each chiral linking phosphorus in a chiral internucleotide linkage within an oligonucleotide is controlled.

[0019] Chirality-controlled oligonucleotide composition: As used herein, the terms "chirality-controlled oligonucleotide composition," "chirality-controlled nucleic acid composition," and the like refer to a composition comprising multiple oligonucleotides (or nucleic acids) that share 1) a common base sequence, 2) a common backbone bridge pattern, and 3) a common backbone phosphorus modification pattern, where the multiple oligonucleotides share the same stereochemistry at one or more chiral internucleotide bridges (chirality-controlled internucleotide bridges), and the level of the multiple oligonucleotides in the composition is predetermined. In some embodiments, each chiral internucleotide linkage is a chiral-controlled internucleotide linkage, and the composition is a completely chiral-controlled oligonucleotide composition. In some embodiments, not all chiral internucleotide linkages are chiral-controlled internucleotide linkages, and the composition is a partially chiral-controlled oligonucleotide composition. In some embodiments, the chiral-controlled oligonucleotide composition comprises a predetermined level of individual oligonucleotide or nucleic acid types. In some embodiments, the multiple oligonucleotides share the same configuration, optionally in various forms (e.g., acid, base, salt, etc.).

[0020] Alicyclic: The term "alicyclic group," as used herein, refers to a saturated or partially unsaturated aliphatic monocyclic, bicyclic, or polycyclic ring system, e.g., having 3 to 30 ring members, where the aliphatic ring system is optionally substituted. Alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, cycloalkyl has 3 to 6 carbons. The term "alicyclic group" can also include an aliphatic ring fused to one or more aromatic or non-aromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where a radical or point of attachment is on the aliphatic ring. In some embodiments, a carbocyclic group is bicyclic. In some embodiments, a carbocyclic group is tricyclic. In some embodiments, a carbocyclic group is polycyclic. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon, or a C8-C8 ring that is fully saturated or contains one or more units of unsaturation but is not aromatic, with a single point of attachment to the rest of the molecule. 10 Bicyclic hydrocarbons or C9-C6 rings that are fully saturated or contain one or more units of unsaturation but are not aromatic, with a single point of attachment to the rest of the molecule 16 Refers to tricyclic hydrocarbons.

[0021] Halogen: The term "halogen" means F, Cl, Br or I.

[0022] Heteroaliphatic: The term "heteroaliphatic" has its ordinary meaning in the art and refers to an aliphatic group, as described herein, in which one or more carbon atoms have been replaced with a heteroatom (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.).

[0023] Heteroalkyl: The term "heteroalkyl" is given its ordinary meaning in the art and refers to an alkyl group, as described herein, in which one or more carbon atoms have been replaced with a heteroatom (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). Examples of heteroalkyl include, but are not limited to, alkoxy, poly(ethylene glycol)-, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[0024] Heteroaryl: The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to a monocyclic, bicyclic, or polycyclic ring system having a total of 5 to 30 ring members, in which at least one ring in the system is aromatic and at least one aromatic ring atom is a heteroatom. In some embodiments, heteroaryl groups are groups 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, heteroaryl groups have 6, 10, or 14 pi electrons shared in the cyclic arrangement, and have 1 to 5 heteroatoms in addition to the carbon atoms. Heteroaryl groups include, but are not limited to, 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. The terms "heteroaryl" and "heteroar-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, 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. Heteroaryl groups can be monocyclic, bicyclic, or polycyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," and any of these terms include optionally substituted rings.The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl group, where the alkyl and heteroaryl portions independently are optionally substituted.

[0025] Heteroatom: The term "heteroatom" means an atom that is not carbon or hydrogen. In some embodiments, a heteroatom is oxygen, sulfur, nitrogen, phosphorus, or silicon (nitrogen, sulfur, phosphorus, or silicon in any oxidized form; any basic nitrogen or substitutable nitrogen of a heterocyclic ring (e.g., N as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including N-substituted pyrrolidinyl) and the like).

[0026] Heterocyclyl: The terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocyclic ring," as used herein, are used interchangeably and refer to a monocyclic, bicyclic, or polycyclic ring moiety (e.g., 3-30 members) 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 has, in addition to carbon atoms, one or more, preferably 1 to 4, 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 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or +It can be 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 groups include, but are not limited to, 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 group" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can 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.

[0027] Oligonucleotide Type: As used herein, the phrase "oligonucleotide type" refers to an oligonucleotide having a particular base sequence, a pattern of backbone linkages (i.e., a pattern of internucleotide linkage types, e.g., phosphate, phosphorothioate, etc.), a pattern of backbone chiral centers (i.e., a pattern of bond phosphorus stereochemistry (Rp / Sp)), and a pattern of backbone phosphorus modifications (e.g., "-XLR" in Formula I). 1 " type" is used to define oligonucleotides having a pattern of "groups." In some embodiments, oligonucleotides of a commonly designated "type" are structurally identical to each other.

[0028] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass groups with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0029] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose amount suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those suitable for: oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual and those targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., as a sterile solution or suspension or sustained release formulation, e.g., by subcutaneous, intramuscular, intravenous or epidural injection; topical application, e.g., as a cream, ointment or controlled release patch or spray applied to the skin, lungs or oral cavity; vaginal or rectal, e.g., as a suppository, cream or foam; sublingual; ocular; transdermal; or intranasal, pulmonary and other mucosal surface application.

[0030] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that 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.

[0031] 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 that encapsulates a material, which is involved in carrying or transporting a compound of interest from one organ or part of the body to another. 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 that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, 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; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffer solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic, compatible substances utilized in pharmaceutical formulations.

[0032] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of such compounds that are suitable for use in a pharmaceutical context, i.e., salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by other methods used in the art, such as ion exchange. In some embodiments, pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, These include, but are not limited to, salts of 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, and the like.In some embodiments, pharmaceutically acceptable salts include non-toxic base addition salts, such as, but not limited to, those formed by acidic groups of provided compounds (e.g., phosphate linkage groups of oligonucleotides, phosphorothioate linkage groups of oligonucleotides, etc.) with bases. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. In some embodiments, pharmaceutically acceptable salts are ammonium salts. In some embodiments, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates, as appropriate.

[0033] Predetermined: Predetermined (or pre-determined) means, for example, intentionally selected, as opposed to occurring randomly or achieved without control. Those skilled in the art will understand, upon reading this specification, that the present disclosure provides techniques that allow for the incorporation of selected specific chemical and / or stereochemical features into oligonucleotide compositions, and further allow for the controlled preparation of oligonucleotide compositions having such chemical and / or stereochemical features. A composition so provided is "predetermined," as described herein. A composition that may contain a particular oligonucleotide because it has arisen by chance through a process that cannot be controlled to intentionally generate specific chemical and / or stereochemical features is not a "predetermined" composition. 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 predeterminable level of a plurality of oligonucleotides in a composition means that the absolute and / or relative amounts (ratios, percentages, etc.) of the plurality of oligonucleotides in the composition are controlled.

[0034] Protecting group: As used herein, the phrase "protecting group" refers to a temporary substituent that protects a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. A "Si-protecting group" is a protecting group containing a Si atom, such as Si-trialkyl (e.g., trimethylsilyl, tributylsilyl, t-butyldimethylsilyl), Si-triaryl, Si-alkyl-diphenyl (e.g., t-butyldiphenylsilyl), or Si-aryl-dialkyl (e.g., Si-phenyldialkyl). Generally, Si-protecting groups are attached to an oxygen atom. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Such protecting groups (and related protecting moieties) are described in detail below.

[0035] Protecting hydroxyl groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rdedition, John Wiley & Sons, 1999 (incorporated herein by reference in its entirety). Examples of suitable protected hydroxyl groups further include, but are not limited to, esters, carbonates, sulfonates, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of suitable esters include formates, acetates, propionates, valerates, crotonates, and benzoates. Specific examples of suitable esters include formates, benzoyl formates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates, 4,4-(ethylenedithio)pentanoates, pivalates (trimethylacetates), crotonates, 4-methoxy-crotonates, benzoates, benzyl p-benzoates, and 2,4,6-trimethylbenzoates. Examples of suitable carbonates include 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl carbonates. Examples of suitable silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl ether, and other trialkylsilyl ethers. Examples of suitable alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, and allyl ethers or derivatives thereof. Examples of alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, β-(trimethylsilyl)ethoxymethyl, and tetrahydropyran-2-yl ether. Examples of suitable arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl ethers.

[0036] Protected amines are well known in the art and include those described in detail in Greene (1999). Suitable mono-protected amines further include, but are not limited to, aralkylamines, carbamates, allylamines, amides, and the like. Examples of suitable mono-protected amino moieties include triphenylmethylamino (-NH-CPh), t-butyloxycarbonylamino (-NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxycarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethylcarbonyl (-NHFmoc), formamide, acetamide, chloroacetamide, dichloroacetamide, trichloroacetamide, phenylacetamide, trifluoroacetamide, benzamide, t-butyldiphenylsilyl, and the like. Suitable di-protected amines include amines substituted with two substituents independently selected from those described above as mono-protected amines, and further include cyclic imides such as phthalimide, maleimide, succinimide, etc. Suitable di-protected amines also include pyrroles, 2,2,5,5-tetramethyl-[1,2,5]azadisilolidine, etc., and azides.

[0037] Protected aldehydes are well known in the art and include those described in detail in Greene (1999). Suitable protected aldehydes further include, but are not limited to, acyclic acetals, cyclic acetals, hydrazones, imines, etc. Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3-dioxanes, 1,3-dioxolanes, semicarbazones, and derivatives thereof.

[0038] Protected carboxylic acids are well known in the art and include those described in detail in Greene (1999). Suitable protected carboxylic acids further include, but are not limited to, optionally substituted C 1~6 These include aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, etc. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl esters, where each group is optionally substituted. Further suitable protected carboxylic acids include oxazolines and orthoesters.

[0039] Protected thiols are well known in the art and include those described in detail in Greene (1999). Suitable protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioesters, to name a few.

[0040] Substituted: As described herein, compounds of the present disclosure may contain optionally substituted and / or substituted moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that remain substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0041] Suitable monovalent substituents are halogen; -(CH2) 0~4 R o ;-(CH2) 0~4 OR o ;-O(CH2) 0~4 R o , -O-(CH2) 0~4 C(O)OR o ;-(CH2) 0~4 CH(OR o )2;R o may be substituted with -(CH2) 0~4 Ph;R o may be substituted with -(CH2) 0~4 O(CH2) 0~1 Ph;R o may be substituted with -CH=CHPh; R o may be substituted with -(CH2) 0~4 O(CH2) 0~1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0~4 N(R)2;-(CH2) 0~4 N(R)C(O)R;-N(R)C(S)R;-(CH2) 0~4N(R)C(O)NR2;-N(R)C(S)NR2;-(CH2) 0~4 N(R)C(O)OR;-N(R)N(R)C(O)R;-N(R)N(R)C(O)NR2;-N(R)N(R)C(O)OR;-(CH2) 0~4 C(O)R;-C(S)R;-(CH2) 0~4 C(O)OR;-(CH2) 0~4 C(O)SR;-(CH2) 0~4 C(O)OSiR3;-(CH2) 0~4 OC(O)R;-OC(O)(CH2) 0~4 SR, -SC(S)SR;-(CH2) 0~4 SC(O)R;-(CH2) 0~4 C(O)NR2;-C(S)NR2;-C(S)SR;-SC(S)SR, -(CH2) 0~4 OC(O)NR2;-C(O)N(OR)R;-C(O)C(O)R;-C(O)CH2C(O)R;-C(NOR)R;-(CH2) 0~4 SSR;-(CH2) 0~4 S(O)R;-(CH) 0~4 S(O)2OR;-(CH2) 0~4 OS(O)2R;-S(O)2NR2;-(CH2) 0~4 S(O)R;-N(R)S(O)2NR2;-N(R)S(O)2R;-N(OR)R;-C(NH)NR2;-P(O)2R;-P(O)R2;-OP(O)R2;-OP(O)(OR)2;-SiR3;-OSiR3;-(C 1~4 linear or branched alkylene)ON(R)2, or -(C 1~4 straight-chain or branched alkylene)C(O)ON(R)2, where each R may be substituted as defined below and independently represents hydrogen, C 1~20 C having 1 to 5 heteroatoms independently selected from aliphatic, nitrogen, oxygen, sulfur, silicon, and phosphorus 1~20 Heteroaliphatic, -CH2-(C 6~14 aryl), -O(CH2) 0~1 (C 6~14aryl), -CH2- (a 5-14 membered heteroaryl ring), a 5-20 membered, monocyclic, bicyclic or polycyclic saturated, partially unsaturated or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or notwithstanding the above definitions, two independent occurrences of R taken together with their intervening atoms form a 5-20 membered, monocyclic, bicyclic or polycyclic saturated, partially unsaturated or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined below.

[0042] Suitable monovalent substituents on R (or the ring formed by two independent occurrences of R taken together with their intervening atoms) are independently halogen, —(CH) 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、 -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ●is unsubstituted or, when preceded by "halo", is substituted with one or more halogens only, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R include =0 and =S.

[0043] Suitable divalent substituents include: =O, =S, =NNR. * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O- or -S(C(R * 2)) 2~3 S-, where R * Each independent occurrence of is hydrogen, C which may be substituted as defined below 1~6 The group is selected from aliphatic and unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of is hydrogen, C which may be substituted as defined below 1~6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0044] R * Suitable substituents on the aliphatic groups are halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH2, -NHR ● , -NR ● 2 or -NO2, where each R ● is unsubstituted or, when preceded by "halo", is substituted with one or more halogens only, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0045] In some embodiments, a suitable substituent on a substitutable nitrogen is —R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R † )S(O)2R † wherein each R † are independently hydrogen, C which may be substituted as defined below 1~6 Aliphatic, unsubstituted -OPh or unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or R † two independent occurrences of together with their intervening atoms form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0046] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH2, -NHR ● , -NR ● 2 or -NO2, where each R ● is unsubstituted or, when preceded by "halo", is substituted with one or more halogens only, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0047] Unsaturated: The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0048] 2. Detailed Description of Specific Embodiments Chiral compounds have a variety of uses. For example, chiral compounds containing -OH and -NH- groups are widely used chiral auxiliaries. In some embodiments, the chiral compounds described herein are chiral auxiliaries containing -OH and -NH- groups. In some embodiments, the compounds disclosed herein are used to prepare phosphoramidites. In some embodiments, the phosphoramidites of the present disclosure are used as monomers for oligonucleotide synthesis.

[0049] Among other things, the present disclosure provides techniques (e.g., compounds, methods, etc.) for the stereoselective preparation of chiral compounds. In some embodiments, the provided techniques are particularly useful because they offer higher selectivity, shorter synthetic routes, higher overall yields, milder reaction conditions, lower manufacturing costs, and / or easier scale-up compared to existing techniques (e.g., those reported in U.S. Pat. No. 9,598,458). For example, in some embodiments, the provided techniques utilize more stable intermediates compared to existing techniques (e.g., ketones, which are more stable compared to aldehydes). In some embodiments, the provided techniques do not require cryogenic conditions and can be carried out on a larger scale with easier operating conditions. In some embodiments, the provided techniques provided chiral compounds with higher stereopurity. In some embodiments, the provided techniques provided chiral compounds with higher chemical purity.

[0050] In some embodiments, the present disclosure provides stereoselective methods for preparing chiral compounds. In some embodiments, the present disclosure provides methods for preparing chiral compounds that are useful for a variety of purposes, such as chiral auxiliaries, synthetic materials, biological agents, etc.

[0051] In some embodiments, the present disclosure provides a compound of formula P: [ka] or a salt thereof, comprising: Formula INT-1: [ka] or a salt thereof to provide a compound of formula P or a salt thereof, wherein PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; R a and R b together with their intervening atoms to form ring B, where ring B is R b is an optionally substituted 4- to 15-membered ring having 0-4 heteroatoms in addition to the nitrogen atom to which is attached; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0052] In some embodiments, the compound of formula P has the structure of formula Pa. In some embodiments, the compound of formula INT-1 has the structure of formula INT-1-a.

[0053] In some embodiments, the present disclosure provides a compound of formula Pa: [ka] or a salt thereof, comprising: Formula INT-1-a: [ka] or a salt thereof to provide a compound of formula P or a salt thereof; The reduction of the compound of formula INT-1-a or a salt thereof is carried out in the presence of a reducing agent, n is 0, 1, 2, or 3; PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R 2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0054] In some embodiments, the compound of formula P or Pa has a structure of formula Pb, where each variable is independently as described herein. [ka]

[0055] In some embodiments, the compound of formula INT-1 or INT-1-a has the structure of formula INT-1-b. In some embodiments, the present disclosure provides compounds of formula Pb: [ka] or a salt thereof, comprising: Formula INT-1-b: [ka] or a salt thereof to provide a compound of formula P or a salt thereof; The reduction of the compound of formula INT-1-b or a salt thereof is carried out in the presence of a reducing agent, Each variable is independently as described herein.

[0056] In some embodiments, the compound of formula P has the structure P-1, P-2, P-3, or P-4, where each variable is independently as described herein. In some embodiments, the compound of formula Pa has the structure Pa-1, Pa-2, Pa-3, or Pa-4, where each variable is independently as described herein. In some embodiments, the compound of formula Pb has the structure Pb-1, Pb-2, Pb-3, or Pb-4, where each variable is independently as described herein. [ka] [ka]

[0057] In some embodiments, the compound of formula INT-1 has the structure of INT-1-1 or INT-1-2, where each variable is independent as described herein. In some embodiments, the compound of formula INT-1-a has the structure of INT-1-a-1 or INT-1-a-2, where each variable is independent as described herein. In some embodiments, the compound of formula INT-1 has the structure of INT-1-b-1 or INT-1-b-2, where each variable is independent as described herein. [ka]

[0058] In some embodiments, provided are methods in which the compound of formula P or a salt thereof is a compound of formula P-1, Pa-1, Pb-1 or a salt thereof, and the compound of INT-1 is a compound of formula INT-1-1, INT-1-a-1, or INT-1-b-1, respectively, or a salt thereof. In some embodiments, provided are methods in which the compound of formula P or a salt thereof is a compound of formula P-2, Pa-2, Pb-2 or a salt thereof, and the compound of INT-1 is a compound of formula INT-1-2, INT-1-a-2, or INT-1-b-2, respectively, or a salt thereof. In some embodiments, provided are methods in which the compound of formula P or a salt thereof is a compound of formula P-3, Pa-3, Pb-3 or a salt thereof, and the compound of INT-1 is a compound of formula INT-1-2, INT-1-a-2, or INT-1-b-2, respectively, or a salt thereof. In some embodiments, in the provided methods, the compound of formula P or a salt thereof is a compound of formula P-4, Pa-4, Pb-4 or a salt thereof, and the compound of INT-1 is a compound of formula INT-1-1, INT-1-a-1, or INT-1-b-1, or a salt thereof. In some embodiments, a mixture of compounds of formulas INT-1-1 and INT-1-2, or compounds of formulas INT-1-a-1 and INT-1-a-2, or compounds of formulas INT-1-b-1 and INT-1-b-2, or a salt thereof, is utilized. In some embodiments, the compound of formula INT-1-1, INT-1-a-1, or INT-1-b-1, or a salt thereof, is selectively reduced. In some embodiments, the compound of formula INT-1-2, INT-1-a-2, or INT-1-b-2, or a salt thereof, is selectively reduced. In some embodiments, the product is formed stereoselectively as described herein.

[0059] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, R s is R as described herein. In some embodiments, R sis an optionally substituted group selected from H, halogen, CN, COOR, OR, N(R), or phenyl and 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R s is an optionally substituted group selected from H, Cl, Br, CN, COOMe, COOEt, OMe, NMe, or phenyl and 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. s is H. In some embodiments, R s is halogen. In some embodiments, R s is F. In some embodiments, R s is Cl. In some embodiments, R s is Br. In some embodiments, R s is CN. In some embodiments, R s is COOR. In some embodiments, R s is COOR and R is not H. In some embodiments, R s is OR. In some embodiments, R s is OR and R is not H. In some embodiments, R s is N(R). In some embodiments, R s is R as described herein.

[0060] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, it has the structure [ka] or a salt thereof. In some embodiments, R s is R as described herein. In some embodiments, R sis an optionally substituted group selected from H, halogen, CN, COOR, OR, N(R), or phenyl and 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R s is an optionally substituted group selected from H, Cl, Br, CN, COOMe, COOEt, OMe, NMe, or phenyl and 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. s is H. In some embodiments, R s is halogen. In some embodiments, R s is F. In some embodiments, R s is Cl. In some embodiments, R s is Br. In some embodiments, R s is CN. In some embodiments, R s is COOR. In some embodiments, R s is COOR and R is not H. In some embodiments, R s is OR. In some embodiments, R s is OR and R is not H. In some embodiments, R s is N(R). In some embodiments, R s is R as described herein.

[0061] In some embodiments, R s is —H. In some embodiments, R s is halogen. In some embodiments, R s is optionally substituted C 1~6 In some embodiments, R s is an optionally substituted C 1~6 In some embodiments, the compound of formula Pa is [ka] or a salt thereof. In some embodiments, the compound of formula Pa is [ka] In some embodiments, the compound of formula Pa is [ka] In some embodiments, the compound of formula Pa is [ka] In some embodiments, the compound of formula Pa has the structure: [ka] It has the following structure.

[0062] In some embodiments, the compound of formula Pa is [ka] or a salt thereof, wherein: PG is an amino protecting group, R is independently -H or C 1~30 In some embodiments, R is an optionally substituted group selected from an aliphatic group. 1~6 In some embodiments, it is aliphatic. [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, R is optionally substituted C 1~10 It is aliphatic.

[0063] In some embodiments, the compound of formula Pa is [ka] or a salt thereof, R is independently -H or C 1~30 In some embodiments, R is an optionally substituted group selected from an aliphatic group. 1~6 It is aliphatic.

[0064] In some embodiments, the compound of formula Pa is [ka] or a salt thereof, R is independently -H or C 1~30 In some embodiments, R is an optionally substituted group selected from an aliphatic group. 1~6 It is aliphatic.

[0065] In some embodiments, the compound of formula Pa is [ka] or a salt thereof, R is independently -H or C 1~30In some embodiments, R is an optionally substituted group selected from an aliphatic group. 1~6 It is aliphatic.

[0066] In some embodiments, the compound of formula Pa is [ka] or a salt thereof, R is independently -H or C 1~30 In some embodiments, R is an optionally substituted group selected from an aliphatic group. 1~6 It is aliphatic.

[0067] In some embodiments, the compound of formula Pa is [ka] or a salt thereof, R is independently -H or C 1~30 In some embodiments, R is an optionally substituted group selected from an aliphatic group. 1~6 It is aliphatic.

[0068] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof, wherein R is an optionally substituted group selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, it is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof.

[0069] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof, wherein: PG is an amino protecting group, Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, it is an optionally substituted group selected from [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof.

[0070] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof, wherein: Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 Aryl is an optionally substituted group selected from heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0071] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof, Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 Aryl is an optionally substituted group selected from heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0072] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof, Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 Aryl is an optionally substituted group selected from heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0073] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof, Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 Aryl is an optionally substituted group selected from heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0074] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof, Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 Aryl is an optionally substituted group selected from heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0075] As described herein, in some embodiments, each R is independently —H or a C group having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.1~10 aliphatic, C 1~10 Heteroaliphatic, C 6~10 Aryl, C 6~20 C having 1 to 5 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~20 an optionally substituted group selected from arylheteroaliphatic, 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-10 membered heterocyclyl having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-15 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 15-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0076] In some embodiments, each R is independently C 1~10 C having 1 to 5 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~10 Heteroaliphatic, C 6~10 Aryl, C 6~20 C having 1 to 5 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~20 an optionally substituted group selected from arylheteroaliphatic, 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-10 membered heterocyclyl having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-15 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 15-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0077] In some embodiments, each R is independently selected from C, e.g., -Si(R). 1~10 C having 1 to 5 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~10 Heteroaliphatic, C 6~10 Aryl, C 6~20 C having 1 to 5 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~20 Aryl is an optionally substituted group selected from heteroaliphatic, 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-10 membered heterocyclyl having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0078] In some embodiments, the compound of formula Pa is [ka] In some embodiments, it is [ka] In some embodiments, it is [ka] In some embodiments, it is [ka] In some embodiments, it is [ka] is.

[0079] In some embodiments, the compound of formula INT-1 or a salt thereof is [ka] or a salt thereof, wherein each variable is independently as described herein. [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, t is 1, which is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, Rs is R as described herein. In some embodiments, R s is an optionally substituted group selected from H, halogen, CN, COOR, OR, N(R), or phenyl and 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R s is an optionally substituted group selected from H, Cl, Br, CN, COOMe, COOEt, OMe, NMe, or phenyl and 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. s is H. In some embodiments, R s is halogen. In some embodiments, R s is F. In some embodiments, R s is Cl. In some embodiments, R s is Br. In some embodiments, R s is CN. In some embodiments, R s is COOR. In some embodiments, R s is COOR and R is not H. In some embodiments, R s is OR. In some embodiments, R s is OR and R is not H. In some embodiments, R s is N(R). In some embodiments, R s is R as described herein.

[0080] In some embodiments, the compound of formula INT-1 or a salt thereof is [ka] or a salt thereof, wherein each variable is independently as described herein. [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, R s is R as described herein. In some embodiments, R s is an optionally substituted group selected from H, halogen, CN, COOR, OR, N(R), or phenyl and 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R s is an optionally substituted group selected from H, Cl, Br, CN, COOMe, COOEt, OMe, NMe, or phenyl and 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. s is H. In some embodiments, R s is halogen. In some embodiments, R s is F. In some embodiments, R s is Cl. In some embodiments, R s is Br. In some embodiments, R s is CN. In some embodiments, R s is COOR. In some embodiments, R s is COOR and R is not H. In some embodiments, R s is OR. In some embodiments, R s is OR and R is not H. In some embodiments, R s is N(R). In some embodiments, R s is R as described herein.

[0081] In some embodiments, the compound of formula INT-1 or a salt thereof is [ka] or a salt thereof, wherein each variable is independently as described herein. [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, R s is R as described herein. In some embodiments, R s is an optionally substituted group selected from H, halogen, CN, COOR, OR, N(R), or phenyl and 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R s is an optionally substituted group selected from H, Cl, Br, CN, COOMe, COOEt, OMe, NMe, or phenyl and 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. s is H. In some embodiments, R s is halogen. In some embodiments, R s is F. In some embodiments, R s is Cl. In some embodiments, R s is Br. In some embodiments, R s is CN. In some embodiments, R s is COOR. In some embodiments, R s is COOR and R is not H. In some embodiments, R s is OR. In some embodiments, R sis OR and R is not H. In some embodiments, R s is N(R). In some embodiments, R s is R as described herein.

[0082] In some embodiments, R s is —H. In some embodiments, R s is halogen. In some embodiments, R s is optionally substituted C 1~6 In some embodiments, R s is an optionally substituted C 1~6 In some embodiments, the compound of formula INT-1 or a salt thereof is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof.

[0083] In some embodiments, the compound of formula INT-1 is [ka] or a salt thereof, wherein PG is an amino protecting group and R is independently —H or C 1~30 In some embodiments, it is an optionally substituted group selected from aliphatic. [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, R is optionally substituted C 1~6 It is aliphatic.

[0084] In some embodiments, the compound of formula INT-1 or a salt thereof is [ka] or a salt thereof, wherein R is independently —H, or C 1~30 In some embodiments, it is an optionally substituted group selected from aliphatic. [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof. In some embodiments, R is optionally substituted C 1~6 It is aliphatic.

[0085] In some embodiments, the compound of formula INT-1 or a salt thereof is [ka] or a salt thereof, wherein R is an optionally substituted group selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, it is [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof.

[0086] In some embodiments, the compound of formula INT-1 or a salt thereof is [ka] or a salt thereof, wherein: PG is an amino protecting group, Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, it is an optionally substituted group selected from [ka] or a salt thereof. In some embodiments, it is [ka] or a salt thereof.

[0087] In some embodiments, the compound of formula INT-1 or a salt thereof is [ka] or a salt thereof, Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 Aryl is an optionally substituted group selected from heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0088] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof, wherein: Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 Aryl is an optionally substituted group selected from heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0089] In some embodiments, the compound of formula Pa or a salt thereof is [ka] or a salt thereof, wherein: Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 Aryl is an optionally substituted group selected from heteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0090] In some embodiments, the compound of formula INT-1 is [ka] It has the following structure.

[0091] In some embodiments, the compound of formula INT-1, INT-1-a, or INT-1-b is [ka] In some embodiments, it is [ka] is.

[0092] In some embodiments, the compound of formula INT-1, INT-1-a, or INT-1-b is [ka] In some embodiments, it is [ka] In some embodiments, it is [ka] In some embodiments, it is [ka] In some embodiments, it is [ka] In some embodiments, it is [ka] is.

[0093] In some embodiments, the reduction is carried out in the presence of a reducing agent that is HCOOH or a salt thereof and a metal complex, such as a Ru complex described herein. In some embodiments, the reducing agent is HCOONa. In some embodiments, the reduction is carried out in the presence of water. In some embodiments, the reduction is carried out in a suitable solvent system, such as or including EtOAc, in accordance with the present disclosure.

[0094] A variety of techniques are available for preparing compounds of formula INT-1 or salts thereof according to the present disclosure.

[0095] In some embodiments, the present disclosure provides compounds of formula INT-1: [ka] or a salt thereof, Formula INT-2: [ka] or a salt thereof with a compound of formula INT-3: R 1 -LH INT-3 or a salt thereof to provide a compound of formula INT-1 or a salt thereof, In the formula, R 3 is R, and other viability is independently as described herein.

[0096] In some embodiments, the compound of formula INT-1 has the structure of formula INT-1-a. In some embodiments, the compound of formula INT-2 has the structure of formula INT-2-a. In some embodiments, the compound of formula INT-2-a has the structure of formula INT-2-b.

[0097] In some embodiments, the present disclosure provides a compound of formula INT-1-a: [ka] or a salt thereof, comprising: Formula INT-2-a: [ka] or a salt thereof with a compound of formula INT-3: R 1 -LH INT-3 or a salt thereof to provide a compound of formula INT-1-a or a salt thereof, wherein R 3 and R, and the viability of each is independently as described herein.

[0098] In some embodiments, the present disclosure provides a compound of formula INT-1-b: [ka] or a salt thereof, comprising: Formula INT-2-b: [ka] or a salt thereof with a compound of formula INT-3: R 1 -LH INT-3 or a salt thereof to provide a compound of formula INT-1-b or a salt thereof, wherein R 3 and R, and the viability of each is independently as described herein.

[0099] In some embodiments, the compound of formula INT-2 has the structure of INT-2-1 or INT-2-2, where each variable is independent as described herein. In some embodiments, the compound of formula INT-2-a has the structure of INT-2-a-1 or INT-2-a-2, where each variable is independent as described herein. In some embodiments, the compound of formula INT-2 has the structure of INT-2-b-1 or INT-2-b-2, where each variable is independent as described herein. [ka]

[0100] In some embodiments, provided are methods in which the compound of formula INT-1 or a salt thereof is a compound of formula INT-1-1, INT-1-a-1, INT-1-b-1, or a salt thereof, and the compound of INT-2 is a compound of formula INT-2-1, INT-2-a-1, or INT-2-b-1, or a salt thereof. In some embodiments, provided are methods in which the compound of formula INT-1 or a salt thereof is a compound of formula INT-1-2, INT-1-a-2, INT-1-b-2, or a salt thereof, and the compound of INT-2 is a compound of formula INT-2-2, INT-2-a-2, or INT-2-b-2, or a salt thereof. In some embodiments, the product is formed stereoselectively as described herein.

[0101] In some embodiments, the compound of formula INT-3 or a salt thereof is a salt. + It's salt.

[0102] In some embodiments, the reaction with the compound of formula INT-3 or a salt thereof is carried out in the presence of a base. In some embodiments, the base is a lithium salt. In some embodiments, the base is LiHMDS. In some embodiments, a useful solvent system is or includes THF.

[0103] A variety of techniques can be utilized to prepare compounds of formula INT-2 or salts thereof according to the present disclosure. In some embodiments, the present disclosure provides methods for preparing compounds of formula INT-2 or salts thereof, comprising: Expression INT-4: [ka] or a salt thereof; reacting a compound of formula INT-4, or a salt thereof, with an amino protecting agent to provide a compound of formula INT-2, or a salt thereof, wherein each variable is independently as described herein; The present invention provides a method comprising:

[0104] In some embodiments, the compound of formula INT-4 has the structure of formula INT-4-a. In some embodiments, the disclosure provides a method for preparing a compound of formula INT-2-a or a salt thereof, comprising: Formula INT-4-a: [ka] or a salt thereof; reacting a compound of formula INT-4-a, or a salt thereof, with an amino protecting agent to provide a compound of formula INT-2-a, or a salt thereof, wherein each variable is independently as described herein; The present invention provides a method comprising:

[0105] In some embodiments, the compound of formula INT-4 or INT-4-a has the structure of formula INT-4-b. In some embodiments, the disclosure provides a method for preparing a compound of formula INT-2-b or a salt thereof, comprising: Formula INT-4-b: [ka] or a salt thereof; reacting a compound of formula INT-4-b, or a salt thereof, with an amino protecting agent to provide a compound of formula INT-2-b, or a salt thereof, wherein each variable is independently as described herein; The present invention provides a method comprising:

[0106] In some embodiments, the compound of formula INT-4 has the structure of INT-4-1 or INT-4-2, where each variable is independently as described herein. In some embodiments, the compound of formula INT-4-a has the structure of INT-4-a-1 or INT-4-a-2, where each variable is independently as described herein. In some embodiments, the compound of formula INT-4 has the structure of INT-4-b-1 or INT-4-b-2, where each variable is independently as described herein. [ka]

[0107] In some embodiments, provided are methods in which the compound of formula INT-2 or a salt thereof is a compound of formula INT-2-1, INT-2-a-1, INT-2-b-1, or a salt thereof, and the compound of INT-4 is a compound of formula INT-4-1, INT-4-a-1, or INT-4-b-1, respectively, or a salt thereof. In some embodiments, provided are methods in which the compound of formula INT-2 or a salt thereof is a compound of formula INT-2-2, INT-2-a-2, INT-2-b-2, or a salt thereof, and the compound of INT-4 is a compound of formula INT-4-2, INT-4-a-2, or INT-4-b-2, respectively, or a salt thereof. In some embodiments, the product is formed stereoselectively as described herein.

[0108] Suitable techniques for protecting amino groups, e.g., amino protecting agents, methods, etc., are widely known and can be utilized in accordance with the present disclosure. In some embodiments, the amino protecting agent has the structure PG-LG, where LG is a leaving group and PG is as described herein. In some embodiments, LG is -Cl. In some embodiments, LG is -OH. In some embodiments, the amino protecting agent is TrtCl ( [ka] In some embodiments, the protection reaction is carried out in the presence of a base. In some embodiments, the base is N(R). In some embodiments, each R is independently C 1~6 In some embodiments, the base is TEA. In some embodiments, a useful solvent system is or comprises DCM.

[0109] Various techniques can be used to prepare compounds of formula INT-4-a or salts thereof according to the present disclosure. Certain useful methods are described below. Those skilled in the art will understand that other suitable techniques, such as various esterification techniques, can be used according to the present disclosure. In some embodiments, the present disclosure provides compounds of formula INT-4: [ka] or a salt thereof, comprising: Formula INT-5: [ka] or a salt thereof; The compound of formula INT-5 or a salt thereof is reacted with R 3 and reacting a compound having the structure: INT-4, INT-5, INT-6, INT-7, INT-8, INT-9, INT-10, INT-11, INT-12, INT-13, INT-14, INT-15, INT-16, INT-17, INT-18, INT-19, INT-20, INT-21, INT-22, INT-23, INT-24, INT-25, INT-26, INT-27, INT-28, INT-29 ...9, INT-20, INT-21, INT-22, INT-23,

[0110] In some embodiments, the compound of formula INT-5 has the structure of formula INT-5-a. In some embodiments, the present disclosure provides compounds of formula INT-4-a: [ka] or a salt thereof, comprising: Formula INT-5-a: [ka] or a salt thereof; The compound of formula INT-5-a or a salt thereof is reacted with R 3 and reacting a compound having the structure: INT-4-a, INT-4-b, INT-4-c, INT-4-d, INT-4-e, INT-4-f, INT-4-g, INT-4-h, INT-4-i, INT-4-j ...

[0111] In some embodiments, the compound of formula INT-5 or INT-5-a has the structure of formula INT-5-b. In some embodiments, the present disclosure provides compounds of formula INT-4-b: [ka] or a salt thereof, comprising: Formula INT-5-b: [ka] or a salt thereof; The compound of formula INT-5-b or a salt thereof is reacted with R 3 and reacting a compound having the structure: INT-4-b, INT-4-c, INT-4-d, INT-4-e, INT-4-f, INT-4-g, INT-4-h, INT-4-i, INT-4-j ...

[0112] In some embodiments, R 3 is R as described herein. In some embodiments, R 3 is an optionally substituted C 1~10 In some embodiments, R s is C 1~6 In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is butyl.

[0113] In some embodiments, the compound of formula INT-5 has the structure of INT-5-1 or INT-5-2, where each variable is independently as described herein. In some embodiments, the compound of formula INT-5-a has the structure of INT-5-a-1 or INT-5-a-2, where each variable is independently as described herein. In some embodiments, the compound of formula INT-5 has the structure of INT-5-b-1 or INT-5-b-2, where each variable is independently as described herein. [ka]

[0114] In some embodiments, provided are methods in which the compound of formula INT-4 or a salt thereof is a compound of formula INT-4-1, INT-4-a-1, INT-4-b-1, or a salt thereof, and the compound of INT-5 is a compound of formula INT-5-1, INT-5-a-1, or INT-5-b-1, respectively, or a salt thereof. In some embodiments, provided are methods in which the compound of formula INT-4 or a salt thereof is a compound of formula INT-4-2, INT-4-a-2, INT-4-b-2, or a salt thereof, and the compound of INT-5 is a compound of formula INT-5-2, INT-5-a-2, or INT-5-b-2, respectively, or a salt thereof. In some embodiments, the product is formed stereoselectively as described herein.

[0115] In some embodiments, the PG of a compound can be removed, e.g., a compound having a structure of formula P, P-1, P-2, P-3, P-4, Pa, Pa-1, Pa-2, Pa-3, Pa-4, Pb, Pb-1, Pb-2, Pb-3, or Pb-4, or a salt thereof. A variety of suitable deprotection techniques are available in the art and can be utilized in accordance with the present disclosure. In some embodiments, the method includes removing a protecting group. In some embodiments, the method includes removing a protecting group in a compound having a structure of formula P, P-1, P-2, P-3, P-4, Pa, Pa-1, Pa-2, Pa-3, Pa-4, Pb, Pb-1, Pb-2, Pb-3, or Pb-4, or a salt thereof, to provide a compound having a structure of formula DP, DP-1, DP-2, DP-3, DP-4, DP-a, DP-a-1, DP-a-2, DP-a-3, DP-a-4, DP-b, DP-b-1, DP-b-2, DP-b-3, or DP-b-4, or a salt thereof, wherein each variable is independently described herein. [ka] A variety of protection / deprotection techniques are available to one of skill in the art and can be utilized in accordance with the present disclosure. For example, in some embodiments, the Trt protecting group ( [ka] ) can be removed under acidic conditions, for example with HCl.

[0116] Those skilled in the art can combine various preparation methods to provide a multi-step process. For example, in some embodiments, the present disclosure provides a compound of formula DP: [ka] or a salt thereof, comprising: (a) Formula INT-2: [ka] or a salt thereof; (b) reacting a compound of formula INT-2 or a salt thereof with a compound of formula INT-3: R 1 -LH INT-3 or a salt thereof to form a compound of formula a, formula INT-1: [ka] or a salt thereof; (c) reducing a compound of formula INT-1 or a salt thereof to form a compound of formula P: [ka] or a salt thereof, wherein the reduction of the compound of formula INT-1 or the salt thereof is carried out in the presence of a reducing agent; (d) deprotecting the compound of formula P to provide a compound of formula DP or a salt thereof; wherein each variable is independently as described herein; and The present invention provides a method comprising:

[0117] In some embodiments, the present disclosure provides compounds of formula DP-a: [ka] or a salt thereof, comprising: (a) Formula INT-2-a: [ka] or a salt thereof; (b) reacting a compound of formula INT-2-a or a salt thereof with a compound of formula INT-3: R 1 -LH INT-3 or a salt thereof to form a compound of formula a, formula INT-1-a: [ka] or a salt thereof; (c) reducing a compound of formula INT-1-a or a salt thereof to obtain a compound of formula Pa: [ka] or a salt thereof, wherein the reduction of the compound of formula INT-1-a or the salt thereof is carried out in the presence of a reducing agent; (d) deprotecting the compound of formula Pa to provide a compound of formula DP-a or a salt thereof; a method comprising: During the ceremony, n is 0, 1, 2, or 3; PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R 2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0118] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a salt thereof, the method comprising: (a) Formula INT-2-b: [ka] and providing a compound having the structure: During the ceremony, PG is an amino protecting group, R3 is -H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; (b) a compound of formula INT-2-b or a salt thereof; [ka] or a salt thereof to form a compound of formula INT-1-c: [ka] or a salt thereof; (c) reducing the compound of formula INT-1-c to form a compound of formula PI: [ka] or a salt thereof, wherein the reduction of the compound of formula INT-1-c or a salt thereof is carried out in the presence of a reducing agent; (d) deprotecting the compound of formula Pc or a salt thereof to provide the compound of formula I or a salt thereof; Includes.

[0119] Those of skill in the art reading this disclosure will appreciate that the various reactions can be carried out in accordance with this disclosure utilizing a variety of techniques, e.g., reagents, conditions, etc. Certain useful techniques are described herein by way of example.

[0120] reduction A variety of reduction techniques are available to one skilled in the art for carrying out the reduction reaction according to the present disclosure. In particular, a variety of reducing agents and related conditions can be utilized to convert a compound of formula INT-1 or a salt thereof to a compound of formula P or a salt thereof.

[0121] In some embodiments, the reducing agent is a hydride compound. In some embodiments, the reducing agent comprises BH. In some embodiments, the reducing agent is a borohydride. In some embodiments, as demonstrated herein, the reducing agent is NaBH. In some embodiments, as demonstrated herein, the reducing agent is LiBH. In some embodiments, the reducing agent is NaBHCN. In some embodiments, the reducing agent is LiAlH. In some embodiments, the borohydride reducing agent provides a trans amino alcohol compound, for example, after reduction and / or deprotection (e.g., a compound of formula P-3, Pa-3, Pb-3, P-4, Pa-4, Pb-4, DP-3, DP-a-3, DP-b-3, DP-4, DP-a-4, or DP-b-4, or a salt thereof).

[0122] In some embodiments, for example, the reduction of a compound of formula INT-1 or a salt thereof is carried out in the presence of HCOOH or a salt thereof. In some embodiments, the reduction is carried out in the presence of HCOONa. In some embodiments, the reduction is carried out in the presence of HCOOK. In some embodiments, the reduction is carried out in the presence of HCOOLi. In some embodiments, the reduction is carried out in the presence of HCOONH4. In some embodiments, the reducing agent is hydrogen.

[0123] In some embodiments, for example, the reduction of a compound of formula INT-1 or a salt thereof is carried out in the presence of H. In some embodiments, the reduction of a compound of formula INT-1 or a salt thereof is carried out in the presence of an agent that generates H in situ. In some embodiments, another agent, for example, an agent that promotes, facilitates, or catalyzes the reduction by H, is utilized in the presence of H. In some embodiments, such an agent is or includes a metal. In some embodiments, such an agent is or includes a metal complex. In some embodiments, the metal is Ru. In some embodiments, the reduction is carried out in the presence of an agent that includes a metal and one or more ligands. In some embodiments, the reduction is carried out in the presence of an agent that includes a metal and one or more chiral ligands. In some embodiments, the chiral ligand includes phosphorus. In some embodiments, the chiral ligand includes nitrogen. In some embodiments, the reduction is stereoselective, for example, in the presence of an agent that includes a metal, e.g., Ru, and one or more chiral ligands. Certain useful metal complexes are described herein.

[0124] In some embodiments, the reducing agent is or comprises HCOOH or a salt thereof and is utilized in the presence of a metal complex described herein. In some embodiments, such reduction techniques provide, for example, after reduction and / or deprotection (e.g., a compound of formula P-1, Pa-1, Pb-1, P-2, Pa-2, Pb-2, DP-1, DP-a-1, DP-b-1, DP-2, DP-a-2, or DP-b-2 or a salt thereof), a cis amino alcohol compound.

[0125] metal complexes In some embodiments, the reduction is carried out in the presence of an agent comprising a metal. In some embodiments, such an agent is a metal complex comprising a suitable metal and one or more suitable ligands. In some embodiments, the metal is a transition metal. In some embodiments, the metal is Ru. In some embodiments, the metal is Rh. In some embodiments, the metal is Pd. In some embodiments, the metal is Fe. In some embodiments, the metal is Co. In some embodiments, the metal is Ni. In some embodiments, the metal is Os. In some embodiments, the metal is Ir. In some embodiments, the metal is Pt.

[0126] In some embodiments, the metal complex comprises one or more nitrogen ligands. In some embodiments, the ligands are NHR M1 -CH2-CH2-N(-)S(O)2R M2 where R M1 and R M2 is independently R as described herein, and each -CH2- is independently as described herein. In some embodiments, the ligand is NHR M1 -C(R M3 )2-C(R M4 )2-N(-)S(O)2R M2 where R M1 , R M2 , R M3 and R M4 is independently R as described herein, and each -CH2- is independently as described herein. In some embodiments, the ligand is NHR M1 -CHR M3 -CHR M4 -N(-)S(O)2R M2 where R M1 , R M2 , R M3 and R M4 is independently R as described herein, and each —CH— is independently as described herein. In some embodiments, the metal complex is M1-CH2-CH2-N(-)S(O)2R M2 ](R M5 )(R M6 -R M7 ) or a salt thereof, where each -CH2- is independently optionally substituted and each variable is independently as described herein. In some embodiments, the metal complex comprises or has the structure Ru[NHR M1 -C(R M3 )2-C(R M4 )2-N(-)S(O)2R M2 ](R M5 )(R M6 -R M7 ) or a salt thereof, where each variable is as independently described herein. In some embodiments, the metal complex comprises or has the structure Ru[NHR M1 -CHR M3 -CHR M4 -N(-)S(O)2R M2 ](R M5 )(R M6 -R M7 or a salt thereof, wherein each variable is as independently described herein.

[0127] In some embodiments, R M1 is —H. In some embodiments, R M1 is not -H.

[0128] In some embodiments, R M2 is —H. In some embodiments, R M2 is not —H. In some embodiments, R M2 is optionally substituted phenyl. In some embodiments, R M2 is p-methylphenyl. In some embodiments, R M2 is pentafluorophenyl.

[0129] In some embodiments, R M3 is not —H. In some embodiments, R M3 is optionally substituted phenyl. In some embodiments, RM3 is phenyl. In some embodiments, R M4 is not —H. In some embodiments, R M4 is optionally substituted phenyl. In some embodiments, R M4 is phenyl. In some embodiments, -NHR M1 and -N(-)S(O)2R M2 is trans. In some embodiments, the agent is stereoisomerically enriched. In some embodiments, the agent is sterically hindered.

[0130] In some embodiments, the metal complex contains a ligand R that is a halogen. M5 In some embodiments, R M5 is -Cl.

[0131] In some embodiments, the metal complex comprises a ligand R M6 -H, where R M6 is R, where R is an optionally substituted aryl or heteroaryl as described herein. In some embodiments, the metal complex comprises a ligand R M6 -R M7 where R M6 is R, where R is an optionally substituted aryl or heteroaryl as described herein, and R M7 is R as described herein. In some embodiments, R M7 is —H. In some embodiments, R M7 is an optionally substituted C 1~6 In some embodiments, R M7 is methyl. In some embodiments, R M7 is isopropyl. In some embodiments, R M6 is optionally substituted phenyl. In some embodiments, R M6 -H is p-cymene. In some embodiments, R M6 -H is mesitylene. In some embodiments, R M7 and R M1together form a linker, e.g., an optionally substituted divalent C having 1 to 3 heteroatoms. 1~6 Forms a linear or branched aliphatic or heteroaliphatic group. In some embodiments, R M7 and R M1 together form an optionally substituted divalent C having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1~6 Forms a straight or branched aliphatic or heteroaliphatic group. In some embodiments, the linker is an optionally substituted -(CH2)m-, where m is 1 to 6. In some embodiments, the linker is -(CH2)m-, where n is 6. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6.

[0132] In some embodiments, the agent is N-[(1S,2S)-2-amino-1,2-diphenyl-ethyl]-4-methyl-benzenesulfonamide; chlororuthenium; 1-isopropyl-4-methyl-benzene( [ka] or Ru-[(S,S)-Ts-DPEN] or RuCl(p-cymene)[(S,S)-Ts-DPEN], CAS number: 192139-90-5).

[0133] In some embodiments, the agent is N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-4-methyl-benzenesulfonamide; chlororuthenium; 1-isopropyl-4-methyl-benzene( [ka] or Ru-[(R,R)-Ts-DPEN] or RuCl(p-cymene)[(R,R)-Ts-DPEN], CAS number: 192139-92-7).

[0134] In some embodiments, the agent is [N-[(1S,2S)-2-(amino-κN)-1,2-diphenylether]-2,3,4,5,6-pentafluorobenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium ( [ka] or RuCl(p-cymene)[(S,S)-Fsdpen] or RuCl[(S,S)-FsDPEN](p-cymene), CAS number: 1026995-72-1).

[0135] In some embodiments, the agent is [N—[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-2,3,4,5,6 pentafluorobenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium ( [ka] or RuCl(p-cymene)[(R,R)-Fsdpen] or RuCl[(R,R)-FsDPEN](p-cymene), CAS number: 1026995-71-0).

[0136] In some embodiments, the agent is RuCl[(S,S)-TsDPEN](mesitylene). In some embodiments, the agent is RuCl[(R,R)-TsDPEN](mesitylene).

[0137] In some embodiments, the agent is [(R,R)-Teth-TsDpen RuCl]. In some embodiments, the agent is [(S,S)-Teth-TsDpen RuCl].

[0138] In some embodiments, the agent, e.g., a metal-containing agent, is utilized in an amount of about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.04, 0.03, 0.025, 0.02, 0.01, or 0.005 equivalents or less of the compound to be reduced. In some embodiments, the agent is utilized in an amount of about 0.05 equivalents or less. In some embodiments, the agent is utilized in an amount of about 0.025 equivalents or less. In some embodiments, the agent is utilized in an amount of about 0.01 equivalents or less.

[0139] In some embodiments, RuCl(p-cymene)[(S,S)-Ts-DPEN] is utilized in an amount of about 0.05 equivalents or less. In some embodiments, RuCl(p-cymene)[(S,S)-Ts-DPEN] is utilized in an amount of about 0.025 equivalents or less. In some embodiments, RuCl(p-cymene)[(S,S)-Ts-DPEN] is utilized in an amount of about 0.01 equivalents or less.

[0140] In some embodiments, RuCl(p-cymene)[(R,R)-Ts-DPEN] is utilized in an amount of about 0.05 equivalents or less. In some embodiments, RuCl(p-cymene)[(R,R)-Ts-DPEN] is utilized in an amount of about 0.025 equivalents or less. In some embodiments, RuCl(p-cymene)[(R,R)-Ts-DPEN] is utilized in an amount of about 0.01 equivalents or less.

[0141] In some embodiments, RuCl(p-cymene)[(S,S)-Fsdpen] is utilized in an amount of about 0.05 equivalents or less. In some embodiments, RuCl(p-cymene)[(S,S)-Fsdpen] is utilized in an amount of about 0.025 equivalents or less. In some embodiments, RuCl(p-cymene)[(S,S)-Fsdpen] is utilized in an amount of about 0.01 equivalents or less.

[0142] In some embodiments, RuCl(p-cymene)[(R,R)-Fsdpen] is utilized in an amount of about 0.05 equivalents or less. In some embodiments, RuCl(p-cymene)[(R,R)-Fsdpen] is utilized in an amount of about 0.025 equivalents or less. In some embodiments, RuCl(p-cymene)[(R,R)-Fsdpen] is utilized in an amount of about 0.01 equivalents or less.

[0143] Selectivity In some embodiments, the provided techniques provide high selectivity. For example, in various embodiments, products are formed with high selectivity. In some embodiments, chiral elements, e.g., chiral centers, are formed with high stereoselectivity. In some embodiments, the stereoselectivity is or includes diastereoselectivity. In some embodiments, the selectivity is or includes enantioselectivity. In some embodiments, the selectivity is or includes the selective conversion of a particular stereoisomer (e.g., a diastereomer, an enantiomer, etc.). In some embodiments, the selectivity is or includes the selective conversion of an enantiomer. In some embodiments, the selectivity is or includes the selective conversion of a diastereomer. In some embodiments, the selectivity is or includes the selective production of a particular stereoisomer. In some embodiments, the selectivity is or includes the selective production of a particular diastereomer. In some embodiments, the selectivity is or includes the selective production of a particular enantiomer. In some embodiments, the reaction conditions of the present disclosure do not cause epimerization of chiral centers (e.g., in some embodiments, less than about 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, or 0.1%; in some embodiments, no detectable epimerization).

[0144] In some embodiments, selectivity is expressed, for example, as the ratio of two potential configurations of a chiral center (e.g., R or S) or two forms of a compound (e.g., trans or cis). In some embodiments, the ratio is about or at least about 1.5:1, 2:1, 2.5:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 200:1, 500:1 or more. In some embodiments, selectivity is expressed as diastereomeric excess (de) and / or enantiomeric excess (ee). In some embodiments, de is |D1-D2|, where D1 and D2 are the mole fractions of the two diastereomers in the composition (D1+D2=1). In some embodiments, de is |D1-D2|, where D1 and D2 are the mole fraction yields of the two diastereomers formed in the reaction (D1+D2=1). In some embodiments, ee is |F1-F2|, where F1 and F2 are the mole fractions of the two enantiomers in the composition (F1+F2=1). In some embodiments, ee is |F1-F2|, where F1 and F2 are the mole fraction yields of the two enantiomers formed in the reaction (F1+F2=1). In some embodiments, the provided techniques can provide de and / or ee at or above a certain level. In some embodiments, selectivity is expressed as product purity. In some embodiments, the product has a purity at or above a certain level. In some embodiments, the product has a particular diastereomeric purity at or above a particular level. In some embodiments, the product has a particular enantiomeric purity at or above a particular level. In some embodiments, the product has a particular stereopurity at or above a particular level. In some embodiments, the level is about or at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5%. In some embodiments, the level is about or at least about 80%.In some embodiments, the level is about or at least about 85%. In some embodiments, the level is about or at least about 90%. In some embodiments, the level is about or at least about 95%. In some embodiments, the level is about or at least about 97%. In some embodiments, the level is about or at least about 99%.

[0145] In some embodiments, -OH and -N(PG)- are cis in the reduction product. In some embodiments, -OH and -N(PG)- are cis in the reduction product, and the cis product is formed with a selectivity of about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater. In some embodiments, the selectivity is about 90% or greater. In some embodiments, the selectivity is about 94% or greater. In some embodiments, the selectivity is about 95% or greater. In some embodiments, the selectivity is about 96% or greater.

[0146] In some embodiments, -OH and -N(PG)- are trans in the reduction product. In some embodiments, -OH and -N(PG)- are trans in the reduction product, and the trans product is formed with a selectivity of about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater. In some embodiments, the selectivity is about 90% or greater. In some embodiments, the selectivity is about 94% or greater. In some embodiments, the selectivity is about 95% or greater. In some embodiments, the selectivity is about 96% or greater.

[0147] In some embodiments, the purity of the compound is about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.7%, or 99.9% or greater. In some embodiments, the purity of the compound is about 85% or greater. In some embodiments, the purity of the compound is about 85% or greater. In some embodiments, the purity of the compound is about 90% or greater. In some embodiments, the purity of the compound is about 95% or greater. In some embodiments, the purity of the compound is about 96% or greater. In some embodiments, the purity of the compound is about 97% or greater. In some embodiments, the purity of the compound is about 98% or greater. In some embodiments, the purity of the compound is about 99% or greater. In some embodiments, the purity of the compound is about 99.7% or greater. In some embodiments, the purity of the compound is about 99.9% or greater.

[0148] Various chemical reactions are typically carried out in the presence of a solvent system. In some embodiments, the solvent system is a single solvent. In some embodiments, the system is or includes a non-human primate. In some embodiments, the solvent is polar. In some embodiments, the solvent is non-polar. In some embodiments, the solvent is protic. In some embodiments, the solvent is aprotic. In some embodiments, the solvent is polar but not protic. Suitable solvent systems for various reactions are available to those of skill in the art and can be utilized in accordance with the present disclosure. For example, in some embodiments, the reduction of, e.g., a compound of formula INT-1 or a salt thereof, is carried out in the presence of a protic solvent. In some embodiments, the reduction of, e.g., a compound of formula INT-1 or a salt thereof, is carried out in the presence of a combination of two or more protic solvents. In some embodiments, the protic solvent is methanol. In some embodiments, the protic solvent is ethanol. In some embodiments, the solvent system is or includes methanol. In some embodiments, the solvent system is or includes ethanol.

[0149] In some embodiments, the reaction is carried out at, or for a period of time above, below, or near standard ambient temperature (25° C.). In some embodiments, the reaction temperature is below standard ambient temperature. In some embodiments, the temperature is about or about −78, −60, −50, −40, −30, −20, −10, 0, or 10° C. or less. In some embodiments, the temperature is about or about 10° C. or less. In some embodiments, the temperature is about or about 15° C. or less. In some embodiments, the temperature is about or about 20° C. or less. In some embodiments, the reaction temperature is about standard ambient temperature. In some embodiments, the reaction temperature is higher than standard ambient temperature. In some embodiments, the reaction temperature is about or at least about 35, 40, 50, 60, 70, 80, 90, 100, or 100° C. In some embodiments, the reaction involves refluxing in a boiling solvent system, such as, for example, ether, toluene, etc. In some embodiments, the temperature changes during the reaction process, for example, increasing from a lower temperature to a higher temperature, decreasing from a higher temperature to a lower temperature, or both.

[0150] Specific embodiments for various variables in various formulas are described herein as examples. Those skilled in the art who read this disclosure can select embodiments for each variable and combine them. Such combinations are within the scope of this disclosure.

[0151] PG Suitable protecting groups are well known to those of skill in the art and can be utilized as described herein. In some embodiments, as described herein, amino groups are protected to allow various reactions to proceed as described. In some embodiments, protecting a group, e.g., an amino group, reduces or prevents such group from interfering with the reaction and / or reduces or prevents reaction at such group. In some embodiments, a protecting group, e.g., an amino protecting group, is -C(O)R'. An amino protecting group is -C(O)R, where R is as described herein. In some embodiments, it is -C(O)OR, e.g., Boc. In some embodiments, it is -S(O)R, where R is as described herein. In some embodiments, it is R, where R is not hydrogen. In some embodiments, it is an optionally substituted C 1~6 In some embodiments, it is aliphatic. In some embodiments, it is optionally substituted methyl, and one or more of the substituents is an aromatic group. In some embodiments, it is optionally substituted benzyl. In some embodiments, it is -CH2-R, where -CH2- is optionally substituted and is R as described herein and is not -H. In some embodiments, it is -CH2-R, where -CH2- is optionally substituted and R is a C group having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6~10 In some embodiments, it is -CH2-R, where -CH2- is optionally substituted and R is an optionally substituted group selected from phenyl and 5- to 6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, it is -CH2-R, where -CH2- is optionally substituted and R is an optionally substituted phenyl. In some embodiments, it is -CH(R)2, where each R is independently as described herein and is not -H. In some embodiments, it is -CH(R)2, where each R is independently selected from C 6~10In some embodiments, it is -CH(R)2, where each R is independently an optionally substituted group selected from phenyl and 5- to 6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, it is -CH(R)2, where each R is independently an optionally substituted group selected from phenyl and 5- to 6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, it is -CH(R)2, where each R is independently an optionally substituted phenyl. In some embodiments, it is -C(R)3, where each R is independently as described herein and is not -H. In some embodiments, it is -C(R)3, where each R is independently C. 6~10 In some embodiments, it is -C(R)3, where each R is independently an optionally substituted group selected from phenyl and 5- to 6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, it is -C(R)3, where each R is independently an optionally substituted group selected from phenyl and 5- to 6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, it is -C(R)3, where each R is independently an optionally substituted phenyl. In some embodiments, it is -Trt( [ka] )

[0152] Techniques for installing and removing protecting groups are widely known and can be utilized in accordance with the present disclosure. For example, in some embodiments, protecting groups such as Boc, Trt, etc. can be removed by utilizing acid.

[0153] L In some embodiments, L is -CH-. In some embodiments, L is substituted -CH-. In some embodiments, L is -CH- substituted with one or two suitable substituents. In some embodiments, L is monosubstituted. In some embodiments, L is disubstituted. In some embodiments, L is -CH(CN)-.

[0154] R 1 In some embodiments, R 1 is R as described herein. In some embodiments, R 1 is —H. In some embodiments, R 1 is not -H.

[0155] In some embodiments, R 1 is -P(O)(R 2 )2, where each R 2 are independently as described herein. In some embodiments, at least one R 2 is not —H. In some embodiments, each R 2 is not —H. In some embodiments, at least one R 2 is -OR. In some embodiments, at least one R 2 is -OR, and R is as described herein and is not -H. In some embodiments, each R 2 is independently -OR. In some embodiments, each R 2 is independently -OR, and R is as described herein and is not -H. In some embodiments, at least one R 2 is independently —N(R′) 2 , and each R′ is independently as described herein. In some embodiments, at least one R 2 is independently —N(R)2, where each R is independently as described herein. In some embodiments, each R 2 is independently —N(R′) 2 , and each R′ is independently as described herein. In some embodiments, each R2 is independently -N(R)2, and each R is independently as described herein. In some embodiments, at least one R 2 is, as described herein, [ka] In some embodiments, each R 2 are independently, as described herein, [ka] is.

[0156] In some embodiments, R 1 is -S(O)2R 2 In some embodiments, R 2 is R as described herein. In some embodiments, R 2 is R as described herein and is not —H. In some embodiments, R 2 is an optionally substituted C 1~10 In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2is cyclohexyl. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is phenyl. In some embodiments, R 2 is -OR. In some embodiments, R 2 is -OR, where R is not -H. In some embodiments, R 2 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 2 is -N(R)2, where each R is independently as described herein. In some embodiments, R 2 is -NMe. In some embodiments, R 2 teeth, [ka] In some embodiments, ring A is an optionally substituted phenyl ring (as will be appreciated by those skilled in the art, including -S(O)- and R s In addition to the group, ) is R s Various useful embodiments of and t are described herein by way of example. In some embodiments, R 1 is -S(O)2R 2 where R 2 is optionally substituted phenyl. In some embodiments, R 1 is -S(O)2R 2 where R 2 is phenyl.

[0157] In some embodiments, R 1 is -Si(R)3, and each R is independently described therein. In some embodiments, each R is not -H. In some embodiments, R 1 is —Si(R)3, and each R is independently an optionally substituted C 1~30 In some embodiments, R 1is —Si(R)3, and each R is independently an optionally substituted C 1~10 In some embodiments, R 1 is —Si(R)3, where each R is independently selected from the group of methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl. 1 is —Si(R)3, where each R is independently an optionally substituted C 1~4 In some embodiments, R 1 is —Si(R)3, and each R is independently methyl. In some embodiments, R 1 is —Si(R)3, and each R is independently ethyl. In some embodiments, R 1 is —Si(R)3, and each R is independently propyl. In some embodiments, R 1 is —Si(R)3, and each R is independently isopropyl. In some embodiments, R 1 is —Si(R)3, and each R is independently n-butyl. In some embodiments, R 1 is —Si(R)3, where each R is independently tert-butyl.

[0158] In some embodiments, R 1 is -Si(R)3, and each R is independently C 1~30 Aliphatic and C 6~30 aryl. In some embodiments, R 1 is -Si(R)3, and each R is independently C 1~10 is an optionally substituted group selected from aliphatic and phenyl. In some embodiments, R 1 is -Si(R)3, and each R is independently C 1~4 is an optionally substituted group selected from aliphatic and phenyl. In some embodiments, R 1 is -Si(R)3, and each R is independently C 1~4An optionally substituted group selected from aliphatic and phenyl, wherein the substituents are halogen, —CN, —C(O)OR′, —OR′, or —N(R′)2, where R′ is described therein. In some embodiments, R 1 is -Si(R)3, and each R is independently C 1~4 aliphatic or optionally substituted phenyl, wherein the substituents are halogen, —CN, —C(O)OR′, —OR′, or —N(R′)2, where R′ is described therein. In some embodiments, R 1 is -Si(R)3, where each R is independently C 1~4 In some embodiments, R 1 is —Si(R)3, where one R group is an optionally substituted C 1~6 In some embodiments, R is an aliphatic group, and the other two are, independently, optionally substituted phenyl. 1 is -Si(Ph)2Me.

[0159] R 2 In some embodiments, R 2 is R as described herein. In some embodiments, R 2 is —H. In some embodiments, R 2 is not —H. In some embodiments, R 2 is an optionally substituted C 1~10 In some embodiments, R 2 is an optionally substituted C 1~10 In some embodiments, R 2 is C 1~10 In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is phenyl.

[0160] In some embodiments, R 2 is -OR. In some embodiments, R 2 is —OH. In some embodiments, R 2 is -OR, where R is not -H. In some embodiments, R is an optionally substituted C 1~6 It is aliphatic.

[0161] In some embodiments, R 2 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 2 is -NHR', where R' is as described herein. In some embodiments, R 2 is -N(R)2, where each R is independently as described herein. In some embodiments, R 2 is —NHR, where R is as described herein. In some embodiments, R 2 is -NH. In some embodiments, R 2 is -N(R)2, where each R is independently C 1~6 In some embodiments, R 2 is -NMe. In some embodiments, R 2 is -N(Et)2. In some embodiments, R 2 is -N(Me)Et.

[0162] In some embodiments, R 2 is, as described herein, [ka] is.

[0163] In some embodiments, R 2 One of the existence of [ka] In some embodiments, t is 1 and ring A is optionally substituted. [ka] In some embodiments, R 2 is optionally replaced [ka] In some embodiments, R 2 One of the existence of [ka] and the other occurrence is -OR. In some embodiments, R 2 One of the existence of [ka] and other entities are -R.

[0164] Ring A As described herein, ring A is optionally substituted (e.g., [ka] Plus R s In some embodiments, ring A is substituted. In some embodiments, ring A is unsubstituted.

[0165] In some embodiments, ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, ring A is an optionally substituted 5-6 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, ring A is an optionally substituted phenyl ring. In some embodiments, ring A is a phenyl ring. In some embodiments, ring A is an optionally substituted 10 membered bicyclic aryl ring. In some embodiments, ring A is an optionally substituted 5-9 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroatom is nitrogen. In some embodiments, ring A is protected.

[0166] R s In some embodiments, R s is R' as described herein. In some embodiments, R s is R as described herein. In some embodiments, R s Each occurrence of is -H. In some embodiments, R s In some embodiments, R s Each occurrence of is not -H.

[0167] In some embodiments, R s is R as described herein and is not -H. For example, in some embodiments, it is optionally substituted C 6~10In some embodiments, it is an optionally substituted phenyl. In some embodiments, it is an optionally substituted heteroaryl, such as a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0168] In some embodiments, R s In some embodiments, R s In some embodiments, R s In some embodiments, R s In some embodiments, R s In some embodiments, R s The presence of is -CN.

[0169] In some embodiments, R s In each case, C(O)OR', where R' is -H or C 1~30 C having an aliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic and C 6~30 Aryl and C 6~30 C having arylaliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 and optionally substituted groups selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R s is C(O)OR, where R is as described herein. In some embodiments, R s An occurrence of is C(O)OR, where R is as described herein and is not —H. In some embodiments, R s In some embodiments, Rs The presence of is -C(O)OEt.

[0170] In some embodiments, R s In each instance, R is -OR', and R' is -H or C 1~30 C having an aliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic and C 6~30 Aryl and C 6~30 C having arylaliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 In some embodiments, R' is an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R' is an optionally substituted C 1~6 In some embodiments, R s In some embodiments, R s is -OR, where R is as described herein and is not -H. In some embodiments, R s An occurrence of is -OMe. In some embodiments, R s In some embodiments, R s In some embodiments, R s is -O-isopropyl. In some embodiments, R s In some embodiments, R s is -O-tert-butyl. In some embodiments, R s is -O-CH-Ph. In some embodiments, R s The presence of is -O-Ph.

[0171] In some embodiments, R sIn each instance, -N(R')2, R' is -H or C 1~30 C having an aliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic and C 6~30 Aryl and C 6~30 C having arylaliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, each R' is independently H or an optionally substituted C 1~6 In some embodiments, R s is -NH. In some embodiments, R s and each occurrence is -N(R), where each variable is independent as described herein. In some embodiments, R s is -NHMe. In some embodiments, R s is -NMe. In some embodiments, R s In some embodiments, R s The presence of -N(Et)2.

[0172] In some embodiments, R s The presence of optionally substituted C 6~10 In some embodiments, it is aryl. In some embodiments, it is optionally substituted phenyl. In some embodiments, it is phenyl. In some embodiments, R s Each occurrence of R is a 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R2 The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] is.

[0173] t In some embodiments, t is 0. In some embodiments, t is 1 to 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.

[0174] n In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0175] Ring B As described herein, R a and R b together with their intervening atoms to form ring B. In some embodiments, ring B is (R a The nitrogen atom to which R is bonded b is optionally substituted (in addition to the group attached to the carbon atom to which is attached). In some embodiments, Ring B is substituted. In some embodiments, Ring B is unsubstituted.

[0176] In some embodiments, ring B has 4 to 15, 4 to 12, 4 to 10, or 4 to 7 members. In some embodiments, ring B has 4 members. In some embodiments, ring B has 5 members. In some embodiments, ring B has 6 members. In some embodiments, ring B has 7 members. In some embodiments, ring B has 8 members. In some embodiments, ring B has 9 members. In some embodiments, ring B has 10 members. In some embodiments, ring B has 11 members. In some embodiments, ring B has 12 members. In some embodiments, ring B has 13 members. In some embodiments, ring B has 14 members. In some embodiments, ring B has 15 members.

[0177] In some embodiments, Ring B is saturated. In some embodiments, Ring B is partially unsaturated. In some embodiments, R a The carbon to which is bonded is sp 3 is.

[0178] In some embodiments, ring B is monocyclic. In some embodiments, ring B is bicyclic. In some embodiments, ring B is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, 9, or 10)-membered saturated, partially unsaturated, or aromatic ring having 0-5 heteroatoms. In some embodiments, each monocyclic unit is independently a 3-7-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic unit is independently a 4-7-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic unit is independently a 5-7-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic unit is independently saturated or partially unsaturated. In some embodiments, each monocyclic unit is independently saturated.

[0179] In some embodiments, ring B is R b has zero heteroatoms in addition to the nitrogen atom to which is attached. In some embodiments, ring B has 1 to 4 additional heteroatoms. In some embodiments, ring B has 1 additional heteroatom. In some embodiments, ring B has 2 additional heteroatoms. In some embodiments, ring B has 3 additional heteroatoms. In some embodiments, ring B has 4 additional heteroatoms. In some embodiments, each additional heteroatom is independently selected from nitrogen, oxygen, and sulfur.

[0180] In some embodiments, ring B is an optionally substituted azetidine ring. In some embodiments, ring B is an optionally substituted pyrrolidine ring. In some embodiments, ring B is an optionally substituted piperidine ring.

[0181] R' In some embodiments, R' is R as described herein. In some embodiments, R' is -H. In some embodiments, R' is not -H.

[0182] In some embodiments, R' is -C(O)R, where R is as described herein. In some embodiments, R' is -C(O)OR, where R is as described herein. In some embodiments, R' is -C(O)N(R), where each R is independently as described herein. In some embodiments, two R groups, together with the nitrogen to which they are attached, form a ring as described herein. In some embodiments, R' is -S(O)R, where R is as described herein. In some embodiments, R' is -S(O)R, where R is as described herein and is not -H.

[0183] R In some embodiments, each R is independently —H or C 1~10C having an aliphatic and 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1~10 Heteroaliphatic and C 6~10 Aryl and C 6~20 C having arylaliphatic and 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6~20 an optionally substituted group selected from arylheteroaliphatic, 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-10 membered heterocyclyl having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently together with atoms form an optionally substituted 3-15 (e.g., 3-12, 3-10, 3-8, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered, monocyclic, bicyclic, or polycyclic ring having, in addition to the atoms, 0-5 (e.g., 0, 1, 2, 3, 4, or 5) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3-15 (e.g., 3-12, 3-10, 3-8, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered, monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-5 (e.g., 0, 1, 2, 3, 4, or 5) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0184] In some embodiments, each R is independently C 1~10 C having 1 to 5 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~10 Heteroaliphatic, C 6~10 Aryl, C 6~20C having 1 to 5 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~20 an optionally substituted group selected from arylheteroaliphatic, 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-10 membered heterocyclyl having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently together with atoms form an optionally substituted 3-15 (e.g., 3-12, 3-10, 3-8, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered, monocyclic, bicyclic, or polycyclic ring having, in addition to the atoms, 0-5 (e.g., 0, 1, 2, 3, 4, or 5) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3-15 (e.g., 3-12, 3-10, 3-8, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered, monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-5 (e.g., 0, 1, 2, 3, 4, or 5) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0185] In some embodiments, each R is independently C 1~10 C having 1 to 5 heteroatoms independently selected from aliphatic, nitrogen, oxygen, and sulfur 1~10 Heteroaliphatic, C 6~10 Aryl, C 6~20 C having 1 to 5 heteroatoms independently selected from arylaliphatic, nitrogen, oxygen, and sulfur 6~20an optionally substituted group selected from arylheteroaliphatic, 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-10 membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently together with atoms form an optionally substituted 3-15 (e.g., 3-12, 3-10, 3-8, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered, monocyclic, bicyclic, or polycyclic ring, which, in addition to the atoms, has 0-5 (e.g., 0, 1, 2, 3, 4, or 5) heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Two or more R groups optionally and independently, taken together with their intervening atoms, form an optionally substituted 3-15 (e.g., 3-12, 3-10, 3-8, 4-6, 5-6, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) membered, monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-5 (e.g., 0, 1, 2, 3, 4, or 5) heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0186] In some embodiments, each R is independently C 1~10 C having 1 to 5 heteroatoms independently selected from aliphatic, nitrogen, oxygen, and sulfur 1~10 Heteroaliphatic, C 6~10 Aryl, C 6~20 C having 1 to 5 heteroatoms independently selected from arylaliphatic, nitrogen, oxygen, and sulfur 6~20 Aryl is an optionally substituted group selected from heteroaliphatic, 5-10 membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-10 membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0187] In some embodiments, R is -H. In some embodiments, R is not -H.

[0188] In some embodiments, R is an optionally substituted C 1~30 (For example, C 1~25 , C 1~20 , C 1~15 In some embodiments, R is an optionally substituted C 1~10 In some embodiments, the aliphatic group is an alkyl group. In some embodiments, R is C 1~6 In some embodiments, R is C 1~6 In some embodiments, R is alkyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted n-propyl. In some embodiments, R is optionally substituted isopropyl. In some embodiments, R is n-butyl. In some embodiments, R is t-butyl. In some embodiments, R is pentyl. In some embodiments, R is hexyl.

[0189] In some embodiments, the aliphatic group is or includes an alicyclic ring. In some embodiments, R is an optionally substituted C 3~30 (For example, C 3~25 , C 3~20 , C 3~15 , C 4~10 , C 3~9 , C 3~7 , or 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, or 30) alicyclic. 3~10In some embodiments, the aliphatic group is a cycloalkyl group. In some embodiments, the alicyclic group is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit independently has 3 to 10 rings (e.g., C 4~10 , C 3~9 , C 3~7 , or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered alicyclic ring. In some embodiments, the alicyclic group is saturated. In some embodiments, it is partially unsaturated. In some embodiments, R is an optionally substituted cyclopropyl. In some embodiments, R is an optionally substituted cyclobutyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is an optionally substituted cycloheptyl.

[0190] In some embodiments, R is an optionally substituted C having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1~30 (For example, C 1~25 , C 1~20 , C 1~15 In some embodiments, R is an optionally substituted C alkyl group having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1~30 (For example, C 1~25 , C 1~20 , C 1~15 In some embodiments, R is a C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 32 -C 33 -C 40 -C 34 -C 45 -C 46 -C 47 -C 58 -C 59 -C 60 -C 70 -C 71 -C 72 -C 73 -C 74 -C 75 -C 76 -C 77 -C 78 -C 79 -C 1~15 In some embodiments, R is a C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 32 -C 33 -C 40 -C 34 -C 45 -C 36 -C 46 -C 47 -C 48 -C 50 -C 51 -C 52 -C 53 -C 54 -C 55 -C 56 -C 57 -C 58 -C 69 -C 70 -C 1~10In some embodiments, R is a C 1 -C 2 heteroatom having 1 to 2 (e.g., 1, 2, 3, 4, or 5, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1~10 In some embodiments, R is a C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 32 -C 33 -C 40 -C 41 -C 42 -C 43 -C 44 -C 45 -C 56 -C 57 -C 58 -C 59 -C 60 -C 61 -C 62 -C 63 -C 64 -C 65 -C 66 -C 67 -C 1~10 In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[0191] In some embodiments, R is an optionally substituted C 6~30 (For example, C 6~30 , C 6~20 , C 6~10 In some embodiments, R is an optionally substituted C 1~10 In some embodiments, the aryl ring is aryl. In some embodiments, the aryl ring is monocyclic. In some embodiments, the aryl ring is bicyclic. In some embodiments, the aryl ring is polycyclic. In some embodiments, each monocyclic unit is independently a 6-membered aromatic ring. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is an optionally substituted 10-membered aryl. In some embodiments, R is an optionally substituted naphthyl. In some embodiments, R is naphthyl.

[0192] In some embodiments, R is an optionally substituted C 6~30 (For example, C 7~30 , C 7~20 , C 7~15 In some embodiments, R is an optionally substituted C 6~10 Aryl-C 1~20 In some embodiments, R is an optionally substituted C 6~10 Aryl-C 1~15 In some embodiments, R is an optionally substituted C 6~10 Aryl-C1~10 In some embodiments, R is an optionally substituted C 6~10 Aryl-C 1~10 In some embodiments, R is optionally substituted phenyl-C 1~15 Aliphatic. Suitable aryl and aliphatic groups include those described above.

[0193] In some embodiments, R is a C having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6~30 (For example, C 7~30 , C 7~20 , C 7~15 In some embodiments, R is an optionally substituted C alkyl group having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6~10 Aryl-C 1~20 In some embodiments, R is an optionally substituted C alkyl group having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6~10 Aryl-C 1~20 In some embodiments, R is an optionally substituted C alkyl group having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6~10 Aryl-C 1~15 In some embodiments, R is an optionally substituted C alkyl group having 1 to 5 (e.g., 1, 2, 3, 4, or 5, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6~10 Aryl-C 1~10 In some embodiments, the aryl is phenyl. Suitable aryl and heteroaliphatic groups include those described above.

[0194] In some embodiments, R is a 5-30 (e.g., 5-25, 5-20, 5-15, 5-10, 5-9, 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, 29, or 30, etc.) membered heteroaryl having 1 to 10 (e.g., 1 to 5, 1 to 4, or 1, 2, 3, or 4, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 5-10 (e.g., 5-9, or 5 or 6, etc.) membered heteroaryl having 1 to 4 (e.g., 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl ring is monocyclic. In some embodiments, the heteroaryl ring is bicyclic. In some embodiments, the heteroaryl ring is polycyclic. In some embodiments, each monocyclic unit is independently a 5- or 6-membered aromatic ring having 0-4 heteroatoms, e.g., independently selected from nitrogen, oxygen, and sulfur, and at least one monocyclic unit contains 1-4 heteroatoms. In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl ring has one heteroatom. In some embodiments, the heteroaryl ring has two or more heteroatoms. In some embodiments, the heteroaryl ring has three or more heteroatoms. In some embodiments, the heteroaryl ring has four or more heteroatoms. In some embodiments, the heteroatom is nitrogen.In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[0195] In some embodiments, R is a 3-30 (e.g., 3-25, 3-20, 3-15, 3-10, or 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, or 30, etc.) membered heterocyclyl having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3-30 (e.g., 3-25, 3-20, 3-15, 3-10, or 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, or 30, etc.) membered heterocyclyl having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 3-20 (e.g., 3-20, 3-15, 3-10, or 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, etc.) membered heterocyclyl having 1-5 (e.g., 1, 2, 3, 4, or 5, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered heterocyclyl having 1-5 (e.g., 1, 2, 3, 4, or 5, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl group is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 membered (e.g., C 4~10 , C 3~9 , C 3~7, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heterocyclyl rings. In some embodiments, the heterocyclyl group is saturated. In some embodiments, it is partially unsaturated. In some embodiments, the heterocyclyl ring has one heteroatom. In some embodiments, the heterocyclyl ring has two or more heteroatoms. In some embodiments, the heterocyclyl ring has three or more heteroatoms. In some embodiments, the heterocyclyl ring has four or more heteroatoms. In some embodiments, the heteroatom is nitrogen. In some embodiments, the heteroatom is oxygen. In some embodiments, the heteroatom is sulfur.

[0196] In some embodiments, two R groups optionally and independently join together to form a covalent bond, hi some embodiments, two R groups attached to adjacent atoms optionally and independently join together to form a covalent bond.

[0197] In some embodiments, two R groups optionally and independently together with atoms form an optionally substituted 3-30 (e.g., 3-25, 3-20, 3-15, 3-10, or 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, or 30, etc.) membered, monocyclic, bicyclic, or polycyclic ring having, in addition to the atoms, 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3-30 (e.g., 3-25, 3-20, 3-15, 3-10, or 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, or 30, etc.) membered, monocyclic, bicyclic, or polycyclic ring having, in addition to the intervening atoms, 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0198] As described herein, in various cases, there may be more than one R group, or more than one group that is or can be R (e.g., R s, R', etc., together with their intervening atoms can form a ring, which is optionally substituted as described herein. In some embodiments, the ring formed is substituted (in addition to groups attached to the intervening atoms). In some embodiments, the ring formed is unsubstituted. In some embodiments, the ring formed is 3 to 30, 3 to 25, 3 to 20, 3 to 15, 3 to 10, 3 to 8, 3 to 6, 5 to 6, or 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, or 30, etc., members. In some embodiments, the ring formed is a 3-membered ring. In some embodiments, the ring formed is a 4-membered ring. In some embodiments, the ring formed is a 5-membered ring. In some embodiments, the ring formed is a 6-membered ring. In some embodiments, the ring formed is a 7-membered ring. In some embodiments, the ring formed is 8-membered. In some embodiments, the ring formed is 9-membered. In some embodiments, the ring formed is 10-membered. In some embodiments, the ring formed is 11-membered. In some embodiments, the ring formed is 12-membered. In some embodiments, the ring formed is saturated. In some embodiments, the ring formed is partially unsaturated. In some embodiments, the ring formed is aromatic. In some embodiments, the ring formed is monocyclic. In some embodiments, it is bicyclic. In some embodiments, it is polycyclic. In some embodiments, each monocyclic unit is independently saturated, partially unsaturated, or aromatic and is a 3-15 (e.g., 3-15, 3-10, 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, etc.) membered ring having 0-4 heteroatoms. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-10, 3-8, 3-6, 5-6, or 3, 4, 5, 6, 7, 8, 9, or 10, etc.) membered ring that is saturated, partially unsaturated, or aromatic and has 0-4 (e.g., 0, 1, 2, 3, or 4, etc.) heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments, each monocyclic ring unit is independently 3-7 membered. In some embodiments, each monocyclic ring unit is independently 3-6 membered. In some embodiments, each monocyclic ring unit is independently 5-7 membered. In some embodiments, each monocyclic unit is independently saturated or partially unsaturated. In some embodiments, at least one monocyclic unit is saturated. In some embodiments, at least one monocyclic unit is partially unsaturated. In some embodiments, at least one monocyclic unit is aromatic. In some embodiments, the formed ring has, in addition to the intervening atoms, 0-10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, the formed ring has, in addition to the intervening atoms, 0-5 (e.g., 0, 1, 2, 3, 4, or 5, etc.) heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, no additional heteroatoms are present. In some embodiments, 1 additional heteroatom is present. In some embodiments, 2 additional heteroatoms are present. In some embodiments, 3 additional heteroatoms are present. In some embodiments, 4 additional heteroatoms are present. In some embodiments, 5 additional heteroatoms are present. In some embodiments, 6 or more additional heteroatoms are present. In some embodiments, the additional heteroatom is nitrogen. In some embodiments, the additional heteroatom is oxygen. In some embodiments, the additional heteroatom is sulfur.

[0199] In some embodiments, the reduction is carried out in the presence of Ru-[(S,S)-Ts-DPEN] and the product is [ka] wherein each variable is independently as described herein. In some embodiments, the reduction is carried out in the presence of Ru-[(S,S)-Ts-DPEN] and the product is [ka] where R 1 , L, PG, and n are independently as described herein. In some embodiments, the product is [ka] In some embodiments, the product is [ka] In some embodiments, such products are formed with selectivities as described herein.

[0200] In some embodiments, the reduction is carried out in the presence of Ru-[(R,R)-Ts-DPEN] and the product is [ka] wherein each variable is independently as described herein. In some embodiments, the reduction is carried out in the presence of Ru-[(R,R)-Ts-DPEN] and the product is [ka] where R 1 , L, PG, and n are independently as described herein. In some embodiments, the product is [ka] In some embodiments, the product is [ka] In some embodiments, such products are formed with selectivities as described herein.

[0201] In some embodiments, the reduction is carried out in the presence of a hydride-delivering agent, and the product is [ka] wherein each variable is independently as described herein. In some embodiments, the reduction is carried out in the presence of a hydride-delivering agent and the product is [ka] where R 1 , L, PG, and n are independently as described herein. In some embodiments, the agent is NaBH4. In some embodiments, the agent is LiBH4. In some embodiments, the product is [ka] In some embodiments, the product is [ka] In some embodiments, such products are formed with selectivities as described herein.

[0202] In some embodiments, the reduction is carried out in the presence of a hydride-delivering agent, and the product is [ka] wherein each variable is independently as described herein. In some embodiments, the reduction is carried out in the presence of a hydride-delivering agent and the product is [ka] where R 1, L, PG, and n are independently as described herein. In some embodiments, the agent is NaBH4. In some embodiments, the agent is LiBH4. In some embodiments, the product is [ka] In some embodiments, the product is [ka] In some embodiments, such products are formed with selectivities as described herein.

[0203] In some embodiments, the present disclosure provides compounds of formula Pa-1: [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof. In some embodiments, the reduction is carried out in the presence of Ru-[(S,S)-Ts-DPEN].

[0204] In some embodiments, the present disclosure provides compounds of formula Pa-2: [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof. In some embodiments, the reduction is carried out in the presence of Ru—[(R,R)-Ts-DPEN].

[0205] In some embodiments, the present disclosure provides compounds of formula Pa-3: [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof. In some embodiments, the reduction is carried out in the presence of NaBH4. In some embodiments, the agent is LiBH4.

[0206] In some embodiments, the present disclosure provides compounds of formula Pa-4: [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof. In some embodiments, the reduction is carried out in the presence of NaBH4. In some embodiments, the agent is LiBH4.

[0207] Specific Compounds and Compositions In some embodiments, the present disclosure provides various compounds and compositions having the purity described herein and / or produced with the selectivities described herein.

[0208] In some embodiments, the present disclosure provides compounds of formula INT-1: [ka] or a salt thereof, wherein PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R 2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; R a and R b together with their intervening atoms to form ring B, where ring B is R b is an optionally substituted 4- to 15-membered ring having 0-4 heteroatoms in addition to the nitrogen atom to which is attached; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0209] In some embodiments, the disclosure provides a compound of formula INT-1-1 or a salt thereof. In some embodiments, the disclosure provides a compound of formula INT-1-2 or a salt thereof. In some embodiments, the compound of formula INT-1 has the structure of INT-1-a. In some embodiments, the compound of formula INT-1 has the structure of INT-1-b.

[0210] In some embodiments, the present disclosure provides a compound of formula INT-1-a: [ka] or a salt thereof, wherein: n is 0, 1, 2, or 3; PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0211] In some embodiments, the disclosure provides a compound of formula INT-1-a-1 or a salt thereof. In some embodiments, the disclosure provides a compound of formula INT-1-a-2 or a salt thereof. In some embodiments, the disclosure provides a compound of formula INT-1-b-1 or a salt thereof. In some embodiments, the disclosure provides a compound of formula INT-1-b-2 or a salt thereof.

[0212] Specific embodiments of the variables are described above, and one of ordinary skill in the art reading this disclosure will be able to select and combine them.

[0213] In some embodiments, the present disclosure provides: [ka] or a salt thereof. In some embodiments, PG is an amino protecting group other than Boc. In some embodiments, PG is -Trt. In some embodiments, the present disclosure provides a compound having the structure: [ka] or a salt thereof. In some embodiments, the present disclosure provides a compound having the structure: [ka] or a salt thereof. In some embodiments, the present disclosure provides a compound having the structure: [ka] or a salt thereof.

[0214] In some embodiments, the present disclosure provides: [ka] or a salt thereof. In some embodiments, PG is an amino protecting group other than Boc. In some embodiments, PG is -Trt. In some embodiments, the present disclosure provides a compound having the structure: [ka] or a salt thereof. In some embodiments, the present disclosure provides a compound having the structure: [ka] or a salt thereof. In some embodiments, the present disclosure provides a compound having the structure: [ka] or a salt thereof.

[0215] In some embodiments, the present disclosure provides: (1) Formula INT-1: [ka] or a salt thereof, (2) Formula P: [ka] or a salt thereof, A composition comprising: PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R2 )2, -S(O)2R 2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; R a and R b together with their intervening atoms to form ring B, where ring B is R b is an optionally substituted 4- to 15-membered ring having 0-4 heteroatoms in addition to the nitrogen atom to which is attached; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0216] In some embodiments, the present disclosure provides: (1) Formula INT-1-a: [ka] or a salt thereof, (2) Formula Pa: [ka] or a salt thereof, A composition comprising: n is 0, 1, 2, or 3; PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R 2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R sare independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0217] In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof. In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof. In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof. In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof.

[0218] In some embodiments, the composition further comprises a metal complex as described herein. In some embodiments, the composition further comprises a reducing agent as described herein.

[0219] In some embodiments, the compound of formula P is a compound of formula P-1 or P-4, and the compound of formula INT-1 is a compound of formula INT-1-1.

[0220] In some embodiments, the compound of formula P is a compound of formula P-1, and the compound of formula INT-1 is a compound of formula INT-1-1. In some embodiments, the compound of formula P is a compound of formula Pa-1 or Pb-1, and the compound of formula INT-1 is a compound of formula INT-1-a-1 or INT-1-b-1, respectively. In some embodiments, such compositions further comprise a metal complex, such as a Ru complex described herein (e.g., Ru-[(S,S)-Ts-DPEN]). In some embodiments, such compositions further comprise a reducing agent, such as HCOOH or a salt thereof. In some embodiments, the compound of formula P-1, Pa-1, or Pb-1, or a salt thereof, is enriched with a compound of formula P-2, Pa-2, Pb-2, P-3, Pa-3, Pb-3, P-4, Pa-4, and / or Pb-4, or a salt thereof. In some embodiments, the compound or salt of formula P-1, Pa-1, or Pb-1 independently has a purity, diastereomeric purity, and / or enantiomeric purity as described herein.

[0221] In some embodiments, the compound of formula P is a compound of formula P-2, and the compound of formula INT-1 is a compound of formula INT-1-2. In some embodiments, the compound of formula P is a compound of formula Pa-2 or Pb-2, and the compound of formula INT-1 is a compound of formula INT-1-a-2 or INT-1-b-2, respectively. In some embodiments, such compositions further comprise a metal complex, such as a Ru complex described herein (e.g., Ru—[(R,R)-Ts-DPEN]). In some embodiments, such compositions further comprise a reducing agent, such as HCOOH or a salt thereof. In some embodiments, the compound of formula P-2, Pa-2, or Pb-2, or a salt thereof, is enriched with a compound of formula P-1, Pa-1, Pb-1, P-3, Pa-3, Pb-3, P-4, Pa-4, and / or Pb-4, or a salt thereof. In some embodiments, the compound or salt of formula P-1, Pa-1, or Pb-1 independently has a purity, diastereomeric purity, and / or enantiomeric purity as described herein.

[0222] In some embodiments, the compound of formula P is a compound of formula P-3, and the compound of formula INT-1 is a compound of formula INT-1-2. In some embodiments, the compound of formula P is a compound of formula Pa-3 or Pb-3, and the compound of formula INT-1 is a compound of formula INT-1-a-2 or INT-1-b-2, respectively. In some embodiments, such compositions do not contain a transition metal complex, such as a Ru complex described herein (e.g., Ru-[(R,R)-Ts-DPEN] or Ru-[(S,S)-Ts-DPEN]). In some embodiments, such compositions further comprise a reducing agent such as a borohydride (e.g., LiBH4, NaBH4, etc.). In some embodiments, the compound of formula P-3, Pa-3, or Pb-3, or a salt thereof, is enriched in a compound of formula P-1, Pa-1, Pb-1, P-2, Pa-2, Pb-2, P-4, Pa-4, and / or Pb-4, or a salt thereof. In some embodiments, the compound or salt of formula P-1, Pa-1, or Pb-1 independently has a purity, diastereomeric purity, and / or enantiomeric purity as described herein.

[0223] In some embodiments, the compound of formula P is a compound of formula P-4, and the compound of formula INT-1 is a compound of formula INT-1-1. In some embodiments, the compound of formula P is a compound of formula Pa-4 or Pb-4, and the compound of formula INT-1 is a compound of formula INT-1-a-1 or INT-1-b-1, respectively. In some embodiments, such compositions do not contain a transition metal complex, such as a Ru complex described herein (e.g., Ru-[(R,R)-Ts-DPEN] or Ru-[(S,S)-Ts-DPEN]). In some embodiments, such compositions further comprise a reducing agent such as a borohydride (e.g., LiBH4, NaBH4, etc.). In some embodiments, the compound of formula P-4, Pa-4, or Pb-4, or a salt thereof, is enriched in a compound of formula P-1, Pa-1, Pb-1, P-2, Pa-2, Pb-2, P-3, Pa-3, and / or Pb-3, or a salt thereof. In some embodiments, the compound or salt of formula P-1, Pa-1, or Pb-1 independently has a purity, diastereomeric purity, and / or enantiomeric purity as described herein.

[0224] In some embodiments, the present disclosure provides: (1) Formula INT-1: [ka] or a salt thereof, (2) Formula INT-3: R 1 -LH INT-3 or a salt thereof, A composition comprising: PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R 2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; R a and R b together with their intervening atoms to form ring B, where ring B is R b is an optionally substituted 4- to 15-membered ring having 0-4 heteroatoms in addition to the nitrogen atom to which is attached; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0225] In some embodiments, the present disclosure provides: (1) Formula INT-1-a: [ka] or a salt thereof, (2) Formula INT-3: R 1 -LH INT-3 or a salt thereof, A composition comprising: n is 0, 1, 2, or 3; PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R 2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0226] In some embodiments, the compound of formula INT-1 is a compound of formula INT-1-a. In some embodiments, the compound of formula INT-1 is a compound of formula INT-1-b. In some embodiments, the compound of INT-1 is a compound of formula INT-1-1. In some embodiments, the compound of INT-1 is a compound of formula INT-1-2. In some embodiments, the compound of INT-1-a is a compound of formula INT-1-a-1. In some embodiments, the compound of INT-1 is a compound of formula INT-1-a-2. In some embodiments, the compound of INT-1 is a compound of formula INT-1-1. In some embodiments, the compound of INT-1 is a compound of formula INT-1-2.

[0227] In some embodiments, the present disclosure provides: (1) Formula INT-1: [ka] or a salt thereof, (2) Formula INT-2: [ka] or a salt thereof, A composition comprising: PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R 2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; R a and R b together with their intervening atoms to form ring B, where ring B is R b is an optionally substituted 4- to 15-membered ring having 0-4 heteroatoms in addition to the nitrogen atom to which is attached; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0228] In some embodiments, the present disclosure provides: (1) Formula INT-1-a: [ka] or a salt thereof, (2) Formula INT-2-a: [ka] or a salt thereof, A composition comprising: n is 0, 1, 2, or 3; PG is an amino protecting group, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R 2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and R 3 is R, Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0229] In some embodiments, the compound of formula INT-1 is a compound of formula INT-1-a. In some embodiments, the compound of formula INT-1 is a compound of formula INT-1-b. In some embodiments, the compound of INT-1 is a compound of formula INT-1-1. In some embodiments, the compound of INT-1 is a compound of formula INT-1-2. In some embodiments, the compound of INT-1-a is a compound of formula INT-1-a-1. In some embodiments, the compound of INT-1 is a compound of formula INT-1-a-2. In some embodiments, the compound of INT-1 is a compound of formula INT-1-1. In some embodiments, the compound of INT-1 is a compound of formula INT-1-2. In some embodiments, the compound of formula INT-2 is a compound of formula INT-2-a. In some embodiments, the compound of formula INT-2 is a compound of formula INT-2-b. In some embodiments, the compound of INT-2 is a compound of formula INT-2-1. In some embodiments, the compound of INT-2 is a compound of formula INT-2-2. In some embodiments, the compound of INT-2-a is a compound of formula INT-2-a-1. In some embodiments, the compound of INT-2 is a compound of formula INT-2-a-2. In some embodiments, the compound of INT-2 is a compound of formula INT-2-1. In some embodiments, the compound of INT-2 is a compound of formula INT-2-2.

[0230] In some embodiments, a composition comprises a compound of formula INT-1-1, INT-1-a-1, or INT-1-b-1, or a salt thereof, and a compound of formula INT-2-1, INT-2-a-1, or INT-2-b-1, or a salt thereof. In some embodiments, each compound of formula INT-1-1, INT-1-a-1, INT-1-b-1, INT-2-1, INT-2-a-1, or INT-2-b-1, or a salt thereof, independently has a purity, diastereomeric purity, and / or enantiomeric purity described herein.

[0231] In some embodiments, a composition comprises a compound of formula INT-1-2, INT-1-a-2, or INT-1-b-2 or a salt thereof, and a compound of formula INT-2-2, INT-2-a-2, or INT-2-b-2 or a salt thereof. In some embodiments, each compound of formula INT-1-2, INT-1-a-2, INT-1-b-2, INT-2-2, INT-2-a-2, or INT-2-b-2 or a salt thereof independently has a purity, diastereomeric purity, and / or enantiomeric purity described herein.

[0232] In some embodiments, the compound comprising a compound of formula INT-1 or a salt thereof and a compound of formula INT-2 or a salt thereof further comprises a compound of formula INT-3 or a salt thereof. In some embodiments, the compound has the structure of formula INT-3 or a salt thereof, e.g., Li + Contains salt.

[0233] In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof, wherein PG is an amino protecting group as described herein. In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof.

[0234] In some embodiments, the composition comprises: [ka] or a salt thereof, and R 1 In some embodiments, the composition comprises: [ka] or a salt thereof, and R 1 -LH or its salt.

[0235] In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof, wherein PG is an amino protecting group. In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof.

[0236] In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof. In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof.

[0237] In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof, wherein PG is an amino protecting group as described herein. In some embodiments, the composition comprises: [ka] or a salt thereof, and [ka] or a salt thereof.

[0238] Specific Uses of Compounds and Compositions As will be appreciated by those skilled in the art, compounds of the present disclosure, e.g., compounds of formula P, DP, etc., or salts thereof, are useful for many purposes, e.g., as pharmaceuticals, chiral auxiliaries, etc., or agents useful in the preparation thereof.

[0239] In some embodiments, provided compounds, such as compounds of formula P or DP, or salts thereof, are useful as chiral agents for stereoselective synthesis. For example, in some embodiments, they are useful for the chirality-controlled preparation of oligonucleotides. Specific uses are described, for example, in International Publication Nos. 2019 / 055951 and 2020 / 191252, which are incorporated herein by reference.

[0240] Specific phosphoramidite technologies In some embodiments, the present disclosure provides compounds of formula PMT: [ka] or a salt thereof, wherein R NS is a nucleoside, L is optionally substituted —CH—; R 1 is R, -P(O)(R 2 )2, -S(O)2R 2 or -Si(R)3, R 2 is R, -OR, -N(R')2, or [ka] and Ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Each R s are independently R', halogen, -CN, -C(O)OR', -OR', -N(R')2; t is 0, 1, 2, 3, 4, or 5; R a and R b together with their intervening atoms to form ring B, where ring B is R b is an optionally substituted 4- to 15-membered ring having 0-4 heteroatoms in addition to the nitrogen atom to which is attached; each R' is independently R, -C(O)R, -C(O)OR, -C(O)N(R), or -S(O)R; Each R is independently —H or C 1~30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic, C 6~30 Aryl, C 6~30 C having 1 to 10 heteroatoms independently selected from arylaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; or two R groups, optionally and independently, together form a covalent bond, or two R groups optionally and independently, taken together with their atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to their atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or Two or more R groups optionally and independently, together with their intervening atoms, form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having, in addition to their intervening atoms, 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0241] As will be appreciated by those skilled in the art, compounds of formula PMT can exist as various diastereomers. In some embodiments, the present disclosure provides a cis isomer of a phosphoramidite having the structure of formula PMT or a salt thereof. In some embodiments, the cis isomer is R NS , -LR 1 Contains R a is a ring structure [ka] In some embodiments, the cis isomer of a phosphoramidite of formula PMT or a salt thereof has the formula PMT-A: [ka] or a salt thereof. In some embodiments, the cis isomer of the phosphoramidite of formula PMT or a salt thereof has the structure of formula PMT-B: [ka] or a salt thereof.

[0242] In some embodiments, the present disclosure provides a trans isomer of a phosphoramidite having a structure of formula PMT or a salt thereof. In some embodiments, the trans isomer has a ring structure [ka] R points in the opposite direction of the plane defined by NS and -LR 1 In some embodiments, the trans isomer comprises a ring structure [ka] R points in the opposite direction of the plane defined by NS and R a In some embodiments, the trans isomer of a phosphoramidite of formula PMT or a salt thereof comprises a group of formula PMT-A': [ka] or a salt thereof. In some embodiments, the cis isomer of the phosphoramidite of formula PMT or a salt thereof has the structure of formula PMT-B': [ka] or a salt thereof.

[0243] In some embodiments, -LR 1 and R a is a cis.

[0244] In some embodiments, the disclosure provides a method of preparing a compound or composition disclosed herein, comprising preparing a compound or composition having the formula CA: [ka] or a salt thereof, with a nucleoside, wherein each variable is as independently described herein.

[0245] In some embodiments, the compound of formula CA has the formula CA-A: [ka] or a salt thereof, wherein each variable is as independently described herein.

[0246] In some embodiments, the compound of formula CA has formula CA-B: [ka] or a salt thereof, wherein each variable is as independently described herein.

[0247] R NS In some embodiments, R NS is a nucleoside containing a protecting group. In some embodiments, R NS is a suitably protected nucleoside for oligonucleotide synthesis.

[0248] In some embodiments, R NS is -SU-BA, where each SU and BA is independently as described herein. NSis -O-SU-BA, where each SU and BA is independently as described herein. In some embodiments, SU is a sugar as described herein. In some embodiments, BA is a nucleobase as described herein.

[0249] In some embodiments, R NS BA is C 1~30 Alicyclic group, C 6~30 C having 1 to 10 heteroatoms independently selected from aryl, oxygen, nitrogen, sulfur, phosphorus, and silicon 3~30 Heterocyclyl, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 5~30 an optionally substituted group -O-SU-BA selected from heteroaryl, natural nucleobase moieties, and modified nucleobase moieties, wherein -O-SU- is -OL; s -or [ka] wherein -O-SU- is bonded to the phosphorus atom in formula PMT-A or PMT-B through an oxygen atom, and L s is a covalent bond or a C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; 1~30 Aliphatic and C 1~30 a divalent optionally substituted linear or branched group selected from heteroaliphatic groups, wherein one or more methylene units are optionally independently selected from optionally substituted C 1~6 Alkylene, C 1~6 alkenylene, -C≡C-, -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)O-, -OC(O)N(R')-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -N(R')S(O)2-, -SC(O)-, -C(O)S-, -OC(O)-, or -C(O)O-; R 5sis R' or -OR', and R 2s -F, -CN, -N3, -NO, -NO2, -R'-OR', -SR', -N(R')2, -OL s -OR', -OL s -SR' or -OL s -N(R')2, and R 2s is the L that connects C2 to C1, C2, C3, C4 or C5. s and -Cy- is an optionally substituted divalent ring selected from 3- to 30-membered carbocyclylene, 6- to 30-membered arylene, 5- to 30-membered heteroarylene having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and 3- to 30-membered heterocyclylene having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0250] SU In some embodiments, the SU is a sugar described herein. For example, in some embodiments, the SU is an optionally substituted [ka] In some embodiments, the SU is, as described herein, [ka] It is a sugar having the structure:

[0251] In some embodiments, -O-SU- is [ka] is.

[0252] In some embodiments, -O-SU- is -OL s In some embodiments, L s is -Cy-. In some embodiments, L sis an optionally substituted 3- to 30-membered carbocyclylene. In some embodiments, L s is an optionally substituted 6- to 30-membered arylene. In some embodiments, L s is an optionally substituted 5-30 membered heteroarylene ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. s is an optionally substituted 5-30 membered heteroarylene ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, L s is an optionally substituted 3-30 membered heterocyclylene ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. s is an optionally substituted 3-30 membered heterocyclylene having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. s is an optionally substituted 5-30 membered heterocyclylene having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. s is an optionally substituted 5-30 membered heterocyclylene having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. s is an optionally substituted 5-10 membered heterocyclylene ring having one oxygen atom. In some embodiments, L s is an optionally substituted 5-membered heterocyclylene ring having one oxygen atom. In some embodiments, L s is an optionally substituted 6-membered heterocyclylene ring having one oxygen atom. In some embodiments, L s is an optionally substituted 5-10 membered bicyclic heterocyclylene having 1 or 2 oxygen atoms. In some embodiments, L sis an optionally substituted 7-10 membered bicyclic heterocyclylene having 1 or 2 oxygen atoms. In some embodiments, L s is an optionally substituted 7-10 membered bicyclic heterocyclylene having two oxygen atoms. In some embodiments, L s is an optionally substituted seven-membered bicyclic heterocyclylene having two oxygen atoms.

[0253] In some embodiments, SU is a sugar moiety used in oligonucleotide synthesis. In some embodiments, SU is an optionally substituted saturated monocyclic, bicyclic, or polycyclic aliphatic ring in which one or more methylene units are replaced with -O-. In some embodiments, SU is a ribose or deoxyribose moiety found in naturally occurring DNA or RNA molecules.

[0254] In some embodiments, R NS is -SU-BA, where SU is a sugar moiety described herein. In some embodiments, the sugar is [ka] wherein ring A s is an optionally substituted 3-30 membered, monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms in addition to nitrogen, and ring A s is attached to the phosphorus atom of formula PMT-A or PMT-B through a nitrogen atom, and L s is as described herein. In some embodiments, R NS teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, R NS teeth, [ka] In some embodiments, -OH is optionally substituted or protected, for example, -ODMTr.

[0255] In some embodiments, the present disclosure provides PMT-A1: [ka] or a salt thereof, wherein each variable group is independently as described herein. In some embodiments, the present disclosure provides a compound having the structure PMT-B1: [ka] or a salt thereof, wherein each variable is independently as described herein.

[0256] R 5s In some embodiments, R 5s is R'. In some embodiments, R 5s is -OR'. In some embodiments, R 5s is a protected hydroxyl group suitable for oligonucleotide synthesis. In some embodiments, R 5s is -OR', where R' is an optionally substituted C 1~6 In some embodiments, R 5sis DMTrO-. Examples of protecting groups for use in accordance with the present disclosure are widely known in the art. For further examples, see Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991, and WO 2011 / 005761, WO 2013 / 012758, WO 2014 / 012081, WO 2015 / 107425, WO 2010 / 064146, WO 2014 / 010250, WO 2011 / 108682, WO 2012 / 039448, and WO 2012 / 073857, each of which protecting groups are incorporated herein by reference.

[0257] R 2s In some embodiments, R 2s is —H. In some embodiments, R 2s is -F. In some embodiments, R 2s is -CN. In some embodiments, R 2s is -N3. In some embodiments, R 2s is -NO. In some embodiments, R 2s is —NO. In some embodiments, R 2s is -R'. In some embodiments, R 2s is -OR'. In some embodiments, R 2s is -OR', where R' is an optionally substituted C 1~6 In some embodiments, R 2s is -OMe. In some embodiments, R 2s is -SR'. In some embodiments, R 2s is -N(R'). In some embodiments, R 2s is -OL-OR'. In some embodiments, R 2s is -OL-OR', where L is an optionally substituted C 1~6alkylene, and R' is optionally substituted C 1~6 In some embodiments, R 2s is -O-(optionally substituted C 1~6 In some embodiments, R 2s is -O-(optionally substituted C 1~6 alkylene)-OR′, where R′ is an optionally substituted C 1~6 In some embodiments, R 2s is —OCHCHOMe. In some embodiments, R 2s is -OL-SR'. In some embodiments, R 2s is -OLN(R'). In some embodiments, R 2s is an L connecting C2 with C1, C2, C3, C4, or C5. In some embodiments, R 2s is an L that connects C2 with C1. In some embodiments, R 2s is an L connecting C2 with C2. In some embodiments, R 2s is an L that connects C2 with C3. In some embodiments, R 2s is an L connecting C2 with C4. In some embodiments, R 2s is an L connecting C2 and C5. In some embodiments, R 2s is (C2)-O-(optionally substituted methylene)-(C4). In some embodiments, R 2s is (C2)-O-(methylene)-(C4). In some embodiments, R 2s is (C2)-O-(methylmethylene)-(C4). In some embodiments, R 2s is (C2)-O-((R)-methylmethylene)-(C4). In some embodiments, R 2s is (C2)-O-((S)-methylmethylene)-(C4). In some embodiments, R 2s is (C2)-O-(ethylmethylene)-(C4). In some embodiments, R 2sis (C2)-O-((R)-ethylmethylene)-(C4). In some embodiments, R 2s is (C2)-O-((S)ethylmethylene)-(C4). In some embodiments, R 2s contains a chiral carbon in the R configuration. In some embodiments, R 2s contains a chiral carbon in the S configuration.

[0258] BA / nucleobase In some embodiments, in the various formulas, BA is a nucleobase as described herein. In some embodiments, BA is C 3~30 Alicyclic, C 6~30 Aryl, C with 1-10 heteroatoms 5~30 Heteroaryl, C with 1-10 heteroatoms 3~30 In some embodiments, BA is an optionally substituted, saturated, partially unsaturated, or aromatic C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 29 -C 32 -C 26 -C 28 -C 29 -C 33 -C 29 -C 34 -C 29 -C 35 -C 29 -C 36 -C 29 -C 37 -C 29 -C 38 -C 39 -C 3~30 (For example, C 3~25 , C 3~20 , C 3~15 , C 5~30 , C 5~20 , C 5~15 , C 5~10 , 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, etc.) monocyclic, bicyclic, or polycyclic ring. 6~30 (For example, C 6~25 , C 6~20 , C 6~14 In some embodiments, BA is an optionally substituted 6-14 membered aryl. In some embodiments, BA is an optionally substituted C aryl having 1-5 (e.g., 1-3, 1, 2, 3, 4, 5, etc.) heteroatoms. 5~30 (For example, C5~25 、C 5~20 、C 5~15 、C 5~14, 5, 6, 9, 10, 12, 13, 14, etc.) heteroaryl. In some embodiments, the heteroatom is nitrogen. In some embodiments, each monocyclic ring in BA is an optionally substituted 3-10 (e.g., 3-7, 5-10, 3, 4, 5, 6, 7, 8, 9, 10, etc.) membered saturated, partially unsaturated, or aromatic ring having 1-5 (e.g., 1-3, 1, 2, 3, 4, 5, etc.) heteroatoms. In some embodiments, one or more ring heteroatoms is nitrogen. In some embodiments, BA comprises one or more partially unsaturated monocyclic rings. In some embodiments, BA comprises one or more aromatic rings. In some embodiments, BA comprises one or more heteroaryl rings. In some embodiments, BA comprises one or more heteroaryl rings, one or more of which independently comprise a nitrogen atom. In some embodiments, BA comprises one or more heterocyclyl rings, one or more of which independently comprise a nitrogen atom. In some embodiments, the ring, e.g., the monocyclic ring unit in BA, or BA, is 5-membered. In some embodiments, the monocyclic ring unit in BA, or BA, is 6-membered. In some embodiments, the bicyclic ring unit in BA, or BA, is 8-10-membered. In some embodiments, it is 8-membered. In some embodiments, it is 9-membered. In some embodiments, it is 10-membered. A variety of nucleobases can be utilized in the oligonucleotides provided in accordance with the present disclosure. In some embodiments, the nucleobase is a natural nucleobase, the most commonly occurring of which are A, T, C, G, and U. In some embodiments, the nucleobase is a modified nucleobase in that it is not A, T, C, G, or U. In some embodiments, the nucleobase is an optionally substituted A, T, C, G, or U, or a substituted tautomer of A, T, C, G, or U. In some embodiments, the nucleobase is an optionally substituted A, T, C, G, or U, such as 5mC, 5-hydroxymethylC, etc. In some embodiments, the nucleobase is alkyl-substituted A, T, C, G, or U. In some embodiments, the nucleobase is A. In some embodiments, the nucleobase is T. In some embodiments, the nucleobase is C.In some embodiments, the nucleobase is G. In some embodiments, the nucleobase is U. In some embodiments, the nucleobase is 5mC. In some embodiments, the nucleobase is a substituted A, T, C, G, or U. In some embodiments, the nucleobase is a substituted tautomer of A, T, C, G, or U. In some embodiments, the substitution protects certain functional groups in the nucleobase to minimize undesired reactions during oligonucleotide synthesis. Suitable techniques for protecting nucleobases in oligonucleotide synthesis are widely known in the art and can be utilized in accordance with the present disclosure. In some embodiments, the modified nucleobase improves the properties and / or activity of the oligonucleotide. For example, in many instances, 5mC can be utilized in place of C to modulate certain undesired biological effects, such as immune responses. In some embodiments, when determining sequence identity, substituted nucleobases having the same hydrogen bonding pattern are treated the same as unsubstituted nucleobases, e.g., 5mC can be treated the same as C (e.g., an oligonucleotide having 5mC in place of C (e.g., AT5mCG) is considered to have the same base sequence as an oligonucleotide having a C at the corresponding position (e.g., ATCG)). In some embodiments, the nucleobase is or includes an optionally substituted ring having at least one nitrogen atom. In some embodiments, the nucleobase includes a ring BA as described herein, wherein at least one monocyclic ring of the ring BA includes a nitrogen ring atom.

[0259] In some embodiments, the oligonucleotide comprises one or more A, T, C, G, or U. In some embodiments, the oligonucleotide comprises one or more optionally substituted A, T, C, G, or U. In some embodiments, the oligonucleotide comprises one or more 5-methylcytidine, 5-hydroxymethylcytidine, 5-formylcytosine, or 5-carboxylcytosine. In some embodiments, the oligonucleotide comprises one or more 5-methylcytidine. In some embodiments, each nucleobase in the oligonucleotide is selected from the group consisting of optionally substituted A, T, C, G, and U, and optionally substituted tautomers of A, T, C, G, and U. In some embodiments, each nucleobase in the oligonucleotide is optionally protected A, T, C, G, and U. In some embodiments, each nucleobase in the oligonucleotide is optionally substituted A, T, C, G, or U. In some embodiments, each nucleobase in the oligonucleotide is selected from the group consisting of A, T, C, G, U, and 5mC.

[0260] In some embodiments, the nucleobase, e.g., BA, comprises at least one optionally substituted ring containing a heteroatom ring atom. In some embodiments, the nucleobase comprises at least one optionally substituted ring containing a nitrogen ring atom. In some embodiments, such ring is aromatic. In some embodiments, the nucleobase is linked to the sugar via a heteroatom. In some embodiments, the nucleobase is linked to the sugar via a nitrogen atom. In some embodiments, the nucleobase is linked to the sugar via a ring nitrogen atom.

[0261] In some embodiments, the nucleobase, e.g., BA, is selected from the group consisting of U.S. Patent Nos. 9,394,333, 9,744,183, 9,605,019, 9,598,458, 9,982,257, 10,160,969, 10,479,995, U.S. Patent Application Publication No. 2020 / 0056173, 2018 / 0216107, 2019 / 0127733, 10,450,568, 2019 / 0077817, and 2019 / 02491, each of which is incorporated by reference herein. 73, U.S. Patent Application Publication No. 2019 / 0375774, 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, WO 2020 / 191252, WO 2021 / 071858 and / or WO 2022 / 099159.

[0262] In some embodiments, BA is an optionally substituted or protected U, or a tautomer of an optionally substituted or protected U, or an optionally substituted or protected C, or a tautomer of an optionally substituted or protected C, or an optionally substituted or protected A, or a tautomer of an optionally substituted or protected A, or an optionally substituted or protected pseudoisocytosine nucleobase, or a tautomer of an optionally substituted or protected pseudoisocytosine nucleobase.

[0263] In some embodiments, the nucleobase, e.g., BA, is an optionally substituted purine base residue. In some embodiments, the nucleobase is a protected purine base residue. In some embodiments, the nucleobase is an optionally substituted adenine residue. In some embodiments, the nucleobase is a protected adenine residue. In some embodiments, the nucleobase is an optionally substituted guanine residue. In some embodiments, the nucleobase is a protected guanine residue. In some embodiments, the nucleobase is an optionally substituted cytosine residue. In some embodiments, the nucleobase is a protected cytosine residue. In some embodiments, the nucleobase is an optionally substituted thymine residue. In some embodiments, the nucleobase is a protected thymine residue. In some embodiments, the nucleobase is an optionally substituted uracil residue. In some embodiments, the nucleobase is a protected uracil residue. In some embodiments, the nucleobase is an optionally substituted 5-methylcytosine residue. In some embodiments, the nucleobase is a protected 5-methylcytosine residue.

[0264] In some embodiments, the nucleobase, e.g., BA, is an optionally substituted group, which group is [ka] or by removal of -H from its tautomer. In some embodiments, the nucleobase, e.g., BA, is an optionally substituted group, which group is [ka] In some embodiments, the nucleobase, e.g., BA, is an optionally substituted group, which is formed by removing —H from [ka] and tautomeric forms thereof. In some embodiments, the nucleobase, e.g., BA, is an optionally substituted group, which group is selected from: [ka] In some embodiments, the nucleobase, e.g., BA, is an optionally substituted group selected from: [ka] and by removing -H from its tautomer. In some embodiments, the nucleobase, e.g., BA, is an optionally substituted group, which group is [ka] In some embodiments, the nucleobase, e.g., BA, is an optionally substituted group, which is formed by removing —H from [ka] and tautomeric forms thereof. In some embodiments, the nucleobase, e.g., BA, is an optionally substituted group, which group is selected from: [ka] In some embodiments, the nucleobase, e.g., BA, is optionally substituted. [ka] or a tautomeric form thereof. In some embodiments, the nucleobase, e.g., BA, is optionally substituted [ka] In some embodiments, the nucleobase, e.g., BA, is optionally substituted. [ka] or a tautomeric form thereof. In some embodiments, the nucleobase, e.g., BA, is optionally substituted [ka] In some embodiments, the nucleobase, e.g., BA, is optionally substituted. [ka] or a tautomeric form thereof. In some embodiments, the nucleobase, e.g., BA, is optionally substituted [ka] In some embodiments, the nucleobase, e.g., BA, is optionally substituted. [ka] or a tautomeric form thereof. In some embodiments, the nucleobase, e.g., BA, is optionally substituted [ka] In some embodiments, the nucleobase, e.g., BA, is optionally substituted. [ka] or a tautomeric form thereof. In some embodiments, the nucleobase, e.g., BA, is optionally substituted [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] is.

[0265] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the nucleobase, e.g., BA, is [ka] In some embodiments, the protecting group is -Ac. In some embodiments, the protecting group is -Bz. In some embodiments, the protecting group is -iBu on the nucleobase.

[0266] In some embodiments, the nucleobase, eg, BA, is optionally substituted hypoxanthine or a tautomer thereof.

[0267] In some embodiments, the nucleobase, e.g., BA, is an optionally substituted purine base residue. In some embodiments, the nucleobase is a protected purine base residue. In some embodiments, the nucleobase is an optionally substituted adenine residue. In some embodiments, the nucleobase is a protected adenine residue. In some embodiments, the nucleobase is an optionally substituted guanine residue. In some embodiments, the nucleobase is a protected guanine residue. In some embodiments, the nucleobase is an optionally substituted cytosine residue. In some embodiments, the nucleobase is a protected cytosine residue. In some embodiments, the nucleobase is an optionally substituted thymine residue. In some embodiments, the nucleobase is a protected thymine residue. In some embodiments, the nucleobase is an optionally substituted uracil residue. In some embodiments, the nucleobase is a protected uracil residue. In some embodiments, the nucleobase is an optionally substituted 5-methylcytosine residue. In some embodiments, the nucleobase is a protected 5-methylcytosine residue.

[0268] In some embodiments, the nucleobases are selected from the group consisting of those disclosed in U.S. Patent Application Publication Nos. 2011 / 0294124, 2015 / 0211006, 2015 / 0197540, WO 2015 / 107425, WO 2017 / 192679, WO 2018 / 022473, WO 2018 / 098264, WO 2018 / 223056, WO 2018 / 22 3073, 2018 / 223081, 2018 / 237194, 2019 / 032607, 2019 / 055951, 2019 / 075357, 2019 / 200185, 2019 / 217784, 2019 / 032612, 2020 / 191252, 2021 / 071858, and / or 2022 / 099159. In some embodiments, the BA is such a nucleobase.

[0269] R1 In some embodiments, R 1 is R as described herein. In some embodiments, R 1 is —H. In some embodiments, R 1 is not -H.

[0270] In some embodiments, R 1 is -P(O)(R 2 )2, where each R 2 are independently as described herein. In some embodiments, at least one R 2 is not —H. In some embodiments, each R 2 is not —H. In some embodiments, at least one R 2 is -OR. In some embodiments, at least one R 2 is -OR, where R is as described herein and is not -H. In some embodiments, each R 2 is independently -OR. In some embodiments, each R 2 is independently -OR, where R is as described herein and is not -H. In some embodiments, at least one R 2 is independently —N(R′) 2 , and each R′ is independently as described herein. In some embodiments, at least one R 2 is independently —N(R)2, where each R is independently as described herein. In some embodiments, each R 2 is independently —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, each R 2 is independently -N(R)2, where each R is independently as described herein. In some embodiments, at least one R 2 is, as described herein, [ka] In some embodiments, each R 2 are independently, as described herein, [ka] is.

[0271] In some embodiments, R 1 is -S(O)2R 2 In some embodiments, R 2 is R as described herein. In some embodiments, R 2 is R as described herein and is not —H. In some embodiments, R 2 is an optionally substituted C 1~10 In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is phenyl. In some embodiments, R 2 is -OR. In some embodiments, R 2 is -OR, where R is not -H. In some embodiments, R 2is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 2 is —N(R)2, where each R is independently as described herein. In some embodiments, R 2 is -NMe. In some embodiments, R 2 teeth, [ka] In some embodiments, ring A is selected from the group consisting of -S(O)- and R s R is an optionally substituted phenyl ring (in addition to the phenyl group). s Various useful embodiments of and t are described herein by way of example. In some embodiments, R 1 is -S(O)2R 2 where R 2 is optionally substituted phenyl. In some embodiments, R 1 is -S(O)2R 2 where R 2 is phenyl.

[0272] In some embodiments, R 1 is -Si(R)3, where each R is independently as described therein. In some embodiments, each R is not -H. In some embodiments, R 1 is —Si(R)3, where each R is independently an optionally substituted C 1~30 In some embodiments, R 1 is —Si(R)3, where each R is independently an optionally substituted C 1~10 In some embodiments, R 1 is —Si(R)3, where each R is independently selected from the group of methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl. 1is —Si(R)3, where each R is independently an optionally substituted C 1~4 In some embodiments, R 1 is —Si(R)3, where each R is independently methyl. In some embodiments, R 1 is —Si(R)3, where each R is independently ethyl. In some embodiments, R 1 is —Si(R)3, where each R is independently propyl. In some embodiments, R 1 is —Si(R)3, where each R is independently isopropyl. In some embodiments, R 1 is —Si(R)3, where each R is independently n-butyl. In some embodiments, R 1 is —Si(R)3, where each R is independently tert-butyl.

[0273] In some embodiments, R 1 is —Si(R)3, where each R is independently 1~30 Aliphatic and C 6~30 aryl. In some embodiments, R 1 is —Si(R)3, where each R is independently 1~10 is an optionally substituted group selected from aliphatic and phenyl. In some embodiments, R 1 is —Si(R)3, where each R is independently 1~4 is an optionally substituted group selected from aliphatic and phenyl. In some embodiments, R 1 is —Si(R)3, where each R is independently 1~4 An optionally substituted group selected from aliphatic and phenyl, wherein the substituents are halogen, —CN, —C(O)OR′, —OR′, or —N(R′)2, where R′ is described therein. In some embodiments, R 1 is —Si(R)3, where each R is independently C 1~4aliphatic or optionally substituted phenyl, wherein the substituents are halogen, —CN, —C(O)OR′, —OR′, or —N(R′)2, where R′ is described therein. In some embodiments, R 1 is —Si(R)3, where each R is independently 1~4 In some embodiments, R 1 is —Si(R)3, where one R group is an optionally substituted C 1~6 In some embodiments, R is an aliphatic group, and the other two are, independently, optionally substituted phenyl. 1 is -Si(Ph)2Me.

[0274] R 2 In some embodiments, R 2 is R' as described herein. In some embodiments, R 2 is R as described herein. In some embodiments, R 2 is —H. In some embodiments, R 2 is not —H. In some embodiments, R 2 is an optionally substituted C 1~10 In some embodiments, R 2 is an optionally substituted C 1~10 In some embodiments, R 2 is C 1~10 In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 2is optionally substituted phenyl. In some embodiments, R 2 is phenyl.

[0275] In some embodiments, R 2 is -OR. In some embodiments, R 2 is —OH. In some embodiments, R 2 is -OR, where R is not -H. In some embodiments, R is an optionally substituted C 1~6 It is aliphatic.

[0276] In some embodiments, R 2 is —N(R′) 2 , where each R′ is independently as described herein. In some embodiments, R 2 is -NHR', where R' is as described herein. In some embodiments, R 2 is —N(R)2, where each R is independently as described herein. In some embodiments, R 2 is —NHR, where R is as described herein. In some embodiments, R 2 is -NH. In some embodiments, R 2 is —N(R)2, where each R is independently 1~6 In some embodiments, R 2 is -NMe. In some embodiments, R 2 is -N(Et)2. In some embodiments, R 2 is -N(Me)Et.

[0277] In some embodiments, R 2 is, as described herein, [ka] is.

[0278] In some embodiments, R 2One of the existence of [ka] In some embodiments, t is 1 and ring A is optionally substituted. [ka] In some embodiments, R 2 is optionally replaced [ka] In some embodiments, R 2 One of the existence of [ka] and the other occurrence is -OR. In some embodiments, R 2 One of the existence of [ka] and other entities are -R.

[0279] Ring A As described herein, ring A is optionally substituted (e.g., [ka] Plus R s In some embodiments, ring A is substituted. In some embodiments, ring A is unsubstituted.

[0280] In some embodiments, ring A is an optionally substituted 5-10 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, ring A is an optionally substituted 5-6 membered aromatic ring having 0-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, ring A is an optionally substituted phenyl ring. In some embodiments, ring A is a phenyl ring. In some embodiments, ring A is an optionally substituted 10 membered bicyclic aryl ring. In some embodiments, ring A is an optionally substituted 5-9 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroatom is nitrogen. In some embodiments, ring A is protected.

[0281] R s In some embodiments, R s is R' as described herein. In some embodiments, R s is R as described herein. In some embodiments, R s Each occurrence of is -H. In some embodiments, R s In some embodiments, R s Each occurrence of is not -H.

[0282] In some embodiments, R s is R as described herein and is not -H. For example, in some embodiments, it is optionally substituted C 6~10In some embodiments, it is an optionally substituted phenyl. In some embodiments, it is an optionally substituted heteroaryl, such as a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0283] In some embodiments, R s In some embodiments, R s In some embodiments, R s In some embodiments, R s In some embodiments, R s In some embodiments, R s The presence of is -CN.

[0284] In some embodiments, R s occurrence is C(O)OR', where R' is -H or C 1~30 C having an aliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic and C 6~30 Aryl and C 6~30 C having arylaliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 and optionally substituted groups selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R s is C(O)OR, where R is as described herein. In some embodiments, R s An occurrence of is C(O)OR, where R is as described herein and is not —H. In some embodiments, R sIn some embodiments, R s The presence of is -C(O)OEt.

[0285] In some embodiments, R s occurrence of is -OR', where R' is -H or C 1~30 C having an aliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic and C 6~30 Aryl and C 6~30 C having arylaliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 In some embodiments, R' is an optionally substituted group selected from arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R' is an optionally substituted C 1~6 In some embodiments, R s In some embodiments, R s is -OR, where R is as described herein and is not -H. In some embodiments, R s An occurrence of is -OMe. In some embodiments, R s In some embodiments, R s In some embodiments, R s is -O-isopropyl. In some embodiments, R s In some embodiments, R s is -O-tert-butyl. In some embodiments, R s is -O-CH-Ph. In some embodiments, R s The presence of is -O-Ph.

[0286] In some embodiments, R s occurrence is -N(R')2, where R' is -H or C 1~30 C having an aliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1~30 Heteroaliphatic and C 6~30 Aryl and C 6~30 C having arylaliphatic and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6~30 arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, each R' is independently H or an optionally substituted C 1~6 In some embodiments, R s is -NH. In some embodiments, R s In some embodiments, R s is -NHMe. In some embodiments, R s is -NMe. In some embodiments, R s In some embodiments, R s The presence of -N(Et)2.

[0287] In some embodiments, R s The presence of optionally substituted C 6~10 In some embodiments, it is aryl. In some embodiments, it is optionally substituted phenyl. In some embodiments, it is phenyl. In some embodiments, R s Each occurrence of R is a 5-20 membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. sThe existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R 2 The existence of [ka] In some embodiments, R s The existence of [ka] In some embodiments, R s The existence of [ka] is.

[0288] t In some embodiments, t is 0. In some embodiments, t is 1 to 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.

[0289] L In some embodiments, L is -CH-. In some embodiments, L is substituted -CH-. In some embodiments, L is -CH- substituted with one or two suitable substituents. In some embodiments, L is monosubstituted. In some embodiments, L is disubstituted. In some embodiments, L is -CH(CN)-.

[0290] Ring B As described herein, R a and R b together with their intervening atoms form an optionally substituted ring B. In some embodiments, ring B is (R a The nitrogen atom to which R is bonded bis optionally substituted (in addition to the group attached to the carbon atom to which is attached). In some embodiments, Ring B is substituted. In some embodiments, Ring B is unsubstituted.

[0291] In some embodiments, ring B has 4 to 15, 4 to 12, 4 to 10, or 4 to 7 members. In some embodiments, ring B has 4 members. In some embodiments, ring B has 5 members. In some embodiments, ring B has 6 members. In some embodiments, ring B has 7 members. In some embodiments, ring B has 8 members. In some embodiments, ring B has 9 members. In some embodiments, ring B has 10 members. In some embodiments, ring B has 11 members. In some embodiments, ring B has 12 members. In some embodiments, ring B has 13 members. In some embodiments, ring B has 14 members. In some embodiments, ring B has 15 members.

[0292] In some embodiments, Ring B is saturated. In some embodiments, Ring B is partially unsaturated. In some embodiments, R a The carbon to which is bonded is sp 3 is.

[0293] In some embodiments, ring B is monocyclic. In some embodiments, ring B is bicyclic. In some embodiments, ring B is polycyclic. In some embodiments, each monocyclic unit is independently a 3-10 (e.g., 3-7, 4-7, 3-6, 3, 4, 5, 6, 7, 8, 9, or 10)-membered saturated, partially unsaturated, or aromatic ring having 0-5 (e.g., 0, 1-5, 1, 2, 3, 4, 5, etc.) heteroatoms. In some embodiments, each monocyclic unit is independently a 3-7 (e.g., 3, 4, 5, 6, 7, etc.)-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic unit is independently a 4-7-membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic unit is independently a 5-7 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each monocyclic unit is independently saturated or partially unsaturated. In some embodiments, each monocyclic unit is independently saturated.

[0294] In some embodiments, ring B is R b has zero heteroatoms in addition to the nitrogen atom to which is attached. In some embodiments, ring B has 1 to 4 additional heteroatoms. In some embodiments, ring B has 1 additional heteroatom. In some embodiments, ring B has 2 additional heteroatoms. In some embodiments, ring B has 3 additional heteroatoms. In some embodiments, ring B has 4 additional heteroatoms. In some embodiments, each additional heteroatom is independently selected from nitrogen, oxygen, and sulfur.

[0295] In some embodiments, ring B is an optionally substituted azetidine ring. In some embodiments, ring B is an optionally substituted pyrrolidine ring. In some embodiments, ring B is an optionally substituted piperidine ring.

[0296] In some embodiments, Ring B is optionally substituted [ka] and n is 0, 1, 2, or 3. In some embodiments, ring B is optionally substituted [ka] In some embodiments, ring B is [ka] is.

[0297] n In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0298] In some embodiments, the present disclosure provides compounds described herein having a diastereomeric purity of about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%. In some embodiments, compounds described herein have a diastereomeric purity of about or at least about 10%. In some embodiments, compounds described herein have a diastereomeric purity of about or at least about 15%. In some embodiments, compounds described herein have a diastereomeric purity of about or at least about 20%. In some embodiments, compounds described herein have a diastereomeric purity of about or at least about 25%. In some embodiments, compounds described herein have a diastereomeric purity of about or at least about 30%. In some embodiments, compounds described herein have a diastereomeric purity of about or at least about 35%. In some embodiments, compounds described herein have a diastereomeric purity of about or at least about 40%. In some embodiments, the compounds described herein have a diastereomeric purity of about or at least about 45%. In some embodiments, the compounds described herein have a diastereomeric purity of about or at least about 50%. In some embodiments, the compounds described herein have a diastereomeric purity of about or at least about 55%. In some embodiments, the compounds described herein have a diastereomeric purity of about or at least about 60%. In some embodiments, the compounds described herein have a diastereomeric purity of about or at least about 65%. In some embodiments, the compounds described herein have a diastereomeric purity of about or at least about 70%. In some embodiments, the compounds described herein have a diastereomeric purity of about or at least about 75%. In some embodiments, the compounds described herein have a diastereomeric purity of about or at least about 80%. In some embodiments, the compounds described herein have a diastereomeric purity of about or at least about 85%. In some embodiments, the compounds described herein have a diastereomeric purity of about or at least about 90%.In some embodiments, the compounds described herein have about or at least about 100% diastereomeric purity.

[0299] In some embodiments, the present disclosure provides compounds described herein having a purity of about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%. In some embodiments, compounds described herein have a purity of about or at least about 10%. In some embodiments, compounds described herein have a purity of about or at least about 15%. In some embodiments, compounds described herein have a purity of about or at least about 20%. In some embodiments, compounds described herein have a purity of about or at least about 25%. In some embodiments, compounds described herein have a purity of about or at least about 30%. In some embodiments, compounds described herein have a purity of about or at least about 35%. In some embodiments, compounds described herein have a purity of about or at least about 40%. In some embodiments, compounds described herein have a purity of about or at least about 45%. In some embodiments, compounds described herein have a purity of about or at least about 50%. In some embodiments, the compounds described herein have a purity of about or at least about 55%. In some embodiments, the compounds described herein have a purity of about or at least about 60%. In some embodiments, the compounds described herein have a purity of about or at least about 65%. In some embodiments, the compounds described herein have a purity of about or at least about 70%. In some embodiments, the compounds described herein have a purity of about or at least about 75%. In some embodiments, the compounds described herein have a purity of about or at least about 80%. In some embodiments, the compounds described herein have a purity of about or at least about 85%. In some embodiments, the compounds described herein have a purity of about or at least about 90%. In some embodiments, the compounds described herein have a purity of about or at least about 100%.

[0300] In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 50%:50%, about 60%:40%, about 70%:30%, about 80%:20%, about 90%:10%, about 91%:9%, about 92%:8%, about 93%:7%, about 94%:6%, about 95%:5%, about 96%:4%, about 97%:3%, about 98%:2%, about 99%:1%, about 99.5%:0.5%, or about 99.9%:0.1%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 50%:50%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 60%:40%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 70%:30%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 80%:20%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 90%:10%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 91%:9%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 92%:8%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 93%:7%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 94%:6%. In some embodiments, the ratio of a compound described herein to its diastereomer relative to the chiral phosphorus is about or at least about 95%:5%. In some embodiments, the ratio of a compound described herein to its diastereomer relative to the chiral phosphorus is about or at least about 96%:4%.In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 97%:3%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 98%:2%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 99%:1%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 99.5%:0.5%. In some embodiments, the ratio of a compound described herein and its diastereomer to the chiral phosphorus is about or at least about 99.9%:0.1%.

[0301] In some embodiments, the ratio of cis:trans isomers relative to the chiral phosphorus of the compounds described herein is about or at least about 50%:50%, about 60%:40%, about 70%:30%, about 80%:20%, about 90%:10%, about 91%:9%, about 92%:8%, about 93%:7%, about 94%:6%, about 95%:5%, about 96%:4%, about 97%:3%, about 98%:2%, about 99%:1%, about 99.5%:0.5%, or about 99.9%:0.1%. In some embodiments, the ratio of cis:trans isomers relative to the chiral phosphorus is about or at least about 50%:50%. In some embodiments, the ratio of cis:trans isomers relative to the chiral phosphorus is about or at least about 60%:40%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 70%:30%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 80%:20%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 90%:10%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 91%:9%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 92%:8%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 93%:7%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 94%:6%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 95%:5%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 96%:4%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 97%:3%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 98%:2%.In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 99%:1%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 99.5%:0.5%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 99.9%:0.1%.

[0302] In some embodiments, the ratio of trans:cis isomers relative to the chiral phosphorus of the compounds described herein is about or at least about 50%:50%, about 60%:40%, about 70%:30%, about 80%:20%, about 90%:10%, about 91%:9%, about 92%:8%, about 93%:7%, about 94%:6%, about 95%:5%, about 96%:4%, about 97%:3%, about 98%:2%, about 99%:1%, about 99.5%:0.5%, or about 99.9%:0.1%. In some embodiments, the ratio of trans:cis isomers relative to the chiral phosphorus is about or at least about 50%:50%. In some embodiments, the ratio of trans:cis isomers relative to the chiral phosphorus is about or at least about 60%:40%. In some embodiments, the ratio of trans isomers:cis isomers to the chiral phosphorus is about or at least about 70%:30%. In some embodiments, the ratio of trans isomers:cis isomers to the chiral phosphorus is about or at least about 80%:20%. In some embodiments, the ratio of trans isomers:cis isomers to the chiral phosphorus is about or at least about 90%:10%. In some embodiments, the ratio of trans isomers:cis isomers to the chiral phosphorus is about or at least about 91%:9%. In some embodiments, the ratio of trans isomers:cis isomers to the chiral phosphorus is about or at least about 92%:8%. In some embodiments, the ratio of trans isomers:cis isomers to the chiral phosphorus is about or at least about 93%:7%. In some embodiments, the ratio of trans isomers:cis isomers to the chiral phosphorus is about or at least about 94%:6%. In some embodiments, the ratio of trans:cis isomers to the chiral phosphorus is about or at least about 95%:5%. In some embodiments, the ratio of trans:cis isomers to the chiral phosphorus is about or at least about 96%:4%. In some embodiments, the ratio of trans:cis isomers to the chiral phosphorus is about or at least about 97%:3%. In some embodiments, the ratio of trans:cis isomers to the chiral phosphorus is about or at least about 98%:2%.In some embodiments, the ratio of trans:cis isomers to the chiral phosphorus is about or at least about 99%:1%. In some embodiments, the ratio of trans:cis isomers to the chiral phosphorus is about or at least about 99.5%:0.5%. In some embodiments, the ratio of trans:cis isomers to the chiral phosphorus is about or at least about 99.9%:0.1%.

[0303] In some embodiments, the present disclosure provides: [ka] or a salt thereof, wherein the ratio of trans:cis isomers relative to the chiral phosphorus is about or at least about 50%:50%, about 60%:40%, about 70%:30%, about 80%:20%, about 90%:10%, about 91%:9%, about 92%:8%, about 93%:7%, about 94%:6%, about 95%:5%, about 96%:4%, about 97%:3%, about 98%:2%, about 99%:1%, about 99.5%:0.5%, or about 99.9%:0.1%. In some embodiments, the ratio of cis:trans isomers relative to the chiral phosphorus is about or at least about 50%:50%. In some embodiments, the ratio of cis:trans isomers relative to the chiral phosphorus is about or at least about 60%:40%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 70%:30%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 80%:20%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 90%:10%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 91%:9%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 92%:8%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 93%:7%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 94%:6%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 95%:5%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 96%:4%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 97%:3%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 98%:2%.In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 99%:1%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 99.5%:0.5%. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about or at least about 99.9%:0.1%.

[0304] In some embodiments, the present disclosure provides: [ka] or a salt thereof, wherein the ratio of trans:cis isomers relative to the chiral phosphorus is about 50%:50%, about 60%:40%, about 70%:30%, about 80%:20%, about 90%:10%, about 91%:9%, about 92%:8%, about 93%:7%, about 94%:6%, about 95%:5%, about 96%:4%, about 97%:3%, about 98%:2%, about 99%:1%, about 99.5%:0.5%, or about 99.9%:0.1% or less. In some embodiments, the ratio of cis:trans isomers relative to the chiral phosphorus is about 50%:50% or less. In some embodiments, the ratio of cis:trans isomers relative to the chiral phosphorus is about 60%:40% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 70%:30% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 80%:20% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 90%:10% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 91%:9% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 92%:8% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 93%:7% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 94%:6% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 95%:5% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 96%:4% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 97%:3% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 98%:2% or less.In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 99%:1% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 99.5%:0.5% or less. In some embodiments, the ratio of cis:trans isomers to the chiral phosphorus is about 99.9%:0.1% or less.

[0305] In some embodiments, the pair of trans and cis isomers are, respectively: [ka] or a salt thereof, and [ka] or a salt thereof. In some embodiments, the trans and cis isomer pair is, respectively: [ka] or a salt thereof, and [ka] or a salt thereof.

[0306] In some embodiments, the methods provided herein are carried out in the presence of a base. In some embodiments, the base is a sterically hindered base (relative to triethylamine). In some embodiments, the base is less nucleophilic (relative to triethylamine). In some embodiments, the base is a tertiary amine having the structure N(R)3, where the three R groups, together with the nitrogen, form an optionally substituted 8-20 (e.g., 8-10, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered bicyclic or polycyclic ring having 0-3 (e.g., 0, 1-3, 1, 2, 3, etc.) heteroatoms in addition to the nitrogen atom. In some embodiments, the base is a tertiary amine having the structure N(R)3, where the three R groups, together with the nitrogen, form an optionally substituted 8-20 (e.g., 8-10, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) membered bicyclic or polycyclic ring having 0-3 (e.g., 0, 1-3, 1, 2, 3, etc.) nitrogen atoms in addition to the nitrogen atom. In some embodiments, the base is DBU. In some embodiments, the base is DBN. In some embodiments, the base is DABCO. In some embodiments, the base is N-methylmorpholine (NMM). In some embodiments, the base is N,N-diisopropylethylamine (DIPEA). In some embodiments, the base is dibutylaniline. In some embodiments, the base or a mixture of bases comprising the base provides a high level of cis phosphoramidites compared to a reference base, such as TEA.

[0307] In some embodiments, the base equivalents are about or at least about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 per nucleoside. In some embodiments, the base equivalents are about or at least about 1 per nucleoside. In some embodiments, the base equivalents are about or at least about 1.1 per nucleoside. In some embodiments, the base equivalents are about or at least about 1.2 per nucleoside. In some embodiments, the base equivalents are about or at least about 1.3 per nucleoside. In some embodiments, the base equivalents are about or at least about 1.4 per nucleoside. In some embodiments, the base equivalents are about or at least about 1.5 per nucleoside. In some embodiments, the base equivalents are about or at least about 1.6 per nucleoside. In some embodiments, the base equivalents are about or at least about 1.7 per nucleoside. In some embodiments, the base equivalents are about or at least about 1.8 per nucleoside. In some embodiments, the base equivalents are about or at least about 1.9 per nucleoside. In some embodiments, the base equivalents are about or at least about 2 per nucleoside. In some embodiments, the base equivalents are about or at least about 2.5 per nucleoside. In some embodiments, the base equivalents are about or at least about 3 per nucleoside. In some embodiments, the base equivalents are about or at least about 3.5 per nucleoside. In some embodiments, the base equivalents are about or at least about 4 per nucleoside. In some embodiments, the base equivalents are about or at least about 4.5 per nucleoside. In some embodiments, the base equivalents are about or at least about 5 per nucleoside. In some embodiments, the base equivalents per nucleoside are about or at least about 6. In some embodiments, the base equivalents per nucleoside are about or at least about 7. In some embodiments, the base equivalents per nucleoside are about or at least about 8.In some embodiments, the base equivalents are about or at least about 9 relative to the nucleoside. In some embodiments, the base equivalents are about or at least about 10 relative to the nucleoside.

[0308] In some embodiments, the methods provided herein are performed in the presence of another base. In some embodiments, the ratio of the first base to the other base is about or at least about 5:1. In some embodiments, the ratio of the first base to the other base is about or at least about 4:1. In some embodiments, the ratio of the first base to the other base is about or at least about 3:1. In some embodiments, the ratio of the first base to the other base is about or at least about 2:1. In some embodiments, the ratio of the first base to the other base is about or at least about 1:1. In some embodiments, the other base is triethylamine (TEA). In some embodiments, the other base is N-methylmorpholine (NMM). In some embodiments, the first base is DBU. In some embodiments, the first base is DBN. In some embodiments, the equivalents of the first base are about or at least about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 relative to a nucleoside described herein. In some embodiments, the mixture is 1:1 NMM:DBu. In some embodiments, the mixture is 1:1 NMM:DBN. In some embodiments, the mixture is 1:1 DBU:TEA. In some embodiments, the mixture is 1:1 DBN:TEA. In some embodiments, the mixture is 2:1 DBN:TEA. In some embodiments, the mixture is 3:1 DBN:TEA.

[0309] In some embodiments, the acid, e.g., a weakly acidic compound, increases the level of cis cyclic phosphoramidites. In some embodiments, the acid is pentafluorophenol.

[0310] In some embodiments, the methods provided herein are carried out at reduced temperatures. In some embodiments, the methods provided include a reaction temperature from the reduction temperature to ambient temperature (about 25°C). In some embodiments, the reduced temperature is about -78°C. In some embodiments, the reduced temperature is about -20°C. In some embodiments, the reduced temperature is about 0°C.

[0311] In some embodiments, the present disclosure provides a method for isomerizing a compound described herein with respect to its chiral phosphorus, comprising contacting the compound with a phosphoramidite activator for oligonucleotide synthesis.

[0312] In some embodiments, the present disclosure provides a method for isomerizing a compound as described herein with respect to its chiral phosphorus, comprising contacting the compound with an acid for oligonucleotide synthesis.

[0313] In some embodiments, the present disclosure provides a method for preparing an oligonucleotide, comprising: 1) contacting a phosphoramidite composition comprising a compound described herein with an acid to provide an isomerized phosphoramidite composition, wherein the isomerized phosphoramidite composition comprises a reduced level of the compound compared to the phosphoramidite composition; 2) contacting the isomerized phosphoramidite composition with a coupling partner; The present invention provides a method comprising:

[0314] In some embodiments, the present disclosure provides a method for preparing an oligonucleotide, comprising: 1) contacting a phosphoramidite composition comprising a compound described herein with a phosphoramidite activator to provide an isomerized phosphoramidite composition, wherein the isomerized phosphoramidite composition comprises a reduced level of the compound relative to the phosphoramidite composition; 2) contacting the isomerized phosphoramidite composition with a coupling partner; The present invention provides a method comprising:

[0315] In some embodiments, the coupling partner comprises an —OH group. In some embodiments, the coupling partner is or comprises a nucleoside as described herein. In some embodiments, the coupling partner is an oligonucleotide. In some embodiments, the coupling partner is linked to a solid support. In some embodiments, the coupling partner is linked to a solid support via a linker. In some embodiments, the provided techniques provide for epimerization of the P chiral center, for example, in the phosphoramidites described herein.

[0316] The provided technology can be used with a variety of phosphoramidites, for example, U.S. Pat. Nos. 9,394,333, 9,744,183, 9,605,019, 9,982,257, U.S. Patent Application Publication Nos. 20170037399, 20180216108, 20180216107, U.S. Pat. No. 9,598,458, WO 2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO 2017 / 192679, WO 2017 / 210647 ... 2018 / 098264, 2018 / 022473, 2018 / 223056, 2018 / 223073, 2018 / 223081, 2018 / 237194, 2019 / 032607, 2019 / 032612, 2019 / 055951, 2019 / 075357, 2019 / 200185, 2019 / 217784, 2019 / 032612, 2020 / 191252, 2021 / 071858, and / or 2022 / 099159.

[0317] In some embodiments, the activating agent is an acid. In some embodiments, the activating agent is a weak acidic compound. In some embodiments, the acid is a weak acid. In some embodiments, a method for isomerizing a compound described herein with respect to its chiral phosphorus comprises contacting the compound with a weak acidic compound. In some embodiments, the weak acidic compound is a salt of a base and an acid. In some embodiments, the base has the structure N(R)3, where two R groups together with the nitrogen form an optionally substituted 5-10 membered ring having 0-3 (e.g., 0, 1-3, 1, 2, 3, etc.) heteroatoms in addition to the nitrogen atom. In some embodiments, the weak acidic compound is a salt of a heteroaryl base containing an sp2 nitrogen atom. In some embodiments, the weak acidic compound is a salt of a heteroaryl base containing an sp3 nitrogen atom.

[0318] In some embodiments, the activator is a weakly acidic compound. In some embodiments, a method for isomerizing a compound described herein with respect to its chiral phosphorus comprises contacting the compound with a salt of a base. In some embodiments, the salt is a triflate.

[0319] In some embodiments, the activator is CMPT. In some embodiments, the activator is CMIMT. In some embodiments, the activator is 4-nitrophenol.

[0320] In some embodiments, the pKa of a compound, e.g., an acid, an activator, etc., is about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13. In some embodiments, it is about or at least 4. In some embodiments, it is about or at least 5. In some embodiments, it is about or at least 6. In some embodiments, it is about or at least 7. In some embodiments, it is about or at least 8. In some embodiments, it is about or at least 9. In some embodiments, it is about or at least 10. In some embodiments, the pKa is relative to a solvent (e.g., water) at a particular temperature (e.g., about 25°C).

[0321] Particular activators are described in U.S. Patent Nos. 9,394,333, 9,744,183, 9,605,019, 9,982,257, U.S. Patent Application Publication Nos. 20170037399, 20180216108, 20180216107, U.S. Patent No. 9,598,458, WO 2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO 2017 / 192679, WO 2017 / 210647, WO 2018 / 09826, each of which is independently incorporated by reference herein. 4, 2018 / 022473, 2018 / 223056, 2018 / 223073, 2018 / 223081, 2018 / 237194, 2019 / 032607, 2019 / 032612, 2019 / 055951, 2019 / 075357, 2019 / 200185, 2019 / 217784, 2019 / 032612, 2020 / 191252, 2021 / 071858, and / or 2022 / 099159.

[0322] As shown in the figures, in some embodiments, the provided techniques can provide rapid epimerization of the chiral phosphorus in the phosphoramidite. In some embodiments, about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100% epimerization is achieved. In some embodiments, such levels of epimerization are achieved within, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes or less.

[0323] In some embodiments, the present disclosure provides a method for assessing the level of a compound in a composition, comprising using a compound or composition described herein as a reference.

[0324] sugar A variety of sugars, including modified sugars, can be utilized in accordance with the present disclosure. In some embodiments, the present disclosure provides sugar modifications and patterns thereof, optionally in combination with other structural elements (e.g., internucleotide linkage modifications and patterns thereof, patterns of backbone chiral centers thereof, etc.), that, when incorporated into an oligonucleotide, can provide improved properties and / or activity.

[0325] The most common naturally occurring nucleosides comprise a ribose sugar (e.g., in RNA) or a deoxyribose sugar (e.g., in DNA) linked to the nucleobases adenosine (A), cytosine (C), guanine (G), thymine (T), or uracil (U). In some embodiments, the sugar, for example, the various sugars in many of the oligonucleotides in Table 1 (unless otherwise noted), are: [ka] where the nucleobase is attached at the 1' position, and the 3' and 5' positions are linked to internucleotide linkages (as would be understood by one of skill in the art), and in the case of the 5' end of an oligonucleotide, the 5' position can be linked to the 5' terminal group (e.g., -OH), and in the case of the 3' end of an oligonucleotide, the 3' position can be linked to the 3' terminal group (e.g., -OH). In some embodiments, the sugar is [ka] In some embodiments, the sugar is a modified sugar in that it is not a natural DNA or RNA sugar. In some embodiments, the modified sugar may provide improved stability. In some embodiments, the modified sugar may be utilized to alter and / or optimize one or more hybridization properties. In some embodiments, the modified sugar may be utilized to alter and / or optimize target nucleic acid recognition. In some embodiments, the modified sugar may be utilized to optimize Tm. In some embodiments, the modified sugar may be utilized to improve oligonucleotide activity.

[0326] The sugar can be linked to the internucleotide linkage at various positions. As a non-limiting example, the internucleotide linkage can be linked to the 2', 3', 4', or 5' position of the sugar. In some embodiments, unless otherwise specified, the internucleotide linkage connects one sugar at the 5' position and the other sugar at the 3' position, as is most common in naturally occurring nucleic acids.

[0327] In some embodiments, the sugar is a naturally occurring DNA or RNA sugar, which is optionally substituted. In some embodiments, the sugar is an optionally substituted [ka] In some embodiments, the 2' position is optionally substituted. In some embodiments, the sugar is [ka] In some embodiments, the sugar is [ka] having the structure In the formula, R 1s , R 2s , R 3s , R 4s , and R 5s Each of may independently be —H, a suitable substituent, or a suitable sugar modification (e.g., each of the substituents, sugar modifications, R 1s , R 2s , R 3s , R 4s , and R 5sand modified sugars are disclosed in U.S. Patent Nos. 9,394,333, 9,744,183, 9,605,019, 9,982,257, U.S. Patent Application Publication Nos. 20170037399, 20180216108, 20180216107, U.S. Patent No. 9,598,458, WO 2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO 2017 / 192679, WO 2017 / 210647, WO 2018 / 098264, WO 2018 / 2018266, WO 2018 / 2018267, WO 2018 / 2018268, WO 2018 / 2018269 ... 018 / 022473, 2018 / 223056, 2018 / 223073, 2018 / 223081, 2018 / 237194, 2019 / 032607, 2019 / 032612, 2019 / 055951, 2019 / 075357, 2019 / 200185, 2019 / 217784, 2019 / 032612, 2020 / 191252, 2021 / 071858, and / or 2022 / 099159). 1s , R 2s , R 3s , R 4s , and R 5s Each of the groups independently represents R s and each R s are independently -F, -Cl, -Br, -I, -CN, -N3, -NO, -NO2, -L s -R', -L s -OR', -L s -SR', -L s -N(R')2, -OL s -OR', -OL s -SR' or -OL s -N(R')2, where each R' is independently as described herein, and each L s are independently a covalent bond or an optionally substituted divalent C 1~6 aliphatic or heteroaliphatic having 1 to 4 heteroatoms, or two R s Combined, -L s -bridge. In some embodiments, R' is an optionally substituted C1~10 In some embodiments, the sugar is [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, R 5s is an optionally substituted C1~6 In some embodiments, R 5s is an optionally substituted C 1~6 In some embodiments, R 5s is optionally substituted methyl. In some embodiments, R 5s is methyl. In some embodiments, the sugar is [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] A variety of such sugars are available in Table 1. In some embodiments, the sugar is [ka] In some embodiments, the 2'-modified sugar has the structure: [ka] wherein R 2s is a 2'-modification. In some embodiments, the sugar is [ka] wherein R 2s is —H, halogen, or —OR, where R is an optionally substituted C 1~6 In some embodiments, R 2s is —H. In some embodiments, R 2s is -F. In some embodiments, R 2sIn some embodiments, the modified nucleoside is mA, mT, mC, mC, mG, mU, etc., and R 2s is -OMe. In some embodiments, R 2s is -OCH2CH2OMe. In some embodiments, the modified sugar is Aeo, Teo, Ceo, m5Ceo, Geo, Ueo, etc., and R 2s is —OCHCHOMe. In some embodiments, R 2s is -OCH2CH2OH. In some embodiments, the oligonucleotide is [ka] In some embodiments, the oligonucleotide comprises a 2'-F modified sugar having the structure: [ka] (e.g., m(U), m(A), etc.). In some embodiments, the oligonucleotide comprises a 2'-OMe modified sugar having the structure: [ka] (e.g., [moe](G), [moe]([m5C]), etc.).

[0328] In some embodiments, the sugar is [ka] wherein R 2s and R 4s together -L s wherein L s is a covalent bond or an optionally substituted divalent C 1~6It is aliphatic or heteroaliphatic having 1 to 4 heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen, or sulfur. In some embodiments, L s is optionally substituted C2-O-CH2-C4. In some embodiments, L s is C2-O-CH2-C4. In some embodiments, L s is C2-O-(R)-CH(CH2CH3)-C4. In some embodiments, L s is C2-O-(S)-CH(CH2CH3)-C4.

[0329] In some embodiments, the sugar is [ka] wherein each variable is independently as described herein. In some embodiments, the sugar has the structure: [ka] wherein each variable is independently as described herein. In some embodiments, R 5s is —H. In some embodiments, the sugar is [ka] wherein each variable is independently as described herein. In some embodiments, R 3s is —OH. In some embodiments, R 3s is —H. In some embodiments, the sugar is [ka] In some embodiments, the sugar is [ka] is.

[0330] In some embodiments, the sugar is optionally substituted [ka] wherein X s is -S-, -Se-, or an optionally substituted -CH-. In some embodiments, the 2' position is optionally substituted. In some embodiments, the sugar is [ka] In some embodiments, the sugar is [ka] wherein R 1s , R 2s , R 3s , R 4s , and R 5s Each of may independently be —H, a suitable substituent, or a suitable sugar modification (e.g., each substituent, R 1s , R 2s , R 3s , R 4s , and R 5sand modified sugars are disclosed in U.S. Patent Nos. 9,394,333, 9,744,183, 9,605,019, 9,982,257, U.S. Patent Application Publication Nos. 20170037399, 20180216108, 20180216107, U.S. Patent No. 9,598,458, WO 2017 / 062862, WO 2018 / 067973, WO 2017 / 160741, WO 2017 / 192679, WO 2017 / 210647, WO 2018 / 098264, WO 2018 / 2018266, WO 2018 / 2018267, WO 2018 / 2018268, WO 2018 / 2018269 ... 018 / 022473, 2018 / 223056, 2018 / 223073, 2018 / 223081, 2018 / 237194, 2019 / 032607, 2019 / 032612, 2019 / 055951, 2019 / 075357, 2019 / 200185, 2019 / 217784, 2019 / 032612, 2020 / 191252, 2021 / 071858, and / or 2022 / 099159). 1s , R 2s , R 3s , R 4s , and R 5s Each of the groups independently represents R s where each R s are independently -F, -Cl, -Br, -I, -CN, -N3, -NO, -NO2, -L s -R', -L s -OR', -L s -SR', -L s -N(R')2, -OL s -OR', -OL s -SR' or -OL s -N(R')2, where each R' is independently as described herein, and each L s are independently a covalent bond or an optionally substituted divalent C 1~6 aliphatic or heteroaliphatic having 1 to 4 heteroatoms, or two R s Combined, -L s-bridge. In some embodiments, R' is an optionally substituted C 1~10 In some embodiments, the sugar is [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, R 5s is an optionally substituted C 1~6 In some embodiments, R 5s is an optionally substituted C 1~6 In some embodiments, R 5s is optionally substituted methyl. In some embodiments, R 5s is methyl. In some embodiments, the sugar is [ka] In some embodiments, the sugar has the structure: [ka] In some embodiments, the sugar has the structure: [ka] A variety of such sugars are available in Table 1. In some embodiments, the sugar is [ka] In some embodiments, the 2'-modified sugar has the structure: [ka] wherein R 2s is a 2'-modification. In some embodiments, the sugar is [ka] wherein R 2s is —H, halogen, or —OR, where R is an optionally substituted C 1~6 In some embodiments, R 2sis —H. In some embodiments, R 2s is -F. In some embodiments, R 2s is -OMe. In some embodiments, R 2s is —OCHCHOMe. In some embodiments, R 2s is —OCHCHOH. In some embodiments, the modified sugar is [ka] In some embodiments, the modified sugar has the structure: [ka] In some embodiments, the modified sugar has the structure: [ka] In some embodiments, the modified sugar has the structure: [ka] In some embodiments, X s is -S-. In some embodiments, X s is optionally substituted -CH-. In some embodiments, X s is -CH-. In some embodiments, the modified sugar is [ka] In some embodiments, the modified sugar has the structure: [ka] It has the following structure.

[0331] In some embodiments, the sugar is [ka] wherein each R 2s are independently -H, -F, -OH or -OR ak and R ak is an optionally substituted C 1~6 aliphatic, and each of the other variables is independently as described herein. In some embodiments, R 1s , R 3s , R 4s , and R 5s Each of is independently -H. In some embodiments, R 1s , R 3s and R 4s Each of the above and R 5s is independently -H and the other R 5s independently, C 1~6 In some embodiments, R 5s The existence of C 1~6 In some embodiments, R 2s is —H. In some embodiments, R 2s is -F. In some embodiments, R 2s is --OR ak In some embodiments, R 2s is -OMe. In some embodiments, R 2s is —OCH2CH2CH3. In some embodiments, R 2s At least one occurrence of is -H. In some embodiments, R 2s At least one occurrence of X is not —H. s is —O—. In some embodiments, X s is -S-. In some embodiments, X s is optionally substituted -CH-. In some embodiments, X s is -CH2-.

[0332] In some embodiments, the sugar is [ka] wherein R 2s and R 4s together -L s wherein L s is a covalent bond or an optionally substituted divalent C 1~6 It is aliphatic or heteroaliphatic having 1 to 4 heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen, or sulfur. In some embodiments, L s is optionally substituted C2-O-CH2-C4. In some embodiments, L s is C2-O-CH2-C4. In some embodiments, L s is C2-O-(R)-CH(CH2CH3)-C4. In some embodiments, L s is C2-O-(S)-CH(CH2CH3)-C4. In some embodiments, X s is -S-. In some embodiments, X s is optionally substituted -CH-. In some embodiments, X s is -CH-. In some embodiments, X s is -Se-.

[0333] In some embodiments, the sugar is [ka] wherein each variable is independently as described herein. In some embodiments, the sugar has the structure: [ka] wherein each variable is independently as described herein. In some embodiments, R 5s is —H. In some embodiments, the sugar is [ka] wherein each variable is independently as described herein. In some embodiments, R 3s is —OH. In some embodiments, R 3s is —H. In some embodiments, X s is -S-. In some embodiments, X s is optionally substituted -CH-. In some embodiments, X s is -CH2-.

[0334] In some embodiments, the nucleoside comprising a modified sugar is [ka] or a salt thereof, wherein: BA s is —H or an optionally substituted or protected nucleobase (e.g., BA), and R 2s is as described herein. In some embodiments, R 2s is —OH, halogen, or optionally substituted C1-C6 alkoxy. In some embodiments, BA s is —H. In some embodiments, BA s is an optionally substituted or protected nucleobase. In some embodiments, BA s is BA. In some embodiments, R 2s is -F. In some embodiments, the nucleoside comprising a modified sugar is [ka] or a salt form thereof, wherein each variable is independently as described herein. In some embodiments, R 2sis —H, —OH, halogen, or optionally substituted C1-C6 alkoxy. In some embodiments, R 2s is —H. In some embodiments, R 2s is -F. In some embodiments, the nucleoside comprising a modified sugar is [ka] wherein each variable is as described herein. In some embodiments, the nucleoside comprising a modified sugar has the structure: [ka] or a salt form thereof, wherein each variable is independently as described herein. In some embodiments, R 2s is —H, —OH, halogen, or optionally substituted C1-C6 alkoxy. In some embodiments, R 2s is —H. In some embodiments, R 2s is -F. In some embodiments, the nucleoside comprising a modified sugar is [ka] or a salt thereof, wherein R 2s’ is R s and R s , R 2s , and B.A. s and each of R is independently as described herein. 2s and R 2s’ Each of R is independently -H, -OH, halogen, or optionally substituted C1-C6 alkoxy. 2s is —H. In some embodiments, R 2s is —OH. In some embodiments, R 2s is halogen. In some embodiments, R 2sis -F. In some embodiments, R 2s is an optionally substituted C1-C6 alkoxy. In some embodiments, R 2s’ is —H. In some embodiments, R 2s’ is —OH. In some embodiments, R 2s’ is halogen. In some embodiments, R 2s’ is -F. In some embodiments, R 2s’ is optionally substituted C1-C6 alkoxy. In some embodiments, BA s is —H. In some embodiments, BA s is an optionally substituted or protected nucleobase. In some embodiments, BA s is BA. In some embodiments, nucleobases such as BA are optionally substituted or protected for oligonucleotide synthesis. Certain such nucleosides, including sugars and nucleobases, and their uses are described in WO 2020 / 154342. In some embodiments, the oligonucleotide comprises an arabinoside, a 2'-deoxy-2'-fluoro-arabinoside, a 2'-OR arabinoside, adeoxycytidine, a DNA-abasic, a RNA-abasic, or a 2'-OR abasic, where R is not hydrogen (e.g., an optionally substituted C 1~6aliphatic). In some embodiments, the 2'-OR is 2'-OMe. In some embodiments, the 2'-OR is 2'-MOE. In some embodiments, the oligonucleotide comprises 2'-O-methyl-arabinocytidine (amC). In some embodiments, the oligonucleotide comprises such a nucleoside. In some embodiments, the monomer comprises such a nucleoside. In some embodiments, the phosphoramidite comprises such a nucleoside (in some embodiments, one linkage site (e.g., -CH2- linkage site) is attached to an optionally substituted -OH (e.g., (-ODMTr)) and one linkage site (e.g., ring linkage site) is attached to an O that is also attached to a P of the phosphoramidite). In some embodiments, the 5'-immediate nucleoside (e.g., N1), the opposite nucleoside (N0), and the 3'-immediate nucleoside (e.g., N -1 ) is independently such a nucleoside. -1 -3' is amCCA. In some embodiments, the sugar is [ka] wherein each variable is as described herein and C1' is attached to the nucleobase. In some embodiments, the sugar is arabinose. In some embodiments, the sugar is [ka] wherein C1' is attached to the nucleobase.

[0335] In some embodiments, the sugar is optionally substituted [ka] wherein the nucleobase is attached at the 1' position. In some embodiments, the sugar is [ka] where the nucleobase is attached at the 1' position.

[0336] In some embodiments, the sugar is optionally substituted [ka] where position a is attached to the nucleobase and X s is -O-, -S-, -Se-, or optionally substituted -CH-. In some embodiments, the sugar is [ka] In some embodiments, the sugar is optionally substituted [ka] where position a is attached to the nucleobase and X s is -O-, -S-, -Se-, or optionally substituted -CH-. In some embodiments, the sugar is [ka] In some embodiments, X s is —O—. In some embodiments, X s is -S-. In some embodiments, X s is -Se-. In some embodiments, X s is optionally substituted -CH-. In some embodiments, X s is -CH2-. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0337] In some embodiments, the modified sugar comprises an optionally substituted 6-membered ring having 0-1 oxygen atoms. In some embodiments, the modified sugar comprises an optionally substituted 6-membered ring having an oxygen atom. For example, in some embodiments, the modified sugar comprises an optionally substituted 6-membered ring having an oxygen atom. [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar has the structure: [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar is optionally substituted [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar has the structure: [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar has the structure: [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar is optionally substituted [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar has the structure: [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar is optionally substituted [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar has the structure: [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar is optionally substituted [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar has the structure: [ka] where position a is attached to the nucleobase.

[0338] In some embodiments, the nucleoside comprising a modified sugar is [ka] or a salt thereof, wherein R 6s and R 7s Each of the groups independently represents R s and BA s is —H or an optionally substituted or protected nucleobase (e.g., BA), and R s are independently as described herein. In some embodiments, R 6s is -H, -OH, or halogen, and R 7s is -H, -OH, halogen, or optionally substituted C1-C6 alkoxy. In some embodiments, BAs is —H. In some embodiments, BA s is an optionally substituted or protected nucleobase. In some embodiments, BA s In some embodiments, the nucleoside comprising a modified sugar is [ka] or a salt thereof, wherein R 8s and R 9s Each of the s and R s and B.A. s and each of R is independently as described herein. 8s is -H or -halogen, and R 9s is -H, -OH, halogen, or optionally substituted C1-C6 alkoxy. In some embodiments, nucleosides comprising modified sugars include: [ka] or a salt thereof, wherein R 10s and R 11s Each of the groups independently represents R s and R s and B.A. s and each of R is independently as described herein. 10s is -H or -halogen, and R 11s is -H, -OH, halogen, or optionally substituted C1-C6 alkoxy. In some embodiments, nucleosides comprising modified sugars include: [ka] or a salt thereof, wherein: BA s is as described herein. In some embodiments, the nucleoside comprising a modified sugar is [ka] or a salt thereof, wherein: BA s is as described herein. One skilled in the art will appreciate that in some embodiments, the nitrogen may be directly bonded to the bound phosphorus. In some embodiments, the halogen is -F. In some embodiments, BA s is —H. In some embodiments, BA s is an optionally substituted or protected nucleobase. In some embodiments, BA s is BA. In some embodiments, nucleobases such as BA are optionally substituted or protected for oligonucleotide synthesis. In some embodiments, oligonucleotides include alpha-homo-DNA, beta-homo-DNA portions. Certain such nucleosides, including sugars and nucleobases, and their uses are described in WO 2020 / 154343. In some embodiments, oligonucleotides include such nucleosides. In some embodiments, monomers include such nucleosides. In some embodiments, phosphoramidites include such nucleosides (in some embodiments, one linkage moiety (e.g., -CH- linkage moiety) is bonded to an optionally substituted -OH (e.g., -ODMTr) and one linkage moiety (e.g., ring linkage moiety) is bonded to a P of the phosphoramidite (e.g., when the linking ring atom is N) or an O that is also bonded to a P of the phosphoramidite (e.g., when the linking ring atom is C)). In some embodiments, the 5'-immediate nucleoside (e.g., N1), the opposite nucleoside (N0), and the 3'-immediate nucleoside (e.g., N -1 ) is independently such a nucleoside.

[0339] In some embodiments, the modified sugar is [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar has the structure: [ka] wherein position a is attached to the nucleobase. In some embodiments, the modified sugar has the structure: [ka] wherein position a is attached to the nucleobase, position b is attached to the internucleoside bond, and R″ is —H or optionally substituted C 1~6 In some embodiments, the modified sugar is [ka] wherein position a is attached to the nucleobase, position b is attached to the internucleoside bond, and R″ is —H or C 1~6 In some embodiments, the modified sugar is [ka] wherein position a is attached to the nucleobase, position b is attached to the internucleoside bond, and R″ is —H or C 1~6 It is aliphatic. In some embodiments, R″ is methyl.

[0340] In some embodiments, the nucleoside comprising a modified sugar is [ka] or a salt form thereof, wherein each variable is as described herein. In some embodiments, the nucleoside comprising a modified sugar has the structure: [ka] or a salt form thereof, wherein each variable is as described herein. In some embodiments, the nucleoside comprising a modified sugar has the structure: [ka] or a salt form thereof, wherein each variable is as described herein. In some embodiments, the nucleoside comprising a modified sugar has the structure: [ka] or a salt thereof, wherein R 12s is R s and R s and B.A. s and each of R is independently as described herein. 12s is -H, -OH, halogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl or optionally substituted C 1~6 In some embodiments, the halogen is -F. In some embodiments, the nucleoside comprising a modified sugar is [ka] or a salt form thereof, wherein each variable is as described herein. In some embodiments, the nucleotide comprising a modified sugar has the structure: [ka] or a salt thereof, wherein R 13s is R s and R s and B.A. s and each of R is independently as described herein. 13sis —H or an optionally substituted C1-C6 alkyl. In some embodiments, a nucleoside comprising a modified sugar comprises: [ka] or a salt form thereof, wherein each variable is as described herein. In some embodiments, the nucleotide comprising a modified sugar has the structure: [ka] or a salt form thereof, wherein each variable is as described herein. In some embodiments, the bond is an amide bond. In some embodiments, BA s is —H. In some embodiments, BA s is an optionally substituted or protected nucleobase. In some embodiments, BA s is BA. In some embodiments, nucleobases such as BA are optionally substituted or protected for oligonucleotide synthesis. Certain such nucleosides and nucleotides, including sugars and nucleobases, and their uses are described in WO 2020 / 154344. In some embodiments, an oligonucleotide comprises such a nucleoside. In some embodiments, an oligonucleotide comprises such a nucleoside (in some embodiments, one linkage moiety (e.g., -CH2- linkage moiety) is attached to an optionally substituted -OH (e.g., (-ODMTr)), and one linkage moiety (e.g., ring linkage moiety) is attached to an O that is also attached to a P of the phosphoramidite). In some embodiments, the 5'-immediately adjacent nucleoside (e.g., N1), the opposite nucleoside (N0), and the 3'-immediately adjacent nucleoside (e.g., N -1 ) is independently such a nucleoside.

[0341] In some embodiments, the sugar is an acyclic sugar (e.g., a UNA sugar). In some embodiments, the sugar is optionally substituted. [ka] In some embodiments, the 2' position is optionally substituted. In some embodiments, the sugar is [ka] In some embodiments, the sugar is [ka] In some embodiments, R 2s is —OH. In some embodiments, the sugar is [ka] where "*" indicates the carbon atom attached to the nucleobase. In some embodiments, the sugar is [ka] where "*" indicates the carbon atom attached to the nucleobase. In some embodiments, the carbon atom attached to the nitrogen atom of the nucleobase is in the R configuration (e.g., sm18). In some embodiments, the oligonucleotide comprises a sugar described herein.

[0342] In some embodiments, the sugar is optionally substituted [ka] where position a is attached to the nucleobase and X s is -O-, -S-, -Se-, or optionally substituted -CH-. In some embodiments, the sugar is [ka] In some embodiments, X s is —O—. In some embodiments, X s is -S-. In some embodiments, X s is -Se-. In some embodiments, X s is optionally substituted -CH-. In some embodiments, X s is -CH2-. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0343] In some embodiments, sugars are linked without the 5' and 3' positions. One of skill in the art will understand that with respect to such sugars, 5' can refer to the side / direction toward the 5' end of the oligonucleotide and 3' can refer to the side / direction toward the 3' end of the oligonucleotide.

[0344] In some embodiments, R 1s , R 2s , R 3s , R 4s , and R 5s Each of the groups independently represents R s where R s are independently -H, halogen, -CN, -N3, -NO, -NO2, -L s -R', -L s -Si(R')3, -L s -OR', -L s -SR', -L s -N(R')2, -OL s -R', -OL s -Si(R)3, -OL s -OR', -OL s -SR' or -OL s -N(R')2, and L s is L as described herein Band each other variable is independently as described herein. In some embodiments, R 1s and R 2s Each of the groups independently represents R s In some embodiments, R s is —H. In some embodiments, R s is not —H. In some embodiments, L s is a covalent bond. In some embodiments, R 2s and R 4s Each of is independently -H, -F, -OR, -N(R). In some embodiments, R 2s is -H, -F, -OR, -N(R). In some embodiments, R 4s is —H. In some embodiments, R 2s and R 4s is 2'-OL s wherein L s is an optionally substituted C 1~6 In some embodiments, L is alkylene. s is optionally substituted -CH-. In some embodiments, L s is an optionally substituted —CH2—.

[0345] In some embodiments, R is hydrogen. In some embodiments, R is not hydrogen. In some embodiments, R is C 1~10 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1~10 Heteroaliphatic, C 6~20 An optionally substituted group selected from a 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from aryl, oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3- to 20-membered heterocyclic ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0346] In some embodiments, R is an optionally substituted C 1~30In some embodiments, R is an optionally substituted C 1~20 In some embodiments, R is an optionally substituted C 1~15 In some embodiments, R is an optionally substituted C 1~10 In some embodiments, R is an optionally substituted C 1~6 In some embodiments, R is an optionally substituted C 1~6 In some embodiments, R is alkyl. In some embodiments, R is optionally substituted hexyl, pentyl, butyl, propyl, ethyl, or methyl. In some embodiments, R is optionally substituted hexyl. In some embodiments, R is optionally substituted pentyl. In some embodiments, R is optionally substituted butyl. In some embodiments, R is optionally substituted propyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is hexyl. In some embodiments, R is pentyl. In some embodiments, R is butyl. In some embodiments, R is propyl. In some embodiments, R is ethyl. In some embodiments, R is methyl. In some embodiments, R is isopropyl. In some embodiments, R is n-propyl. In some embodiments, R is tert-butyl. In some embodiments, R is sec-butyl. In some embodiments, R is n-butyl. In some embodiments, R is —(CH ) OCH .

[0347] In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl.

[0348] In some embodiments, R 2s is a 2'-modification as described in this disclosure, and R 4s is —H. In some embodiments, R2s is —OR, where R is not hydrogen. In some embodiments, R 2s is -F. In some embodiments, R 2s is -OMe. In some embodiments, R 2s For example, the various X used in Table 1 eo (X is mC, T, G, A, etc.) is —OCH2CH2CH3. In some embodiments, R 2s is selected from -H, -F, and -OR, where R is an optionally substituted C 1~6 In some embodiments, R 2s is selected from -H, -F, and -OMe.

[0349] In some embodiments, the sugar is a bicyclic sugar, e.g., R 2s and R 4s are sugars that together form an optionally substituted ring as described in this disclosure. In some embodiments, the sugars are selected from LNA sugars, BNA sugars, cEt sugars, etc. In some embodiments, the bridge is between the 2'-carbon atom and the 4'-carbon atom (R, which together with these intervening atoms form an optionally substituted ring as described herein). 2s and R 4s In some embodiments, the bridge is between 2'-L a -L b -4', wherein L a is -O-, -S-, or N(R), and L b is an optionally substituted C1-4 divalent aliphatic chain, for example, methylene.

[0350] In some embodiments, the sugar is a 2'-OMe, 2'-MOE, 2'-F, LNA (locked nucleic acid) sugar, ENA (ethylene-bridged nucleic acid) sugar, BNA (NMe) (methylamino-bridged nucleic acid) sugar, 2'-F ANA (2'-F arabinose), alpha-DNA (alpha-D-ribose), 2' / 5' ODN (e.g., a 2' / 5' linked oligonucleotide), Inv (an inverted sugar, e.g., an inverted deoxyribose), AmR (amino-ribose), ThioR (thio-ribose), HNA (hexose nucleic acid), CeNA (cyclohexene nucleic acid), or MOR (morpholino) sugar.

[0351] Those of skill in the art after reading this disclosure will understand that various types of sugar modifications are known and may be utilized in accordance with the present disclosure. In some embodiments, the sugar modification is a 2'-modification (e.g., R 2s In some embodiments, the 2'-modification is 2'-F. In some embodiments, the 2'-modification is 2'-OR, where R is not hydrogen. In some embodiments, the 2'-modification is 2'-OR, where R is an optionally substituted C 1~6 In some embodiments, the 2'-modification is 2'-OR, where R is an optionally substituted C 1~6 In some embodiments, the 2'-modification is -OL, which links the 2'-carbon of the sugar moiety to another carbon of the sugar moiety. b -or-L b -L b In some embodiments, the 2'-modification is 2'-OL, which links the 2'-carbon of the sugar moiety to the 4'-carbon of the sugar moiety. b -4' or 2'-L b -L b In some embodiments, the 2'-modification is an S-cEt. In some embodiments, the modified sugar is an LNA sugar. In some embodiments, the -L b- is -C(R)-. In some embodiments, the 2'-modification is (C2-OC(R)2-C4), where each R is independently as described in this disclosure. In some embodiments, the 2'-modification is an LNA sugar modification (C2-O-CH2-C4). In some embodiments, the 2'-modification is (C2-O-CHR-C4), where R is as described in this disclosure. In some embodiments, the 2'-modification is (C2-O-(R)-CHR-C4), where R is as described in this disclosure and is not hydrogen. In some embodiments, the 2'-modification is (C2-O-(S)-CHR-C4), where R is as described in this disclosure and is not hydrogen. In some embodiments, R is an optionally substituted C 1~6 In some embodiments, R is an optionally substituted C 1~6 In some embodiments, R is an unsubstituted C 1~6 In some embodiments, R is alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, the 2'-modification is (C2-O-CHR-C4), where R is an optionally substituted C 1~6 In some embodiments, the 2'-modification is (C2-O-CHR-C4), where R is an optionally substituted C 1~6 In some embodiments, the 2'-modification is (C2-O-CHR-C4) where R is methyl. In some embodiments, the 2'-modification is (C2-O-CHR-C4) where R is ethyl. In some embodiments, the 2'-modification is (C2-O-(R)-CHR-C4) where R is an optionally substituted C 1~6 In some embodiments, the 2'-modification is (C2-O-(R)-CHR-C4), where R is an optionally substituted C 1~6In some embodiments, the 2'-modification is (C2-O-(R)-CHR-C4) where R is methyl. In some embodiments, the 2'-modification is (C2-O-(R)-CHR-C4) where R is ethyl. In some embodiments, the 2'-modification is (C2-O-(S)-CHR-C4) where R is an optionally substituted C 1~6 In some embodiments, the 2'-modification is (C2-O-(S)-CHR-C4), where R is an optionally substituted C 1~6 In some embodiments, the 2'-modification is (C2-O-(S)-CHR-C4) where R is methyl. In some embodiments, the 2'-modification is (C2-O-(S)-CHR-C4) where R is ethyl. In some embodiments, the 2'-modification is C2-O-(R)-CH(CH2CH3)-C4. In some embodiments, the 2'-modification is C2-O-(S)-CH(CH2CH3)-C4. In some embodiments, the sugar is a natural DNA sugar. In some embodiments, the sugar is a natural RNA sugar. In some embodiments, the sugar is an optionally substituted natural DNA sugar. In some embodiments, the sugar is a 2'-substituted (2'-modified) natural DNA sugar. In some embodiments, the sugar is a 2'-modified (2'-modified) natural DNA sugar.

[0352] In some embodiments, the sugar is an optionally substituted ribose or deoxyribose. In some embodiments, the sugar is an optionally modified ribose or deoxyribose, wherein one or more hydroxyl groups on the ribose or deoxyribose moiety are optionally and independently replaced by a halogen, R', -N(R')2, -OR', or -SR', where each R' is as described herein. In some embodiments, the sugar is an optionally substituted deoxyribose, wherein the 2'-position of the deoxyribose is optionally substituted. In some embodiments, the sugar is an optionally substituted deoxyribose, wherein the 2'-position of the deoxyribose is optionally substituted with a halogen, R', -N(R')2, -OR', or -SR', where each R' is independently as described herein. In some embodiments, the sugar is an optionally substituted deoxyribose, wherein the 2'-position of the deoxyribose is optionally substituted with a halogen. In some embodiments, the sugar is an optionally substituted deoxyribose, and the 2' position of the deoxyribose is optionally substituted with one or more -F. In some embodiments, the sugar is an optionally substituted deoxyribose, and the 2' position of the deoxyribose is optionally substituted with -OR', where each R' is independently as described in this disclosure. In some embodiments, the sugar is an optionally substituted deoxyribose, and the 2' position of the deoxyribose is optionally substituted with -OR', where each R' is independently an optionally substituted C1-C6 aliphatic. In some embodiments, the sugar is an optionally substituted deoxyribose, and the 2' position of the deoxyribose is optionally substituted with -OR', where each R' is independently an optionally substituted C1-C6 alkyl. In some embodiments, the sugar is an optionally substituted deoxyribose, and the 2' position of the deoxyribose is optionally substituted with -OMe. In some embodiments, the sugar is an optionally substituted deoxyribose, and the 2' position of the deoxyribose is optionally substituted with -O-methoxyethyl.

[0353] In some embodiments, provided oligonucleotides comprise one or more modified sugars, hi some embodiments, provided oligonucleotides comprise one or more modified sugars and one or more natural sugars.

[0354] Examples of bicyclic sugars include alpha-L-methyleneoxy (4'-CH2-O-2') LNA, beta-D-methyleneoxy (4'-CH2-O-2') LNA, ethyleneoxy (4'-(CH2)2-O-2') LNA, aminooxy (4'-CH2-ON(R)-2') LNA, and oxyamino (4'-CH2-N(R)-O-2') LNA sugars. In some embodiments, a bicyclic sugar, e.g., an LNA or BNA sugar, is a sugar having at least one bridge between the two sugar carbons. In some embodiments, the bicyclic sugar in a nucleoside can have an alpha-L-ribofuranose or beta-D-ribofuranose stereochemical configuration.

[0355] In some embodiments, bicyclic sugars can be further defined by their isomeric configuration, for example, sugars containing a 4'-(CH2)-O-2' bridge can exist in the alpha-L configuration or the beta-D configuration. In some embodiments, the 4' to 2' bridge is -L-4'-(CH2)-O-2', bD-4'-CH2-O-2', 4'-(CH2)2-O-2', 4'-CH2-ON(R')-2', 4'-CH2-N(R')-O-2', 4'-CH(R')-O-2', 4'-CH(CH3)-O-2', 4'-CH2-S-2', 4'-CH2-N(R')-2', 4'-CH2-CH(R')-2', 4'-CH2-CH(CH3)-2', and 4'-(CH2)3-2', where each R' is as described herein. In some embodiments, R' is -H, a protecting group, or an optionally substituted C1-C 12 In some embodiments, R' is -H or an optionally substituted C1-C 12 It is alkyl.

[0356] In some embodiments, the bicyclic sugar is selected from the group consisting of alpha-L-methyleneoxy (4'-CH2-O-2') BNA, beta-D-methyleneoxy (4'-CH2-O-2') BNA, ethyleneoxy (4'-(CH2)2-O-2') BNA, aminooxy (4'-CH2-ON(R)-2') BNA, oxyamino (4'-CH2-N(R)-O-2') BNA, methyl (methyl The sugars are methylene-thio (4'-CH-S-2') BNA, methylene-amino (4'-CH-N(R)-2') BNA, methyl carbocyclic (4'-CH-CH(CH)-2') BNA, propylene carbocyclic (4'-(CH)-2') BNA, or vinyl BNA.

[0357] In some embodiments, the sugar modification is a modification described in U.S. Patent No. 9,006,198. In some embodiments, the modified sugar is described in U.S. Patent No. 9,006,198. In some embodiments, the sugar modification is any of the sugars described in U.S. Patent Nos. 9,394,333, 9,744,183, 9,605,019, 9,982,257, U.S. Patent Application Publication Nos. 20170037399, 20180216108, 20180216107, U.S. Patent No. 9,598,458, WO 2017 / 062862, WO 2018 / 067973, WO 2...

Claims

[Claim 1] The invention described in the specification.

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