Modified ascarosides

Abstract

This application relates to ascarosides with modified fatty acid-derived side chains. The application further relates to methods of using such modified ascarosides.

Description

[0001] MODIFIED ASCAROSIDES[1] This application claims the benefit of priority to U.S. Provisional Appl. No. 63 / 637,551,filed April 23, 2024, the entirety of which is herein incorporated by reference. FIELD[2] This application generally relates to modified analogues of biologically active compounds,compositions and to methods of treating animals or plants with such compounds to promote health, ameliorate disease, and / or enhance resistance to pathogens. BACKGROUND[3] Ascaroside natural products are secondary metabolites produced by nematodes. A largenumber of structurally diverse ascaroside structures have been identified in nature and the molecules are believed to function as an evolutionarily conserved chemical language used by nematodes to control many aspects of their development. Ascarosides are also perceived by other organisms and have been demonstrated to have a range of effects on numerous non-nematode organisms including bacteria, fungi, plants, and mammals including humans. Ascarosides hold potential as human medicines, agrichemicals, and products for other diverse and valuable applications.[4] Ascarosides have been demonstrated to enhance plant growth and to increase plantresistance to certain pathogens and / or induce the priming of plant defense responses (which can inhibit pathogenic growth and / or infestation) when applied to the plant. By activating and / or priming plants’ innate defenses, ascarosides can thereby prevent proliferation of pathogens.[5] It would be useful to provide ascarosides in forms that enhance their uptake, half-lifeand / or biological activities and / or to modify the physical properties of the compounds to make their formulation or application easier and, further, to provide additional benefits to plants or other organisms to which such modified ascarosides are applied or administered. SUMMARY[6] The disclosure provides compounds, compositions, and methods for delivery. In certainembodiments, such compounds, compositions and methods are particularly useful in an agrichemical context and the disclosure primarily describes such uses—however, it is also recognized that the compounds and related formulations and methods described herein may have applications beyond agriculture—for example as therapeutics to improve the health of humans or Page 1 of 63 BUSINESS.32873149.1 409753-017WO (217367) other animals. The compositions and methods herein relate generally to modified ascarosides which, in some embodiments provide various benefits when administered or applied to an organism (e.g., to a plant, an animal, or a microbe).[7] In general, naturally occurring ascarosides comprise a fatty acid sidechain with a terminalcarboxylic acid or ester group (shown below as terminal carboxylic acid): ascaroside[8] In some embodiments, compounds provided by the present disclosure comprise a modifiedfatty acid sidechain in place of the typical fatty acid sidechain of natural ascarosides. In certain embodiments, the compounds provided herein comprise a fatty acid-derived carbon chain comprising one or more non-hydrogen substitutions at the positions corresponding to alpha and / or beta to a terminal carboxylic acid or ester end group. In certain embodiments, such substitutions feature a halogen (e.g., F) or optionally substituted alkyl substitution (e.g., an optionally substituted C1-4alkyl substituent).[9] In certain embodiments, provided compounds are characterized in that they can exhibitslower metabolism in use than corresponding non-modified ascarosides under the same conditions. Such slower metabolism can lead, in some embodiments, to enhanced ascaroside activity in various organisms over time, e.g., where the organism is a plant, enhanced plant growth over time and / or enhanced plant resistance to certain pathogens, including enhanced inhibition of pathogenic growth and / or infestation. The provided compounds can afford various additional benefits in some embodiments, as will be described in further detail herein.

[0010] These and other features, aspects, and advantages of the disclosure will be apparent froma reading of the following detailed description together with the accompanying drawings, which are briefly described below. The invention includes any combination of two, three, four, or more of the above-noted embodiments as well as combinations of any two, three, four, or more features or elements set forth in this disclosure, regardless of whether such features or elements are expressly combined in a specific embodiment description herein. This disclosure is intended to be read holistically such that any separable features or elements of the disclosed invention, in any Page 2 of 63 BUSINESS.32873149.1 409753-017WO (217367) of its various aspects and embodiments, should be viewed as intended to be combinable unless the context clearly dictates otherwise. Other aspects and advantages of the present disclosure will become apparent from the following. DEFINITIONS

[0011] In order for the present disclosure to be more readily understood, certain terms are firstdefined below. Additional definitions for the following terms and other terms are set forth throughout the specification.

[0012] In this application, unless otherwise clear from context, the term “a” may be understoodto mean “at least one.” As used in this application, the term “or” may be understood to mean “and / or.” In this application, the terms “comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps. As used in this application, the term “comprise” and variations of the term, such as “comprising” and “comprises,” are not intended to exclude other additives, components, integers or steps.

[0013] About, Approximately: As used herein, the terms “about” and “approximately” are usedas equivalents. Unless otherwise stated, the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art. Where ranges are provided herein, the endpoints are included. Any numerals used in this application with or without about / approximately are meant to cover any normal fluctuations appreciated by one of ordinary skill in the relevant art. Unless otherwise stated, the term above refers to within 25% of a given value. In some embodiments, the term “approximately” or “about” refers to a range of values that fall within 20 %, 19 %, 18 %, 17 %, 16 %, 15 %, 14 %, 13 %, 12 %, 11 %, 10 %, 9 %, 8 %, 7 %, 6 %, 5 %, 4 %, 3 %, 2 %, 1 %, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100 % of a possible value).

[0014] Definitions of specific functional groups and chemical terms are described in more detailbelow. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Page 3 of 63 BUSINESS.32873149.1 409753-017WO (217367) Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0015] Certain modified ascarosides provided herein can comprise one or more asymmetriccenters, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. Thus, inventive modified ascarosides and compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, compounds described herein are enantiopure compounds. In certain other embodiments, mixtures of enantiomers or diastereomers are provided.

[0016] Furthermore, certain modified ascaroside as described herein may have one or moredouble bonds that can exist as either a Z or E isomer, unless otherwise indicated. The compounds can be provided as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of enantiomers.

[0017] As used herein, the term “isomers” includes any and all geometric isomers andstereoisomers. For example, “isomers” include cis– and trans–isomers, E– and Z– isomers, R– and S–enantiomers, diastereomers, (D)–isomers, (L)–isomers, racemic mixtures thereof, and othermixtures thereof, as falling within the scope of the disclosure. For instance, a compound may, insome embodiments, be provided substantially free of one or more corresponding stereoisomers, and may also be referred to as “stereochemically enriched.”

[0018] Where a particular enantiomer is preferred, it may, in some embodiments be providedsubstantially free of the opposite enantiomer, and may also be referred to as “optically enriched.” “Optically enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of an enantiomer. In some embodiments the compound is made up of at least about 95%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, or 99.9% by weight of an enantiomer. In some embodiments the enantiomeric excess of provided compounds is at least about 90%, 95%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, or 99.9%. In some embodiments, enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Page 4 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0019] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine(fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), and iodine (iodo, –I).

[0020] The term “aliphatic” or “aliphatic group”, as used herein, denotes a hydrocarbon moietythat may be straight–chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro–fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1– 30 carbon atoms. In certain embodiments, aliphatic groups contain 1–12 carbon atoms. In certain embodiments, aliphatic groups contain 1–8 carbon atoms. In certain embodiments, aliphatic groups contain 1–6 carbon atoms. In some embodiments, aliphatic groups contain 1–5 carbon atoms, in some embodiments, aliphatic groups contain 1–4 carbon atoms, in yet other embodiments aliphatic groups contain 1–3 carbon atoms, and in yet other embodiments aliphatic groups contain 1–2 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0021] The term “heteroaliphatic” or “heteroaliphatic group”, as used herein, denotes an aliphaticgroup where one or more carbon or hydrogen atoms are replaced by a heteroatom (e.g. oxygen, nitrogen, sulfur, phosphorous, boron, etc.). In some embodiments, a heteroaliphatic group is a heterocyclyl group.

[0022] The term "unsaturated", as used herein, means that a moiety has one or more double ortriple bonds.

[0023] The term “alkyl,” as used herein, refers to saturated, straight– or branched–chainhydrocarbon radicals derived from an aliphatic moiety containing between one and six carbon atoms by removal of a single hydrogen atom. Unless otherwise specified, alkyl groups contain 1– 12 carbon atoms. In certain embodiments, alkyl groups contain 1–8 carbon atoms. In certain embodiments, alkyl groups contain 1–6 carbon atoms. In some embodiments, alkyl groups contain 1–5 carbon atoms, in some embodiments, alkyl groups contain 1–4 carbon atoms, in yet other embodiments alkyl groups contain 1–3 carbon atoms, and in yet other embodiments alkyl groups contain 1–2 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n–propyl, isopropyl, n–butyl, iso–butyl, sec–butyl, sec–pentyl, iso–pentyl, tert– butyl, n–pentyl, neopentyl, n–hexyl, sec–hexyl, n–heptyl, n–octyl, n–decyl, n–undecyl, dodecyl, and the like.

[0024] The term “alkenyl,” as used herein, denotes a monovalent group derived from a straight–or branched–chain aliphatic moiety having at least one carbon–carbon double bond by the removal of a single hydrogen atom. Unless otherwise specified, alkenyl groups contain 2–12 carbon atoms. Page 5 of 63 BUSINESS.32873149.1 409753-017WO (217367) In certain embodiments, alkenyl groups contain 2–8 carbon atoms. In certain embodiments, alkenyl groups contain 2–6 carbon atoms. In some embodiments, alkenyl groups contain 2–5 carbon atoms, in some embodiments, alkenyl groups contain 2–4 carbon atoms, in yet other embodiments alkenyl groups contain 2–3 carbon atoms, and in yet other embodiments alkenyl groups contain 2 carbon atoms. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1–methyl–2–buten–1–yl, and the like.

[0025] The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or“aryloxyalkyl”, refers to monocyclic and polycyclic ring systems having a total of five to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to twelve ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term“aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more additional rings, such as benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like.

[0026] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g.,“heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pelectrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently Page 6 of 63 BUSINESS.32873149.1 409753-017WO (217367) are optionally substituted. The term “heteroarylenyl” refers to bivalent heteroaryl groups (e.g., pyridylenyl).

[0027] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and“heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4– dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N–substituted pyrrolidinyl).

[0028] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atomthat results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. In some embodiments, a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0029] As used herein, the term “partially unsaturated” refers to a ring moiety that includes atleast one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0030] As described herein, modified ascaroside as provided herein may contain “optionallysubstituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are 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 when more than one position in any given structure may be substituted with more than one substituent selected from a specified Page 7 of 63 BUSINESS.32873149.1 409753-017WO (217367) group, the substituent may be either the same or different at every position. Combinations of substituents envisioned are preferably those that result in the formation of stable or chemicallyfeasible compounds / derivatives. The term “stable,” as used herein, refers to compounds orderivatives that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0031] Suitable monovalent substituents on a substitutable carbon atom of an “optionallysubstituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O-(CH2)0-4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –NO2; –CN; –N3; –(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; – N(R°)C(S)R°; –(CH2)0-4N(R°)C(O)NR°2; –N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; –N(R°)N(R°)C(O)NR°2; –N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; -C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)N(R°)2; –(CH2)0–4C(O)SR°; –(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; -C(S)NR°2; –C(S)SR°; –SC(S)SR°, –(CH2)0–4OC(O)NR°2; –C(O)N(OR°)R°;–C(O)C(O)R°; -C(O)CH2C(O)R°; –C(NOR°)R°; –(CH2)0–4SSR°; –(CH2)0–4S(O)2R°;–(CH2)0–4S(O)2OR°; -(CH2)0–4OS(O)2R°; –S(O)2NR°2; –(CH2)0–4S(O)R°; –N(R°)S(O)2NR°2; –N(R°)S(O)2R°; -N(OR°)R°; –C(NH)NR°2; –P(O)2R°; –P(O)R°2; –OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C1–4straight or branched alkylene)O–N(R°)2; or –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-8 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or polycyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0032] Suitable monovalent substituents on R° (or the ring formed by taking two independentoccurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R", –(haloR"), –(CH2)0–2OH, –(CH2)0–2OR", –(CH2)0–2CH(OR")2; -O(haloR"), –CN, –N3, –(CH2)0–2C(O)R", –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR", -(CH2)0-4C(O)N(R°)2; –(CH2)0–2SR", –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR", -(CH2)0-2NR"2, –NO2, –SiR"3, –OSiR"3, –C(O)SR", –(C1–4 straight or branched alkylene)C(O)OR", or –SSR"wherein each R"is Page 8 of 63 BUSINESS.32873149.1 409753-017WO (217367) unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, -CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0033] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted”group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] Suitable substituents on the aliphatic group of R* include halogen, –R", -(haloR"), –OH, –OR", –O(haloR"), –CN, –C(O)OH, –C(O)OR", –NH2, –NHR", –NR"2, or –NO2, wherein each R"is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] Suitable substituents on a substitutable nitrogen of an “optionally substituted” groupinclude –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, –S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] Suitable substituents on the aliphatic group of R† are independently halogen, –R",–(haloR"), –OH, –OR", –O(haloR"), –CN, –C(O)OH, –C(O)OR", –NH2, –NHR", –NR"2, or -NO2, wherein each R"is unsubstituted or where preceded by “halo” is substituted only with Page 9 of 63 BUSINESS.32873149.1 409753-017WO (217367) one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] As used herein, the term “substantially” refers to the qualitative condition of exhibitingtotal or near-total extent or degree of a characteristic or property of interest.

[0038] The convention of naming ascarosides by a several-letter prefix followed by a pound sign(#) and a number is sometimes used (for example ascr#18). This convention is used in the scientific literature and the skilled artisan will understand that each such name is associated with a specific chemical structure of known composition and will readily apprehend the structure of the molecule referred to using this naming convention. Unless otherwise indicated, all compound identifiers of this format used herein conform to the definitions described in the C. elegans Small Molecule Identifier Database (SMID-DB) maintained at http: / / www.smid-db.org, the current version of which is hereby incorporated herein by reference.

[0039] The term “pathogen” refers to any bacterium, fungus, oomycete, virus, nematode (e.g.,cyst or root knot nematode) or insect with pathogenic effects on a plant. DETAILED DESCRIPTION

[0040] Compounds, compositions, and methods for the use of disclosed compounds are provided.The disclosure is directed to compounds, as well as to compositions and methods involving modified ascarosides. In certain embodiments, provided compounds, compositions, and methods herein relate generally to modified ascarosides which, in some embodiments, provide various benefits when administered or applied to an organism (e.g., a plant, an animal, or a microbe) and in particular, can exhibit increased half-life and / or potency as compared with a corresponding ascaroside (in unmodified form).

[0041] In general, naturally-occurring ascarosides comprise a fatty acid-derived sidechain (linkedto ascarylose via a glycosidic bond) and having a carboxylic acid or ester group at the chain end. In one aspect, the present invention provides compounds that comprise one or more non-hydrogen substituents at positions corresponding to alpha and / or beta to the chain end carboxylic acid or ester group. In certain embodiments, compounds described herein may comprise chain-end functional groups other than carboxylic acid or ester. In one aspect, the present invention provides compounds that comprise one or more non-hydrogen substituents at positions corresponding to alpha and / or beta to a chain end functional group other than carboxylic acid or ester. Although not intending to be limited by theory, it is believed that such modifications can advantageously slow Page 10 of 63 BUSINESS.32873149.1 409753-017WO (217367) or prevent metabolism of the ascaroside via degradation of the fatty acid-derived side chain (e.g., via beta oxidation, e.g., enzymatic oxidation).I. Compounds

[0042] In one aspect, the present disclosure provides compounds comprising one or more non-hydrogen substituents at positions corresponding to alpha or beta to a carboxylic acid or ester end group typical of ascaroside fatty acid-derived sidechains. In certain embodiments, such compounds are novel and have not previously been synthesized or described, and / or their utility for formulation of compositions with enhanced utility for the treatment of plants and / or animals has not been reported or recognized, and / or they have not been formulated into defined compositions with utility in such applications.

[0043] In certain embodiments, provided compounds are of Formula 1: or salts thereof; wherein: each of Raand Rbis independently -H, or an optionally substituted moiety selected from the group consisting of: C1-20 aliphatic, C1-20 acyl, C1-20 heteroaliphatic, aryl, heteroaryl, a hydroxyl protecting group, a phosphorous-linked functional group, a sulfur-linked functional group, a silicon-linked functional group, a C2-20 carbonate (e.g., -a moiety -C(O)ORc), a C2-20 carbamate (e.g., -a moiety -C(O)N(Rc)2), a C2-20thioester (e.g. a moiety -C(S)Rc), a C2-20thiocarbonate (e.g. a moiety -C(S)ORc), a C2-20 dithiocarbonate (e.g. a moiety -C(S)SRc), a C1-20 thiocarbamate (e.g. a moiety -C(S)N(Rc)2), a sugar moiety, a peptide, a polymer chain, or a linkage via a bond or a carbon-containing linker moiety to an ascaroside molecule; each Rcis independently at each occurrence selected from -H, optionally substituted C1-12aliphatic, optionally substituted C1-12 heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, a polymer chain, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule; and where Raand Rbmay be taken together to form an optionally substituted ring, optionally containing one or more heteroatoms, and optionally containing one or more sites of unsaturation; and Page 11 of 63 BUSINESS.32873149.1 409753-017WO (217367) -Z comprises an optionally unsaturated, optionally substituted C2-40sidechain terminating in a chain end comprising a nitrogen-, oxygen- or sulfur-containing functional group and having at least one non-hydrogen substituent on the carbon atoms that are adjacent to or two atoms away from the chain end.

[0044] As defined above and described herein, Z comprises an optionally unsaturated, optionallysubstituted C2-40 sidechain terminating in a chain end comprising a nitrogen-, oxygen- or sulfur- containing functional group and having at least one non-hydrogen substituent on the carbon atoms that are adjacent to or two atoms away from the chain end. It will be understood that when the chain end is, e.g., a carboxylic acid or ester, the carbon atoms that are adjacent to or two atoms away from the chain end are referred to as the alpha and beta carbon atoms, respectively. To avoid any doubt, the structure below illustrates the location of the one or more non-hydrogen substituents: wherein: Z1is the remaining portion of Z not depicted in the above formula; Chain end is as defined above and described here; each of A and B independently comprise a carbon atom and optionally one or more non-hydrogen substituents, wherein at least one non-hydrogen substituent is present on A or B.

[0045] In some embodiments, provided compounds are of Formula 2, below: or a salt thereof; wherein: each of Raand Rbis as defined above and in the genera and subgenera herein; Rdis -H, halogen (e.g., -F), or optionally substituted C1-6 aliphatic group; Q is or comprises an oxygen-, nitrogen, or sulfur-containing functional group; n is an integer from 1 to 24; and each A1, A2, B1, and B2is independently selected from hydrogen and a non-hydrogen substituent, where at least one of A1, A2, B1, and B2 is a non-hydrogen substituent.

[0046] In some embodiments, provided compounds are of Formula 3, below:Page 12 of 63 BUSINESS.32873149.1 409753-017WO (217367) , or a salt thereof; wherein each of Ra, Rb, Rd, A1, A2, B1, B2, and Q is as defined above and in the genera and subgenera herein.

[0047] In some embodiments, provided compounds are of Formula 4, below:, or a salt thereof; wherein each of Ra, Rb, Rd, A1, A2, B1, B2, and Q is as defined above and in the genera and subgenera herein.

[0048] In some embodiments, provided compounds are of Formula 5, below:, or a salt thereof; wherein each of Ra, Rb, A1, A2, B1, B2, n and Q is as defined above and in the genera and subgenera herein.

[0049] In some embodiments, provided compounds are of any one of the following formulae:Page 13 of 63 BUSINESS.32873149.1 409753-017WO (217367) , wherein each of Ra, Rb, Rd, R2, A1, A2, B1, B2, and n is as defined above and in the genera and subgenera herein; and R2is H, a metal cation, an organic cation, an optionally substituted C1-20 aliphatic group, an optionally substituted C1-20heteroaliphatic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a glycoside, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule.

[0050] In some embodiments, provided compounds are of any one of the following formulae:, wherein each of Ra, Rb, R2, A1, A2, B1, B2, and n is as defined above and in the genera and subgenera herein.

[0051] As described above, the ascarylose sugar moiety in the provided compounds can besubstituted or unsubstituted (i.e., there can be functional groups other than -OH at 2- and 4- positions of the sugar or, stated differently, variables Raand / or Rbcan be other than -H in any of the formulae herein).

[0052] It will be understood that a depiction of a wavy bond, “ ”, at a stereocenter refers to bothgeometries (e.g., “ ” or “ ”). In some embodiments, a bond indicates the compound ispresent in at that position (e.g., racemic). In some embodiments, a wavy bond indicates the compound is one stereoisomer at that position, but the R vs. S assignment is unspecified.

[0053] In certain embodiments, A1, A2, B1, and B2 are not -OH. In certain embodiments, n is not2. In certain embodiments, the compound of Formula 1 is a compound other than one disclosed in WO 2020 / 236621 (e.g. Table 3).

[0054] As defined above and described herein, each of Ra and Rb is independently -H, or anoptionally substituted moiety selected from the group consisting of: C1-20 aliphatic, C1-20 acyl, C1- Page 14 of 63 BUSINESS.32873149.1 409753-017WO (217367)20heteroaliphatic, aryl, heteroaryl, a hydroxyl protecting group, a phosphorous-linked functional group, a sulfur-linked functional group, a silicon-linked functional group, a C2-20 carbonate (e.g., -a moiety -C(O)ORc), a C2-20carbamate (e.g., -a moiety -C(O)N(Rc)2), a C2-20thioester (e.g. a moiety -C(S)Rc), a C2-20 thiocarbonate (e.g. a moiety -C(S)ORc), a C2-20 dithiocarbonate (e.g. a moiety -C(S)SRc), a C1-20thiocarbamate (e.g. a moiety -C(S)N(Rc)2), a sugar moiety, a peptide, a polymer chain, or a linkage via a bond or a carbon-containing linker moiety to an ascaroside molecule.

[0055] In certain embodiments, Ra is -H. In certain embodiments, Rb is -H. In certainembodiments, Raand Rbare the same. In certain embodiments Raand Rbare both -H. In certain embodiments, Raand Rbare different. In certain embodiments, Rais -H, and Rbis other than -H. In certain embodiments, Rais other than -H and Rbis -H. In certain embodiments, Rais -H and Rbis p-hydroxybenzoate. In certain embodiments, Rais -H and Rbis indole-3-carboxylate. In certain embodiments, Rais -H and Rbis (E)-2-methyl-2-butenoate. In certain embodiments, Rais -H and Rbis picolinate. In certain embodiments, Rais -H and Rbis nicotinate. In certain embodiments, Rais -H and Rbis (R)-2-hydroxy-2-(4-hydroxyphenyl)ethyl)amino)-4-oxobutanoate. In certain embodiments, Rais -H and Rbis 4-((4-hydroxyphenethyl)amino)-4-oxobutanoate. In certain embodiments, Racomprises a glycoside, amino acid, a peptide, or nucleotide. In certain embodiments, Rbcomprises a glycoside, amino acid, a peptide, or nucleotide. In certain embodiments, Racomprises a linkage to a second ascaroside molecule. In certain embodiments, Rbcomprises a linkage to an ascaroside molecule. In certain embodiments, Racomprises a sugar. In certain embodiments, Rbcomprises a sugar.

[0056] In some embodiments, Ra is an optionally substituted C1-20 aliphatic group. In someembodiments, Rais an optionally substituted C1-6 aliphatic group. In some embodiments, Rais C1-20aliphatic. In some embodiments, Rais C1-6aliphatic. In some embodiments, Rais methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, Rais C1-20acyl. In some embodiments, Rais -C(O)Rc. In some embodiments, Rais -C(O)H. In some embodiments, Rais -C(O)CH3. In some embodiments, Rais an optionally substituted C1-20 heteroaliphatic. In some embodiments, Rais an optionally substituted C1-6 heteroaliphatic. In some embodiments, Rais C1-20heteroaliphatic. In some embodiments, Rais C1-6heteroaliphatic. In some embodiments, Rais an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rais an optionally substituted 8- to 12-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rais optionally substituted aryl. In some Page 15 of 63 BUSINESS.32873149.1 409753-017WO (217367) embodiments, Rais optionally substituted phenyl. In some embodiments, Rais phenyl. In some embodiments, Rais an optionally substituted heteroaryl group. In some embodiments, Rais an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rais an optionally substituted 8- to 12- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rais an optionally substituted C2-20 carbonate. In some embodiments, Rais -C(O)ORc. In some embodiments, Rais an optionally substituted C2-20carbamate. In some embodiments, Rais -C(O)N(Rc)2. In some embodiments, Rais an optionally substituted C2-20thioester. In some embodiments, Rais -C(S)Rc. In some embodiments, Rais an optionally substituted C2-20 thiocarbonate. In some embodiments, Rais -C(S)ORc. In some embodiments, Rais an optionally substituted C2-20 dithiocarbonate. In some embodiments, Rais -C(S)SRc. In some embodiments, Rais an optionally substituted C1-20thiocarbamate. In some embodiments, Rais -C(S)N(Rc)2.

[0057] In some embodiments, Ra is an optionally substituted hydroxyl protecting group. Suitablehydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999. Examples of suitable oxygen protecting groups include, but are not limitedto, acetyl, benzoyl benzyl, β-methoxyethoxymethyl ether (MEM), dimethoxytrityl (DMT),methoxymethyl ether (MOM), methoxytrityl (MMT), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl, tetrahydropyranyl (THP), tetrahydrofuran (THF), trityl, silyl ethers (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), methyl ethers, and ethoxyethyl ethers. In some embodiments, Rais -ORc.

[0058] In some embodiments, Ra is an optionally substituted phosphorous-linked functionalgroup. It will be appreciated that “phosphorous-linked functional group” as used herein refers to moieties that comprise one or more phosphorous atoms (e.g., phosphine, phosphodiester, phosphonic acid, phosphate). In some embodiments, Rais an optionally substituted sulfur-linked functional group. It will be appreciated that “sulfur-linked functional group” as used herein refers to moieties that comprise one or more sulfur atoms (e.g., thioether, sulfone, sulfonic acid, sulfoxide, thiol, thiocyanate, or disulfide). In some embodiments, Rais an optionally substituted silicon-linked functional group. It will be appreciated that “silicon-linked functional group” as used herein refers to moieties that comprise one or more silicon atoms (e.g., silanol, siloxides, siloxanes, silyl ethers, silyl chlorides, silyl hydrides, silenes, or siloles). Page 16 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0059] In some embodiments, Ra is an optionally substituted sugar moiety. In some embodiments,Rais an optionally substituted peptide. In some embodiments, Rais an optionally substituted polymer chain. In some embodiments, Rais a linkage via a bond or a carbon-containing linker moiety to an ascaroside molecule. In some embodiments, Rais an optionally substituted C1-6 aliphatic or heteroaliphatic comprising an ascaroside.

[0060] In some embodiments, Rb is optionally substituted C1-20 aliphatic. In some embodiments,Rbis optionally substituted C1-6aliphatic. In some embodiments, Rbis C1-20aliphatic. In some embodiments, Rbis C1-6 aliphatic. In some embodiments, Rbis methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments, Rbis C1-20acyl. In some embodiments, Rbis -C(O)Rc. In some embodiments, Rbis -C(O)H. In some embodiments, Rbis -C(O)CH3. In some embodiments, Rbis an optionally substituted C1-20 heteroaliphatic. In some embodiments, Rbis an optionally substituted C1-6heteroaliphatic. In some embodiments, Rbis C1-20 heteroaliphatic. In some embodiments, Rbis C1-6 heteroaliphatic. In some embodiments, Rbis an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rbis an optionally substituted 8- to 12-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rbis optionally substituted aryl. In some embodiments, Rbis optionally substituted phenyl. In some embodiments, Rbis phenyl. In some embodiments, Rbis an optionally substituted heteroaryl group. In some embodiments, Rbis an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rbis an optionally substituted 8- to 12-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rbis an optionally substituted C2-20carbonate. In some embodiments, Rbis -C(O)ORc. In some embodiments, Rbis an optionally substituted C2-20 carbamate. In some embodiments, Rbis -C(O)N(Rc)2. In some embodiments, Rbis an optionally substituted C2-20thioester. In some embodiments, Rbis -C(S)Rc. In some embodiments, Rbis an optionally substituted C2-20 thiocarbonate. In some embodiments, Rbis -C(S)ORc. In some embodiments, Rbis an optionally substituted C2-20dithiocarbonate. In some embodiments, Rbis -C(S)SRc. In some embodiments, Rais an optionally substituted C1-20 thiocarbamate. In some embodiments, Rbis -C(S)N(Rc)2.

[0061] In some embodiments, Rb is an optionally substituted hydroxyl protecting group. In someembodiments, Rbis -ORc. Page 17 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0062] In some embodiments, Rb is an optionally substituted phosphorous-linked functionalgroup. In some embodiments, Rbis an optionally substituted sulfur-linked functional group. In some embodiments, Rbis an optionally substituted silicon-linked functional group.

[0063] In some embodiments, Rb is an optionally substituted sugar moiety. In some embodiments,Rais an optionally substituted peptide. In some embodiments, Rbis an optionally substituted polymer chain. In some embodiments, Rbis a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule. In some embodiments, Rbis an optionally substituted C1-6 aliphatic or heteroaliphatic comprising an ascaroside.

[0064] In some embodiments, Ra and Rb may be taken together to form an optionally substitutedring, optionally containing one or more heteroatoms, and optionally containing one or more sites of unsaturation. In some embodiments, Raand Rbmay be taken together to form an optionally substituted 3- to 12- membered monocyclic or bicyclic saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Raand Rbmay be taken together to form an optionally substituted 5- to 12-membered monocyclic or bicyclic aryl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0065] As defined above and described herein, each Rc is independently at each occurrenceselected from -H, optionally substituted C1-12aliphatic, optionally substituted C1-12heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, a polymer chain, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule.

[0066] In some embodiments, Rc is independently at each occurrence selected from -H, optionallysubstituted C1-12aliphatic, optionally substituted C1-12heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl.

[0067] In some embodiments, an occurrence of Rc is -H. In some embodiments, Rc is anoptionally substituted C1-12 aliphatic group. In some embodiments, Rcis an optionally substituted C1-6aliphatic group. In some embodiments, Rcis an optionally substituted C1-12heteroaliphatic group. In some embodiments, Rcis an optionally substituted C1-6 heteroaliphatic group. In some embodiments, Rcis an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rcis an optionally substituted 8- to 12-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rcis an optionally substituted aryl group. In some embodiments, Rcis optionally substituted phenyl. In some embodiments, R2is phenyl. In some embodiments, Rcis an optionally substituted heteroaryl group. In some embodiments, Rcis an Page 18 of 63 BUSINESS.32873149.1 409753-017WO (217367) optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Rcis an optionally substituted 8- to 12- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0068] As defined above and described herein, Rd is -H, halogen (e.g., -F), or an optionallysubstituted C1-6 aliphatic group. In some embodiments, Rdis -H. In some embodiments, Rdis halogen. In some embodiments, Rdis -F. In some embodiments, Rdis optionally substituted C1-6aliphatic. In some embodiments, Rdis C1-6 aliphatic. In some embodiments, Rdis saturated C1-6 fluoroaliphatic. In some embodiments, Rdis saturated C1-6aliphatic. In certain embodiments, Rdis selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl. In certain embodiments, Rdis methyl. In certain embodiments, Rdis trifluoromethyl. In certain embodiments, Rdis ethyl. In certain embodiments, Rdis pentafluoroethyl. In certain embodiments, Rdis 1,1,1-trifluoroethyl.

[0069] As defined above and described herein, Q is or comprises an oxygen-, nitrogen, or sulfur-containing functional group. It will be appreciated that “an oxygen-containing functional group” refers to moieties that comprise one or more oxygen atoms (e.g., carbonyl-containing groups such as esters, aldehydes, carboxylic acids, and ketones; ethers, hydroxyls, and heterocyclic rings comprising one or more oxygen atoms and / or one of the foregoing functional groups); “a nitrogen- containing functional group” refers to moieties that comprise one or more nitrogen atoms (e.g., amines, amides, carbamates, imines, ureas, oximes, amidines, guanidines, nitriles, azo groups, azides, and heterocyclic rings comprising one or more nitrogen atoms and / or one of the foregoing functional groups); and “a sulfur-containing functional group” refers to moieties that comprise one or more sulfur atoms as defined above and herein.

[0070] In some embodiments, Q is an oxygen-containing functional group. In certainembodiments, Q is a carboxylic acid. In certain embodiments, Q is an aldehyde. In certain embodiments, Q is an ester. In some embodiments, Q is -CO2R2. In some embodiments, Q is - CO2H. In some embodiments, Q is -CO2CH3. In some embodiments, Q is an ester comprising a linker moiety covalently attached to one or more additional ascaroside molecules.

[0071] As defined above and described herein, R2 is -H, a metal cation, an organic cation, anoptionally substituted C1-20 aliphatic group, an optionally substituted C1-20 heteroaliphatic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a glycoside, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule. In some embodiments, R2is -H, a metal cation, an optionally substituted C1-20 aliphatic group, an optionally substituted C1-20 heteroaliphatic group, an Page 19 of 63 BUSINESS.32873149.1 409753-017WO (217367) optionally substituted aryl group, an optionally substituted heteroaryl group, a glycoside, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule. In some embodiments, R2is -H, an optionally substituted C1-20aliphatic group, an optionally substituted C1-20 heteroaliphatic group, or an optionally substituted aryl group, an optionally substituted heteroaryl group.

[0072] In some embodiments, R2 is -H. In some embodiments, R2 is a metal cation. In someembodiments, R2is an organic cation. In some embodiments, R2is an optionally substituted C1-20 aliphatic group. In some embodiments, R2is an optionally substituted C1-6 aliphatic group. In some embodiments, R2is an optionally substituted C1-20heteroaliphatic group. In some embodiments, R2is an optionally substituted C1-6 heteroaliphatic group. In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 8- to 12-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted aryl group. In some embodiments, R2is optionally substituted phenyl. In some embodiments, R2is phenyl. In some embodiments, R2is an optionally substituted heteroaryl group. In some embodiments, R2is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 8- to 12- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0073] In some embodiments, R2 is a glycoside. It will be appreciated that a glycoside refers to amoiety comprising a sugar bound to another functional group via a glycosidic bond.

[0074] In some embodiments, R2 is nucleotide. In some embodiments, R2 is adenosinemonophosphate, cytidine monophosphate, guanosine monophosphate, or uridine monophosphate. In some embodiments, R2is deoxyadenosine monophosphate, deoxycytidine monophosphate, deoxyguanosine monophosphate, or deoxythymidine monophosphate.

[0075] In some embodiments, R2 is a linkage via a bond or a carbon-containing linker moiety toanother ascaroside molecule. In some embodiments, R2is an optionally substituted C1-6aliphatic or heteroaliphatic attached to another ascaroside moiety.

[0076] In some embodiments, Q is a nitrogen-containing functional group. In certainembodiments, Q is an amide, amidine, oxime, imine, guanidine, urea, or a carbamate group. In some embodiments, Q is -N(R3)2, where each R3is independently -H, an optionally substituted C1-20 aliphatic group, an optionally substituted C1-20 heteroaliphatic group, an optionally Page 20 of 63 BUSINESS.32873149.1 409753-017WO (217367) substituted aryl group, an optionally substituted heteroaryl group, a polymer chain, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule, and where both R3groups can be taken together to form an optionally substituted, optionally unsaturated ring optionally containing one or more additional heteroatoms. In some embodiments, Q is -NH2. In some embodiments, Q is -NHR3, wherein each R3is independently -H, an optionally substituted C1-20 aliphatic group, an optionally substituted C1-20 heteroaliphatic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a polymer chain, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon- containing linker moiety to another ascaroside molecule, and where both R3groups can be taken together to form an optionally substituted, optionally unsaturated ring optionally containing one or more additional heteroatoms.

[0077] In certain embodiments, Q is an amide. In certain embodiments, Q is -CON(R3)2. In someembodiments Q is -CONH2. In certain embodiments, Q is -CONHR3. In some embodiments, Q is -CONHCH2CH2OH.

[0078] As defined above and described herein, each R3 is independently -H, an optionallysubstituted C1-20aliphatic group, an optionally substituted C1-20heteroaliphatic group, an optionally substituted aromatic group, an optionally substituted heteroaryl group, a polymer chain, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule, and where both R3groups can be taken together to form an optionally substituted, optionally unsaturated ring optionally containing one or more additional heteroatoms. In some embodiments, each R3is independently selected from -H and C1-8 aliphatic. In some embodiments, one R3is -H and the other R3is other than -H. In some embodiments, neither R3is -H. In some embodiments, each R3is -H. In some embodiments, an occurrence of R3is an optionally substituted C1-20aliphatic group. In some embodiments, an occurrence of R3is an optionally substituted C1-6 aliphatic group. In some embodiments, an occurrence of R3is an optionally substituted C1-20heteroaliphatic group. In some embodiments, an occurrence of R3is an optionally substituted C1-6 heteroaliphatic group. In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 8- to 12-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, occurrence of R3is an optionally substituted aryl group. In some embodiments, R3is optionally substituted phenyl. In some embodiments, R3is phenyl. In some embodiments, R3is an optionally substituted heteroaryl group. In some embodiments, R3is an Page 21 of 63 BUSINESS.32873149.1 409753-017WO (217367) optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 8- to 12- membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0079] In some embodiments, Q is an amide comprising a linker moiety covalently attached toone or more additional ascaroside molecules. In some embodiments, Q is -C(O)NR3-(bivalent optionally substituted C1-6aliphatic or heteroaliphatic)-ascaroside.

[0080] In certain embodiments, Q is a sulfur-containing functional group. In certain embodiments,Q is selected from: thioester, dithioester, thioamide, thiocarbonate, dithiocarbonate, trithiocarbonate, thiocarbamate, dithiocarbamate, thionate, sulfoxide, sulfone.

[0081] In certain embodiments, Q is a thioester. In some embodiments, Q is -C(O)SR2, whereinR2is as defined above and described herein.

[0082] In certain embodiments, Q is a thioamide. In some embodiments, Q is C(S)N(R3)2,wherein each R3is as defined above and described herein.

[0083] In certain embodiments, Q comprises a sulfur-containing functional group covalentlyattached to a linker moiety which is covalently attached to one or more additional ascaroside molecules. In some embodiments, Q is –(thioester or thioamide)-optionally substituted C1-6 aliphatic or heteroaliphatic)-ascaroside.

[0084] In certain embodiments, n is an integer from 1 to 20. In certain embodiments, n is aninteger from 3 to 24. In certain embodiments, n is an integer from 1 to 16. In certain embodiments, n is an integer from 1 to 12. In certain embodiments, n is an integer from 1 to 10. In certain embodiments, n is an integer from 1 to 8. In certain embodiments, n is an integer from 1 to 6. In certain embodiments, n is an integer from 1 to 4. In certain embodiments, n is an integer from 2 to 10. In certain embodiments, n is an integer from 2 to 8. In certain embodiments, n is an integer from 2 to 6. In certain embodiments, n is an integer from 4 to 12. In certain embodiments, n is an integer from 4 to 10. In certain embodiments, n is an integer from 4 to 8. In certain embodiments, n is an integer from 4 to 6. In certain embodiments, n is 10. In certain embodiments, n is 9. In certain embodiments, n is 8. In certain embodiments, n is 7. In certain embodiments, n is 6. In certain embodiments, n is 5. In certain embodiments, n is 4. In certain embodiments, n is 3. In certain embodiments, n is 2. In certain embodiments, n is 1. In certain embodiments, n is greater than 2. In certain embodiments, n is greater than 4.

[0085] As defined above and described herein, each A1, A2, B1, and B2 is independently selectedfrom hydrogen and a non-hydrogen substituent, where at least one of A1, A2, B1, and B2is a non- hydrogen substituent. In some embodiments, A1 is a non-hydrogen substituent and A2, B1, and Page 22 of 63 BUSINESS.32873149.1 409753-017WO (217367) B2are each hydrogen. In some embodiments, A1and A2are each independently non-hydrogen substituents and B1 and B2 are each hydrogen. In some embodiments, B1 is a non-hydrogen substituent and A1, A2, and B2are each hydrogen. In certain embodiments, B1and B2are each independently non-hydrogen substituents and A1 and A2 are each hydrogen. In some embodiments, A1and B1are each independently non-hydrogen substituents and A2and B2are each hydrogen. In some embodiments, A1, A2, and B1 are each independently non-hydrogen substituents and B2is hydrogen. In some embodiments, A1, B1and B2are each independently non- hydrogen substituents and A2 is hydrogen. In some embodiments, A1, A2, B1, and B2 are each independently non-hydrogen substituents. In certain embodiments, any two or more of A1, A2, B1, and B2 may be taken together to form an optionally substituted ring, optionally containing one or more heteroatoms, and optionally containing one or more sites of unsaturation. In some embodiments, any two or more of A1, A2, B1, and B2may be taken together to form an optionally substituted saturated, partially unsaturated, or aromatic 3-12-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, any two or more of A1, A2, B1, and B2 may be taken together to form an optionally substituted saturated, partially unsaturated, or aromatic 4-12-membered monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, any two or more of A1, A2, B1, and B2are taken together to form an optionally substituted 3- to 12- membered monocyclic or bicyclic saturated or partially unsaturated carbocyclyl other than cyclopropyl. In some embodiments, any two or more of A1, A2, B1, and B2may be taken together to form an optionally substituted 3- to 12- membered monocyclic or bicyclic saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, any two or more of A1, A2, B1, and B2may be taken together to form an optionally substituted 4- to 12- membered monocyclic or bicyclic saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, any two or more of A1, A2, B1, and B2 may be taken together to form an optionally substituted 5- to 12-membered monocyclic or bicyclic aryl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0086] In some embodiments, A1, A2, B1, and B2 are other than an oxygen-linked group. In certainembodiments, A1, A2, B1, and B2are other than -OH, =O, or epoxy (e.g. where one A and one B substituent taken together form an epoxide).

[0087] In some embodiments, provided compounds (e.g., of Formula I) can be referred to asalpha-substituted (e.g., wherein A1 and / or A2 is a non-hydrogen substituent), as beta-substituted Page 23 of 63 BUSINESS.32873149.1 409753-017WO (217367) (e.g., wherein B1and / or B2is a non-hydrogen substituent), or as alpha, beta-substituted, e.g., wherein A1 and / or A2 and B1 and / or B2 is a non-hydrogen substituent.

[0088] The composition of the one or more “non-hydrogen substituents” on compounds as usedherein can vary. In certain embodiments, a non-hydrogen substituent is an optionally substituted C1-12aliphatic substituent, an optionally substituted C1-12heteroaliphatic substituent, an optionally substituted C1-12 alkoxy substituent or a halogen substituent. In certain embodiments, “non- hydrogen substituents” on two or more of A1, A2, B1, or B2form spirocyclic rings (e.g. cyclopropyl, cyclobutyl, or a larger carbocycle) or spiroheterocyclic rings (e.g., aziridinyl, oxiranyl, azetidinyl, pyrrolidinyl or larger heterocycles) where one of the ring carbons of the spirocycle or spiroheterocycle comprises the carbon atom adjacent to the chain end and / or two atoms away from the chain end (e.g., the alpha and beta carbon when the chain end is a carboxylic acid or ester). In some embodiments, A1and A2form a cyclopropyl ring. In some embodiments, A1 and B1 form a cyclopropyl ring. In some embodiments, A1 and B1 or A1 and A2 form a ring other than cyclopropyl.

[0089] In some embodiments, a non-hydrogen substituent is an optionally substituted alkyl (e.g.,-CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3), an optionally substituted heteroalkyl, or a halogen (e.g., F, Cl, Br, or I). In some embodiments, a non-hydrogen substituent is methyl or fluoro.

[0090] In some embodiments, where two or more non-hydrogen substituents A1, A2, B1, and B2are present, the two or more non-hydrogen substituents are the same substituent, such that the modified ascaroside comprises two of the same non-hydrogen substituents at the noted positions, three or more of the same non-hydrogen substituents at the noted positions, or four of the same non-hydrogen substituents at the noted positions. For example, A1 and A2 may be the same non- hydrogen substituent, B1, and B2may be the same non-hydrogen substituent, A1and B1may be the same non-hydrogen substituent, A1, A2, and B1 may be the same non-hydrogen substituent, A1, B1, and B2may be the same non-hydrogen substituent, or A1, A2, B1, and B2are all the same non-hydrogen substituent (where the remaining A1, A2, B1, and B2, where present, can be hydrogen or a different non-hydrogen substituent).

[0091] In some embodiments where two or more non-hydrogen substituents A1, A2, B1, and B2are present, the two or more non-hydrogen substituents comprise two or more different substituents, such that the modified ascaroside comprises two or more different non-hydrogen substituents at the noted positions, three or more different non-hydrogen substituents at the noted positions, or four different non-hydrogen substituents at the noted positions. For example, A1and A2 may be different non-hydrogen substituents, B1, and B2 may be different non-hydrogen Page 24 of 63 BUSINESS.32873149.1 409753-017WO (217367) substituents, A1and B1may be different non-hydrogen substituents, A1, A2, and B1may be different non-hydrogen substituents, A1, B1, and B2 may be different non-hydrogen substituents, or A1, A2, B1, and B2are all different non-hydrogen substituents (where the remaining A1, A2, B1, and B2, where present, can be hydrogen or the same non-hydrogen substituent as another non- hydrogen substituent on the modified ascaroside).

[0092] In some embodiments, each of A1, A2, B1, and B2 is independently hydrogen, methyl, orfluoro. In some embodiments, A1is methyl or fluoro. In some embodiments, A2is methyl or fluoro. In some embodiments, B1 is methyl or fluoro. In some embodiments, B2 is methyl or fluoro.

[0093] Certain, non-limiting examples of provided compounds include the following:, where each of Ra, Rb, Rd, n and Q is as defined above and in the genera and subgenera herein.

[0094] Certain, non-limiting examples of provided compounds include the following:Page 25 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0002] , where each of Ra, Rb, n and Q is as defined above and in the genera and subgenera herein.

[0095] Certain, non-limiting examples of provided compounds include the following:, Page 26 of 63 BUSINESS.32873149.1 409753-017WO (217367) where each of Ra, Rb, R2, and n is as defined above and in the genera and subgenera herein.

[0096] Certain, non-limiting examples of provided compounds include the following:, where each of R2and n is as defined above and in the genera and subgenera herein.

[0097] Certain, non-limiting examples of provided compounds include the following:, where each of Ra, Rb, Rd, n and Q is as defined above and in the genera and subgenera herein. Page 27 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0098] Certain, non-limiting examples of provided compounds include the following: or salts thereof; where each of Ra, Rb, n and Q is as defined above and in the genera and subgenera herein.

[0099] Certain, non-limiting examples of provided compounds include the following:, Page 28 of 63 BUSINESS.32873149.1 409753-017WO (217367) or salts thereof; where each of Ra, Rb, R2, and n is as defined above and in the genera and subgenera herein.

[0100] Certain, non-limiting examples of provided compounds include the following:, where each of R2, and n is as defined above and in the genera and subgenera herein.

[0101] Certain, non-limiting examples of provided compounds include the following:, Page 29 of 63 BUSINESS.32873149.1 409753-017WO (217367) where each of Ra, Rb, Rd, R2, n and Q is as defined above and in the genera and subgenera herein.

[0102] Certain, non-limiting examples of provided compounds include the following:, where each of Ra, Rb, Rd, n and Q is as defined above and in the genera and subgenera herein.

[0103] Certain, non-limiting examples of provided compounds include the following:, Page 30 of 63 BUSINESS.32873149.1 409753-017WO (217367) where each of Ra, Rb, n and Q is as defined above and in the genera and subgenera herein.

[0104] Certain, non-limiting examples of provided compounds include the following:, where each of Ra, Rb, R2, and n is as defined above and in the genera and subgenera herein.

[0105] Certain, non-limiting examples of provided compounds include the following:, Page 31 of 63 BUSINESS.32873149.1 409753-017WO (217367) or salts thereof; where each of R2, and n is as defined above and in the genera and subgenera herein.

[0106] Certain, non-limiting examples of provided compounds include the following: or salts thereof; where each of Ra, Rb, Rd, n and Q is as defined above and in the genera and subgenera herein.

[0107] Certain, non-limiting examples of provided compounds include the following:, Page 32 of 63 BUSINESS.32873149.1 409753-017WO (217367) or salts thereof; where each of Ra, Rb, n and Q is as defined above and in the genera and subgenera herein.

[0108] Certain, non-limiting examples of provided compounds include the following:, where each of Ra, Rb, R2, n and Q is as defined above and in the genera and subgenera herein.

[0109] Certain, non-limiting examples of provided compounds include the following:, Page 33 of 63 BUSINESS.32873149.1 409753-017WO (217367) where each of R2and n is as defined above and in the genera and subgenera herein.

[0110] Certain, non-limiting examples of provided compounds include the following:or salts where each of A1, B1, Ra, Rb, n and Q is as defined above and in the genera and subgenera herein.

[0111] Certain, non-limiting examples of provided compounds include the following: or salts thereof; where each of Ra, Rb, Rd, R2, n and Q is as defined above and in the genera and subgenera herein.

[0112] Certain, non-limiting examples of provided compounds include the following:Page 34 of 63 BUSINESS.32873149.1 409753-017WO (217367) , or salts where each of Rb, Ra, Rd, n and Q is as defined above and in the genera and subgenera herein.

[0113] Certain, non-limiting examples of provided compounds include the following:, where each of Rb, Ra, Rd, R2, n and Q is as defined above and in the genera and subgenera herein.

[0114] Certain, non-limiting examples of provided compounds include the following: Page 35 of 63 BUSINESS.32873149.1 409753-017WO (217367) or salts thereof; where each of Rb, Ra, and n is as defined above and in the genera and subgenera herein. Page 36 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0115] Of course, many other compounds not specifically shown in the examples provided aboveare encompassed within the scope of this application. For example, although the specific structures shown herein comprise a carboxylic acid terminal end group, this moiety can vary. In some embodiments, the terminal end group can be, e.g., an ester moiety, a salt moiety, or another moiety.

[0116] It is to be further understood that the principles provided herein are applicable to a widerange of compounds, as the substitution(s) described herein alpha and / or beta to the end group of the ascaroside fatty acid-derived side chain can be relevant to allow for the modification of any ascaroside-based compound that may benefit from a reduction in the likelihood and / or extent of beta oxidation of its side chain.

[0117] In some embodiments, provided compounds include, but are not limited to, analogues ofthe ascaroside ascr#18 (or esters or salts thereof), modified as described herein.

[0118] For example, can include compoundsof the following structure (where A1, A2, B1, and B2 are as described herein): , or salts thereof; where Ra, RbR2, A1, A2, B1and B2are as defined above and in the genera and subgenera herein.

[0119] In certain embodiments, such provided compounds have a formula selected from:Page 37 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0003] , or salts where R2is as defined above and in the genera and subgenera herein.

[0120] In some embodiments, provided compounds include, but are not limited to, analogues ofthe ascaroside oscr#16 (or esters or salts thereof), modified as described herein.

[0121] For example, such can include compoundsof the following structure (where A1, A2, B1, and B2are as described herein): , Page 38 of 63 BUSINESS.32873149.1 409753-017WO (217367) or salts thereof; where Ra, RbR2, A1, A2, B1 and B2 are as defined above and in the genera and subgenera herein.

[0122] In certain embodiments, such provided compounds have a formula selected from:, or salts where R2is as defined above and in the genera and subgenera herein.

[0123] In certain embodiments, a compound is an analogue of an ascaroside selected from thegroup consisting of: ascr#9, ascr#12, ascr#14, ascr#1, ascr#10, ascr#16, ascr#18, ascr#20, ascr#22, ascr#24, ascr#26, ascr#28, ascr#30, ascr#32, ascr#34, and ascr#36, modified as described herein. In certain embodiments, a provided compound comprises an analogue of an ascaroside selected from the group consisting of: ascr#10, ascr#16, ascr#18, ascr#20, ascr#22, and ascr#24, modified as described herein. In certain embodiments, a provided compound is an analogue of an ascaroside Page 39 of 63 BUSINESS.32873149.1 409753-017WO (217367) selected from the group consisting of: ascr#9, ascr#14, ascr#10, and ascr#18, modified as described herein.

[0124] In certain embodiments, a provided compound is an analogue of an ascaroside selectedfrom the group consisting of: ascr#5, oscr#9, oscr#12, oscr#1, oscr#14, oscr#10, oscr#16, oscr#18, oscr#20, oscr#22, oscr#24, oscr#26, oscr#28, oscr#30, oscr#32, oscr#34, and oscr#36, modified as described herein. In certain embodiments, a provided compound is an analogue of an ascaroside selected from the group consisting of: oscr#10, oscr#16, oscr#18, oscr#20, and oscr#22, modified as described herein. In certain embodiments, a provided compound is an analogue of an ascaroside selected from the group consisting of: bhas#5, oscr#9, oscr#12, oscr#1, oscr#14, oscr#10, oscr#16, oscr#18, oscr#20, oscr#22, oscr#24, oscr#26, oscr#28, oscr#30, oscr#32, oscr#34, and oscr#36, modified as described herein. In certain embodiments, a provided compound is an analogue of an ascaroside selected from the group consisting of: oscr#10, oscr#16, oscr#18, oscr#20, and oscr#22, modified as described herein.

[0125] In certain embodiments, a provided compound is an analogue of an ascaroside selectedfrom the group consisting of: bhas#9, bhas#10, bhas#16, bhas#18, bhas#22, bhas#24, bhas#26, bhas#28, bhas#30, bhas#32, bhas#34, bhas#36, bhas#38, bhas#40, and bhas#42, modified as described herein.

[0126] In certain embodiments, a provided compound is an analogue of an ascaroside selectedfrom the group consisting of: bhos#10, bhos#16, bhos#18, bhos#22, bhos#24, bhos#26, bhos#28, bhos#30, bhos#32, bhos#34, bhos#36, bhos#38, bhos#40, and bhos#42, modified as described herein.

[0127] In certain embodiments, a provided compound is an analogue of an ascaroside selectedfrom the group consisting of: ascr#18, oscr#16, oscr#17, oscr#15, bhas#18, bhos#16, glas#18, dhas#18, ibha#18, ibho#16, icas#18, icos#15, and icos#16, modified as described herein.

[0128] In certain embodiments, provided compound are characterized in that the extent or rate ofmetabolism of the ascaroside sidechain by an organism contacted or treated with the compound is reduced relative to the metabolism of the corresponding unmodified ascaroside sidechain (i.e., comprising no non-hydrogen substituents alpha or beta to the terminal carboxylic acid or ester group) under the same conditions. In certain embodiments, provided compound are characterized in that their metabolism by an organism contacted with the compound is slower than metabolism of the corresponding unmodified ascaroside (i.e., comprising no non-hydrogen substituents at positions corresponding to alpha or beta to the terminal carboxylic acid or ester group) under the same conditions. In certain embodiments, provided compound are characterized in that the extent of their metabolism by an organism contacted with the compound is less than that of the Page 40 of 63 BUSINESS.32873149.1 409753-017WO (217367) corresponding unmodified ascaroside (i.e., comprising no non-hydrogen substituents at positions corresponding to alpha or beta to the terminal carboxylic acid or ester group) under the same conditions (e.g., a smaller percentage of the material in contact with the organism is metabolized).

[0129] It is generally understood that ascarosides are subject to metabolism via iterative sidechainshortening caused by beta oxidation of the sidechain. This beta oxidation commonly occurs via enzymatic oxidation (e.g., via p450 enzymes), as described in Nat. Comm.11, 208 (2020), which is incorporated herein by reference in its entirety. Without intending to be limited by theory, it is believed that by incorporating one or more substituents at certain position(s) on the ascaroside sidechain of the disclosed compounds , the provided compounds are rendered less susceptible to such oxidation than the corresponding ascaroside. As such, the sidechain shortening commonly observed for ascarosides can be reduced or eliminated in use by replacing at least a portion of the ascaroside to be applied to an organism with a compound as described herein. Application of a compound as described herein to an organism may, in some embodiments, provide for decreased production of metabolites over time than when an unmodified ascaroside is applied to that organism under the same conditions.

[0130] In some embodiments, the rate of metabolism of compounds described herein can bemeasured according to methods known in the art, e.g., as described in described in U.S. Patent Application Publication No 2022 / 0183291; Manohar, M. et al. Nature Communications (2020) 11:208; or Yu, Y. et al. ACS Chem Biol. (2021) 16(6): 1050-1058.

[0131] Advantageously, in certain embodiments, the compounds and / or modifications(s)described herein do not significantly impact the activity of the corresponding ascaroside, e.g., in enhancing plant growth and / or increasing plant resistance to certain pathogens and / or inducing the priming of plant defense responses (which can inhibit pathogenic growth and / or infestation) when applied to the plant. In some embodiments, minimizing the degradation of an ascaroside’s side chain can lead to enhanced potency over time as compared with a corresponding non- modified ascaroside, as a greater proportion of the modified ascaroside is maintained unchanged (in as-applied form) over time. In certain embodiments, compounds as provided herein are thus characterized in that their half-life in an organism contacted with the modified ascaroside is increased relative to the half-life of the corresponding unmodified ascaroside in that organism under the same conditions. This increased half-life can, in some embodiments, extend the beneficial effects of the ascaroside on the organism relative to an unmodified ascaroside (e.g., providing for an extended period of plant growth enhancement and / or an extended period of increased plant resistance to certain pathogens). It will be understood that “half-life” refers to the Page 41 of 63 BUSINESS.32873149.1 409753-017WO (217367) time required for the amount of compound (or unmodified ascaroside) administered to be reduced by half its initial value.

[0132] Further, in certain embodiments, the provided compounds are less susceptible tobiodegradation in the environment (e.g., via microbes in the soil) than corresponding non- modified ascarosides under the same conditions.

[0133] Ascarosides can be obtained from natural sources (e.g., nematodes) or they may beprepared synthetically. Ascarosides and the compounds described herein can also be preparedsynthetically, for example, by converting 1-O-substituted rhamnose to 1-O-substituted ascarylose.An exemplary method of preparing ascarosides includes: providing as a feedstock a 1-O- substituted rhamnose; forming a mono-sulfonate ester at the 3-OH group of the feedstock; and treating the mono-sulfonate ester with a hydride source to form a 1-O-substituted ascarylose. In certain embodiments, forming the mono-sulfonate ester is conducted on a substrate without hydroxyl protecting groups at the 2- or 4-position of the rhamnose feedstock. In certain embodiments, such methods comprise contacting the feedstock with a sulfonating agent (i.e., a sulfonyl halide, sulfonic anhydride or similar reagent) in the presence of a Lewis acid. Specific details regarding the synthesis of 1-O-substituted ascarylose can be found in PCT Application No. PCT / US2021 / 056981 (WO2022 / 024067), which is incorporated herein by reference.

[0134] In certain embodiments, compounds as provided herein have utility as bioactivemolecules. In certain embodiments, provided compounds have utility in agricultural applications. In certain embodiments, provided compounds have utility as modulators of plant defenses, plant growth regulators, pesticides, fungicides, antimicrobrial agents, biostimulants, antivirals, antibacterial agents, antihelminthic agents, pheromones, and the like. In certain embodiments, the present disclosure provides methods of treating a plant with any one of the provided compounds to improve the health of the plant.

[0135] In certain embodiments, provided compounds have utility in pharmaceutical, nutritionalor therapeutic treatments for mammals or other animals. In certain embodiments, provided compounds have utility in the treatment or amelioration of human diseases or health disorders. In certain embodiments, provided compounds have utility as immunomodulators, antibiotics, antiproliferative agents, antihypertensive agents, antiviral agents, and other pharmaceutical uses. In certain embodiments, the present disclosure provides methods of treating an animal with any one of the provided compounds to improve the health or wellbeing of the animal.

[0136] Compounds described herein can be synthesized from an isolated or synthesizedascaroside using known reactions for transformations of functional groups. In other embodiments, the provided compounds may be synthesized from starting materials other than ascarosides—for Page 42 of 63 BUSINESS.32873149.1 409753-017WO (217367) example, a sidechain already functionalized with one or more non-hydrogen substituents at the appropriate position(s) (or a precursor to such one or more non-hydrogen substituents) can be appended to ascarylose or a suitable ascarylose precursor. In some embodiments, an ascaroside or ascaroside precursor (e.g., side chain) can be reacted to halogenate the carbon atom alpha to a terminal carboxylic acid using Hell-Volhard-Zelinksy halogenation conditions. In some embodiments, it may be advantageous, e.g., to employ an ascaroside or ascaroside precursor (e.g., sidechain) with a double bond adjacent to the carboxylic acid or ester, allowing e.g., for reaction via Michael addition to functionalize the alpha and / or beta positions with the desired substituent(s). One of skill in the art will recognize suitable reagents and corresponding reaction conditions to modify ascarosides accordingly to obtain the desired compound(s) described herein.

[0137] The compounds disclosed herein can, in some embodiments, exhibit enhanced physicalproperties as compared with a corresponding ascaroside without the disclosed non-hydrogen substituent on the sidechain. For example, in some embodiments, provided compounds can exhibit greater solubility in certain solvents (e.g., water or organic solvents) than the corresponding ascaroside. This can simplify the preparation of certain formulations. In some embodiments, providing a compound described herein renders it more compatible with certain components of a desired composition, thus stabilizing the composition. In some embodiments, the compounds described herein have improved application characteristics (e.g. enhanced ability to wet or adhere to surfaces such as leaves or skin), enhanced bioavailability, or enhanced uptake (e.g. by a plant, microorganism, or mammal).II. Formulated Compositions

[0138] In another aspect, the present invention provides formulated compositions comprisingagriculturally or therapeutically-useful concentrations one or more of the provided compounds described herein. Such formulated compositions may take a variety of forms. In certain embodiments provided formulated compositions are solid formulations (e.g. powders, granules, tablets, prills, wettable powders, pastes, dusts and the like). In certain embodiments, such solids are soluble (for example in water) and are intended to be dissolved prior to use. In certain embodiments, such solids are suitable for application as solids (e.g. by dusting, mixing with soil etc.) In certain embodiments, provided formulated compositions are liquids (e.g., directly sprayable or dilutable solutions), emulsions, (e.g., emulsion concentrates and diluted emulsions), suspensions, pastes, suspension-emulsion concentrates, and the like). In certain embodiments, provided formulated compositions include encapsulation into polymeric materials, natural or synthetic materials impregnated with active compound and microencapsulations in polymeric Page 43 of 63 BUSINESS.32873149.1 409753-017WO (217367) substances. These compositions can be produced in a known manner, for example, by mixing the modified ascaroside(s) with one or more agronomically acceptable carriers, such as liquid solvents or solid carriers, optionally with the use of additional components including, but not limited to, surfactants, including emulsifiers, dispersants, foam-formers, colorants, processing aids, lubricants, fillers, reinforcements, flame retardants, light stabilizers, ultraviolet radiation absorbers, weather stabilizers, plasticizers, release agents, perfumes, heat-retaining additives (e.g., silica), cross-linking agents, antioxidants, anti-foaming agents, buffers, pH modifiers, compatibility agents, drift control additives, extenders / stickers, tackifiers, plant penetrants, safeners, spreaders, wetting agents, and the like. Where such compositions are intended for application to crops, they may further include one or more additional agriculturally useful products such as fungicides, antimicrobials, plant nutrients, insecticides, miticides, nematacides, herbicides and the like. In some embodiments, the modified ascaroside is combined with other active ingredients, e.g., fungicides as disclosed in International Patent Application Publication No. WO2023 / 230092, which is incorporated by reference in its entirety.

[0139] Methods of preparing solid and liquid compositions for agrichemical use are generallyknown and can be employed according to the present disclosure (where such methods involve incorporating one or more modified ascarosides within such compositions). Compositions according to the present disclosure can, in some embodiments, be in the form of granular material (including dusts, pellets, soluble powders, flowable powders, water-dispersible granules, and the like). In some embodiments, compositions according to the present disclosure can be in liquid form (e.g., solutions, suspensions, or emulsions). In some embodiments, compositions are in the form of a granular material treated with a modified ascaroside- containing liquid. In some embodiments, a composition comprising a modified ascaroside is formed into fibers or filaments and in some such embodiments, a woven or non-woven textile (e.g., film) can be produced therefrom. In some embodiments, a composition as provided herein is pelletized. In some embodiments, a composition as provided herein is in the form of a film, e.g., plastic mulch. Any of the solid compositions provided herein can optionally be coated via methods generally known in the art to delay release of the modified ascaroside.

[0140] In certain embodiments, provided ascaroside derivatives can be utilized in the formulationof time-release formulations such as those disclosed in published PCT application WO 2023212362 the entirety of which is incorporated herein by reference.

[0141] In certain embodiments, provided compositions include salts of the provided ascarosidederivatives according to the methods and compositions disclosed in published PCT application WO 2023220174 the entirety of which is incorporated herein by reference. Page 44 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0142] In certain embodiments provided formulated compositions comprise formulations suitablefor therapeutic use (e.g. for the treatment of animals or humans). Such therapeutic formulations include those suitable for oral administration, injection, topical application, suppositories and the like and may include pharmaceutically acceptable excipients and additives and / or additional therapeutic agents.

[0143] In some embodiments, the present disclosure provides compositions comprising 20% orless by weight of one or more provided compounds. In some embodiments, the present disclosure provides compositions comprising 0.005 wt. % to 0.05 wt. % of one or more provided compounds. Such compositions are further described in WO 2025 / 038824, which is incorporated herein by reference.III. Methods of use

[0144] In some embodiments, provided compounds described herein and compositions containingsuch compounds are useful in agriculture. In certain embodiments, the compounds described herein and compositions containing such derivatives are useful for improving the pathogen resistance, health, vigor, or agricultural yield of plants. Therefore, in one aspect, the disclosure provides methods of treating plants. In certain embodiments, such methods comprise a step of contacting a plant, a seed, the soil surrounding a plant, or the soil in which seeds / seedlings are to be planted, or a solution in which the plant is in contact (e.g., in a hydroponic system) with a composition containing any one or more of the compounds described herein.

[0145] In some embodiments, the compounds described herein is applied to a portion of a plant,e.g., one or more of a root, stem, bark, leaf, seed, and / or flower. Such methods can be conducted at any one or more stages in the life cycle of a plant, e.g., from seed to seedling to growing plant to just prior to or after harvest.

[0146] The disclosed treatment methods can, in some embodiments, protect growing plants in themanner described in U.S. Patent No.10,136,595, which is incorporated by reference herein in its entirety. For example, such methods can enhance pathogen resistance and / or induce or prime one or more plant defense responses (thereby inhibiting pathogen growth and / or infestation) in a plant to (or near) which the modified ascaroside is applied. Pathogens against which the disclosed methods can enhance resistance include, but are not limited to, fungi, oomycetes, bacteria,nematodes, viruses, and insects, e.g., including but not limited to, Pseudomonas syringae,Phytophthora infestans, Blumeria graminis, Heterodera schachtii, Meloidogyne incognita,Meloidogyne hapla, and turnip crinkle virus. Page 45 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0147] The disclosed treatment methods can, in some embodiments, protect growing plants in themanner described in U.S. Patent Application Publication No. US2022 / 0183291, which is incorporated by reference herein in its entirety. For example, such methods can repel nematodes from a plant, or can be taken up by a plant and metabolized to compounds that repel nematodes from the treated plant.

[0148] In certain embodiments, provided compounds and compositions containing suchcompounds may be used to mitigate or prevent the proliferation of human pathogens on fruit, fresh produce and edible sprouts and / or extend the storage life of fruit or fresh produce. The disclosed treatment methods can in some embodiments be used according to methods disclosed in published PCT application numbers WO2023115054 and WO2023196636 the entirety of both of which are hereby incorporated herein by reference.

[0149] The exact method by which a plant or soil is treated with a compound described herein isnot particularly limited. Treatment of plants and / or soil according to the present disclosure can be carried out, e.g., by immersion, spraying, evaporation, fogging, scattering, painting on, side dressing, or in-furrow application. For example, in certain embodiments, plants or soil can be sprayed with a suitable liquid composition, a solid plastic mulch composition can be applied on soil around plants, and / or a granular composition can be provided for in-furrow application or side-dressing.

[0150] The type of plants that can be treated according to the presently disclosed methods is notparticularly limited and can be, for example, fruit and vegetable plants, turfgrass, trees, and shrubs. Non-limiting examples of plants that can be treated according to the disclosed methods include, but are not limited to, plants selected from the group consisting of tobacco, Arabidopsis, tomato, barley, potato, sweet potato, yam, cotton, soybean, strawberry, sugar beet, corn, rice, wheat, rye, oat, sorghum, millet, bean, pea, apple, banana, pear, cherry, peach, plum, apricot, almond, grape, kiwi, mango, melon, papaya, walnut, hazelnut, pistachio, raspberry, blackberry, loganberry, blueberry, cranberry, orange, lemon, grapefruit, tangerine, lettuce, carrots, onions, broccoli, cabbage, avocado, cocoa, cassava, cotton, and flax.

[0151] In the methods provided herein, provided compounds can be directly applied to the plantand / or soil or can be formulated into a composition that can be applied to the plant and / or soil. As such, the present disclosure provides compositions that generally comprise at least one modified ascaroside and one or more inert ingredients, e.g., one or more agronomically acceptable carriers. It is preferred that non-toxic carriers be used in the methods of the present disclosure. The provided compound-containing compositions provided herein can be in various forms, including solid and liquid forms. Page 46 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0152] The term “agronomically acceptable carrier” includes any carrier suitable foradministration to a plant or soil, e.g., customary excipients in formulation techniques, such as used to form solutions (e.g., directly sprayable or dilutable solutions), emulsions, (e.g., emulsion concentrates and diluted emulsions), wettable powders, suspensions, soluble powders, powders, dusts, pastes, soluble powders, granules, suspension-emulsion concentrates, encapsulation into polymeric materials, coatable pastes, natural and synthetic materials impregnated with active compound and microencapsulations in polymeric substances. These compositions can be produced in a known manner, for example, by mixing the modified ascaroside(s) with one or more agronomically acceptable carriers, such as liquid solvents or solid carriers, optionally with the use of additional components including, but not limited to, surfactants, including emulsifiers, dispersants, foam-formers, colorants, processing aids, lubricants, fillers, reinforcements, flame retardants, light stabilizers, ultraviolet radiation absorbers, weather stabilizers, plasticizers, release agents, perfumes, heat-retaining additives (e.g., silica), cross-linking agents, antioxidants, anti- foaming agents, buffers, pH modifiers, compatibility agents, drift control additives, extenders / stickers, tackifiers, plant penetrants, safeners, spreaders, wetting agents, and the like.

[0153] In some embodiments, the provided compound is the only active agent within thecomposition. In some embodiments, the composition includes one or more additional ascarosides (e.g., an ascaroside, an ascaroside derivative, another modified ascaroside, or another compound described herein). In some embodiments, one or more other active agents are included within the composition (e.g., one or more pesticides, fungicides, antibacterial compounds, herbicides fertilizers, etc.). In some embodiments, the provided compound is combined with other active ingredients, e.g., fungicides as disclosed in International Patent Application Publication No. WO2023 / 230092, which is incorporated by reference in its entirety. In some embodiments, the present disclosure provides methods of enhancing activity of other active ingredients, e.g., fungicides as disclosed in International Patent Application Publication No. WO2023 / 230092, comprising co-administering to a plant, plant part, or soil surround the plant or plant part, the fungicide and one or more provided compounds.

[0154] In some embodiments, the present disclosure provides methods of reducing the phytotoxicside effects of other active ingredients on crop plants, comprising administering one or more provided compounds and one or more other active ingredients. In some embodiments, provided methods result in reduced phytotoxic side effects on crop plants as compared to phytotoxic side effects on plants associated with application of the herbicide alone.

[0155] In some embodiments the other active ingredients are selected from fungicides,insecticides, fertilizers, e.g., as disclosed in WO 2024 / 254180, the entirety of which is Page 47 of 63 BUSINESS.32873149.1 409753-017WO (217367) incorporated herein by reference. In some embodiments the other active ingredients are selected from herbicides, e.g., as disclosed in WO 2025 / 006909, the entirety of which is incorporated herein by reference. In some embodiments, the other active ingredients are selected from insecticides, e.g., as disclosed in WO 2025 / 109329, the entirety of which is incorporated herein by reference.

[0156] In some embodiments, the present disclosure provides composition comprising one ormore provided compounds and one or more other active ingredients, characterized in that application of the composition to a plant results in less phytotoxicity than an application of an equivalent composition without the one or more provided compounds.

[0157] In some embodiments the other active ingredients are selected from fungicides,insecticides, fertilizers, e.g., as disclosed in WO 2024 / 254180, the entirety of which is incorporated herein by reference. In some embodiments the other active ingredients are selected from herbicides, e.g., as disclosed in WO 2025 / 006909, the entirety of which is incorporated herein by reference. In some embodiments, the other active ingredients are selected from insecticides, e.g., as disclosed in WO 2025 / 109329, the entirety of which is incorporated herein by reference.

[0158] In some embodiments, the present disclosure provides methods of providing nutrients andprotection against pathogens to a plant, comprising contacting a plant, a plant part, or soil surrounding a plant with one or more plant nutrients, e.g., as described in WO 2025 / 024509, the entirety of which is incorporated herein by reference, and one or more provided compounds. In some embodiments, the present disclosure provides methods of providing nutrients and protection against pathogens to a plant, comprising contacting a plant, a plant part, or soil surrounding a plant with one or more plant nutrients, e.g., as described in WO 2025 / 024509, the entirety of which is incorporated herein by reference, wherein the plant, plant part, or soil surrounding the plant is receiving or has received one or more provided compounds (e.g., via administration to the plant, plant part, or soil surrounding the plant or plant part). In some embodiments, the present disclosure provides methods of providing nutrients and protection against pathogens to a plant, comprising contacting a plant, a plant part, or soil surrounding a plant with one or more provided compounds, wherein the plant, plant part, or soil surrounding the plant is receiving or has received one or more plant nutrients, e.g., as described in WO 2025 / 024509, the entirety of which is incorporated herein by reference (e.g., via administration to the plant, plant part, or soil surrounding the plant or plant part). Page 48 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0159] In some embodiments, the present disclosure provides composition comprising one ormore plant nutrients, e.g., as described in WO 2025 / 024509, the entirety of which is incorporated herein by reference, and one or more provided compounds.

[0160] In some embodiments, the present disclosure provides methods for controlling insectinfestation of a plant, comprising administering to a plant, a plant part, or soil surrounding a plant an insecticide, e.g., as described in WO 2025 / 109329, the entirety of which is incorporated herein by reference, and one or more provided compounds. In some embodiments, the present disclosure provides methods for controlling insect infestation of a plant, comprising administering to a plant, a plant part, or soil surrounding a plant an insecticide, e.g., as described in WO 2025 / 109329, the entirety of which is incorporated herein by reference, wherein the plant, plant part, or soil surrounding the plant is receiving or has received one or more provided compounds (e.g., via administration to the plant, plant part, or soil surrounding the plant or plant part). In some embodiments, the present disclosure provides methods for controlling insect infestation of a plant, comprising administering to a plant, a plant part, or soil surrounding a plant with one or more provided compounds, wherein the plant, plant part, or soil surrounding the plant is receiving or has received an insecticide, e.g., as described in WO 2025 / 109329, the entirety of which is incorporated herein by reference (e.g., via administration to the plant, plant part, or soil surrounding the plant or plant part).

[0161] In some embodiments, the present disclosure provides composition comprising one ormore insecticides, e.g., as described in WO 2025 / 109329, the entirety of which is incorporated herein by reference, and one or more provided compounds.

[0162] If the agronomically acceptable carrier is water, in some embodiments, an organic solventmay be incorporated as an auxiliary liquid solvent. Suitable liquid solvents include, for example, aromatics (e.g., xylene, toluene and alkylnaphthalenes); chlorinated aromatics or chlorinated aliphatic hydrocarbons (e.g., chlorobenzenes, chloroethylenes and methylene chloride); aliphatic hydrocarbons (e.g., cyclohexane); paraffins (e.g., petroleum fractions, mineral and vegetable oils); alcohols (e.g., ethanol, butanol, glycol, propylene glycol and their ethers and esters); ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone) and strongly polar solvents (e.g., dimethylformamide, acetonitrile and dimethyl sulfoxide).

[0163] Suitable solid agronomically acceptable carriers include, for example, ammonium saltsand ground natural minerals (e.g., kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite and diatomaceous earth); ground synthetic minerals (e.g., highly disperse silica, alumina and silicates); crushed and fractionated natural rocks (e.g., calcite, marble, pumice, sepiolite and Page 49 of 63 BUSINESS.32873149.1 409753-017WO (217367) dolomite); synthetic granules of inorganic and organic meals; granules of organic material (e.g., sawdust, coconut shells, maize cobs and tobacco stalks).

[0164] Suitable emulsifiers and foam-formers include, for example, nonionic and anionicemulsifiers (e.g., polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example, alkylaryl polyglycol ethers, alkylsulfonates, alkyl sulphates and arylsulfonates) protein hydrolysates.

[0165] Suitable dispersants include, for example, lignin-sulfite waste liquors and methylcellulose.Tackifiers such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or lattices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, as well as natural phospholipids, such as cephalins and lecithins, and synthetic phospholipids, can be used in the disclosed compositions. Other additives may include, for example, mineral and vegetable oils.

[0166] Colorants such as inorganic pigments, for example, iron oxide, titanium oxide and PrussianBlue, and organic dyestuffs, such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc may also be included in the compositions.

[0167] Methods of preparing solid and liquid compositions for agrichemical use are generallyknown and can be employed according to the present disclosure (where such methods involve incorporating one or more modified ascarosides within such compositions). Compositions according to the present disclosure can, in some embodiments, be in the form of granular material (including dusts, pellets, soluble powders, flowable powders, water-dispersible granules, and the like). In some embodiments, compositions according to the present disclosure can be in liquid form (e.g., solutions, suspensions, or emulsions). In some embodiments, compositions are in the form of a granular material treated with a modified ascaroside- containing liquid. In some embodiments, a composition comprising a modified ascaroside is formed into fibers or filaments and in some such embodiments, a woven or non-woven textile (e.g., film) can be produced therefrom. In some embodiments, a composition as provided herein is pelletized. In some embodiments, a composition as provided herein is in the form of a film, e.g., plastic mulch. Any of the solid compositions provided herein can optionally be coated via methods generally known in the art to delay release of the modified ascaroside.

[0168] In certain embodiments, the compounds described herein and compositions containingsuch derivatives have utility for the treatment of diseases or disorders in animals including the treatment of human diseases and disorders. As such, in certain embodiments, the invention provides pharmaceutical compositions containing one or more compounds as described herein. In Page 50 of 63 BUSINESS.32873149.1 409753-017WO (217367) certain embodiments, the modified ascarosides are useful to formulate compositions and to treat disorders as described in US Patent No. 11,077,151 the entirety of which is hereby incorporated herein by reference.IV. ExamplesAspects of the present disclosure are more fully illustrated by the following examples, which are set forth to illustrate certain aspects of the present disclosure and are not to be construed as limiting thereof.

[0169] Example 1. Synthesis of ascaroside analogs

[0170] Examples 1.1a through 1.1e demonstrate the syntheses of ascaroside analogs havingsubstitution at the alpha and / or beta carbons of the sidechains. Some of these Examples rely on a convergent synthetic approach wherein a sidechain precursor having the desired alpha and / or beta substitution is coupled to a known protected ascarylose precursor using methods described in ACS Chem Biol. 2021 May 21;16(6):1050–1058 (doi: 10.1021 / acschembio.1c00217). A general scheme showing this approach is shown below: sidechain precursor is synthesized from known enantiopure bromo-alcohol 1a-1, which is coupled with the lithium enolate derived from 2-methyl-ethylpropionate. This is followed by desilylation with HF as shown below. The resulting chiral alcohol is then coupled with ascarylose precursor 1-SM-a followed by deprotection to give the desired ascaroside derivative. olefinmetathesis between a protected ascarylose derivative 2-SM-a having a sidechain with a terminal double bond and a sidechain precursor 2-SM-b with a terminal olefin. Metathesis is followed by hydrogenation of the resulting coupled product followed by global deprotection to provide the Page 51 of 63 BUSINESS.32873149.1 409753-017WO (217367) desired ascaroside derivative 1-PD. This sequence is performed using conditions described in ACS Chem Biol. 2021 May 21;16(6):1050–1058 (doi: 10.1021 / acschembio.1c00217), as shown in the scheme below: sidechain precursors are made according to the references shown and then coupled to the olefinic ascarylose precursor 2-SM-a and deprotected as shown above.

[0174] Example 1.1bOH seedlings.

[0179] The products of Examples 1.1a to 1.1e (hereafter referred to as compounds 1a, 1b, 1c, 1d,and 1e) are evaluated in a wheat pathogen assay to assess the potential of these analogs to prevent crop damage caused by a fungal pathogen. Wheat seeds of cv. Louise are planted in potting soil and grown for two weeks in a growth chamber at 26 °C and 23 °C, respectively, with 16 hours of light per day. After two weeks, the plants are sprayed with a 1 µM solution of ascr#18, or 1a, 1b, Page 52 of 63 BUSINESS.32873149.1 409753-017WO (217367) 1c, 1d, or 1e containing 0.1% (v / v) Tween®-20 in water solution, or with a mock solution only containing 0.1% (v / v) Tween®-20.48 hours after treatment, the wheat plants are inoculated with a Bipolaris sorokiniana spore solution (with 15000 spores / mL) and placed in a dark grow tent with high humidity (>80% RH) for 24 hours at 23 °C. Subsequently, the plants are moved to a high humidity environment (>80% RH) at 23 °C and with 12 hours of light and dark per day until fungal infection was visible on the leaves of the mock-treated plants (usually after about four days). Symptoms are evaluated by photographing the infected leaves and processing the images through machine learning image analysis software (Ilastik) to determine the symptomatic areas relative to the total leaf area.

[0180] The infection levels in the treated plants are compared to ascertain the effectiveness of theascaroside analogs in reducing fungal infection in wheat.

[0181] Example 3. Metabolism of ascaroside derivatives in plants.

[0182] Compounds 1a, 1b, 1c, 1d, or 1e are evaluated in alfalfa seedlings to assess whether plantstake up these analogs and to what extent they are metabolized (e.g. to what extent the molecules are beta oxidized and / or chain shortened). The ascr#18 metabolism is evaluated by assaying the plant tissues for the known ascaroside metabolite ascr#9.

[0183] Alfalfa seeds are germinated in the dark on culture plates (10 seeds per plate) containingGelzan growth medium and are allowed to grow for 3-4 days before treatment. Treatment consists of flooding the plates with a 10 µM aqueous solutions of one of the ascaroside analogs 1a, 1b, 1c, 1d, 1e, or with ascr#18 (as a positive control), or with plain water as a mock treatment (5 mL total volume, solutions prepared in MQ water). Each experiment is performed in duplicate. After 24 hours, the plates are moved to an illuminated growth chamber for 4 hours before sampling. Sprouts are collected, thoroughly rinsed with MQ water, dried, flash-frozen, and homogenized. The homogenized tissues are extracted with 100% ethanol and the extracts are analyzed using high- resolution liquid chromatography–mass spectrometry (LC-MS). LC-MS analysis is performed using a Dionex 3000 UPLC coupled with a Thermo Q Exactive high-resolution mass spectrometer equipped with a HESI ion source. To measure ascarosides, samples are chromatographed using an Agilent Zorbax Eclipse column (150 mm x 2.1 mm, particle size 1.98 µm) maintained at 40 °C with a 0.5 mL / min flow rate. Solvent A: 0.1% formic acid in water; Solvent B: 0.1% formic acid in acetonitrile. A solvent mixture using 1% B is used for 1.5 min after injection, followed by a linear gradient up to 99% B at 9.5 min, followed by 0.75 min at 99% B, then back to 1% B over 0.5 min, and finally held at 1% B for an additional 1.25 min to re-equilibrate the column (total time: 12 min, with needle washing and file writing: ~14 min). Mass spectrometer parameters: spray voltage (-3.0 kV or +3.5 kV); capillary temperature 380 °C; probe heater temperature 400 Page 53 of 63 BUSINESS.32873149.1 409753-017WO (217367) °C; sheath, auxiliary, and sweep gas 60, 20, and 2 AU, respectively—S-Lens RF level: 50, resolution 120,000 at m / z 200, AGC target 3E6. Samples are injected and analyzed in negative electrospray ionization mode with an m / z range of 100-1000. Ascr#18 (C17H32O6) ionizes in negative ion mode as C17H31O6, m / z = 331.2126, retention time 6 minutes using the above chromatographic conditions. Samples are also analyzed in positive ionization mode.

[0184] The LCMS results are evaluated and particular attention given to ascaroside analogs thatshow little or none of ascaroside metabolite ascr#9 that would be formed by chain-shortenting metabolism of these analogs.

[0185] Example 4 Metabolism of ascaroside derivatives in plants.

[0186] To evaluate the relative rates of metabolism of the ascaroside derivatives, their rate ofdegradation in a biologically active soil matrix is evaluated. Soil is obtained from an agricultural source, homogenized, and sifted to ensure it is free of pebbles and large debris.0.5 mL of soil is placed into 2 mL centrifuge tubes.0.1 mL of 100 µM aqueous solutions of compounds 1a, 1b, 1c, 1d, 1e or ascr#18 (as a positive control) are placed in the tubes and vortexed briefly to ensure thorough mixing. Samples are made in replicates and kept at room temperature for sampling at different time points. Samples are made in replicate and are processed at 0 h, 6 h, 12 h, 24 h, and 48 h. To extract ascarosides and / or metabolites 0.9 mL of 100% EtOH is added to the centrifuge tube, vortexed briefly and then placed on a shaker for 5 minutes. The tubes are then centrifuged at 13000 rpm for 5 mins. Supernatant (0.1 mL) is removed and placed in a prepared LCMS vial. The relative abundance of the ascarosides and any chain-shortened metabolites are quantified by LCMS using the method described in Example 3.

[0187] It will be appreciated that additional molecules described in embodiments hereinabove canreadily be produced with these methods by utilizing different modified sidechain precursors, and / or other ascarylose derivatives.

[0188] It is contemplated that compounds, compositions, and methods of the present applicationencompass variations and adaptations developed using information from the embodiments described in the present disclosure. Adaptation or modification of the methods and processes described in this specification may be performed by those of ordinary skill in the relevant art.

[0189] It will be appreciated that use of headers in the present disclosure are provided for theconvenience of the reader. The presence and / or placement of a header is not intended to limit the scope of the subject matter described herein. Unless otherwise specified, embodiments located in one section of the application apply throughout the application to other embodiments, both singly and in combination. Page 54 of 63 BUSINESS.32873149.1 409753-017WO (217367)

[0190] Throughout the description, where compositions, compounds, or products are described ashaving, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are articles, devices, and systems of the present application that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present application that consist essentially of, or consist of, the recited processing steps.

[0191] It should be understood that the order of steps or order for performing certain action isimmaterial so long as the described method remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0192] All publications and patent applications mentioned in the specification are indicative ofthe level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0193] Although the foregoing invention has been described in some detail by way of illustrationand example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims. Page 55 of 63 BUSINESS.32873149.1 409753-017WO (217367)

Claims

CLAIMS What is claimed is:

1. A compound of Formula 1:or a salt thereof; wherein: each of Raand Rbis independently -H, or an optionally substituted moiety selected from the group consisting of: C1-20aliphatic, C1-20acyl, C1-20heteroaliphatic, aryl, heteroaryl, a hydroxyl protecting group, a phosphorous-linked functional group, a sulfur-linked functional group, a silicon-linked functional group, a C2-20carbonate (e.g., -a moiety -C(O)ORc), a C2-20carbamate (e.g., -a moiety -C(O)N(Rc)2), a C2-20 thioester (e.g. a moiety -C(S)Rc), a C2-20 thiocarbonate (e.g. a moiety -C(S)ORc), a C2-20dithiocarbonate (e.g. a moiety -C(S)SRc), a C1-20thiocarbamate (e.g. a moiety -C(S)N(Rc)2), a sugar moiety, a peptide, a polymer chain, or a linkage via a bond or a carbon-containing linker moiety to an ascaroside molecule; each Rcis independently at each occurrence selected from -H, optionally substituted C1-12 aliphatic, optionally substituted C1-12 heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, a polymer chain, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule; and where Raand Rbmay be taken together to form an optionally substituted ring, optionally containing one or more heteroatoms, and optionally containing one or more sites of unsaturation; and -Z comprises an optionally unsaturated, optionally substituted C2-40sidechain terminating in a chain end comprising a nitrogen-, oxygen- or sulfur-containing functional group and having at least one non-hydrogen substituent on the carbon atoms that are adjacent to or two atoms away from the chain end. Page 56 of 63 BUSINESS.32873149.1 409753-017WO (217367)2. The compound of claim 1, wherein the compound is of Formula 2: ,or a salt thereof; wherein: Rdis -H, halogen (e.g., -F), or optionally substituted C1-6 aliphatic group; Q is or comprises an oxygen-, nitrogen, or sulfur-containing functional group; n is an integer from 1 to 24; and each A1, A2, B1, and B2is independently selected from hydrogen and a non-hydrogen substituent, where at least one of A1, A2, B1, and B2 is a non-hydrogen substituent.

3. The compound of claim 1 or 2, wherein the compound is of Formula 3:or a salt thereof.

4. The compound of claim 1 or 2, wherein the compound is of Formula 4:or a salt thereof. Page 57 of 63 BUSINESS.32873149.1 409753-017WO (217367)5. The compound of claim 1 or 2, wherein the compound is of Formula 5:or a salt thereof.

6. The compound of any one of claims 2-5, wherein Q is: a carboxylic acid, an aldehyde, or an ester; or an amide, amidine, oxime, imine, guanidine, urea, carbamate or carbamate group; a thioester, dithioester, thioamide, thiocarbonate, dithiocarbonate, trithiocarbonate, thiocarbamate, dithiocarbamate, thionate, sulfoxide, or sulfone.

7. The compound of any one of claims 2-6, wherein Q is -CON(R3)2, wherein each R3is independently -H, an optionally substituted C1-20 aliphatic group, an optionally substituted C1-20 heteroaliphatic group, an optionally substituted aromatic group, an optionally substituted heteroaryl group, a polymer chain, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule, and where both R3groups can be taken together to form an optionally substituted, optionally unsaturated ring optionally containing one or more additional heteroatoms.

8. The compound of claim 7, wherein each R3is independently selected from -H and C1-8aliphatic.

9. The compound of any one of claims 2-6, wherein Q is -C(O)SR2, wherein R2is -H, a metal cation, an organic cation, an optionally substituted C1-20aliphatic group, an optionally substituted C1-20heteroaliphatic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a glycoside, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule. Page 58 of 63 BUSINESS.32873149.1 409753-017WO (217367)10. The compound of claim 9, wherein R2is -H, an optionally substituted C1-20aliphatic group, an optionally substituted C1-20 heteroaliphatic group, or an optionally substituted aryl group, an optionally substituted heteroaryl group.

11. The compound of any one of claims 2-6, wherein Q is C(S)N(R3)2, wherein R3is independently -H, an optionally substituted C1-20 aliphatic group, an optionally substituted C1-20 heteroaliphatic group, an optionally substituted aromatic group, an optionally substituted heteroaryl group, a polymer chain, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule, and where both R3groups can be taken together to form an optionally substituted, optionally unsaturated ring optionally containing one or more additional heteroatoms.

12. The compound of claim 11, wherein each R3is independently selected from -H and C1-8 aliphatic.

13. The compound of claim 2, having a formula selected from:R2is -H, a metal cation, an organic cation, an optionally substituted C1-20 aliphatic group, an optionally substituted C1-20heteroaliphatic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a glycoside, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule.

14. The compound of claim 2, having a formula selected from:Page 59 of 63 BUSINESS.32873149.1 409753-017WO (217367)R2is -H, a metal cation, an organic cation, an optionally substituted C1-20aliphatic group, an optionally substituted C1-20 heteroaliphatic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a glycoside, an amino acid, a peptide, a nucleotide, or a linkage via a bond or a carbon-containing linker moiety to another ascaroside molecule.

15. The compound of claim 13 or 14, wherein R2is -H, an optionally substituted C1-20 aliphatic group, an optionally substituted C1-20heteroaliphatic group, or an optionally substituted aryl group, an optionally substituted heteroaryl group.

16. The compound of any one of claims 2-15, wherein two or more of A1, A2, B1, and B2 may be taken together to form an optionally substituted 4- to 12- membered monocyclic or bicyclic saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

17. The compound of any one of claims 2-15, wherein A1, A2, B1, and B2 are other than - OH, =O, or epoxy.

18. The compound of any one of claims 2-15, wherein each of A1, A2, B1, or B2is independently a non-hydrogen substituent selected from an optionally substituted C1-12 aliphatic substituent, an optionally substituted C1-12heteroaliphatic substituent, an optionally substituted C1-12 alkoxy substituent or a halogen substituent.

19. The compound of any one of claims 2-15, wherein each of A1, A2, B1, or B2 is independently a non-hydrogen substituent selected from an optionally substituted alkyl (e.g., -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3), an optionally substituted heteroalkyl, or a halogen (e.g., F, Cl, Br, or I).

20. The compound of any one of claims 2-15, wherein each of A1, A2, B1, or B2 is independently selected from hydrogen, methyl, or fluoro.

21. The compound of any one of claims 13-20, wherein R2is hydrogen or methyl.

22. The compound of any one of claims 2-21, wherein each of Raand Rbis independently selected from hydrogen or an optionally substituted C1-6 aliphatic. Page 60 of 63 BUSINESS.32873149.1 409753-017WO (217367)23. The compound of any one of claims 2-21, wherein Raand Rbare both -H.

24. A method of modifying an ascaroside to increase its half-life, the ascaroside comprising a fatty acid-derived sidechain linked to ascarylose via a glycosidic bond and having a carboxylic acid or ester group at the sidechain end, comprising incorporating a non- hydrogen substituent on one or both sp3 carbon atoms alpha or beta to the carboxylic acid or ester group to give the compound of any one of claims 1-23.

25. The method of claim 24, comprising reacting an ascaroside with a reagent that provides the non-hydrogen substituent on one or both sp3 carbon atoms alpha or beta to the carboxylic acid or ester group to provide the compound of any one of claims 1-23.

26. The method of claim 24, comprising reacting an ascaroside precursor with a reagent to provide a substituted precursor; and further reacting the substituted precursor to provide the compound of any one of claims 1-23.

27. A method of treating an organism, comprising contacting the organism with the compound of any of claims 1-23.

28. The method of claim 27, wherein the organism is a plant.

29. The method of claim 27, wherein the organism is a human.

30. A method of extending half-life of an ascaroside in an agricultural setting, comprising: applying the compound of any of claims 1-23 in place of at least a portion of ascaroside to be applied in the agricultural setting.

31. A method of mitigating or preventing the proliferation of human pathogens on fruit, fresh produce, or edible sprouts and / or extend the storage life of fruit or fresh produce comprising treating plants or seeds that produce such fruit, fresh produce or edible sprouts with a compound of any one of claims 1-23. Page 61 of 63 BUSINESS.32873149.1 409753-017WO (217367)32. A method of enhancing activity of other active ingredients comprising co-administering to a plant, plant part, or soil surrounding the plant or plant part, the other active ingredients and a compound of any one of claims 1-23. Page 62 of 63 BUSINESS.32873149.1 409753-017WO (217367)

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