ITACONATE AND METHYL ITACONATE PRODRUGS

Abstract

Itaconic acid and 1- and 4-methyl itaconic acid prodrugs are revealed and used to treat a disease / disorder associated with inflammation.

Description

ITACONATE AND METHYL ITACONATE PRODRUGS GOVERNMENT-SPONSORED DEVELOPMENT OR RESEARCH The present invention was made with government support through grants AR068280 and AR064297 awarded by the National Institutes of Health. The government holds certain rights in the invention. BACKGROUND Inflammatory macrophages show considerable accumulation of itaconate, which has been shown to exert profound anti-inflammatory activity by inhibiting succinate dehydrogenase and inducing electrophilic stress that activates NRF2-dependent antioxidant responses. Given its charged nature, however, itaconate itself does not exhibit good pharmacokinetic or cell permeation properties. Thus, the therapeutic potential of exogenous itaconate administration has not yet been realized. SUMMARY The subject matter disclosed herein provides prodrugs of itaconic acid and 1- and 4-methylitaconic acid and their use for treating a disease, disorder, or condition associated with inflammation. More particularly, in some respects, the subject matter disclosed herein provides a compound of formula (I): I heard); in which: Ri and R2 can be the same or different, and each is selected independently from one or more of the following and combinations thereof: (a) -OR3, wherein R3 is H or linear or branched C1-C6 alkyl substituted or unsubstituted; or (b)v / n, wherein n is an integer selected from 1, 2, 3 and 4; R4 is substituted or unsubstituted linear or branched C1-C6 alkyl or -ORs, wherein Rs is substituted or unsubstituted linear or branched Ci-Oθ alkyl; ^oR6(c) mp , wherein m is an integer selected from 1, 2, and 4; p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; and Re is H or linear or branched substituted or unsubstituted Ci-Ce alkyl; A(d), where R7 is selected from: (i) -C(=O)-O-R8, wherein Rs is a linear or branched Ci-Ce alkyl substituted or unsubstituted; O y^A0-Ri°Rl2Rl1\ ,nr9(¡i)Ri3 ° , wherein R9 is H or linear or branched C1-C4 alkyl substituted or unsubstituted; R10 is linear or branched Ci-Ce alkyl substituted or unsubstituted; Rn and R12 are each independently H or a protecting group; and R13 is linear or branched Ci-Ce alkyl substituted or unsubstituted; (iii)Ri5q, in which q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Rn and R12 are each independently H or a protecting group; R14 is H or linear or branched C1-C4 alkyl substituted or unsubstituted; and R15 is H or linear or branched C1-C6 alkyl substituted or unsubstituted; I R18 (iv) NR16R17,en|aqUer16y r17 seseleccionan cada uno independientemente entre H, unsubstituted or substituted linear or branched chain C1-C4 alkyl, and a protecting group; Ríe es aryl; , F19(e) O0θη where R19 is a linear or branched C1-C4 alkyl substituted or unsubstituted; aZ (f) , in which u is an integer selected from 1, 2, 3 and 4; R20 is H or linear or branched C1-C4 alkyl substituted or unsubstituted; and R21 is -OR22, wherein R22 is linear or branched C1-C6 alkyl substituted or unsubstituted or -NR23R24, wherein R23 and R24 are each independently H or linear or branched C1-C4 alkyl unsubstituted or substituted; provided that R1 and R2 cannot both be -OH or both -OR3 at the same time; and pharmaceutically acceptable salts thereof. In other respects, the subject matter disclosed herein provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In other respects, the subject matter disclosed herein provides a method for treating a disease, disorder, or condition associated with inflammation, the method comprising administering to a subject in need of treatment a compound of formula (I) or a pharmaceutical composition thereof. Certain aspects of the subject matter disclosed herein, as indicated above, are addressed in whole or in part within the subject matter disclosed herein. Other aspects will become apparent as the description progresses when considered in conjunction with the accompanying examples and drawings, as best described herein below. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one color drawing. The Office will provide copies of this patent or patent application publication with color drawings upon request and payment of the applicable fee. Having therefore described the subject matter disclosed in this document in general terms, reference will now be made to the attached figures, which are not necessarily drawn to scale and in which: Figure 1 shows the stability in mouse plasma for the representative prodrugs; Figure 2 shows the release of active monomethyl itaconate (in plasma) from representative prodrugs; and Figure 3 shows the release of active itaconic acid (in plasma) from representative prodrugs. DETAILED DESCRIPTION The subject matter disclosed herein shall be described more fully hereafter with reference to the accompanying figures, which show some, but not all, embodiments of the inventions. Similar numbers refer to similar elements throughout this document. The subject matter disclosed herein can be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein; rather, these embodiments are provided so as to satisfy applicable legal requirements for this disclosure.In fact, many modifications and other embodiments of the subject matter of this disclosure will occur to a person skilled in the art to which the subject matter belongs, who has benefited from the teachings presented in the preceding descriptions and associated figures. It should therefore be understood that the subject matter disclosed herein is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. I. NEW ITACONATE AND METHYL ITACONATE PRODRUGS Inflammatory macrophages exhibit considerable accumulation of itaconate, which has been shown to exert profound anti-inflammatory activity by inhibiting succinate dehydrogenase and inducing electrophilic stress that activates NRF2-dependent antioxidant responses. Given its charged nature, however, itaconate itself does not exhibit good pharmacokinetic or cell permeation properties. Given the profound therapeutic potential of exogenous itaconate administration, the subject matter disclosed herein provides prodrugs of both itaconic acid and 1- and 4-methyl-itaconic acid, which have the ability to achieve enhanced cell permeation and release active itaconic acid and the respective methyl itaconate after oral, systemic, or topical / local administration. The prodrugs disclosed herein also exert anti-inflammatory effects on keratinocytes. A. Representative Compounds of Formula (I) In some embodiments, the object material disclosed herein provides a compound of formula (I): EITHER in which: Ri and R2 can be equal or different, and each is selected independently from one or more of the following and combinations thereof: (a) -OR3, wherein R3 is H or linear or branched Ci-Ce alkyl substituted or unsubstituted; or r4(b) 'n, where n is an integer selected from 1, 2, 3 and 4; R4 is linear or branched Ci-Ce alkyl substituted or unsubstituted or -ORs, wherein Rs is linear or branched C1-C6 alkyl substituted or unsubstituted; (c) mp θη where m is an integer selected from 1, 2, and 4; p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; and Rs is linear or branched Ci-Ce alkyl substituted or unsubstituted; (d) , in which R7 is selected from: (i) -C(=O)-O-R8, wherein Rs is a substituted or unsubstituted linear or branched C1-C6 alkyl; R12RuN R10 NRg Rl3 θ, wherein R9 is H or linear or branched C1-C4 alkyl substituted or unsubstituted; Rio is linear or branched Ci-Ce alkyl substituted or unsubstituted; Rn and R12 are each independently H or a protecting group; and R13 is H or linear or branched Ci-Ce alkyl substituted or unsubstituted; N R11R12 R^N^^O (iii)Ki5, wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; R11 and R12 are each independently H or a protecting group; R14 is H or linear or branched C1-C4 alkyl substituted or unsubstituted; and R15 is H or linear or branched Ci-Ce alkyl substituted or unsubstituted; I R18 (iv) nr16r17 en|aqUer16y r17 each is independently selected from H, unsubstituted or substituted linear or branched C1-C4 alkyl, and a protecting group; Ríe is aryl; Z Γ19(e) or , wherein R19 is a substituted or unsubstituted linear or branched C1-C4 alkyl; fN ύZ (f) where u is an integer selected from 1, 2, 3 and 4; R20 is H or linear or branched C1-C4 alkyl substituted or unsubstituted; and R21 is -OR22, wherein R22 is linear or branched C1-C6 alkyl substituted or unsubstituted or -NR23R24, wherein R23 and R24 are each independently H or linear or branched C1-C4 alkyl unsubstituted or substituted; provided that R1 and R2 cannot both be -OH or both -OR3 at the same time; and pharmaceutically acceptable salts thereof. In certain embodiments of the compound of formula (I): or (a) R1 is -OR3 and R2 is selected from -OR3, 'n in which R7 is selected from -C(=O)-O-Rs, in which R? is selected from -C(=O)-O-Rs, Ri is ^o-(^4moHRey R2 is selected from -OR3, in which R? is selected from -C(=O)-O-R8, Ri es , in which R? is -C(=O)-O-Rs and R2 is selected between Re, ^20R21 Rio the one that R7selects between -C(=O)-O-Re, - y R12R11N nr9 R13 or (h) R1 is O by R7 R.5^ r R18 NRl6R17 R7, in which R7es and R2 is selected M R7 knows that (i) R1 is O r7, in which R7es R AR15M select r R18 NR16R17 between -C(=O)-O-Rs, O r R18 NR16Ri7y R2 is selected O between -OR3,v / n,ü selects between -C(=O)-O-Rs, provided that Ri and R2 cannot both be -OH or both -OR3 at the same time; and pharmaceutically acceptable salts thereof. In more specific embodiments of the compound of formula (I): C(=O)-O-Rs; , in which R7 is - , in which R7 is selected from -C(=O)-O-R8, r4(b) Ri is / n and R2 is selected from: -OR3, R6 OR3; (c) R1 is (d) Ri (e) R1 is is (g) R1 and R2 is -OR3; (f) R1 , where R7 is -C(=O)-O-Rs and R2 is -OR3; , or RA , in which R7 is ri5 and R2 is -OR3; In some embodiments of the compound of formula (I), R3, R4, Rs, Re, Rs, R9, R10, R13, R15 and R22 may each independently be a substituted or unsubstituted linear or branched C1, C2, C3, C4, C5 or Ce alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In some embodiments of the compound of formula (I), R9, R14, R17, R19, R20, R23 and R24 may each independently be a substituted or unsubstituted linear or branched C1, C2, C3 or C4 chain alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl and t-butyl. Representative substituent groups include, but are not limited to, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, mercapto, and alkylthio. In certain embodiments of the compound of formula (I), the protecting group is selected from tert-butoxycarbonyl (boc), carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), 9-fluorenylmethyloxycarbonyl group (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), Troc (trichloroethyl chloroformate), (4-nitrophenyl)sulfonyl (nosilo), and nitrophenylsulfenyl (Nps). In particular embodiments, the protecting group is fert-butoxycarbonyl (boc). In some embodiments of the compound of formula (I), Ris is selected from phenyl. In certain embodiments of the compound of formula (I): (ai) Ri is -OH and R2 is selected from: (a-¡¡) R1 is selected from -OCH3, -OCH(CH3)2 and -OC(CH3)3 and R2 is (c) R1 is O and R2es -0CH3 (12, 13); (27); (d) Ri is and R2 is selected from: -OCH3 (11) and and R2 is -OCH3 (14); (e) R1 is In certain embodiments of the compound of formula (I), the compound is In certain embodiments, the compound of formula (I) comprises a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is an acid salt. In particular embodiments, the pharmaceutically acceptable salt is trifluoroacetate (TFA). Representative compounds of formula (I) and the active agent released by each respective prodrug are provided in Table 1._________________________ Table 1. Prodrugs of itaconic acid and methyl itaconate 0 R <Vr Comp. Estructura Resto liberado Ri r2 Ácido itacónico (1) 0 -vr HO- -OH IS-100- 127 (2) 0 H U(TO Itaconato HO- H O^o IS0100- 128 (3) o o / 4-MP ( o -OCH3 Table 1. Prodrugs of itaconic acid and methyl itaconate 0 Comp. Structure Released Ri r2 IS-100- 129 (4) 0 Óó 4-MI hna H2A^ o -och3 IS-100- 142 (5) 4-MI IA -och3 IS-100- 143 (6) O 0 4-1^MI 0 0 >Ο 146 (7) Ithaconate 0 IS-100- 147 (8) 11 0 0 Ithaconate HO- νο^ΟγΑ o IS-100- 148 (9) 0 0 I 1 11 0 0 Ithaconate 0 A^o-0^oA 14 aA O 0 1 Ithachonato i 0 I n \ O qA O . LTP-1025 (11) \ 0 °A 4-MI ( O Ύ o -och3 Table 1. Prodrugs of itaconic acid and methyl itaconate RO -Vf Comp. Structure Rest released R1 R2 MK-933 (12) 0 AY 4-MI _^^0A 15 -och3 MK-937 (13) ω q M djo / 4-MI .^¿4ολ J13 J2 -OCH3 MK-939 MK0-4-MI (14-4) 0 (15) BocHN 4-MI BocHN °γ Ol \ \|^NH -OCH3 MK-941 (16) h2n A^°Ví°' 4-MI h2n a χ^,ΝΗ -OCH3 MK-942 (17) I 0 BocHN 4-BOMICH ao ΑΑθΑ — -OCH3 MK-943 (18) Q c rf o < o / 4-MI c 0 coAm \ NHBoc^ / ^Ox' -OCH3 MK-944 (19) I 0 η,ν nh —¢-Πa 11 0 / ο 4-MI A\ -OCH3 MK-945 (20) / 0 0 -p 0 b 4-MI 0 A Voa -OCH3 Table 1. Prodrugs of itaconic acid and methyl taconate 0 Comp. Structure Released residue Ri R2 IS-101- 088 (21) 11 0 0 1 1-MI* CH3O- [f 0 22 11 oo 1 Ithaconate HO- 0 1 IS-101- 089 (23) 1-MI CH30 / > γγγ 1-MI CH3O- ^NH 26 0 o ''1 1-MI CH3O- X-„, NH 27 Itaconate Y 0 O c>\ cy 28 0 '“Yy0# 1-MI CH3O- °yo yO^Jw^0 29 0 1-MI H ^5 I<0ta CHV30°- 1 Table 1. Prodrugs of itaconic acid and methyl itaconate Comp. Structure Remainder released Ri R2 31 0 r II q LJ 2 13 1-MI CH3O- y°H°# i- b L -113 32 0 1-MI CH3O- 33 0 -“Vr0^ Itaconate HO- 34 ΑτιχΥ NHBoc 1-MI CH3O- ΗνΉ> NHBoc 35 'Αν-η nh2 1-MI CH3O- HN^ NH? 36 0 Vl· ^Vv0^ HN NHBoc OI 1-MI CH3O- 0 2— \ Y η HN NHBoc 0 । 37 / oo ¡' ° o 8 b 1-MI CH3O- q 0 °x or 38 0 ib HN NH o '; 1-E CH3O- ° y— / \ Y η η HN nh2 0 । IS-102- 081 0 0 I 1-MI CH3O- \ / οχ / ο\ / ο\χ^ < ϊ χ 0 1 14-MI refers to 4-methyl itaconate; φ 1-MI refers to 1-methyl itaconate Even in other embodiments, the subject matter disclosed herein provides a method for treating a disease, disorder, or condition associated with inflammation, the method comprising administering to a subject in need of treatment a compound of formula (I) or a pharmaceutical composition thereof. As used herein, the term "treat" may include reversing, alleviating, inhibiting the progression of, preventing, or reducing the likelihood of the disease, disorder, or condition to which the term applies, or one or more symptoms or manifestations of such disease, disorder, or condition. "Prevent" refers to avoiding the occurrence of a disease, disorder, condition, or symptom or manifestation thereof, or the worsening of its severity. Accordingly, the compounds disclosed herein may be administered prophylactically to prevent or reduce the incidence or recurrence of the disease, disorder, or condition. The term "subject treated by the methods disclosed herein in their various embodiments" is, ideally, a human subject, although it is understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included under the term "subject." Accordingly, a subject may include a human subject for medical purposes, such as for the treatment of an existing condition or disease or prophylactic treatment to prevent the onset of a condition or disease, or an animal subject for medical, veterinary, or developmental purposes.Suitable animal subjects include mammals, including, but not limited to, primates, e.g., humans, monkeys, apes and the like; bovines, e.g., cattle, oxen and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, wild boars and the like; equines, e.g., horses, donkeys, zebras and the like; Felines, including wild and domestic cats; canids, including dogs; lagomorphs, including rabbits, hares, and similar animals; and rodents, including mice, rats, and similar animals. An animal may be a transgenic animal. In some embodiments, the subject is a human being, including, but not limited to, fetal, neonatal, juvenile, and adult subjects. Likewise, a subject may include a patient affected by, or suspected of being affected by, a condition or disease. Thus, the terms subject and patient are used interchangeably herein. The term subject refers to an organism, tissue, cell, or group of cells within a subject. In general, the effective dose of an active agent or drug delivery device refers to the amount required to elicit the desired biological response. As those familiar with the technique will appreciate, the effective dose of an agent or device can vary depending on factors such as the desired biological endpoint, the agent being delivered, the formulation of the pharmaceutical composition, the target tissue, and similar considerations. The term "combination" is used in its broadest sense and means that a subject is administered at least two agents, more particularly a compound of formula (I) and at least one beta-lactam antibiotic and, optionally, one or more antibacterial agents. More particularly, the term "in combination" refers to the concomitant administration of two (or more) active agents for the treatment of, for example, a single disease state. As used herein, the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same day or on separate days. In one embodiment of the subject matter disclosed herein, the active agents are combined and administered in a single dosage form.In another embodiment, the active agents are administered in separate dosage forms (for example, when it is desirable to vary the amount of one but not the other). The single dosage form may include additional active agents for the treatment of the pathological condition. Furthermore, the compounds of formula (I) described herein may be administered alone or in combination with adjuvants that enhance the stability of the compounds of formula (I), alone or in combination with one or more antibacterial agents, facilitate the administration of the pharmaceutical compositions containing them in certain embodiments, provide greater dissolution or dispersion, increase inhibitory activity, provide complementary therapies, and similar purposes, including other active ingredients. Advantageously, such combination therapies utilize lower doses than conventional therapies, thus avoiding the potential toxicity and adverse side effects that occur when these agents are used as monotherapies. The timing of administration of a compound of formula (I) and at least one additional therapeutic agent may vary, provided that the beneficial effects of the combination of these agents are achieved. Accordingly, the expression "in combination with" refers to the administration of a compound of formula (I) and at least one additional therapeutic agent simultaneously, sequentially, or in combination. Therefore, a subject administered a combination of a compound of formula (I) and at least one additional therapeutic agent may receive the compound of formula (I) and at least one additional therapeutic agent at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in any order, on the same day or on different days), provided that the effect of the combination of both agents is achieved in the subject. When administered sequentially, the agents may be administered with an interval of 1, 5, 10, 30, 60, 120, 180, 240 minutes or more. In other embodiments, the sequentially administered agents may be administered with an interval of 1.5, 10, 15, 20 or more days. When the compound of formula (I) and at least one additional therapeutic agent are administered simultaneously, they may be administered to the subject as separate pharmaceutical compositions, each comprising one compound of formula (I) or at least one additional therapeutic agent, or they may be administered to a subject as a single pharmaceutical composition comprising both agents. When administered in combination, the effective concentration of each agent to elicit a particular biological response may be lower than the effective concentration of each agent when administered alone, thus allowing for a reduction in the dose of one or more agents compared to the dose that would be required if the agent were administered as a single agent. The effects of multiple agents may, but are not necessarily, additive or synergistic. The agents may be administered multiple times. In some embodiments, when administered in combination, the two or more agents may have a synergistic effect. As used herein, the terms synergy, synergistic, synergistically, and derivatives thereof, such as in a synergistic effect, a synergistic combination, or a synergistic composition, refer to circumstances in which the biological activity of a combination of a compound of formula (I) and at least one additional therapeutic agent is greater than the sum of the biological activities of the respective agents when administered individually. Synergy can be expressed in terms of a synergy index (SI), which can generally be determined using the method described by FC Kull et al., Applied Microbiology 9, 538 (1961), based on the relationship determined by: Qa / QA + Qó / Qb = synergy index (SI) where: Qa is the concentration of a component A, acting alone, that produced an endpoint relative to component A; Qa is the concentration of component A, in a mixture, that produced an endpoint; Qb is the concentration of a component B, acting alone, that produced an endpoint relative to component B; and Qb is the concentration of component B, in a mixture, that produced an endpoint. Generally, when the sum of Q3 / Qa and Qb / QB is greater than one, antagonism is indicated. When the sum equals one, additivity is indicated. When the sum is less than one, synergism is demonstrated. The lower the IS, the greater the synergy exhibited by that particular mixture. Thus, a synergistic combination has a higher activity than would be expected based on the observed activities of the individual components when used alone. Similarly, a synergistically effective amount of a component refers to the amount of that component required to produce a synergistic effect on, for example, another therapeutic agent present in the composition. In another embodiment, the subject matter disclosed herein provides a pharmaceutical composition comprising a compound of formula (I) alone or in combination with one or more additional therapeutic agents mixed with a pharmaceutically acceptable excipient. A person skilled in the art will recognize that pharmaceutical compositions include pharmaceutically acceptable salts of the compounds described above. Pharmaceutically acceptable salts are generally well known to those skilled in the art and include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituent residues found in the compounds described herein.When the compounds in this disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent, or by ion exchange, whereby one basic counterion (base) in an ionic complex is replaced by another. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or a similar salt. When the compounds in this disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient quantity of the desired acid, either pure or in a suitable inert solvent, or by ion exchange, whereby one acid counterion (acid) in an ionic complex is replaced by another.Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrophosphoric, dihydrophosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, italic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids, such as arginate and the like, and salts of organic acids such as glucuronic or galacturonic acids, and the like (see, for example, Berge et al., Pharmaceutical Salts). Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds in this disclosure contain both basic and acidic functionalities that allow the compounds to be converted into addition salts of both bases and acids. Accordingly, pharmaceutically acceptable salts suitable for use with the subject matter disclosed herein include, by way of example but not limitation, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsilate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or theoclate. Other pharmaceutically acceptable salts can be found in, for example, Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).In therapeutic and / or diagnostic applications, the compounds disclosed can be formulated for various modes of administration, including systemic and topical or localized administration. Techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy (20th ed.) and Lippincott, Williams & Wilkins (2000). Depending on the specific conditions being treated, these agents may be formulated in liquid or solid dosage forms and administered systemically or locally. The agents may be administered, for example, in a controlled or sustained-release form, as is known to those skilled in the technique. Techniques for formulation and administration can be found in Remington: The Science and Practice of Pharmacy (20th ed.) and Lippincott, Williams & Wilkins (2000). Appropriate routes may include oral, buccal, inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral administration, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal or infraocular injections or other modes of administration. For injection, the disseminating agents can be formulated and diluted in aqueous solutions, such as physiologically compatible buffers like Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, appropriate penetrants are used in the formulation to determine the barrier to be permeated. These penetrants are generally known in the art. The use of pharmaceutically acceptable inert vehicles to formulate the compounds disclosed herein for the purposes of this disclosure in doses suitable for systemic administration is within the scope of this disclosure. With appropriate vehicle selection and manufacturing practices, the compositions in this disclosure, particularly those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds may be readily formulated using pharmaceutically acceptable vehicles well known in the art with dosages suitable for oral administration. Such vehicles allow the compounds in this disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, pastes, suspensions, and the like, for oral ingestion by a subject (e.g., patient) undergoing treatment. For nasal or inhalation administration, the disseminating agents may also be formulated using methods known to those skilled in the art and may include, for example, but without limitation, examples of solubilizing, diluting, or dispersing substances such as saline solution; preservatives such as benzyl alcohol; absorption promoters; and fluorocarbons. The pharmaceutical compositions suitable for use in this disclosure include compositions in which the active ingredients are contained in an amount effective to achieve the intended purpose. Determining effective amounts is clearly within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds described in the disclosure are effective over a broad dosage range. For example, in the treatment of adult humans, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg daily, and 5 to 40 mg daily are examples of dosages that may be used. A non-limiting dosage range is 10 to 30 mg daily.The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject to be treated, the bioavailability of the compound(s), the adsorption, distribution, metabolism and excretion toxicity (ADME) of the compound(s), and the preference and experience of the attending physician. In addition to the active ingredients, these pharmaceutical compositions may contain suitable, pharmaceutically acceptable vehicles comprising excipients and adjuvants that facilitate the processing of the active compounds into preparations suitable for pharmaceutical use. Preparations formulated for oral administration may be in the form of tablets, coated tablets, capsules, or solutions. Pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, optionally milling the resulting mixture, and processing the granule mixture, after adding suitable adjuvants if desired, to obtain tablets or coated tablet cores. Suitable excipients include, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone). Disintegrating agents, such as crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added if desired. The coated tablet cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lake solutions, and suitable organic solvents or solvent mixtures. Colorants or pigments may be added to the tablets or coated tablets for identification or to characterize different dosage combinations of active compounds. Pharmaceutical preparations for oral administration include pressure-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Pressure-fit capsules may contain the active ingredients mixed with a filler, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). Stabilizers may also be added. In other embodiments, the compounds of formula (I) disclosed herein may be formulated as a viscous lotion, cream, ointment, suspension, paste, gel, oil, spray or aerosol and administered topically.Such viscous lotions, creams, or ointments may be water-based and may further comprise an oil (water-in-oil or oil-in-water), such as liquid paraffin or vegetable oil, for example, peanut oil or castor oil, or a solvent, and may include one or more components, including, but not limited to, penetration enhancers, for example, ethanol and propylene glycol, moisturizing agents, including, but not limited to, glycerin and / or glycerol, thickening and / or gelling agents, including, but not limited to, soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, wool grease, beeswax, carboxypolymethylene and cellulose derivatives, and / or glyceryl monostearate and / or non-ionic emulsifying agents, stabilizing agents, dispersing agents, and suspending agents.By way of example only, a common liquid formulation may comprise between approximately 10% and approximately 60% water, between 10% and approximately 70% ethanol, between approximately 5% and approximately 10% propylene glycol, and between approximately 2% and approximately 5% wetting agent. II. Definitions Although specific terms are used in this document, they are employed solely in a generic and descriptive sense and not for the purpose of limitation. Unless otherwise defined, all scientific and technical terms used herein have the same meaning commonly understood by a person skilled in the art to which the subject matter described herein belongs. Although it is believed that those skilled in the art are well aware of the following terms in relation to compounds of formula (I), the following definitions are set forth to facilitate the explanation of the subject matter disclosed herein. These definitions are intended to supplement and illustrate, not to exclude, the definitions that would be obvious to a person skilled in the art after reviewing this disclosure. The terms substituted, whether or not preceded by the term optionally, and substituent, as used herein, refer to the ability, as appreciated by someone skilled in the art, to change one functional group for another functional group in a molecule, provided that the valency of all atoms is maintained. When more than one position in any given structure can be substituted with more than one substituent selected from a specific group, the substituent may be the same or different at each position. Substituents may also be substituted (for example, a substituent on an aryl group may have another substituent, such as another aryl group, which is further substituted at one or more positions). When substituent groups or linking groups are specified by their conventional chemical formulas, written from left to right, these also include the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-; C(=O)O- is equivalent to -OC(=O)-; -OC(=O)NR- is equivalent to -NRC(=O)O- and so forth. When the expression "independently selected" is used, the substituents being referred to (e.g., R groups, such as R1, R2, and the like, or variable groups, such as m and n) may be identical or different. For example, both R1 and R2 may be substituted alkyls, or R1 may be hydrogen and R2 may be a substituted alkyl, and so on. The terms "a," "one," or "an," when used in reference to a group of substituents herein, mean at least one. For example, when a compound is substituted with an alkyl or aryl group, the compound is optionally substituted with at least one alkyl and / or at least one aryl group. Likewise, when a moiety is substituted with a substituent R, the group may be referred to as R-substituted. When a moiety is substituted with R, the moiety is substituted with at least one substituent R, and optionally each substituent R is different. A cited R group or compound will generally have the structure recognized in the art as corresponding to a group of that name, unless otherwise stated herein. For illustrative purposes, certain representative R groups, as set out above, are defined below. The descriptions of the compounds in this disclosure are limited by the principles of chemical bonding known to those skilled in the art. Accordingly, when a group can be substituted with one or more of a number of substituents, such substitutions are selected to comply with the principles of chemical bonding and to give compounds that are not inherently unstable and / or that a person skilled in the art would know to be unstable under ambient conditions, such as aqueous, neutral, and various known physiological conditions. For example, a heterocycloalkyl or heteroaryl group is linked to the rest of the molecule by a heteroatom on the ring in accordance with the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds. Unless explicitly defined otherwise, a substituent group, as used herein, includes a functional group selected from one or more of the following residues, which are defined herein: The term hydrocarbon, as used herein, refers to any chemical group comprising hydrogen and carbon. Hydrocarbons may be substituted or unsubstituted. As someone skilled in this field would understand, all valences must be satisfied when making any substitution. A hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Illustrative hydrocarbons are defined in more detail below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, terebutyl, ethynyl, cyclohexyl, and the like. The term alkyl, by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e., unbranched) or branched, acyclic or cyclic hydrocarbon group or a combination thereof, which may be fully saturated, mono- or polyunsaturated and may include di- and multivalent groups, having the number of carbon atoms indicated (i.e., C1-10 means from one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 carbons).In particular embodiments, the term alkyl refers to C1-20, inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbon atoms, linear (i.e., straight-chain), branched or cyclic, saturated, or at least partially, and in some cases totally, unsaturated (i.e., alkenyl and alkynyl) hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by the removal of a single hydrogen atom. Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tere-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, ondecyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers thereof. Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. Lower alkyl refers to an alkyl group having from 1 to approximately 8 carbon atoms (i.e., a C1-e alkyl), for example, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Higher alkyl refers to an alkyl group having from approximately 10 to approximately 20 carbon atoms, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, alkyl refers, in particular, to linear C1-s alkyls. In other embodiments, alkyl refers, in particular, to branched C1-8 alkyls. Alkyl groups may be optionally substituted (a substituted alkyl) with one or more alkyl group substituents, which may be the same or different. The term alkyl group substituent includes, but is not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. Optionally, one or more substituted or unsubstituted oxygen, sulfur, or nitrogen atoms may be inserted along the alkyl chain, wherein the nitrogen substituent is hydrogen, a lower alkyl (also referred to herein as alkylaminoalkyl), or aryl. Thus, as used herein, the term substituted alkyl includes alkyl groups, as defined herein, wherein one or more atoms or functional groups of the alkyl group are substituted by another atom or functional group, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto. The term heteroalkyl, by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain having from 1 to 20 carbon atoms or heteroatoms, or a cyclic hydrocarbon group having from 3 to 10 carbon atoms or heteroatoms, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen, phosphorus, and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, P, S, and Si may be placed in any interior position of the heteroalkyl group or in the position where the alkyl group is attached to the rest of the molecule.Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -SI(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. As described above, heteroalkyl groups, as used herein, include groups that are bonded to the rest of the molecule through a heteroatom, such as -C(O)NR', ​​-NR'R, -OR', -SR, -S(O)R, and / or -S(O2)R'. When the term heteroalkyl is used, followed by references to specific heteroalkyl groups, such as -NR'R or the like, it should be understood that the terms heteroalkyl and -NR'R are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are referenced for clarity. Thus, the term heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R or the like. Cyclic and cycloalkyl refer to a non-aromatic monocyclic or multicyclic ring system of approximately 3 to approximately 10 carbon atoms, for example, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group may optionally be partially unsaturated. The cycloalkyl group may also optionally be substituted with an alkyl substituent group as defined herein, oxo, and / or alkylene. Optionally, one or more substituted or unsubstituted oxygen, sulfur, or nitrogen atoms may be inserted along the cyclic alkyl chain, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl.Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, noradamantyl, and fused ring systems such as dihydro- and tetrahydronaphthalene, and the like. The terms cycloalkyl and heterocycloalkyl, alone or in conjunction with other terms, represent, unless otherwise stated, cyclic versions of alkyl and heteroalkyl, respectively. Additionally, for heterocycloalkyl, a heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The terms cycloalkylene and heterocycloalkylene refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively. An unsaturated hydrocarbon has one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkyl groups that are limited to hydrocarbon groups are called homoalkyl. More specifically, the term alkenyl as used herein refers to a monovalent group derived from a linear or branched C2-20 hydrocarbon moiety, inclusive, having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl. The term cycloalkenyl, as used herein, refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl. The term alkynyl, as used herein, refers to a monovalent group derived from a linear or branched C2-20 hydrocarbon of a designated number of carbon atoms containing at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl, and the like. The term alkylene, by itself or as part of another substituent, refers to a linear or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to approximately 20 carbon atoms, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group may be linear, branched, or cyclic. The alkylene group may also be optionally unsaturated and / or substituted with one or more alkyl group substituents. Optionally, one or more substituted or unsubstituted oxygen, sulfur, or nitrogen atoms (also referred to herein as alkylaminoalkyl) may be inserted along the alkylene group, wherein the nitrogen substituent is alkyl as previously described.Illustrative alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexylene (-CeHw-); CH=CH-CH=CH-; -CH=CH-CH2-; -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2CSCCH2, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2)qN(R)-(CH2)r-, wherein each of q and r is independently an integer from 0 to approximately 20, e.g., 0, 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and R is hydrogen or lower alkyl; methylenedioxyl (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). An alkylene group can have from approximately 2 to approximately 3 carbon atoms and can also have 6-20 carbons. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being some embodiments of this disclosure. A lower alkyl or lower alkylene is a shorter-chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term heteroalkylene, either by itself or as part of another substituent, means a divalent group derived from heteroalkyl, as illustrated, but not limited to, by -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatoms may also occupy either or both ends of the chain (e.g., alkylenoxo, alkylenedioxo, alkylenamino, alkylenediamino, and the like). Furthermore, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the linking group formula is written. For example, the formula -C(O)OR' represents both -C(O)OR'- and -R'OC(O)-. The term aryl means, unless otherwise stated, an aromatic hydrocarbon substituent that may be a single ring or multiple rings (such as 1 to 3 rings), which are fused or covalently bonded. The term heteroaryl refers to aryl groups (or rings) containing from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom or atoms are optionally quaternized. A heteroaryl group may be attached to the rest of the molecule through a carbon or heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-Benzimidazolyl, 5-Indolyl, 1-Isoquinolyl, 5-Isoquinolyl, 2-Quinoxalinyl, 5-Quinoxalinyl, 3-Quinoxalinyl, and 6-Quinoxalinyl. The substituents for each of the aryl and heteroaryl ring systems listed above are selected from the group of acceptable substituents described below. The terms arylene and heteroarylene refer to the divalent forms of aryl and heteroaryl, respectively. For the sake of brevity, the term aryl, when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl and heteroaryl rings as defined above. Thus, the terms arylalkyl and heteroarylalkyl are intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like), including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like). However, the term haloaryl, as used herein, is intended to cover only aryls substituted with one or more halogens. When a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g., 3 to 7 members), the term member refers to a carbon or heteroatom. Likewise, a structure generally represented by the formula: As used herein, it refers to a ring structure, for example, but without limitation, an aliphatic, cyclic, aromatic compound of 3, 4, 5, 6, 7 carbon atoms, and the like, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group may be present or absent, and when present, one or more R groups may each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and the number of R groups is determined by the value of the variable n, which is an integer that generally ranges from 0 up to the number of carbon atoms in the ring available for substitution.Each R group, if there is more than one, is substituted on an available carbon of the ring structure instead of on another R group. For example, the above structure where n is 0 to 2 would comprise compound groups including, but not limited to: r2y similar. A dashed line representing a bond in a cyclic ring structure indicates that the bond may be present or absent in the ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure. The symbol (Λν'Λν^ ) indicates the point of attachment of a residue to the rest of the molecule. When a cited atom of an aromatic ring or a heterocyclic aromatic ring is defined as absent, the cited atom is replaced by a direct bond. As used herein, the term acyl refers to an organic acid group in which the -OH of the carboxyl group has been replaced by another substituent and has the general formula RC(=O)-, where R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or aromatic heterocyclic group as defined herein. As such, the term acyl specifically includes arylacyl groups, such as 2-(furan-2-yl)acetyl and 2-phenylacetyl. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups are also intended to include amides, -RC(=O)NR', ​​esters, -RC(=O)OR', ketones, -RC(=O)R', and aldehydes, -RC(=O)H. The terms alkoxyl or alkoxy are used interchangeably herein and refer to a saturated (i.e., alkyl—O—) or unsaturated (i.e., alkenyl-O- and alkynyl—O—) group attached to the main molecular moiety through an oxygen atom, wherein the terms alkyl, alkenyl, and alkynyl are as described above and may include linear, branched, or cyclic C1-20 oxo-hydrocarbon chains, inclusive, saturated or unsaturated, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, ferc-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl, and the like. The term alkoxyalkyl, as used herein, refers to an alkyl-O-alkyl ether, e.g. a methoxyethyl group or an ethoxymethyl group. Aryloxyl refers to an aryl-O- group in which the aryl group is as described above, including a substituted aryl group. The term aryloxyl, as used herein, may refer to phenyloxyl or hexyloxyl and alkyl, substituted alkyl, halo, or alkoxyl-substituted phenyloxyl or hexyloxyl. Aralkyl refers to an aryl-alkyl group in which the aryl and alkyl groups are as described above, and includes substituted aryl and substituted alkyl groups. Examples of aralkyl groups include benzyl, phenylethyl, and naphthylmethyl. Aralkyloxyl refers to an aralkyl-O- group in which the aralkyl group is as described above. An example of an aralkyloxyl group is benzyloxyl, i.e., C6H5-CH2-O-. An aralkyloxyl group may be optionally substituted. Alkoxycarbonyl refers to an alkyl group -OC(=O)-. Example alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl. Aryloxycarbonyl refers to an α-OC(=O)- group. Example aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl. Aralkoxycarbonyl refers to an aralkyl-OC(=O)- group. An example of an aralkoxycarbonyl group is benzyloxycarbonyl. Carbamoyl refers to an amide group of the formula -C(=O)NH2. Alkylcarbamoyl refers to a group R'RN-C(=O)- in which one of R and R' is hydrogen and the other of R and R' is alkyl and / or substituted alkyl as described above. Dialkylcarbamoyl refers to a group R'RN-C(=O)- in which each of R and R1 is independently alkyl and / or substituted alkyl as described above. The term carbonyldioxyl, as used herein, refers to a carbonate group of the formula -OC(=O)-OR. Acyloxyl refers to an acyl-O- group in which acyl is as previously described. The term amino refers to the -NH2 group and also to a nitrogen-containing group, as technically known, derived from ammonia by replacing one or more hydrogen atoms with organic radicals. For example, the terms acylamino and alkylamino refer to specific N-substituted organic radicals with acyl and alkyl substituent groups, respectively. An aminoalkyl, as used herein, refers to an amino group covalently bonded to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino, as used herein, refer to one, two, or three, respectively, alkyl groups, as defined above, bonded to the precursor molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR', wherein R' is an alkyl group, as defined above; while the term dialkylamino refers to a group having the structure -NR'R, wherein R' and R are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure NR'RR', wherein R', R, and R are each independently selected from the group consisting of alkyl groups.Additionally, R', Ry / or R' taken together can optionally be -(CH2)k- where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidine, trimethylamino, and propylamino. The amino group is -NR'R, wherein R' and R are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) group attached to the main molecular moiety through a sulfur atom. Examples of thioalkoxy moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like. Acylamino refers to an acyl-NH- group where acyl is as described above. Aroylamino refers to an aroyl-NH- group where aroyl is as described above. The term carbonyl refers to the -C(=O)- group and may include an aldehyde group represented by the general formula RC(=O)H. The term carboxyl refers to the -COOH group. Such groups are also referred to in this document as a carboxylic acid moiety. The term cyano refers to the group -OξN. The terms halo, halide, or halogen as used herein refer to fluorine, chlorine, bromine, and iodine groups. Additionally, terms such as haloalkyl are intended to include monohaloalkyl and polyhaloalkyl. For example, the expression haloalkyl (Cm) is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The term hydroxyl refers to the -OH group. The term hydroxyalkyl refers to an alkyl group substituted with an OH group. The term mercapto refers to the -SH group. The term oxo, as used herein, means an oxygen atom bonded by a double bond to a carbon atom or another element. The term nitro refers to the -NO2 group. The term "uncle" refers to a compound described earlier in this document in which a carbon or oxygen atom is replaced by a sulfur atom. The term sulfate refers to the -SO4 group. The term thiohydroxyl or thiol, as used herein, refers to a group of the formula -SH. More specifically, the term sulfide refers to a compound that has a group with the formula -SR. The term sulfone refers to a compound that has a sulfonyl group S(O2)R. The term sulfoxide refers to a compound that has a sulfinyl group S(O)R The term ureide refers to a urea group with the formula -NH—CO—NH2. Throughout the descriptive memorandum and claims, a given chemical formula or name must include all tautomers, congeners, optical isomers and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist. Certain compounds in this disclosure may possess asymmetric carbon atoms (chiral or optical centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S) or, for amino acids, as D- or L-, and individual isomers are included within the scope of this disclosure. This disclosure is intended to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)- or D- and L- isomers can be prepared using chiral synthons or chiral reagents, or can be resolved using conventional techniques. Where compounds described herein contain olefinic linkages or other centers of geometric asymmetry, unless otherwise stated, the compounds are understood to include both E- and Z-geometric isomers. Unless otherwise stated, the structures represented herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, individual stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds present are within the scope of disclosure. It will be evident to a person skilled in the art that certain compounds in this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. The term tautomer, as used herein, refers to one of two or more structural isomers that exist in equilibrium and that can readily be converted from one isomeric form to the other. Unless otherwise stated, the structures represented herein are intended to include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, compounds having the structures shown herein with the substitution of a hydrogen atom by a deuterium or tritium atom or the substitution of a carbon atom by an isotope-enriched 13C- or 14C-carbon atom are within the scope of this disclosure. The compounds in this disclosure may also contain non-natural proportions of atomic isotopes in one or more of the atoms that make up those compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds in this disclosure, whether radioactive or not, are included within the scope of this disclosure. Certain compounds in this disclosure may exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of this disclosure. Certain compounds in this disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated in this disclosure and are intended to be within the scope of this disclosure. The term protecting group refers to chemical residues that block some or all of the reactive residues of a compound and prevent those residues from participating in chemical reactions until the protecting group is removed. Examples include the residues listed and described in T.W. Greene and P.G.M. Wuts, *Protective Groups in Organic Synthesis*, 3rd ed., John Wiley & Sons (1999). When employing different protecting groups, it can be advantageous for each (different) protecting group to be extractable by a different means. Protecting groups that cleave under entirely different reaction conditions allow for the differential removal of such groups. For example, protecting groups can be removed by acid, base, and hydrogenolysis.Groups such as trityl, dimethoxytrityl, acetal, and tert-butyldimethylsilyl are acid-labile and are used to protect reactive carboxylic and hydroxyl groups in the presence of amino groups protected with Cbz groups, which are extractable by hydrogenolysis, and Fmoc groups, which are base-labile. Reactive carboxylic acid and hydroxyl groups can be blocked with base-labile groups, such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines blocked with acid-labile groups such as tert-butyl carbamate, or with carbamates that are both acid- and base-stable but hydrolytically removable. Reactive carboxylic acid and hydroxyl groups can be blocked by hydrolytically effaceable protecting groups, such as the benzyl group, while amine groups capable of hydrogen bonding with acids can be blocked by base-labile groups, such as Fmoc. Reactive carboxylic acid groups can be blocked by oxidatively effaceable protecting groups, such as 2,4-dimethoxybenzyl, while coexisting amino groups can be blocked by fluoride-labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base-protecting groups because the former are stable and can subsequently be removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected by a palladium(O)-catalyzed reaction in the presence of acid-labile tert-butyl carbamate or base-labile amine acetate protecting groups. Another form of protecting group is a resin to which a compound or intermediate can bind. As long as the residue is bound to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react. Typical blocking / protecting groups include, but are not limited to, the following residues: p-methoxybenzylcarbonyl (Moz or MeOZ), 3,4-dimethoxybenzyl (DMPM), Troc (trichloroethyl chloroformate), (4-nitrophenyl)sulfonyl (nosyl) and nitrophenylsulfenyl (Nps), and aillo Bn Cbz H3CAlloc Me Theoc Boc CH3 H3C--i CH3t-butyl Following an old patent law convention, the terms a, one, and the refer to one or more subjects when used in this application, including the claims. Thus, for example, reference to a subject includes a plurality of subjects, unless the context clearly indicates otherwise (e.g., a plurality of subjects), and so on. Throughout this specification and in the claims, the terms "include," "comprises," and "comprising" are used in a non-exclusive sense, except where the context requires otherwise. Similarly, the term "include" and its grammatical variants are intended to be non-limiting, so that the listing of items does not preclude other similar items that may be substituted for or added to the listed items. For the purposes of this descriptive memorandum and the attached claims, unless otherwise indicated, all numbers expressing quantities, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, amounts, characteristics and other numerical values ​​used in the descriptive memorandum and the claims shall be understood to be modified in all cases by the term approximately even if the term approximately does not expressly appear with the value, quantity or range.Accordingly, unless otherwise stated, the numerical parameters set out in the following descriptive report and the attached claims are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding, measurement error and the like, and other factors known to those skilled in the art depending on the desired properties to be obtained by means of the subject matter disclosed herein.For example, the term approximately, when referring to a value, may mean that it encompasses variations of, in some embodiments, ±100%, in some embodiments ±50%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% of the specified amount, since such variations are suitable for performing the disclosed methods or employing the disclosed compositions. Likewise, the term "approximately," when used in relation to one or more numbers or numerical intervals, should be understood to refer to all those numbers, including all numbers within a range, and to modify that interval by extending the limits above and below the stated numerical values. The citation of numerical intervals by final criteria includes all numbers, for example, whole numbers, including fractions thereof, subsumed within that interval (for example, the citation of 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, for example, 1.5, 2.25, 3.75, 4.1, and so forth) and any interval within that interval. EXAMPLES The following examples have been included to provide guidance to a person of ordinary skill in the art to practice representative embodiments of the subject matter disclosed herein. In light of this disclosure and the general level of skill in the art, those skilled may appreciate that the following examples are intended to be illustrative only and that numerous changes, modifications, and alterations may be employed without departing from the scope of the subject matter disclosed herein. The synthetic descriptions and specific examples that follow are for illustrative purposes only and should not be construed as limiting in any way the manufacture of compounds of the disclosure by other methods. EXAMPLE 1 Stability of prodrugs in mouse skin homogenate and plasma The stability of mouse skin homogenate was assessed using washed mouse skin, diluted 10-fold in 0.1 M potassium phosphate buffer and homogenized using a tissue homogenizer or CD1 mouse plasma. To assess the stability of the intact prodrug, a 1 mL aliquot of the skin or plasma homogenate was enriched with prodrug to a final assay concentration of 20 ppm. The enriched plasma and skin homogenate samples were incubated on an orbital shaker at 37 °C for 1 hour, after which the reactions were quenched in triplicate with three volumes of acetonitrile containing the internal standard (IS; losartan: 0.5 ppm). The samples were vortexed for 30 s and centrifuged at 10,000 x g for 10 minutes at 4 °C. Fifty microliters of the supernatant were diluted with 50 pl of water and transferred to a 250 pl polypropylene vial sealed with a Teflon cap.The release of itaconic acid or methyl itaconate was measured by liquid chromatography with tandem mass spectrometry (LC-MS / MS). EXAMPLE 2 Pharmacokinetics in mice Male CD1 mice (25–30 g) were obtained from Harian and maintained on a 12-hour light-dark cycle with ad libitum access to food and water. S-100-142, MK939, and MK941 were administered at a molar equivalent dose of 10 mg / kg of monomethyl itaconate via oral gavage. Blood samples were collected at 0.25 and 1 hour post-dose (n = 3 per time point). Mice were euthanized with carbon dioxide at specific time points after drug administration, and blood samples (~0.8 mL) were drawn into heparinized microtubes by cardiac puncture. Blood samples were centrifuged at 4 °C at 3000 g for 10 minutes. Plasma samples (~300 µL) were collected in polypropylene tubes and stored at -80 °C until bioanalysis. Calibration standards were prepared using intact mouse plasma enriched with monomethyl itaconate.Monomethyl itaconate standards and samples were extracted from plasma by one-step protein precipitation using methanol (100% v / v) containing methyl succinate as an internal standard (5 μM). An aliquot of the supernatant (100 μL) was diluted with water (100 μL) and transferred to a 250 μL polypropylene vial sealed with a Teflon cap and analyzed by LC-MS / MS. EXAMPLE 3 Treatment of human keratinocytes with itaconate prodrugs Neonatal human epidermal keratinocyte (NHEK) isolates were seeded from neonatal foreskin at a density of 100,000 cells per well and maintained in KGM supplemented with growth factors (KGM-GOLD Bullet kit, no. 192060). Prodrugs were reconstituted in DMSO. The NHEK were pretreated with vehicle (0.1% DMSO) or prodrug. After 2 days, the NHEK were treated with 50 µg / µL of poly(LC) for 24 hours. EXAMPLE 4 Quantitative real-time isolation of RNA and POR Total RNA was isolated and purified from cultured NHEK using the RNeasy Mini Kit (Qiagen, Valencia, CA, No. 74106). After assessing RNA purity and concentrations using a NanoDrop 2000 UV-Vis spectrophotometer, the RNA was converted to cDNA using a reverse transcription kit and random hexamer primers (Applied Biosystems, No. 4368814). mRNA expression was determined by qRT-PCR using fluorophore-based gene-specific TaqMan probes and a universal master mix (Applied Biosystems, No. 4366072). qRT-PCR reactions were multiplexed using target and reference gene probes (RPLP0). The number of relative mRNA changes was then quantified using the AACt method. EXAMPLE 5 Representative compounds (S)-4-((1-ethoxy-1-oxo-3-phenylpropan-2-yl)amino)-2-methylene-4-oxobutanoic acid (IS100-127) Itaconic anhydride (50 mg, 0.45 mmol) was dissolved in anhydrous THF (5 mL), and solid potassium carbonate (0.19 g, 1.34 mmol) was added, followed by L-phenylalanine ethyl ester hydrochloride (0.1 g, 0.45 mmol). The reaction mixture was stirred at room temperature for 16 hours. The volatiles were then evaporated, the residue was redissolved in DCM (30 mL), and extracted with 1 M aqueous HCl (10 mL) and brine (10 mL). The organic phase was dried with Na₂SO₄, the volatiles were evaporated, and the residue was subjected to final purification by reversed-phase HPLC to yield 100 mg (73%) of the desired compound as a colorless semisolid. 1H NMR (401 MHz, DMSO-ó6):óh 1.25 (t, J = 7.1 Hz, 3H), 3.13 (dd, J = 13.9, 5.9 Hz, 2H), 3.28 (s, 2H), 4.18 (c, J = 7.2 Hz, 2H), 4.86 (dt, J = 7.8, 6.0 Hz, 1H), 5.90 (s, 1H), 6.46 (s, 1H), 6.65 (d, J = 8.0 Hz, 1H), 7.06-7.38 (m, 5H), 9.98 (s, 1H). ESI MS: 304,1 ([M - H]+). HRMS (ESI): Calculated for CieHisOsN 304.11905. Found: 304.11910. (S)-3-((1-ethoxy-1-oxo-3-phenylpropan-2-yl)carbamoyl)but-3-enoate methyl (IS-100128) β-Methyl itaconate (50 mg, 0.35 mmol) and HATL (0.13 g, 0.34 mmol) were dissolved in anhydrous DMF (3 mL), N,N-diisopropylethylamine (0.12 mL, 0.69 mmol) was added, and the mixture was stirred for 5 minutes at room temperature. L-Phenylalanine ethyl ester hydrochloride (80 mg, 0.35 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The volatiles were then evaporated, the residue was redissolved in DCM (30 mL), and extracted with 1 M aqueous HCl (10 mL) and brine (10 mL). The organic phase was dried with Na2SO4, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60-70-230 mesh silica gel, solvent: cyclohexane / ethyl acetate 2:1) to provide 100 mg (90%) of compound IS-100-128 as a colorless semisolid. RMN1H (401 MHz, DMSO-ó6):óh 1.27 (t, J = 7.1 Hz, 3H), 3.19 (dd, J = 5.7, 4.6 Hz, 2H), 3.37 (d, J = 1.1 Hz, 2H), J = 3.69 (s Hz, 2H), 4.90 (dt, J = 7.6, .7 Ηζ, 1Η), 5.50 (t, J = 1.2 Hz, 1H), 5.74 (s, 1H), 6.60 (d, J= 7.6 Hz, 1H), 7.29 ( 7.2 , 1H −7.36 (m, 3H). RMN13C (101 MHz, CDCI3): óc 12.76, 36.46, 36.53, 50.77, 52.04, 60.20, 120.63, 125.72, 127.13, 128.506, 13.1 165.52, 169.86, 170.01. ESI MS: 342.1 ([M + Na]+). HRMS (ESI): Calculated for C17H22O5N 320.14925. Found: 320.14892. (S)-3-((1-amino-1-oxo-3-phenylpropane-2-yl)carbamoyl)but-3-methyl enoate (IS-100129) β-Methyl itaconate (70 mg, 0.49 mmol) and HATU (0.18 g, 0.49 mmol) were dissolved in anhydrous DMF (5 mL), N,N-Diisopropylethylamine (0.17 mL, 0.97 mmol) was added, and the mixture was stirred for 5 minutes at room temperature. Hydroxylamine hydrochloride (97 mg, 0.49 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The volatiles were then evaporated, the residue was redissolved in DCM (30 mL), and extracted with 1 M aqueous HCl (10 mL) and brine (10 mL). The organic phase was dried with Na2SO4, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60-70-230 mesh silica gel, solvent: dichloromethane / methanol 20:1) to provide 120 mg (85%) of compound IS-100129 as a colorless semisolid. NMR1H (401 MHz, DMSO-d6):óH3.14 - 3.31 (m, 3H), 3.46 - 3.56 (m, 1H), 3.68 (s, 3H), 4.77 (dt, J = 8.0, 6.8 Hz, 1H), 5.43 (s, 1H), 5.57 - 5.63 (m, 1H), 5.67 (s, 1H), 6.38 (s, 1H), 6.67 (d, J= 8.0 Hz, 1H), 7.21 -7.38 (m, 5H). RMN13C (101 MHz, CDCI3): oc 37.45, 38.05, 52.24, 54.01, 121.42, 127.11, 128.76, 129.32, 136.60, 138.22, 167.87, 171.74, 173.19. ESI MS: 313.1 ([M + Na]+). HRMS (ESI): Calculated for Ci5HisO4N2Na 313.11588. Found: 313.11545. 1-(((1sopropoxycarbonyl)oxy)methyl)4-methyl 2-methylensuccinate (IS-100-142) -O^°-°Yoy O o1 β-Methyl itaconate (0.2 g, 1.39 mmol), isopropyl chloromethyl carbonate (0.22 mL, 1.66 mmol), and potassium carbonate (0.29 g, 2.08 mmol) were dissolved in anhydrous MeCN (5 mL), and the mixture was stirred for 16 hours at room temperature. EtOAc (60 mL) was added, and the mixture was washed with brine (20 mL). The organic phase was dried with Na₂SO₄, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60-70-230 mesh silica gel, solvent: cyclohexane / ethyl acetate 5:1) to yield 90 mg (25%) of compound IS-100-142 as a colorless oil. 1H NMR (401 MHz, DMSO-ó6):óh 1.34 (d, J = 6.3 Hz, 6H), 3.38 (s, 2H), 3.72 (s, 3H), 4.86-5.02 (m, 1H), 5.82-5.88 (m, 3H), 6.46 (s, 1H). 13C NMR (101 MHz, CDCb): oc 21.64, 37.20, 52.12, 73.10, 82.20, 130.50, 132.76, 153.29, 164.52, 170.77. ESI MS: 283.1 ([M + Na]+). HRMS (ESI): Calculated for CnHieOyNa 283.07882. Found: 283.07855. 4-Methyl 1-((pivaloyloxy)methyl)2-methylenesuccinate (IS-100-143) β-Methyl itaconate (0.2 g, 1.39 mmol), chloromethyl pivalate (0.26 mL, 1.8 mmol), sodium iodide (50 mg, 0.33 mmol), and potassium carbonate (0.29 g, 2.08 mmol) were dissolved in anhydrous MeCN (5 mL), and the mixture was stirred for 16 hours at 40 °C. EtOAc (60 mL) was added, and the mixture was washed with brine (20 mL). The organic phase was dried with Na₂SO₄, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60-70-230 mesh silica gel, solvent: cyclohexane / ethyl acetate 5:1) to yield 0.33 g (92%) of compound IS-100143 as a colorless oil. 1H NMR (401 MHz, DMSO-d6): óH1.20 (s, 9H), 3.34 (s, 2H), 3.68 (s, 3H), 5.79 (d, J = 1.1 Hz, 1H), 5.82 (s, 2H), 6.39 (s, 1H). 13C NMR (101 MHz, CDCh): oc 26.95, 37.38, 38.90, 52.21, 79.91, 130.30, 133.06, 164.82, 170.90, 177.19. ESI MS: 281.1 ([M + Na]+). HRMS (ESI): Calculated for C^HieOeNa 281.09956. Found: 281.09921. 4-((pivaloyloxy)methyl) 1-(tere-butyl) 2-methylenesuccinate (IS-100-146) 3-(tert-Butoxycarbonyl)but-3-enoic acid (0.2 g, 1.07 mmol), chloromethyl pivalate (0.2 ml, 1.4 mmol), sodium iodide (30 mg, 0.21 mmol) and potassium carbonate (0.22 g, 1.61 mmol) were dissolved in anhydrous MeCN (4 ml) and the mixture was stirred for 16 hours at 45 °C. EtOAc (60 ml) was added and the mixture was washed with brine (20 ml). The organic phase was dried with Na2SO4, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60 70-230 mesh silica gel, solvent: cyclohexane / ethyl acetate 6:1) to provide 0.23 g (71%) of compound IS-100-143 as a colorless oil. 1HNMR (401 MHz, DMSO-d6):OH 1.21 (s, 9H), 1.48 (s, 9H), 3.33 (d, J = 1.2 Hz, 2H), 5.63 (d, J = 1.2 Hz, 1H), 5.76 (s, 2H), 6.25 (d, J = 1.0 Hz, 1H). 13C NMR (101 MHz, CDCI3): oc 27.00, 28.10, 37.72, 38.90, 79.88, 81.44, 127.92, 134.86, 165.13, 169.79, 177.23. ESI MS: 323.2 ([M + Na]+). HR ESI MS: Calculated for Ci5H240eNa 323.14651. Found: 323.14622. 2-methylene-4-oxo-4-((pivaloyloxy)methoxy)butanoic acid (IS-100-147) 1-(tert-butyl)-4-((pivaloyloxy)methyl) 2-methylenesuccinate (0.14 g, 0.47 mmol) was dissolved in anhydrous DCM (0.5 mL) with trifluoroacetic acid (4 mL), and the mixture was stirred for 2 hours at room temperature. The volatiles evaporated, and the residue was dissolved in DCM (3 x 15 mL) and evaporated three times to give 0.11 g (97%) of compound IS-100-147 as a colorless oil. 1H NMR (401 MHz, DMSO-ó6):óh 1.21 (s, 9H), 3.37 (s, 2H), 5.77 (s, 2H), 5.87 (s, 1H), 6.49 (s, 1H), 11.12 (s, 1H). RMN13C (101 MHz, CDCh): oc 26.81, 36.97, 38.76, 79.66, 131.36, 132.54, 169.22, 171.11, 177.13. ESI MS: 267.1 ([M + Na]+). HRMS (ESI): Calculated for CnHieOeNa 267.08391. Found: 267.08375. Bis((pivaloyloxy)methyl) 2-methylensuccinate (IS-100-148) Itaconic acid (0.2 g, 1.53 mmol), chloromethyl pivalate (0.55 mL, 3.84 mmol), sodium iodide (50 mg, 0.3 mmol), and potassium carbonate (0.64 g, 4.60 mmol) were dissolved in anhydrous MeCN (5 mL), and the mixture was stirred for 16 hours at 45 °C. EtOAc (60 mL) was added, and the mixture was washed with brine (20 mL). The organic phase was dried with Na₂SO₄, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60-70-230 mesh silica gel, solvent: cyclohexane / ethyl acetate 5:1) to provide 0.20 g (36%) of compound IS-100148 as a colorless oil. 1HNMR (401 MHz, DMSO-ó6):óh 1.20 (s, 18H), 3.38 (d, J = 1.0 Hz, 2H), 5.74 (s, 2H), 5.82 (s, 3H), 6.41 (s, 1H). 13C NMR (101 MHz, CDCI3): oc 26.83, 26.84, 37.12, 38.75, 38.78, 79.70, 79.82, 130.52, 132.33, 164.45, 169.12, 177.07. ESI MS: 381.2 ([M + Na]+). HRMS (ESI): Calculated for Cn^eOsNa 381.15199. Found: 381.15158. Bis(((isopropoxycarbonyl)oxy)methyl) 2-methylene succinate (IS-100-149) Itaconic acid (0.2 g, 1.53 mmol), chloromethyl isopropyl carbonate (0.51 mL, 3.84 mmol), sodium iodide (50 mg, 0.3 mmol), and potassium carbonate (0.64 g, 4.60 mmol) were dissolved in anhydrous MeCN (5 mL), and the mixture was stirred for 16 hours at 45 °C. EtOAc (60 mL) was added, and the mixture was washed with brine (20 mL). The organic phase was dried with Na₂SO₄, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60-70-230 mesh silica gel, solvent: cyclohexane / ethyl acetate 5:1) to provide 80 mg (14%) of compound IS-100149 as a colorless oil. 1H NMR (401 MHz, DMSO-ó6):óh 1.31 (d, J = 6.3 Hz, 12H), 3.41 (s, 2H), 4.82 4.98 (m, 2H), 5.75 (s, 2H), 5.82 (s, 2H), 5.85 (s, 1H), 6.46 (s, 1H). 13C NMR (101 MHz, CDCI3): oc 21.63, 36.95, 73.13, 82.00, 82.22, 131.05, 131.99, 153.26, 153.29, 164.28, 168.95. ESI MS: 385.1 ([M + Na]+). HRMS (ESI): Calculated for Ci5H220ioNa 385.11052. Found: 385.11069. 4-Methyl 1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-methylensuccinate (LTP1025) the β-Methyl itaconate (200 mg, 1.39 mmol) was dissolved in anhydrous MeCN (5 mL). K₂CO₃ (384 mg, 2.78 mmol, 2 equiv.) and Na₂ (416 mg, 2.78 mmol, 2 equiv.) were added, and the resulting mixture was heated at 40 °C for 10 minutes under inert conditions. Finally, (4-chloromethyl)-5-methyl-1,3-dioxol-2-one (412 mg, 303 μL, 2.78 mmol, 2 equiv.) was added, and the mixture was heated at 40 °C for 48 hours. The MeCN was evaporated, EtOAc (50 mL) was added, and the organic phase was washed with 10% Na2S20s (50 mL), distilled H2O (50 mL), and saturated NaCl (2 x 50 mL). The organic phase was dried over MgSO4, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60-70-230 mesh silica gel, solvent: cyclohexane / EtOAc, 2:1) to produce 320 mg (90%) of compound LTP1025 as a light yellow oil. 1H NMR (401 MHz, CDCI3): oh 2.15 (s, 3H), 3.31 (s, 2H), 3.65 (s, 3H), 4.89 (s, 2H), 5.75 (s, 1H), 6.33 (s, 1H). 13C NMR (101 MHz, CDCI3): oc 9.36, 37.36, 52.12, 54.28, 129.98, 132.99, 133.36, 140.30, 152.11, 165.51, 170.91. ESI MS: 279.1 ([M + Na]+). HRMS (ESI): Calculated for CnH^OzNa 279.04752. Found: 279.04757. R = alkyl, aryl, alkyl salicylicyl, Boc-tyrosyl alkylamide, boc-tyrosyl ester, (di)peptide with terminal tyrosyl ester, (di)peptide with terminal tyrosyl alkylamide Examples of R-OH for β-methyl alkyl taconates include, but are not limited to: The general procedure was carried out according to the modified process described in Boschert, D.; Schneider-Chaabane, A.; Himmelsbach, A.; Eickenscheidt, A.; Lienkamp, ​​K. Synthesis and Bioactivity of Polymer-Based Synthetic Mimics of Antimicrobial Peptides (SMAMPs) Made from Asymmetrically Disubstituted Itaconates. Chem. Eur. J. 2018, 24, 8217-8227. L-Tyrosyl alkylamides were synthesized according to McKenna, CE; Kashemirov, B. A; Krylov, IS; Zakharova, VM Method to improve antiviral activity of nucleotide analogue drugs.US9550803 B2, January 24, 2017; and Hidaka, K.; Gohda, K.; Teño, N.; Wanaka, K.; Tsuda, Y. Active site-directed plasmin inhibitors: Extension on the P2 residue. Bioorg. Med. Chem. 2016, 24, 545-553. β-Methyl itaconate (1 mmol) was dissolved in dry dichloromethane (3 mL). The appropriate hydroxy derivative (1.2 mmol) and DMAP (1.5 mmol) were added, and the solution was cooled to 0 °C. A solution of DCC (1.5 mmol) in dichloromethane (2 mL) was added dropwise under a nitrogen atmosphere, and the mixture was stirred for 1 hour at 0 °C and then overnight at room temperature. The mixture was filtered, and the solution was extracted with 10% aqueous KHSO4 (3 x 5 mL) and saturated NaHCO3 (5 mL). The organic phase was dried over sodium sulfate, evaporated, and the residue was chromatographed on a silica gel column using the system described below. 1-(2-(hexadecycloxy)ethyl)4-methyl 2-methylenesuccinate (MK-933) Chromatography in the cyclohexane-ethyl acetate system (80:15). Yield: 253 mg (61%) of a colorless liquid. NMR1H (CDCI3, ppm) δ: 0.88 (t, 3H, Jch3,ch2 = 7.1, CH3(18')), 1.38-1.20 (m, 26H, 13 x CH2 (5 -17')), 1.57 (m, 2H, CH2, 3', 3H), (d, 3', J2=ch = 1.1, CH2(2)), 3.46 (t, 2H, J3 ,4 = 6.7, OCH2 (3')), 3.65 (m, 2H, OCH2 (2')), 3.69 (s, 3H, OCH3), 4.30 (m, 2H, OCH) (ΓH, 2, 17), Jc = Jh,2= 1.1, =CHa), 6.37 (m, 1H, =CHb). NMR of (CDCI3, ppm) δ: 14.11 (C-18′), 22.68 (C-17′), 26.05 (C-5′), 29.35, 29.46, 29.61 and 29.68 (C-4′, C-6′- C-15′), (C-1.16′), (C-15′), (C-15′), 37.48 (C-2), 52.03 (OCH3), 64.29 (C-Γ), 68.39 (C-2′), 71.46 (C-3′), 128.74 (=CH2), 133.64 (C-3), 166.08 (C-4), 171 (C-1). Cl MS: 413.3 (MH)+(60). HRMS (Cl): For C24H45O5(MH)+calculated: 413.3267; found: 413.3264. 1-(4-(tetradecyloxy)butyl) 2-methylenesuccinate from 4-methyl (MK-937) Chromatography in cyclohexane - ethyl acetate (7:1) system. Yield: 259 mg (63 %) of a colorless liquid. RMN1H (CDCb, ppm) δ: 0,87 (t, 3H, Jch3,ch2 = 7,1, CH3(18')), 1,37-1,20 (m, 22H, 11 xCH2(7'-17')), 1,55 (m, 2H, CH2(6')), 1,64 (m, 2H, CH2(3')), 1,74 (m, 2H, CH2 (2')), 3,33 (d, 2H, J2,=ch = 1,1, CH2(2)), 3,38 (t, 2H, J5',6'= 6,7, OCH2(5')), 3,42 (t, 2H, J4 ,3 = 6,4, OCH2(4')), 3,69 (s, 3H, OCH3), 4,18 (t, 2H, J1,2 = 6,6, OCH2 (Γ)), 5,70 (c, 1H, Jgem = JHa,2= 1,1, =CHa), 6,32 (m, 1H, =CHb). RMN13C (CDCI3, ppm) δ: 14,10 (C-18), 22,67 (C-17'), 25,46 (C-2'), 26,17 y 26,21 (C-3', C-7'), 29,34, 29,49, 29,60, 29,65 y 29,73 (C-6'y C-8'- C-15'), 31,90 (C-16'), 37,53 (C-2), 52,01 (OCH3), 64,93 (C-1'), 70,10 (C-4'), 71,05 (C-5'), 128,36 (=CH2), 133,89 (C-3), 166,11 (C-4), 171,15 (C-1). Cl MS: 412,3 (M)+(6). HRMS (Cl): Para C24H44O5 (M)+calculado: 412,3189; encontrado: 412,3187. 2-metilensuccinato de 1-(2-(Butoxicarbonil)fenil)4-metilo (MK-939) Chromatography in the cyclohexane - ethyl acetate system (6:1). Yield: 230 mg (72%) of a colorless liquid. RMN1H (CDCI3, ppm) δ: 0.94 (t, 3H, CH3(4')), 1.42 (m, 2H, CH2 (3')), 1.67 (m, 2H, CH2 (2')), 3.48 (d, 2H, Jch2,h =1.1, CH2-C=O), 3.73 (s, 3H, OCH3), 4.25 (t, 2H, Jv? = 6.7, OCH2 (Γ)), 5.94 (c, 1H, Jgem = JHa,CH2 =1.1, =CHa), 6.62 (m, 1H, =CHb), 7.14 (ddd, 1H, J3.4 = 8.1, 1 / 3.5 = 1.2, J3.6 = 0.6, H-3), 7.32 (ddd, 1H, J5,6 = 7.9, J5,4 = 7.4, J5,3 = 1.2, H-5), 7.56 (ddd, 1H, = 8.1, J4.5 = 7.4, J4,6= 1.7, H-4), 8.02 (ddd, 1H, J6.5 = 7.9, J6,4= 1.7, J6,3 = 0.3, H-6). RMN13C (CDCb, ppm) δ: 13.70 (C-4'), 19.16 (C-3'), 30.60 (C-2'), 37.43 CH2C=O), 52.09 (OCH3), 65.05 (C-1'), 123.70 (C-1), 123.80 (C-3), 126.06 (C-5), 130.41 (=CH2), 131.74 (C-6), 133.18 (C=CH2), 133.64 (C-4), 150.43 (C-2), 164.52 (COOBu), 164.70 (COOPh), 170.95 (COOMe). ESI MS: 343.1 (M+Na)+(100). HRMS (ESI): For Cu^oOeNa (M+Na)+calculated: 343.11521; found: 343.11487. 2-methylenesuccinate of (S)-1 -(4-(2-((tert-butoxycarbonyl)amino)-3-(octylamino)-3oxopropyl)phenyl)4-methyl (MK-940) Chromatography in cyclohexane - ethyl acetate (2:1) system, followed by further chromatography in 1.5% MeOH system in CHCh. Yield: 325 mg (63 %) of a white amorphous solid. NMR Ή (CDCI3, ppm) δ: 0.86 (t, 3H, Jch3,ch2 = 7.1, CH3 (1Γ)), 1.14-1.31 (m, 10H, 5 x CH2 (6 −10')), 1.36 (m, 2H, CH2, 5', 1,9H), CH3 (f-Bu)), 3.02 and 3.06 (m, 2H, CH2 (tyrosine)), 3.14 (m, 2H, CH2 (4')), 3.44 (s, 2H, CH2-C=O), 3.71 (s, 3H, OCH3), 4.25 (m, CH, 2'), 5.09 (sa, 1H, 2'-NH), 5.83 (sa, 1H, 3'-NH), 5.88 (m, 1H, =CHa), 6.53 (s, 1H, =CHb), 7.04 (d, 2H, J2,3= 8.4, H-2 (arom. 2, 2, 2, 2). 8.4, H3 (arom.)). RMN13C (CDCI3, ppm) δ: 14.04 (C-11'), 22.58 (C-10'), 26.75 (C-6'), 28.24 (CH3 (í-Bu)), 29.10, 29.13 and 29.32 (C-5', C-7', C-8'), 31.74 (C-9'), 37.48 (CH2C=O), 37.91 (CΓ), 39.49 (C-4'), 52.11 (OCH3), 55.90 (C-2'), 80.16 (C(CH3)3), 121.59 (C-2), 130.08 (=CH2), 130.29 (C-3), 133.36 (C=CH2), 134.51 (C-4), 149.61 (C-1), 155.38 (NH-COO), 164.60 (COOPh), 170.75 and 170.91 (C-3', CH3O-C=O). ESI MS: 1059.6 (2M+Na)+(10), 541.3 (M+Na)+(100). HRMS (ESI): Para C28H42O?N2Na (M+Na)+calculated: 541.28842; incontrado: 541.28735. 2-methylenesuccinate de 1 -(4-((S)-2-((S)-2-((terc-butox¡carbonyl)amino)-3 methylbutanamido)-3-isopropoxy-3-oxopropyl)phenyl)4-methyl (MK-942) Chromatography in cyclohexane - acetone system (4:1). Yield: 420 mg (77%) of a white colored solid. 1H RMN (DMSO-cfe, ppm) δ: 0.77-0.80 (m, 6H, CH(CH3)2). 1.05 y 1.13 (2x d, 6H, Jch3,ch= 6.3, OCH(CH3)2). 1.37 (s, 9H, C(CH3)3). 1.85 (m, 1H, CH(CH3)2), 2.94 (dd, 1H, J3 a,2 = 8.5, Jgem = 13.9, Η-3'a), 3.00 (dd, 1H, J3 b,2 = 6.4, Jgem = 13.9, Η-3'b), 3.50 (s, 2H, CH2-COOMe). 3.62 (s, 3H, OCH3), 3.80 (dd, 1H, J2.nh = 9.2, = 7.1, H-2), 4.42 (m, 1H, H-2'), 4.81 (sept, 1H, Jch,ch3= 6.3, OCH(CH3)2), 6.02 y 6.42 (2 xd, 2H, Jgem= 1,1, =CH2), 6.60 (d, 1H, JNH,2 = 9.2, NH-2), 7.00 (m, 2H, H-arom. (2)), 7.28 (m, 2H, H-arom. (3)), 8.29 (d, Jnh,2 = 7.5, NH-2'). RMN13C (DMSO-cfe, ppm) δ: 18,39 y 19,35 (C-4), 21,54 y 21,69 (O-CH(CH3)2), 28,38 (C(CH3)3), 30,73 (C-3 '), 36,24 (C-3'), 37,16 (CH2-COOMe), 52,01 (OCH3), 53.70 (C-2'), 59.61 (C-2), 68.23 (O-CH(CH3)2), 78.16 (C(CH3)3), 121.43 (C-2), 130.47 (C-3), 130.88 (=CH2), 133.59 (C=CH2), 135.00 (C-4), 149,24 (C-1), 155.50 (NH-COO), 164.61 (COO-Ph), 170.96 y 171.02 (C-1', COOMe), 171.63 (C-1). ESI MS: 571.3 (M+Na)+(100), 549.3 (MH)+(2). HRMS (ESI): Para C28H4oOgN2Na (M+Na)+calculator: 571,26260; encontrado: 571,26247. 2-metilensuccinato de (S)-1 -(4-(3-(Benciloxi)-2-((terc-butoxicarbonil)amino)-3oxopropil)fenil)4-metilo (MK-943) Cromatografía en sistema ciclohexano - acetona (4:1). Rendimiento: 439 mg (88%) in a jar of color. RMN1H (DMSO-cfe, ppm) δ: 1,32 (s, 9H, C(CH3)3), 2,90 (dd, 1H, J3 a,2 = 10,0, Jgem = 13,8, H-3 a), 3,02 (dd, 1H, J3'b,2'=5,4, Jgem=13,8, Η-3'b), 3.51 (s, 2H, CH2COOMe), 3.63 (s, 3H, OCH3), 4.21 (ddd, 1H, J2,3= 10,0 y 5,4, Λ,nh = 8,0, (H-2'), 5,10 (s, 2H, O-CH2Ph), 6,04 y 6,43 (2 xd, 2H, Jgem=1,1, =CH2), 7,02 (m, 2H, H-2 (arom.)), 7,27-7,37 (m, 7H, H-3, H-2”, H-3”, H-4” (arom.)), 7,41 (da, 1H, Jnhch = 8,0, NH). NMR13C (DMSO-de, ppm) δ: 28.33 (C(CH3)3), 35.85 (C-3'), 37.18 (CH2-COOMe), 52.04 (OCH3), 55.60 (C-2'), 66.17 (O-CH2Ph), 78.60 (C(CH3)3), 121.51 (C-2) 155.68 (NH-CO), 164.68 (COO-C(1)), 171.04 (COO-Me), 172.19 (C-Γ). ESI MS: 1017.5 (2M+Na)+(15), 520.2 (M+Na)+(100). HRMS (ESI): For C27H3iOsNNa (M+Na)+ calculated: 520.19419; found: 520.19394. Deprotection of the tert-butoxycarbonyl group (Boc). General procedure. A mixture of dichloromethane and trifluoroacetic acid (1:1, 16 mL) was added to the appropriate Boc derivative (0.8 mmol). The solution was stirred at room temperature for 20 minutes and evaporated. The residue was either crystallized (MK-944) or chromatographed on a silica gel column (100 mL) in the system described below, followed by reversed-phase HPLC purification and lyophilization (compounds MK-941, MK-945). The following compounds were synthesized: (S)-1-(4-(2-amino-3-(octylamino)-3-oxopropyl)phenyl) 4-methyl 2-methylenesuccinate, trifluoroacetate salt (MK-941) Chromatography in an ethyl acetate-methanol (15:2) system yielded 183 mg (43%) of a yellowish foam, which was subjected to final purification by reversed-phase HPLC (20–60% CH3CN gradient in 0.1% TFA / H2O for 40 minutes, retention time = 36.8 min). Yield: 124 mg (29%) of a white solid. RMN1H (DMSO-d6, ppm) δ: 0,85 (t, 3H, Jch3,ch2 = 7,0, CH3), 1,11-1,32 (m, 12H, 6 x CH2 (2-7)), 2,94 (m, 1H, NH-CHa), 3,00 (m, 2H, Ph-CH2), 3,11 (m, 1H, NH-CHb), 3,51 (s, 2H, CH2COOMe), 3,63 (s, 3H, OCH3), 3,91 (m, 1H, CH-NH3+), 6,05 y 6,42 (2 x d, Jgem = 1,1, =CH2), 7,08 (m, 2H, H-2 (arom.)), 7,26 (m, 2H, H-3 (arom.)), 8,22 (s a, 3H, NH3+), 8,31 (ta, 1H, Jnh.i = 5,6, NH). RMN13C (DMSO-de, ppm) δ: 14,44 (CH3 (8)), 22,57 (CH2 (7'')), 26,76 (CH2 (3”), 29,07, 29,13 y 29,15 (CH2 (2”,4”,5”)), 31,73 (CH2 (6”), 36,93 (Ph-CH2), 37,37 (CH2COOMe), 39,12 (NH-CH2), 52,26 (OCH3), 53,96 (CH-NH3+), 122,04 (C-2 (arom.)), 131,05 (C-3 (arom.)), 131,21 (=CH2), 133,12 (C-4 (arom.)), 133,80 (C=CH2), 149,98 (C1 (arom.)), 164,80 (COO), 167,89 (NH-C=O), 171,26 (COOMe). ESI MS: 441,2 (M+Na)+(100), 419,3 (MH)+(35). HRMS (ESI): Para C23H34O5N2Na (M+Na)+calculated: 441.23599; found: 441.23569. For C23H35O5 N2 (MH)+calculated: 419.25405; found: 419.25385. 2-methylenesuccinate de 1 -(4-((S)-2-((S)-2-amino-3-methylbutanamido)-3-isopropoxy¡-3oxopropyl)phenyl) 4-methyl, salt trifluoroacetate (MK-944) Crystallized in ethyl acetate with addition of dietary ether. Yield: 324 mg (72%) of white crystals. RMN1H (DMSO-Ó6, ppm) δ: 0.93 y 0.97 (2 xd, 6H, Jchs.ch = 6.9, CH(CH3)2), 1.07 y 1.15 (2 xd, 6H, Jch3,ch = 6.2, O-CH(CH3)2). 2.13 (m, 1H, CH(CH3)2), 2.99 (dd, 1H, J3 a,2 = 8.3, Jgem = 14.1, H-3 a), 3.04 (dd, 1H, J3b,2 = 6.3, Jgem =14.1, Η-3'b), 3.51 (s, 2H, CH2-COOMe), 3.63 (s, 3H, OCH3), 3.65 (d, 1H, Jzy = 5.1, H-2), 4.50 (m, 1H, H2'), 4.85 (sept, 1H, Jch,ch3 = 6.2, O-CH(CH3)2), 6.04 y 6.43 (2 xm, 2H, =CH2), 7.05 (m, 2H, H-2), 7.32 (m, 2H, H-3), 8.09 (sa, 3H, NH3+), 8.90 (d, 1H, Jnh,2- = 7.0, NH). 13C NMR (DMSO-O6, ppm) δ: 17.44 y 18.56 (C-4), 21.52 y 21.69 (O-CH(CH3)2), 30.10 (C-3), 36.03 (C-3'), 37.16 (CH2-COOMe), 52.03 (OCH3), 54.27 (C-2'), 57.24 (C2), 68.66 (O-CH(CH3)2), 121.66 (C-2), 130.53 (C-3), 131.04 (=CH2), 133.54 (C=CH2), 134.68 (C-4), 149.41 (C-1), 164.71 (COO-Ph), 168.41 (NH-CO), 170.56 (COO- / Pr), 171.07 (COOMe). ESI MS: 471.2 (M+Na)+(58), 449.2 (MH)+(100). HRMS (ESI): For C23H32O7N2Na (M+Na)+ calculated: 471.21017; found: 471.20999. For C23H33O? N2(MH)+ calculated: 449.22823; found: 449.22815. (S)-1-(4-(2-Amino-3-(benzyloxy)-3-oxopropyl)phenyl) 4-methyl 2-methylensuccinate, trifluoroacetate salt (MK-945) Chromatography in a dichloromethane-methanol (50:2) system yielded 270 mg (68%) of a yellowish syrup, which was then subjected to final purification by reversed-phase HPLC (15–50% CH3CN gradient in 0.1% TFA / H2O for 40 minutes, retention time = 37.1 min). Yield: 85 mg (21%) of a semi-solid gum. 1H NMR (DMSO-Ó6, ppm) δ: 3.08 (dd, 1H, J3a,2 = 7.7, Jgem = 14.1, H-3 a), 3.16 (dd, 1H, J3b,2 = 6.0, Jgem = 14.1, Η-3'b), 3.53 (s, 2H, CH2-COOMe), 3.63 (s, 3H, OCH3), 4.40 (dd, 1H, J2-,3'= 7.6 and 6.1, H-2'), 5.13 and 5.17 (2 xd, 2H, J3em= 12.3, Q-CH2Ph), 6.06 and 6.45 (2 xd, 2H, Jgem= 1.1, =CH2), 7.05 (m, 2H, H-2 (arom.)), 7.24 (m, 2H, H-3 (arom.)), 7.26 (m, 2H, H-2”), 7.34-7.38 (m, 3H, H-3”, H-4”(arom.)), 8.58 (sa, 3H, NH3+). 13C NMR (DMSO-cfe, ppm) δ: 35.68 (C-3), 37.21 (CH2-COOMe), 52.07 (OCH3), 53.35 (C-2'), 67.44 (O-CH2Ph), 121.97 (C-2), 128.05 (C-2), 128.67-128.69 (C-2”, C3”, C-4”), 130.87 (C-3), 131.13 (=CH2), 132.48 (C-4), 133.56 (C=CH2), 135.02 (C-1”), 149.86 (C-1), 164.62 (CH2-COO), 169.20 (COO-Bn), 171.11 (COO-Me), ESI MS: 420.1 (M+Na)+(38), 398.2 (MH)+(100). HRMS (ESI): For C22H23O6NNa (M+Na)+calculated: 420.14176; found: 420.14120. For C22H24O6N (MH)+calculated: 398.15981; found: 398.15939. Alkyl α-methyl itaconates R = alkyl, aryl, alkyl salicylicyl, Boc-tyrosyl alkylamide, boc-tyrosyl ester, (di)peptide with terminal tyrosyl ester, (di)peptide with terminal tyrosyl alkylamide Examples of R-OH for α-methyl alkyl itaconates include, but are not limited to: α-Methyl itaconate (1 mmol) was dissolved in dry dichloromethane (3 mL). The appropriate hydroxy derivative (1.2 mmol) and DMAP (1.5 mmol) were added, and the solution was cooled to 0 °C. A solution of DCC (1.5 mmol) in dichloromethane (2 mL) was added dropwise under a nitrogen atmosphere, and the mixture was stirred for 1 hour at 0 °C and then overnight at room temperature. The mixture was filtered, and the solution was extracted with 10% aqueous KHSO₄ (3 x 5 mL) and saturated NaHCO₃ (5 mL). The organic phase was dried over sodium sulfate, evaporated, and the residue was chromatographed on a silica gel column using the system described below. 4-(4-(tetradecyloxy)butyl) 1-methyl 2-methylenesuccinate (MK-956) Chromatography in the cyclohexane-ethyl acetate system (10:1). Yield: 244 mg (59%) of a colorless liquid. RMN1H (CDCI3, ppm) δ: 0,87 (t, 3H, Jch3,ch2 = 7,0, CH3 (14)), 1,24-1,33 (m, 22H, 11 x CH2 (3-13)), 1,54 (m, 2H, CH2 (2)), 1,62 (m, 2H, COO(CH2)2CH2CH2O), 1,69 (m, 2Η, COO-CH2CH2), 3,33 (d, 2H, Jch2,c=ch2= 1,2, CH2-COO), 3,38 (t, 2H, Ji,2= 6,7, CH2(1)), 3,41 (t, 2H, Jch2,ch2 = 6,4, COO-(CH2)3CH2O), 3,76 (s, 3H, OCH3), 4,12 (t, 2H, JcH2,CH2 = 6,5, COO-CH2), 5,70 (C, 1H, JHa,CH2 = Jgem 1,1, =CHa), 6,32 (d, 1H, Jgem 1,1, =CHb). RMN13C (CDCI3, ppm) δ: 14,11 (C-14), 22,67 (C-13), 25,42 (COO-CH2-CH2), 26,14 y 26,17 (C-3, COO(CH2)2CH2CH2O), 29,34 - 29,73 (m, C-2, C-4 - C-11), 31,91 (C-12), 37,75 (CH2COO), 52,10 (OCH3), 64,81 (COO-CH2), 70,10 (COO-(CH2)3CH2O), 71,05 (C-1), 128,44 (C=CH2), 133,75 (C=CH2), 166,65 (COO-CH3), 170,72 (CH2-COO). ESI MS: 847,6 (2M+Na)+(10), 435,3 (M+Na)+(100). HRMS (ESI): Para C24H440sNa (M+Na)+calculado: 435,30810; encontrado: 435,30841. 2-metilensuccinato de 4-(3-(Hexadeciloxi)propil)1-metilo (MK-957) Cromatografía en sistema ciclohexano - acetato de etilo (80:15). Rendimiento: 120 mg (28 %) de un líquido incoloro. RMN1H (CDCI3, ppm) δ: 0,87 (t, 3H, Jch3,ch2 = 7,0, CH3 (16)), 1,23-1,33 (m, 26 H, 13 x CH2 (3-15)), 1,54 (m, 2H, CH2(2)), 1,88 (p, 2H, OCH2-CH2-CH2Q), 3,33 (d, 2H, Jch2,c=ch2=1,2, CH2-CQO), 3,38 (t, 2H, Ji,2= 6,7, OCH2(1)), 3,45 (t, 2H, Jch2.ch2= 6,3, COO-(CH2)2CH2O), 3,76 (s, 3H, OCH3), 4,19 (t, 2H, Jch2,ch2 = 6,5, COO-CH2), 5,70 (c, 1H, JHa,CH2 = Jgem 1,1, =CHa), 6,32 (d, 1H, Jgem 1,1, =CHb). RMN13C (CDCI3, ppm) δ: 14,10 (C-16), 22,67 (C-15), 26,14 (C-3), 28,98 (OCH2CH2-CH2O), 29,34-29,69 (m, C-2, C-4 - C-13), 31,91 (C-14), 37,72 (CH2COO), 52,10 (OCH3), 62,27 (COO-CH2), 66,99 (COO-(CH2)2CH2O), 71,16 (C-1), 128,44 (C=CH2), 133,73 (C=CH2), 166,63 (COO-CH3), 170,64 (CH2-COO). ESI MS: 875,7 (2M+Na)+(5), 449,3 (M+Na)+(100). HRMS (ESI): Para C25H460sNa (M+Na)+calculado: 449,32375; encontrado: 449,32382. 2-methylenesuccinate of 4-(2-(Butoxycarbonyl)phenyl)1 -methyl (MK-961) Chromatography in cyclohexane - ethyl acetate (6:1) system. Yield: 63 mg (20 %) of a colorless liquid. NMR1H (CDCb, ppm) δ: 0.97 (t, 3H, Jch3,ch2 = 7.4, CH3(4')), 1.45 (m, 2H, CH2(3')), 1.72 (m, 2H, CH2(2')), 3.67 (d, 2H, CH2(2') = c CH2-C=O), 3.81 (s, 3H, OCH3), 4.27 (t, 2H, J1 .2 = 6.7, OCH2 (Γ)), 5.89 (c, 1H, Jgem= JHa,CH2 = 1.1, =CHa), 6.42 (d, 1H, 1H, Jgem, = 1.1, dd, CH 1H, J3.4 = 8.1, J3.5 =1.1, H-3), 7.30 (m, 1H, H-5), 7.54 (ddd, 1H, Ja,3 = 8.2, Ja,5 = 7.4, Ja,6 = 1.7, H-4), H6). NMR13C (CDCb, ppm) δ: 13.74 (C-4′), 19.20 (C-3′), 30.68 (C-2′), 37.50 CH2C=O), 52.20 (OCH3), 64.97 (C-Γ), 123.43 (C-13), 19.7 (C-2), 126.04 (C-5), 129.30 (=CH2), 131.59 (C-6), 133.19 (C=CH2), 133.67 (C-4), 150.56 (C-2), 164.38 (COOBu), 166.59 (COOCH3.3), 1623 (COO-COO). ESI MS: 343.1 (M+Na)+(100). HRMS (ESI): Para Ci7H2oOeNa (M+Na)+calculated: 343.11521; encontrado: 343,11532. 2-methylenesuccinate de 4-(4-((S)-2-((S)-2-((terc-butoxycarbonyl)amino)-3methylbutanamido)-3-isopropoxy-3-oxopropyl)phenyl)1-methyl (MK-962) Chromatography in cyclohexane - acetone system (4:1). Yield: 255 mg (47%) of a white colored solid. RMN1H (DMSO-Ó6, ppm) δ: 0.77-0.79 (m, 6H, CH(CH3)2). 1.04 y 1.12 (2x d, 6H, Jch3,ch= 6.2, OCH(CH3)2), 1.37 (s, 9H, C(CH3)3) 1.85 (m, 1H, CH(CH3)2), 2.93 (dd, 1H, J3a,2 = 8.5, Jgem = 14.0, Η-3'a), 2.99 (dd, 1H, J3b,2- = 6.6, Jgem= 14.0, Η-3'b), 3.62 (s, 2H, CH2-COOMe), 3.72 (s, 3H, OCH3), 3.80 (m, 1H, H-2), 4.42 (c, 1H, J2-,3-= J2-,nh = 7.4, H-2'), 4.81 (sept, 1H, Jch.chs = 6.2, OCH(CH3)2), 5.96 y 6.28 (2 xs, 2H, =CH2), 6.57 (d, 1H, Jnh.2” = 9.2, NH-2), 6.97 (m, 2H, H-arom. (2)), 7.26 (m, 2H, H-arom. (3)), 8.26 (d, Jnh,2- = 7.4, NH-2'). NMR13C (DMSO-de, ppm) δ: 18.35 y 19.31 (C-4), 21.50 y 21.65 (O-CH(CH3)2), 28.36 (C(CH3)3), 30.71 (C-3), 36.24 (C-3'), 37.38 (CH2-COOMe), 52.29 (OCH3) (C-4), 149.24 (C-1), 155.48 (NH-COO), 166.27 (COO-Me), 169.38 (COO-Ph), 170.94 (C-1'), 171.59 (C-1). ESI MS: 571.3 (M+Na)+(100). HRMS (ESI): For C28H4o09N2Na (M+Na)+ calculated: 571.26260; found: 571.26280. (S)-4-(4-(3-(Benzyloxy)-2-((tert-butoxycarbon¡l)amino)-3 oxopropyl)phenyl)1-methyl 2-methylensuccinate (MK-963) Chromatography using a cyclohexane - acetone system (4:1). Yield: 223 mg (45%) of an amorphous solid. RMN Ή (CDCb, ppm) δ: 1,41 (s, 9H, C(CH3)3). 3,04 (dd, 1H, J3a,2 = 6,0, Jgem= 14,0, Η-3'a), 3,09 (dd, 1H, J3b,2· = 6,0, Jgem= 13,9, Η-3'b), 3,56 (d, 2H, Jch2,c=ch2 = 1,1, CH2-COOMe), 3,80 (s, 3H, OCH3), 4,60 (m, 1H, CH-NH), 4,99 (d, Jnh.ch = 8,3, NH), 5,09 y5,17(2xd,2H, Jgem — 12,2, O-CH2Ph), 5,82 (c, 1H, JcH2,=CHa — Jgem — 1,1, =CHa), 6,40 (d, 1H, Jgem = 0,8, =CHb), 6,95 (m, 2H, H-2 (arom.)), 7,02 (m, 2H, H-3 (arom.)), 7,287,38 (m, 5H, H-2”, H-3”, H-4”(arom.)). RMN13C (CDCb, ppm) δ: 28,25 (C(CH3)3), 37,51 (C-3'), 37,86 (CH2-COOMe), 52,23 (OCH3), 54,31 (C-2'), 67,15 (O-CH2Ph), 79,97 (C(CH3)3), 121,40 (C-2), 128,48 (C4”), 128,58 y 128,60 (C-2”, C-3), 129,00 (=CH2), 130,28 (C-3), 133,29 (C=CH2), 133,50 (C-4), 135,06 (C-1 ”), 149,61 (C-1), 155,02 (NH-CO), 166,47 (COO-Me), 169,07 (CH2-COO), 171,51 (C-1'). ESI MS: 1017,7 (2M+Na)+(3), 520,3 (M+Na)+(100). HRMS (ESI): For C2?H3iO8NNa (M+Na)+ calculated: 520.19419; found: 520.19324. For C27H32O8N (MH)+ calculated: 498.21224; found: 498.21161. Deprotection of the tert-butoxycarbonyl group (Boc). General procedure. A mixture of dichloromethane and trifluoroacetic acid (1:1, 16 mL) was added to the appropriate Boc derivative (0.8 mmol). The solution was stirred at room temperature for 20 minutes and evaporated. The residue was treated as described below. 4-(4-((S)-2-((S)-2-amino-3-methylbutanamido)-3-isopropoxy-379 oxopropyl)phenyl) 1-methyl 2-methylenesuccinate, trifluoroacetate salt (MK-964) The residue crystallized in a mixture of ethyl acetate and diethyl ether. Yield: 340 mg (75%) of white crystals. NMR1H (DMSO-cfe, ppm) δ: 0,93 y 0,97 (2 xd, 6H, CH(CH3)2). 1,06 y 1,14 (2 xd, 6H, Jch3,ch = 6,2, O-CH(CH3)2), 2,12 (sept d, 1H, Jy,y = 6,9, Jy, 2- = 5,0, H-3), 2,98 (dd, 1H, J3a,2· = 8,2, Jgem = 14,2, Η-3'a), 3.03 (dd, 1H, J3b,2-= 6.6, Jgem = 14.2, Η-3'b), 3.64 (m, 2H, CH2-COOMe), 3.65 (d, 1H, Jy.y = 5.1, H-2), 3.73 (s, 3H, OCH3), 4.49 (m, 1H, H-2'), 4.84 (Sept. 1H, Jch,ch3 = 6.2, O-CH(CH3)2), 5.96 (c, 1H, JcH2,=CHa = Jgem = 1,2, =CHa), 6.28 (d, 1H, Jgem = 1,2, =CHb), 7.02 (m, 2H, H-2), 7.31 (m, 2H, H-3), 8.09 (sa, 3H, NH3+), 8.89 (d, 1H, Jnh,2- = 7.0, NH). RMN13C (DMSO-Ó6, ppm) δ: 17,43 y 18,51 (C-4), 21,47 y 21,65 (O-CH(CH3)2), 30,07 (C-3), 36,03 (C-3'), 37,40 (CH2-COOMe), 52,32 (OCH3), 54,23 (C-2'), 57,23 (C2), 68,60 (O-CH(CH3)2), 121,62 (C-2), 129,72 (=CH2), 130,47 (C-3), 133,60 (C=CH2), 134,56 (C-4), 149,40 (C-1), 166,30 (COO-Me), 168,37 (NH-CO), 169.51 (CH2-COO), 170.53 (COO- / Pr). ESI MS: 471.2 (M+Na)+(20), 449.2 (MH)+(100). HRMS (ESI): For C23H33O? N2 (MH)+calculated: 449.22823; found: 449.22745. 2-methylenesuccinate of (S)-4-(4-(2-Amino-3-(benzyloxy)-3-oxopropyl)phenyl) 1-methyl, trifluoroacetate salt (MK-965) The residue was chromatographed on silica gel column (60 mi) in a cyclohexane - acetone (1:1 to 1:4) gradient, followed by the chloroform - methanol (1:1) system to give 380 mg (93 %) of a white sticky foam. RMN1H (DMSO-cfe, ppm) δ: 3.07 (dd, 1H, J3a,2· = 7.5, Jgem= 14.1, H-3 a), 3.15 (dd, 1H, J3b,2- = 6.1, Jgem = 14.1, Η-3'b, 26, d Jch2,c=ch2= 1,2, CH2-COOMe). 3.73 (s, 3H, OCH3), 4.37 (dd, 1H, J2 .3· = 7.6 y 6.1, H-2 ), 5.13 y 5.17 (2 xd, 2H, Jgem= 12.3, O-CH2Ph), 5.98 (c, 1H, Jgem, = CH = 1,2 =CHa), 6.30 (d, 1H, Jgem = 1.2, =CHb), 7.02 (m, 2H, H-2 (arom.)), 7.22 (m, 2H, H-3 (arom.)), 7.26 (m, 2H, H-2(arom.)), 7.34-7 (m, 2H, H-2(arom.), H-4(arom.)), 8.48 (all, 3H, NH3+). RMN13C (DMSO-cfe, ppm) δ: 35.71 (C-3'), 34.73 (CH2-COOMe), 52.33 (OCH3), 53.35 (C-2), 67.35 (O-CH2Ph), 121.88 (C-2), 128.60 (C-2”, C-3”), 128.63 (C-4) (CH2-COO). ESI MS: 420.1 (M+Na)+(15), 398.2 (MH)+(100). HRMS (ESI): For C22H23O6NNa (M+Na)+ calculated: 420.14176; found: 420.14105. For C22H24O6N (MH)+ calculated: 398.15981; found: 398.15930. 4-(((1sopropoxycarbonyl)oxy)methyl) 1-methyl 2-methylensuccinate (IS-101-088) (21) the α-Methyl itaconate (0.2 g, 1.39 mmol), chloromethyl isopropyl carbonate (0.22 ml, 1.66 mmol), sodium iodide (50 mg, 0.33 mmol) and potassium carbonate (0.29 g, 2.08 mmol) were dissolved in anhydrous MeCN (5 ml) and the mixture was stirred for 16 hours at 50 °C. EtOAc (60 ml) was added and the mixture was washed with brine (20 ml). The organic phase was dried with Na2SO4, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60-70-230 mesh silica gel, solvent: cyclohexane / ethyl acetate 5:1) to provide 0.34 g (93%) of compound IS-101 088 (21) as a colorless oil. 1H NMR (401 MHz, CDCI3): óh 1.31 (d, J = 6.2 Hz, 6H), 3.37 - 3.43 (m, 2H), 3.76 (d, J = 0.6 Hz, 3H), 4.85-4.97 (m, 1H), 5.72-5.78 (m, 3H), 6.36 (d, J = 0.8 Hz, 1H). 13C NMR (101 MHz, CDCI3): oc 21.6, 21.7, 37.3, 52.2, 73.1, 81.9, 129.2, 132.9, 153.3, 166.3, 169.2. ESI MS: 283.1 ([M + Na]+). HRMS (ESI): Calculated for CnHieOzNa 283.07882. Found: 283.07925. 1-Methyl 4-((pivaloyloxy)methyl) 2-methylenesuccinate (IS-101-089) (23) α-Methyl itaconate (0.2 g, 1.39 mmol), chloromethyl pivalate (0.26 mL, 1.8 mmol), sodium iodide (50 mg, 0.33 mmol), and potassium carbonate (0.29 g, 2.08 mmol) were dissolved in anhydrous MeCN (5 mL), and the mixture was stirred for 16 hours at 40 °C. EtOAc (60 mL) was added, and the mixture was washed with brine (20 mL). The organic phase was dried with Na₂SO₄, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60-70-230 mesh silica gel, solvent: cyclohexane / ethyl acetate 5:1) to provide 0.33 g (92%) of compound IS-101089 (23) as a colorless oil. 1H NMR (401 MHz, CDCI3): óh 1.21 (s, 9H), 3.38 (d, J = 1.2 Hz, 2H), 3.76 (s, 3H), 5.74 (d, J = 1.1 Hz, 1H), 5.76 (s, 2H), 6.35 (d, J = 0.8 Hz, 1H). RMN13C (101 MHz, CDCI3): oc 26.9, 37.4, 38.8, 52.2, 79.7, 129.0, 133.0, 166.3, 169.4, 177.1. ESI MS: 281.1 ([M + Na]+). HRMS (ESI): Calculated for C^HisOeNa 281.09956. Found: 281.09993. 1-(((tert-butoxycarbonyl)oxy)methyl) 4-methyl 2-methylensuccinate (IS-102-081) β-Methyl itaconate (1.00 g, 6.94 mmol), tere-butyl (chloromethyl) carbonate (1.27 g, 7.60 mmol), sodium iodide (0.20 g, 1.33 mmol), and potassium carbonate (1.44 g, 10.4 mmol) were dissolved in anhydrous MeCN (20 mL) and the mixture was stirred for 16 hours at 50 °C. The volatiles were then evaporated, the residue was redissolved in EtOAc (60 mL), and the mixture was washed with a saturated solution of sodium thiosulfate (20 mL) and brine (70 mL). The organic phase was dried with Na2SO4, the volatiles were evaporated, and the residue was subjected to ultrafast column chromatography (60-70-230 mesh silica gel, solvent: cyclohexane / ethyl acetate 5:1) to provide 1.65 g (87%) of compound IS-102-081 as a colorless oil. 1H NMR (401 MHz, CDCI3): óh 1.49 (s, 9H), 3.34 (s, 2H), 3.68 (s, 3H), 5.78 (s, 2H), 5.81 (s, 1H), 6.42 (s, 1H). 13C NMR (101 MHz, CDCh): oc 27.7, 37.3, 52.2, 82.0, 83.7, 130.5, 133.0, 152.0, 164.7, 170.9. ESI MS: 297.1 ([M + Na]+). HRMS (ESI): Calculated for C^HisOzNa 297.09447. Found: 297.09465. Scheme 1. Numbering of structures for NMR assignment (alkyl β-methyl itaconates) Scheme 2. Numbering of structures for NMR assignment (alkyl a-methyl itaconates) ΜΚ-963, ΜΚ-965 R = Η, BOC EXAMPLE 6 In vitro data. Stability in mouse plasma To evaluate the stability of the intact prodrug in mouse plasma over time, the prodrug was added to mouse plasma to a final assay concentration of 10 μM. Enriched samples were incubated on an orbital shaker at 37 °C for 1 hour, after which the reactions were quenched with three volumes of acetonitrile containing the internal standard (IS; losartan: 0.5 μM). The samples were vertex-mixed and centrifuged at 16,000 g for 5 minutes at 4 °C. Fifty microliters of the supernatant were diluted with 50 μL of water and transferred to a 250 μL polypropylene vial sealed with a Teflon cap. Prodrug disappearance was monitored over time by liquid chromatography-mass spectrometry (LC-MS). The results for the representative prodrugs disclosed in this document are shown in FIG. 1.The release of active monomethyl itaconate (in plasma) from representative prodrugs is shown in FIG. 2. The release of active itaconic acid (in plasma) from representative prodrugs is shown in FIG. 3. REFERENCES All publications, patent applications, patents, and other references mentioned in the descriptive memorandum are indicative of the level of expertise in the field to which the subject matter disclosed herein belongs. All publications, patent applications, patents, and other references are incorporated herein by reference to the same degree as if each individual publication, patent application, patent, and other reference were specifically and individually indicated for incorporation by reference. It is understood that, although several patent applications, patents, and other references are mentioned herein, such reference does not constitute an admission that any of these documents forms part of the customary general knowledge of the art. The publication of the international patent application PCT WO2017142855 granted to Artyomov et al., for Immunomodulatory Agents and Methods of Use Thereof, published on Thursday, August 24, 2017; The publication of the international patent application PCT WO2019036509 granted to Artyomov et al., for Methods and Compositions for the Treatment of Diseases Associated with Cancer, Inflammation, or Immune Response, published on February 21, 2019; O'Neill, LAJ and Artyomov, MN, Itaconate: the poster child of metabolic reprogramming in macrophage function, Nature Reviews: lmmunology, 19, 273-281 (2019). Boschert, D.; Schneider-Chaabane, A.; Himmelsbach, A.; Eickenscheidt, A.; Lienkamp, ​​K. Synthesis and Bioactivity of Polymer-Based Synthetic Mimics of Antimicrobial Peptides (SMAMPs) Made from Asymmetrically Disubstituted Itaconates. Chem. Eur. J. 2018, 24, 8217-8227. McKenna, C.E.; Kashemirov, B. A; Krylov, I.S.; Zakharova, VM Method to improve antiviral activity of nucleotide analogue drugs.US9550803 B2, January 24, 2017. Hidaka, K.; Gohda, K.; Teño, N.; Wanaka, K.; Tsuda, Y. Active site-directed plasmin inhibitors: Extension on the P2 residue. Bioorg. Med. Chem. 2016, 24, 545-553. Although the subject matter above has been described in some detail by way of illustration and example for the purpose of clarity of understanding, those skilled in the art will understand that certain changes and modifications may be made within the scope of the appended claims.

Claims

1. A compound of formula (I): O wherein: Ri and R2 may be the same or different and each is independently selected from one or more of the following and combinations thereof: (a) -OR3, wherein R3 is H or linear or branched Ci-Cs alkyl substituted or unsubstituted; or R4 (b) n , wherein n is an integer selected from 1, 2, 3 and 4; R4 is linear or branched Ci-Cs alkyl substituted or unsubstituted or -ORs, wherein Rs is linear or branched Ci-Cs alkyl substituted or unsubstituted; (c) mp , wherein m is an integer selected from 1, 2, 3 and 4; p is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; and Rs is substituted or unsubstituted linear or branched Ci-Cs alkyl; A (d) O , wherein R7 is selected from: (i) -C(=O)-O-R8, wherein Rs is substituted or unsubstituted linear or branched Ci-Cs alkyl;(ii) Ri3°, wherein Rg is H or substituted or unsubstituted linear or branched C1-C4 alkyl; R10 is substituted or unsubstituted linear or branched C1-C6 alkyl; R11 and R12 are each independently H or a protecting group; and R13 is H or substituted or unsubstituted linear or branched C1-C6 alkyl; v / X^-NR^R^ r14n'xxd RA (iii) Ki5, wherein q is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Rn and R12 are each independently H or a protecting group; R14 is H or substituted or unsubstituted linear or branched C1-C4 alkyl; and R15 is H or substituted or unsubstituted linear or branched C1-C6 alkyl; (iv) nr16r17, wherein Ri6 and Rl7 are each independently selected from H, unsubstituted or substituted linear or branched C1-C4 alkyl, and a protecting group; R-is is aryl; Z Γ13 (e) O, wherein R19 is substituted or unsubstituted linear or branched C1-C4 alkyl; wherein u is an integer selected from 1, 2, 3 and 4;R20 is H or linear or branched C1-C4 alkyl, substituted or unsubstituted; and R21 is -OR22, wherein R22 is linear or branched C1-C6 alkyl, substituted or unsubstituted, or -NR23R24, wherein R23 and R24 are each independently H or linear or branched C1-C4 alkyl, unsubstituted or substituted; provided that R1 and R2 cannot both be -OH or both -OR3 at the same time; and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein: between -OR3, selects between -C(=O)-O-R8, wherein R7 is or NRi6R17 (b) Ri is I R4 n R2 is selected between -OR3, R20 selects between oH°Hr' Ri2RhN -SR; Río NRg R13 O the one that R7 is , in Rl5^ -C(=O)-O-R8, or R18 NR16Ri7 (c) R1 is my R2 is selected between R20 -C(=O)-O-R8i selects between O NR16R17 -or3, I R4 n R12R1 or R13 n^or R13 R7 is selected between NR16R17 O r Ríe (e) R1 is selected between (d) Ri is R2q R21 R2 o / Y°HR6 is selected between An / » -OR3, -C(=O)-O-R8, R10 R12R11N yo nr9 R73 O r18 O r18 NRwRl7 (f) R1 is O -OR3, R7 , in which R7 is -C(=O)-O-Rs and R2 is selected between R20 Γ -^r7 O , in which R12R11N River NR9 Rl3 (g) R1 is r7 , selected between -OR3, R2 selects NR16Ri7 which R7 is between -C(=O)-O-R8, r R18 or R12R11N R10 NR9 Rl3 and R2 is or r7 , in which R7 is selected between -C(=O)-O-R8, OO Rl2^11wherein R7 is between -OR3, Ri2R-i 1N J. Jj-R7 or , in the Rw nr9 R13 O (i) Ri is selected r15^ r r18 NR16R17 and R2 is selected R15 Ί r R18 between -C(=O)-O-R8, NRirR17 NR16R17 R18 , wherein R7 is and R2 is selected that R7 is selected between -C(=O)-O-R8, O provided that Ri and R2 cannot both be -OH or both -OR3 at the same time; and pharmaceutically acceptable salts thereof., 3. The compound of claim 1, wherein: (ai) R1 is -OH and R2 is selected from: C(=O)-O-R8; , in which R7 is (a-¡¡) R1 is -OR3 and R2 is selected between: AnxR2» Or (b) R1 is xny R2 is selected between: O -or3, v / n (c) R1 is υ v A z Γ19 A'°^£>c (d) R1 is 0 ° A jCrR? (e) R1 is fz Γ19 oAÁ=° ΆΆΑοΖΑ6 u ξ 'm ' 'p , y 0 ; ^6 and R2 is -OR3; Z Γ19 ) °'X^Tí)f=0 Ac> and R2 is selected between: -OR3 and 0 ; in which R7 is -C(=O)-O-Rsy ​​R2 is -OR3; 0 zAA'^A'^10 R12R11N l_ A (f) R1 is 0 , in which R7 is and R2 is -OR3; Is it JaAr? (g) R1 is 0 , in which R7 is FA JCar? (h) R1 is 0 ^^ , in which R7 is ύΖ (i) R1 is aa and r2 is -OR3. R-I3 ONR ί ί R 2 r14n^^o , A ^15 and R2 is -OR3; 0 0-^ r 1 β NR16R17 yR2es-ORs;y 4. The compound of any of claims 1-3, wherein R3, R4, R5, Re, Rs, R9, R10, R13, R15 and R22 are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane.

5. The compound of any of claims 1-4, wherein R9, R14, R17, R19, R20, R23 and R24 are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl and t-butyl.

6. The compound of any of claims 1-5, wherein the protecting group is selected from tert-butoxycarbonyl (boc), carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), 9-fluorenylmethyloxycarbonyl group (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), Troc (trichloroethyl chloroformate), (4-nitrophenyl)sulfonyl (nosilo) and nitrophenylsulfenyl (Nps).

7. The compound of any of claims 1-6, wherein Rw is selected from phenyl.

8. The compound of any of claims 1-7, wherein: (a-i) R1 is -OH and R2 is selected from: (33); (a-ii) R1 is selected from -OCH3, -OCH(CH3)2 and -OC(CH3)3 and R2 is selected from: (c) R1 is L J2 13 or (d) R1 is and R2 is selected from: -OCH3 (11) and O and R2 is -OCH3(3, 4). or ^ and R2 is -OCH3(18, 20); and 9. The compound of any of claims 1-8, wherein the compound and pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition comprising a compound of any of claims 1-9 and a pharmaceutically acceptable excipient.

11. A method for treating a disease, disorder, or condition associated with inflammation, the method comprising administering to a subject in need of treatment a compound of any of claims 1-9 or a composition of claim 10.