Inhibitors of onecut2

Abstract

The design, synthesis and in-vitro / in-vivo testing of a series of ONECUT2 inhibitors is described. The compounds such as JYX072 feature a trihydroxy benzene moiety that binds to the ONECUT2 target. This advanced series of compounds has improved drug-like properties over earlier leads. The disclosed compounds are useful for the treatment of prostate cancer, particularly castration-resistant prostate cancer.

Description

[0001] INHIBITORS OF ONECUT2

[0002] RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 727,406, filed December 3, 2024, which is incorporated herein by reference.

[0004] GOVERNMENT SUPPORT

[0005] This invention was made with government support under Grant Nos. 1R01CA271750, 2P50CA092131, and 1R01CA220327 awarded by the National Institutes of Health, and W81XWH- 22-1-0940 awarded by the Department of Defense. The government has certain rights in the invention.

[0006] BACKGROUND OF THE INVENTION

[0007] Over 30,000 American men die from prostate cancer (PC) each year, making it the second- leading cause of death from cancer in men. The annual number of PC deaths continues to increase, highlighting an unmet need for effective therapies against advanced disease. Despite recent clinical advances with androgen receptor (AR) signaling inhibitors (ARSIs), such as abiraterone and enzalutamide, and aggressive treatment with chemotherapy, progression to treatment-resistant disease, known as “castration-resistant” PC (CRPC), remains a major clinical dilemma. In its early stages, PC is dependent on the AR, a nuclear receptor transcription factor (TF) and the primary PC oncoprotein. Treatment resistance can involve AR signaling perturbations that amplify AR activity, or that generate constitutively active AR variants. Consequently, the AR axis remains a principal target in new drug development.

[0008] Importantly, however, therapeutic resistance can also arise from “lineage plasticity,” a process that gives rise to tumor cells that lose dependence on AR, and that show Stem-like and Neuroendocrine (NE) features. The mechanisms underlying the adaptive switch from AR-dependent to AR-indifferent cell states are not understood, and the key molecular networks that “take over” from the AR remain unresolved. Multi-omic profiling has shown that over 30% of CRPC tumors contain lineage plastic subtypes not recognizable by histologic criteria. Emergence of these subtypes is associated with shortened disease-specific survival. Despite the high frequency of resistance to AR-targeted therapy with disease progression, there are no precision therapeutic strategies for CRPC outside the androgen- AR axis. This dearth of targeting strategies has hampered clinical advances against lethal PC.

[0009] We were the first to identify the CUT / Hox TF ONECUT2 (HNF6 , hereafter OC2) as a critical driver of lethal PC and a potential therapeutic target (Nat. Med., 24(12), 1887). A major role

[0010] 1

[0011] 550.004W01 fre001648 for OC2 in disease progression was confirmed independently by another lab shortly after our original report (Nat. Comm n., 10(1), 278). Our published and ongoing work has shown that OC2 governs a broad growth, survival and lineage identity network that promotes AR indifference and the emergence of treatment-resistant variants. A study from our group demonstrated that OC2 can promote diverse treatment resistance mechanisms in both adenocarcinoma as well as NEPC. In one metastatic CRPC series from a rapid autopsy cohort, OC2 was expressed in the majority of specimens, including those with high AR activity based on gene signature analysis. These findings suggest that suppressing OC2 clinically would confer substantial benefit against treatment-resistant disease in many cases.

[0012] Accordingly, there is an urgent need for the development of new drugs to treat castrationresistant prostate cancer and other cancers that overexpress OC2.

[0013] SUMMARY

[0014] We have shown that OC2 can be targeted directly with a novel small molecule inhibitor (SMI), CSRM-617 (Chartl), which caused regression of pre-formed human CRPC metastases in vivo. TFs are notoriously hard to inhibit with small molecules. About 300 out of over 1,600 TFs encoded by the human genome are linked to a specific disease, and of these only a tiny percentage can be suppressed with SMIs. This makes OC2 a particularly interesting therapeutic target. In work described below, we have developed new OC2 inhibitors with improved and more drug-like features. This novel class of SMIs represents an opportunity to interrogate OC2 functions in lethal disease. However, they also provide a foundation for further optimization into an entirely new class of precision agents against lethal PC.

[0015] Accordingly, this disclosure provides a compound of Formula I:

[0016] Ax— R2— R1(I), wherein,

[0017] R1is:

[0018] NH(C=O)NHaryl, NH(C=O)NHalkyl, NH(C=O)heterocycloalkyl, or CONH(aryl);

[0019] Rlais (C4-C6)cycloalkyl, (Ci-Ce)alkyl, cyclopropyl, (Cs-Cejheterocycloalkyl, phenyl, or pyridyl;

[0020] 2

[0021] 550.004W01 fre001648 Rlbis H; or

[0022] Rlaand Rlbform a 5- or 6-membered heterocycloalkyl with the nitrogen atom to which they are attached;

[0023] Rlcis (Ci-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, phenyl, pyridyl, (C2-Ce)alkoxy, (C2-C6)aminoalkyl, or H;

[0024] Rldis (C2-Ce)alkoxy, (C2-C6)aminoalkyl, phenyl, benzyl, pyridyl, (C3-C6)heterocycloalkyl, (C3-C6)cycloalkyl, or CH2(C3-C6)cycloalkyl;

[0025] Rleis H, (Ci-C6)alkyl, (C3-C6)cycloalkyl, CH2(C3-C6)cycloalkyl, or benzyl; or

[0026] Rldand Rleform a 5- or 6-membered heterocycloalkyl with the nitrogen atom to which they are attached;

[0027] R2is absent, CH2, CH2CH2, phenyl, pyrazole, piperazine, or CH=N;

[0028] Ax is: each R3is independently OH, halo, CN, O(Ci-C6)alkyl, OCH2CH2OH, CH2OH, NH2,

[0029] NHCOCH3, NH(C=O)CH=CH2, CF2H, B(OH)2, NH(C=O)CH2CH2OH, pyridyl, tetrazolyl, or phenyl; or when present, two R3taken together form a 5 -membered heteroaryl, 5- membered heterocycloalkyl, or benzo group with the carbon atoms to which they are attached; m is 3, 2, or 1; each R4is independently OH or halo; n is 0, 1, 2, or 3; each R5is independently OH or H, wherein at least one R5is OH; and

[0030] R6is OH or H; wherein Ax is optionally further substituted with a substituted sulfur atom; phenyl, aryl, pyridyl, and heteroaryl are optionally substituted; (Ci-Ce)alkyl is optionally unbranched or branched; and (C4-C6)cycloalkyl is optionally saturated or unsaturated; or a pharmaceutically acceptable salt thereof.

[0031] 3

[0032] 550.004W01 fre001648 This disclosure also provides a method for treating cancer in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof.

[0033] The invention provides novel compounds of Formulas I-III, intermediates for the synthesis of compounds of Formulas I-III, as well as methods of preparing compounds of Formulas I-III. The invention also provides compounds of Formulas I-III that are useful as intermediates for the synthesis of other useful compounds. The invention provides for the use of compounds of Formulas I-III for the manufacture of medicaments useful for the treatment of cancer in a mammal, such as a human.

[0034] The invention provides for the use of the compositions described herein for use in medical therapy. The medical therapy can be treating cancer, including but not limited to breast cancer, lung cancer, pancreatic cancer, prostate cancer, or colon cancer. The invention also provides for the use of a composition as described herein for the manufacture of a medicament to treat a disease in a mammal, for example, cancer in a human. The medicament can include a pharmaceutically acceptable diluent, excipient, or carrier.

[0035] BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The following drawings form part of the specification and are included to further demonstrate certain embodiments or various aspects of the invention. In some instances, embodiments of the invention can be best understood by referring to the accompanying drawings in combination with the detailed description presented herein. The description and accompanying drawings may highlight a certain specific example, or a certain aspect of the invention. However, one skilled in the art will understand that portions of the example or aspect may be used in combination with other examples or aspects of the invention.

[0037] Figure 1A-B. Initial experiments showing anti-tumor efficacy of JYX072cis in vivo. Human 22Rvl CRPC subcutaneous xenografts in SCID / Beige mice were used. Tumor volume (A) and tumor weight (B) data are shown.

[0038] Figure 2. Comparison of cell viability of compound JYX060 against JYX057 and JYX058.

[0039] DETAILED DESCRIPTION

[0040] We have successfully obtained crystals of OC2DBDbound to CSRM-843. This was accomplished by soaking CSRM-843 into preformed crystals containing OC2DBD. The crystals diffract to a modest resolution of 2.8 A. In a preliminary diffraction data analysis, after the co-crystal structure was refined with bulk-solvent correction, we observe a large unaccounted electron density adjacent to C362, which likely represents CSRM-843. Subsequently, we have modeled the triphenol fragment of the inhibitor in the electron density and further refined it. The co-crystal structure of the triphenol shows it is bound to OC2DBD, with electron density favoring the meta-hydroxyl positioned

[0041] 4

[0042] 550.004W01 fre001648 at a distance less than 3.5 A from the R359 backbone carbonyl. The triphenol fragment is also positioned near the sulfhydryl of C362, resembling a thiol-aromatic interaction as previously characterized (J. Am. Chem. Soc. 139(5), 1842). Further refinements of the crystal structure are expected to be useful for the structure based optimization of OC2 inhibitors such as the compounds shown in Chart 1.

[0043] Chart 1. Examples of ONECUT2 Inhibitors.

[0044] Additional information by the inventors is provided with the disclosure of PCT Publication Nos. WO 2017 / 213897, titled 'Compositions and Methods for Treating Cancer', and

[0045] WO 2019 / 040647, titled 'Compositions and Methods for Treating Cancer', which applications are hereby incorporated by reference in their entirety.

[0046] Definitions.

[0047] The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the recited terms have the following meanings. All other terms and phrases used in this specification have their ordinary meanings as one of skill in the art would understand. Such ordinary meanings may be obtained by reference to technical dictionaries, such as Hawley ’s Condensed Chemical Dictionary 14thEdition, by R. J. Lewis, John Wiley & Sons, New York, N.Y., 2001.

[0048] References in the specification to "one embodiment", "an embodiment", etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. An embodiment can also relate more than one aspect of the technology and encompass various embodiments. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described.

[0049] The singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such

[0050] 550.004W01 fre001648 compounds, so that a compound X includes a plurality of compounds X. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with any element described herein, and / or the recitation of claim elements or use of "negative" limitations.

[0051] The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated. The phrases "one or more" and "at least one" are readily understood by one of skill in the art, particularly when read in context of its usage. For example, the phrase can mean one, two, three, four, five, six, ten, 100, or any upper limit approximately 10, 100, or 1000 times higher than a recited lower limit. For example, one or more substituents on a phenyl ring refers to one to five, or one to four, for example if the phenyl ring is disubstituted.

[0052] As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability resulting from the standard deviations found in their respective testing measurements. When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value without the modifier "about" also forms a further aspect.

[0053] The terms "about" and "approximately" are used interchangeably. Both terms can refer to a variation of ± 5%, ± 10%, ± 20%, or ± 25% of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent, or as otherwise defined by a particular claim. For integer ranges, the term "about" can include one or two integers greater than and / or less than a recited integer at each end of the range. Unless indicated otherwise herein, the terms "about" and "approximately" are intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, composition, or embodiment. The terms "about" and "approximately" can also modify the endpoints of a recited range as discussed above in this paragraph.

[0054] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible subranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. It is therefore understood that each unit between two particular units are also disclosed. For example, if 10 to 15 is disclosed, then 11, 12, 13, and 14 are also disclosed, individually, and as part of a range. A recited range (e.g., weight percentages or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at

[0055] 6

[0056] 550.004W01 fre001648 least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as "up to", "at least", "greater than", "less than", "more than", "or more", and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0057] This disclosure provides ranges, limits, and deviations to variables such as volume, mass, percentages, ratios, etc. It is understood by an ordinary person skilled in the art that a range, such as “number 1” to “number ”, implies a continuous range of numbers that includes the whole numbers and fractional numbers. For example, 1 to 10 means 1, 2, 3, 4, 5, ... 9, 10. It also means 1.0, 1.1, 1.2. 1.3, ... , 9.8, 9.9, 10.0, and also means 1.01, 1.02, 1.03, and so on. If the variable disclosed is a number less than “numberlO”, it implies a continuous range that includes whole numbers and fractional numbers less than numberlO, as discussed above. Similarly, if the variable disclosed is a number greater than “numberlO”, it implies a continuous range that includes whole numbers and fractional numbers greater than numberlO. These ranges can be modified by the term “about”, whose meaning has been described above.

[0058] The recitation of a), b), c), ... or i), ii), iii), or the like in a list of components or steps do not confer any particular order unless explicitly stated.

[0059] One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation.

[0060] The term "contacting" refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo.

[0061] 7

[0062] 550.004W01 fre001648 An "effective amount" refers to an amount effective to treat a disease, disorder, and / or condition, or to bring about a recited effect. For example, an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art. The term "effective amount" is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host. Thus, an "effective amount" generally means an amount that provides the desired effect.

[0063] Alternatively, the terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations. However, the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration of the compositions, the type or extent of supplemental therapy used, ongoing disease process and type of treatment desired (e.g., aggressive vs. conventional treatment).

[0064] The terms "treating", "treat" and "treatment" include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and / or (iv) diminishing symptoms associated with the disease, pathologic or medical condition. Thus, the terms "treat", "treatment", and "treating" can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated. As such, the term "treatment" can include medical, therapeutic, and / or prophylactic administration, as appropriate.

[0065] As used herein, "subject" or “patient” means an individual having symptoms of, or at risk for, a disease or other malignancy. A patient may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, the patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., human or non-human) that may benefit from the administration of compositions contemplated herein. Examples of

[0066] 8

[0067] 550.004W01 fre001648 mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods provided herein, the mammal is a human.

[0068] As used herein, the terms “providing”, “administering,” “introducing,” are used interchangeably herein and refer to the placement of a compound of the disclosure into a subject by a method or route that results in at least partial localization of the compound to a desired site. The compound can be administered by any appropriate route that results in delivery to a desired location in the subject.

[0069] The compound and compositions described herein may be administered with additional compositions to prolong stability and activity of the compositions, or in combination with other therapeutic drugs.

[0070] The terms "inhibit", "inhibiting", and "inhibition" refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells. The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting.

[0071] The term “substantially” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, being largely but not necessarily wholly that which is specified. For example, the term could refer to a numerical value that may not be 100% the full numerical value. The full numerical value may be less by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20%.

[0072] Wherever the term “comprising” is used herein, options are contemplated wherein the terms “consisting of’ or “consisting essentially of’ are used instead. As used herein, “comprising” is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of' excludes any element, step, or ingredient not specified in the aspect element. As used herein, "consisting essentially of' does not exclude materials or steps that do not materially affect the basic and novel characteristics of the aspect. In each instance herein any of the terms "comprising", "consisting essentially of' and "consisting of' may be replaced with either of the other two terms. The disclosure illustratively described herein may be suitably practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.

[0073] This disclosure provides methods of making the compounds and compositions of the invention. The compounds and compositions can be prepared by any of the applicable techniques described herein, optionally in combination with standard techniques of organic synthesis. Many

[0074] 9

[0075] 550.004W01 fre001648 techniques such as etherification and esterification are well known in the art. However, many of these techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6; as well as standard organic reference texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed., by M. B. Smith and J. March (John Wiley & Sons, New York, 2001); Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modem Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing); Advanced Organic Chemistry, Part B: Reactions and Synthesis, Second Edition, Cary and Sundberg (1983); for heterocyclic synthesis see Hermanson, Greg T., Bioconjugate Techniques, Third Edition, Academic Press, 2013.

[0076] The formulas and compounds described herein can be modified using protecting groups. Suitable amino and carboxy protecting groups are known to those skilled in the art (see for example, Protecting Groups in Organic Synthesis, Second Edition, Greene, T. W., and Wuts, P. G. M., John Wiley & Sons, New York, and references cited therein; Philip J. Kocienski; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), and references cited therein); and Comprehensive Organic Transformations, Larock, R. C., Second Edition, John Wiley & Sons, New York (1999), and referenced cited therein.

[0077] The term "halo" or "halide" refers to fluoro, chloro, bromo, or iodo. Similarly, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0078] The term "alkyl" refers to a branched or unbranched hydrocarbon having, for example, from 1-20 carbon atoms, and often 1-12, 1-10, 1-8, 1-6, or 1-4 carbon atoms; or for example, a range between 1-20 carbon atoms, such as 2-6, 3-6, 2-8, or 3-8 carbon atoms. As used herein, the term “alkyl” also encompasses a “cycloalkyl”, defined below. Examples include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl (Ao-propyl), 1 -butyl, 2-methyl-l -propyl (isobutyl 2-butyl (secbutyl), 2-methyl-2-propyl (Lbutyl), 1 -pentyl, 2-pentyl, 3 -pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl,

[0079] 3 -methyl- 1 -butyl, 2-methyl-l -butyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,

[0080] 4-methyl-2-pentyl, 3 -methyl-3 -pentyl, 2-methyl-3 -pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, hexyl, octyl, decyl, dodecyl, and the like. The alkyl can be unsubstituted or substituted, for example, with a substituent described below or otherwise described herein. The alkyl can also be optionally partially or fully unsaturated. As such, the recitation of an alkyl group can include an alkenyl group or an alkynyl group. The alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., an alkylene).

[0081] An alkylene is an alkyl group having two free valences at a carbon atom or two different carbon atoms of a carbon chain. Similarly, alkenylene and alkynylene are respectively an alkene and an alkyne having two free valences at two different carbon atoms, or an alkenylene can have the two

[0082] 10

[0083] 550.004W01 fre001648 free valences on the same carbon.

[0084] The term "cycloalkyl" refers to cyclic alkyl groups of, for example, from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings. Cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like. The cycloalkyl can be unsubstituted or substituted. The cycloalkyl group can be monovalent or divalent and can be optionally substituted as described for alkyl groups. The cycloalkyl group can optionally include one or more cites of unsaturation, for example, the cycloalkyl group can include one or more carbon-carbon double bonds, such as, for example, 1 -cyclopent- 1-enyl, 1 -cyclopent-2-enyl, 1 -cyclopent-3 -enyl, cyclohexyl, 1- cyclohex-l-enyl, l-cyclohex-2-enyl, 1 -cyclohex-3 -enyl, and the like.

[0085] The term “heteroatom” refers to any atom in the periodic table that is not carbon or hydrogen. Typically, a heteroatom is O, S, N, or P. The heteroatom may also be a halogen, metal or metalloid.

[0086] The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3- to 10-membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,3-diazapanyl, 1,4-diazapanyl, 1 ,4-oxazepanyl, and 1,4- oxathiapanyl. The group may be a terminal group or a bridging group.

[0087] The term "aryl" refers to an aromatic hydrocarbon group derived from the removal of at least one hydrogen atom from a single carbon atom of a parent aromatic ring system. The radical attachment site can be at a saturated or unsaturated carbon atom of the parent ring system. The aryl group can have from 6 to 30 carbon atoms, for example, about 6-10 carbon atoms. The aryl group can have a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. The aryl can be unsubstituted or optionally substituted with a substituent described below. For example, a phenyl moiety or group may be substituted with one or more substituents Rxwhere Rxis at the ortho-, meta-, or ara-position, and X is an integer variable of 1 to 5.

[0088] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. The heteroaryl can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, as described in the definition of "substituted". Typical heteroaryl groups contain 2-20 carbon atoms in the ring skeleton in addition to the one or more heteroatoms, wherein the ring skeleton comprises a 5-membered ring, a 6-membered ring, two 5- membered rings, two 6-membered rings, or a 5 -membered ring fused to a 6-membered ring.

[0089] 11

[0090] 550.004W01 fre001648 Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H- quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, -carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, tetrazolyl, and xanthenyl. In one embodiment the term "heteroaryl" denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, aryl, or (Ci-C6)alkylaryl. In some embodiments, heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benzo-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.

[0091] As used herein, the term "substituted" or “substituent” is intended to indicate that one or more (for example, in various embodiments, 1-10; in other embodiments, 1-6; in some embodiments 1, 2, 3, 4, or 5; in certain embodiments, 1, 2, or 3; and in other embodiments, 1 or 2) hydrogens on the group indicated in the expression using “substituted” (or “substituent”) is replaced with a selection from the indicated group(s), or with a suitable group known to those of skill in the art, provided that the indicated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. Suitable indicated groups include, e.g., alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, carboxyalkyl, alkylthio, alkylsulfmyl, and alkylsulfonyl. Substituents of the indicated groups can be those recited in a specific list of substituents described herein, or as one of skill in the art would recognize, can be one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfmyl, alkylsulfonyl, and cyano. Suitable substituents of indicated groups can be bonded to a substituted carbon atom include F, Cl, Br, I, OR', OC(O)N(R')2, CN, CF3, OCF3, R', O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R')2, SR', SOR', SO2R', SO2N(R')2, SO3R', C(O)R', C(O)C(O)R', C(O)CH2C(O)R', C(S)R', C(O)OR', OC(O)R', C(O)N(R')2, OC(O)N(R')2, C(S)N(R')2, (CH2)O-2NHC(0)R', N(R')N(R')C(O)R', N(R')N(R')C(O)OR', N(R')N(R')CON(R')2, N(R')SO2R’, N(R')SO2N(R')2, N(R')C(O)OR', N(R')C(O)R', N(R')C(S)R', N(R')C(O)N(R')2, N(R')C(S)N(R')2, N(COR')COR', N(OR')R', C(=NH)N(R')2, C(O)N(OR')R', or C(=NOR')R' wherein R’ can be hydrogen or a carbon-based moiety (e.g., (Ci-C6)alkyl), and wherein the carbon-based moiety can

[0092] 12

[0093] 550.004W01 fre001648 itself be further substituted. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. When a substituent is divalent, such as O, it is bonded to the atom it is substituting by a double bond; for example, a carbon atom substituted with O forms a carbonyl group, C=O.

[0094] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, which form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane- polarized light. In describing an optically active compound, the prefixes D and L, or R and S. are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate (defined below), which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0095] The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0096] The term “IC50” is generally defined as the concentration required to inhibit a specific biological or biochemical function by half, or to kill 50% of the cells in a designated time period, typically 24 hours.

[0097] The term “EC50” in pharmacology refers to the half-maximal effective concentration. It is defined as the concentration of a drug, antibody, or toxicant that induces a biological response halfway between the baseline and maximum after a specified exposure timel. For a drug, it is the concentration required to achieve 50% of its maximal effect.

[0098] The term “warhead” refers to the reactive functionalities of drugs that engage in covalent interactions with an enzyme or receptor residue in either a reversible or an irreversible manner. For example, a substituent on a biologically active small molecule such as a Michael acceptor characterized by having an alpha, / >eta-unsaturated carbonyl group that is capable of undergoing a 1,4-nucleophilic addition reaction with a nucleophile. The nucleophile may be, for example, a thiol

[0099] 13

[0100] 550.004W01 fre001648 group of an enzyme that adds to the Michael acceptor which causes the enzyme to become inactivated.

[0101] Embodiments of the Technology.

[0102] 1. This disclosure provides a compound of Formula I:

[0103] Ax— R2— R1(I), wherein,

[0104] R1is:

[0105] NH(C=O)NHaryl, NH(C=O)NHalkyl, NH(C=O)heterocycloalkyl, or CONH(aryl);

[0106] Rlais (C4-C6)cycloalkyl, (Ci-C6)alkyl, cyclopropyl, (C3-C6)heterocycloalkyl, phenyl, or pyridyl;

[0107] Rlbis H; or

[0108] Rlaand Rlbform a 5- or 6-membered heterocycloalkyl with the nitrogen atom to which they are attached;

[0109] Rlcis (Ci-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)heterocycloalkyl, phenyl, pyridyl, (C2-Cg)alkoxy, (C2-C6)aminoalkyl, or H;

[0110] Rldis (C2-Ce)alkoxy, (C2-C6)aminoalkyl, phenyl, benzyl, pyridyl, (C3-C6)heterocycloalkyl, (C3-C6)cycloalkyl, or CH2(C3-C6)cycloalkyl;

[0111] Rleis H, (Ci-C6)alkyl, (C3-C6)cycloalkyl, CH2(C3-C6)cycloalkyl, or benzyl; or

[0112] Rldand Rleform a 5- or 6-membered heterocycloalkyl with the nitrogen atom to which they are attached;

[0113] R2is absent, CFb, CH2CH2, NH, phenyl, pyrazole, piperazine, or CH=N;

[0114] Ax is:

[0115] 14

[0116] 550.004W01 fre001648 each R3is independently OH, halo, CN, O(Ci-C6)alkyl, OCH2CH2OH, CH2OH, NH2,

[0117] NHCOCH3, NH(C=O)CH=CH2, CF2H, B(OH)2, NH(C=O)CH2CH2OH, pyridyl, tetrazolyl, or phenyl; or when present, two R3taken together form a 5 -membered heteteroaryl, 5- membered heterocycloalkyl, or benzo group with the carbon atoms to which they are attached; m is 3, 2, 1, or 0; each R4is independently OH or halo; n is 0, 1, 2, or 3; each R5is independently OH or H, wherein at least one R5is OH; and

[0118] R6is OH or H; wherein Ax is optionally further substituted with a substituted sulfur atom or a warhead; wherein phenyl, aryl, pyridyl, and heteroaryl are optionally substituted; wherein (Ci-Ce)alkyl is optionally unbranched or branched; and wherein (C4-C6)cycloalkyl is optionally saturated or unsaturated; wherein substituents of the optionally substituted phenyl, aryl, pyridyl, and heteroaryl are selected from the group consisting of fluoro, chloro, hydroxy, methoxy, ethoxy, methyl, ethyl, methylenehydroxy, amino, aminomethyl, aminoethyl, dimethylamino, diethylamino, thiol, thiomethyl, thioethyl, carboxy, methyl ester, ethyl ester, amido, methylamido, dimethylamido, phenyl, and substituted phenyl; preferably fluoro, hydroxy, and methoxy wherein a substituted sulfur atom on Ax is substituted with methyl, ethyl, phenyl, benzyl, a protein, or an enzyme; or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, when Rlcis (C3-C6)heterocycloalkyl or (C2-Ce)alkoxy, the bonding of the (C3-C6)heterocycloalkyl or (C2-Ce)alkoxy is such that the substituent does not form a peroxide bond with Formula la, lb, Ic, or Id.

[0120] In some embodiments, the compound is not 2-amino-3 -hydroxy -N-(2, 3,4- trihy droxyphenethyl)propenamide (C SRM- 122), (E)-2-amino-3 -hy droxy-N'-(2,3 ,4- trihydroxybenzylidene)propanehydrazide (CSRM-617), N-hydroxy-2-(2-(2,3,4- trihydroxyphenyl)acetamido)acetamide (CSRM-843). In some embodiments, the compound is not a CSRM compound.

[0121] 2. The compound of embodiment 1, wherein R1is represented by Formula la or lb:

[0122] 15

[0123] 550.004W01 fre001648

[0124] In some embodiments, R1is represented by Formula la. In some embodiments, R1is represented by Formula lb.

[0125] 3. The compound of embodiment 1 or 2, wherein Rlais cyclobutyl, CFb, or CH2CH2. In some embodiments, Rlais cyclobutyl.

[0126] 4. The compound of embodiment 1, wherein R1is represented by Formula Ic or Id:

[0127] In some embodiments, R1is represented by Formula Ic. In some embodiments, R1is represented by Formula Id.

[0128] 5. The compound of any one of embodiments 1-4, wherein Rlcis (Ci-C6)alkyl or (C3- C6)cycloalkyl. In some embodiments, Rlcis methyl.

[0129] 6. The compound of any one of embodiments 1-5, wherein R2is absent, CH2, CH2CH2, phenyl, or CH=N wherein the atom C of CH=N forms a carbon-carbon bond with Ax. In some embodiments, R2is absent, CH2, CH2CH2, or phenyl. In some embodiments, R2is absent.

[0130] 7. The compound of any one of embodiments 1-6, wherein Ax is: wherein optionally at least one R3is OH.

[0131] In some embodiments, Ax is:

[0132] In some embodiments, Ax is: , wherein each Wh is a warhead; and n 1 or 2.

[0133] 16

[0134] 550.004W01 fre001648 In some embodiments, Ax is: , wherein each Wh is independently a warhead or H.

[0135] 8. The compound of any one of embodiments 1-7, wherein R3is OH.

[0136] 9. The compound of any one of embodiments 1-8, wherein m is 3.

[0137] 10. The compound of any one of embodiments 1-9, wherein Formula I is represented by

[0138] Formula II: or a pharmaceutically acceptable salt thereof.

[0139] 11. The compound of any one of embodiments 1-9, wherein Formula I is represented by

[0140] Formula Hb: or a pharmaceutically acceptable salt thereof.

[0141] 12. The compound of any one of embodiments 1-11, wherein Rlais: wherein each = is independently a single bond, double bond, or aromatic bond; and

[0142] X is CH2, O, NH, or N(Ci-C6)alkyl when = is a single bond; or

[0143] X is CH or N when each = is an aromatic bond.

[0144] In some embodiments, X is CH2or CH. In some embodiments, Rlais

[0145] 13. The compound of any one of embodiments 1-9, wherein Formula I is represented by Formula

[0146] III:

[0147] 17

[0148] 550.004W01 fre001648 or a pharmaceutically acceptable salt thereof.

[0149] 14. The compound of embodiment 1, wherein the compound is JYX072 cis or trans or a pharmaceutically acceptable salt thereof.

[0150] 18

[0151] 550.004W01 fre001648

[0152]

[0153] 550.004W01 fre001648

[0154]

[0155] 550.004W01 fre001648

[0156] or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the compound rotates plane polarized light levorotatory. In some embodiments, the compound rotates plane polarized light dextrorotatory. In some embodiments, the compound has a stereocenter that has the (^-configuration. In some embodiments, the compound has a stereocenter that has the ( / ? (-configuration.

[0158] 16. A composition or combination comprising a compound of any one of embodiments 1-15 and an excipient. In some embodiments the composition or combination comprises enzalutamide, apalutamide, or both.

[0159] 17. A method for treating cancer in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound, composition, or combination of any one of embodiments 1-16. In some embodiments, the compound, or the compound in the composition or combination is in the form of a pharmaceutically acceptable salt. In some embodiments, the cancer overexpresses ONECUT2.

[0160] 18. The method of embodiment 17, wherein the cancer is prostate cancer, breast cancer, lung cancer, colon cancer, renal cancer, gastric cancer, brain cancer, or medulloblastoma. In some embodiments, the cancer is castration resistant prostate cancer (CRPC). In some other embodiments, the cancer is neuroblastoma, small cell lung cancer (SCLC), large cell neuroendocrine cancer (LCNEC), large-cell carcinoma (LCC), squamous cell carcinoma (SqCC), adenocarcinoma (AC).

[0161] 21

[0162] 550.004W01 fre001648 19. The method of embodiment 17 or 18, wherein the compound inhibits the cancer therapeutic target ONECUT2 with an ECso of less than about 5 micromolar in 22Rvl cells. In some embodiments, the ECso in 22Rvl cells is less than about 10 micromolar, about 5 micromolar, about 4 micromolar, about 3 micromolar, about 2 micromolar, about 1 micromolar, or about 0.5 micromolar.

[0163] 20. The method of embodiments 17-19, wherein a subject is treated for having prostate cancer by administering a combination of a ONECUT2 inhibitor with an androgen receptor signaling inhibitor (ARSI). In some embodiments the ARSI is enzalutamide. In other embodiments the ARSI is apalutamide.

[0164] 21. The method of embodiments 17-20, wherein the compound is 2,3,4-trihydroxy-N-((ls,3s)-3- (methoxycarbamoyl)cyclobutyl)benzamide (JYX072cis).

[0165] Results and Discussion.

[0166] The original OC2 inhibitor, CSRM-617 (SPR KD 4.5 pM, viability EC50 9.6 pM against human 22Rvl PC cells (Chart 2)), was modified to remove the PAINS (pan-assay interference compounds) phenolic-hydrazone chemotype to obtain CSRM-843, which maintains potency and selectivity (SPR KD 4.0 pM, viability EC50 13.2 pM) and shows substantially improved solubility. Based on this encouraging result, several CSRM-617 / 843 derivatives were synthesized using empirical, structure-activity relationship (SAR) criteria. One of these compounds, JYX057, deleted the methylene unit between the aryl and amide groups, while maintaining in vitro cell-based activity (EC50 10.8 pM, Chart 2). JYX057 contains an amide carbonyl directly attached to the triphenol ring, thus reducing aromatic ring electron density. JYX059 adds one methylene unit between the two amide groups and shows a modest improvement in cell activity (EC50 9.3 pM). The length of the side chains in CSRM-843 and JYX059 are very similar, but the data on JYX059 suggest the increased rigidity of the side chain was effective. Subsequently, compounds were synthesized with aliphatic rings as linkers between the two amides; for example, JYX072, both cis and trans isomers, JYX073 and JYX074 (Chart 2).

[0167] Chart 2. Summary of structure-activity relationship (SAR) studies from CSRM-617 to JYX072cis.

[0168] ECso values refer to results from a cell viability assay performed on 22Rvl human PC cells (values are average of 2-3 repeats).

[0169] 22

[0170] 550.004W01 fre001648

[0171] JYX072, which has a rigid cyclobutane in the cis configuration, trended in the right direction in affinity and potency (SPR KD 3.0 pM, viability EC50 2.0 pM), and anti -tumor efficacy in-vivo comparable to the parent compound. JYX072cis remained highly soluble, but also showed dramatic improvement in half-life and stability in comparison to other analogs, with 100% and 93% detectable in human and mouse plasma, respectively, after 1 h (Table 1). Based on these highly encouraging findings, compound JYX072cis is the lead analog for rational-based design to further optimize potency, in-vitro selectivity, and metabolic stability to derive suitable candidates to advance into in vivo PK and toxicology studies.

[0172] Table 1. In-vitro human / mouse plasma stability of selected analogs. High stability in human and mouse plasma of JYX072 is observed.

[0173] Potency optimization. The synthetic path of the lead compound JYX072cis is shown in

[0174] Scheme 1. Additional analogs can be prepared following a similar synthetic strategy, for example by

[0175] 550.004W01 fre001648 replacing starting material 1 with the corresponding new building block. Based on the success of rigid JYX072cis, we can screen additional analogs with different linker ring systems (Chart 3A), and different substituents at the end of the side chain (Chart 3B). Preliminary CSRM-843 / OC2 co-crystal data show interactions of meta-OH of the 1,2, 3 -tri oxygenated phenyl ring with Arg359, and the aromatic ring with Cys362 sulfhydryl group. Additional data from the crystallization can be used to further refine the optimization efforts.

[0176] Scheme 1. JYX072cis synthetic pathway.

[0177] Chart 3. Examples of analogs that could improve potency with linker variations (A); and alkyl variations on the end of side chain (B).

[0178] 24

[0179] 550.004W01 fre001648 Optimization of JYX072cis to enhance DMPKand safety. Because of the possibility that the terminal O-methyl hydroxamate group of JYX072cis may show affinity for zinc, we can replace it with an amide, as shown in Chart 4. JYX072cis in PK studies showed substantially improved metabolic stability based on half-life in both human and mouse plasma (Table 1). JYX072cis contains a carbonyl group directly attached to the triphenol ring (Chart 2) to reduce electron density, and hence minimize its metabolic oxidation rate. Notably, there are FDA- approved drugs on the market with similar 1,2, 3 -tri oxygenated phenyl units. Preliminary co-crystal OC2 / CSRM-843 data show that the meta-hydroxy group of CSRM-843 may be important for binding, with a close hydrogen-bond interaction with Arg359 backbone carbonyl oxygen. Therefore, we have prepared analogs with monohydroxyphenyl and dihydroxyphenyl units, while keeping the meta-OH to retain the activity of the JYX072cis structure (Chart 5A). In addition, we can test some isoteric replacements (Chart 5B), and changing the 1,2, 3 -trihydroxyphenyl to a 1,2,3- trihydroxy cycloalkyl unit is also possible (Chart 5C). In vivo experiments show that JYX072cis exhibits anti-tumor efficacy similarly to CSRM-617 (Figure 1).

[0180] Chart 4. Examples of terminal amide targets.

[0181] Chart 5. Examples of mono- and dihydroxy-analogs based on JYX072 structure (A); bioisosteres of phenol and catechol groups (B); 1,2, 3 -trihydroxy cycloalkyl analogs (C).

[0182] 25

[0183] 550.004W01 fre001648

[0184]

[0185] In summary, the in-vitro data shows bioavailability is 21%, half-life is 0.67 h IV or 3.7 h PO, and AUC is 105 IV; 25.4 PO, which result is considered moderately low. However, CL is 160 IV or 657 PO, which is high and indicates that the compound is easily cleared. Since P450 oxidation is acceptable, glucuronidation could most likely be a responsible factor that affects clearance due to the three aromatic hydroxyls. Thus, P450 oxidation results indicate that the triphenols are not oxidizing to quinones, which can be toxic. Also, the in-vitro pharmacology safety profile appears to be clean. However, COX2 was inhibited at over 50% (i.e. 71%) at 10 uM, similar to compound CSRM-617.

[0186] Pharmaceutical Formulations.

[0187] The compounds described herein can be used to prepare therapeutic pharmaceutical compositions, for example, by combining the compounds with a pharmaceutically acceptable diluent, excipient, or carrier. The compounds may be added to a carrier in the form of a salt or solvate. For example, in cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, and -glycerophosphate. Suitable inorganic

[0188] 26

[0189] 550.004W01 fre001648 salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts.

[0190] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods.

[0191] The compounds of the formulas described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms. The forms can be specifically adapted to a chosen route of administration, e.g., oral or parenteral administration, by intravenous, intramuscular, topical or subcutaneous routes.

[0192] The compounds described herein may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. For oral administration, compounds can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet. Compounds may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations typically contain at least 0.1% of active compound. The percentage of the compositions and preparations can vary and may conveniently be from about 0.5% to about 60%, about 1% to about 25%, or about 2% to about 10%, of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions can be such that an effective dosage level can be obtained.

[0193] The tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate. A sweetening agent such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring, may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0194] 27

[0195] 550.004W01 fre001648 The active compound may be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil. Under ordinary conditions of storage and use, preparations may contain a preservative to prevent the growth of microorganisms.

[0196] Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions, dispersions, or sterile powders comprising the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and / or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by agents delaying absorption, for example, aluminum monostearate and / or gelatin.

[0197] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, optionally followed by fdter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation can include vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the solution.

[0198] For topical administration, compounds may be applied in pure form, e.g., when they are liquids. However, it will generally be desirable to administer the active agent to the skin as a composition or formulation, for example, in combination with a dermatologically acceptable carrier, which may be a solid, a liquid, a gel, or the like.

[0199] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, or water-alcohol / glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol sprayer.

[0200] 28

[0201] 550.004W01 fre001648 Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

[0202] Examples of dermatological compositions for delivering active agents to the skin are known to the art; for example, see U.S. Patent Nos. 4,992,478 (Geria), 4,820,508 (Wortzman), 4,608,392 (Jacquet et al.), and 4,559,157 (Smith et al.). Such dermatological compositions can be used in combinations with the compounds described herein where an ingredient of such compositions can optionally be replaced by a compound described herein, or a compound described herein can be added to the composition.

[0203] Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent No. 4,938,949 (Borch et al.). The amount of a compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of an attendant physician or clinician.

[0204] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

[0205] The invention provides therapeutic methods of treating cancer in a mammal, which involve administering to a mammal having cancer an effective amount of a compound or composition described herein. A mammal includes a primate, human, rodent, canine, feline, bovine, ovine, equine, swine, caprine, bovine and the like. Cancer refers to any various type of malignant neoplasm, for example, colon cancer, breast cancer, melanoma and leukemia, and in general is characterized by an undesirable cellular proliferation, e.g., unregulated growth, lack of differentiation, local tissue invasion, and metastasis.

[0206] The following Examples are intended to illustrate the above invention and should not be construed as to narrow its scope. One skilled in the art will readily recognize that the Examples suggest many other ways in which the invention could be practiced. It should be understood that numerous variations and modifications may be made while remaining within the scope of the invention.

[0207] 29

[0208] 550.004W01 fre001648 EXAMPLES

[0209] Example 1. Experimental Section.

[0210] General: Tetrahydrofuran (THF) was distilled from sodium under an argon atmosphere.

[0211] Dichloromethane (DCM) was distilled from calcium hydride under an argon atmosphere. All other solvents or reagents were purified according to literature procedures.1H NMR spectra were recorded on Bruker spectrometers at 400 MHz or 500 MHz and are reported relative to deuterated solvent signals. Data for1H NMR spectra are reported as follows: chemical shift (8 ppm), multiplicity, coupling constant (Hz) and integration. Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad.13C NMR spectra were recorded on Bruker Spectrometers at 100 MHz or 125 MHz. Data for13C NMR spectra are reported as follows: chemical shift (8 ppm), multiplicity and coupling constant (Hz). Splitting patterns are designated as the same in1H NMR. High resolution mass spectrometry was taken on a Thermo Fisher Scientific Exactive Plus mass spectrometer equipped with an lonSense ID-CUBE DART ion source.

[0212] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(2,3,4-trihydroxyphen- ethyl)propanamide, JYX001:

[0213] To a solution of 1 (0.75 g, 1.71 mmol), 2 (0.61 g, 2.55 mmol) and 1 -hydroxybenzotriazole hydrate (HOBT, 0.39 g, 2.55 mmol) in anhydrous DCM (15.0 ml) was added diisopropyl-ethylamine (DIPEA, 1.5 ml) at 0 °C under argon. After stirring at 0 °C for 15 min, a suspension of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC-HC1, 0.49 g, 2.55 mmol) in DCM (5.0 ml) was added dropwise. Then the mixture was warmed to 21 °C and stirred for 16 h. The mixture was diluted with DCM, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give compound 3 (0.71 g, 63%). Compound 3 (0.71 g, 1.07 mmol) was dissolved in a mixture of ethanol (10.0 ml) and ethyl acetate (10.0 ml) and 5%-Pd / C (115 mg, 0.054 mmol) was then added. The resulting mixture was then stirred at 21 °C for 12 h under hydrogen. The reaction mixture was filtered through a Celite plug, and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give JYX001 (156 mg, 57%). 'H NMR (400 MHz, CD3OD) 8 6.43 (d, J= 8.4 Hz,lH), 6.27 (d, J = 8.4 Hz,lH), 3.73 (dd, J= 11.2, 4.8 Hz,lH), 3.62 (dd, J= 10.8, 6.4 Hz,lH), 3.51 (dd, J= 6.4, 4.8 Hz,lH), 3.42-3.37 (m, 2H), 2.73 (t, J= Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.1, 145.8,

[0214] 550.004W01 fre001648 145.5, 134.3, 121.4, 118.7, 107.9, 65.4, 57.8, 41.4, 30.7; HRMS (ESI, m / z): calcd for C11H15N2O5 ([M-H]’): 255.0986, Found: 255.0986.

[0215] Synthesis and Characterization of (S)-2-Amino-N-(2,4-dihydroxyphenethyl)-3-hydroxy- propanamide, JYX002:

[0216] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(2,4-bis(benzyloxy)phenyl)ethan-l -amine.JH NMR (400 MHz, CD3OD) 8 6.84 (d, J= 8.0 Hz,lH), 6.26 (d, J= 2.4 Hz,lH), 6.20 (dd, J= 8.0, 2.4 Hz, 1H), 3.73 (dd, J= 11.2, 4.4 Hz, 1H), 3.62 (dd, J= 11.2, 6.4 Hz, 1H), 3.53 (dd, J= 6.4, 4.8 Hz,lH), 3.42-3.33 (m, 2H), 2.69 (t, J = 7.2 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 172.3, 158.1, 157.4, 132.1, 117.7, 107.5, 103.5, 64.0, 57.2, 41.1, 30.4; HRMS (ESI, m / z): calcd for C11H15N2O4 ([M-H]’): 239.1037, Found: 239.1029.

[0217] Synthesis and Characterization of (S)-2-Amino-N-(2,4-difluoro-3-hydroxyphenethyl)-3- hydroxypropanamide, JYX003:

[0218] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(3 -(benzyl oxy)-2,4-difluorophenyl)ethan-l -amine. 'H NMR (400 MHz, g-DMSO) 8 7.97 (t, J = 5.6 Hz, 1H), 6.87 (td, J = 9.6, 1.6 Hz, 1H), 6.64-6.58 (m, 1H), 3.45 (dd, J= 10.4, 4.8 Hz, 1H), 3.32 (dd, J= 10.4, 6.4 Hz, 1H), 3.25-3.19 (m, 2H), 3.16 (dd, J= 6.4, 4.4 Hz,lH), 2.64 (t, J= 7.0 Hz, 2H);13C NMR (100 MHz, r / g-DMSO) 8 173.0, 151.5 (dd, J= 239.0, 12.7 Hz), 151.4 (dd, J = 239.4, 13.4 Hz), 134.2 (t, J= 16.5 Hz), 123.0 (dd, J= 14.2, 3.1 Hz), 119.3 (dd, J = 7.6, 6.2 Hz), 111.4 (dd, J = 18.0, 3.4 Hz), 64.4, 57.2, 39.0, 28.9; HRMS (ESI, m / z): calcd for C11H13F2N2O3 ([M-H]’): 259.0900, Found: 259.0896.

[0219] Synthesis and Characterization of (S)-2-Amino-N-(3-fluoro-2,4-dihydroxyphenethyl)-3- hydroxypropanamide, JYX004;

[0220] 31

[0221] 550.004W01 fre001648

[0222] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(2,4-bis(benzyloxy)-3-fluorophenyl)ethan-l -amine.JH NMR (400 MHz, CD3OD) 8 6.65 (dd, J= 8.4, 2.0 Hz, 1H), 6.30 (t, J= 8.2 Hz, 1H), 3.65 (dd, J= 10.8, 4.8 Hz, 1H), 3.56 (dd, J= 10.8, 6.0 Hz, 1H), 3.39-3.33 (m, 3H), 2.72 (t, J= 7.2 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.0, 145.4 (d, J= 11.1 Hz), 145.0 (d, J= 11.9 Hz), 143.0 (d, J = 230.9 Hz), 125.5 (d, J= 3.8 Hz), 120.0, 108.7 (d, J= 1.2 Hz), 65.4, 57.8, 40.8, 30.5 (d, J = 2.3 Hz); HRMS (ESI, m / z): calcd for C11H16FN2O4 ([M+H]+): 259.1089, Found: 259.1075.

[0223] Synthesis and Characterization of (S)-2-Amino-N-(2,4-dihydroxy-3-methoxyphenethyl)-3- hydroxypropanamide, JYX005:

[0224] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(2,4-bis(benzyloxy)-3-methoxyphenyl)ethan-l -amine. 'H NMR (400 MHz, CD3OD) 8 6.63 (d, J= 8.4 Hz, 1H), 6.26 (d, J= 8.4 Hz, 1H), 3.75 (s, 3H), 3.66 (dd, J= 10.8, 4.8 Hz, 1H), 3.57 (dd, J = 11.2, 6.4 Hz, 1H), 3.40-3.35 (m, 3H), 2.71 (t, J= 7.2 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 174.5, 150.2, 149.8, 136.9, 126.1, 118.6, 108.1, 65.1, 60.8, 57.7, 41.0, 30.6; HRMS (ESI, m / z): calcd for C12H17N2O5 ([M-H]-): 269.1143, Found: 269.1124.

[0225] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(2,3,4-tris(2-hydroxy- ethoxy)phenethyl)propanamide, JYX006:

[0226] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(2,3,4-tris(2-(benzyloxy)ethoxy)phenyl)ethan-l-amine. 'H NMR (400 MHz, CD3OD) 8 6.88 (d, J= 8.4 Hz, 1H), 6.72 (d, J= 8.4 Hz, 1H), 4.12-4.08 (m, 4H), 4.04-4.01 (m, 2H), 3.86-3.82 (m,

[0227] 32

[0228] 550.004W01 fre001648 4H), 3.76-3.74 (m, 2H), 3.63 (dd, J= 10.8, 4.8 Hz, 1H), 3.56 (dd, J= 10.8, 6.0 Hz, 1H), 3.38 (t, J =

[0229] 7.2 Hz, 2H), 3.32-3.30 (m, 1H) , 2.79 (t, J= 7.0 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.6, 153.2, 152.5, 142.8, 127.0, 126.1, 110.7, 76.2, 76.0, 71.9, 65.6, 62.6, 62.3, 61.7, 58.0, 41.5, 30.6; HRMS (ESI, m / z): calcd for C17H29N2O8 ([M+H]+): 389.1918, Found: 389.1907.

[0230] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(3,4,5-trihydroxyphen- ethyl)propanamide, JYX007:

[0231] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(3,4,5-tris(benzyloxy)phenyl)ethan-l-amine.XH NMR (400 MHz, CD3OD) 8 6.19 (s, 2H), 3.64 (dd, J= 10.8, 4.8 Hz, 1H), 3.56 (dd, J= 10.8, 6.0 Hz, 1H), 3.35-3.31 (m, 3H), 2.56 (t, J= 7.4 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.2, 147.0, 132.6, 131.4, 108.7, 65.5, 57.9, 42.1, 36.1; HRMS (ESI, m / z): calcd for C11H15N2O5 ([M-H]’): 255.0986, Found: 255.0991.

[0232] Synthesis and Characterization of (S)-2-Amino-N-(3,5-dihydroxy-4-methoxyphenethyl)-3- hydroxypropanamide, JYX008:

[0233] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(3,5-bis(benzyloxy)-4-methoxyphenyl)ethan-l-amine. 'H NMR (400 MHz, CD3OD) 8 6.21 (s, 2H), 3.73 (s, 3H), 3.64 (dd, J= 10.8, 5.2 Hz, 1H), 3.56 (dd, J= 10.8, 6.0 Hz, 1H), 3.37-3.30 (m, 3H), 2.58 (t, J= 7.4 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.3, 151.6, 136.4, 135.4, 109.0, 65.6, 60.8, 57.9, 41.8, 36.2; HRMS (ESI, m / z): calcd for C12H17N2O5 ([M-H]’): 269.1143, Found: 269.1143.

[0234] Synthesis and Characterization of (S)-2-Amino-N-(2,6-dihydroxyphenethyl)-3-hydroxy- propanamide, JYX009:

[0235] 33

[0236] 550.004W01 fre001648 This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(2,6-bis(benzyloxy)phenyl)ethan-l -amine.JH NMR (400 MHz, CD3OD) 8 6.80 (t, J= 8.2 Hz, 1H), 6.28 (d, J= 8.0 Hz, 2H), 3.65 (dd, J= 10.8, 4.8 Hz, 1H), 3.55 (dd, J= 10.8, 6.0 Hz, 1H), 3.36 (td, J= 7.0, 2.8 Hz, 2H), 3.32-3.30 (m, 1H), 2.85 (t, J= 7.0 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.3, 157.7, 128.2, 113.6, 107.6, 65.4, 58.0, 40.4, 23.5; HRMS (ESI, m / z): calcd for C11H15N2O4 ([M-H]'): 239.1037, Found: 239.1039.

[0237] Synthesis and Characterization of (S)-2-Amino-N-(2,5-dihydroxyphenethyl)-3-hydroxy- propanamide, JYX010:

[0238] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(2,5-bis(benzyloxy)phenyl)ethan-l-amine. 'H NMR (400 MHz, CD3OD) 8 6.58 (d, J= 8.4 Hz, 1H), 6.54 (d, 7 = 2.8 Hz, 1H), 6.47 (dd, 7= 8.4, 2.8 Hz, 1H), 3.65 (dd, 7= 10.8, 4.8 Hz, 1H), 3.57 (dd, 7= 10.8, 6.0 Hz, 1H), 3.40 (td, 7= 7.2, 1.6 Hz, 2H), 3.34-3.31 (m, 1H), 2.72 (t, 7= 7.2 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.2, 151.1, 149.4, 127.6, 118.2, 116.8, 114.9, 65.5, 57.9, 40.8, 31.1; HRMS (ESI, m / z): calcd for C11H15N2O4 ([M-H]'): 239.1037, Found: 239.1041.

[0239] Synthesis and Characterization of (S)-2-Amino-N-(3,4-dihydroxyphenethyl)-3-hydroxy- propanamide, JYX011:

[0240] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(3,4-bis(benzyloxy)phenyl)ethan-l -amine. 'H NMR (400 MHz, CD3OD) 8 6.66 (d, 7= 8.0 Hz, 1H), 6.63 (d, 7= 2.0 Hz, 1H), 6.51 (dd, 7= 8.0, 2.0 Hz, 1H), 3.64 (dd, 7= 10.8, 5.2 Hz, 1H), 3.56 (dd, 7= 10.8, 6.0 Hz, 1H), 3.37-3.31 (m, 3H), 2.62 (t, 7= 7.4 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.1, 146.3, 144.8, 132.0, 121.1, 116.9, 116.4, 65.5, 57.8, 42.1, 35.9; HRMS (ESI, m / z): calcd for C11H15N2O4 ([M-H]'): 239.1037, Found: 239.1040.

[0241] Synthesis and Characterization of (S)-2-Amino-N-(2,3-dihydroxyphenethyl)-3-hydroxy- propanamide, JYX012:

[0242] 34

[0243] 550.004W01 fre001648

[0244] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(2,3-bis(benzyloxy)phenyl)ethan-l -amine. 'H NMR (400 MHz, CD3OD) 8 6.65-6.62 (m, 1H), 6.58-6.56 (m, 2H), 3.65 (dd, J= 10.8, 4.8 Hz, 1H), 3.57 (dd, J = 10.8, 6.4 Hz, 1H), 3.41 (td, .7 = 7,2, 2.8 Hz, 2H), 3.35 (dd, J= 6.4, 4.8 Hz, 1H), 2.79 (t, J= 7.0 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 174.9, 146.2, 144.7, 127.1, 122.4, 120.4, 114.6, 65.3, 57.8, 40.8, 30.9; HRMS (ESI, m / z): calcd for C11H15N2O4 ([M-H]’): 239.1037, Found: 239.1039.

[0245] Synthesis and Characterization of (S)-2-Amino-N-(3,5-dihydroxyphenethyl)-3-hydroxy- propanamide, JYX013:

[0246] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(3,5-bis(benzyloxy)phenyl)ethan-l-amine. 'H NMR (400 MHz, CD3OD) 8 6.14 (d, J= 2.4 Hz, 2H), 6.10 (t, J= 2.2 Hz, 1H), 3.65 (dd, J= 10.8, 5.2 Hz, 1H), 3.57 (dd, J= 10.8, 6.0 Hz, 1H), 3.39-3.34 (m, 3H), 2.62 (t, J= 7.2 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.0, 159.6, 142.6, 108.3, 101.7, 65.4, 57.8, 41.7, 36.5; HRMS (ESI, m / z): calcd for C11H15N2O4 ([M-H]’): 239.1037, Found: 239.1040.

[0247] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(2-hydroxyphenethyl)- propanamide, JYX014:

[0248] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(2-(benzyloxy)phenyl)ethan-l -amine. 'H NMR (400 MHz, CD3OD) 8 7.06-6.98 (m, 2H), 6.74-6.70 (m, 2H), 3.64 (dd, J= 10.8, 4.8 Hz, 1H), 3.56 (dd, J= 10.8, 6.0 Hz, 1H), 3.41 (td, J= 7.2, 3.2 Hz, 2H), 3.34-3.31 (m, 1H), 2.79 (t, J= 7.2 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.1,

[0249] 35

[0250] 550.004W01 fre001648 156.6, 131.7, 128.7, 126.7, 120.6, 116.0, 65.4, 57.9, 40.7, 31.1; HRMS (ESI, m / z): calcd for C11H15N2O3 ([M-H]'): 223.1088, Found: 223.1091.

[0251] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(4-hydroxyphenethyl)- propanamide, JYX015:

[0252] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(4-(benzyloxy)phenyl)ethan-l -amine.JH NMR (400 MHz, CD3OD) 8 7.03-7.00 (m, 2H), 6.70-6.68 (m, 2H), 3.63 (dd, J= 10.8, 4.8 Hz, 1H), 3.56 (dd, J= 10.8, 6.4 Hz, 1H), 3.38-3.31 (m, 3H), 2.68 (t, J = 7.4 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.2, 157.0, 131.2, 130.8, 116.3, 65.5, 57.8, 42.2, 35.7; HRMS (ESI, m / z): calcd for C11H15N2O3 ([M-H]'): 223.1088, Found: 223.1091.

[0253] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(3-hydroxyphenethyl)- propanamide, JYX016:

[0254] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(3 -(benzyl oxy )phenyl)ethan-l -amine. 'H NMR (400 MHz, CD3OD) 8 7.06 (t, J= 7.8 Hz, 1H), 6.68-6.59 (m, 3H), 3.64 (dd, J= 10.8, 4.8 Hz, 1H), 3.56 (dd, J= 10.8, 6.0 Hz, 1H), 3.39 (td, J= 7.6, 1.6 Hz, 2H), 3.33-3.30 (m, 1H), 2.70 (t, J= 7.4 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.4, 158.6, 141.9, 130.5, 121.0, 116.6, 114.3, 65.6, 57.9, 41.8, 36.4; HRMS (ESI, m / z): calcd for C11H15N2O3 ([M-H]'): 223.1088, Found: 223.1091.

[0255] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(2-(5-hydroxy-lH-indol-3- yl)ethyl)propanamide, JYX017:

[0256] 550.004W01 fre001648 This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(5-(benzyloxy)-l / f-indol-3-yl)ethan-l-amine.JH NMR (400 MHz, CD3OD) 8 7.13 (dd, J = 8.8, 0.4 Hz, 1H), 7.00 (s, 1H), 6.92 (dd, J = 2.4, 0.8 Hz, 1H), 6.64 (dd, J= 8.8, 2.0 Hz, 1H), 3.63 (dd, J= 10.8, 5.2 Hz, 1H), 3.56 (dd, J= 10.8, 6.0 Hz, 1H), 3.46 (t, J= 7.2 Hz, 2H), 3.32-3.29 (m, 1H), 2.86 (t, J = 7.0 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 175.4, 151.1, 133.1, 129.4, 124.4, 112.7, 112.4 (2C overlapping), 103.5, 65.6, 57.9, 41.2, 26.2; HRMS (ESI, m / z): calcd for C13H16N3O3 ([M- H]’): 262.1197, Found: 262.1197.

[0257] Synthesis and Characterization of (S)-2-Oxo-N-(3,4,5-trihydroxyphenethyl)oxazolidine-4- carboxamide, JYX018:

[0258] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(3,4,5-tris(benzyloxy)phenyl)ethan-l-amine and (8)-2-oxooxazolidine-4-carboxylic acid. 'H NMR (500 MHz, CD3OD) 8 6.19 (s, 2H), 4.55 (dd, J= 9.1, 9.0 Hz, 1H), 4.30 (dd, J= 9.5, 5.0 Hz, 1H), 4.21 (dd, J= 9.0, 5.5 Hz, 1H), 3.41-3.36 (m, 2H), 2.59 (td, J= 7.3, 3.5 Hz, 2H);13C NMR (125 MHz, CD3OD) 8 172.8, 162.1, 147.1, 132.7, 131.1, 108.7, 69.5, 56.1, 42.2, 35.9; HRMS (ESI, m / z): calcd for C12H15N2O6 ([M+H]+): 283.0925, Found: 283.0922.

[0259] Synthesis and Characterization of l-(4-Methoxyphenyl)-3-(3,4,5-trihydroxyphen-ethyl)urea, JYX019:

[0260] A mixture of 4 (1.32 g, 3.00 mmol) and 5 (0.54 g, 3.62 mmol) in anhydrous DCM (20.0 ml) was stirred at 21 °C for 12 h under argon. The solvent was removed under vacuum and the resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give compound 6 (1.41 g, 80%). Compound 6 (1.41 g, 2.40 mmol) was dissolved in a mixture of ethanol (15.0 ml) and ethyl acetate (15.0 ml) and 5%-Pd / C (255 mg, 0.12 mmol) was then added. The resulting mixture was then stirred at 21 °C for 12 h under hydrogen. The reaction mixture was filtered through a Celite plug, and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give JYX019 (0.53 g, 69%). 'H NMR (400 MHz, CD3OD) 8 7.17-7.15 (m, 2H), 6.80-6.78 (m, 2H), 6.21 (s, 2H), 3.71 (s, 3H), 3.32 (t, J= 7.0 Hz, 2H),

[0261] 37

[0262] 550.004W01 fre001648 2.56 (t, J = 7.0 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 158.8, 157.1, 147.1, 133.6, 132.6, 131.6, 122.9, 115.1, 108.7, 55.9, 42.5, 36.9; HRMS (ESI, m / z): calcd for C16H17N2O5 ([M-H]’): 317.1143, Found: 317.1143.

[0263] Synthesis and Characterization of l-(4-Fluorophenyl)-3-(3,4,5-trihydroxyphenethyl)-urea, JYX020:

[0264] This product was prepared according to the synthetic procedure used for JYX019, starting with 2-(3,4,5-tris(benzyloxy)phenyl)ethan-l-amine and l-fluoro-4-isocyanatobenzene.1H NMR (400 MHz, CD3OD) 8 7.29-7.26 (m, 2H), 6.94 (t, J= 9.0 Hz, 2H), 6.21 (s, 2H), 3.33 (t, J= 7.0 Hz, 2H), 2.57 (t, J = 7.0 Hz, 2H);13C NMR (100 MHz, CD3OD) 8 159.8 (d, J= 238.3 Hz), 158.4, 147.1, 137.1 (d, J= 2.7 Hz), 132.6, 131.5, 122.1 (d, J= 7.6 Hz), 116.1 (d, J= 22.6 Hz), 108.7, 42.4, 36.8; HRMS (ESI, m / z): calcd for C15H14FN2O4 ([M-H]'): 305.0943, Found: 305.0945.

[0265] This product was prepared according to the synthetic procedure used for JYX019, starting with 2-(3,4,5-tris(benzyloxy)phenyl)ethan-l-amine and isocyanatoethane. 'H NMR (400 MHz, CD3OD) 8 6.18 (s, 2H), 3.24 (t, J= 7.2 Hz, 2H), 3.09 (q, J= 7.2 Hz, 2H), 2.51 (t, J= 7.4 Hz, 2H), 1.04 (t, J= 7.2 Hz, 3H);13C NMR (100 MHz, CD3OD) 8 161.2, 147.0, 132.5, 131.7, 108.7, 42.7, 37.1, 35.8, 15.7; HRMS (ESI, m / z): calcd for C11H15N2O4 ([M-H]'): 239.1037, Found: 239.1039.

[0266] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N'-(3,4,5-trihydroxybenzyl-

[0267] A mixture of 7 (154 mg, 1.0 mmol) and 8 (119 mg, 1.0 mmol) in ethanol (10.0 ml) was stirred at 21 °C for 24 h under argon. The precipitated product was collected by filtration, washed with ethanol and ether, and dried in vacuo to give product JYX022 (222 mg, 87%).1H NMR (500

[0268] 38

[0269] 550.004W01 fre001648 MHz, r / e-DMSO), indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, signals of major isomer marked with an asterisk, 8 7.96* (s, 0.7H), 7.68 (s, 0.3H), 6.60* (s, 1.4H), 6.55 (s, 0.6H), 4.08 (t, J= 5.3 Hz, 0.3H), 3.59 (dd, J= 10.5, 4.5 Hz, 0.3H), 3.50* (dd, J= 10.0, 5.5 Hz, 0.7H), 3.49-3.41 (m, 1H), 3.25* (t, J= 5.8 Hz, 0.7H);13C NMR (125 MHz, c / 6-DMSO) indicated that it was a mixture of (E / Z isomers, in a molar ratio of ca. 7:3, signals of major isomer marked with an asterisk, 8 174.8, 170.0*, 148.1*, 146.8, 146.7*, 144.5, 136.3*, 136.2, 125.0*, 124.9, 106.7*, 106.4, 64.9*, 64.3, 56.9*, 53.8; HRMS (ESI, m / z): calcd for C10H14N3O5 ([M+H]+): 256.0928, Found: 256.0926.

[0270] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N'-(4-hydroxy-3,5-dimethoxy- benzylidene)propanehydrazide, JYX023:

[0271] This product was prepared according to the synthetic procedure used for JYX022, starting with 4-hydroxy-3, 5 -dimethoxybenzaldehyde.1H NMR (500 MHz, r / g-DMSO), indicated that it was a mixture of (E / Z isomers, in a molar ratio of ca. 7:3, signals of major isomer marked with an asterisk, 8 8.12* (s, 0.7H), 7.83 (s, 0.3H), 6.91* (s, 1.4H), 6.89 (s, 0.6H), 4.13 (t, J= 5.3 Hz, 0.3H), 3.78* (s, 4.2H), 3.77 (s, 1.8H), 3.60 (dd, J= 10.0, 4.5 Hz, 0.3H), 3.51* (dd, J= 10.5, 6.0 Hz, 0.7H), 3.47-3.41 (m, 1H), 3.28* (t, J= 5.8 Hz, 0.7H);13C NMR (125 MHz, c / r DMSO) indicated that it was a mixture of (E / Z isomers, in a molar ratio of ca. 7:3, signals of major isomer marked with an asterisk, 8 175.3, 170.3*, 148.7, 148.6*, 147.9*, 143.8, 138.3*, 138.1, 125.1*, 125.0, 105.0*, 104.8, 64.9*, 64.7, 56.9*, 56.5*, 53.8; HRMS (ESI, m / z): calcd for C12H18N3O5 ([M+H]+): 284.1241, Found: 284.1238.

[0272] Synthesis and Characterization of (S)-2-Amino-N-(2-(2,3-dioxo-l,2,3,4-tetrahydro-

[0273] This product was prepared according to the synthetic procedure used for JYX001, starting with starting with 6-(2-aminoethyl)-l,4-dihydroquinoxaline-2,3-dione. 'H NMR (500 MHz, d&- DMSO) 8 7.90 (t, J= 5.8 Hz, 1H), 7.02 (d, J= 8.5 Hz, 1H), 6.92-6.90 (m, 2H), 3.46 (dd, J= 10.0, 4.5 Hz, 1H), 3.26-3.20 (m, 3H), 3.14 (t, J= 5.5 Hz, 1H), 2.64 (t, J= 7.5 Hz, 2H);13C NMR (125 MHz,

[0274] 39

[0275] 550.004W01 fre001648 6 / 6-DMSO) 8 173.5, 155.8, 155.5, 135.0, 126.0, 124.4, 124.1, 115.6, 115.5, 64.7, 57.4, 49.1, 35.3;

[0276] HRMS (ESI, m / z): calcd for C13H15N4O4 ([M-H]’): 291.1099, Found: 291.1098.

[0277] Synthesis and Characterization of (S)-2-Amino-N-(4-amino-3,5-dihydroxyphenethyl)-3- hydroxypropanamide, JYX025:

[0278] This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(3,5-bis(benzyloxy)-4-nitrophenyl)ethan-l-amine. 'H NMR (500 MHz, CD3OD) 8 6.18 (s, 2H), 3.65 (dd, J= 11.0, 5.0 Hz, 1H), 3.57 (dd, J= 11.0, 6.0 Hz, 1H), 3.36-3.32 (m, 3H), 2.57 (t, J = 7.3 Hz, 2H);13C NMR (125 MHz, CD3OD) 8 175.4, 147.6, 131.0, 121.4, 108.4, 65.6, 57.9, 42.1, 36.1; HRMS (ESI, m / z): calcd for C11H18N3O4 ([M+H]+): 256.1292, Found: 256.1287.

[0279] Synthesis and Characterization of (S)-2-Amino-N'-(2,3-dihydroxybenzylidene)-3- hydroxypropanehy dr azide, JYX026:

[0280] This product was prepared according to the synthetic procedure used for JYX022, starting with 2,3 -dihydroxybenzaldehyde. 'H NMR (500 MHz, CD3OD) 8 8.31 (s, 1H), 6.87-6.85 (m, 2H), 6.75 (dd, J= 8.0, 7.0 Hz, 1H), 3.74 (d, J= 5.5 Hz, 2H), 3.49 (t, J= 5.3 Hz, 1H);13C NMR (125 MHz, CD3OD) 8 171.8, 151.9, 147.5, 146.8, 122.5, 120.5, 119.4, 118.7, 65.5, 57.1; HRMS (ESI, m / z): calcd for C10H14N3O4 ([M+H]+): 240.0979, Found: 240.0978.

[0281] Synthesis and Characterization of (S)-2-Amino-N'-(3,4-dihydroxybenzylidene)-3- hydroxypropanehy dr azide, JYX027:

[0282] This product was prepared according to the synthetic procedure used for JYX022, starting with 3,4-dihydroxybenzaldehyde.1H NMR (500 MHz, CD3OD) indicated that it was a mixture of

[0283] 40

[0284] 550.004W01 fre001648 (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 7.99* (s, 0.7H), 7.78 (s, 0.3H), 7.29* (d, J= 1.5 Hz, 0.7H), 7.18 (d, J= 2.0 Hz, 0.3H), 7.00* (dd, J = 8.0, 1.5 Hz, 0.7H), 6.93 (dd, J= 8.0, 1.5 Hz, 0.3H), 6.77 (d, J= 8.0 Hz, 1H), 4.37 (t, J = 5.0 Hz, 0.3H), 3.87 (dd, J= 11.0, 4.0 Hz, 0.3H), 3.74-3.70* (m, 1.4H), 3.60 (dd, J= 14.0, 7.0 Hz, 0.3H), 3.46* (t, J= 5.8 Hz, 0.7H);13C NMR (125 MHz, CD3OD) indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 175.4, 172.1*, 150.8*, 149.9*, 149.5, 147.0, 146.93*, 146.91, 127.4, 127.1*, 122.7*, 121.9, 116.3, 116.2*, 114.1*, 113.7, 65.5*, 64.7, 57.1*, 54.8; HRMS (ESI, m / z): calcd for C10H14N3O4 ([M+H]+): 240.0979, Found: 240.0976.

[0285] Synthesis and Characterization of (S)-2-Amino-N'-(2,5-dihydroxybenzylidene)-3- hydroxypropanehydrazide, JYX028:

[0286] This product was prepared according to the synthetic procedure used for JYX022, starting with 2,5-dibhydroxybenzaldehyde. 'H NMR (500 MHz, CD3OD) 8 8.28 (s, 1H), 6.83 (d, J= 2.5 Hz, 1.0 Hz, 1H), 6.74-6.76 (m, 2H), 3.73 (d, J= 5.5 Hz, 2H), 3.48 (t, J= 5.8 Hz, 1H);13C NMR (125 MHz, CD3OD) 8 171.9, 152.5, 151.2, 151.1, 120.5, 119.5, 118.3, 116.4, 65.5, 57.1; HRMS (ESI, m / z): calcd for C10H14N3O4 ([M+H]+): 240.0979, Found: 240.0978.

[0287] Synthesis and Characterization of (S)-2-Amino-N'-(3,4-dihydroxy-5-methoxybenzyl-idene)-3- hydroxypropanehydrazide, JYX029:

[0288] This product was prepared according to the synthetic procedure used for JYX022, starting with 3,4-dihydroxy-5-methoxybenzaldehyde.1H NMR (500 MHz, CD3OD) indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 8.04* (s, 0.7H), 7.76 (s, 0.3H), 6.76-6.75 (m, 1H), 6.74* (d, J= 1.5 Hz, 0.7H), 6.69 (d, J = 1.5 Hz, 0.3H), 4.11 (dd, J= 6.0, 5.0 Hz, 0.3H), 3.76* (s, 2.1H), 3.75 (s, 0.9H), 3.73-3.71 (m, 0.3H), 3.60 (dd, J= 10.5, 5.0 Hz, 0.3H), 3.50* (dd, J= 10.5, 5.5 Hz, 0.7H), 3.45* (dd, J= 10.5, 6.0 Hz, 0.7H), 3.26* (t, J = 5.8 Hz, 0.7H);13C NMR (125 MHz, r / g-DMSO) indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8

[0289] 41

[0290] 550.004W01 fre001648 175.1, 170.1*, 149.0*, 148.9, 148.0*, 146.5, 146.4*, 144.1, 137.2*, 137.0, 125.1*, 125.0, 108.8*, 107.7, 103.4, 102.8*, 64.9*, 64.5, 56.9*, 56.37, 56.35*, 53.8; HRMS (ESI, m / z): calcd for C11H16N3O5 ([M+H]+): 270.1084, Found: 270.1082.

[0291] Synthesis and Characterization of (S)-2-Amino-N'-(3-fluoro-2,4-dihydroxybenzylidene)-3- hydroxypropanehy dr azide, JYX030:

[0292] This product was prepared according to the synthetic procedure used for JYX022, starting with 3-fluoro-2,4-dihydroxybenzaldehyde.JH NMR (500 MHz, CD3OD) 8 8.24 (s, 1H), 6.98 (dd, J = 7.8, 1.5 Hz, 1H), 6.44 (dd, J= 8.0, 8.0 Hz, 1H), 3.75 (d, J= 5.0 Hz, 2H), 3.52 (t, J= 5.5 Hz, 1H);13C NMR (125 MHz, CD3OD) 8 171.0, 151.7 (d, J= 3.1 Hz), 150.6 (d, J= 10.5 Hz), 149.1 (d, J= 10.6 Hz). 140.0 (d, J= 235.6 Hz), 126.7 (d, J = 3.9 Hz,), 112.8 (d, J= 1.9 Hz), 109.8 (d, J= 1.3 Hz), 65.2, 57.0; HRMS (ESI, m / z): calcd for C10H13FN3O4 ([M+H]+): 258.0885, Found: 258.0876.

[0293] Synthesis and Characterization of (S)-2-Amino-N'-(2,4-dihydroxy-3-(hydroxymethyl)- benzylidene)-3-hydroxypropanehydrazide, JYX031:

[0294] This product was prepared according to the synthetic procedure used for JYX022, starting with 2,4-dihydroxy-3-(hydroxymethyl)benzaldehyde.1H NMR (500 MHz, CD3OD) 8 8.21 (s, 1H), 7.06 (d, J= 10.5 Hz, 1H), 6.39 (d, J= 10.5 Hz, 1H), 4.76 (s, 2H), 3.71 (d, J= 6.8 Hz, 2H), 3.45 (t, J = 6.8 Hz, 1H);13C NMR (125 MHz, r / g-DMSO) 8 170.0, 159.6, 158.5, 150.1, 131.3, 114.9, 110.4, 107.8, 64.7, 56.5, 53.0; HRMS (ESI, m / z): calcd for C11H16N3O5 ([M+H]+): 270.1084, Found: 270.1084.

[0295] Synthesis and Characterization ofN-(6-((2-(L-Seryl)hydrazineylidene)methyl)-2,3- dihydroxypheny I) acetamide, JYX032:

[0296] 550.004W01 fre001648

[0297] This product was prepared according to the synthetic procedure used for JYX022, starting with A-(6-formyl-2,3-dihydroxyphenyl)acetamide. 'H NMR (500 MHz, CD3OD) indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 8:2, with signals of the major isomer marked with an asterisk, 8 8.14* (s, 0.8H), 7.84 (s, 0.2H), 7.14 (d, J= 8.5 Hz, 0.2H), 7.05* (d, J= 6.4 Hz, 0.8H), 6.70 (d, J= 8.0 Hz, 1H), 3.61-3.58 (m, 0.4H), 3.51-3.47* (m, 1.6H), 3.28 (t, J= 5.3 Hz, 1H), 2.18* (s, 2.4H), 2.03 (s, 0.6H);13C NMR (125 MHz, c / r,-DMSO) indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 8:2, with signals of the major isomer marked with an asterisk, 8 173.5,

[0298] 170.3*, 169.5*, 169.4, 148.3*, 147.3, 146.1*, 141.9, 140.4, 139.1*, 125.1*, 121.8, 119.4*, 119.2*,

[0299] 116.0, 113.5, 112.9*, 112.6, 63.8*, 63.1, 55.7*, 52.7, 22.8*, 22.5; HRMS (ESI, m / z): calcd for C12H15N4O5 ([M-H]-): 295.1048, Found: 295.1049.

[0300] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-l-(6, 7 ,8-trihydroxy-3,4-

[0301] To a solution of 9 (0.84 g, 1.86 mmol), 2 (0.45 g, 1.88 mmol) and hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU, 0.71 g, 1.87 mmol) in anhydrous DCM (20.0 ml) was dropwise added diisopropylethylamine (DIPEA, 0.65 ml) at 0 °C under argon. After stirring at 0 °C for 15 min, the mixture was warmed to 21 °C and stirred for 2 h. The mixture was diluted with DCM, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give the compound 10 (1.08 g, 86%). Compound 10 (1.08 g, 1.61 mmol) was dissolved in a mixture of ethanol (10.0 ml) and ethyl acetate (10.0 ml) and 5%-Pd / C (172 mg, 0.081 mmol) was then added. The resulting mixture was then stirred at 21 °C for 12 h under hydrogen. The reaction mixture was filtered through a Celite plug, and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give JYX033 (150 mg, 35%). 'H NMR (500 MHz, CD3OD) indicated that it was a mixture of rotamers, in a molar ratio ca. 1:1, 8 6.16 (s, 1H), 4.65-4.51 (m, 2H), 4.04 (t, J= 6.0 Hz, 0.5H), 3.99 (t, J= 6.0 Hz, 0.5H), 3.79-3.65 (m, 3H), 3.59-3.51 (m, 1H), 2.74 (br s, 1H), 2.65 (t, J= 5.8 Hz, 1H);13C 43

[0302] 550.004W01 fre001648 NMR (125 MHz, CD3OD), indicated that it was a mixture of rotamers, in a molar ratio ca. 1:1, 8 173.8, 173.5, 146.2, 145.9, 144.1, 143.8, 132.5, 132.4, 126.8, 126.3, 112.9, 112.6, 107.4, 107.2, 65.8, 65.5, 54.2, 53.8, 44.7, 44.0, 42.0, 41.8, 30.1, 28.9; HRMS (ESI, m / z): calcd for C12H17N2O5 ([M+H]+): 269.1132, Found: 269.1129.

[0303] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(2',3',4'-trihydroxy-[l, - biphenyl]-2-yl)propanamide, JYX034:

[0304] To a solution of 11 (1.95 g, 4.00 mmol), 2 (1.44 g, 6.02 mmol) and HATU (2.28 g, 6.00 mmol) in anhydrous DMF (30.0 ml) was added diisopropylethylamine (DIPEA, 1.4 ml) under argon. The mixture was then heated to 60 °C and stirred for 5 h. The mixture was cooled to 21 °C and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give compound 12 (1.77 g, 62%). Compound 12 (1.77 g, 2.50 mmol) was dissolved in a mixture of isopropanol (15.0 ml) and THF (15.0 ml) and 5%-Pd / C (266 mg, 0.125 mmol) was then added. The resulting mixture was then stirred at 21 °C for 12 h under hydrogen. The reaction mixture was filtered through a Celite plug, and the filtrate was concentrated to about 5.0 ml under reduced pressure. The precipitated product was collected by filtration, washed with isopropanol and ether, and dried in vacuo to give product JYX034 (298 mg, 39%).1H NMR (500 MHz, CD3OD) indicated that it was a mixture of rotamers, in a molar ratio of ca. 8:2, with signals of the major isomer marked with asterisk, 8 7.94* (d, J= 8.0 Hz, 0.8H), 7.86 (d, J = 8.0 Hz, 0.2H), 7.29 (td, J = 7.8, 1.5 Hz, 1H), 7.24 (dd, J= 7.5, 1.5 Hz, 1H), 7.17 (qd, J= 7.8, 1.0 Hz, 1H), 6.51-6.48 (m, 1H), 6.46-6.44 (m, 1H), 4.41-4.40 (m, 0.2H), 3.93-3.90 (m, 0.2H), 3.70-3.69 (m, 1H), 3.64-3.61* (m, 0.8H), 3.41* (m, 0.8H);13C NMR (125 MHz, CD3OD), indicated that it was a mixture of rotamers, in a molar ratio of ca. 8:2, with signals of the major isomer marked with asterisk, 8 173.8*, 170.5,

[0305] 147.2, 147.1*, 144.5*, 144.3, 136.6*, 136.1, 134.6*, 134.5, 133.8, 133.2*, 132.3, 132.2*, 128.3*,

[0306] 128.2, 126.4, 125.9*, 124.5, 123.7*, 122.6, 122.3*, 119.4, 119.0*, 108.9, 108.7*, 66.9*, 65.1*, 65.0, 62.7; HRMS (ESI, m / z): calcd for C15H17N2O5 ([M+H]+): 305.1132, Found: 305.1127.

[0307] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(2',3',4'-trihydroxy-[l, - biphenyl]-3-yl)propanamide, JYX035:

[0308] 44

[0309] 550.004W01 fre001648

[0310] This product was prepared according to the synthetic procedure used for JYX034, starting with 2',3',4'-tris(benzyloxy)-[l,l'-biphenyl]-3-amine. 'H NMR (500 MHz, CD3OD) 8 7.69-7.68 (m, 1H), 7.54-7.52 (m, 1H), 7.30-7.28 (m, 2H), 6.63 (d, J= 8.5 Hz, 1H), 6.41 (d, J= 8.5 Hz, 1H), 3.83- 3.77 (m, 2H), 3.64 (t, J = 5.5 Hz, 1H);13C NMR (125 MHz, CD3OD) 8 172.7, 146.6, 144.6, 141.3,

[0311] 138.9, 134.5, 129.3, 126.5, 122.2, 122.0, 121.5, 119.2, 108.3, 64.9, 58.1; HRMS (ESI, m / z): calcd for C15H15N2O5 ([M-H]’): 303.0986, Found: 303.0974.

[0312] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(2',3',4'-trihydroxy-[l, - biphenyl] -4-yl)propanamide, JYX036:

[0313] This product was prepared according to the synthetic procedure used for JYX034, starting with 2',3',4'-tris(benzyloxy)-[l,l'-biphenyl]-4-amine.JH NMR (500 MHz, CD3OD) 8 7.57 (d, J= 8.5 Hz, 2H), 7.49 (d, J = 9.0 Hz, 2H), 6.62 (d, J= 8.5 Hz, 1H), 6.40 (d, J= 8.5 Hz, 1H), 3.81-3.78 (m, 2H), 3.62 (t, J= 5.5 Hz, 1H);13C NMR (125 MHz, CD3OD) 8 172.8, 146.4, 144.6, 137.3, 136.8, 134.5, 130.5, 121.8, 121.3, 120.9, 108.3, 65.0, 58.2; HRMS (ESI, m / z): calcd for C15H15N2O5 ([M-H]’ ): 303.0986, Found: 303.0973.

[0314] Synthesis and Characterization ofN-(4-Fluorophenyl)-3-(2,3,4-trihydroxyphenyl)-lH- pyrazole-1 -carboxamide, JYX037:

[0315] This product was prepared according to the synthetic procedure used for JYX019, starting with 3-(2,3,4-tris(benzyloxy)phenyl)-l / f-pyrazole and l-fluoro-4-isocyanatobenzene. 'H NMR (500 MHz, CD3OD) 8 8.35 (d, J= 3.0 Hz, 1H), 7.68-7.65 (m, 2H), 7.14-7.10 (m, 3H), 6.91 (d, J= 3.0 Hz, 1H), 6.46 (d, J= 8.5 Hz, 1H);13C NMR (125 MHz, CD3OD) 8 161.3 (d, J = 241.3 Hz), 156.3, 149.4,

[0316] 550.004W01 fre001648 148.3, 146.2, 134.7 (d, J = 2.9 Hz), 134.4, 131.1, 124.6 (d, J= 8.1 Hz), 119.7, 116.4 (d, J = 22.8 Hz),

[0317] 110.2, 108.7, 107.6; HRMS (ESI, m / z): calcd for C16H11FN3O4 ([M-H]’): 328.0739, Found: 328.0735.

[0318] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-l-(4-(2,3,4-trihydroxy- phenyl) piper azin- 1-y I) propan- 1 -one, JYX038:

[0319] This product was prepared according to the synthetic procedure used for JYX033, starting with l-(2,3,4-tris(benzyloxy)phenyl)piperazine. *H NMR (500 MHz, CD3OD) 8 6.42 (d, J= 9.0 Hz, 1H), 6.28 (d, J= 8.5 Hz, 1H), 3.95 (t, J = 6.0 Hz, 1H), 3.78-3.73 (m, 4H), 3.65 (dd, J= 11.0, 6.0 Hz, 1H), 3.56 (dd, J= 10.5, 6.0 Hz, 1H), 2.86-2.81 (m, 4H);13C NMR (125 MHz, CD3OD) 8 173.4, 144.6, 141.4, 134.3, 133.5, 111.7, 107.0, 65.9, 53.8, 53.3, 53.2, 47.1, 43.7; HRMS (ESI, m / z): calcd for CI3HI8N3O5([M-H]’): 296.1252, Found: 296.1247.

[0320] Synthesis and Characterization ofN-Hydroxy-2-(2-(3,4,5-trihydroxyphenyl)-acet-

[0321] To a solution of 13 (1.30 g, 2.86 mmol), 14 (0.62 g, 2.86 mmol) and 1 -hydroxybenzotriazole hydrate (HOBT, 0.66 g, 4.31 mmol) in anhydrous DCM (20.0 ml) was added diisopropyl-ethylamine (DIPEA, 1.0 ml) at 0 °C under argon. After stirring at 0 °C for 15 min, a suspension of EDC HC1 (0.83 g, 4.33 mmol) in DCM (5.0 ml) was added dropwise. Then the mixture was warmed to 21 °C and stirred for 16 h. The mixture was diluted with DCM, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give the compound 15 (1.31 g, 74%). Compound 15 (1.31 g, 2.12 mmol) was dissolved in a mixture of ethanol (15.0 ml) and anhydrous THF (15.0 ml) and 5%-Pd / C (226 mg, 0.106 mmol) was then added. The resulting mixture was stirred at 21 °C for 12 h under hydrogen. The reaction mixture was filtered through a celite plug, and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give JYX039 (261 mg, 48%).1H NMR (500 MHz, CD3OD) 8 6.28 (s, 2H), 3.76 (s, 2H), 3.34 (s, 2H);13C NMR (125 MHz, CD3OD) 8 175.2, 168.7, 147.1, 133.3, 127.1, 109.2, 43.3, 41.4; HRMS (ESI, m / z): calcd for C10H11N2O6 ([M-H]’): 255.0623, Found: 255.0620.

[0322] 46

[0323] 550.004W01 fre001648 Synthesis and Characterization of 2-(2,4-Dihydroxy-3-methoxyphenyl)-N-(2-(hydroxy- amino) -2 -oxoethyl) acetamide, JYX040:

[0324] This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(2,4-bis(benzyloxy)-3-methoxyphenyl)acetic acid. 'H NMR (500 MHz, CD3OD) 8 6.71 (d, J = 8.0 Hz, 1H), 6.32 (d, J= 8.5 Hz, 1H), 3.78 (s, 3H), 3.47 (s, 2H), 3.34 (s, 2H);13C NMR (125 MHz,

[0325] CD3OD) 8 175.6, 168.6, 151.1, 150.0, 137.2, 126.6, 115.0, 108.5, 60.8, 41.6, 38.5; HRMS (ESI, m / z): calcd for C11H13N2O6 ([M-H]’): 269.0779, Found: 269.0778.

[0326] Synthesis and Characterization of 2-(3-Fluoro-2 ,4-dihydroxyphenyl)-N-(2-(hydroxy-amino)- 2-oxoethyl)acetamide, JYX041:

[0327] This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(2,4-bis(benzyloxy)-3-fluorophenyl)acetic acid.JH NMR (500 MHz, CD3OD) 8 6.73 (dd, J = 8.5, 2.0 Hz, 1H), 6.37 (dd, J= 8.3, 8.3 Hz, 1H), 3.78 (s, 2H), 3.50 (s, 2H);13C NMR (125 MHz, CD3OD) 8 175.3, 168.6, 146.2 (d, J = 10.9 Hz), 145.2 (d, J= 12.1 Hz), 143.1 (d, J = 232.3 Hz), 126.0 (d, J = 4.1 Elz), 116.1, 109.0 (d, J = 0.9 Hz), 41.6, 38.1 (d, J = 2.1 Hz); HRMS (ESI, m / z): calcd for C10H10FN2O5 ([M-H]’): 257.0579, Found: 257.0570.

[0328] Synthesis and Characterization ofN-Hydroxy-2-(2-(2,3,4-trimethoxyphenyl)-aceta- mido) acetamide, JYX042:

[0329] This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(2,3,4-trimethoxyphenyl)acetic acid. 'H NMR (500 MHz, c / r,-DMSO) 8 10.46 (s, 1H), 8.79 (d, .7= 1.5 Hz, 1H), 8.05 (t, J= 5.8 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.70 (d, J= 8.5 Hz, 1H), 3.74 (s,

[0330] 47

[0331] 550.004W01 fre001648 3H), 3.71 (s, 3H), 3.70 (s, 3H), 3.59 (d, J= 6.0 Hz, 2H), 3.36 (s, 2H);13C NMR (125 MHz, d6-

[0332] DMSO) 8 171.3, 166.4, 152.8, 152.0, 142.2, 125.4, 122.6, 108.1, 61.1, 60.8, 56.3, 40.6, 36.7; HRMS

[0333] (ESI, m / z): calcd for C13H17N2O6 ([M-H]’): 297.1092, Found: 297.1085.

[0334] Synthesis and Characterization ofN-Hydroxy-2-(2-(2,3,4-trifluorophenyl)acetamido)- acetamide, JYX043:

[0335] This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(2,3,4-trifluorophenyl)acetic acid.XH NMR (500 MHz, r / g-DMSO) 8 10.53 (s, 1H), 8.82 (s, 1H), 8.37 (t, J= 5.5 Hz, 1H), 7.24-7.21 (m, 1H), 7.20-7.16 (m, 1H), 3.60 (d, J= 6.0 Hz, 2H), 3.56 (s, 2H);13C NMR (125 MHz, r / g-DMSO) 8 169.3, 166.2, 150.6 (td, J= 9.8, 3.0 Hz), 148.6 (td, J = 10.9, 3.0 Hz), 139.3 (dt, J= 246.0, 15.6 Hz), 126.4 (m), 121.9 (m), 112.6 (dd, J= 16.8, 3.5 Hz), 42.5, 35.0; HRMS (ESI, m / z): calcd for CoHsF^Ch ([M-H]'): 261.0493, Found: 261.0494.

[0336] Synthesis and Characterization of N-Hydroxy-2-(2-(3-hydroxy-2 ,4-dimethoxyphenyl)- acetamido) acetamide, JYX044:

[0337] This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(3-(benzyloxy)-2,4-dimethoxyphenyl)acetic acid?H NMR (500 MHz, CD3OD) 8 6.67 (m, 2H), 3.83 (s, 6H), 3.78 (s, 2H), 3.50 (s, 2H);13C NMR (125 MHz, CD3OD) 8 175.1, 168.7, 149.8, 147.4, 140.8, 122.3, 121.5, 108.1, 60.7, 56.7, 41.6, 38.3; HRMS (ESI, m / z): calcd for C12H17N2O6 ([M+H]J: 285.1081, Found: 285.1075.

[0338] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N-(3-hydroxy-2,4-dimethoxy- phenethylfpropanamide, JYX045:

[0339] 48

[0340] 550.004W01 fre001648 This product was prepared according to the synthetic procedure used for JYX001, starting with 2-(3 -(benzyl oxy)-2,4-dimethoxyphenyl)ethan-l -amine.JH NMR (500 MHz, CD3OD) 8 6.65 (d, .7 = 8,5 Hz, 1H), 6.62 (d, J= 8.5 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.67 (dd, J= 10.5, 5.0 Hz, 1H), 3.58 (dd, J= 10.5, 6.0 Hz, 1H), 3.40-3.34 (m, 3H), 2.75 (t, J= 7.3 Hz, 2H);13C NMR (125 MHz, CD3OD) 8 175.0, 149.1, 147.6, 140.7, 126.0, 120.7, 108.2, 65.3, 60.9, 57.9, 56.7, 41.5, 30.6; HRMS (ESI, m / z): calcd for C13H21N2O5 ([M+H]+): 285.1445, Found: 285.1437.

[0341] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N'-(3-hydroxy-2,4-dimethoxy- benzylidene)propanehydrazide, JYX046:

[0342] This product was prepared according to the synthetic procedure used for JYX022, starting with 3-hydroxy-2,4-dimethoxybenzaldehyde.1H NMR (500 MHz, CD3OD) indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 8.42* (s, 0.7 H), 8.19 (s, 0.3H), 7.54* (d, J= 8.5 Hz, 0.7H), 7.34 (d, J= 9.0 Hz, 0.3H), 6.79-6.77 (m, 1H), 4.45 (t, J= 5.0 Hz, 0.3H), 3.92 (dd, J= 11.0, 4.5 Hz, 0.3H), 3.88 (s, 3H), 3.85* (s, 2.1H), 3.84 (s, 0.9H), 3.77 (dd, J= 10.5, 5.0 Hz, 0.3H), 3.75-3.73* (m, 1.4H), 3.49* (t, J = 5.8 Hz, 0.7H);13C NMR (125 MHz, CD3OD) indicated that it was a mixture of (E7Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 174.2, 171.8*, 152.4*, 152.1, 149.1*, 148.9, 146.6*, 143.0, 140.6, 140.4*, 121.5, 121.3*, 118.0*, 117.3, 108.7, 108.6*, 65.4*, 64.0, 61.9*, 61.8, 57.0*, 56.70, 56.68*, 55.0; HRMS (ESI, m / z): calcd for Ci2Hi8N3O5([M+H]+): 284.1241, Found: 284.1234.

[0343] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N'-(pyridin-2-ylmethylene)- propanehy dr azide, JYX047:

[0344] This product was prepared according to the synthetic procedure used for JYX022, starting with picolinaldehyde.1H NMR (500 MHz, CD3OD) indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 8.55 (d, J= 5.0 Hz, 1H), 8.21 (s, 1H), 8.20 (s, 0.3H), 7.99-7.97* (m, 0.7H), 7.88-7.85 (m, 1H), 7.42-7.40 (m, 1H), 4.43 (t, J = 5.0 Hz, 0.3H), 3.86 (dd, J= 11.0, 4.0 Hz, 0.3H), 3.76-3.73 (m, 1.7H), 3.52* (t, J = 5.3 Hz, 0.7H);13C NMR (125 MHz, CD3OD), indicated that it was a mixture of (E / Z) isomers, in a molar 49 550.004W01 fre001648 ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 176.4, 173.1*, 154.4*, 154.3, 150.3, 150.2*, 148.9*, 144.9, 138.7, 138.6*, 126.1*, 125.8, 122.3*, 122.0, 65.5*, 65.1, 57.2*, 54.7; HRMS (ESI, m / z): calcd for C9H13N4O2 ([M+H]+): 209.1033, Found: 209.1027.

[0345] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N'-(pyridin-3-ylmethylene)- propanehydrazide, JYX048:

[0346] This product was prepared according to the synthetic procedure used for JYX022, starting with nicotinaldehyde.JH NMR (500 MHz, CD3OD), indicated that it was a mixture of ( / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 8.84* (d, J = 1.5 Hz, 0.7H), 8.77 (d, J= 1.5 Hz, 0.3H), 8.55-8.54 (m, 1H), 8.30* (dt, J= 8.0, 1.8 Hz, 0.7H), 8.23* (s, 0.7H), 8.16 (d, J = 8.0 Hz, 0.3H), 7.99 (s, 0.3H), 7.48 (dd, J= 8.0, 5.0 Hz, 1.0H), 4.40 (t, J= 5.0 Hz, 0.3H), 3.86 (dd, J= 11.0, 4.5 Hz, 0.3H), 3.76-3.72 (m, 1.7H), 3.51* (t, J= 5.5 Hz, 0.7H);13C NMR (125 MHz, CD3OD), indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 176.3, 172.9*, 151.4*, 151.1, 149.8*, 149.2, 146.5*, 142.5, 136.1*, 135.6, 132.3, 132.2*, 125.53, 125.50*, 65.5*, 65.1, 57.2*, 54.7; HRMS (ESI, m / z): calcd for C9H13N4O2 ([M+H]+): 209.1033, Found: 209.1021.

[0347] Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N'-(pyridin-4-ylmethylene)- propanehydrazide, JYX049:

[0348] This product was prepared according to the synthetic procedure used for JYX022, starting with isonicotinaldehyde. 'H NMR (500 MHz, CD3OD), indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 8.57 (dd, J= 5.0, 1.5 Hz, 2H), 8.20* (s, 0.7H), 7.95 (s, 0.3H), 7.78* (dd, J= 4.5, 1.5 Hz, 1.4H), 7.68 (dd, J = 4.5, 1.5 Hz, 0.6H), 4.44 (t, J= 5.3 Hz, 0.3H), 3.88 (dd, J= 11.5, 4.0 Hz, 0.3H), 3.78-3.74 (m, 1.7H), 3.54* (t, J = 5.5 Hz, 0.7H);13C NMR (125 MHz, CD3OD), indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 176.0, 173.1*, 150.8*, 150.7* (2C), 146.8*, 144.0, 142.9, 123.1*, 122.6, 65.4*, 64.8, 57.2*, 54.8; HRMS (ESI, m / z): calcd for C9H13N4O2 ([M+H]+): 209.1033, Found: 209.1029.

[0349] 50

[0350] 550.004W01 fre001648 Synthesis and Characterization of (S)-2-Amino-3-hydroxy-N'-((4-oxo- 1 ,4-dihydropyri-din-3- yl)methylene)propanehydrazide, JYX050:

[0351] This product was prepared according to the synthetic procedure used for JYX022, starting with 4-oxo- l,4-dihydropyridine-3-carbaldehy de.JH NMR (500 MHz, g-DMSO), indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 8.37* (s, 0.7H), 8.12-8.11 (m, 1H), 8.09 (s, 0.3H), 7.68-7.65 (m, 1H), 6.22-6.19 (m, 1H), 4.10 (t, J= 5.5 Hz, 0.3H), 3.57 (dd, J= 10.5, 4.5 Hz, 0.3H), 3.50-3.40 (m, 1.7H), 3.25* (t, J = 5.8 Hz, 0.7H);13C NMR (125 MHz, g-DMSO), indicated that it was a mixture of (E / Z) isomers, in a molar ratio of ca. 7:3, with signals of the major isomer marked with an asterisk, 8 175.1, 174.8, 174.0, 169.4*, 142.1*, 138.5*, 138.1, 137.6, 135.3, 134.5, 121.2*, 120.9*, 117.0*, 116.9*, 63.9*, 63.5, 55.8*, 52.8; HRMS (ESI, m / z): calcd for C9H13N4O3 ([M+H]+): 225.0982, Found: 225.0976.

[0352] Synthesis and Characterization ofN-Methoxy-2-(2-(2,3,4-trihydroxyphenyl)acetamido)- acetamide, JYX051:

[0353] This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(2,3,4-tris(benzyloxy)phenyl)acetic acid and 2-amino-N-methoxyacetamide.1H NMR (500 MHz, CD3OD) 8 6.49 (d, J= 8.0 Hz, 1H), 6.32 (d, J= 8.0 Hz, 1H), 3.76 (s, 2H), 3.67 (s, 3H), 3.48 (s, 2H);13C NMR (125 MHz, CD3OD) 8 176.0, 168.5, 146.6, 145.5, 134.9, 121.8, 115.0, 108.2, 64.4, 41.7, 38.8; HRMS (ESI, m / z): calcd for C11H13N2O6 ([M-H]’): 269.0779, Found: 269.0780.

[0354] Synthesis and Characterization of 2-(3-Hydroxy-2 ,4-dimethoxyphenyl)-N-(2-(methoxy- amino) -2 -oxoethyl) acetamide, JYX052:

[0355] 51

[0356] 550.004W01 fre001648 This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(3 -(benzyl oxy)-2,4-dimethoxyphenyl)acetic acid 2-amino-jV-methoxyacetamide.JH NMR (500 MHz, CD3OD) 8 6.68 (m, 2H), 3.83 (s, 6H), 3.76 (s, 2H), 3.67 (s, 3H), 3.50 (s, 2H);13C NMR

[0357] (125 MHz, CD3OD) 8 175.2, 168.5, 149.9, 147.3, 140.8, 122.3, 121.4, 108.1, 64.4, 60.7, 56.7, 41.7, 38.2; HRMS (ESI, m / z): calcd for C13H19N2O6 ([M+H]+): 299.1238, Found: 299.1233.

[0358] Synthesis and Characterization of 2-(2,4-Dihydroxy-3-(2-hydroxyethoxy)phenyl)-N-(2-

[0359] (hydroxyamino)-2-oxoethyl)acetamide, JYX053:

[0360] This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(2,4-bis(benzyloxy)-3-(2-(benzyloxy)ethoxy)phenyl)acetic acid.1H NMR (500 MHz, CD3OD) 8 6.75 (d, J= 8.5 Hz, 1H), 6.36 (d, J= 8.0 Hz, 1H), 4.06 (t, J= 4.3 Hz, 2H), 3.81 (t, J= 4.5 Hz, 2H), 3.79 (s, 2H), 3.48 (s, 2H);13C NMR (125 MHz, CD3OD) 8 175.6, 168.7, 151.1, 150.1, 136.1, 127.0, 115.0, 108.6, 75.9, 62.0, 41.6, 38.3; HRMS (ESI, m / z): calcd for C12H15N2O7 ([M-H]’): 299.0885, Found: 299.0876.

[0361] Synthesis and Characterization of 2-(3-Amino-2 ,4-dihydroxyphenyl)-N-(2-(hydroxy-amino)- 2 -oxoethyl) acetamide, JYX054:

[0362] This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(2,4-bis(benzyloxy)-3-nitrophenyl)acetic acid. 'H NMR (500 MHz, CD3OD) 8 6.40 (d, J= 8.0 Hz, 1H), 6.30 (d, J= 8.5 Hz, 1H), 3.77 (s, 2H), 3.49 (s, 2H);13C NMR (125 MHz, CD3OD) 8 176.4, 168.5, 147.1, 145.6, 125.3, 121.1, 115.4, 108.3, 41.5, 39.6; HRMS (ESI, m / z): calcd for C10H12N3O5 ([M-H]’): 254.0782, Found: 254.0782.

[0363] Synthesis and Characterization of 2-(3-Acetamido-2,4-dihydroxyphenyl)-N-(2-(hydroxy- amino)-2-oxoethyl)acetamide, JYX055:

[0364] 52

[0365] 550.004W01 fre001648

[0366] This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(3-acetamido-2,4-bis(benzyloxy)phenyl)acetic acid.1H NMR (500 MHz, CD3OD) 8 6.41 (d, J = 10.0 Hz, 1H), 6.28 (d, J= 10.0 Hz, 1H), 4.31 (s, 2H), 3.52 (s, 2H), 2.35 (s, 3H);13C NMR (125

[0367] MHz, CD3OD) 8 176.5, 172.3, 170.4, 147.1, 145.8, 124.9, 121.1, 115.2, 108.1, 44.9, 39.5, 24.4;

[0368] HRMS (ESI, m / z): calcd for C12H14N3O6 ([M-H]’): 296.0888, Found: 296.0889.

[0369] Synthesis and Characterization ofN-Hydroxy-2-(3-(2,3,4-trihydroxyphenyl)ureido)- acetamide, JYX056:

[0370] To a solution of 16 (0.88 g, 2.00 mmol) in toluene (10 mL) under argon was added diphenylphosphoryl azide (DPPA, 0.61 g, 2.22 mmol) and EtsN (0.31 mL, 2.22 mmol) at 21 °C. The mixture was heated at 75 °C until complete disappearance of the starting material as monitored by TLC. Then 14 (0.52 g, 2.40 mmol) and additional EtsN (0.45 mL, 3.23 mmol) were added. The reaction was stirred additionally at 75 °C for 12 h, cooled to 21 °C and subsequently washed with IN HC1 and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give compound 17 (0.32 g, 26%). Compound 17 (0.32 g, 0.52 mmol) was dissolved in a mixture of ethanol (14 ml) and THF (6 ml) and 5%-Pd / C (113 mg, 0.053 mmol) was then added. The resulting mixture was stirred at 21 °C for 12 h under hydrogen. The reaction mixture was filtered through a celite plug, and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (DCM / MeOH) to give JYX056 (85 mg, 64%).1H NMR (500 MHz, CD3OD) 8 6.60 (d, J= 9.0 Hz, 1H), 6.29 (d, J= 9.0 Hz, 1H), 3.80 (s, 2H);13C NMR (125 MHz, CD3OD) 8 169.8, 159.5, 144.3, 140.1, 135.5, 120.2, 115.0, 107.6, 42.2; HRMS (ESI, m / z): calcd for C9H12N3O6 ([M+H]+): 258.0721, Found: 258.0715.

[0371] Synthesis and Characterization of 2,3,4-Trihydroxy-N-(2-(hydroxyamino)-2-oxoethyl)- benzamide, JYX057:

[0372] 53

[0373] 550.004W01 fre001648

[0374] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid.JH NMR (500 MHz, CD3OD) 8 7.16 (d, J= 9.0 Hz, 1H), 6.36 (d, J= 9.0 Hz, 1H), 3.95 (s, 2H);13C NMR (125 MHz, CD3OD) 8 172.2, 169.0, 151.6, 151.0, 133.9, 119.6, 108.7, 107.9, 41.4; HRMS (ESI, m / z): calcd for C9H9N2O6 ([M-H]’): 241.0466, Found: 241.0467.

[0375] Synthesis and Characterization ofN-(2-(Hydroxyamino)-2-oxoethyl)-3-(2,3,4-trihydroxy- phenyl)propanamide, JYX058:

[0376] This product was prepared according to the synthetic procedure used for JYX039, starting with 3-(2,3,4-tris(benzyloxy)phenyl)propanoic acid. 'H NMR (500 MHz, CD3OD) 8 6.41 (d, J= 8.5 Hz, 1H), 6.26 (d, J= 8.0 Hz, 1H), 3.75 (s, 2H), 2.80 (t, J= 7.5 Hz, 2H), 2.51 (t, J= 7.8 Hz, 2H);13C NMR (125 MHz, CD3OD) 8 176.7, 168.8, 145.5, 145.1, 134.4, 120.7, 120.5, 107.9, 41.5, 37.6, 26.9; HRMS (ESI, m / z): calcd for C11H15N2O6 ([M+H]+): 271.0925, Found: 271.0924.

[0377] Synthesis and Characterization of 2,3, 4-Trihydroxy-N-(3-(hydroxyamino)-3- oxopropyl)benzamide, JYX059:

[0378] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 3-amino-N-(benzyloxy)propanamide.1H NMR (500 MHz, CD3OD) 8 7.09 (d, J= 8.5 Hz, 1H), 6.34 (d, J= 8.5 Hz, 1H), 3.60 (t, J= 6.8 Hz, 2H), 2.40 (t, J = 6.8 Hz, 2H);13C NMR (125 MHz, CD3OD) 8 171.9, 170.8, 151.6, 150.8, 134.0, 119.2, 108.8, 107.8, 36.9, 33.6; HRMS (ESI, m / z): calcd for C10H11N2O6 ([M-H]'): 255.0623, Found: 255.0620.

[0379] Synthesis and Characterization ofN-Hydroxy-2-(2-(2,3,4-trihydroxynaphthalen-l- yl)acetamido)acetamide, JYX060:

[0380] 54

[0381] 550.004W01 fre001648

[0382] This product was prepared according to the synthetic procedure used for JYX039, starting with 2-(2,3,4-tris(benzyloxy)naphthalen-l-yl)acetic acid. ' H NMR (500 MHz, CD3OD) 8 8.00 (d, J = 8.5 Hz, 1H), 7.74 (d, J= 8.5 Hz, 1H), 7.28 (t, J= 7.5 Hz, 1H), 7.22 (t, J= 7.3 Hz, 1H), 3.98 (s, 2H), 3.73 (s, 2H);13C NMR (125 MHz, CD3OD) 8 175.7, 168.6, 147.2, 139.5, 133.1, 129.1, 125.3, 123.4, 123.3 (2C overlapping), 122.3, 106.9, 41.5, 33.5; HRMS (ESI, m / z): calcd for C14H13N2O6 ([M-H]’): 305.0779, Found: 305.0774.

[0383] Synthesis and Characterization of 2,3,4-Trihydroxy-N-(2-(methoxyamino)-2- oxoethyl)benzamide, JYX061:

[0384] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 2-amino-JV-methoxyacetamide.1H NMR (500 MHz, CD3OD) 8 7.16 (d, J= 9.0 Hz, 1H), 6.37 (d, J= 9.0 Hz, 1H), 3.93 (s, 2H), 3.69 (s, 3H);13C NMR (125 MHz, CD3OD) 8 172.2, 168.9, 151.6, 151.0, 134.0, 119.6, 108.6, 108.0, 64.4, 41.5; HRMS (ESI, m / z): calcd for C10H11N2O6 ([M-H]'): 255.0623, Found: 255.0618.

[0385] Synthesis and Characterization of 2,3,4-Trihydroxy-N-(2-(isopropoxyamino)-2- oxoethyl)benzamide, JYX062:

[0386] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 2-amino-JV-isopropoxyacetamide. 'H NMR (500 MHz, CD3OD) 8 7.16 (d, J= 9.0 Hz, 1H), 6.37 (d, J= 8.5 Hz, 1H), 4.11-4.06 (m, 1H), 3.94 (s, 2H), 1.21 (d, J= 6.0 Hz, 6H);13C NMR (125 MHz, CD3OD) 8 172.2, 169.1, 151.6, 151.0, 134.0, 119.6, 108.7, 107.9, 79.1, 41.5, 20.8; HRMS (ESI, m / z): calcd for C12H15N2O6 ([M-H]'): 283.0936, Found: 283.0947.

[0387] Synthesis and Characterization ofN-(2-(tert-Butoxyamino)-2-oxoethyl)-2,3,4- trihydroxybenzamide, JYX063:

[0388] 55

[0389] 550.004W01 fre001648

[0390] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 2-amino- / V-( / c / 7-butoxy)acetamide.1H NMR (500 MHz, CD3OD) 8 7.16 (d, J= 8.5 Hz, 1H), 6.36 (d, J= 9.0 Hz, 1H), 3.95 (s, 2H), 1.24 (s, 9H);13C NMR

[0391] (125 MHz, CD3OD) 8 172.2, 170.2, 151.6, 151.0, 134.0, 119.5, 108.7, 107.9, 83.4, 41.5, 26.6; HRMS (ESI, m / z): calcd for C13H17N2O6 ([M-H]’): 297.1092, Found: 297.1098.

[0392] Synthesis and Characterization ofN-(2-((Cyclohexyloxy)amino)-2-oxoethyl)-2,3,4- trihydroxybenzamide, JYX064:

[0393] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 2-amino- / V-(cyclohexyloxy)acetamide.1H NMR (500

[0394] MHz, CD3OD) 8 7.16 (d, J= 8.5 Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 3.93 (s, 2H), 3.82-3.77 (m, 1H), 1.95-1.93 (m, 2H), 1.77-1.76 (m, 2H), 1.54-1.52 (m, 1H), 1.43-1.37 (m, 2H), 1.33-1.23 (m, 3H);13C

[0395] NMR (125 MHz, CD3OD) 8 172.2, 169.0, 151.6, 151.0, 134.0, 119.6, 108.7, 107.9, 84.3, 41.5, 31.5, 26.7, 24.7; HRMS (ESI, m / z): calcd for C15H21N2O6 ([M+H]+): 325.1394, Found: 325.1394.

[0396] Synthesis and Characterization ofN-(2-((Cyclopentyloxy)amino)-2-oxoethyl)-2,3,4- trihydroxybenzamide, JYX065:

[0397] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 2-amino- / V-(cyclopentyloxy)acetamide.1H NMR (500 MHz, CD3OD) 8 7.16 (d, J= 8.5 Hz, 1H), 6.37 (d, J = 9.0 Hz, 1H), 4.47-4.45 (m, 1H), 3.93 (s, 2H), 1.85-1.82 (m, 2H), 1.75-1.67 (m, 4H), 1.58-1.54 (m, 2H);13C NMR (125 MHz, CD3OD) 8 172.2, 168.9, 151.6, 151.0, 134.0, 119.6, 108.7, 107.9, 88.9, 41.5, 32.0, 24.5; HRMS (ESI, m / z): calcd for C14H17N2O6 ([M-H]’): 309.1092, Found: 309.1087.

[0398] Synthesis and Characterization ofN-(2-(Cyclobutoxyamino)-2-oxoethyl)-2,3,4- trihydroxybenzamide, JYX066:

[0399] 550.004W01 fre001648

[0400] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 2-amino-jV-cyclobutoxyacetamide.JH NMR (500 MHz, CD3OD) 8 7.16 (d, J= 9.0 Hz, 1H), 6.37 (d, J= 9.0 Hz, 1H), 4.44-4.38 (m, 1H), 3.93 (s, 2H), 2.20- 2.08 (m, 4H), 1.77-1.73 (m, 1H), 1.56-1.51 (m, 1H);13C NMR (125 MHz, CD3OD) 8 172.2, 169.2,

[0401] 151.6, 151.0, 134.0, 119.6, 108.7, 107.9, 79.8, 41.5, 29.6, 13.1; HRMS (ESI, m / z): calcd for C13H15N2O6 ([M-H]’): 295.0936, Found: 295.0918.

[0402] Synthesis and Characterization ofN-(2-(Ethoxyamino)-2-oxoethyl)-2,3,4-trihydroxy- benzamide, JYX067:

[0403] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 2-amino-N-ethoxyacetamide.1H NMR (500 MHz, CD3OD) 8 7.16 (d, J= 8.5 Hz, 1H), 6.37 (d, J= 8.5 Hz, 1H), 3.93 (s, 2H), 3.90 (q, J = 7.0 Hz, 2H), 1.23 (t, J= 7.0 Hz, 3H);13C NMR (125 MHz, CD3OD) 8 172.2, 169.0, 151.6, 151.0, 134.0, 119.6,

[0404] 108.6, 108.0, 72.9, 41.5, 13.7; HRMS (ESI, m / z): calcd for C11H13N2O6 ([M-H]’): 269.0779, Found: 269.0776.

[0405] Synthesis and Characterization of 2,3, 4-Trihydroxy-N-(4-(methoxyamino)-4-oxobutyl)- benzamide, JYX068:

[0406] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 4-amino-JV-methoxybutanamide.1H NMR (500 MHz, CD3OD) 8 7.11 (d, J= 9.0 Hz, 1H), 6.34 (d, J= 9.0 Hz, 1H), 3.65 (s, 3H), 3.38 (t, J= 6.8 Hz, 2H), 2.15 (t, J = 7.3 Hz, 2H), 1.92-1.86 (m, 2H);13C NMR (125 MHz, CD3OD) 8 172.2, 172.0, 151.7,

[0407] 150.7, 134.0, 119.0, 108.8, 107.8, 64.3, 39.7, 31.2, 26.4; HRMS (ESI, m / z): calcd for C12H15N2O6 ([M-H]’): 283.0936, Found: 283.0926.

[0408] Synthesis and Characterization of 2,3,4-Trihydroxy-N-(5-(methoxyamino)-5-oxopentyl)- benzamide, JYX069:

[0409] 57

[0410] 550.004W01 fre001648

[0411] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 5-amino-jV-methoxypentanamide.JH NMR (500 MHz, CD3OD) 8 7.11 (d, J = 8.5 Hz, 1H), 6.34 (d, J = 9.0 Hz, 1H), 3.67 (s, 3H), 3.35 (t, J= 6.5 Hz, 2H), 2.12 (t, J = 7.0 Hz, 2H), 1.69-1.60 (m, 4H);13C NMR (125 MHz, CD3OD) 8 172.5, 171.9, 151.7,

[0412] 150.7, 134.0, 119.0, 108.9, 107.8, 64.3, 39.8, 33.3, 29.9, 23.9; HRMS (ESI, m / z): calcd for C13H17N2O6 ([M-H]’): 297.1092, Found: 297.1090.

[0413] Synthesis and Characterization of 2,3, 4-Trihydroxy-N-(6-(methoxyamino)-6-oxohexyl)- benzamide, JYX070:

[0414] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 6-amino-N-methoxyhexanamide. 'H NMR (500 MHz, CD3OD) 8 7.11 (d, J= 9.0 Hz, 1H), 6.34 (d, J= 8.5 Hz, 1H), 3.64 (s, 3H), 3.34 (t, J= 7.0 Hz, 2H), 2.08 (t, J= 7.3 Hz, 2H), 1.66-1.59 (m, 4H), 1.39-1.36 (m, 2H);13C NMR (125 MHz, CD3OD) 8

[0415] 172.7, 171.8, 151.6, 150.6, 134.0, 119.0, 108.9, 107.8, 64.3, 40.1, 33.6, 30.2, 27.4, 26.2; HRMS (ESI, m / z): calcd for C14H19N2O6 ([M-H]’): 311.1249, Found: 311.1247.

[0416] Synthesis and Characterization of 2,3,4-Trihydroxy-N-(7-(methoxyamino)-7-oxoheptyl)- benzamide, JYX071:

[0417] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 7-amino-N-methoxyheptanamide.1H NMR (500 MHz, CD3OD) 8 7.12 (d, J = 9.0 Hz, 1H), 6.34 (d, J= 8.5 Hz, 1H), 3.66 (s, 3H), 3.33 (t, J = 7.0 Hz, 2H), 2.07 (t, J= 7.5 Hz, 2H), 1.63-1.58 (m, 4H), 1.38-1.37 (m, 4H);13C NMR (125 MHz, CD3OD) 8

[0418] 172.8, 171.8, 151.6, 150.6, 134.0, 119.0, 108.9, 107.8, 64.3, 40.2, 33.7, 30.4, 29.8, 27.6, 26.5; HRMS (ESI, m / z): calcd for C15H21N2O6 ([M-H]’): 325.1405, Found: 325.1405.

[0419] Synthesis and Characterization of 2,3, 4-Trihydroxy-N-(3-(methoxycarbamoyl)cyclo- butyl)benzamide, JYX072 (Mixture of isomers):

[0420] 58

[0421] 550.004W01 fre001648

[0422] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 3 - amino-JV-methoxy cyclobutane- 1 -carboxamide.JH NMR (500 MHz, CD3OD) 8 7.15 (d, J = 8.5 Hz, 1H), 6.32 (d, J= 9.0 Hz, 1H), 4.45-4.39 (m, 1H), 3.64 (s, 3H), 2.65-2.60 (m, 1H), 2.51-2.46 (m, 2H), 2.30-2.24 (m, 2H);13C NMR (125 MHz, CD3OD) 8 173.3, 171.2, 151.8, 150.9, 134.0, 119.3, 108.5, 107.8, 64.3, 41.8, 34.0, 31.1; HRMS (ESI, m / z): calcd for C13H15N2O6 ([M-H]’): 295.0936, Found: 295.0922.

[0423] Synthesis and Characterization of cis-2, 3, 4-Trihydroxy-N-(3-(methoxycarbamoyl)cyclo- butyl)benzamide, JYX072-cis:

[0424] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and c7.s-3-amino- / V-methoxy cyclobutane- 1 -carbox-amide. 'H NMR (500 MHz, CD3OD) 8 7.18 (d, J= 9.0 Hz, 1H), 6.35 (d, J= 9.0 Hz, 1H), 4.49-4.42 (m, 1H), 3.67 (s, 3H), 2.68-2.63 (m, 1H), 2.54-2.49 (m, 2H), 2.33-2.26 (m, 2H);13C NMR (125 MHz, CD3OD) 8 173.3, 171.2, 151.8, 150.9, 134.0, 119.2, 108.4, 107.8, 64.3, 41.8, 34.0, 31.1; HRMS (ESI, m / z): calcd for C13H15N2O6 ([M-H]’): 295.0936, Found: 295.0891.

[0425] Synthesis and Characterization of trans-2,3,4-Trihydroxy-N-(3-(methoxycarbamoyl)- cyclobutyl)benzamide, JYX072-trans:

[0426] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and / ra / r.s-3 -ami no-N-methoxy cyclobutane- 1 -carbox-amide. 'H NMR (500 MHz, CD3OD) 8 7.17 (d, J = 9.0 Hz, 1H), 6.34 (d, J= 9.0 Hz, 1H), 4.73-4.67 (m, 1H), 3.69 (s, 3H), 2.92-2.86 (m, 1H), 2.60-2.55 (m, 2H), 2.41-2.35 (m, 2H);13C NMR (125 MHz, CD3OD)

[0427] 59

[0428] 550.004W01 fre001648 8 174.7, 171.4, 151.7, 150.7, 133.9, 119.2, 108.5, 107.7, 64.3, 44.4, 33.5, 32.2; HRMS (ESI, m / z): calcd for C13H15N2O6 ([M-H]’): 295.0936, Found: 295.0893.

[0429] Synthesis and Characterization of 2,3,4-Trihydroxy-N-((lS,3R)-3-(methoxycarbamoyl)- cyclopentyl)benzamide, JYX073:

[0430] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and ( YR, 3 )-3-amino- / V-methoxy cyclopentane- 1 - carboxamide. 'H NMR (500 MHz, CD3OD) 8 7.16 (d, J= 8.5 Hz, 1H), 6.37 (d, J= 9.0 Hz, 1H), 4.45-4.41 (m, 1H), 3.70 (s, 3H), 2.73-2.67 (m, 1H), 2.19-2.14 (m, 1H), 2.02-1.96 (m, 1H), 1.92-1.79 (m, 4H);13C NMR (125 MHz, CD3OD) 8 176.3, 171.1, 151.9, 150.7, 134.0, 118.9, 108.7, 107.9, 64.4, 52.4, 41.1, 36.7, 34.4, 29.2; HRMS (ESI, m / z): calcd for C14H17N2O6 ([M-H]’): 309.1092, Found: 309.1091.

[0431] Synthesis and Characterization of 2,3,4-Trihydroxy-N-((lr,4r)-4-(methoxycarbamoyl)- cyclohexyl)benzamide, JYX074:

[0432] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and / ra / rs-4-amino- / V-methoxy cyclohexane- 1 -carboxamide.XH NMR (500 MHz, CD3OD) 8 7.15 (d, J= 9.0 Hz, 1H), 6.33 (d, J= 9.0 Hz, 1H), 3.88-3.83 (m, 1H), 3.66 (s, 3H), 2.06-2.02 (m, 3H), 1.87-1.84 (m, 2H), 1.64 (qd, J= 13.0, 3.0 Hz, 2H), 1.40 (qd, J =

[0433] 12.7, 3.0 Hz, 2H);13C NMR (125 MHz, CD3OD) 8 175.2, 171.1, 151.6, 150.7, 134.0, 119.2, 108.9,

[0434] 107.7, 64.3, 49.1, 42.5, 32.6, 29.4; HRMS (ESI, m / z): calcd for C15H19N2O6 ([M-H]’): 323.1249, Found: 323.1243.

[0435] Synthesis and Characterization of 2,3, 4-Trihydroxy-N-(3-(methoxyamino)-3-oxopro- pyl)benzamide, JYX075:

[0436] 60

[0437] 550.004W01 fre001648

[0438] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 3-amino-X-methoxypropanamide. 'H NMR (500 MHz, CD3OD) 8 7.09 (d, J= 9.0 Hz, 1H), 6.34 (d, J= 9.0 Hz, 1H), 3.65 (s, 3H), 3.61 (t, J= 6.8 Hz, 2H), 2.38 (t, J = 6.8 Hz, 2H);13C NMR (125 MHz, CD3OD) 8 171.9, 170.6, 151.6, 150.8, 134.0, 119.2, 108.8, 107.8, 64.4, 36.7, 33.7; HRMS (ESI, m / z): calcd for C11H13N2O6 ([M-H]’): 269.0779, Found: 269.0778.

[0439] Synthesis and Characterization ofN-(2-(Cyclopropoxyamino)-2-oxoethyl)-2,3,4- trihydroxybenzamide, JYX076:

[0440] This product was prepared according to the synthetic procedure used for JYX039, starting with 2,3,4-tris(benzyloxy)benzoic acid and 2-amino-jV-cyclopropoxyacetamide.JH NMR (500 MHz, CD3OD) 8 7.16 (d, J= 8.5 Hz, 1H), 6.37 (d, J = 9.0 Hz, 1H), 3.97-3.93 (m, 3H), 0.82-0.80 (m, 2H), 0.57-0.56 (m, 2H);13C NMR (125 MHz, CD3OD) 8 172.2, 168.8, 151.6, 151.0, 134.0, 119.6, 108.7, 107.9, 59.7, 41.4, 6.2; HRMS (ESI, m / z): calcd for C12H13N2O6 ([M-H]’): 281.0779, Found: 281.0777.

[0441] Example 2. Pharmaceutical Dosage Forms.

[0442] The following formulations illustrate representative pharmaceutical dosage forms that may be used for the therapeutic or prophylactic administration of a compound of a formula described herein, a compound specifically disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (hereinafter referred to as 'Compound X'):

[0443] (i) Tablet 1 mg / tablet

[0444] 'Compound X' 100.0

[0445] Lactose 77.5

[0446] Povidone 15.0

[0447] Croscarmellose sodium 12.0

[0448] Microcrystalline cellulose 92.5

[0449] Magnesium stearate 3,0

[0450] 300.0

[0451] (ii) Tablet 2 mg / tablet 'Compound X' 20.0

[0452] 550.004W01 fre001648 Microcrystalline cellulose 410.0 Starch 50.0

[0453] Sodium starch glycolate 15.0 Magnesium stearate 5,0

[0454] 500.0

[0455] (hi) Capsule mg / capsule

[0456] 'Compound X' 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5

[0457] Pregelatinized starch 120.0 Magnesium stearate 3,0 600.0

[0458] (iv) Injection 1 (1 mg / mL) mg / mL 'Compound X' (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5

[0459] 1.0 N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL

[0460] (v) Injection 2 (10 mg / mL) mg / mL 'Compound X' (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0

[0461] 0.1 N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL

[0462] (vi) Aerosol mg / can

[0463] 'Compound X' 20 Oleic acid 10

[0464] Tri chloromonofluoromethane 5,000 Dichlorodifluoromethane 10,000 Dichlorotetrafluoroethane 5,000

[0465] (vii) Topical Gel 1 wt.% 'Compound X' 5% Carbomer 934 1.25%

[0466] T ri ethanol amine q.s. (pH adjustment to 5-7) Methyl paraben 0.2% Purified water q.s. to 100g

[0467] (viii) Topical Gel 2 wt.% 'Compound X' 5% Methylcellulose 2% Methyl paraben 0.2% Propyl paraben 0.02% Purified water q.s. to 100g

[0468] 62

[0469] 550.004W01 fre001648 (ix) Topical Ointment wt.% 'Compound X' 5% Propylene glycol 1% Anhydrous ointment base 40% Polysorbate 80 2% Methyl paraben 0.2% Purified water q.s. to 100g

[0470] (x) Topical Cream 1 wt.% 'Compound X' 5% White bees wax 10% Liquid paraffin 30% Benzyl alcohol 5% Purified water q.s. to 100g

[0471] (xi) Topical Cream 2 wt.% 'Compound X' 5% Stearic acid 10%

[0472] Glyceryl monostearate 3%

[0473] Polyoxyethylene stearyl ether 3% Sorbitol 5%

[0474] Isopropyl palmitate 2 %

[0475] Methyl Paraben 0.2%

[0476] Purified water q.s. to 100g

[0477] These formulations may be prepared by conventional procedures well known in the pharmaceutical art. It will be appreciated that the above pharmaceutical compositions may be varied according to well-known pharmaceutical techniques to accommodate differing amounts and types of active ingredient 'Compound X'. Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes. Ingredients may be exchanged for suitable equivalents and proportions may be varied, according to the desired properties of the dosage form of interest.

[0478] All publications, patents, and patent documents cited herein are incorporated by reference as though individually incorporated by reference. No limitations inconsistent with this disclosure are to be understood therefrom. The invention has been described with reference to various specific and preferred embodiments and techniques. However, many variations and modifications may be made while remaining within the spirit and scope of the invention.

[0479] While specific embodiments have been described above with reference to the disclosed embodiments and examples, such embodiments are only illustrative and do not limit the scope of the invention. Changes and modifications can be made in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.

[0480] 63

[0481] 550.004W01 fre001648

Claims

What is claimed is:

1. A compound of Formula I:Ax— R2— R1(I), wherein,R1is:-NH(C=O)NHaryl, -NH(C=O)NHalkyl, -NH(C=O)heterocycloalkyl, or -CONH(aryl);Rlais -(C4-C6)cycloalkyl, -(Ci-C6)alkyl, cyclopropyl, -(C3-C6)heterocycloalkyl, phenyl, or pyridyl;Rlbis H; orRlaand Rlbform a 5- or 6-membered heterocycloalkyl with the nitrogen atom to which they are attached;Rlcis -(Ci-C6)alkyl, -(C3-C6)cycloalkyl, -(C3-C6)heterocycloalkyl, phenyl, pyridyl, -(C2-Ce)alkoxy, -(C2-C6)aminoalkyl, or H;Rldis -(C2-Ce)alkoxy, -(C2-C6)aminoalkyl, phenyl, benzyl, pyridyl, -(C3-C6)heterocycloalkyl, -(C3-C6)cycloalkyl, or CH2(C3-C6)cycloalkyl;Rleis H, -(Ci-C6)alkyl, -(C3-C6)cycloalkyl, CH2(C3-C6)cycloalkyl, or benzyl; orRldand Rleform a 5- or 6-membered heterocycloalkyl with the nitrogen atom to which they are attached;R2is absent, CH2, CH2CH2, phenyl, pyrazole, piperazine, or CH=N;Ax is:64550.004W01 fre001648each R3is independently OH, halo, CN, O(Ci-Ce)alkyl, OCH2CH2OH, CH2OH, NH2, NHCOCH3, NH(C=O)CH=CH2, CF2H, B(OH)2, NH(C=O)CH2CH2OH, pyridyl, tetrazolyl, or phenyl; or when present, two R3taken together form a 5 -membered heteteroaryl, 5-membered heterocycloalkyl, or benzo group with the carbon atoms to which they are attached; m is 3, 2, or 1; each R4is independently OH or halo; n is 0, 1, 2, or 3; each R5is independently OH or H, wherein at least one R5is OH; and R6is OH or H; wherein Ax is optionally further substituted with a substituted sulfur atom; phenyl, aryl, pyridyl, and heteroaryl are optionally substituted; -(Ci-C6)alkyl is optionally unbranched or branched; and -(C4-C6)cycloalkyl is optionally saturated or unsaturated; or a pharmaceutically acceptable salt thereof; wherein the compound is not 2-amino-3-hydroxy-A-(2,3,4-trihydroxyphenethyl)propenamide (CSRM122), (A)-2-amino-3-hydroxy- / V'-(2,3,4-trihydroxybenzylidene)propanehydrazide (CSRM- 617), or A-hydroxy-2-(2-(2,3,4-trihydroxyphenyl)acetamido)acetamide (CSRM-843).

2. The compound of claim 1, wherein R1is represented by Formula la or lb:.

3. The compound of claim 1, wherein Rlais cyclobutyl, CH2, or CH2CH2.

4. The compound of claim 1, wherein R1is represented by Formula Ic or Id:

5. The compound of claim 1, wherein Rlcis -(Ci-C6)alkyl or -(C3-C6)cycloalkyl.

6. The compound of claim 1, wherein R2is absent, CH2, CH2CH2, phenyl, or CH=N wherein the atom C of CH=N forms a carbon-carbon bond with Ax.65550.004W01 fre0016487. The compound of claim 1 , wherein Ax is:wherein optionally at least one R3is OH.

8. The compound of claim 1, wherein R3is OH.

9. The compound of claim 1, wherein m is 3.

10. The compound of claim 1 , wherein Formula I is represented by Formula II:or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein Formula I is represented by Formula lib:or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein Rlais:wherein each = is independently a single bond, double bond, or aromatic bond; andX is CH2, O, NH, or N(Ci-C6)alkyl when = is a single bond; orX is CH or N when each = is an aromatic bond.66550.004W01 fre00164813. The compound of claim 1, wherein Formula I is represented by Formula III:or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, wherein the compound is JYX072 cis or transor a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein the compound is any one of:67550.004W01 fre001648550.004W01 fre00164869550.004W01 fre001648or a pharmaceutically acceptable salt thereof.

16. A composition comprising a compound of any one of claims 1-15 and an excipient.70550.004W01 fre00164817. A method for treating cancer in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the cancer is prostate cancer.

19. The method of claim 17, wherein the compound inhibits the cancer therapeutic target 0NECUT2 with an ECso of less than about 5 micromolar in 22Rvl cells.

20. The method of claim 17, wherein the compound is 2,3,4-trihydroxy- / V-(( l s,3s)-3- (methoxycarbamoyl)cyclobutyl)benzamide (JYX072cis).71550.004W01 fre001648

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