Inhibitors of hur-mrna interaction, compositions thereof, and therapeutic uses thereof

Abstract

The present technology is directed to compounds that inhibit of the interaction of RNA-binding protiens with RNA, intermediaes thereof, compositions thereof, and methods of treatment utilizing such compounds, where the compounds are of Formula: (I).

Description

INHIBITORS OF HuR-mRNA INTERACTION, COMPOSITIONS THEREOF, AND THERAPEUTIC USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 666,474, filed July 1, 2024, which is incorporated by reference herein in its entirety for any and all purposes.U.S. GOVERNMENT RIGHTS

[0002] This invention was made with government support under CAI 91785 awarded by National Institutes of Health, and W81XWH-21-1-0573 awarded by the Defense Health Agency, Medical Research and Development Branch. The government has certain rights in the invention.FIELD

[0003] The present technology is directed to compounds (as well as intermediates thereof), compositions, and methods related to inhibition of the interaction between RNA-binding protein Hu antigen R (HuR) and the cellular targets of HuR. The technology is suited to treat diseases, disorders, and conditions associated with HuR dysregulation, including varying types of cancer as well as fibrotic diseases of the kidney, liver, lung and / or heart.SUMMARY

[0004] In an aspect, the present technology provides a compound or a pharmaceutically acceptable salt thereof according to Formula IwhereinZ1is aryl, heteroaryl, or cycloalkyl;R1is methyl, isopropyl, -CH(CH3)(CH2CH3), - CH2CH(CH3)2, -L1is absent, -CH2-, -CH2-CH2-, or -CH=CH-;X1is O, NH, or S;X2is OH, NH2, NH-OH, NH-NH2, or O-(Ci-C6alkyl); and X3is S(O)2or C(O).

[0005] In a related aspect, a method is provided the includes administering a compound of Formula I to a subject. In any embodiment herein, it may be the subject is suffering from a condition, where the condition is a hyperproliferative disease with HuR overexpression and / or a fibrotic disease. The hyperproliferative disease with HuR overexpression may include one or more of a colon cancer, a prostate cancer, a breast cancer, a brain cancer, an ovarian cancer, a pancreatic cancer, or a lung cancer. The fibrotic disease may include kidney fibrosis, liver fibrosis, a pulomonary fibrosis, and / or cardiac fibrosis.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIGs. 1A-B provide the results of Western blot studies illustrating that exemplary compounds of the present technology — KH309, KH311 and KH312 — inhibited the protein expression levels of HuR target XIAP, Bcl-2 and Survivin but not HuR in a dose-dependent manner in PC-3 cells (FIG. 1 A) and also induced the cleavage of three apoptosis markers PARP, Caspase 8, and Caspase 3, and the conversion of LC3, an autophagy marker (FIG. IB), according to the working examples.

[0007] FIGs. 2A-2C provide the results of PC-3 colony formation experiments using multiple doses of KH309 (FIG. 2A), KH311 (FIG. 2B), and KH312 (FIG. 2C), where allthree compounds inhibited colony formation of PC-3 cells in a dose-dependent manner, according to the working examples.

[0008] FIG. 3 provides the results of a pharmacokinetic study of intraperitoneal (i.p.) injection of 25 mg / kg KH309, according to the working examples.

[0009] FIGs. 4A-4B graphically summarize the in vivo antitumor activity of KH309 in a mouse xenograft model using a more aggressive subline of PC-3 (“PC-3 a”), according to the working examples. FIG. 4A illustrates that KH309 treatment significantly inhibited PC-3a tumor growth compared to that of vehicle control group (P < 0.01) and KH309 in combination with docetaxel inhibited PC-3 a tumor growth significantly more than KH309 alone and docetaxel alone; FIG. 4B provides Kaplan-Meier curves of overall survival of the mice with no treatment (“Control”), mice treated with KH309 alone, mice treated with docetaxel alone, and mice treated with KH309 in combination with docetaxel.DETAILED DESCRIPTION

[0010] The following terms are used throughout as defined below.

[0011] As used herein and in the appended claims, singular articles such as “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0012] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context inwhich it is used, “about” will mean up to plus or minus 10% of the particular term - for example, “about 10 wt.%” would be understood to mean “9 wt.% to 11 wt.%.” It is to be understood that when “about” precedes a term, the term is to be construed as disclosing “about” the term as well as the term without modification by “about” - for example, “about 10 wt.%” discloses “9 wt.% to 11 wt.%” as well as disclosing “10 wt.%.”

[0013] The phrase “and / or” as used in the present disclosure will be understood to mean any one of the recited members individually or a combination of any two or more thereof - for example, “A, B, and / or C” would mean “A, B, C, A and B, A and C, B and C, or the combination of A, B, and C.”

[0014] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium, C14, P32and S35are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.

[0015] In general, “substituted” refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group is substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include: halogens (z.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxylates; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; pentafluorosulfanyl (z.e., SFs), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (z.e., CN); and the like.

[0016] Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and ring systems in which a bond to a hydrogen atom isreplaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

[0017] Alkyl groups include straight chain and branched chain alkyl groups having from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of straight chain alkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tertbutyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Alkyl groups may be substituted or unsubstituted. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above, and include without limitation haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.

[0018] Cycloalkyl groups include mono-, bi- or tricyclic alkyl groups having from 3 to 12 carbon atoms in the ring(s), or, in some embodiments, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Exemplary monocyclic cycloalkyl groups include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Bi- and tricyclic ring systems include both bridged cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl, decalinyl, and the like. Cycloalkyl groups may be substituted or unsubstituted. Substituted cycloalkyl groups may be substituted one or more times with, non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be monosubstituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2, 6-di substituted cyclohexyl groups, which may be substituted with substituents such as those listed above.

[0019] Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above. In some embodiments, cycloalkylalkyl groups have from 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms. Cycloalkylalkyl groups may be substitutedor unsubstituted. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group. Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri -substituted with substituents such as those listed above.

[0020] Alkenyl groups include straight and branched chain alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Alkenyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, among others. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri -substituted with substituents such as those listed above.

[0021] Cycloalkenyl groups include cycloalkyl groups as defined above, having at least one double bond between two carbon atoms. In some embodiments the cycloalkenyl group may have one, two or three double bonds but does not include aromatic compounds. Cycloalkenyl groups have from 4 to 14 carbon atoms, or, in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl. Cycloalkenyl groups may be substituted or unsubstituted.

[0022] Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Cycloalkenylalkyl groups may be substituted or unsubstituted. Substituted cycloalkenylalkyl groups may be substituted at the alkyl, the cycloalkenyl or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above.

[0023] Alkynyl groups include straight and branched chain alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Alkynyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to -C=CH, -OCCH3, -CH2C=CCH3, -C=CCH2CH(CH2CH3)2, among others. Alkynyl groups may be substituted or unsubstituted. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or trisubstituted with substituents such as those listed above.

[0024] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups. In some embodiments, the aryl groups are phenyl or naphthyl. Although the phrase “aryl groups” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Aryl groups may be substituted or unsubstituted. Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.

[0025] Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. In some embodiments, aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Aralkyl groups may be substituted or unsubstituted. Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.

[0026] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and nonaromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms. In some embodiments, heterocyclyl groups includemono-, bi- and tricyclic rings having 3 to 16 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclyl groups encompass aromatic, partially unsaturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase “heterocyclyl group” includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotri azolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl,azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotri azolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadi azolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [1,3] dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be monosubstituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.

[0027] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl,benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotri azolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused ring compounds in which all rings are aromatic such as indolyl groups and include fused ring compounds in which only one of the rings is aromatic, such as 2,3- dihydro indolyl groups. The phrase “heteroaryl groups” includes fused ring compounds. Heteroaryl groups may be substituted or unsubstituted. Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.

[0028] Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Heterocyclylalkyl groups may be substituted or un substituted. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group. Representative heterocyclyl alkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyri din-3 - yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above.

[0029] Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Heteroaralkyl groups may be substituted or unsubstituted. Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above.

[0030] Groups described herein having two or more points of attachment (i.e., divalent, trivalent, or polyvalent) within the compound of the present technology are designated by use of the suffix, “ene.” For example, divalent alkyl groups are alkylene groups, divalent aryl groups are arylene groups, divalent heteroaryl groups are divalent heteroarylene groups, and so forth. Substituted groups having a single point of attachment to the compound of thepresent technology are not referred to using the “ene” designation. Thus, e.g., chloroethyl is not referred to herein as chloroethylene.

[0031] Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Alkoxy groups may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.

[0032] The terms “alkanoyl” and “alkanoyloxy” as used herein can refer, respectively, to - C(O)-alkyl groups and -O-C(O)-alkyl groups, each containing 2-5 carbon atoms. Similarly, “aryloyl” and “aryloyloxy” refer to -C(O)-aryl groups and -O-C(O)-aryl groups.

[0033] The terms "aryloxy" and “arylalkoxy” refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Aryloxy and arylalkoxy groups may each be may be substituted or unsubstituted. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.

[0034] The term “carboxylate” as used herein refers to a -COOH group.

[0035] The term “ester” as used herein refers to -COOR70and -C(O)O-G groups. R70is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. G is a carboxylate protecting group. Carboxylate protecting groups are well known to one of ordinary skill in the art. An extensive list of protecting groups for the carboxylate group functionality may be found in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein and which is hereby incorporated by reference in its entirety and for any and all purposes as if fully set forth herein.

[0036] The term “amide” (or “amido”) includes C- and N-amide groups, i.e., -C(O)NR71R72, and -NR71C(O)R72groups, respectively. R71and R72are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). In some embodiments, the amide is -NR71C(O)-(CI-5 alkyl) and the group is termed "carbonylamino," and in others the amide is -NHC(O)-alkyl and the group is termed "alkanoylamino."

[0037] The term “nitrile” or “cyano” as used herein refers to the -CN group.

[0038] Urethane groups include N- and O-urethane groups, i.e., -NR73C(O)OR74and -OC(O)NR73R74groups, respectively. R73and R74are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R73may also be H.

[0039] The term “amine” (or “amino”) as used herein refers to -NR75R76groups, wherein R75and R76are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0040] The term “sulfonamido” includes S- and N-sulfonamide groups, i.e., -SO2NR78R79and -NR78SO2R79groups, respectively. R78and R79are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO2NH2). In some embodiments herein, the sulfonamido is -NHSCh-alkyl and is referred to as the "alkylsulfonylamino" group.

[0041] The term “thiol” refers to -SH groups, while “sulfides” include -SR80groups, “sulfoxides” include -S(O)R81groups, “sulfones” include -SO2R82groups, and “sulfonyls” include -SO2OR83. R80, R81, R82, and R83are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. In some embodiments the sulfide is an alkylthio group, -S-alkyl.

[0042] The term “urea” refers to -NR84-C(O)-NR85R86groups. R84, R85, and R86groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0043] The term “amidine” refers to -C(NR87)NR88R89and -NR87C(NR88)R89, wherein R87, R88, and R89are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0044] The term “guanidine” refers to -NR90C(NR91)NR92R93, wherein R90, R91, R92and R93are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0045] The term “enamine” refers to -C(R94)=C(R95)NR96R97and -NR94C(R95)=C(R96)R97, wherein R94, R95, R96and R97are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0046] The term “halogen” or “halo” as used herein refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.

[0047] The term “hydroxyl” as used herein can refer to -OH or its ionized form, -O . A “hydroxyalkyl” group is a hydroxyl-substituted alkyl group, such as HO-CH2-.

[0048] The term “imide” refers to -C(O)NR98C(O)R99, wherein R98and R99are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0049] The term “imine” refers to -CR100(NR101) and -N(CR100R101) groups, wherein R100and R101are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R100and R101are not both simultaneously hydrogen.

[0050] The term “nitro” as used herein refers to an -NO2 group.

[0051] The term “trifluoromethyl” as used herein refers to -CF3.

[0052] The term “trifluoromethoxy” as used herein refers to -OCF3.

[0053] The term “azido” refers to -N3.

[0054] The term “trialkyl ammonium” refers to a -N(alkyl)3 group. A trialkylammonium group is positively charged and thus typically has an associated anion, such as halogen anion.

[0055] The term “isocyano” refers to -NC.

[0056] The term “isothiocyano” refers to -NCS.

[0057] The term “pentafluorosulfanyl” refers to -SFs.

[0058] 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 disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. 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,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

[0059] Pharmaceutically acceptable salts of compounds described herein are within the scope of the present technology and include acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, allergenic, or irritating, and is bioavailable). When the compound of the present technology has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g. alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonicacid, benzenesulfonic acid, naphthalene sulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the present technology has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g. Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia or organic amines (e.g. dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g. arginine, lysine and ornithine). Such salts can be prepared in situ during isolation and purification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed.

[0060] Those of skill in the art will appreciate that compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and / or stereoisomerism. As the formula drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, stereochemical or geometric isomeric forms, it should be understood that the present technology encompasses any tautomeric, conformational isomeric, stereochemical and / or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms. The phrase “and / or” as used in this paragraph and the present disclosure will be understood to mean any one of the recited members individually or a combination of any two or more thereof - for example, “A, B, and / or C” would mean “A, B, C, A and B, A and C, or B and C ”

[0061] “ Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, quinazolinones may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0062] As another example, guanidines may exhibit the following isomeric forms in protic organic solution, also referred to as tautomers of each other:

[0063] Because of the limits of representing compounds by structural formulas, it is to be understood that all chemical formulas of the compounds described herein represent all tautomeric forms of compounds and are within the scope of the present technology.

[0064] Stereoisomers of compounds (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated. Thus, compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.

[0065] The compounds of the present technology may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.

[0066] Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. Also within this disclosure are Arabic numerals referring to referenced citations, the full bibliographic details of which are provided preceding the claims. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure.

[0067] The Present Technology

[0068] Post-transcriptional gene regulation occurs at the levels of pre-mRNA splicing and maturation, as well as mRNA transport, editing, storage, stability, and translation. This level of gene regulation is essential for normal development, but when dysregulated, has many implications in disease conditions, including cancer. These functions are mediated by RNA- binding proteins (RBPs), which thus present targets for cancer therapy.

[0069] The RBP Hu antigen R (“HuR”) is a member of the embryonic lethal abnormal vision (“ELAV”) family that binds to adenine- and uridine-rich elements (collectively, “ARE”) located in the 3'- or 5 '-untranslated region (“UTR”) of target mRNAs.1HuR is elevated in a broad range of cancer tissues compared with the corresponding normal tissues2. In early reports, upregulated HuR in brain and colon cancers was linked to the enhanced expression of COX-2, VEGF, TGF-P, IL-8, and other cancer-associated proteins3,4Subsequent studies revealed that HuR was broadly overexpressed in virtually all malignancies tested, including cancers of the colon2’5,6, prostate7’8, breast9, brain3, ovaries10, pancreasn, and lung12. Elevated cytoplasmic accumulation of HuR correlates with highgrade malignancy and serves as a prognostic factor of poor clinical outcome in those cancers13‘15. Cytoplasmic HuR expression in 135 breast cancer patients’ samples was examined where it was found that high cytoplasmic HuR expression correlates with advanced tumor grade of breast cancer and poor overall and distant disease-free survival of breast cancer patients .

[0070] Moreover, HuR is proposed to play a causal role in tumor development / progression. Cancer cells with elevated HuR produced significantly larger tumors than those arising from control populations in a mouse xenograft model2, while reduced HuR level led to decreased tumor size16. HuR CRISPR knockout (KO) clones in several cancer cell lines were examined where it was found that HuR knockout decreased cell growth, colony formation, and invasive capacity in vitro, and delayed tumor growth in vivo39.

[0071] HuR contains three RNA recognition motifs (“RRM”), of which RRM1 and RRM2 are involved in RNA binding, whereas RRM3 does not contribute to RNA binding but is needed for cooperative assembly of HuR oligomers on RNA.17Recently the crystal structure of two N-terminal RRM domains (namely, RRM1 and RRM2) of HuR complexed with RNA was reported.18HuR target mRNAs bear AREs in their 3'- or 5'-UTRs. Many cytokine andproto-oncogene mRNAs have been identified as containing AREs within their 3'-UTRs, which confer a short mRNA half-life.19Cytoplasmic binding of HuR to these ARE- containing mRNAs is generally accepted to lead to mRNA stabilization and increased translation20,21. HuR promotes tumorigenesis by interacting with a subset of mRNAs which encode proteins implement in different tumor processes including cell proliferation, cell survival, angiogenesis, invasion, and metastasis13'15. HuR also promotes the translation of several target mRNAs encoding proteins that are involved in cancer treatment resistance 15,22,23repOrtec[ ^hat HuR regulates sensitivity to 5 -fluorouracil treatment in TNBC cell line MDA-MB-23140. Another study revealed that HuR is responsible for the enhanced aggressiveness of MDA-MB-231 cells in vitro and in orthotopic mice after laptinib treatment41. Recently, it was reported that inhibition of HuR cytoplasmic translocation synergizes cisplatin in urothelial carcinoma of the bladder in vivo42.

[0072] HuR up-regulates the oncogenic Musashil (Msil)24, Musashi2 (Msi2)25,26and anti- apoptotic proteins, Bcl-222and XIAP23, via binding AREs and promoting mRNA stability and translation, thus leading to activation of Wnt / Notch signaling pathways and inhibition of apoptosis. Wnt / Notch pathways are involved in cancer stem cells (CSCs)27'30.

[0073] Besides cancer, HuR is implicated in other pathological conditions, including inflammation, cardiovascular, muscle, kidney, and liver diseases43, 44. Green et al.45reported that cardiomyocyte-specific HuR-deletion in mice reduces pathological cardiac hypertrophy and Janice Sanchez et al.46found that depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy.

[0074] Although there are many examples of compounds which specifically interfere with protein-protein interactions, there is limited success of drug discovery for protein-RNA interactions, especially for HuR.

[0075] The present technology is directed to compounds and compositions that inhibit the binding of RNA and HuR, as well as methods of using such compounds and compositions for inducing preferential inhibition and death of the cells with HuR overexpression and / or downstream signaling dysregulation, and for sensitizing such cells to the induction of cell death and / or growth inhibition by the conventional therapies.

[0076] In an aspect, the present technology provides a compound according to Formula IwhereinZ1is aryl, heteroaryl, or cycloalkyl;R1is methyl, isopropyl, -CH(CH3)(CH2CH3), - CH2CH(CH3)2, -CH2CH2SCH3, benzyl,L1is absent, -CH2-, -CH2-CH2-, or -CH=CH-;X1is O, NH, or S;X2is OH, NH2, NH-OH, NH-NH2, or O-(Ci-C6alkyl); and X3is S(O)2or C(O).

[0077] In any embodiment herein, it may be that Z1isR6are each independently H, halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, Ci-Ce alkyl, cycloalkyl, Ci-Ce alkoxy, cycloalkoxy, aryl, aryloxy, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, Ci-Ce alkanoyl, Ci-Cs alkanoyloxy, aryloyl, or aryloyloxy, where any two adjacent R2, R3, R4, R5, and R6may join to form a 5-membered alkyl, heteroalkyl, aryl or heteroaryl.

[0078] In any embodiment herein, it may be that the compound is of Formula IA or pharmaceutically acceptable salt thereof

[0079] In any embodiment herein, it may be that the compound is of Formula IB or pharmaceutically acceptable salt thereof

[0080] In any embodiment herein, it may be that R2, R3, R4, R5, and R6are each independently H, halo, hydroxy, amino, cyano, trifluoromethyl, thiol, nitro, pentafluorosulfanyl, Ci-Ce alkyl, cycloalkoxy, aryl, aryloxy, heterocyclylalkyl, heterocyclyloxy, or heterocyclylalkoxy, where any two adjacent R2, R3, R4, R5, and R6may join to form a 5-membered or 6-membered alkyl or aryl, and provided that at least one of R2, R3, R4, R5, and R6is not H. In any embodiment herein, it may be that R2, R3, R4, R5, and R6are each independently H, halo, amino, trifluoromethyl, nitro, pentafluorosulfanyl, C1-C4 alkyl, cycloalkoxy, aryl oxy, heterocyclyloxy, or heterocyclylalkoxy, where any two adjacent R2, R3, R4, R5, and R6may join to form a 5-membered or 6-membered alkyl or aryl, and provided that at least one R2, R3, R4, R5, and R6is not H.

[0081] In any embodiment herein, it may be that X1is NH or S. In any embodiment herein, it may be that L1is -CH=CH-

[0082] In any embodiment herein, it may be that the compound is of Formula IC or pharmaceutically acceptable salt thereofwherein R2is halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, Ci-Ce alkyl, cycloalkyl, Ci-Ce alkoxy, cycloalkoxy, aryl, aryloxy, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, Ci-Ce alkanoyl, Ci-Cs alkanoyloxy, aryloyl, or aryloyloxy. In any embodiment herein where the compound is of Formula IC or pharmaceutically acceptable salt thereof, it may be that R2is halo, hydroxy, amino, cyano, trifluoromethyl, thiol, nitro, pentafluorosulfanyl, Ci-Ce alkyl, cycloalkoxy, aryl, aryloxy, heterocyclylalkyl, heterocyclyloxy, or heterocyclylalkoxy. In any embodiment herein where the compound is of Formula IC or pharmaceutically acceptable salt thereof, it may be that R2is halo, amino, trifluoromethyl, nitro, pentafluorosulfanyl, C1-C4 alkyl, cycloalkoxy, aryloxy, heterocyclyloxy, or heterocyclylalkoxy.

[0083] In any embodiment herein, it may be that X2is OH, NH2, NH-OH, or NH-NH2. It should be noted that compounds where X2is O-(Ci-Ce alkyl) are especially suited as intermediates in the synthesis of active compounds where X2is OH, NH2, NH-OH, or NH- NH2, as illustrated in the working examples. However, compounds where X2is O-(Ci-Ce alkyl) may themselves be used as pro-drug compounds (for example, where esterases in a subject will convert X2in vivo into OH).

[0084] In a related aspect of the present technology, a composition is provided that includes any embodiment disclosed herein of a compound of the present technology and a pharmaceutically acceptable carrier, excipient, filler, or agent (collectively referred to as “pharmaceutically acceptable carrier” unless otherwise indicated and / or specified). In a related aspect, a pharmaceutical composition is provided, the pharmaceutical composition including an effective amount of a compound of the present technology for treating a condition; and where the condition is a hyperproliferative disease with HuR overexpression. The hyperproliferative disease with HuR overexpression may include one or more of a coloncancer, a prostate cancer, a breast cancer (e.g., triple negative breast cancer), a brain cancer, an ovarian cancer, a pancreatic cancer, or a lung cancer.

[0085] In a further related aspect, a method is provided the includes administering a compound of the present technology to a subject. It may be the subject is suffering from a condition, where the condition is a hyperproliferative disease with HuR overexpression. The hyperproliferative disease with HuR overexpression may include one or more of a colon cancer, a prostate cancer, a breast cancer (e.g., triple negative breast cancer), a brain cancer, an ovarian cancer, a pancreatic cancer, or a lung cancer. It may be the method includes administering an effective amount of a compound of the present technology. Administration of a compound of the present technology may be via administration a pharmaceutical composition (as described herein) that includes a compound of the present technology.

[0086] “Effective amount” refers to the amount of a compound or composition required to produce a desired effect. One example of an effective amount includes amounts or dosages that yield acceptable toxicity and bioavailability levels for therapeutic (pharmaceutical) use including, but not limited to, the treatment of a hyperproliferative disease with HuR overexpression and / or a fibrotic disease. Another example of an effective amount includes amounts or dosages that reduce the size of tumors associated with one or more of a colon cancer, a prostate cancer, a breast cancer (e.g., triple negative breast cancer), a brain cancer, an ovarian cancer, a pancreatic cancer, or a lung cancer that exhibit HuR overexpression. As used herein, a “subject” or “patient” is a mammal, such as a cat, dog, rodent or primate. Typically the subject is a human, and, preferably, a human suffering from or suspected of suffering from an addiction. The term “subject” and “patient” can be used interchangeably.

[0087] Thus, the instant present technology provides pharmaceutical compositions and medicaments comprising one or more compounds of the present technology and a pharmaceutically acceptable carrier or one or more excipients or fillers. The compositions may be used in the methods and treatments described herein. Such compositions and medicaments include a theapeutically effective amount of any compound as described herein, including but not limited to a compound of Formula I. The pharmaceutical composition may be packaged in unit dosage form. The unit dosage form is effective in treating a hyperproliferative disease with HuR overexpression and / or a fibrotic disease when administered to a subject in need thereof.

[0088] The pharmaceutical compositions and medicaments may be prepared by mixing one or more compounds of the present technology with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to prevent and treat a hyperproliferative disease with HuR overexpression and / or prevent and treat a fibrotic disease. The compounds and compositions described herein may be used to prepare formulations and medicaments that prevent or treat a variety of disorders associated with a hyperproliferative disease with HuR overexpression and / or a fibrotic disease. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injections. The following dosage forms are given by way of example and should not be construed as limiting the instant present technology.

[0089] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant present technology. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0090] Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant present technology.

[0091] Those skilled in the art are readily able to determine an effective amount, such as by simply administering a compound of the present technology to a patient in increasing amounts until the progression of the condition / disease state is decreased or stopped. The compounds of the present technology can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is sufficient. The specific dosage used, however, can vary or may be adjusted as considered appropriate by those of ordinary skill in the art. For example, the dosage candepend on a number of factors including the requirements of the patient, the severity of the condition being treated and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.

[0092] Various assays and model systems can be readily employed to determine the therapeutic effectiveness of the treatment according to the present technology.

[0093] The compounds of the present technology may also be administered to a patient along with other conventional therapeutic agents that may be useful in the treatment of a hyperproliferative disease with HuR overexpression and / or the treatment of a fibrotic disease. The administration may include oral administration, parenteral administration, or nasal administration. In any of these embodiments, the administration may include subcutaneous injections, intravenous injections, intraperitoneal injections, or intramuscular injections. In any of these embodiments, the administration may include oral administration. The methods of the present technology can also comprise administering, either sequentially or in combination with one or more compounds of the present technology, a conventional therapeutic agent in an amount that can potentially or synergistically be effective for the treatment of a hyperproliferative disease with HuR overexpression and / or the treatment of a fibrotic disease.

[0094] In one aspect, a compound of the present technology is administered to a patient in an amount or dosage suitable for therapeutic use. Generally, a unit dosage comprising a compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitant therapies and the like. An exemplary unit dosage based on these considerations can also be adjusted or modified by a physician skilled in the art. For example, a unit dosage for a patient comprising a compound of the present technology can vary from 1 x 104g / kg to 1 g / kg, preferably, 1 x I O3g / kg to 1.0 g / kg. Dosage of a compound of the present technology can also vary from 0.01 mg / kg to 100 mg / kg or, preferably, from 0.1 mg / kg to 10 mg / kg.

[0095] The terms “associated” and / or “binding” can mean a chemical or physical interaction, for example, between a compound of the present technology and a target of interest. Examples of associations or interactions include covalent bonds, ionic bonds,hydrophilic-hydrophilic interactions, hydrophobic-hydrophobic interactions and complexes. Associated can also refer generally to “binding” or “affinity” as each can be used to describe various chemical or physical interactions. Measuring binding or affinity is also routine to those skilled in the art. For example, compounds of the present technology can bind to or interact with a target of interest or precursors, portions, fragments and peptides thereof and / or their deposits.

[0096] The examples herein are provided to illustrate advantages of the present technology and to further assist a person of ordinary skill in the art with preparing or using the compounds of the present technology. The examples herein are also presented in order to more fully illustrate the preferred aspects of the present technology. The examples should in no way be construed as limiting the scope of the present technology, as defined by the appended claims. The examples can include or incorporate any of the variations, aspects or embodiments of the present technology described above. The variations, aspects or embodiments described above may also further each include or incorporate the variations of any or all other variations, aspects or embodiments of the present technology.EXAMPLES

[0097] All solvents and reagents were used as received from commercial suppliers, unless noted otherwise.1H and13C NMR spectra were recorded on a Bruker AM or Varian 400 spectrometer (operating at 400 and 101 MHz respectively) or a Bruker AVIII spectrometer (operating at 500 and 126 MHz respectively) in CDCh with 0.03% TMS as an internal standard. The chemical shifts (5) reported are given in parts per million (ppm) and the coupling constants (J) are in Hertz (Hz). The spin multiplicities are reported as s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet, td = triplet of doublet, and m = multiplet. Microwave reactions were carried out using a Biotage Initiator Classic. Column chromatography separations were performed using the Teledyne Isco CombiFlash Rf using RediSep Rf silica gel columns. The analytical RPLC method used an Agilent 1200 RRLC system with UV detection (Agilent 1200 DAD SL) and mass detection (Agilent 6224 TOF). The analytical method conditions included a Waters Aquity BEH Cl 8 column (2.1 x 50 mm, 1.7 pm) and elution with a linear gradient of 5% acetonitrile in pH 9.8 buffered aqueous ammonium formate to 100% acetonitrile at 0.4 mL / min flow rate. Automated preparative RP HPLC purification was performed using an Agilent 1200 Mass-Directed Fractionation system (PrepPump G1361 with gradient extension, make-up pump G1311A, pH modification pump G1311A, HTS PAL autosampler, UV-DAD detection G1315D, fraction collector G1364B, and Agilent 6120 quadrapole spectrometer G6120A). The preparative chromatography conditions included a Waters X-Bridge C18 column (19 x 150 mm, 5 um, with 19 x 10-mm guard column), elution with a water and acetonitrile gradient, which increases 20% in acetonitrile content over 4 min at a flow rate of 20 mL / min (modified to pH 9.8 through addition of NH40H by auxiliary pump), and sample dilution in DMSO. The preparative gradient, triggering thresholds, and UV wavelength were selected according to the analytical RP HPLC analysis of each crude sample. Compound purity was measured on the basis of peak integration (area under the curve) from UV-Vis absorbance at 214 nm, and compound identity was determined on the basis of mass spectral and NMR analyses.

[0098] An exemplary synthetic protocol for indole-containing esters, carboxylic acids, hydroxamic acids, and acyl hydrazides is illustrated inScheme 1.Scheme 1.Reagents and conditions: (a) CDI, NaBH4, Anhydrous THF, EtOH; (b) MnCh, DMF; (c) Toluene, reflux; (d) Fe, NH4CI, EtOH, H2O; (e) L-Pheor L-Leu, NaOH, Acetonitrile; (f) HATU, DIPEA, DCM; (g) NaOH, EtOH, H2O, reflux; or NH2OH HCI, KOH, 1,4-Dioxane; (h) N2H4 H2O, reflux; (i) Bromocyclopentane, K2CO3, DMF; (j) NaOH, EtOH, H2O, reflux; (k) L-Phe, HATU, DIPEA, DCM.

[0099] An exemplary synthetic protocol for benzothiophene-containing esters, carboxylic acids, and hydroxamic acids is illustrated in Scheme 2.Scheme 2.Reagents and conditions: (a) EtsN, DMF; (b) Toluene, reflux; (c) Fe, NH4CI, EtOH; (d) L-Phe or L-Leu, HATU, DIPEA, DCM; (e) HATU, DIPEA, DCM; (f) NaOH, EtOH, H2O, reflux; or NH2OH HC1, KOH, 1,4-Dioxane.

[0100] Exemplary Synthesis: Ethyl (E)-3-(5-(2-(4-(tert-butyl)benzamido)-4- methylpentanamido)-lH-indol-2-yl)acrylate (KH301B)DIPEA (774 mg, 6 mmol) and HATU (2280 mg, 6 mmol) were added to a solution of (4- (tert-butyl)benzoyl)-L-leucine (1746 mg, 6 mmol ) in CH2CI2 (30 mL). The mixture was stirred at RT for 0.5 h. Ethyl (E)-3-(5-amino-lH-indol-2-yl)acrylate (920 mg, 4 mmol) was then added to the solution. The mixture was stirred at RT and reaction was monitored by TLC. After completion of the reaction, residue was extracted with CH2CI2, washed with brine, and dried over MgSO4. The evaporated residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain the compound as an off- white solid (1046 mg, 52.6%). ‘H NMR (400 MHz, DMSO-t / e) 5 11.55 (s, 1H), 10.01 (s, 1H), 8.54 (d, J= 8 Hz, 1H), 7.97 (d, J= 1.9 Hz, 1H), 7.89 (d, J= 8.5 Hz, 2H), 7.61 (d, J= 15.9 Hz, 1H), 7.49 (d, J= 8.5 Hz, 2H), 7.36 - 7.38 (m, 1H), 7.33 (d, J= 8.8 Hz, 1H), 6.88 (d, J= 2.0 Hz, 1H), 6.54 (d, J= 15.9 Hz, 1H), 4.73 - 4.67 (m, 1H), 4.19 (q, J= 7.1 Hz, 2H), 1.87 - 1.73 (m, 2H), 1.65 - 1.58 (m, 1H), 1.30 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H), 0.95 (dd, J= 12.0, 6.5 Hz, 6H).13C NMR (101 MHz, DMSO-t / e) 5 171.07, 166.38, 166.35, 154.14, 134.92, 134.72, 134.31, 131.89, 131.40, 127.70, 127.50, 124.98, 118.13, 115.47, 111.45, 111.21, 108.37, 59.97, 52.70, 40.58, 34.64, 30.99, 24.64, 23.12, 21.59, 14.27. HPLC purity 94.686%.

[0101] Compounds KH302B, KH303B, KH304B, KH305B, KH306B, KH308B, KH309B, KH310B, KH311B, and KH312B were synthesized using a similar procedure as described for KH301B.

[0102] Exemplary Synthesis: (E)-3-(5-(2-(4-(tert-butyl)benzamido)-4- methylpentanamido)-lH-indol-2-yl)acrylic acid (KH301A)To a solution of ethyl (E)-3-(5-(2-(4-(tert-butyl)benzamido)-4-methylpentanamido)-lH- indol-2-yl)acrylate (251 mg, 0.5 mmol) in ethanol (5 ml) was added IM sodium hydroxide (2ml), and the reaction was refluxed (70 °C). Upon completion, the reaction mixture was acidified with 2M HC1 under ice-water bath. The precipitated solid was filtered, washed with distilled water, and dried to give a light green solid (200 mg, 84.2%).JH NMR (400 MHz, DMSO-tA) 5 10.27 (s, 1H), 8.55 (d, J= 7.7 Hz, 1H), 8.28 (s, 1H), 7.90 - 7.86 (m, 4H), 7.80 (s, 1H), 7.58 (dd, J= 8.8, 2.1 Hz, 1H), 7.48 (d, J= 8.4 Hz, 2H), 6.22 (d, J= 15.7 Hz, 1H), 4.71 - 4.65 (m, 1H), 1.86 - 1.72 (m, 2H), 1.64 - 1.57 (m, 1H), 1.30 (s, 9H), 0.94 (dd, J= 11.8, 6.4 Hz, 6H).13C NMR (101 MHz, DMSO-t / e) 5 172.22, 167.47, 166.98, 154.70, 140.36, 140.27, 137.81, 137.13, 134.71, 131.82, 129.91, 128.01, 125.48, 123.34, 120.62, 119.90, 114.73, 53.31, 40.85, 35.15, 31.48, 25.12, 23.58, 22.04. HPLC purity 97.908%.

[0103] Compounds KH302A, KH303A, KH304A, KH305A, KH306A, KH308A, KH309A, KH310A, KH311A, and KH312A were synthesized using a similar procedure as described for KH301A.

[0104] Exemplary Synthesis: (E)-4-(tert-butyl)-N-(l-((2-(3-(hydroxyamino)-3- oxoprop-l-en-l-yl)-lH-indol-5-yl)amino)-4-methyl-l-oxopentan-2-yl)benzamide (KH301)To a solution of ethyl (E)-3-(5-(2-(4-(tert-butyl)benzamido)-4-methylpentanamido)-lH- indol-2-yl)acrylate (251 mg, 0.5 mmol) in 1,4-Dioxane (5 ml) was added a mixture of hydroxylamine hydrochloride (348 mg, 5 mmol) and potassium hydroxide (1120 mg, 20 mmol) in distilled water (10 ml). The mixture was stirred at RT and reaction was monitored by TLC. Upon completion, the reaction mixture was acidified with 2M HC1 under ice-water bath. The precipitated solid was filtered, washed with distilled water, and dried. The crude was purified via silica gel chromatography (DCM: MeOH = 30:1) to give a brown solid (90 mg, 36.7%). 'H NMR (400 MHz, DMSO-t / e) 5 11.45 (s, 1H), 9.94 (s, 1H), 8.50 (d, J= 8.0 Hz, 1H), 7.90 - 7.86 (m, 3H), 7.50 - 7.44 (m, 3H), 7.30 (s, 2H), 6.70 (s, 1H), 6.39 (d, J= 15.4 Hz, 1H), 4.71 - 4.65 (m, 1H), 1.85 - 1.71 (m, 2H), 1.64 - 1.57 (m, 1H), 1.30 (s, 9H), 0.94 (dd, J= 12.2, 6.4 Hz, 6H).13C NMR (101 MHz, DMSO-t / e) 5 170.96, 166.32, 154.12, 135.11, 134.49, 131.67, 131.40, 129.23, 127.84, 127.48, 124.97, 117.17, 117.03, 111.25, 110.98, 105.66, 52.67, 40.58, 34.65, 30.99, 24.62, 23.11, 21.59. HPLC purity 92.383%.

[0105] Compounds KH302, KH303, KH304, KH305, KH306, KH308, KH309, KH310, KH311, and KH312 were synthesized using a similar procedure as described for KH301.

[0106] Exemplary Synthesis: 4-(tert-butyl)-N-(l-((2-(3-hydrazinyl-3-oxopropyl)-lH- indol-5-yl)amino)-4-methyl-l-oxopentan-2-yl)benzamide (KH301E)Ethyl (E)-3-(5-(2-(4-(tert-butyl)benzamido)-4-methylpentanamido)-lH-indol-2-yl)acrylate (251 mg, 0.5 mmol) was dissolved in hydrazine hydrate (5 ml), and the reaction was refluxed (100 °C). Upon completion, the precipitated solid was filtered, washed with distilled water, and dried. The crude was purified via silica gel chromatography (DCM: MeOH = 30: 1) to give a yellow solid (80 mg, 32.6%). 'H NMR (400 MHz, DMSO-t / e) 5 10.83 (s, 1H), 9.83 (s, 1H), 9.06 (s, 1H), 8.48 (d, J= 8.1 Hz, 1H), 7.87 (d, J= 8.6 Hz, 2H), 7.74 (d, J= 1.8 Hz, 1H), 7.49 (d, J= 8.5 Hz, 2H), 7.20 - 7.14 (m, 2H), 6.08 (d, J= 1.2 Hz, 1H), 4.71 - 4.65 (m, 1H), 4.24 (s, 2H), 2.92 (t, J= 7.8 Hz, 2H), 2.44 (t, J= 8.0 Hz, 2H), 1.84 - 1.70 (m, 2H), 1.63 - 1.56 (m, 1H), 1.30 (s, 9H), 0.94 (dd, J= 12.5, 6.4 Hz, 6H). HPLC purity 94.652%.

[0107] Compound KH303E was synthesized using a similar procedure as described for KH301E

[0108] Ethyl (E)-3-(5-(2-(4-(tert-butyl)benzamido)-3-phenylpropanamido)-lH-indol-2- yl)acrylateWhite solid (58.7% yield).XH NMR (400 MHz, DMSO-t / e) 5 11.54 (s, 1H), 10.10 (s, 1H), 8.66 (d, J= 8.2 Hz, 1H), 7.95 (s, 1H), 7.78 (d, J= 8.5 Hz, 2H), 7.60 (d, J= 15.9 Hz, 1H), 7.47 (d, J= 8.5 Hz, 2H), 7.42 (d, J= 8.3 Hz, 2H), 7.33 (s, 2H), 7.28 (t, J= 7.6 Hz, 2H), 7.20 - 7.16 (m, 1H), 6.89 (d, = 2.0 Hz, 1H), 6.53 (d, J= 16.0 Hz, 1H), 4.90 - 4.84 (m, 1H), 4.19 (q, J= 7.1 Hz, 2H), 3.18 - 3.09 (m, 2H), 1.29 (s, 9H), 1.25 (t, J= 7.1 Hz, 3H).13C NMR (101 MHz, DMSO-6 / 6) 5 170.08, 166.36, 166.31, 154.17, 138.35, 134.95, 134.69, 134.34, 131.73,131.27, 129.30, 128.11, 127.70, 127.36, 126.32, 124.99, 118.09, 115.51, 111.50, 111.24,108.35, 59.97, 55.74, 37.40, 34.64, 30.96, 14.26. HPLC purity 94.686%.

[0109] (E)-3-(5-(2-(4-(tert-butyl)benzamido)-3-phenylpropanamido)-lH-indol-2- yl)acrylic acid (Light green solid (76.6% yield). 'HNMR (400 MHz, DMSO-t / e) 5 12.34 (s, 1H), 11.52 (d, J = 2.0 Hz, 1H), 10.09 (s, 1H), 8.64 (d, J= 8.2 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J= 8.0 Hz, 2H), 7.57 - 7.53 (m, 1H), 7.47 (s, 1H), 7.46 - 7.42 (m, 3H), 7.33 (s, 2H), 7.28 (t, J= 8.0 Hz, 2H), 7.20 - 7.16 (m, 1H), 6.84 (d, J= 2.0 Hz, 1H), 6.45 (d, J= 16.0 Hz, 1H), 4.91 - 4.85 (m, 1H), 3.19 - 3.10 (m, 2H), 1.29 (s, 9H).13C NMR (101 MHz, DMSO-t / e) 5 170.57, 168.28, 166.82, 154.69, 138.86, 135.42, 135.02, 134.87, 132.17, 131.79, 129.81, 128.61, 128.23, 127.87, 126.83, 125.50, 118.42, 117.24, 111.95, 111.75, 108.34, 56.24, 37.92, 35.14, 31.47. HPLC purity 98.154%.

[0110] (E)-4-(tert-butyl)-N-(l-((2-(3-(hydroxyamino)-3-oxoprop-l-en-l-yl)-lH-indol-5- yl)amino)-l-oxo-3-phenylpropan-2-yl)benzamide (KH303)Brown solid (38.9% yield).XH NMR (400 MHz, DMSO-t / e) 5 10.14 (s, 1H), 8.73 (dd, J= 12.8, 8.3 Hz, 1H), 7.91 (s, 1H), 7.79 (d, J= 8.5 Hz, 2H), 7.47 - 7.40 (m, 5H), 7.30 - 7.25 (m, 4H), 7.20 - 7.15 (m, 1H), 6.71 (s, 1H), 6.51 - 6.39 (m, 1H), 4.89 - 4.84 (m, 1H), 3.18 - 3.13 (m, 2H), 1.29 (s, 9H).13C NMR (101 MHz, DMSO ) 5 170.08, 166.30, 162.99, 154.16, 138.45, 135.26, 134.56, 131.58, 131.31, 129.34, 129.06, 128.12, 127.88, 127.40, 126.33, 125.01, 117.33, 117.13, 111.32, 111.01, 105.65, 55.89, 37.44, 34.66, 30.98. HPLC purity 95.251%.

[0111] 4-(tert-butyl)-N-(l-((2-(3-hydrazinyl-3-oxopropyl)-lH-indol-5-yl)amino)-l-oxo- 3-phenylpropan-2-yl)benzamide (KH303E)Yellow solid (36.9% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.84 (s, 1H), 9.94 (s, 1H), 9.06 (s, 1H), 8.61 (d, J= 8.3 Hz, 1H), 7.79 - 7.74 (m, 3H), 7.46 (d, J= 8.6 Hz, 2H), 7.42 (d, J = 7.0 Hz, 2H), 7.28 (t, J= 7.5 Hz, 2H), 7.22 - 7.14 (m, 3H), 6.10 (s, 1H), 4.91 - 4.85 (m, 1H), 4.27 (s, 2H), 3.19 - 3.08 (m, 2H), 2.94 (t, J= 7.7 Hz, 2H), 2.45 (t, J= 7.7 Hz, 2H), 1.29 (s, 9H).13C NMR (101 MHZ, DMSO-t / e) 5 170.77, 169.77, 166.27, 154.16, 140.09, 138.40, 132.85, 131.32, 130.71, 129.31, 128.13, 128.09, 127.34, 126.30, 124.99, 114.06, 110.40, 110.35, 98.27, 55.67, 37.50, 34.63, 32.83, 30.96, 23.71. HPLC purity 98.723%.

[0112] Ethyl (E)-3-(5-(2-(4-(cyclopentyloxy)benzamido)-3-phenylpropanamido)-lH- indol-2-yl)acrylateWhite solid (67.7% yield). 'HNMR (400 MHz, DMSO ) 5 11.55 (s, 1H), 10.11 (s, 1H), 8.58 (d, J= 8.2 Hz, 1H), 7.96 (s, 1H), 7.82 (d, J= 8.8 Hz, 2H), 7.61 (d, J= 15.9 Hz, 1H), 7.43 (d, J= 7.0 Hz, 2H), 7.34 (s, 2H), 7.28 (t, J= 7.5 Hz, 2H), 7.19 (d, J= 7.4 Hz, 1H), 6.94 (d, J= 8.9 Hz, 2H), 6.89 (d, J= 2.0 Hz, 1H), 6.54 (d, J= 15.9 Hz, 1H), 4.90 - 4.83 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.19 - 3.06 (m, 2H), 1.97 - 1.89 (m, 2H), 1.75 - 1.54 (m, 6H), 1.27 (t, .7= 7.1 Hz, 3H).13C NMR (101 MHz, DMSO-t / e) 5 170.23, 166.35, 165.97, 160.13, 138.42, 134.94, 134.67, 134.33, 131.77, 129.36, 129.29, 128.08, 127.69, 126.29, 125.79,118.07, 115.51, 114.69, 111.47, 111.20, 108.32, 78.88, 59.95, 55.83, 37.37, 32.25, 23.64, 14.24. HPLC purity 96.193%.

[0113] (E)-3-(5-(2-(4-(cyclopentyloxy)benzamido)-3-phenylpropanamido)-lH-indol-2- yl)acrylic acid (KH308A)White solid (72.3% yield). 'H NMR (400 MHz, DMSO-t / e) 5 11.49 (d, J= 2.2 Hz, 1H), 10.05 (s, 1H), 8.54 (d, J= 8.2 Hz, 1H), 7.93 (s, 1H), 7.82 - 7.78 (m, 2H), 7.54 (d, J= 15.9 Hz, 1H), 7.42 (d, J= 7.0 Hz, 2H), 7.32 (s, 2H), 7.28 (t, J= 7.6 Hz, 2H), 7.18 (t, J= 7.4 Hz, 1H), 6.95 - 6.92 (m, 2H), 6.83 (d, J= 2.0 Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H), 4.90 - 4.82 (m, 2H), 3.18 - 3.08 (m, 2H), 1.98 - 1.91 (m, 2H), 1.72 - 1.58 (m, 6H).13C NMR (101 MHz, DMSO ) 5170.17, 167.72, 165.95, 160.12, 138.40, 134.87, 134.47, 134.32, 131.65, 129.34, 129.26,128.07, 127.70, 126.28, 125.79, 117.85, 116.70, 114.68, 111.40, 111.17, 107.78, 78.88, 55.76, 37.42, 32.24, 23.62.

[0114] (E)-4-(cyclopentyloxy)-N-(l-((2-(3-(hydroxyamino)-3-oxoprop-l-en-l-yl)-lH- indol-5-yl)amino)-l-oxo-3-phenylpropan-2-yl)benzamide (KH308)Brown solid (34.1% yield).XH NMR (400 MHz, DMSO- e) 6 11.48 (s, 1H), 10.08 (s, 1H), 8.59 (d, J= 8.2 Hz, 1H), 7.90 (s, 1H), 7.80 (d, J= 8.8 Hz, 2H), 7.44 - 7.39 (m, 3H), 7.30 - 7.26 (m, 4H), 7.20 - 7.16 (m, 1H), 6.94 (d, J= 8.9 Hz, 2H), 6.71 (s, 1H), 6.38 (d, J= 15.6 Hz, 1H), 4.90 - 4.81 (m, 2H), 3.17 (d, J= 5.0 Hz, 2H), 2.00 - 1.88 (m, 2H), 1.72 - 1.54 (m, 6H).

[0115] Ethyl (E)-3-(5-(2-(4-(tert-butyl)benzamido)-4- methylpentanamido)benzo[b]thiophen-2-yl)acrylate (KH302B)White solid (70.7% yield). 'HNMR (400 MHz, DMSO ) 5 10.28 (s, 1H), 8.55 (d, J= 7.7 Hz, 1H), 8.29 (s, 1H), 7.93 (d, J= 6.2 Hz, 1H), 7.89 (d, J= 4.6 Hz, 2H), 7.86 (d, J= 5.5 Hz,2H), 7.59 (dd, J= 8.8, 2.1 Hz, 1H), 7.49 (d, J= 8.5 Hz, 2H), 6.30 (d, J= 15.7 Hz, 1H), 4.72 - 4.66 (m, 1H), 4.20 (q, J= 7.1 Hz, 2H), 1.87 - 1.74 (m, 2H), 1.64 - 1.58 (m, 1H), 1.31 (s, 9H), 1.27 (t, J= 7.1 Hz, 3H), 0.95 (dd, J= 11.7, 6.4 Hz, 6H).13C NMR (101 MHz, DMSO-t / e) 5 171.85, 166.62, 165.76, 154.31, 139.80, 139.74, 137.83, 136.70, 134.42, 131.34, 129.98, 127.58, 125.08, 122.97, 119.62, 118.95, 114.37, 60.42, 52.89, 40.38, 34.72, 31.04, 24.70, 23.16, 21.58, 14.28. HPLC purity 99.312%.

[0116] (E)-3-(5-(2-(4-(tert-butyl)benzamido)-4-methylpentanamido)benzo[b]thiophen- 2-yl)acrylic acidWhite solid (79.7% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.27 (s, 1H), 8.55 (d, J= 7.8 Hz, 1H), 8.28 (s, 1H), 7.90 - 7.82 (m, 4H), 7.80 (s, 1H), 7.58 (dd, J= 8.8, 2.1 Hz, 1H), 7.48 (d, J= 8.4 Hz, 2H), 6.22 (d, J= 15.7 Hz, 1H), 4.71 - 4.65 (m, 1H), 1.86 - 1.72 (m, 2H), 1.64 - 1.57 (m, 1H), 1.30 (s, 9H), 0.94 (dd, J= 11.8, 6.4 Hz, 6H).13C NMR (101 MHz, DMSO ) 5 172.22, 167.47, 166.98, 154.70, 140.36, 140.27, 137.81, 137.13, 134.71, 131.82, 129.91, 128.01, 125.48, 123.34, 120.62, 119.90, 114.73, 53.31, 40.85, 35.15, 31.48, 25.12, 23.58, 22.04. HPLC purity 98.133%.

[0117] (E)-4-(tert-butyl)-N-(l-((2-(3-(hydroxyamino)-3-oxoprop-l-en-l- yl)benzo[b]thiophen-5-yl)amino)-4-methyl-l-oxopentan-2-yl)benzamide (KH302)White solid (35.0% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.34 (s, 1H), 8.66 (d, J= 7.9 Hz, 1H), 8.24 (s, 1H), 7.87 (t, J= 8.3 Hz, 3H), 7.70 - 7.66 (m, 2H), 7.57 (dd, J= 8.7, 2.0 Hz, 1H), 7.49 (d, J= 8.2 Hz, 2H), 6.27 (d, J= 15.6 Hz, 1H), 4.71 - 4.66 (m, 1H), 1.88 - 1.72 (m, 2H), 1.64 - 1.57 (m, 1H), 1.30 (s, 9H), 0.94 (dd, J= 12.4, 6.4 Hz, 6H).13C NMR (101 MHz, DMSO-6 / 6) 5 171.74, 166.45, 162.09, 154.17, 140.94, 139.98, 136.60, 133.40, 131.32, 127.78, 127.52, 124.98, 122.72, 121.05, 118.87, 113.97, 52.90, 40.33, 34.65, 30.98, 24.62, 23.09, 21.53. HPLC purity 94.686%.

[0118] Ethyl (E)-3-(5-(2-(4-(tert-butyl)benzamido)-3- phenylpropanam ido)benzo [b]thiophen-2-yl)acrylate (KH304B)White solid (59.7% yield). 'HNMR (400 MHz, DMSO ) 5 10.40 (s, 1H), 8.73 (d, J= 8.1 Hz, 1H), 8.28 (d, J= 2.0 Hz, 1H), 7.94 - 7.87 (m, 3H), 7.78 (d, J= 8.5 Hz, 2H), 7.57 (dd, J= 8.8, 2.1 Hz, 1H), 7.48 - 7.42 (m, 4H), 7.29 (t, J= 7.6 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), 6.31 (d, J= 15.7 Hz, 1H), 4.90 - 4.84 (m, 1H), 4.20 (q, = 7.2 Hz, 2H), 3.20 - 3.10 (m, 2H), 1.29 (s, 9H), 1.26 (d, J= 7.1 Hz, 3H).13C NMR (101 MHz, DMSO-t / e) 5 170.80, 166.45, 165.68, 154.26, 139.72, 138.23, 137.76, 136.54, 134.44, 131.18, 129.94, 129.31, 128.17, 127.41, 126.41, 125.03, 122.97, 119.52, 118.92, 114.28, 60.34, 55.94, 37.21, 34.67, 30.97, 14.23. HPLC purity 96.300%.

[0119] (E)-3-(5-(2-(4-(tert-butyl)benzamido)-3-phenylpropanamido)benzo[b]thiophen- 2-yl)acrylic acidWhite solid (71.1% yield).XH NMR (400 MHz, DMSO-t / e) 5 10.40 (s, 1H), 8.73 (d, J= 8.0 Hz, 1H), 8.27 (d, J= 2.1 Hz, 1H), 7.91 (d, J= 8.7 Hz, 1H), 7.86 - 7.82 (m, 2H), 7.78 (d, J= 8.5 Hz, 2H), 7.56 (dd, J= 8.8, 2.1 Hz, 1H), 7.47 (d, J= 8.5 Hz, 2H), 7.43 (d, J= 7.1 Hz, 2H), 7.29 (t, J= 7.6 Hz, 2H), 7.18 (t, J= 7.2 Hz, 1H), 6.23 (d, J= 15.7 Hz, 1H), 4.90 - 4.84 (m, 1H), 3.20 - 3.09 (m, 2H), 1.29 (s, 9H).13C NMR (101 MHz, DMSO-t / e) 5 171.24, 167.50, 166.94, 154.74, 140.43, 140.27, 138.71, 137.74, 136.99, 134.80, 131.70, 129.88, 129.78, 128.65, 127.89, 126.89, 125.51, 123.41, 120.75, 119.88, 114.75, 56.39, 37.72, 35.15, 31.47. HPLC purity 97.741%.

[0120] (E)-4-(tert-butyl)-N-(l-((2-(3-(hydroxyamino)-3-oxoprop-l-en-l- yl)benzo[b]thiophen-5-yl)amino)-l-oxo-3-phenylpropan-2-yl)benzamide (KH304)Mahogany brown solid (42.1% yield).1H NMR (400 MHz, DMSO-t / e) 5 10.39 (s, 1H), 8.73 (s, 1H), 8.24 (s, 1H), 7.89 (d, J= 8.1 Hz, 1H), 7.78 (s, 2H), 7.72 (d, J= 13.9 Hz, 2H), 7.48 - 7.42 (m, 5H), 7.30 (d, J= 7.4 Hz, 2H), 7.19 (d, J= 7.0 Hz, 1H), 6.29 (d, J= 14.8 Hz, 1H), 4.94 - 4.83 (m, 1H), 3.21 - 3.14 (m, 2H), 1.29 (s, 9H).13C NMR (101 MHz, DMSO ) 5 170.68, 166.40, 162.49, 154.19, 141.66, 140.09, 138.23, 136.37, 133.36, 131.21, 129.27, 128.11, 127.38, 126.59, 126.34, 124.97, 122.82, 122.63, 118.58, 113.88, 55.97, 37.22, 34.61, 30.93. HPLC purity 94.868%.

[0121] Ethyl (E)-3-(5-(2-((4-(tert-butyl)phenyl)sulfonamido)-4- methylpentanamido)benzo[b] thiophen-2-yl)acrylate (KH305B)White solid (74.1% yield).1H NMR (400 MHz, Chloroform-^ 5 8.42 (s, 1H), 7.94 (s, 1H), 7.85 - 7.78 (m, 3H), 7.57 (d, J= 8.2 Hz, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.30 - 7.20 (m, 3H), 6.26 (d, J= 15.6 Hz, 1H), 4.28 (q, J= 7.1 Hz, 2H), 3.94 - 3.84 (m, 1H), 1.72 - 1.64 (m, 1H), 1.59 - 1.47 (m, 2H), 1.35 (t, J= 7.1 Hz, 3H), 1.19 (s, 9H), 0.83 (d, J= 6.1 Hz, 3H), 0.62 (d, J = 5.8 Hz, 3H).13C NMR (101 MHz, DMSO-t / e) 5 170.26, 166.16, 155.59, 140.03, 138.29, 138.25, 136.55, 134.95, 130.36, 127.04, 125.97, 123.14, 119.87, 119.34, 114.67, 60.81, 55.94, 41.89, 35.03, 30.99, 24.47, 23.31, 21.93, 14.72. HPLC purity 93.439%.

[0122] (E)-3-(5-(2-((4-(tert-butyl)phenyl)sulfonamido)-4- methylpentanamido)benzo[b]thiophen-2-yl)acrylic acid (KH305A)White solid (82.2% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.01 (s, 1H), 8.02 (d, J= 9.3 Hz, 1H), 7.95 (d, J= 2.1 Hz, 1H), 7.85 - 7.79 (m, 2H), 7.72 (s, 1H), 7.68 (d, J= 8.5 Hz, 2H), 7.36 (d, J= 8.5 Hz, 2H), 7.29 (dd, J= 8.8, 2.0 Hz, 1H), 6.20 (d, J= 15.7 Hz, 1H), 3.92 - 3.86 (m, 1H), 1.66 - 1.56 (m, 1H), 1.49 - 1.32 (m, 2H), 1.02 (s, 9H), 0.85 (d, J= 6.6 Hz, 3H), 0.77 (d, .7= 6.6 Hz, 3H).13C NMR (101 MHz, DMSO-t / e) 5 169.76, 166.99, 155.10, 139.75, 139.57, 137.81, 137.33, 136.02, 134.33, 129.38, 126.55, 125.48, 122.61, 120.06, 119.25, 114.15, 55.45, 41.41, 35.14, 30.50, 23.98, 22.82, 21.43. HPLC purity 98.782%.

[0123] (E)-2-((4-(tert-butyl)phenyl)sulfonamido)-N-(2-(3-(hydroxyamino)-3-oxoprop- l-en-l-yl)benzo[b]thiophen-5-yl)-4-methylpentanamide (KH305)Off-white solid (38.7% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.85 (s, 1H), 10.01 (s, 1H), 9.17 (s, 1H), 8.05 (d, J= 9.1 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J= 8.7 Hz, 1H), 7.72 - 7.68 (m, 3H), 7.62 (s, 1H), 7.38 (d, J= 8.5 Hz, 2H), 7.28 (dd, J= 8.7, 2.0 Hz, 1H), 6.26 (d, J= 15.5 Hz, 1H), 3.94 - 3.88 (m, 1H), 1.65 - 1.57 (m, 1H), 1.50 - 1.34 (m, 2H), 1.04 (s, 9H), 0.87 (d, J= 6.6 Hz, 3H), 0.78 (d, J= 6.5 Hz, 3H).13C NMR (101 MHz, DMSO-t / e) 5 169.80, 162.14, 155.18, 140.66, 139.81, 137.83, 136.00, 133.71, 132.09, 128.14, 126.61, 125.54, 122.58, 120.43, 118.91, 114.06, 55.51, 41.47, 34.59, 30.56, 24.04, 22.87, 21.48. HPLC purity 91.843%.

[0124] Ethyl (E)-3-(5-(2-((4-(tert-butyl)phenyl)sulfonamido)-3- phenylpropanamido)benzo[b] thiophen-2-yl)acrylate (KH306B)Golden yellow solid (72.3% yield). 'H NMR (400 MHz, DMSO ) 5 10.04 (s, 1H), 8.26 (d, J= 9.5 Hz, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.91 (d, J= 15.7 Hz, 1H), 7.82 (d, J= 8.7 Hz, 1H), 7.79 (s, 1H), 7.54 (d, J= 8.5 Hz, 2H), 7.29 (d, J= 8.6 Hz, 2H), 7.25 (d, J= 2.1 Hz, 1H), 7.22 - 7.15 (m, 5H), 6.29 (d, J = 15.7 Hz, 1H), 4.21 (q, J= 7.1 Hz, 2H), 4.18- 4.10 (m, 1H), 2.94 (dd, J= 13.7, 6.0 Hz, 1H), 2.79 (dd, J= 13.7, 8.9 Hz, 1H), 1.27 (t, J= 7.2 Hz, 3H), 1.06 (s, 9H).13C NMR (101 MHz, DMSO-t / e) 5 169.14, 165.80, 155.02, 139.69, 139.63, 137.85, 137.80, 137.02, 136.01, 134.62, 129.94, 129.44, 128.21, 126.65, 126.48, 125.51, 122.78, 119.47, 118.99, 114.27, 60.47, 58.45, 38.52, 34.60, 30.62, 14.31. HPLC purity 90.995%.

[0125] (E)-3-(5-(2-((4-(tert-butyl)phenyl)sulfonamido)-3- phenylpropanamido)benzo[b]thiophen-2-yl)acrylic acid (KH306A)Yellow green solid (76.5% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.07 (s, 1H), 8.29 (d, J = 9.5 Hz, 1H), 7.96 (d, J= 2.0 Hz, 1H), 7.86 - 7.81 (m, 2H), 7.75 (s, 1H), 7.54 (d, J= 8.6 Hz, 2H), 7.30 - 7.25 (m, 3H), 7.23 - 7.16 (m, 5H), 6.22 (d, J= 15.8 Hz, 1H), 4.16- 4.10 (m, 1H), 2.94 (dd, J= 13.7, 5.9 Hz, 1H), 2.79 (dd, J= 13.7, 9.0 Hz, 1H), 1.06 (s, 9H).13C NMR (101 MHz, DMSO-6 / 6) 5 169.04, 166.99, 154.86, 139.79, 139.57, 137.78, 137.31, 136.97, 135.93, 134.37, 129.34, 128.09, 126.51, 126.36, 125.39, 122.65, 120.10, 119.22, 114.10, 58.38, 38.42, 34.51, 30.54. HPLC purity 93.525%.

[0126] (E)-3-(5-(2-((4-(tert-butyl)phenyl)sulfonamido)-3- phenylpropanamido)benzo[b]thiophen-2-yl)-N-hydroxyacrylamide (KH306)Yellow solid (43.0% yield). *H NMR (400 MHz, DMSO-t / e) 5 10.84 (s, 1H), 10.04 (s, 1H), 9.16 (s, 1H), 8.29 (d, J = 9.5 Hz, 1H), 7.93 (dd, J= 14.7, 2.1 Hz, 1H), 7.84 - 7.71 (m, 2H), 7.65 (d, J = 21.2 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.25 - 7.16 (m, 6H), 6.25 (d, J = 15.5 Hz, 1H), 4.15 - 4.09 (m, 1H), 2.93 (dd, J = 13.7, 5.9 Hz, 1H), 2.78 (dd, J = 13.7, 9.0 Hz, 1H), 1.06 (s, 9H).13C NMR (101 MHz, DMSO-t / e) 5 169.01, 162.02, 154.86, 140.65, 139.75, 137.80, 136.98, 135.87, 133.67, 131.96, 129.34, 128.09, 126.52, 126.36, 125.40, 122.57, 120.43, 118.81, 113.95, 58.38, 38.43, 34.51, 30.54. HPLC purity 94.686%.

[0127] Ethyl (E)-3-(5-(4-methyl-2-(4- phenoxybenzamido)pentanamido)benzo[b]thiophen-2-yl)acrylate (KH310B)White solid (69.1% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.29 (s, 1H), 8.59 (d, J = 7.7 Hz, 1H), 8.29 (s, 1H), 8.00 - 7.95 (m, 2H), 7.92 (d, J = 5.5 Hz, 1H), 7.89 (d, J = 1.3 Hz, 1H), 7.85 (s, 1H), 7.60 - 7.57 (m, 1H), 7.47 - 7.42 (m, 2H), 7.24 - 7.19 (m, 1H), 7.11 - 7.04 (m, 4H), 6.30 (d, J = 15.8 Hz, 1H), 4.71 - 4.66 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.87 - 1.73 (m, 2H), 1.64 - 1.58 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.95 (dd, J = 10.0, 6.0 Hz, 6H).13C NMR (101 MHz, DMSO-6 / 6) 5 171.74, 165.86, 165.64, 159.53, 155.74, 139.71, 139.64, 137.73, 136.65, 134.32, 130.27, 129.89, 128.74, 124.27, 122.87, 119.51, 119.42, 118.87, 117.42, 114.25, 60.30, 52.86, 40.29, 24.59, 23.09, 21.49, 14.20. HPLC purity 97.272%.

[0128] (E)-3-(5-(4-methyl-2-(4-phenoxybenzamido)pentanamido)benzo[b]thiophen-2- yl)acrylic acid (White solid (78.8% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.30 (s, 1H), 8.61 (d, J= 7.8 Hz, 1H), 8.28 (s, 1H), 7.97 (d, J= 8.4 Hz, 2H), 7.90 - 7.80 (m, 3H), 7.58 (d, J= 8.7 Hz, 1H), 7.44 (t, J= 7.8 Hz, 2H), 7.21 (t, J= 7.4 Hz, 1H), 7.07 (dd, J= 14.8, 8.3 Hz, 4H), 6.22 (d, J= 15.6 Hz, 1H), 4.71 - 4.64 (m, 1H), 1.86 - 1.70 (m, 2H), 1.62 - 1.57 (m, 1H), 0.94 (dd, J= 10.9, 6.3 Hz, 6H).13C NMR (101 MHz, DMSO-t / e) 5 171.75, 167.00, 165.86, 159.54, 155.75, 139.87, 139.77, 137.32, 136.64, 134.20, 130.29, 129.91, 129.45, 128.75, 124.29, 122.87, 120.14, 119.44, 119.38, 117.43, 114.21, 52.87, 40.30, 24.60, 23.11, 21.50. HPLC purity 96.823%.

[0129] (E)-N-(l-((2-(3-(hydroxyamino)-3-oxoprop-l-en-l-yl)benzo[b]thiophen-5- yl)amino)-4-methyl-l-oxopentan-2-yl)-4-phenoxybenzamide (KH310)Light yellow solid (33.9% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.37 (s, 1H), 8.70 (d, J= 7.9 Hz, 1H), 8.21 (d, J= 2.0 Hz, 1H), 8.00 (d, J= 8.8 Hz, 2H), 7.84 (d, J= 8.7 Hz, 1H), 7.57 - 7.53 (m, 3H), 7.46 - 7.42 (m, 2H), 7.21 (t, J= 7.4 Hz, 1H), 7.10 - 7.04 (m, 4H), 6.26 (d, J= 15.5 Hz, 1H), 4.72 - 4.66 (m, 1H), 1.89 - 1.72 (m, 2H), 1.65 - 1.58 (m, 1H), 0.94 (dd, J= 11.4, 6.5 Hz, 6H).13C NMR (101 MHZ, DMSO ) 5 172.89, 171.68, 166.35, 160.03, 156.23, 142.55, 140.67, 138.45, 136.78, 133.65, 130.79, 130.35, 129.34, 126.58, 124.79, 123.13, 119.92, 118.73, 117.95, 114.09, 52.63, 24.99, 23.67, 22.13, 21.90. HPLC purity 96.625%.

[0130] Ethyl (E)-3-(5-(2-(4-phenoxybenzamido)-3- phenylpropanam ido)benzo [b]thiophen-2-yl)acrylate (KH309B)White solid (66.5% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.42 (s, 1H), 8.78 (d, J= 8.0 Hz, 1H), 8.29 (d, J= 2.0 Hz, 1H), 7.94 (d, J= 3.5 Hz, 1H), 7.91 - 7.87 (m, 4H), 7.57 (dd, J= 8.8, 2.1 Hz, 1H), 7.44 (t, J= 7.0 Hz, 4H), 7.29 (t, J= 7.5 Hz, 2H), 7.21 (t, J= 9.1 Hz, 2H), 7.10 - 7.02 (m, 4H), 6.31 (d, J= 15.7 Hz, 1H), 4.91 - 4.85 (m, 1H), 4.20 (q, = 7.2 Hz, 2H), 3.20 - 3.10 (m, 2H), 1.27 (t, J= 7.1 Hz, 3H).13C NMR (101 MHz, DMSO-t / e) 5 170.79,165.83, 165.66, 159.60, 155.65, 139.73, 139.70, 138.20, 137.75, 136.51, 134.44, 130.30,129.92, 129.80, 129.28, 128.57, 128.17, 126.41, 124.33, 122.96, 119.50, 118.92, 117.37,114.27, 60.33, 56.01, 37.17, 14.22. HPLC purity 93.826%.

[0131] (E)-3-(5-(2-(4-phenoxybenzamido)-3-phenylpropanamido)benzo[b]thiophen-2- yl)acrylic acid (White solid (81.1% yield).XH NMR (400 MHz, DMSO- e) 6 10.41 (s, 1H), 8.78 (d, J= 8.0 Hz, 1H), 8.27 (s, 1H), 7.92 - 7.81 (m, 5H), 7.57 (d, J= 8.8 Hz, 1H), 7.44 (t, J= 7.6 Hz, 4H), 7.29 (t, J= 7.5 Hz, 2H), 7.21 (t, J= 8.4 Hz, 2H), 7.09 - 7.02 (m, 4H), 6.24 (d, J= 15.6 Hz, 1H), 4.91 - 4.85 (m, 1H), 3.21 - 3.12 (m, 2H).13C NMR (101 MHz, DMSO-t / e) 5 170.75, 167.02, 165.81, 159.58, 155.65, 139.95, 139.77, 138.19, 137.14, 136.47, 134.28, 130.27, 129.78, 129.33, 129.26, 128.58, 128.15, 126.39, 124.31, 122.89, 120.36, 119.48, 119.34, 117.36, 114.22, 55.99, 37.18. HPLC purity 95.140%.

[0132] (E)-N-(l-((2-(3-(hydroxyamino)-3-oxoprop-l-en-l-yl)benzo[b]thiophen-5- yl)amino)-l-oxo-3-phenylpropan-2-yl)-4-phenoxybenzamide (KH309)Light yellow solid (36.4% yield).1H NMR (400 MHz, Ethanol-de) 8 10.57 (s, 1H), 8.87 (d, J= 8.1 Hz, 1H), 8.24 (d, J= 2.0 Hz, 1H), 7.92 - 7.90 (m, 2H), 7.87 (d, J= 8.7 Hz, 1H), 7.65 (t, J= 7.7 Hz, 2H), 7.59 (dd, J= 8.8, 2.0 Hz, 1H), 7.46 - 7.42 (m, 4H), 7.28 (t, J= 7.5 Hz, 2H), 7.21 - 7.18 (m, 2H), 7.08 (d, J= 7.7 Hz, 2H), 7.02 (d, J= 8.8 Hz, 2H), 6.29 (d, J= 15.5 Hz, 1H), 4.91 - 4.85 (m, 1H), 3.19 - 3.12 (m, 2H).13C NMR (101 MHz, DMSO-t / e) 5 170.79, 165.85, 162.02, 159.61, 155.66, 140.81, 140.39, 139.87, 138.24, 136.47, 134.13, 130.31, 129.82, 129.30, 128.75, 128.59, 128.19, 126.42, 124.35, 122.87, 119.52, 119.18, 118.95, 117.38, 114.15, 56.07, 37.20. y 95.886%.

[0133] Tert-butyl (E)-4-((4-((l-((2-(3-ethoxy-3-oxoprop-l-en-l-yl)benzo[b]thiophen-5- yl)amino)-l-oxo-3-phenylpropan-2-yl)carbamoyl)phenoxy)methyl)piperidine-l- carboxylate (White solid (77.8% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.39 (s, 1H), 8.65 (d, J= 8.0 Hz, 1H), 8.28 (d, J= 2.1 Hz, 1H), 7.93 - 7.81 (m, 5H), 7.56 (dd, J= 8.8, 2.1 Hz, 1H), 7.42 (d, J= 7.1 Hz, 2H), 7.28 (t, J= 7.6 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 6.98 (d, J= 8.9 Hz, 2H), 6.31 (d, J= 15.4 Hz, 1H), 4.87 - 4.82 (m, 1H), 4.20 (q, J= 7.2 Hz, 2H), 4.02 - 3.93 (m, 2H), 3.89 (d, J= 6.4 Hz, 2H), 3.18 - 3.09 (m, 2H), 2.84 - 2.65 (m, 2H), 1.96 - 1.87 (m, 1H), 1.75 (d, J= 12.2 Hz, 2H), 1.40 (s, 9H), 1.26 (t, J= 7.1 Hz, 3H), 1.17 - 1.11 (m, 2H).13C NMR (101 MHz, DMSO-6 / 6) 5 170.95, 166.05, 165.69, 161.17, 153.95, 139.75, 139.72, 138.27, 137.77, 136.55, 134.43, 129.95, 129.45, 129.31, 128.17, 126.44, 126.00, 122.98, 119.59, 119.00, 114.26, 113.94, 78.59, 71.87, 60.36, 56.08, 37.20, 35.32, 28.32, 28.15, 18.62, 14.24. HPLC purity 99.151%.

[0134] (E)-3-(5-(2-(4-((l-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)benzamido)-3- phenylpropanamido)benzo[b]thiophen-2-yl)acrylic acid (KH311A)White solid (87.0% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.40 (s, 1H), 8.66 (d, J= 7.9 Hz, 1H), 8.27 (d, J= 2.0 Hz, 1H), 7.91 (d, J= 8.8 Hz, 1H), 7.87 - 7.82 (m, 4H), 7.56 (dd, J= 8.8, 2.0 Hz, 1H), 7.42 (d, J= 7.4 Hz, 2H), 7.28 (t, J= 7.5 Hz, 2H), 7.18 (t, J= 13 Hz, 1H), 6.98 (d, J= 9.0 Hz, 2H), 6.23 (d, J= 15.7 Hz, 1H), 4.87 - 4.82 (m, 1H), 4.02 - 3.95 (m, 2H), 3.89 (d, J= 6.3 Hz, 2H), 3.17 - 3.12 (m, 2H), 2.82 - 2.64 (m, 2H), 1.97 - 1.89 (m, 1H), 1.75 (d, J = 12.4 Hz, 2H), 1.40 (s, 9H), 1.17 - 1.13 (m, 2H).13C NMR (101 MHz, DMSO-t / e) 5 170.97, 167.00, 166.12, 161.15, 153.92, 139.91, 139.77, 138.37, 138.27, 137.26, 136.52, 129.43, 129.29, 128.15, 126.43, 126.05, 122.95, 120.16, 119.35, 116.11, 114.17, 113.92, 78.56, 71.86, 56.08, 54.97, 37.22, 35.30, 28.34, 28.14. HPLC purity 99.266%.

[0135] Tert-butyl (E)-4-((4-((l-((2-(3-(hydroxyamino)-3-oxoprop-l-en-l- yl)benzo[b]thiophen-5-yl)amino)-l-oxo-3-phenylpropan-2- yl)carbamoyl)phenoxy)methyl)piperidine-l-carboxylate (KH311)Off-white solid (33.0% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.42 (d, J= 6.6 Hz, 1H), 8.69 (d, J= 7.9 Hz, 1H), 8.26 (d, J= 11.6 Hz, 1H), 7.90 (t, J= 8.8 Hz, 1H), 7.85 - 7.81 (m, 3H), 7.72 (d, J= 12.9 Hz, 1H), 7.55 (t, J= 8.9 Hz, 1H), 7.43 (d, J= 7.5 Hz, 2H), 7.28 (t, J= 7.5 Hz, 2H), 7.18 (t, J= 13 Hz, 1H), 6.98 (d, J= 8.6 Hz, 2H), 6.23 (d, J= 15.6 Hz, 1H), 4.87 - 4.81 (m, 1H), 4.02 - 3.95 (m, 2H), 3.89 (d, J= 6.3 Hz, 2H), 3.17 - 3.10 (m, 2H), 2.81 - 2.69 (m, 2H), 1.99 - 1.85 (m, 1H), 1.75 (d, J= 11.1 Hz, 2H), 1.40 (s, 9H), 1.19 - 1.13 (m, 2H).13C NMR (101 MHz, DMSO-t / e) 5 171.37, 166.52, 162.86, 161.66, 154.44, 141.26, 140.29, 138.75, 136.99, 134.73, 134.10, 130.16, 129.92, 129.78, 128.63, 126.87, 126.55,123.36, 121.12, 119.81, 114.65, 114.43, 79.05, 72.38, 56.48, 37.71, 36.32, 35.80, 28.79, 28.64. HPLC purity 95.025%.

[0136] Ethyl (E)-3-(5-(3-phenyl-2-(4-((tetrahydro-2H-pyran-4-yl)methoxy)benzamido) propanamido)benzo[b]thiophen-2-yl)acrylate (KH312B)White solid (71.4% yield). *H NMR (400 MHz, DMSO-t / e) 5 10.35 (s, 1H), 8.61 (d, J= 8.0 Hz, 1H), 8.24 (d, J= 2.0 Hz, 1H), 7.89 (d, J= 3.5 Hz, 1H), 7.86 (d, J= 3.4 Hz, 1H), 7.82 - 7.78 (m, 3H), 7.52 (dd, J= 8.8, 2.0 Hz, 1H), 7.38 (d, J= 6.8 Hz, 2H), 7.24 (t, J= 7.6 Hz, 2H), 7.14 (t, J= 13 Hz, 1H), 6.95 (d, J= 8.9 Hz, 2H), 6.27 (d, J= 15.7 Hz, 1H), 4.84 - 4.78 (m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.85 - 3.82 (m, 4H), 3.29 - 3.25 (m, 2H), 3.14 - 3.08 (m, 2H), 2.00 - 1.92 (m, 1H), 1.65 - 1.61 (m, 2H), 1.34 - 1.26 (m, 2H), 1.22 (t, J= 7.1 Hz, 3H).13C NMR (101 MHZ, DMSO ) 5 171.40, 166.54, 166.15, 161.69, 140.23, 140.19, 138.74, 138.22, 137.03, 134.93, 130.36, 129.92, 129.78, 128.64, 126.88, 126.51, 123.42, 120.01, 119.43, 114.78, 114.42, 72.68, 67.14, 60.82, 56.56, 34.91, 29.70, 19.08, 14.70. HPLC purity 92.347%.

[0137] (E)-3-(5-(3-phenyl-2-(4-((tetrahydro-2H-pyran-4- yl)methoxy)benzamido)propanamido)benzo[b]thiophen-2-yl)acrylic acid (KH312A)White solid (74.0% yield). 'H NMR (400 MHz, DMSO-t / e) 5 10.39 (s, 1H), 8.65 (d, J= 7.9 Hz, 1H), 8.27 (d, J= 2.0 Hz, 1H), 7.91 (d, J= 8.7 Hz, 1H), 7.87 - 7.82 (m, 4H), 7.57 (dd, J= 8.8, 2.1 Hz, 1H), 7.43 (d, J= 7.0 Hz, 2H), 7.28 (t, J= 7.5 Hz, 2H), 7.18 (t, J= 7.4 Hz, 1H), 6.99 (d, J= 8.9 Hz, 2H), 6.24 (d, J= 15.7 Hz, 1H), 4.89 - 4.83 (m, 1H), 3.90 - 3.86 (m, 4H), 3.34 (dd, J= 11.7, 2.1 Hz, 2H), 3.18 - 3.13 (m, 2H), 2.05 - 1.95 (m, 1H), 1.69 - 1.65 (m, 2H), 1.38 - 1.28 (m, 2H).13C NMR (101 MHz, DMSO-t / e) 5 170.89, 166.98, 166.01, 161.18,139.91, 139.76, 138.25, 137.26, 136.50, 134.27, 129.42, 129.27, 128.13, 126.37, 126.00,122.89, 120.19, 119.35, 114.20, 113.91, 72.15, 66.63, 55.96, 37.18, 34.40, 29.19.

[0138] (E)-N-(l-((2-(3-(hydroxyamino)-3-oxoprop-l-en-l-yl)benzo[b]thiophen-5- yl)amino)-l-oxo-3-phenylpropan-2-yl)-4-((tetrahydro-2H-pyran-4- yl)methoxy)benzamide (KH312)Off-white solid (39.1% yield). 'H NMR (400 MHz, DMSO ) 5 10.33 (d, J= 5.6 Hz, 1H), 8.60 (d, J= 8.0 Hz, 1H), 8.22 (t, J= 13.2 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.79 (d, J= 8.4 Hz, 2H), 7.74 - 7.65 (m, 2H), 7.38 (d, J= 7.4 Hz, 1H), 7.27 - 7.12 (m, 5H), 6.95 (d, J= 8.6 Hz, 2H), 6.21 (t, J= 16.8 Hz, 1H), 4.84 - 4.76 (m, 1H), 3.86 - 3.81 (m, 4H), 3.26 - 3.23 (m, 2H), 3.13 - 3.08 (m, 2H), 2.02 - 1.90 (m, 1H), 1.63 (d, J= 13.4 Hz, 2H), 1.34 - 1.24 (m, 2H).13C NMR (101 MHz, DMSO-t / e) 5 170.95, 166.09, 165.96, 161.22, 139.98, 138.32, 137.69, 136.49, 136.23, 133.61, 129.48, 129.34, 129.26, 128.19, 128.10, 126.44, 126.01, 122.89, 119.21, 114.15, 113.96, 72.19, 66.68, 56.06, 37.64, 34.44, 29.23. HPLC purity 95.860%.

[0139] HuR inhibitory activity via a Fuorescenese Polarization (FP) assay

[0140] A fluorescence polarization (FP)-based binding assay33was utilized to assess the inhibition of HuR protein interaction with the ARE site of Msil mRNA (“HuR-AREMs11”) by various compounds of the present technology. Briefly, full-length human HuR protein was produced by the KU COBRE-PSF Protein Purification Group and ARE RNA oligo (16 nt) of Msil mRNA according to literature precedent24 25. Fluorescein labeled RNA was purchased from Dharmacon with the following sequence: 5'-GCUUUUAUUUAUUUUG-3'- fluorescein. RNA was pretreated by heating at 95°C for 5 min and immediately cooling on ice for 5 min. Compounds with six doses of compounds were added to the wells prior to the protein-RNA complex (10 nM HuR and 2 nM Msil RNA). Anisotropy measurements were taken after incubation at room temperature for 2 hr. IC50, the concentration causing 50% inhibition, was calculated via sigmoid fitting of dose response curve using GraphPad Prism 9. Ki was calculated using free online software(http: / / swl6.im.med.umich.edu / software / calc_ki / ). The percentage of inhibition was calculated by comparing to DMSO control, the FP value of HuR-AREMsil complex with DMSO was defined as 0% inhibition, the FP value of labeled Msil RNA only was defined as 100% inhibition. The results of this assay are provided in Table 1 alongside the compound structures as well as ID numbers for ease of reference.

[0141] Cytotoxicity of Compounds of the Present Technology Against Cancer Cells

[0142] The cytotoxicity of various compounds of the present technology in different cancer cell lines (triple-negative breast cancer cell line MDA-MB-231 and prostate cancer cell line PC-3) was assessed by a cytotoxicity assay. Cells were seeded in 96-well culture plates (3,000-5,000 cells / well) and treated with titrated compounds in triplicate. After 96 h incubation, cell growth medium was removed and proliferation reagent WST-8 (Sigma) was added to each well and incubated at 37 °C for 1-3 h. Absorbance was then measured with a plate reader at 450 nm with correction at 650 nm. The results were expressed as the percentage of absorbance of treated wells versus that of vehicle control. ICso, the drug concentration causing 50% growth inhibition, was calculated via sigmoid curve fitting using GraphPad Prism 9. The results for those compounds tested against MDA-MB-231 and PC-3 are provided in Table 1.Table 1: Results of HuR inhibitory activity in FP assay and cytotoxicity assays for compounds of the present technology“ND” = not yet determined

[0143] Histone deacetylase (HD AC) inhibitory activity via fluorometric assay

[0144] A HD AC Activity Fluorometric Assay Kit was utilized to assess the selectivity and potential off target of various compounds of the present technology following the manufacture’s instruction (BioVision, catalog #: K330). Briefly, compounds with six doses of compounds were added to the wells with fluoro- substrate pepetide followed by adding fluoro-deacetylated peptide and HD AC enzyme. Fluorescence intensity at Ex / Em = 355 / 460 nm was measured after incubation at room temperature for 30-60 min. The percentage of inhibition was calculated by comparing to DMSO control, which was defined as 0% inhibition. ICso, the concentration causing 50% inhibition, was calculated via sigmoid fitting of dose response curve using GraphPad Prism 9. The results of this assay are provided in Table 2 alongside the compound ID numbers for ease of reference.Table 2: Results of HDAC inhibitory activity in HDAC activity fluorometric assay for compounds of the present technology

[0145] Surface Plasmon Resonance (“SPR”) validation

[0146] A BiaCore 3000 instrument will be used to further validate certain findings from the FP assay and will be used on compounds of the present technology. BiaCore 3000 is a SPR- based, high performance research system available for label free studies of biomolecule interactions in real time. Thus, such studies will provide both equilibrium data and kinetic parameters of queried interactions. Both the full length HuR protein as well as its fragments RRM1 and RRM1 / 2 will be immobilized in separate chambers on a Biacore sensor chip CM5, and then compounds of interst (such as compounds of the present technology) will beinjected at a series of concentrations as soluble analytes. Curves will be determined from the experimentally observed curves by successive subtractions of signals obtained for the reference surface and signals for the running buffer injected under the same conditions as the compounds of interest. The data will provide the association / dissociation characteristics of specific interactions of compounds of interest with HuR and its fragments.

[0147] Inhibition of endogenous HuR-mRNA interaction of HuR-inhibitors

[0148] Two pull-down assays will be further used to illustrate the inhibition of the HuR- mRNA interaction by compounds of the present technology.

[0149] Pull-down Assay #1 - RNA Immunoprecipitation (RNA-IP): Cells with HuR overexpression will be treated with compounds, then the cell cytoplasmic lysates were collected using NE-PER Nuclear and Cytoplasmic Extraction Kit (Thermo Scientific), and subsequently to the cell cytoplasmic lysates were added the biotinylated target ARE oligo from Msil mRNA (AREMsil-Biotin). Following this, streptavidin beads will be added to pull down HuR protein bound to AREMsil-Biotin. Unlabeled target AREs will be used as positive control. Compounds of the present technology are expected to block the HuR pull-down by the biotinylated ARE oligo, illustrating inhibition of the HuR-mRNA interaction.

[0150] Pull-down Assay #2 - Ribonuleoprotein Immunoprecipitation (RNP-IP): Cells with HuR overexpression will be treated with compounds, then the cell cytoplasmic lysates collected using NE-PER Nuclear and Cytoplasmic Extraction Kit (Thermo Scientific), then the cell cytoplasmic lysates will be incubated with anti-HuR antibody, and subsequently Protein G agarose beads (from Roche) will be added to pull down HuR protein. The HuR- bound target mRNAs pulled down will be measured by qRT-PCR using a reported method (Ji, Q., el al.. MicroRNA miR-34 inhibits human pancreatic cancer tumor -initiating cells. PLoS One, 2009. 4(8): p. e6816, incorporated herein by reference). Mouse IgG will be used as negative control. Compounds of the present technology are expected to block the target mRNAs pulled down by HuR antibody.

[0151] Inhibition of protein levels of HuR targets

[0152] Because HuR modulates the translation of target mRNAs, the effect of compounds of the present technology on protein expression levels of HuR targets was probed by Western blot analysis. As illustrated in FIGs. 1 A-1B, KH309, KH311 and KH312 inhibited theprotein expression levels of HuR target XIAP, Bcl-2 and Survivin but not HuR in a dosedependent manner in PC-3 cells (FIG. 1 A) and also induced the cleavage of three apoptosis markers PARP, Caspase 8, and Caspase 3, and the conversion of LC3, an autophagy marker (FIG. IB).

[0153] Inhibition of colony formation

[0154] Colony formation assay was used to assess the effect of compounds on cell proliferation. Briefly, cancer cells were seeded in 6-well plates (200 cells / well, in triplicate) and treated with compounds of the present technology at different doses. 0.5 ml FBS was added per well on Day 3-5. After 9-12 days incubation, plates were gently washed with PBS and stained with 0.05% of crystal violet. Colonies with over 50 cells were manually counted. FIGs. 2A-2C provide the results of such experiments with PC-3 cells using multiple doses of KH309 (FIG. 2A), KH311 (FIG. 2B), and KH312 (FIG. 2C), where all three compounds inhibited colony formation of PC-3 cells in a dose-dependent manner.

[0155] Inhibition of cancer cell metastasis

[0156] To examine the anti-metastatic effect of compounds of the present technology, an invasion assay using Matrigel Invasion Chambers coated with Matrigel Matrix will be performed. To perform the assays, cancer cells with HuR HuR overexpression pretreated with compounds for 24 hours will be added to the chambers and then incubated for 20 hours. Subsequently, cells that remain on the upper surface of the chamber will be completely removed with a cotton swab. Cells that emigrated or invaded through the membrane / Matrigel to the bottom of the chamber will be fixed and stained with 0.2% crystal violet and photographed. Compounds of the present technology are expected to inhibit cancer cell invasion.

[0157] In vivo anti-tumor activity

[0158] Initially, the maximum tolerated dose (MTD) will be determined. MTD studies will be conducted as a series of doses and schedule on groups of 3 mice per dose per schedule. Single-dose MTD will be determined first, followed by multi-dose MTD using a schedule that would be used for efficacy studies. Gross necropsies will be performed on all animals as well as selective pathology assessment, including those euthanized, moribund, found dead, orat termination. Liver, heart, kidneys, and other organs will be examined histologically for abnormalities resulting from drug toxicity.

[0159] In accordance with the above protocol, the MTD for KH309 was determined: for single-dose administration via intraperitoneal (i.p.) injection, the MTD of KH309 was identified as 30 mg / kg i.p.; for multiple-dose administration, the MTD was 25 mg / kg i.p.; for single-dose oral administration (p.o.) MTD was 50 mg / kg. In addition, a pharmacokinetic (PK) study was performed with a single i.p. injection of 25 mg / kg KH309 to mice.Following injection, blood samples (3 mice / time point) were collected at the following time points: 0.5, 1, 2, 4, 8, and 24 h. Plasma were harvested for analysis. Plasma concentrations of KH309 were determined using a 2-dimensional Solid Phase Extraction (SPE) coupled liquid chromatography-tandem mass spectrometry (LC-MS / MS) assay. PK parameters, derived from plasma drug concentration time data, were determined using non-parametric PK data analysis employing WinNonlin®, where the results are provided in FIG. 3. In particular, the plasma concentrations of KH309 peaked at approximately 2.5 pM, 0.5 h after injection, with a 24-hour area under the curve (AUC) reached at 6.9 pM*h.

[0160] Xenograft and orthotopic models of cancer cell lines with HuR overexpression will be used to test the in vivo therapeutic potential of compounds of the present technology. A person of ordinary skill in the art is well apprised of HuR overexpression (including high cytoplasmic Hur) with respect to cancer cell lines, as exemplified by references 2-12 cited herein in the “References” section. Tumor models will be established as described in Xu, L., et al., (-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer. Mol Cancer Ther, 2005. 4(2): p. 197-205.35Briefly, 4-6 week old athymic NCr-nu / nu mice or 8-10-week-old NOD / SCID mice will be inoculated subcutaneously on both sides of flanks with 0.1 ml of a cell suspension of 1-5 x 106tumor cells. Tumors will be allowed to grow to approximately 100 mm3, when the blood vessel supplies to the tumor are established. Each group will contain at least 5 animals with at least 10 tumors across the five animals. Animals will be given compounds or vehicle i.v., i.p. or q.o.d. x 2-3 weeks as described in Xu, L., et al., Systemic p53 gene therapy of cancer with immunolipoplexes targeted by anti-transferrin receptor scFv. Mol Med, 2001. 7(10): p. 723- 34 and Xu, L., et al., Self-assembly of a virus-mimicking nanostructure system for efficient tumor-targeted gene delivery. Hum Gene Ther, 2002. 13(3): p. 469-81.36,37Compound doses will be less than their predetermined MTD. The tumor sizes and animal body weights will bemeasured twice a week. The end points for assessing anti-tumor activity will be according to NCI standard procedures.38,35All animal experiments will be carried out according to the protocol approved by the Institutional Animal Use and Care Committee at the University of Kansas.

[0161] In accordance with the above protocol, the n vivo antitumor efficacy of KH309 was examined on its own as well as in combination with docetaxel (the most common type of chemotherapy used for prostate cancer) using a prostate cancer cell PC-3 a mouse xenograft model to determine the effect of KH309 on sensitization of cancer cells to chemotherapy. PC-3 a was generated from a PC-3 formed subcutaneous tumor through multiple rounds of in vivo selection in mice, where PC-3a is more aggressive than PC-3. Tumor-bearing male athymic mice were randomized into four groups, with 20 mice in control and combination treatment groups and 10 mice in docetaxel and KH309 single agent treatment groups. Mice in treatment groups were treated with KH309 i.p. five times per week (20 mg / kg for first week and 15 mg / kg for the following three weeks), docetaxel i.v. five times per week (10 mg / kg for first week and 5 mg / kg for the following two weeks), or the combination of KH309 and docetaxel i.p. five times per week, respectively, while one group of mice remained untreated. FIG. 4A presents the tumor growth curves of four groups. Tumor sizes in the three treated groups after two-week treatment were all significantly smaller than those in the untreated control group (P < 0.01, P <0.0001, P < 0.0001). Additionally, the tumor sizes in the combination group (KH309 and docetaxel) were significantly smaller than those in the docetaxel -treated group at the end of the experiment (P < 0.0001). Furthermore, the treatments also improved the overall survival of mice. The median survival days were elongated from 22 days in the control group, to 25.5 days in the KH309 group, to 33.5 days in the docetaxel group, and to 42 days in the combination group, as illustrated in FIG. 4B. The survival days were also significantly extended in the combination group compared to that in docetaxel group (P < 0.05, FIG. 4B). The increased survival days in the combination group were greater than the sum of delayed days in the two single-agent treatment groups. These results indicate that KH309 sensitizes prostate cancer xenografts to docetaxel treatment and that the combination of KH309 with docetaxel displays a synergistic effect.

[0162] Based on preliminary results evidencing that the Ki indicated in the FP assay correlates with in vivo anti-tumor activity, it is expected that additional compounds of thepresent technology will significantly decrease tumor growth as compared to the vehicle control in xenograft models (P < 0.005).

[0163] Chemo-sensitization and Overcoming Chemo-resistance via Compounds of the Present Technology

[0164] HuR promotes the translation of several target mRNAs that encode proteins involved in cancer treatment resistance, as discussed in U.S. Pat. Appl. No. 63 / 001,631 filed March 30, 2020 and U.S. Pat. Publ. No. 2023 / 0131501 (each incorporated herein by reference) as well as in the relevant literature. Accordingly, studies utilizing compounds of the present technolgy are expected to illustrate that compounds of the present technology may be administered to overcome acquired chemo-resistance as well as be used in combination with a chemotherapeutic compound (e.g., docetaxel or doxorubicin) to sensitize cancer cell lines (including chemo-resistance cancer cell lines) to chemotherapy.

[0165] Cytotoxicity assays (as described earlier in this disclosure) for various cancer cell lines will also be performed utilizing concentrations of a compound of the present technolgy that are below the lethal threshold for the compound for the particular cancer (a “sub-lethal concentration”) in combination with a chemotherapeutic compound e.g., docetaxel or doxorubicin) to illustrate compounds of the present technology sensitize cancer cell lines to chemotherapy. Results of these studies are expected to indicate that not only are compounds of the present technology by themselves effective in treating tumors, but also that using a compound of the present technology in combination with chemotherapeutic sensitizes the tumor cells to the chemotherapeutic.

[0166] To further mimic clinical conditions and assess overcoming acquired chemoresistance via compounds of the present technology, cytotoxicity assays will be performed to assess the chemo-resistance of the chemoresistant cell lines and then used assess the sensititivy of such chemo-resistant cell lines to compounds of the present technology. Chemorestitant cell lines may be acquired or may be produced - for example, docetaxelresistant and doxorubicin-resistant MDA-MB-231 cells may be generated by continuous exposure of cells to increasing concentrations of docetaxel (TXT) or doxorubicin (DXR). It is expected that the results will demonstrate that the compounds of the present technology are effective against chemo-resistant cancers and overcome acquired chemo-resistance.

[0167] Further, in vivo xenograft models of chemoresistant cell lines (as provided in this disclosure for other cancel cell lines) are likewise expected to demonstrate that the compounds of the present technology are effective against chemo-resistant cancers and overcome acquired chemo-resistance.REFERENCES:1. Brennan, C.M. and J. A. Steitz, HuR and mRNA stability. Cell Mol Life Sci, 2001. 58(2): p. 266-77.2. Lopez de Silanes, I., et al., Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene, 2003. 22(46): p. 7146-54.3. Nabors, L.B., et al., HuR, a RN A stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3' untranslated regions of cytokine and angiogenic factor mRNAs. Cancer Res, 2001. 61(5): p. 2154- 61.4. Dixon, D. A., et al., Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells. J Clin Invest, 2001. 108(11): p. 1657-65.5. Young, L.E., et al., The mRNA binding proteins HuR and tristetraprolin regulate cyclooxygenase 2 expression during colon carcinogenesis . Gastroenterology, 2009. 136(5): p. 1669-79.6. Yoo, P.S., et al., Tissue microarray analysis of 560 patients with colorectal adenocarcinoma: high expression of HuR predicts poor survival. Ann Surg Oncol, 2009. 16(1): p. 200-7.7. Niesporek, S., et al., Expression of the ELAV-like protein HuR in human prostate carcinoma is an indicator of disease relapse and linked to COX-2 expression. Int J Oncol, 2008. 32(2): p. 341-7.8. Barbisan, F., et al., Overexpression of ELAV-like protein HuR is associated with increased COX-2 expression in atrophy, high-grade prostatic intraepithelial neoplasia, and incidental prostate cancer in cystoprostatectomies. Eur Urol, 2009. 56(1): p. 105-12.9. Heinonen, M., et al., Prognostic role of HuR in hereditary breast cancer. Clin Cancer Res, 2007. 13(23): p. 6959-63.10. Denkert, C., et al., Overexpression of the embryonic-lethal abnormal vision-like protein HuR in ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase 2 expression. Cancer Res, 2004. 64(1): p. 189-95.11. Costantino, C.L., et al., The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res, 2009. 69(11): p. 4567-72.12. Wang, J., et al., The expression of RNA-binding protein HuR in non-small cell lung cancer correlates with vascular endothelial growth factor -C expression and lymph node metastasis. Oncology, 2009. 76(6): p. 420-9.Abdelmohsen, K. and M. Gorospe, Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip Rev RNA, 2010. 1(2): p. 214-29. Srikantan, S. and M. Gorospe, HuR function in disease. Front Biosci, 2012. 17: p. 189-205. Wang, J., et al., Multiple Functions of the RNA-Binding Protein HuR in Cancer Progression, Treatment Responses and Prognosis. Int J Mol Sci, 2013. 14(5): p. 10015-41. Abdelmohsen, K., et al., miR-519 suppresses tumor growth by reducing HuR levels. Cell Cycle, 2010. 9(7): p. 1354-9. Fialcowitz- White, E.J., et al., Specific protein domains mediate cooperative assembly of HuR oligomers on AU-rich mRNA-destabilizing sequences. J Biol Chem, 2007. 282(29): p. 20948-59. Wang, EL, et al., The structure of the ARE-binding domains of Hu antigen R (HuR) undergoes conformational changes during RNA binding. Acta Crystallogr D Biol Crystallogr, 2013. 69(Pt 3): p. 373-80. Doller, A., J. Pfeilschifter, and W. Eberhardt, Signalling pathways regulating nucleo- cytoplasmic shuttling of the mRNA-binding protein HuR. Cell Signal, 2008. 20(12): p. 2165-73. Zhu, Z., et al., Cytoplasmic HuR expression correlates with P-gp, HER-2 positivity, and poor outcome in breast cancer. Tumour Biol, 2013. Barker, A., et al., Sequence requirements for RNA binding by HuR andAUFl. J Biochem, 2012. 151(4): p. 423-37. Filippova, N., et al., The RNA-binding protein HuR promotes glioma growth and treatment resistance . Mol Cancer Res, 2011. 9(5): p. 648-59. Durie, D., et al., RNA-binding protein HuR mediates cytoprotection through stimulation ofXIAP translation. Oncogene, 2011. 30(12): p. 1460-9. Vo, D.T., et al., The oncogenic RNA-binding protein Musashil is regulated by HuR via mRNA translation and stability in glioblastoma cells. Mol Cancer Res, 2012. 10(1): p. 143-55. Lebedeva, S., et al., Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR. Mol Cell, 2011. 43(3): p. 340-52. Choudhury, N.R., et al., Tissue-specific control of brain-enriched miR-7 biogenesis. Genes Dev, 2013. 27(1): p. 24-38. W ang, L . , et al . , A TDC / TRIM29 Phosphorylation by A TM / MAPKAP Kinase 2 Mediates Radioresistance in Pancreatic Cancer Cells. Cancer Research, 2014. 74(6): p. 1778-1788. Deng, L., et al., microRNAlOO inhibits self-renewal of breast cancer stem-like cells and breast tumor development. Cancer Research, 2014. Ginestier, C., et al., ALDH1 Is aMarker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome. Cell Stem Cell, 2007. 1(5): p. 555-567. Al-Hajj, M., et al., Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A, 2003. 100(7): p. 3983-8.31. Ishimaru, D., et al., Regulation ofBcl-2 expression by HuR in HL60 leukemia cells andA431 carcinoma cells. Mol Cancer Res, 2009. 7(8): p. 1354-66.32. Ratti, A., et al., A role for the ELAV RNA-binding proteins in neural stem cells: stabilization ofMsil mRNA. J Cell Sci, 2006. 119(Pt 7): p. 1442-52.33. Wu, X., et al., Identification and Validation of Novel Small Molecule Disruptors of HuR-mRNA Interaction. ACS Chem Biol, 2015.34. Mills, N.L., A. A. Shelat, and R.K. Guy, Assay Optimization and Screening of RNA- Protein Interactions by AlphaScreen. J Biomol Screen, 2007. 12(7): p. 946-55.35. Xu, L., et al., (-)-Gossypol enhances response to radiation therapy and results in tumor regression of human prostate cancer. Mol Cancer Ther, 2005. 4(2): p. 197-205.36. Xu, L., et al., Systemic p53 gene therapy of cancer with immunolipoplexes targeted by anti-transferrin receptor scFv. Mol Med, 2001. 7(10): p. 723-34.37. Xu, L., et al., Self-assembly of a virus-mimicking nanostructure system for efficient tumor-targeted gene delivery. Hum Gene Ther, 2002. 13(3): p. 469-81.38. Corbett, T.H., Transplantable syngeneic rodent tumors. Tumor Models in Cancer Research, ed. B.A. Teicher. 2002, Totowa: Humana Press. pp41-71.39. Wu, X., et al., Targeting the interaction between RNA-binding protein HuR and FOXQ1 suppresses breast cancer invasion and metastasis. Commun Biol, 2020. 3(1): p. 193.40. Li, Y., et al., Involvement of post-transcriptional regulation ofFOXOl by HuR in 5- FU-induced apoptosis in breast cancer cells. Oncol Lett, 2013. 6(1): p. 156-160.41. Hsia, T.C., et al., Lapatinib-mediated cyclooxygenase-2 expression via epidermal growth factor receptor / HuR interaction enhances the aggressiveness of triplenegative breast cancer cells. Mol Pharmacol, 2013. 83(4): p. 857-6942. Guo, J., et al., Inhibiting cytoplasmic accumulation of HuR synergizes genotoxic agents in urothelial carcinoma of the bladder. Oncotarget, 2016.43. Srikantan, S. and M. Gorospe, HuR function in disease. Front Biosci, 2012. 17: p. 189-205.44. Liu, R., et al., Human antigen R: A potential therapeutic target for liver diseases. Pharmacol Res, 2020: p. 104684.45. Green, L.C., et al., Human antigen R as a therapeutic target in pathological cardiac hypertrophy. JCI Insight, 2019. 4(4).46. Janice Sanchez, B., et al., Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy. Nat Commun, 2019. 10(1): p. 4171.

[0168] While certain embodiments have been illustrated and described, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures thereof as set forth herein. Each aspect and embodimentdescribed above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and embodiments.

[0169] The present technology is also not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.

[0170] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0171] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with aproviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0172] 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 disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. 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,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0173] All publications, patent applications, issued patents, and other documents (for examplejournals, articles and / or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0174] The present technology may include, but is not limited to, the features and combinations of features recited in the following lettered paragraphs, it being understood that the following paragraphs should not be interpreted as limiting the scope of the claims as appended hereto or mandating that all such features must necessarily be included in such claims:A. A compound or a pharmaceutically acceptable salt thereof according to Formula IwhereinZ1is aryl, heteroaryl, or cycloalkyl;R1is methyl, isopropyl, -CH(CH3)(CH2CH3), - CH2CH(CH3)2, -L1is absent, -CH2-, -CH2-CH2-, or -CH=CH-;X1is O, NH, or S;X2is OH, NH2, NH-OH, NH-NH2, or O-(Ci-C6alkyl); and X3is S(O)2or C(O).B. The compound or pharmaceutically acceptable salt thereof of Paragraph A, wherein Z1isR5, and R6are each independently H, halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, Ci-Ce alkyl, cycloalkyl, Ci-Ce alkoxy, cycloalkoxy, aryl, aryloxy, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, Ci-Ce alkanoyl, Ci-Cs alkanoyloxy, aryloyl, or aryloyloxy, where any two adjacent R2, R3, R4, R5, and R6may join to form a 5-membered alkyl, heteroalkyl, aryl or heteroaryl.C. The compound or pharmaceutically acceptable salt thereof of Paragraph A or ParagraphB, wherein the compound is of Formula IA or pharmaceutically acceptable saltthereofD. The compound or pharmaceutically acceptable salt thereof of Paragraph B or ParagraphC, where the compound is of Formula IB or pharmaceutically acceptable salt thereofE. The compound or pharmaceutically acceptable salt thereof of any one of Paragraphs B-D, wherein R2, R3, R4, R5, and R6are each independently H, halo, hydroxy, amino, cyano, trifluoromethyl, thiol, nitro, pentafluorosulfanyl, Ci-Ce alkyl, cycloalkoxy, aryl, aryloxy, heterocyclylalkyl, heterocyclyloxy, or heterocyclylalkoxy, where any two adjacent R2, R3, R4, R5, and R6may join to form a 5-membered or 6-membered alkyl or aryl, and provided that at least one of R2, R3, R4, R5, and R6is not H.F. The compound or pharmaceutically acceptable salt thereof of any one of Paragraphs B-E, wherein R2, R3, R4, R5, and R6are each independently H, halo, amino, trifluoromethyl, nitro, pentafluorosulfanyl, C1-C4 alkyl, cycloalkoxy, aryloxy, heterocyclyloxy, or heterocyclylalkoxy, where any two adjacent R2, R3, R4, R5, and R6may join to form a 5-membered or 6-membered alkyl or aryl, and provided that at least one R2, R3, R4, R5, and R6is not H.G. The compound or pharmaceutically acceptable salt thereof of any one of Paragraphs A-F, wherein X1is NH or S.H. The compound or pharmaceutically acceptable salt thereof of any one of Paragraphs A-G, wherein L1is -CH=CH-I. The compound or pharmaceutically acceptable salt thereof of any one of Paragraphs A-H, wherein X2is OH, NH2, NH-OH, or NH-NH2.J. The compound or pharmaceutically acceptable salt thereof of any one of Paragraphs B-I, wherein the compound is of Formula IC or pharmaceutically acceptable salt thereofwhereinR2is halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, Ci-Ce alkyl, cycloalkyl, Ci-Ce alkoxy, cycloalkoxy, aryl, aryloxy, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, Ci-Ce alkanoyl, Ci-Cs alkanoyloxy, aryloyl, or aryloyloxy.K. A composition comprising a compound or pharmaceutically acceptable salt thereof of any one of Paragraphs A-J; and a pharmaceutically acceptable carrier.L. A pharmaceutical composition comprising an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of Paragraphs A-J for treating a hyperproliferative disease with HuR overexpression; and a pharmaceutically acceptable carrier.M. The pharmaceutical composition of Paragraph L, wherein the hyperproliferative disease with HuR overexpression is a colon cancer, a prostate cancer, a breast cancer, a brain cancer, an ovarian cancer, a pancreatic cancer, or a lung cancer.N. The pharmaceutical composition of Paragraph L or Paragraph M, wherein the compound or pharmaceutically acceptable salt thereof is a compound or pharmaceutically acceptable salt thereof of Paragraph I or Paragraph J.O. A pharmaceutical composition comprising an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of Paragraphs A-J for treating a fibrotic disease; and a pharmaceutically acceptable carrier.P. The pharmaceutical composition of Paragraph O, wherein the fibrotic disease comprisesHuR overexpression.Q. The pharmaceutical composition of Paragraph O or Paragraph P, wherein the fibrotic disease comprises kidney fibrosis, liver fibrosis, a pulomonary fibrosis, and / or cardiac fibrosis.R. A method comprising administering a compound or pharmaceutically acceptable salt thereof of any one of Paragraphs A-J to a subject suffering from a hyperproliferative disease with HuR overexpression; and / or administering a pharmaceutical composition of any one of Paragraphs L-N to a subject suffering from a hyperproliferative disease with HuR overexpression.S. The method of Paragraph R, wherein the method comprises administering an effective amount of the compound or pharmaceutically acceptable salt thereof, wherein the effective amount is an amount effective to treat the hyperproliferative disease with HuR overexpression.T. The method of Paragraph R, wherein the method comprises administering a first amount of the compound or pharmaceutically acceptable salt thereof (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 105 mg / kg, about 110 mg / kg, about 115 mg / kg, about 120 mg / kg, about125 mg / kg, about 130 mg / kg, about 135 mg / kg, about 140 mg / kg, about 145 mg / kg, about 150 mg / kg, about 160 mg / kg, or any range including and / or inbetween any two of these values — such as about 25 mg / kg to about 150 mg / kg); and administering a second amount of a therapeutic agent (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 105 mg / kg, about 110 mg / kg, about 115 mg / kg, about 120 mg / kg, about 125 mg / kg, about 130 mg / kg, about 135 mg / kg, about 140 mg / kg, about 145 mg / kg, about 150 mg / kg, about 160 mg / kg, or any range including and / or in-between any two of these values — such as about 60 mg / kg to about 100 mg / kg); wherein the first amount and second amount combined are effective to treat the hyperproliferative disease with HuR overexpression.U. The method of Paragraph R or Paragraph T, wherein the method comprises administering the pharmaceutical composition; and administering a second amount of a therapeutic agent.V. The method of Paragraph T or Paragraph U, wherein the therapeutic agent is a chemotherapeutic compound, radiation, or both.W. The method of any one of Paragraphs T-V, wherein the therapeutic agent comprises docetaxel, doxorubicin, or both.X. The method of any one of Paragraphs T-W, wherein the hyperproliferative disease withHuR overexpression is a colon cancer, a prostate cancer, a breast cancer, a brain cancer, an ovarian cancer, a pancreatic cancer, or a lung cancer.Y. A method comprising administering a compound or pharmaceutically acceptable salt thereof of any one of Paragraphs A-J to a subject suffering from a fibrotic disease; and / or administering a pharmaceutical composition of any one of Paragraphs O-Q to a subject suffering from a fibrotic disease.Z. The method of Paragraph Y, wherein the method comprises administering an effective amount of the compound or pharmaceutically acceptable salt thereof, wherein the effective amount is an amount effective to treat the fibrotic disease.AA. The method of Paragraph Y, wherein the method comprises administering a first amount of the compound or pharmaceutically acceptable salt thereof (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 105 mg / kg, about 110 mg / kg, about 115 mg / kg, about 120 mg / kg, about 125 mg / kg, about 130 mg / kg, about 135 mg / kg, about 140 mg / kg, about 145 mg / kg, about 150 mg / kg, about 160 mg / kg, or any range including and / or inbetween any two of these values — such as about 25 mg / kg to about 150 mg / kg); and administering a second amount of a therapeutic agent (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 105 mg / kg, about 110 mg / kg, about 115 mg / kg, about 120 mg / kg, about 125 mg / kg, about 130 mg / kg, about 135 mg / kg, about 140 mg / kg, about 145 mg / kg, about 150 mg / kg, about 160 mg / kg, or any range including and / or in-between any two of these values — such as about 60 mg / kg to about 100 mg / kg); wherein the first amount and second amount combined are effective to treat the fibrotic disease.AB. The method of Paragraph Y or Paragraph AA, wherein the method comprises administering the pharmaceutical composition; and administering a second amount of a therapeutic agent.AC. The method of any one of Paragraphs Y-AB, wherein the fibrotic disease comprisesHuR overexpression.AD. The method of any one of Paragraphs Y-AC, wherein the fibrotic disease comprises kidney fibrosis, liver fibrosis, a pulomonary fibrosis, and / or cardiac fibrosis.

[0175] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

Claims

CLAIMS1. A compound or a pharmaceutically acceptable salt thereof according to Formula IwhereinZ1is aryl, heteroaryl, or cycloalkyl;R1is methyl, isopropyl, -CH(CH3)(CH2CH3), - CH2CH(CH3)2, -L1is absent, -CH2-, -CH2-CH2-, or -CH=CH-;X1is O, NH, or S;X2is OH, NH2, NH-OH, NH-NH2, or O-(Ci-C6alkyl); and X3is S(O)2or C(O).

2. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein Z1isR5, and R6are each independently H, halo, hydroxy, amino, cyano, trifluoromethyl,thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, Ci-Ce alkyl, cycloalkyl, Ci-Ce alkoxy, cycloalkoxy, aryl, aryloxy, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, Ci-Ce alkanoyl, Ci-Cs alkanoyloxy, aryloyl, or aryloyloxy, where any two adjacent R2, R3, R4, R5, and R6may join to form a 5-membered alkyl, heteroalkyl, aryl or heteroaryl.

3. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein the compound is of Formula IA or pharmaceutically acceptable salt thereof4. The compound or pharmaceutically acceptable salt thereof of Claim 2, where the compound is of Formula IB or pharmaceutically acceptable salt thereof5. The compound or pharmaceutically acceptable salt thereof of Claim 2, wherein R2, R3, R4, R5, and R6are each independently H, halo, hydroxy, amino, cyano, trifluoromethyl, thiol, nitro, pentafluorosulfanyl, Ci-Ce alkyl, cycloalkoxy, aryl, aryloxy, heterocyclylalkyl, heterocyclyloxy, or heterocyclylalkoxy, where any two adjacent R2, R3, R4, R5, and R6may join to form a 5-membered or 6-membered alkyl or aryl, and provided that at least one of R2, R3, R4, R5, and R6is not H.

6. The compound or pharmaceutically acceptable salt thereof of Claim 2, wherein R2, R3, R4, R5, and R6are each independently H, halo, amino, trifluoromethyl, nitro, pentafluorosulfanyl, C1-C4 alkyl, cycloalkoxy, aryloxy, heterocyclyloxy, orheterocyclylalkoxy, where any two adjacent R2, R3, R4, R5, and R6may join to form a 5-membered or 6-membered alkyl or aryl, and provided that at least one R2, R3, R4, R5, and R6is not H.

7. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein X1is NH or S.

8. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein L1is-CH=CH-9. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein X2is OH,NH2, NH-OH, or NH-NH2.

10. The compound or pharmaceutically acceptable salt thereof of Claim 2, wherein the compound is of Formula IC or pharmaceutically acceptable salt thereofwhereinR2is halo, hydroxy, amino, cyano, trifluoromethyl, thiol, alkylthio, sulfoxide, sulfone, nitro, pentafluorosulfanyl, carboxylate, amide, ester, Ci-Ce alkyl, cycloalkyl, Ci-Ce alkoxy, cycloalkoxy, aryl, aryloxy, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, Ci-Ce alkanoyl, Ci-Cs alkanoyloxy, aryloyl, or aryloyloxy.

11. A composition comprising a compound or pharmaceutically acceptable salt thereof of any one of Claims 1-10; and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of Claims 1-10 for treating a hyperproliferative disease with HuR overexpression; and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of Claim 12, wherein the hyperproliferative disease with HuR overexpression is a colon cancer, a prostate cancer, a breast cancer, a brain cancer, an ovarian cancer, a pancreatic cancer, or a lung cancer.

14. The pharmaceutical composition of Claim 12, wherein the compound or pharmaceutically acceptable salt thereof is a compound or pharmaceutically acceptable salt thereof of Claim 9 or Claim 10.

15. A pharmaceutical composition comprising an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of Claims 1-10 for treating a fibrotic disease; and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of Claim 15, wherein the fibrotic disease comprisesHuR overexpression.

17. The pharmaceutical composition of Claim 15, wherein the fibrotic disease comprises kidney fibrosis, liver fibrosis, a pulomonary fibrosis, and / or cardiac fibrosis.

18. A method comprising administering a compound or pharmaceutically acceptable salt thereof of any one of Claims 1-10 to a subject suffering from a hyperproliferative disease with HuR overexpression.

19. The method of Claim 18, wherein the method comprises administering an effective amount of the compound or pharmaceutically acceptable salt thereof, wherein the effective amount is an amount effective to treat the hyperproliferative disease with HuR overexpression.

20. The method of Claim 18, wherein the method comprisesadministering a first amount of the compound or pharmaceutically acceptable salt thereof; and administering a second amount of a therapeutic agent; wherein the first amount and second amount combined are effective to treat the hyperproliferative disease with HuR overexpression.

21. The method of Claim 18, wherein the method comprises administering the pharmaceutical composition; and administering a second amount of a therapeutic agent.

22. The method of Claim 20, wherein the therapeutic agent is a chemotherapeutic compound, radiation, or both.

23. The method of Claim 20, wherein the therapeutic agent comprises docetaxel, doxorubicin, or both.

24. The method of Claim 18, wherein the hyperproliferative disease with HuR overexpression is a colon cancer, a prostate cancer, a breast cancer, a brain cancer, an ovarian cancer, a pancreatic cancer, or a lung cancer.

25. A method comprising administering a compound or pharmaceutically acceptable salt thereof of any one ofClaims 1-10 to a subject suffering from a fibrotic disease.

26. The method of Claim 25, wherein the method comprises administering an effective amount of the compound or pharmaceutically acceptable salt thereof, wherein the effective amount is an amount effective to treat the fibrotic disease.

27. The method of Claim 25, wherein the method comprises administering a first amount of the compound or pharmaceutically acceptable salt thereof; and administering a second amount of a therapeutic agent; wherein the first amount and second amount combined are effective to treat the fibrotic disease.

28. The method of Claim 25, wherein the method comprises administering the pharmaceutical composition; andadministering a second amount of a therapeutic agent.

29. The method of Claim 25, wherein the fibrotic disease comprises HuR overexpression.

30. The method of Claim 25, wherein the fibrotic disease comprises kidney fibrosis, liver fibrosis, a pulomonary fibrosis, and / or cardiac fibrosis.

Images