Selective androgen receptor modulator based radiopharmaceuticals for imaging androgen receptor

Abstract

The present disclosure relates to non-steroid selective androgen receptor modulator (SARM) compounds of Formula (I): or a pharmaceutically acceptable salt and / or solvate thereof, as well as compositions and uses thereof.

Description

SELECTIVE ANDROGEN RECEPTOR MODULATOR BASED RADIOPHARMACEUTICALS FOR IMAGING ANDROGEN RECEPTORCROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Appl. No. 63 / 580,301, filed September 1, 2023, the contents of which are incorporated herein by reference in their entirety for any and all purposes.FIELD

[0002] The present technology is directed to selective androgen receptor modulator (SARM) compounds. The present technology is also directed to compositions including such SARM compounds, and respective methods of use.SUMMARY

[0003] In an aspect, the present technology provides a non-steroid selective androgen receptor modulator (SARM) compound of Formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, wherein R1is H or Ci-3 alkyl; andR2is a boronic acid, fluoro, iodo, a fluoro radioisotope, or an iodo radioisotope.

[0004] In an aspect, a composition is provided that includes a non-steroid SARM of any embodiment disclosed herein (collectively, “a compound of the present technology” or the like), as well as a pharmaceutically acceptable carrier or one or more excipients, fillers oragents (collectively referred to hereafter as “pharmaceutically acceptable carrier” unless otherwise indicated and / or specified).

[0005] In a related aspect, a medicament for treating a disease (e.g., cancer) in a subject is provided that includes administering to the subject an effective amount of a compound of any embodiment disclosed herein and optionally a pharmaceutically acceptable carrier.

[0006] In a related aspect, a pharmaceutical composition is provided that includes (i) an effective amount of a compound of any embodiment disclosed herein, wherein the effective amount of the compound is effective to treat a disease (e.g., cancer).

[0007] In further related aspects, the present technology provides methods including a compound of any aspect or embodiment disclosed herein and / or a composition of any embodiment disclosed herein and / or a medicament of any embodiment disclosed herein. Such methods include a method of treating a subject suffering from a disease (e.g., cancer), where the method includes administering to the subject an effective amount of a compound of any embodiment disclosed herein.

[0008] In an aspect, the present technology provides a method including administering to a subject an effective amount of a compound of any embodiment disclosed herein and / or an effective amount of a composition of any embodiment disclosed herein for imaging a cancer, and subsequent to the administering, detecting one or more of positron emission, gamma rays from positron emission and annihilation, and Cerenkov radiation due to positron emission.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 shows radio-HPLC (red) and UV-HPLC (black) chromatographs of the synthesized [18F]F-SARM3 and F-SARM, respectively. The chromatographs demonstrate that the synthesized [18F]F-SARM3 and F-SARM have an identical retention time.

[0010] FIG. 2A shows the results of the in vitro stability assay of [18F]F-SARM3 in PBS and mouse blood.

[0011] FIG. 2B shows the in vitro assay of the amount of human serum protein bound [18F]F-SARM3.[0012 J FIG. 3 shows the results of the [18F]F-SARM3 cell binding assay in LNCaP and MyC-CaP prostate cancer cells. The cells were incubated in charcoal stripped media 48 h prior to the addition of [18F]F-SARM3 only or [18F]F-SARM3 with additional F-SARM3 or DHT (100 nM) for blocking.

[0013] FIG. 4 shows the results of the [18F]F-SARM3 cell binding assay in LNCaP, PC3 and 22Rvl prostate cancer cells. The cells were incubated in charcoal stripped media 24 h prior to the addition of [18F]F-SARM3 only or [18F]F-SARM3 with additional F-SARM3 or DHT (100 nM) for blocking.

[0014] FIG. 5A shows the results of the competitive cell binding assay of [18F]F-SARM3 in LNCaP, 22Rvl and MyC-CaP cell lines.

[0015] FIG. 5B shows the results of the competitive cell binding assay of [18F]F- SARM3and [18F]FDHT in LNCaP cell lines (B).

[0016] FIG. 6 shows live cell imaging of PC3-AR-GFP 2 h after the cells were treated with vehicle, DHT (100 nM) or F-SARM3 (100 nM).

[0017] FIG. 7 shows the blood half-life curve for [18F]F-SARM3 in male nude mice.

[0018] FIG. 8 shows the in vivo biodistribution of [18F]F-SARM3 in LNCaP tumor bearing male nude mice 2 h post injection. The castrated mice cohorts were castrated surgically 4 days prior to the [18F]F-SARM3 injection.

[0019] FIG. 9A shows the axial PET / CT images of [18F]F-SARM3 in castrated male nude mice 45 and 120 min post injection. Location of the subcutaneous LNCaP tumors are indicated with red arrows and red circles.

[0020] FIG. 9B shows the coronal PET / CT images of [18F]F-SARM3 in castrated male nude mice 45 and 120 min post injection. Location of the subcutaneous LNCaP tumors are indicated with red arrows and red circles.DETAILED DESCRIPTION

[0021] The following terms are used throughout as defined below.

[0022] 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.

[0023] 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 in which 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.%.”

[0024] 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.”

[0025] 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 orH, 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.

[0026] 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; and nitriles (z.e., CN).

[0027] 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 is replaced 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.

[0028] 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. Alkyl groups may be substituted or unsubstituted.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, tert-butyl, neopentyl,isopentyl, and 2,2-dimethylpropyl groups. 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.

[0029] 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. Cycloalkyl groups may be substituted or unsubstituted. 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. 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 mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.

[0030] 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. Cycloalkylalkyl groups may be substituted or unsubstituted. In some embodiments, cycloalkylalkyl groups have from 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms. 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.

[0031] 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 maybe substituted or unsubstituted. 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 carboncarbon 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. 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.

[0032] Cycloalkenyl groups include cycloalkyl groups as defined above, having at least one double bond between two carbon atoms. Cycloalkenyl groups may be substituted or unsubstituted. 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.

[0033] 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.

[0034] 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 may be substituted or unsubstituted. 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 carboncarbon triple bonds. Examples include, but are not limited to -C=CH, -C=CCH3, -CH2C=CCH3, and -C=CCH2CH(CH2CH3)2, among others.Representative substituted alkynyl groups may be mono-substituted or substituted morethan once, such as, but not limited to, mono-, di- or tri -substituted with substituents such as those listed above.

[0035] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems. Aryl groups may be substituted or unsubstituted. 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. The phrase “aryl groups” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). Representative substituted aryl groups may be mono-substituted (e.g., tolyl) 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.

[0036] 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. Aralkyl groups may be substituted or unsubstituted. In some embodiments, aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. 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.

[0037] 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. Heterocyclyl groups may be substituted or unsubstituted. In some embodiments, the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms. In some embodiments, heterocyclyl groups include mono-, 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 unsaturatedand 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. The phrase includes heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members, referred to as “substituted heterocyclyl groups”. 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, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadi azolyl, benzo [1,3] dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), tri azol opyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrol opy ri dy 1 , tetrahy dropy razol opy ri dy 1 , tetrahy droimi dazopy ri dy 1 , tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be mono-substituted 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.[0038| 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. Heteroarylgroups may be substituted or unsubstituted. 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, benzothiadi azolyl, 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. Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.

[0039] 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 unsubstituted. 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-m ethyl, 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.

[0040] 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.

[0041] 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, divalentaryl 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 the present technology are not referred to using the “ene” designation. Thus, e.g., chloroethyl is not referred to herein as chloroethylene.

[0042] 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. Alkoxy groups may be substituted or unsubstituted. 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. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.

[0043] 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.

[0044] 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. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.

[0045] The term “carboxylate” as used herein refers to a -COOH group.

[0046] 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 inProtective 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.

[0047] 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."

[0048] The term “nitrile” or “cyano” as used herein refers to the -CN group.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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-.

[0059] 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.

[0060] 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.[00611 The term “nitro” as used herein refers to an -NO2 group.

[0062] The term “trifluoromethyl” as used herein refers to -CF3.

[0063] The term “trifluoromethoxy” as used herein refers to -OCF3.

[0064] The term “azido” refers to -N3.

[0065] The term “trialkyl ammonium” refers to a -N(alkyl)s group. A trialkylammonium group is positively charged and thus typically has an associated anion, such as halogen anion.

[0066] The term “isocyano” refers to -NC.

[0067] The term “isothiocyano” refers to -NCS.

[0068] The term “pentafluorosulfanyl” refers to -SF5.

[0069] 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.

[0070] As understood by one of ordinary skill in the art, “molecular weight” (also known as “relative molar mass”) is a dimensionless quantity but is converted to molar mass by multiplying by 1 gram / mole or by multiplying by 1 Da - for example, a compound with a weight-average molecular weight of 5,000 has a weight-average molar mass of 5,000 g / mol and a weight-average molar mass of 5,000 Da.

[0071] 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, methanesulfonic acid, 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., di cyclohexylamine, trimethylamine, tri ethylamine, 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.

[0072] Those of skill in the art will appreciate that compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometricisomerism, 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.

[0073] “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:

[0074] As another example, guanidines may exhibit the following isomeric forms in protic organic solution, also referred to as tautomers of each other:

[0075] 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.

[0076] Stereoisomers of compounds (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry isexpressly 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.

[0077] 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.

[0078] 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 subsequent to the Examples section. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure to more fully describe the present technology.

[0079] The Present Technology

[0080] Compounds o f The Present Technology[0081 J In an aspect, the present technology provides a non-steroid selective androgen receptor modulator (SARM) compound according to Formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, whereinR1is H or C1-3 alkyl; andR2is a boronic acid, fluoro, iodo, a fluoro radioisotope, or an iodo radioisotope.

[0082] In any embodiment herein, it may be that R1is C1-3 alkyl. In any embodiment herein, it may be that R1is H. In any embodiment herein, it may be that R1is methyl.

[0083] In any embodiment herein, it may be that R2is a fluoro radioisotope. In some embodiments, the fluorine radioisotope is18F.

[0084] In any embodiment herein, it may be that R2is an iodo radioisotope. In some embodiments, the iodo radioisotope is selected from the group consisting of123I,124I,125I,126I, or131I. For example, the iodo radioisotope may be131I.

[0085] In any embodiment herein, it may be that R2is a boronic acid.

[0086] In any embodiment herein, it may be that R1is methyl and R2is18F.

[0087] In any embodiment herein, it may be that R1is methyl and R2is131I.

[0088] In any embodiment herein, it may be that R1is methyl and R2is a boronic acid.

[0089] Compositions and Methods

[0090] For ease of reference, the compounds included in any aspect or embodiment herein (a non-steroid selective androgen receptor modulator of the present technology) may be referred to anywhere in this disclosure as “a compound of the present technology,” “compounds of the present technology,” or the like. Similarly for ease of reference, the compositions, medicaments, and pharmaceutical compositions of the present technology may collectively be referred to herein as “compositions,” “compositions of the present technology,” or the like.

[0091] In an aspect, a composition is provided that includes a compound of any aspect or embodiment disclosed herein as well as a pharmaceutically acceptable carrier or one or more excipients, fillers or agents (collectively referred to hereafter as “pharmaceutically acceptable carrier” unless otherwise indicated and / or specified). In a related aspect, amedicament for treating a disease described herein (e.g., cancer (e.g., prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer)) in a subject is provided that includes a compound of any embodiment disclosed herein and optionally a pharmaceutically acceptable carrier. The medicament of any embodiment herein may include an effective amount of the compound for treating the disease described herein. In a related aspect, a pharmaceutical composition is provided that includes (i) an effective amount of a compound of any embodiment disclosed herein, wherein the effective amount of the compound may be effective to treat a disease described herein (e.g., cancer (e.g., prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer)); and (ii) a pharmaceutically acceptable carrier. In any embodiment herein, the disease may be cancer (e.g., prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer).[0092J “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, reduction of a tumor mass. In any aspect or embodiment disclosed herein (collectively referred to herein as “any embodiment herein,” “any embodiment disclosed herein,” or the like) of the compositions, pharmaceutical compositions, and methods including compounds of the present technology, the effective amount may be an amount effective in treating a disease described herein (e.g., cancer (e.g., prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer)). By way of example, the effective amount of any embodiment herein including a compound of the present technology may be from about 0.01 pg to about 200 mg of the compound (such as from about 0.1 pg to about 50 mg of the compound or about 10 pg to about 20 mg of the compound). The methods and uses according to the present technology may include an effective amount of a compound of any embodiment disclosed herein. In any aspect or embodiment disclosed herein, the effective amount may be determined in relation to asubject. 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 pain. The term “subject” and “patient” can be used interchangeably.

[0093] Thus, the instant present technology provides pharmaceutical compositions and medicaments including a compound of any embodiment disclosed herein (or a composition of any embodiment disclosed herein) and a pharmaceutically acceptable carrier. The compositions may be used in the methods and treatments described herein. The pharmaceutical composition may be packaged in unit dosage form. The unit dosage form may be effective in treating a disease described herein (e.g., cancer (e.g., prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer)). The unit dosage form may be effective in treating a tumor by reducing a tumor volume when administered to a subject in need thereof. Generally, a unit dosage including 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 may 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 may vary from 1 * 1CH g / kg to 1 g / kg, preferably, 1 x I O3g / kg to 1.0 g / kg. Dosage of a compound of the present technology may also vary from 0.01 mg / kg to 100 mg / kg or, preferably, from 0.1 mg / kg to 10 mg / kg. Suitable unit dosage forms, include, but are not limited to parenteral solutions, oral solutions, powders, tablets, pills, gelcaps, capsules, lozenges, suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, mucoadherent films, topical varnishes, lipid complexes, liquids, etc.

[0094] The pharmaceutical compositions and medicaments may be prepared by mixing one or more compounds and / or compositions of the present technology with pharmaceutically acceptable carriers, excipients, binders, diluents or the like. 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 beformulated 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.

[0095] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant present technology, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semisynthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.

[0096] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.

[0097] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, com oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleumhydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.

[0098] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

[0099] For injection, the pharmaceutical formulation and / or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.

[0100] Compounds of the present technology may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars and / or sugar alcohols. Aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols are typically used for delivery of compounds of the present technology by inhalation.

[0101] Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds of the present technology include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. The active component may be mixedunder sterile conditions with a pharmaceutically-acceptable carrier or excipient, and with any preservatives, or buffers, which may be required. Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Absorption enhancers can also be used to increase the flux of the compounds of the present technology across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane (e.g., as part of a transdermal patch) or dispersing the compound in a polymer matrix or gel.

[0102] 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.

[0103] The formulations of the present technology may be designed to be short-acting, fastreleasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.

[0104] The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and / or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.

[0105] 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 formscontaining effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant present technology.

[0106] Those skilled in the art are readily able to determine an effective amount by simply administering a compound of the present technology to a patient in increasing amounts until, for example, there is a reduction in the mass of a tumor in a subject. 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 can depend on a number of factors including the requirements of the patient, the severity of the cancer (e.g., prostate cancer), 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. Various assays and model systems can be readily employed to determine the therapeutic effectiveness of the treatment according to the present technology.

[0107] Effectiveness of the compositions (as well as determination of effective amounts) and methods of the present technology may also be demonstrated by a decrease in the mass of a tumor and / or slowing the growth of a tumor.

[0108] For each of the indicated conditions described herein, test subjects will exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75-90%, or 95% or greater, reduction, in one or more symptom(s) caused by, or associated with, the disorder in the subject, compared to placebo-treated or other suitable control subjects.

[0109] The compounds of the present technology can also be administered to a patient along with other conventional therapeutic agents that may be useful in the treatment of tumors or in vaccination. The administration may include oral administration, parenteral administration, or nasal administration. In any of these embodiments, the administration may include intratumoral injections, 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 canalso include 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 disease described herein (e.g., cancer (e.g., prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer)).

[0110] In an 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.

[0111] In an aspect, the present technology provides a method of treating a disease where the method includes administering to a subject an effective amount of a non-steroid selective androgen receptor modulator (SARM) compound of any embodiment disclosed herein. The disease may associated with the androgen receptor, and in any embodiment herein the disease may be cancer e.g., prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer). In any embodiment herein, the method may include administering the SARM compound locally to a tumor comprising the cancer. In any embodiment herein, the method may include intratumoral injection of the SARM compound.

[0112] In another aspect, the present technology provides methods of identifying a target of interest including contacting the target of interest with a detectable or imaging effective quantity of a labeled compound of the present technology. A detectable or imaging effective quantity is a quantity of a labeled compound of the present technology necessaryto be detected by the detection method chosen. For example, a detectable quantity can be an administered amount sufficient to enable detection of binding of the labeled compound to a target of interest. Suitable labels are known by those skilled in the art and can include, for example, radioisotopes, radionuclides, isotopes, fluorescent groups, biotin (in conjunction with streptavidin complexation), and chemiluminescent groups. Upon binding of the labeled compound to the target of interest, the target may be isolated, purified and further characterized such as by determining the amino acid sequence. In any embodiment herein, the target of interest is an androgen receptor. In any embodiment herein, the radioisotope is a fluoro radioisotope, or an iodo radioisotope.

[0113] 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.

[0114] As indicated previously in this disclosure, in an aspect a method of treating a subject suffering from a disease associated with proteasome activity such as cancer (e.g., prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer) is provided, where the method includes administering to the subject an effective amount of a compound of any embodiment disclosed herein or administering a composition of any embodiment disclosed herein. In any embodiment herein of the method, the administering may include intratumoral administration. In any embodiment herein, the disease may be prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer.

[0115] In any embodiment herein, the administering may include local administration of the compound to a site in the subject including the cancer or local administration of thecomposition to a site in the subject including the cancer. In any embodiment herein, the administering may include oral, rectal, nasal, vaginal, transdermal, intravenous, intramuscular, or inhalation administration. In any embodiment herein, the administering may include injection of the compound into the site in the subject including the cancer or proximal to the site in the subject including the cancer.

[0116] In another aspect, the present disclosure also provides a process for preparing a SARM compound of any embodiment disclosed herein.

[0117] 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 and compositions 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

[0118] Example 1: Synthesis of SARM compounds

[0119] Materials And Methods

[0120] (2S, 3S)-2methylpyrrolidin-3-ol hydrochloride was purchased from A2B Chem. 4- Fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzonitrile was purchased from AmBeed. Anhydrous acetonitrile 99.9% over Molecular Sieves was bought from Acros Organics. The rest of the chemicals were purchased from Sigma Aldrich.

[0121] Fluorine- 18 in [18O]H2O was purchased from Radiochemistry & Molecular Imaging Probe (RMIP) Core Facility at Memorial Sloan Kettering Cancer Center. [18F]FDHT was kindly provided from RMIP Core Facility as well.

[0122] The reverse phase column used for the purification and quality control for all the described compounds was Waters XBridge Prep C18 5pm (10x250 mm) Column.

[0123] Synthesis and characterization of B(0H) 2-SARM3 radiolabelins precursor

[0124] The synthesis of B(OH)2-SARM3 is shown in Scheme 1 below.

[0125] Scheme 1. Reaction scheme for the synthesis of B(OH)i-SARM3.

[0126] (2S,3S)-2,3-dimethyl-3-pyrrolidinol (145.0 mg; 1.43 mmol; 1.9 eq.), 4-fluoro-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (185.0 mg; 0.75 mmol; 1.0 eq.), lithium carbonate (290.0 mg; 3.92 mmol; 5.2 eq.) were mixed with dimethylsulfoxide (2.0 mL) in a glass reaction vial with a magnetic stirrer. The reaction was heated overnight at 85°C. The crude product mixture was spun down and the supernatant was collected and diluted with acetonitrile (1.0 mL).

[0127] The crude product solution was purified with a reverse phase HPLC purification system. The HPLC method used for the purification of the compound consisted of 0.1 % trifluoroacetic acid in mQ water (solvent A) and 0.1 %trifluoroacetic acid in acetonitrile (solvent B), where the percentage of solvent B was increased from 5 to 95 over a 22 minute gradient run with a 4 mL / min flow rate. The product fraction was collected and concentrated with a rotary evaporator and a lyophilizer.

[0128] The final product was characterized with HRMS and 'H-NMR: HRMS (ESI)(+) m / z calculated for Ci2Hi6BN2O3+[M+H]+: 247.1254, measured: 247.1252.JH NMR (500 MHz, dimethylsulfoxide-d6); 1.047 (3H, d), 1.248 (2H, m), 1.949 (1H, m), 2.130 (1H, m), 3.385 (1H, m), 3.871 (1H, m), 4.266 (1H, m), 6.566 (2H, m), 7.395 (1H, d).

[0129] The radiolabeling precursor, B(OH)2-SARM3 was synthesized with a reaction yield of 8.9 %, and the synthesis resulted in a chemical purity of 89.0 %.

[0130] Synthesis and characterization of F-SARM3

[0131] The synthesis of F-SARM3 is shown in Scheme 2 below.

[0132] Scheme 2. Reaction scheme for the synthesis of F-SARM3.F-SARM3

[0133] (2S,3S)-2,3-dimethyl-3-pyrrolidinol (14.8 mg; 0.11 mmol; 1.0 eq.), 2,4-difluoro-3- methylbenzonitrile (25.4 mg; 0.18 mmol; 1.6 eq.), lithium carbonate (13.5 mg; 0.18 mmol; 1.6 eq.) were mixed with dimethylsulfoxide (0.750 mL) in a glass reaction vial with a magnetic stirrer. The reaction was heated overnight at 85°C. The crude product mixture was spun down and the supernatant was collected and diluted with acetonitrile (0.5 mL).

[0134] The crude product solution was purified with a reverse phase HPLC purification system. The HPLC method used for the purification of the compound consisted of 0.1 % trifluoroacetic acid in mQ water (solvent A) and 0.1 %trifluoroacetic acid in acetonitrile (solvent B), where the percentage of solvent B was increased from 5 to 95 over a 22 minutegradient run with a 4 mL / min flow rate. The product fraction was collected and concentrated with a rotary evaporator and a lyophilizer.

[0135] The final product was characterized with HRMS and 'H-NMR: HRMS (ESI)(+) m / z calculated for Ci2Hi4FN2O+[M+H]+: 221.1090, measured: 221.1089. *HNMR (500 MHz, dimethylsulfoxide-d6); 1.022 (d, 3H), 1.906 (m, 1H), 2.100 (m, 1H), 3.156 (m, 1H), 3.382 (t, 1H), 3.883 (q, 1 H), 4.250 (m, 1H), 6.480 (m, 2H), 7.520 (t, 1H).

[0136] The non-radioactive reference compound for the tracer (F-SARM3) was synthesized with a reaction yield of 54.1 %, and the synthesis resulted in a chemical purity of 97.6 %.

[0137] Radiosynthesis and characterization of [I8F]F-SARM3

[0138] The radiosynthesis of [18F]F-SARM3 is shown in Scheme 3 below.

[0139] Scheme 3. Radiosynthesis of [18F]F-SARM3 from B(OH)2-SARM3 with a copper catalyzed radiofluorination approach.B(0H)2-SARM3 [1SF]F-SARM3

[0140] Fluorine-18 in [18O]H2O (8.8 - 17.0 GBq) was trapped to a light Sep-Pak Plus Light QMA cartridge (Waters) that was pretreated with ethanol (10 mL), potassium triflate (10 mL; 900 mg) and mQ water (10 mL). Fluorine-18 (7.4-13.8 GBq) was eluted with a QMA eluate (0.6 mL mQ water; 5 mg potassium carbonate, 50 pg potassium triflate) to a glass V- vial. The fluorine-18 solution was heated at 120 °C under argon gas flow until dry. Anhydrous acetonitrile (0.2 mL) was added to the vial and the drying step was repeat.

[0141] B(OH)2-SARM3 (0.5-1.0 mg; 2.0-4.1 nmol); copper triflate (5.0 mg; 13.8 nmol) and anhydrous pyridine (50 pL; 49.1 mg; 620.7 nmol) were dissolved in anhydrous dimethylformamide (0.3 mL) and the solution was added to the dried fluorine-18 vial. The labeling solution was heated at 110 °C for 20 minutes.

[0142] The solution was cooled down to room temperature and diluted with mQ water (0.7 mL). The crude [18F]F-SARM3 solution was injected to a reverse phase HPLC purification system and the [18F]F-SARM3 product was manually collected in four fractions. The HPLC method used for the purification and quality control for the final compound consisted of 0.1 % trifluoroacetic acid in mQ water (solvent A) and 0.1 %trifluoroacetic acid in acetonitrile (solvent B), where the percentage of solvent B was increased from 5 to 95 over a 20 minute gradient run with a 4 mL / min flow rate. The product fraction with the highest activity concentration was trapped to Sep-Pak Cl 8 cartridge which was pretreated with ethanol (2.0 mL) and mQ water (10 mL). [18F]F-SARM3 was eluted with 100% ethanol in four fraction (0.1 mL x 4).

[0143] The radiochemical purity of the compound was determined with UV-radio-HPLC by performing a co-injection of the F-SARM3 with an [18F]F-SARM3 aliquot. The molar activity of each [18F]F-SARM3 radiosyntheses was determined by forming mole:area under the curve calibration curve to determine the amount of F-SARM3 synthesized in each synthesis.

[0144] [18F]F-SARM3 was radiosynthesized successfully with a radiochemical yield of 2.7±1.4 %, radiochemical purity of 97.9±2.3 % and molar activity 7.1±4.4 GBq / pmol (FIG. 1).

[0145] Example 2. In vitro characterization of F-SARM3

[0146] Materials And Methods

[0147] PC3-AR-GFP cell line, an AR-GFP fusion protein transfected PC3 prostate cancer cell line, was kindly provided by Dr. Darren Veach. All the other cell lines were purchased from ATCC. The medium for cell culturing was purchased from Media Preparation Facility at Memorial Sloan Kettering Cancer Center. The LNCaP cells were cultured in RPML1640base media that was supplemented with 10 % FCS, NEAA, 10 mM HEPES, 1 mM sodium pyruvate, 2 mM L-glutamine, 1.5 g / L sodium bicarbonate, 4.5 g / L glucose and penicillinstreptomycin. The MyC-CaP, 22Rvl and PC3(-AR-GFP) cells were cultured in DMEM, RPMI-1640 or F-12K base medias respectively which were all supplemented with 10 % FCS and penicillin-streptomycin.

[0148] In vitro stability o f [18F]F-SARM3 in PBS and mouse blood

[0149] Freshly synthesized [18F]F-SARM3 (185 KBq; 2-5 pL) was mixed with PBS (1.2 mL) or mouse blood (0.3 mL) and incubated at 37°C. For PBS samples, an aliquot of the samples (0.1 mL) was taken for stability analysis on radio-HPLC 0, 60, and 120 minutes post incubation start time. For the mouse blood samples, an aliquot (0.1 mL) was mixed with acetonitrile (0.15 mL) and placed on ice for 2 minutes before sample centrifugation for 5 minutes (10 000 rpm). The mouse blood was analyzed 15 and 120 minutes post incubation start time. The supernatant was collected and injected to radio-HPLC for stability analysis.

[0150] [18F]F-SARM3 demonstrated high in vitro stability in PBS and in mouse blood up to the last investigated timepoint of 120 minutes, where the tracer remained 98.5+1.2 % intact in PBS and 98.6+1.5 % mouse blood (FIG. 2A).

[0151] Human plasma protein bound [I8F]F-SARM3

[0152] Human serum sample (1.2 mL) was mixed with [18F]F-SARM3 (185 KBq; 3 pL in ethanol) and incubated at 37°C. 20 and 90 minutes post incubation start time an aliquot (0.15 mL) was mixed with acetonitrile (0.15 mL) and placed on ice for 5 minutes before sample centrifugation for 5 minutes (10 000 rpm). The supernatant was discarded, the protein pellet was measured with a gamma counter to measure the fraction of radioactivity bound to the human serum proteins.

[0153] A negligible amount of [18F]F-SARM3 was measured to be bound to the human serum proteins when 99.5+1.7 % of the added tracer remained unbound after a 90 min incubation period (FIG. 2B).

[0154] In vitro cell binding assay of fI8F]F-SARM3

[0155] Freshly synthesized [18F]F-SARM3 diluted with PBS (37 kBq; 2-4 pL) was added to 6-well plates plated with LNCaP, 22Rvl, MyC-CaP, and PC3 that were incubated in charcoal stripped FBS media 24-48 h prior the addition of the tracer. For blocking treated cells, F-SARM3 or DHT (100 nM; 4.4 pL in mQ H2O) was added to the wells. The agents were incubated with the cells for 60 minutes at 37 °C.

[0156] Media was aspirated, the cells were washed twice with PBS (1 mL x 2) followed by the addition of trypsin (1 mL x 2) for cell collection. The cell samples were counted with gamma counter. The number of cells used for each cell lines was determined with a cell counter in order to determine relative [18F]F-SARM3 binding for each cell line.

[0157] The selectivity of [18F]F-SARM3 was determined with a cell binding assay in multiple prostate cancer cell lines with varying AR expression (AR+ / AR-). With the addition of DHT or F-SARM3, the binding of [18F]F-SARM3 was sufficiently blocked in all of the tested AR+ cell lines, LNCaP, MyC-CaP (FIG. 3), and 22Rvl (FIG. 4) (p<0.01). [18F]F-SARM3 showed minimal binding to AR- cells (PC3), and its binding was not blockable with the addition of DHT or F-SARM3 (FIG. 4, p>0.25).

[0158] Competitive cell binding assay of f18F]F-SARM3 and [18F]FDHT

[0159] Freshly synthesized [18F]F-SARM3 or [18F]FDHT PBS diluted tracer (37 KBq) was added to 6-well plates plated with LNCaP, MyC-CaP, or 22Rvl prostate cancer cells (incubated in charcoal stripped media 24 hours prior to the experiment). Varying amounts of DHT or F-SARM3 (0.01 nM - 1000 nM; 2-4 pL) were added to the wells along with the tracer. The cells were incubated at 37 °C for one hour.

[0160] The media was aspirated and the cells were washed twice with PBS (1 mL). The cells were dissociated with trypsin (1 mL) and collected to tubes. The samples were counted with a gamma counter. Competitive cell binding assay for [18F]FDHT was performed only with the LNCaP cell line.

[0161] The in vitro affinity F-SARM3 towards AR was measured in LNCaP, MyC-CaP, and 22Rvl prostate cancer cells with a competitive binding assay where [18F]F-SARM3 was displaced with varying amounts of DHT or F-SARM3 (FIG. 5A). F-SARM3 showed similar binding to AR as DHT in all of the cell lines. The DHT or F-SARM3 concentrations needed to block 50 % of the [18F]F-SARM3 binding were 4.7 nM and 4.7 nM in LNCaP cells, 1.2 nM and 1.3 nM in MyC-CaP cells and 7.8 nM and 3.4 nM in 22Rvl cells. Additionally, the concentrations of DHT and F-SARM3 needed to block 50 % pf the binding of [18F]FDHT was studied in LNCaP cells (FIG. 5B), which again revealed that both DHT and F-SARM3 have similar affinity to AR. The IC50 blocking concentration of [18F]FDHT were 2.4 nM and 2.1 nM for DHT and F-SARM3 respectively.

[0162] Live cell imaging of AR-GFP fusion protein with F-SARM3

[0163] Vehicle, dihydrotestosterone (DHT, 100 nM; 4 pL in mQ water) or F-SARM3 (100 nM; 4 pL in mQ water) were added to 6 well plates plated with PC3-AR-GFP cells that had been cultured in charcoal stripped media 24 h prior to the addition of the ligands. The cell plates were transferred immediately to Incucyte S3 microscope incubator where the cells were imaged (phase and fluorescence) every 30 minutes up to 4 hours to assess the localization of the AR-GFP fusion protein.

[0164] The live cell imaging of PC3 -AR-GFP cells that were treated with DHT and F- SARM3 showed the localization of the AR-GFP fusion protein to the nucleus but revealed the confinement of the fusion protein in the cytosol when only treated with the vehicle (FIG. 6). The AR agonistic feature of DHT was demonstrated with the translocation of the receptor to the nucleus which was also revealed to be the case with F-SARM3.

[0165] Example 3: In vivo characterization of [18F]F-SARM3

[0166] Materials And Methods

[0167] Male outbred athymice mice (8 weeks of age) from The Jackson Laboratory were used for all the in vivo studies. For experiments including xenografted mice the cells were injected subcutaneously to the right shoulder of the mouse (LNCaP; 5 million in 100 pL ofPBS and Matrigel 1 : 1). The mice were used for the experiments when tumors reached ~300 mm3volume (4-8 weeks).

[0168] In vivo blood half-life of [I8F]F-SARM3

[0169] Freshly synthesized [18F]F-SARM3 in ethanol was diluted with sterile saline (10% ethanol) and injected via the tail vein to male nude mice (8.4-9.5 MBq in 200 uL; n=3). 5- 10 pL of blood was collected from the mice 0.5, 2, 5, 15, 30, 60, 90 minutes post injection from the tail vein to preweighted tubes with a heparinized micro-hematocrit capillary tubes. The blood samples were weighed and measured with a gamma counter. Percent injected dose per gram (%ID / g) was calculated for each sample and these values were presented as a function of time. Two phase decay curve was plotted and with the given %fast, %slow, tl / 2fast and tl / 2siow, blood half-life for [18F]F-SARM3 was calculated with the equation shown below. tl / 2Weighted = tl / 2siow X %fast + tl / 2fastx %slow[0170| The clearance of the [18F]F-SARM3 from the blood pool post intravenous injection was extremely quick. The weighted blood half-life of the compound was measured to be 2.8 min (FIG. 7).

[0171] In vivo study of 118F1F-SARM3 in LNCaP tumor bearing mice

[0172] Two out of three cohorts of LNCaP tumor bearing male nude mice (n=5 / cohort) were surgically castrated 4 days prior to the injection of [18F]F-SARM3 (7.0-7.4 MBq in 200 pL saline) via the tail vein to all of the cohorts of mice. One of the castrated cohorts was additionally injected with non-radioactive F-SARM3 (135 nmol) as a blocking agent. The mice were imaged 45 and 120 min post injection with a small animal PET / CT scanner with a 10 minute static scan (Inveon Siemens). The last imaging timepoint was followed with a terminal in vivo biodistribution which included the collection of all the relevant organs. The organs were collected to preweighted tubes and counted with a gamma counter to determine each organs %ID / g value.

[0173] Based on the in vivo biodistribution study, 2 h post injection, tumor uptake of [18F]F- SARM3 in the castrated LNCaP tumor bearing mice was on average higher in the experimental cohort compared to the blocking one, 1.0+0.7 %ID / g and 0.2+0.1 %ID / g respectively (p=0.08). The tumor uptake in the non-castrated mice was similar to the blocking cohort (0.1+0.0 %ID / g) revealing that DHT levels present in these mice competed with the binding of the tracer to AR. The clearance of the tracer occurred through the kidneys and the intestine, however the presence of radioactivity was low already 2 h post injection (kidneys; 0.6+0.2 %ID / g, small intestine; 4.9+1.1 %ID / g and liver; 0.8+0.6 %ID / g). Furthermore, the presence of [18F]F-SARM3 in the blood 2 h post injection was minimal (0.2+0.1 %ID / g) which corroborated with the in vivo blood half-life studies (FIG.8)

[0174] The PET / CT imaging study of [18F]F-SARM3 allowed great tumor delineation of the subcutaneous LNCaP tumors at both of the investigated timepoints (45, 120 min p.i.) in the experimental castrated mouse cohort. The selective blocking of the tracer with F- SARM3 was demonstrated with PET imaging showing that no tumor uptake was present in the blocking cohort (FIGs. 9A-9B).

[0175] 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 embodiment described 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.

[0176] 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 foregoingdescriptions. 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.

[0177] 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.

[0178] 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 a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0179] 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 downinto 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.

[0180] All publications, patent applications, issued patents, and other documents (for example, journals, 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.

[0181] 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 non-steroid selective androgen receptor modulator (SARM) of Formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, whereinR1is H or Ci-3 alkyl; andR2is a boronic acid, fluoro, iodo, a fluoro radioisotope, or an iodo radioisotope.B. The non-steroid SARM of Paragraph A, wherein R1is C1-3 alkyl.C. The non-steroid SARM of Paragraph A or Paragraph B, wherein R1is methyl.D. The non-steroid SARM of Paragraph A, wherein R1is H.E. The non-steroid SARM of any one of Paragraphs A-D, wherein R2is a fluoro radioisotope.F. The non-steroid SARM of Paragraph E, wherein the fluorine radioisotope is18F.G. The non-steroid SARM of any one of Paragraphs A-D, wherein R2is an iodo radioisotope.H. The non-steroid SARM of Paragraph G, wherein the iodo radioisotope is selected from the group consisting of123I,124I,125I,126I,131I.I. The non-steroid SARM of Paragraph G or Paragraph H, wherein the iodo radioisotope is131I.J. The non-steroid SARM of any one of Paragraphs A-D, wherein R2is a boronic acid.K. The non-steroid SARM of Paragraph A, wherein R1is methyl and R2is18F.L. The non-steroid SARM of Paragraph A, wherein R1is methyl and R2is131I.M. The non-steroid SARM of Paragraph A, wherein R1is methyl and R2is a boronic acid.N. A composition comprising the non-steroid SARM of any one of Paragraphs A-M; and a pharmaceutically acceptable carrier.O. A pharmaceutical composition comprising an effective amount of the non-steroid SARM of any one of Paragraphs A-M to treat a disease associated with androgen receptor; and a pharmaceutically acceptable carrier.P. A method of treating a disease comprising administering to a subject an effective amount of the non-steroid SARM of any one of Paragraphs A-M.Q. The method of Paragraph P, wherein the disease is a cancer.R. The method of Paragraph Q, wherein the cancer comprises prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer.S. The method of Paragraph Q or Paragraph R, wherein the cancer is prostate cancer.T. A method comprising administering to a subject an effective amount of the non-steroid SARM of any one of Paragraphs A-M for imaging a cancer; and subsequent to the administering, detecting one or more of positron emission, gamma rays from positron emission and annihilation, and Cerenkov radiation due to positron emission.U. The method of Paragraph T, wherein the cancer comprises prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer.V. The method of Paragraph T or Paragraph U, wherein the cancer is prostate cancer.

[0182] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

Claims

WHAT IS CLAIMED IS:

1. A non-steroid selective androgen receptor modulator (SARM) of Formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, whereinR1is H or Ci-3 alkyl; andR2is a boronic acid, fluoro, iodo, a fluoro radioisotope, or an iodo radioisotope.

2. The non-steroid SARM of claim 1, wherein R1is C1-3 alkyl.

3. The non-steroid SARM of claim 1, wherein R1is methyl.

4. The non-steroid SARM of claim 1, wherein R1is H.

5. The non-steroid SARM of any claim 1, wherein R2is a fluoro radioisotope.

6. The non-steroid SARM of claim 5, wherein the fluorine radioisotope is18F.

7. The non-steroid SARM of claim 1, wherein R2is an iodo radioisotope.

8. The non-steroid SARM of claim 7, wherein the iodo radioisotope is selected from the group consisting of123I,124I,125I,126I,131I.

9. The non-steroid SARM of claim 7, wherein the iodo radioisotope is131I.

10. The non-steroid SARM of claim 1, wherein R2is a boronic acid.

11. The non-steroid SARM of claim 1, wherein R1is methyl and R2is18F.

12. The non-steroid SARM of claim 1, wherein R1is methyl and R2is131I.

13. The non-steroid SARM of claim 1, wherein R1is methyl and R2is a boronic acid.

14. A composition comprising the non-steroid SARM of any one of claims 1-13; and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising an effective amount of the non-steroid SARM of any one of claims 1-13 to treat a disease associated with androgen receptor; and a pharmaceutically acceptable carrier.

16. A method of treating a disease comprising administering to a subject an effective amount of the non-steroid SARM of any one of claims 1-13.

17. The method of claim 16, wherein the disease is a cancer.

18. The method of claim 17, wherein the cancer comprises prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer.

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

20. A method comprising administering to a subject an effective amount of the non-steroid SARM of any one of claims 1-13 for imaging a cancer; and subsequent to the administering, detecting one or more of positron emission, gamma rays from positron emission and annihilation, and Cerenkov radiation due to positron emission.

21. The method of claim 20, wherein the cancer comprises prostate cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, liver cancer, renal cell carcinoma esophageal cancer, colorectal cancer, or pancreatic cancer.

22. The method of claim 20, wherein the cancer is prostate cancer.

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