Double targeted constructs to affect tumor kill

Abstract

To provide compounds, compositions, medicaments and methods related to the treatment of cancers expressing prostate specific membrane antigen ("PSMA").SOLUTION: The compounds are those represented by Formula I or the like or pharmaceutically acceptable salts thereof. The present technology is especially suited for use in treating prostate cancer.SELECTED DRAWING: Figure 7A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is incorporated by reference in its entirety for all purposes. Benefit of priority claimed to U.S. Provisional Application No. 62 / 353,735, filed June 23, 2013 .

[0002] The present technology relates to the treatment of tumors expressing prostate-specific membrane antigen ("PSMA"). The present technology is directed to compounds, compositions, and methods related to the treatment of prostate cancer. Particularly suitable for Summary of the Invention

[0003] In one embodiment, a compound according to formula I

[0004] [ka] or a pharmaceutically acceptable salt thereof (wherein X 1 teeth, 124 I, 125 I, 127 I, 131 I, 211 At, or Sn(R 4 )3;R 1 , R 2 , and R 3 are, respectively independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl; ;R 4 is independently at each occurrence an alkyl group; n is 1 or 2; and m is 0, 1, 2 , or 3) is provided.

[0005] In one embodiment, a compound of formula II

[0006] [ka] or a pharmaceutically acceptable salt thereof (wherein X 2 teeth, 124 I, 125 I, 127 I, 131 I, 211 At, or Sn(R 8 )3;R 5 , R 6 , and R 7 are, respectively independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl; ;R 8 is independently at each occurrence an alkyl group; W1 is a bond or -NH-alkylene; and p is 0, 1, 2, or 3).

[0007] In a related embodiment, a compound of Formula I or II and a pharmaceutically acceptable carrier is provided. A composition is provided.

[0008] In a similar embodiment, a method for treating prostate cancer comprising administering to a patient a therapeutically effective amount of a compound of Formula I or II. A pharmaceutical composition comprising the compound is provided.

[0009] In one embodiment, a subject suffering from prostate cancer is administered a compound of Formula I or II. A method is provided that includes the steps of:

[0010] In one embodiment, a treatment for tumors presenting prostate-specific membrane antigen ("PSMA") is provided. A method for enhancing uptake of a therapeutic agent is provided, the method comprising administering a PMSA targeting moiety and a radioactive a first therapeutic agent comprising a human serum albumin binding moiety containing a nuclide, the ... administering to a subject having a cancer tumor; detecting distribution of the first therapeutic agent in the subject and modifying the first therapeutic agent to provide a second therapeutic agent. [Brief explanation of the drawings]

[0011] [Figure 1A] FIG. 1 shows the biodistribution of 131I-RPS-001 in male nude mice bearing PSMA+LNCaP human tumor xenografts at 24, 48, 72, and 96 hours after injection. [Figure 1B] FIG. 1 shows the biodistribution of 131I-RPS-005 in male nude mice bearing PSMA+LNCaP human tumor xenografts at 24, 48, 72, and 96 hours after injection of the compound of the present technology. [Figure 2] FIG. 1 shows the biodistribution of 131I-RPS-020 in male nude mice bearing PSMA+LNCaP human tumor xenografts at 1, 6, 12, 24, and 48 hours after injection. [Figure 3] FIG. 1 shows the biodistribution of 131I-RPS-022 in male nude mice bearing PSMA+LNCaP human tumor xenografts at 1, 6, 12, 24, and 48 hours after injection. [Figure 4] FIG. 1 shows the biodistribution of 131I-RPS-027 in male nude mice bearing PSMA+LNCaP human tumor xenografts at 1, 3, 6, 12, 18, 24, 48, and 72 hours after injection. [Figure 5] FIG. 1 shows the results of μPET / CT imaging of LNCaP xenograft mice by μPET / CT using 124I-RPS-027 (7.4 MBq, 200 μCi). [Figure 6A] FIG. 1 shows plots of blood time activity curves derived from biodistribution data. [Figure 6B] FIG. 1 shows plots of tumor time activity curves derived from biodistribution data. [Figure 6C] FIG. 1 shows plots of renal time activity curves derived from biodistribution data. [Figure 7A]FIG. 1 shows tumor to blood ratios relative to background and further illustrates the effect of enhanced albumin-binding on tumor delivery of each compound. [Figure 7B] FIG. 10 shows tumor to kidney ratios relative to background and further illustrates the effect of enhanced albumin-binding on tumor delivery of each compound. DETAILED DESCRIPTION OF THE INVENTION

[0012] In various embodiments, the present technology provides a method for the preparation of a compound for treating a PSMA-expressing cancer. Compositions and methods are provided herein that are particularly suitable for treating prostate cancer. The compounds can be formulated into useful pharmaceutical compositions and medicaments by the disclosed methods. Use of the compounds in pharmaceutical formulations and in the preparation of medicaments is also provided.

[0013] The following terms are used throughout as defined below.

[0014] As used in this specification and the appended claims, "a" and "an" and and "the" and the context in which elements are described (particularly in the following claim sentences). Similar indications in the context of the present invention are used unless otherwise indicated herein or apparent from the context. Unless otherwise contradicted, the terms "a," "the," "the," and "the" are to be construed as including both the singular and the plural. The description of a range of values ​​within the range includes each separate value falling within the range, unless otherwise stated herein. It is merely intended to serve as a shorthand way of listing the values ​​individually and Each value is incorporated herein as if it were individually set forth herein. All methods described herein are by the method of the present invention unless otherwise specified herein or otherwise, in any suitable order unless clearly contradicted by the context. Any examples or exemplary language provided herein (e.g., "such as") The use of is merely intended to make the embodiments more clear and does not affect the claims unless otherwise specified. No limitation is imposed on the scope of the invention. No component should be construed as being required.

[0015] As used herein, "about" is understood by those of ordinary skill in the art and is used to The use of terms that are not clear to those skilled in the art will vary to some extent depending on the context in which they are used. If there is any, taking into account the context in which it is used, "about" is used within a certain limit plus or minus. This would mean up to 10%.

[0016] In general, a reference to a certain element, such as hydrogen or H, refers to all isotopes of that element. For example, if an R group is defined to include hydrogen, or H, then: It also includes deuterium and tritium. Thus, tritium, 14 C. 32 P, O Call 35 Compounds containing radioactive isotopes such as S are within the scope of the present technology. Procedures for incorporating such labels into compounds of the present technology will be readily apparent to those skilled in the art based on this disclosure. It should be obvious.

[0017] Generally, "substituted" refers to one or more substitutions of a hydrogen atom contained in an organic group. wherein the bond of is replaced by a bond to a non-hydrogen or non-carbon atom, A substituted group refers to an organic group (e.g., an alkyl group) that is substituted with a carbon(s). or one or more bonds to a hydrogen atom(s) are to a heteroatom This also includes groups that are replaced by one or more bonds, including double or triple bonds. Thus, a substituted group, unless otherwise specified, is substituted with one or more substituents. In some embodiments, the substituted groups are 1, 2, 3, 4, 5, or 6 Examples of substituents include halogens (i.e., F, Cl, Br, and I), hydroxyl, alkoxy, alkenoxy, aryloxy, aralkyl Oxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclyl Cyclylalkoxy group, carbonyl (oxo), carboxylate, ester, ureta amines, oximes, hydroxylamines, alkoxyamines, aralkoxyamines, thiols , sulfide, sulfoxide, sulfone, sulfonyl, pentafluorosulfanyl ( i.e., SF5), sulfonamides, amines, N-oxides, hydrazines, hydrazides, Hydrazone, azide, amide, urea, amidine, guanidine, enamine, imide, iso Cyanate, isothiocyanate, cyanate, thiocyanate, imine, nitro group, nitro Tolyl (i.e., CN) and the like.

[0018] substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups, etc. A substituted ring group is a ring group in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. and ring systems, thus including substituted cycloalkyl, aryl, heterocyclyl and The heteroaryl and heteroaryl groups are substituted or unsubstituted alkyl, alkenyl, and aryl groups as defined below. and alkynyl groups.

[0019] Alkyl groups have from 1 to 12 carbon atoms, and typically from 1 to 10 carbon atoms, or or, in some embodiments, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. The alkyl group may be substituted or may be unsubstituted. Examples of straight chain alkyl groups include methyl, ethyl, n-propyl, n -butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups Examples of branched alkyl groups include isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups Representative substituted alkyl groups include, but are not limited to, those listed above. The alkyl group may be substituted one or more times, such as with a haloalkyl group (e.g., thiazolinone ... (trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkyla aminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, etc. Including, but not limited to:

[0020] Cycloalkyl groups have 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 The cycloalkyl group includes monocyclic, bicyclic or tricyclic alkyl groups having 1 to 3 carbon atoms. Exemplary monocyclic cycloalkyl groups include cycloalkyl groups such as cycloalkyl groups, ... cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and In some embodiments, cyclohexyl groups include, but are not limited to, cyclooctyl and cyclooctyl groups. Cycloalkyl groups have from 3 to 8 ring members, but in other embodiments, the ring carbon atoms The number of rings ranges from 3 to 5, 3 to 6, or 3 to 7. includes both bridged cycloalkyl groups and fused rings, e.g., bicyclo[2.1.1]hexa These include, but are not limited to, cyclohexyl ... The alkyl group may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups may be straight-chain or substituted as defined above. Also includes rings substituted with branched alkyl groups. Representative substituted cycloalkyl groups may be substituted once or more than once, e.g., 2,2-, 2,3-, 2,4- cyclohexyl groups, such as, but not limited to, 2,5- or 2,6-disubstituted cyclohexyl groups. They may be optionally substituted, such as those listed above. good.

[0021] A cycloalkylalkyl group is one in which the bond between a hydrogen or carbon atom to the alkyl group is as defined above. is an alkyl group as defined above replaced by a bond to a cycloalkyl group. The cycloalkylalkyl group may be substituted or unsubstituted. In this embodiment, the cycloalkylalkyl group is selected from 4 to 16 carbon atoms, 4 to 12 and typically 4 to 10 carbon atoms. The alkylalkyl group is an alkyl, cycloalkyl or alkyl and cycloalkyl group. Representative substituted cycloalkylalkyl groups are: , mono-substituted or substituted two or more times, such as with the substituents listed above, mono-, It may be, but is not limited to, di- or tri-substituted.

[0022] An alkenyl group has at least one double bond between two carbon atoms. , including straight and branched chain alkyl groups as defined above. Alkenyl groups are substituted or Alkenyl groups may be substituted or unsubstituted. Alkenyl groups have from 2 to 12 carbon atoms, typically 2 to 10 carbons, or in some embodiments, 2 to 8, 2 to 6, or 2 In some embodiments, the alkenyl group has 1, 2, or 4 carbon atoms. has three carbon-carbon double bonds. Examples include vinyl, allyl, -CH=C, among others. H(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=C Examples include, but are not limited to, -H(CH3), -C(CH2CH3)=CH2. Representative substituted alkenyl groups may be monosubstituted or substituted more than once. may be mono-, di-, or tri-substituted, e.g., with the substituents listed above. It may be, but is not limited to, these.

[0023] A cycloalkenyl group is defined as having at least one double bond between two carbon atoms. Cycloalkenyl groups include cycloalkyl groups as defined above. Cycloalkenyl groups may be substituted or unsubstituted. In some embodiments, the cycloalkenyl group may be substituted with 1, 2, or 3 alkyl groups. The cycloalkenyl group may have a double bond of, but does not include aromatic compounds. 4 to 14 carbon atoms, or in some embodiments, 5 to 14 carbon atoms; having 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, and cyclohexadiene. cyclobutadienyl, and cyclopentadienyl.

[0024] Cycloalkenylalkyl groups are those in which the hydrogen or carbon bond of the alkyl group is as defined above. An alkyl group as defined above replaced by a bond to a cycloalkenyl group. A cycloalkenylalkyl group can be substituted or unsubstituted. The cycloalkenylalkyl group may be selected from the group alkyl, cycloalkenyl or alkyl and Both the cycloalkenyl and cycloalkenyl portions may be substituted. Alkenylalkyl groups may be substituted one or more times, such as with the substituents listed above. That's fine.

[0025] An alkynyl group is an alkyl group except that there is at least one triple bond between two carbon atoms. Alkynyl groups include straight and branched chain alkyl groups as defined above. Alkynyl groups are substituted or unsubstituted. Alkynyl groups may be substituted or unsubstituted. Alkynyl groups have from 2 to 12 carbon atoms, typically 2 to 10 carbons, or in some embodiments, 2 to 8, 2 to 6, or 2 In some embodiments, an alkynyl group has 1, 2, or 4 carbon atoms. has three carbon-carbon triple bonds. Examples include, among others, -C≡CH, -C≡CCH3 , -CH2C≡CCH3, -C≡CCH2CH(CH2CH3)2, but these Representative substituted alkynyl groups include, but are not limited to, those listed above. , mono-substituted or more than twice substituted, for example mono-, di- or tri-substituted It may be, but is not limited to, these.

[0026] An aryl group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. The aryl group in the present invention may be monocyclic, bicyclic, or unsubstituted. Thus, aryl groups include phenyl, azulenyl, hydroxybenzoates, benzophenones, benzotriazole ... butalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl Examples of alkyl groups include, but are not limited to, aryl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups are 6 to 14 carbons, and in others, the The ring portion contains 6 to 12 or even 6 to 10 carbon atoms. In embodiments, the aryl group is phenyl or naphthyl. The phrase "aryl group" refers to a fused Rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.) Representative substituted aryl groups include groups containing the following: For example, a monosubstituted aryl group can be 2-, 3-, or 4-substituted. , 4-, 5-, or 6-substituted phenyl or naphthyl groups, The alkyl group may be substituted with, but is not limited to, a substituent such as a substituted alkyl group.

[0027] An aralkyl group is one in which the hydrogen or carbon bond of an alkyl group is substituted with an aryl group as defined above. An aralkyl group is an alkyl group as defined above, substituted with a bond In some embodiments, the aralkyl group may be substituted or unsubstituted. containing from 1 to 16 carbon atoms, from 7 to 14 carbon atoms, or from 7 to 10 carbon atoms Substituted aralkyl groups are alkyl, aryl or alkyl and aryl groups. Both moieties may be substituted. Representative aralkyl groups include benzyl and phenethyl. aryl groups and fused (cycloalkylaryl)alkyl groups, such as 4-indanylethyl Representative substituted aralkyl groups include, but are not limited to, those listed above. It may be substituted one or more times with such substituents as listed.

[0028] Heterocyclyl groups are aromatic rings (also called heteroaryls) containing three or more ring members. and non-aromatic ring compounds, wherein one or more of the members are N, O, and and heteroatoms such as, but not limited to, S. Heterocyclyl groups are substituted or unsubstituted. In some embodiments, the heterocyclyl group is In some embodiments, heterocyclyl contains 1, 2, 3, or 4 heteroatoms. The group includes monocyclic, bicyclic and tricyclic rings having from 3 to 16 ring members, whereas and other such groups may be 3 to 6, 3 to 10, 3 to 12, or 3 to 14. Heterocyclyl groups include aromatic, partially unsaturated and saturated ring systems, Examples include imidazolyl, imidazolinyl and imidazolidinyl groups. "Heterocyclyl groups" include fused aromatic and non-aromatic groups, e.g., benzotriazolyl groups. 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxonyl This term also includes fused ring species, including groups including quinuclidyl, etc., with the proviso that This also includes bridged polycyclic ring systems containing, but not limited to, heteroatoms. Includes aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, and pyrazolidinyl , thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, Furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyra Zolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl , thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pi Peridyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetramethyl tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl , pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydro Rhodithionyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, Indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, isoindolyl Benzotriazolyl, benzimidazolyl, benzofuranyl, benzothio Phenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodi Thiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothia zolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, piazolopyridyl, iridyl Midazopyridyl (azabenzimidazolyl), thiazolopyridyl, isoxazolopyridyl quinolinyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, Quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyl dihydrobenzothiazinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofura dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindolyl Tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl Zolyl, tetrahydropyrrolopyridyl, tetrahydropiazolopyridyl, tetrahydroisopropyl Contains midazopyridyl, tetrahydrothiazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups include, but are not limited to, monosubstituted heterocyclyl groups. or substituted more than once, for example, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 22-, 23-, 24-, 25-, 26-, , 3-, 4-, 5-, or 6-substituted or disubstituted pyridyl or morpho The alkyl group may be, but is not limited to, a linyl group.

[0029] Heteroaryl groups are aromatic ring compounds containing five or more ring members, One or more of the bars may be heteroatoms, such as, but not limited to, N, O, and S. Heteroaryl groups can be substituted or unsubstituted. The aryl group includes pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, and oxazolyl. , isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl phenyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, aza Indolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl Nyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzo Triazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazolyl Zopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, azopyridinyl Denynyl, guanyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolinyl These include, but are not limited to, groups such as salinyl, and quinazolinyl groups. Aryl groups include fused ring compounds in which all rings are aromatic, such as indolyl groups, and Includes fused ring compounds in which only one of the rings is aromatic, such as a 2,3-dihydroindolyl group. The phrase "heteroaryl group" includes fused ring compounds. Representative substituted heteroaryls Groups may be optionally substituted one or more times with various of the substituents listed above.

[0030] Heterocyclylalkyl groups are alkyl groups as defined above, and may be any of the alkyl group hydrogens or alkyl groups. or carbon bond is replaced with a bond to a heterocyclyl group as defined above. A heterocyclylalkyl group can be substituted or unsubstituted. The heterocyclylalkyl group may be an alkyl, heterocyclyl, or alkyl and heterocyclyl group. Both the heterocyclyl and heterocyclyl portions may be substituted. Representative heterocyclylalkyl Groups include morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazole-4 -yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl Representative examples include, but are not limited to, indol-2-yl-propyl. Optionally substituted heterocyclylalkyl groups may be substituted one or more times with any of the substituents listed above. It may be substituted multiple times.

[0031] Heteroaralkyl groups are alkyl groups as defined above, where the hydrogen or carbon of the alkyl group is substituted. The bond is replaced with a bond to a heteroaryl group as defined above. The aralkyl group may be substituted or unsubstituted. The alkyl group may be an alkyl, heteroaryl, or both alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups are listed above. It may be substituted one or more times with such substituents as listed.

[0032] The compounds of the present technology may have more than one point of attachment (i.e., bivalent, trivalent, or (is polyvalent) Groups described herein are designated by the use of the suffix "ene". For example, A divalent alkyl group is an alkylene group, a divalent aryl group is an arylene group, and a divalent hetero group is an The aryl group is a divalent heteroarylene group, etc. Substituted groups with a point of attachment of 1 to 1 are not represented using the "ene" designation. Thus, for example, chloroethyl would not be referred to herein as chloroethylene.

[0033] An alkoxy group is one in which the bond to the hydrogen atom is a substituted or unsubstituted alkyl group as defined above. A hydroxyl group (-OH) is replaced by a bond to a carbon atom of an alcohol group. The alkoxy group may be substituted or unsubstituted. Examples of linear alkoxy groups include: , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, etc. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-bromoalkoxy, and the like. These include butyloxy, tert-butoxy, isopentoxy, isohexoxy, etc. Examples of cycloalkoxy groups include cyclopropyloxy, cyclobutyloxy, and the like. cyclohexyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups include those substituted one or more times by any of the substituents listed above. It may be substituted multiple times.

[0034] As used herein, the terms "alkanoyl" and "alkanoyloxy" refer to -C(O)-alkyl groups and -OC( Similarly, "aryloyl" and "aryloyl" can refer to any alkyl group. "Oxy" refers to the groups --C(O)-aryl and --OC(O)-aryl.

[0035] The terms "aryloxy" and "arylalkoxy" each refer to an aryl group bonded to an oxygen atom. substituted or unsubstituted aryl groups, and substituted or unsubstituted alkyl groups attached to oxygen atoms; aryloxy refers to substituted aralkyl groups. Examples include phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and aryloxy groups include, but are not limited to, aryloxy and aryloxy groups. The alkylalkoxy group may be substituted one or more times, such as with the substituents listed above. Good too.

[0036] As used herein, the term "carboxylate" refers to a -C(O)OH group. The term "protected carboxylate" refers to the group -C(O)OG, where G is a carboxylate. Carboxylate protecting groups are well known to those skilled in the art. The expanded list of protecting groups for sylate functionality is as if fully described herein. Protect ive Groups in Organic Synthesis, Greene, T. .W.;Wuts, PGM, John Wiley&Sons, New York , NY (3rd ed., 1999), and those protecting groups are described in the above publications. They can be added or removed using the procedures disclosed.

[0037] As used herein, the term "ester" refers to an ester of -COOR 70 R 70 teeth, Substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkoxy ... is an aryl, aralkyl, heterocyclylalkyl or heterocyclyl group .

[0038] The term "amide" (or "amido") refers to C- and N-amide groups, i.e., -C( O)NR 71 R 72 , and -NR 71 C(O)R 72 R 71 Oh BiR 72 are independently hydrogen or substituted or unsubstituted alkyl as defined herein; Alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl An amide group is therefore a carbamoyl group (-C(O) Examples of suitable alkyl groups include, but are not limited to, alkyl groups (-NH2) and formamide groups (-NHC(O)H). In some embodiments, the amide is —NR 71 C(O)-(C 1~5 alkyl) The group is referred to as "carbonylamino", and another example is amide -NHC(O)-. When it is alkyl, the group is referred to as "alkanoylamino."

[0039] As used herein, the term "nitrile" or "cyano" refers to a -CN group.

[0040] The urethane groups include N- and O-urethane groups, i.e., -NR 73 C(O)OR 74 oh and -OC(O)NR73 R 74 R 73 and R 74 are, independently, Substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkenyl, or cycloalkenyl as defined herein. alkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group. R 73 may be H.

[0041] As used herein, the term "amine" (or "amino") refers to a group selected from the group consisting of -NR 75 R 7 6 R refers to the group 75 and R 76 are independently hydrogen or a substituted or unsubstituted alkyl group as defined herein. or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl In some embodiments, the heterocyclyl group is a heterocyclylalkyl or heterocyclyl group. The amine may be an alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH, methylamino, dimethylamino , ethylamino, diethylamino, propylamino, isopropylamino, phenylamino or benzylamino.

[0042] The term "sulfonamide" refers to S- and N-sulfonamide groups, i.e., -SON R 78 R 79 and -NR 78 SO2R 79 R 78 and R 79 teeth , independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, or aryl group as defined herein. aryl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or or heterocyclyl group. A sulfonamide group is therefore a sulfamoyl group (-SO 2NH2). In some embodiments herein, , sulfonamide is -NHSO2- alkyl, "alkylsulfonylamino" group It is called.

[0043] The term "thiol" refers to the -SH group, while "sulfide" refers to the -SR group. 80 containing a group "Sulfoxide" is -S(O)R 81 group, and "sulfone" is -SO2R 82 Contains and "sulfonyl" is -SO2OR 83 Includes: R 80 , R 81 , R 82 , and R 83 each independently represents a substituted or unsubstituted alkyl, cycloalkyl, or cycloalkyl group, as defined herein; alkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl or heterocycloalkyl In some embodiments, the sulfide is an alkylthio group, -S - alkyl.

[0044] The term "urea" refers to -NR 84 -C(O)-NR 85 R 86 R refers to the group 84 , R 85 , and R 86 The groups are independently hydrogen or substituted or unsubstituted alkyl groups as defined herein. alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclo aryl, or heterocyclylalkyl groups.

[0045] The term "amidine" refers to a -C(NR 87 )NR 88 R 89 and -NR 87 C(NR 88 )R 89 refers to R 87 , R 88 , and R 89 are each independently hydrogen, or Substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl as defined above , arylaralkyl, heterocyclyl or heterocyclylalkyl groups.

[0046] The term "guanidine" refers to -NR 90 C(NR 91 )NR 92 R 93 refers to R 90 , R 91 , R 92 and R 93 are each independently hydrogen or a substituted or unsubstituted group as defined herein. or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl , heterocyclyl or heterocyclylalkyl group.

[0047] The term "enamine" refers to a group consisting of -C(R 94 )=C(R 95 )NR 96 R 97 and -NR 94 C(R 95 )=C(R 96 )R 97 refers to R 94 , R 95 , R 96 and R 97 is, each each independently hydrogen, substituted or unsubstituted alkyl, cycloalkyl as defined herein; , alkenyl, alkynyl, arylaralkyl, heterocyclyl or heterocyclyl It is an alkyl group.

[0048] As used herein, the term "halogen" or "halo" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In the formula, the halogen is chlorine or bromine.

[0049] As used herein, the term "hydroxyl" refers to -OH or its ionized form. , -O - A "hydroxyalkyl" group can refer to a hydroxyl-substituted alkyl group. Alkyl groups, such as HO-CH2-.

[0050] As will be appreciated by those skilled in the art, a specifically written description is provided for all purposes. In terms, all ranges disclosed herein include all possible subranges and their Any listed ranges are fully understood to be within the meaning of the present invention. It can be recognized in the same range at least half, one-third, one-quarter, one-fifth, It may be possible to divide it equally into tenths, etc. Non-limiting examples As such, each range discussed herein may be divided into a lower third, a middle third, and an upper third. As will also be appreciated by those skilled in the art, all Phrases such as "up to," "at least," "greater than," "less than," etc. and numbers that refer to ranges that can then be divided into subranges as discussed above. As will be understood by one of ordinary skill in the art, a range includes each individual member. For example, a group having 1 to 3 atoms refers to a group having 1, 2, or 3 atoms. Similarly, a group having 1 to 5 atoms refers to a group having 1, 2, 3, 4, or 5 atoms, etc. This is about various things.

[0051] Pharmaceutically acceptable salts of the compounds described herein are within the scope of the present invention. , retain the desired pharmacological activity and are not biologically undesirable (e.g., salts Acids that are not overly toxic, allergenic, or irritating, and that are bioavailable The compounds of the present technology include basic groups, such as amino groups, and base addition salts. When the compound has the formula (I), the pharmaceutically acceptable salts are those formed from inorganic acids (hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and the like). and phosphoric acid), organic acids (e.g., alginic acid, formic acid, acetic acid, trifluoroacetic acid, benzoic acid, Acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid , malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p -toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid) The compounds of the present technology may be formed with an acidic group, e.g., a carboxylic acid group. etc., it is alkali metals and alkaline earth metals (e.g., Na +、 L i +、 K +、 Ca 2+ , Mg 2+、 ZN 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, pyridine, choline, ethanolamine, diethanolamine, triethanolamine) or basic Salts can be formed with amino acids such as arginine, lysine and ornithine. Such salts may be used in situ during the isolation and purification of the compounds or by converting the purified compounds into salts in situ. by separately reacting each in its free base or free acid form with an appropriate acid or base, It can be prepared by isolating the salt so formed.

[0052] Those skilled in the art will appreciate that the compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and It will be recognized that the compounds may exhibit stereoisomerism and / or stereoisomerism. The formula diagram of is one of the possible tautomeric, conformational, stereochemical or geometric isomeric forms The present technology can be implemented using one or more of the methods described herein. Any tautomeric, conformational, stereochemical and / or geometrical variations of the compounds that have utility in It should be understood that the present invention encompasses all forms of the compound, as well as mixtures of these various different forms. be.

[0053] "Tautomers" refer to isomeric forms of a compound that exist in equilibrium with each other. The presence and concentration may depend on the environment in which the compound is found, for example, whether the compound is a solid or or may differ depending on whether it is in an organic or aqueous solution. Nazolinone can exhibit the following isomeric forms, which are called tautomers of each other: can be.

[0054] [ka] As another example, guanidine can exhibit the following isomeric forms in protic organic solutions: As a result, they are said to be tautomers of each other.

[0055] [ka]

[0056] Due to the limitations of representing compounds by structural formulas, all of the compounds described herein are It is understood that the chemical formulas represent all tautomeric forms of the compounds and are within the scope of the present technology. It should be.

[0057] Stereoisomers (also known as optical isomers) of a compound are those that have a specific stereochemistry. Unless otherwise indicated, chiral, diastereomeric, and racemic forms of all structures are included. Thus, the compounds used in the technology of the present invention may be any or all of the compounds apparent from the description. Enriched or resolved optical isomers at the asymmetric atom of Mixtures of both stereoisomers, as well as the individual optical isomers, are not necessarily confined to their enantiomers. or can be isolated or synthesized so as to be substantially free of its diastereomeric counterpart. All of these stereoisomers are within the scope of the present invention.

[0058] The compounds of the present technology may also exist as solvates, particularly hydrates. Hydrates may also be formed during the preparation of the compound or compositions containing the compound, or hydrates may be formed during the preparation of the compound or compositions containing the compound. , may form over time due to the hygroscopic nature of the compound. The compounds are particularly well known in organic solvent solvates, including solvates of DMF, ethers, and alcohols. The identification and preparation of any particular solvate may be performed by the It is within the skill of one of ordinary skill in the art of synthetic organic chemistry or medicinal chemistry.

[0059] Considerations of the present invention's technology Prostate-specific membrane antigen ("PSMA")-targeted radiation therapy for prostate cancer (PCa) has recently emerged as a promising approach for the treatment of widespread disease. PSMA is expressed by gliomas, cervical cancer, vulvar cancer, endometrial cancer, and primary ovarian cancer. Focal carcinoma, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, and several other types, including (but not limited to) renal cell carcinoma It is expressed in the neovasculature of tumors. For example, Wernicke AG, Kim S, Liu H,Bander NH,Pirog EC.Prostate-specific Membrane Antigen(PSMA)Expression in the Neovasculature of Gynecologic Malignanci es:Implications for PSMA-targeted Therap y.Appl Immunohistochem Mol Morphol.2016 Feb 9(doi:10.1097 / PAI.0000000000000297); Wang HL, Wang SS, Song WH, Pan Y, Yu HP, Si T G,Liu Y,Cui XN,Guo Z.Expression of prost ate-specific membrane antigen in lung ca cancer cells and tumor neovasculature endo thelial cells and their clinical significa nce.PLoS One.2015 May 15;10(5):e0125924 (doi:10.1371 / journal.pone.0125924);Sampl aski MK, Heston W, Elson P, Magi-Galluzzi C ,Hansel DE.Folate hydrolase(prostate-spe cific membrane antigen)1 expression in b ladder cancer subtypes and associated tu mor neovasculature.Mod Pathol.2011 Nov;2 4(11):1521~9ページ (doi:10.1038 / modpathol.2 011.112);Haffner MC,Kronberger IE,Ross J S,Sheehan CE,Zitt M,Muhlmann G,Ofner D,Z elger B,Ensinger C,Yang XJ,Geley S,Margr eiter R,Bander NH.Prostate-specific memb rane antigen expression in the neovascul ature of gastric and colorectal cancers. Hum Pathol.2009 Dec;40(12):1754~61ページ (d oi:10.1016 / j.humpath.2009.06.003);Baccal a A,Sercia L,Li J,Heston W,Zhou M.Expres sion of prostate-specific membrane antig en in tumor-associated neovasculature of renal neoplasms.Urology.2007 Aug;70(2): 385~90ページ (doi:10.1016 / j.urology.2007.03 .025);and Chang SS,Reuter VE,Heston WD,B ander NH,Grauer LS,Gaudin PB.Five differ ent anti-prostate-specific membrane anti gen(PSMA)antibodies confirm PSMA express ion in tumor-associated neovasculature.C Ancer Res.1999 Jul 1;59(13):319See pages 2-8 each of which is incorporated herein by reference.

[0060] A few ligands have been evaluated in patients, and early tumor responses have been promising, but the parotid and salivary glands These compounds localize to the lacrimal glands and kidneys, resulting in dose-limiting toxicity and It causes adverse events that affect quality of life.

[0061] In the absence of stable isotopes of astatine, iodine has been used as a surrogate for drug development and It has been used to predict radiation dosimetry. In recent studies, e.g., by ref. Kiess AP, Minn I, Vaidyanathan, incorporated herein by reference. G. et al. (2S)-2-(3-(1-Carboxy-5-(4-[ 211 At] a statobenzamido)pentyl)ureido)-pentanedio ic acid for PSMA-targeted α-particle rad iopharmaceutical therapy.J Nucl Med.2016 ;57:1569-1575, small molecule PSMA inhibitors 131 I -DCIBzL and its astatine analog (2S)-2-(3-(1-carboxy- 5-(4- 211 At-astatobenzamido)pentyl)ureido)-pentanedioic acid ( " 211 It was confirmed that the pharmacokinetics of α- and α-At-6 were similar in preclinical prostate cancer models. It was.

[0062] The promise of dose-limiting toxicities with PSMA-targeted radiation therapy is noteworthy PSMA is expressed at low levels in the parotid and lacrimal glands, and recent studies have shown that it is expressed in PM PA was extracted from the salivary glands of rats. 68 Used to expel Ga-PSMA-HBED-CC It has been reported that it has been shown that it is possible to O'Keefe DS, Bacich DJ, Heston WDW.Compa rative analysis of prostate-specific mem brane antigen(PSMA)versus a prostate-spe cific membrane antigen-like gene.Prostat e.2004;58:200-210 and Wustemann T, Nikol opoulou A,Amor-Coarasa A,ra Protecting sa livary glands:displacement of off-target bound prostate-specific membrane antigen n ligands.Eur J Nucl Med Mol Imaging.201 See 6:43(Suppl 1):S15. These findings suggest that these structures These results suggest that radiopharmaceutical uptake in the tumour is PSMA-mediated.

[0063] Indeed, the dose-limiting toxicity to the salivary glands is 131 About I-MIP-1095 High renal uptake was also observed in mice. 131 About I-MIP-1095 This was suspected to be dose-limiting during early clinical evaluation of the monotherapy cycle in humans. Zechman, incorporated herein by reference. n CM, Afshar-Oromieh A, Armour T, et al. Radiatio n dosimetry and first therapy results wi th a 124 I / 131 I-labeled small molecule (MI P-1095)targeting PSMA for prostate cancer r therapy.Eur J Nucl Med Mol Imaging.201 4;41:1280-1292. Moderate dry mouth 177 Lu -PSMA-617 has been reported, but the use of this ligand in targeted α-particle therapy has not been reported. 225 Conversion to Ac-PSMA-617 resulted in severe and persistent xerostomia. Kratochwil C, Giesel FL, St efanova M, et al. PSMA-Targeted Radionuclide T therapy of Metastatic Castration-Resistan Prostate Cancer with 177 Lu-Labeled PSM A-617.J Nucl Med.2016;57:1170~1176 pages,Fe ndler WP, Reinhardt S, Ilhan H, et al. Prelimina ry experience with dosimetry,response an d patient reported outcome after 177 Lu-P SMA-617 therapy for metastatic castratio n-resistant prostate cancer.Oncotarget.2 017;8:3581-3590 and Kratochwil C, Bruche rtseifer F, Giesel FL, et al. 225 Ac-PSMA-617fo r PSMA targeting alpha-radiation therapy of patients with metastatic castration- resistant prostate cancer.J Nucl Med.201 See pages 6;57:1941-1944.

[0064] The technology of the present invention provides high affinity and potent agonist for PSMA with the aim of providing a higher therapeutic index. It shows suitable affinity for human serum albumin (HSA) and is suitable for targeted alpha therapy (TAT). Therefore, compounds suitable for the treatment of PSMA-expressing cancers (also referred to herein as (also referred to as "dual-targeting constructs," "dual-targeting compounds," and "dual-targeting ligands") The technology of the present invention is particularly suitable for treating prostate cancer. Compositions incorporating such compounds are also included as methods related to the treatment of current cancers. Furthermore, the present technology provides a dual targeting construct for tumors presenting PSMA. The incorporation of therapeutic agents, such as human serum albumin constructs, can be enhanced by modifying the human serum albumin binding moiety of such agents. The present invention provides a method for enhancing the activity of the hydroxybenzoates by

[0065] Thus, in one embodiment, a compound according to formula I

[0066] [ka] or a pharmaceutically acceptable salt thereof (wherein X 1 teeth, 124 I, 125 I, 127 I, 131 I, 211 At, or Sn(R 4 )3;R 1 , R 2 , and R 3 are, respectively independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl; ;R 4 is independently at each occurrence an alkyl group; n is 1 or 2; m is 0, 1 , 2, or 3). In any embodiment herein, R 1 , R 2 , and R 3 may each independently be H or tert-butyl. 4 teeth and, independently at each occurrence, methyl, ethyl, propyl, propyl, or butyl. In any embodiment herein, when n is 2, m may be any number other than 2. In any embodiment herein, X 1 teeth, 124 I, 125 I, 1 31 I or 211 In any embodiment herein, the formula The compound of I may be a compound of formula Ia or a pharmaceutically acceptable salt thereof:

[0067] [ka]

[0068] In one embodiment, a compound of formula II

[0069] [ka] or a pharmaceutically acceptable salt thereof (wherein X 2 teeth, 124 I, 125 I, 127 I, 131 I, 211 At, or Sn(R 8 )3;R 5 , R 6 , and R 7 are, respectively independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl; ;R 8 is independently at each occurrence an alkyl group; W1 is a bond or -NH-alkylene- and p is 0, 1, 2, or 3. In terms of form, R 5 , R 6 , and R 7 are each independently H or tert-butyl. W 1 is an alkylene having a bond or a carboxylate as a substituent. In any embodiment herein, W 1 is the bond, -NH-CH(C O(O)H)-(CH2)3-, or -NH-CH(CO(O)H)-(CH2)4- In any embodiment herein, R 8 is calculated independently for each occurrence. , methyl, ethyl, propyl, or butyl. In any embodiment, X 1 teeth,124 I, 125 I, 131 I, or 211 At In any embodiment herein, the compound of formula II may be a) or a pharmaceutically acceptable salt thereof.

[0070] [ka]

[0071] In one aspect of the present technology, a compound of Formula I-II and a pharmaceutically acceptable carrier is Compositions comprising any one of the aspects and embodiments are provided. As used herein, "pharmaceutically acceptable carrier" includes carriers and / or excipients. an effective amount of a compound of any one of the compound aspects and embodiments of Formulas I-II and a pharmaceutical composition comprising the compound of formula (I) for treating a condition in which the PSMA is expressed. In further related embodiments, the compounds of Formulas I-II are administering (e.g., administering an effective amount of) any one of the compounds of the present invention ), or an effective amount of a compound of any one of the compound aspects and embodiments of Formulas I-II The method includes administering a pharmaceutical composition comprising the compound to a subject suffering from a PSMA-expressing cancer. The cancer may be glioma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, Metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colon cancer The cancer may include one or more of rectal adenocarcinoma, renal cell carcinoma, and prostate cancer. It may also include prostate cancer that is resistant to removal of the lesion.

[0072] "Effective amount" refers to the amount of a compound or composition required to produce a desired effect. One example of an effective dose is a therapeutic (pharmaceutical) dose, including, but not limited to, the treatment of cancer, such as prostate cancer. ) For use, the amount or dose that results in acceptable levels of toxicity and bioavailability Another example of an effective amount is a dose that reduces symptoms associated with cancer, e.g., a dose that reduces the amount of cancer in circulation. As used herein, the term "amount" includes an amount or dosage that can reduce the number of cells. A "subject" or "patient" is a mammal, such as a cat, dog, rodent, or primate. Typically, the subject is a human, preferably a patient with a PSMA-expressing cancer, such as prostate cancer. A human suffering from or suspected of suffering from adenocarcinoma, etc. "Patient" may be used interchangeably.

[0073] Thus, the present technology provides compounds disclosed herein (e.g., compounds of Formulas I-IV). and one or more (total of) a pharmaceutically acceptable carrier or excipient or filler. Generally, such carriers, excipients, fillers, etc. are referred to as "carriers," "excipients," "fillers," etc., unless a more specific term is used. Pharmaceutical compositions and pharmaceutical compositions containing either a pharmaceutically acceptable carrier (hereinafter referred to as a "pharmaceutically acceptable carrier") The compositions can be used in the methods and treatments described herein. Such compositions and medicaments may be used to treat one or more of the conditions described herein. and any of the compounds described herein, including but not limited to compounds of Formulas I-II, for The pharmaceutical composition may also be packaged in a unit dosage form. For example, the unit dosage forms, when administered to a subject in need thereof, do not express PSMA. Such PSMA-expressing cancers include glioma, cervical cancer, and , vulvar cancer, uterine cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer one or more of the following cancers: primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer includes plural.

[0074] The pharmaceutical compositions and medicaments are associated with cancers that express PSMA, such as prostate cancer. One or more compounds of the present technology, their pharmaceutical compositions, and the like, can be used to prevent and treat disorders. physiologically acceptable salts thereof, their stereoisomers, their tautomers, or their solvates by mixing the substance with a pharmaceutically acceptable carrier, excipient, binder, diluent, or the like. The compounds and compositions described herein can also be used to treat cancers such as those described above. It may also be used to prepare formulations and medicaments for preventing or treating various disorders related to Such compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, etc. The formulation may be in the form of a preparation, injection, emulsion, elixir, suspension or solution. The compositions of the present invention can be administered, for example, orally, parenterally, topically, rectally, intranasally, intravaginally, or The compounds can be formulated for various routes of administration, such as parenteral or by implanted reservoirs. Oral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injection. The following dosage forms are provided by way of example only and should not be construed as limiting the scope of the present invention. No.

[0075] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules Capsules, gelcaps, and caplets are acceptable solid dosage forms. , for example, one or more compounds of the present technology, or pharmaceutically acceptable salts thereof. or their tautomers with at least one additive such as starch or other additives. Suitable additives include sucrose, lactose, Cellulose sugars, mannitol, maltitol, dextran, starch, agar, algin Acid salts, chitin, chitosan, pectin, gum tragacanth, gum arabic, gelatin, cola The sugars may be lactic acid bacteria, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, the oral dosage form may contain other ingredients to aid in administration, such as an inert diluent. or lubricants, such as magnesium stearate, or preservatives, such as parabens or sorbic acid, or antioxidants, e.g., ascorbic acid, tocopherol or cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavorings or fragrances Tablets and pills may contain any suitable coating known in the art. It may be further treated with a coating material.

[0076] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, syrups, The formulations may be in the form of pharmaceutical preparations, elixirs, suspensions, and solutions, which may be prepared by adding an aqueous or other insoluble component. Active diluents may also be included. Pharmaceutical formulations and medicaments may contain, for example, oil, water, alcohol, etc. Suspension using sterile liquids such as, but not limited to, It may also be prepared as a suspension or solution. A saturating agent may be added for oral or parenteral administration.

[0077] As mentioned above, the suspension may also contain an oil. Such oils include peanut oil. oil, including, but not limited to, sesame oil, cottonseed oil, corn oil, and olive oil. Suspension formulations may be prepared using esters of fatty acids, e.g., ethyl oleate, isomyristate, It contains propyl, fatty acid glycerides and acetylated fatty acid glycerides. The suspension formulation may also be prepared by dissolving the liquid in an alcohol, such as ethanol or isopropyl alcohol. , hexadecyl alcohol, glycerol, and propylene glycol. Examples of suitable polymers include, but are not limited to, poly(ethylene glycol). Petroleum hydrocarbons, including but not limited to ether, mineral oil, and petrolatum; and water suspension formulations It may be used in

[0078] Injectable dosage forms are generally prepared using suitable dispersing or wetting agents and suspending agents. Injectable forms include aqueous or oily suspensions that can be prepared in solution or suspension form. It may be in the form of a solvent or diluent, which is prepared using an acceptable solvent or diluent. Vehicles include sterile water, Ringer's solution, or isotonic saline solution. Alternatively, sterile oils may be used as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile and may be natural or synthetic. Contains natural oils, fatty acids, mono-, di- or triglycerides.

[0079] For injection, the pharmaceutical formulation and / or medicament is reconstituted with a suitable solution as described above. Examples of these include freeze-dried, rotary-dried, and powders suitable for use in pharmaceutical preparations. or spray dried powders, amorphous powders, granules, precipitates, or particles, which For injection, the formulation may contain stabilizers, pH modifiers, surfactants, bioagents, etc. Availability modifiers and combinations thereof may also optionally be included.

[0080] The compounds of the present technology may also be administered to the lungs by inhalation through the nose or mouth. Pharmaceutical formulations suitable for inhalation may be prepared by mixing any suitable solvent and optionally, for example, Stabilizers, antimicrobials, antioxidants, pH modifiers, surfactants, bioavailability modifiers and and combinations thereof. , spray, dry powder, or aerosol. Carriers and stabilizers are used to Although requirements vary, typically nonionic surfactants (Tween, Pluronic, or (polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or Contains sugar alcohols. Aqueous and non-aqueous (e.g., propellants in fluorocarbons) air Aerosols are typically used to deliver the compounds of the present technology by inhalation.

[0081] Dosage forms for topical (including buccal and sublingual) or oral administration of the compounds of the present technology Dermal administration can be in the form of powders, sprays, ointments, pastes, creams, lotions, gels, The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier or The powders may be mixed with excipients, and any preservatives or buffers that may be required. and sprays, for example, containing excipients such as lactose, talc, silicic acid, aluminum hydroxide. aluminum, calcium silicate and polyamide powder, or a mixture of these materials. Ointments, pastes, creams and gels can be prepared using excipients such as Animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and The present invention may also include an absorption enhancer such as zinc oxide, zinc nitrite, or a mixture thereof. Such compositions can be used to increase the flux of compounds of the invention across the skin. The flux can be controlled by either providing a rate-controlling membrane (e.g., as part of a transdermal patch) or by It can be controlled by either dispersing it in a polymer matrix or in a gel. do.

[0082] In addition to these exemplary dosage forms described above, pharmaceutically acceptable excipients and carriers may be used. Such structures are commonly known to those skilled in the art and are therefore included in the technology of the present invention. Excipients and carriers are described, for example, in "Remington s Pharmaceutical Sciences” Mack Pub.Co., It is described in New Jersey (1991).

[0083] The formulations of the present technology may be short-acting, fast-releasing, long-acting, or The pharmaceutical formulations can also be designed to be fast-acting and sustained-release. They may also be formulated for controlled release or delayed release.

[0084] The compositions of the present invention may be, for example, micelles or liposomes, or some other capsule. The compound may also include an encapsulated form or may be administered in a sustained release form for extended storage and / or administration. Therefore, the pharmaceutical formulation and the medicament may be provided in the form of pellets or It is compressed into a cylinder and delivered intramuscularly or subcutaneously as a depot injection or as an implant such as a stent. Such implants may be implanted as a graft. Known inert materials such as degradable polymers may also be used.

[0085] The specific dosage will vary depending on the disease state, the subject's age, weight, general health, sex, and diet. , can be adjusted depending on the dosage interval, route of administration, excretion rate, and drug combination. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation, and therefore, This is well within the skill of the present invention.

[0086] One skilled in the art would be able to administer a compound of the present technology to a patient, for example, until the tumor size is reduced. Effective amounts can be easily determined by simply administering increasing amounts. The compounds of the technology are administered to patients at dosage levels ranging from about 0.1 to about 1,000 mg per day. For a normal human adult weighing approximately 70 kg, a dose of 1 kg of body weight is Dosages in the range of about 0.01 to about 100 mg per day are sufficient. The particular dosage used can be varied as deemed appropriate by those skilled in the art. For example, dosage may be adjusted depending on the needs of the patient, the condition being treated, This may depend on many factors, including the severity and pharmacological activity of the compound used. Determination of optimal dosages for a subject is well known to one of ordinary skill in the art.

[0087] Various assays and model systems are available to determine the therapeutic efficacy of treatments according to the technology of the present invention. It can be easily used to determine

[0088] The efficacy of the compositions and methods of the present technology has been demonstrated in PSMA-expressing cancer conditions. reduction in the volume of tumors, such as those associated with prostate cancer. The effectiveness of the compositions and methods of the present technology may be seen in the number of circulating cancer cells. This can also be indicated by a decrease in

[0089] For each of the indicated conditions described herein, test subjects were treated with a placebo. the degree of variability caused by or associated with the disorder in the subject compared to controls or other suitable control subjects or one or more of the symptoms associated with it, 10%, 20%, 30%, %, 50% or more, 75-90% reduction, or 95% or more reduction It will be.

[0090] The compounds of the present technology are effective in treating cancers that express PSMA, such as prostate cancer. It may also be administered to a patient along with other conventional therapeutic agents that may be useful. The pharmaceutical compositions of the present technology may further comprise an anti-cancer agent different from the compounds of Formulas I-II. Administration can include oral administration, parenteral administration, or intranasal administration. In some embodiments, administration may include subcutaneous, intravenous, intraperitoneal, or intramuscular injection. In any of these embodiments, administration can also include oral administration. The method of the present invention may involve the administration of one or more compounds of the present technology together with conventional therapeutic agents, either sequentially or in combination. or in combination for the treatment of PSMA-expressing cancers, such as prostate cancer. It can also include administering in amounts that may be potentially or synergistically effective.

[0091] In one embodiment, the compounds of the present technology are administered to a patient in an amount or doses appropriate for therapeutic use. Generally, a unit dosage containing a compound of the present technology is administered according to the patient's needs. Such considerations may vary depending on, for example, age, protocol, condition, This includes gender, extent of disease, contraindications, concurrent therapy, etc. An exemplary unit dose based on these considerations is: The dosage can also be adjusted or modified by a physician skilled in the art. , the unit dosage containing the compound of the present technology is 1×10 -4 g / kg to 1g / kg, preferably Preferably 1 x 10 -3 The range of the present invention can be varied from 1.0 g / kg to 1.0 g / kg. The dosage of the compounds of the technology is from 0.01 mg / kg to 100 mg / kg or, preferably, , can vary from 0.1 mg / kg to 10 mg / kg.

[0092] The compounds of the present technology may be used in a variety of applications, including those with poor pharmacokinetic properties, toxicity, or bioavailability (e.g., For example, covalent attachment of organic moieties to improve the solubility (e.g., increased in vivo half-life) of the compound. The conjugates may be linear or branched. The polymeric group may be, for example, a hydrophilic polymeric group, a fatty acid group, or a fatty acid ester group. For example, modifications may be made to improve pharmacokinetic properties, toxicity, or bioavailability. Exemplary conjugates may each comprise a molecular weight of about 8 to about Polyalkane glycols (e.g., polyethylene glycols) which may independently contain 70 carbon atoms. Polyethylene glycol (PEG), polypropylene glycol (PPG), carbohydrate polymers , an amino acid polymer or polyvinylpyrrolidone and a fatty acid or fatty acid ester group The conjugate may include polyethyleneamine (PEI), polyglycine, Hybrids of PEI and polyglycine, polyethylene glycol (PEG) or The compounds of the present invention may also contain mPEG. In one embodiment, the conjugate for use with The compounds of the present technology and their applications and related techniques can be improved. Other exemplary conjugates for use are described in U.S. Pat. No. 6,429,629, which is incorporated herein by reference. Including those generally described in U.S. Pat. No. 5,672,662.

[0093] The techniques of the present invention involve the administration of a target of interest in a detectable or imageable amount of the techniques of the present invention. The present invention provides a method for identifying a target of interest comprising contacting a target with a compound of the present invention. A detectable or imageable amount is the amount of material needed to be detected by the detection method chosen. For example, a detectable amount is a detectable amount of a compound of the present invention. For example, glioma, cervical cancer, vulvar cancer, uterine cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, Cellular lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma and / or against targets of interest, including but not limited to prostate cancer. The dosage may be sufficient to allow detection of the binding of the labeled compound. Upon binding of the compound to the target of interest, the target may be isolated, purified, and used in accordance with the techniques of the present invention. Further studies can be carried out, such as by determining the amino acid sequence of the protein to which the therapeutic compound binds. It can be characterized as:

[0094] The terms "associated with" and / or "binding" refer to, for example, the binding of a compound to a compound of the present technology. It can refer to a chemical or physical interaction between the target and the target. Examples of interactions are covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, and hydrophobic-hydrophobic interactions. These include interaction and complexation. Each describes a different chemical or physical interaction. "Binding" or "affinity" can also be referred to generally when used to describe Measurement of binding or affinity is also routine for those skilled in the art. The compounds may be any of the targets or precursors of interest, parts, fragments and peptides thereof, and and / or their deposits.

[0095] In one embodiment, a treatment for tumors presenting prostate-specific membrane antigen ("PSMA") is provided. A method for enhancing uptake of a therapeutic agent is provided, the method comprising administering a PMSA targeting moiety and a radioactive A first therapeutic agent comprising a human serum albumin binding moiety containing a nuclide is administered to a patient expressing PSMA. administering to a subject having one or more cancer tumors; a first therapeutic agent in the subject detecting the distribution of the first therapeutic agent; and modifying the first therapeutic agent to provide a second therapeutic agent. The second therapeutic agent may, of course, have a structure different from that of the first therapeutic agent. Thus, the second therapeutic agent may contain the same PMSA targeting moiety and a second human targeting moiety as the first therapeutic agent. The PMSA targeting moiety may be described as comprising a serum albumin binding moiety. It may contain a urea-glutamate moiety or a glutamate-urea-lysine moiety. SMA-expressing cancers include glioma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, Metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colon cancer The cancer may be one or more of rectal adenocarcinoma, renal cell carcinoma, and prostate cancer. It may also be a prostate cancer that is resistant to removal of the lesion.

[0096] The human serum albumin binding moiety is 124 I-substitution, 125 I-substitution, 131 I-substitution, or 211 It may also contain an At-substituted phenyl moiety. Human serum albumin binding moiety is 4-( 124 I)-substitution, 4-( 125 I)-substitution, 4-( 131 I)-Substitution, or is 4-( 211 It may also contain (At)-substituted phenyl moieties. Human serum albumin binding The moiety may also include 1,4-phenylene, the group at the 4-position being 124 I, 125 I, 131 I, or 211 In any embodiment herein, The step of modifying one therapeutic agent may involve lengthening or modifying the carbohydrate chain of the human serum albumin binding moiety. The step of modifying the first therapeutic agent may include shortening the first therapeutic agent. Glycols (e.g., polyethylene glycol (PEG), polypropylene glycol) Polypropylene glycol (PPG), methoxypolyethylene glycol (mPEG), polyethyleneamine ( PEI), polyglycine, hybrid of PEI and polyglycine, carbohydrate polymer, amino acid polymer, polyvinylpyrrolidone, fatty acid, and / or fatty acid ester groups, It may also include a step of conjugating to a human serum albumin binding moiety. The conjugation step involves the addition of polyalkane glycol, polyethyleneamine (PEI), poly(ethylene glycol), and poly(ethylene glycol). Glycine, carbohydrate polymers, amino acid polymers, polyvinylpyrrolidone, fatty acids, fats The fatty acid ester group, or any combination of two or more thereof, may be used to bind the PMSA targeting moiety and the human The conjugate may also include a step of inserting the conjugate between the serum albumin binding moiety and the The step of forming a polyalkane glycol, polyethyleneamine (PEI), polyglycerin Carbohydrate polymer, amino acid polymer, polyvinylpyrrolidone, fatty acid, fatty acid ester a tertiary group, or a combination of any two or more thereof, attached to a heterocyclic group distal to the PMSA targeting moiety The method may also include conjugating the antibody at the site of the antibody's serum albumin binding moiety. In any embodiment herein, the first therapeutic agent is a compound of Formula I or II. In any embodiment herein, the second therapeutic agent may be a compound of Formula I or I It may also be a compound of formula I.

[0097] The method includes administering a second therapeutic agent to a subject having one or more cancer tumors that express PSMA. administering the second therapeutic agent to an animal; and detecting distribution of the second therapeutic agent in the subject. The modification of the first therapeutic agent may allow the second therapeutic agent to interact with non-tumor tissue of the subject. In comparison, the compound exhibited higher tumor uptake than that exhibited by the first therapeutic agent. In any embodiment of the above method, the step of administering the first therapeutic agent can be administered intravenously. and / or parenteral administration, such as intra-arterial administration.

[0098] The examples herein are provided to illustrate the advantages of the teachings of the present invention and to enable those skilled in the art to understand the present invention. The compounds or salts of the technology, pharmaceutical compositions thereof, derivatives, solvates, metabolites, prodrugs, The present invention is provided to further aid in the preparation or use of compounds, racemic mixtures, or tautomeric forms. The examples herein are provided to more fully illustrate preferred embodiments of the present technology. The examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise specified. The examples should not be construed as limiting the scope of the present invention in any way. It may include or incorporate any of the variations or aspects described above. The embodiments each further include any or all other variations or variations of the embodiments of the present technology. or may be incorporated. [Example]

[0099] General synthesis and analytical details: All solvents were purchased from Sigma Aldrich and used according to reagent standards unless otherwise noted. The solvent was purified by filtration through an activated stainless steel column (Pure Process Technology, LLC) column or activated by distillation The samples were either dehydrated over molecular sieves or dehydrated over 1000 ml of water. Reagents were purchased from Sigma A. The reagents were purchased from Idrich or Alfa Aesar and were of reagent grade. All reactions described were carried out in dry glassware. Purification was carried out using VWR (registered trademark) ) using silica chromatography on high-purity silica gel 60Å or CombiF Flash chromatography using lashRf+ (Teledyne Isco) Preparative HPLC was performed using an XBridge™ Preparative C18 5 μm OB A D™ 19 x 100 mm column (Waters) was inserted into an Agilent ProStar Dual-pump Agilent ProS with 325 dual-wavelength UV-Vis detector The analysis was carried out using tar HPLC. UV absorption was monitored at 220 nm and 280 nm. In a binary solvent system, solvent A contained H2O + 0.01% TFA and solvent B contained 90% v Solvent B was composed of / vMeCN / H2O + 0.01% TFA. Purification was carried out according to the following procedure. Gradient HPLC method: 0% B for 0-1 min, 0-100% B for 1-28 min, 100-0% The final product was purified by thin layer chromatography (TLC) at a flow rate of 12 mL / min for 28-30 min. Identification and characterization using HPLC, analytical HPLC, mass spectrometry and NMR spectroscopy. Analytical HPLC was performed using an XSelect™ CSH™ C18 5 μm column. A 4.6 × 50 mm column (Waters) was used at a flow rate of 2 mL / min, and a gradient of 0 to 100% B was performed. Mass determination was performed using a Waters SQ De Waters ACQUITY UPLC® coupled with the tector2 NMR analysis was performed using a Bruker Avance I The measurements were performed using a 11 500 MHz spectrometer. Spectra are reported as ppm. , solvent in DMSO-d6 or chloroform-d (Sigma Aldrich) The purity of all compounds assessed by biological assay was determined by LC -MS and 1 It was >95% pure as determined by 1 H NMR.

[0100] Representative Synthesis of Compounds of the Present Technology. A representative synthetic procedure is shown in Scheme 1 below. In the exemplary compounds of the present invention, the use of iodine and / or radioactive iodine is not related to the use of radioactive halogens. 2 11 It should further be understood as a surrogate for At. Kelly, J.M., Amor-Coarasa, A., Nikolopoulo. u, A., Wustemann, T., Barelli, P., Kim, D., Will. iams, C. Jr., Zheng, X., Bi, C., Hu, B., Warren, J. D., Hage, D.S., DiMagno, S.G., and Babich, J.W. .Double Targeting Ligands with Modulated Pharmacokinetics for Endoradiotherapy o f Prostate Cancer,J.Nucl.Med.(April 27,2 017)(doi:10.2967 / jnumed.116.188722) sea ​​bream.

[0101] [ka] The synthesis of exemplary compounds is shown below.

[0102] Di-tert-butyl (((S)-6-amino-1-(tert-butoxy)-1-o (hexohexan-2-yl)carbamoyl)-L-glutamate (EuK.3OtBu) ( 1) The title compound is prepared as described in Maresca KP, Hill, J. Med., 1999, 14, 130-132, which is incorporated herein by reference. ier SM,Femia FJ,Barone DKC,Joyal JL,Zimm erman CN, Kozikowski AP, Barrett JA, Eckelm an WC,Babich JW.A series of halogenated heterodimeric inhibitors of prostate spe cific membrane antigen(PSMA)as radiolabe led probes for targeting prostate cancer J. Med. Chem. 2009;52:347-357 The synthesis was carried out according to the method described in the literature. mol) was suspended in CH2Cl2 (20 mL) at 0 °C and stirred under Ar. The suspension was treated with DMAP (50 mg, 0.4 mmol) and NEt3 (3.6 mmol). L, 25.7 mmol) was added. The resulting mixture was stirred for 5 min at 0 °C. Then CH Fine 2-carbonyldiimidazole (1.78 g, 11 mmol) in Cl2 (15 mL) A suspension of l) was added and the reaction was allowed to warm to room temperature with stirring under Ar overnight. It was then diluted with CH Dilute with 2Cl2 (30 mL) and add saturated NaHCO3 solution, HO (×2) and saturated N The organic fraction was dried over MgSO4, filtered, and concentrated under reduced pressure to give a clear, crystalline toluene solution. A clear oil was formed. The crude product was purified by flash chromatography (EtOAc / Hexane 0-10% EtOAc over 12 min, then 10-30% EtOAc over 12-16 min , then 30% EtOAc in 16-20 min) and purified by di-tert-butyl (1H- Imidazole-1-carbonyl)-L-glutamate (Eu.2OtBu) was dissolved in a clear oil (2.14 g; 61%).

[0103] Compound Eu.2OtBu (293 mg, 0.83 mmol) in 1,2-dichloroethane To a solution cooled to 0 °C in (6 mL) was added MeOTf (93 μL, 0.85 mmol) and and NEt3 (237 μL, 1.70 mmol) were added, and the resulting mixture was heated at 27°C for 30 min. The mixture was stirred under RT. Next, H-Lys(Z)-OtBu HCl (310 mg, 0.83 mmHg) was added. ol) was added in one portion and the reaction was stirred for 4 hours at 40°C. It was then cooled to room temperature and The crude product was concentrated under reduced pressure and dissolved in CH2Cl2 (15 mL) and diluted with 1% v / v AcO The mixture was washed with HCl, dried over MgSO4, filtered, and concentrated under reduced pressure to give an oil. Purification by column chromatography (EtOAc:hexane = 1:1) gave tri-te rt-Butyl(9S,13S)-3,11-dioxo-1-phenyl-2-oxa-4, 10,12-triazapentadecane-9,13,15-tricarboxylate (EuK( Z).3OtBu) was obtained as a colorless oil that partially solidified upon standing (28 4mg; 55%).

[0104] EuK(Z).3OtBu (284 mg, 0.46 mmol) in EtOH (6 mL) To this solution was added 10% palladium on carbon (8 mg). The suspension was heated to 40°C and The reaction was stirred overnight under an atmosphere of H. The reaction was then cooled to room temperature and filtered through Celite. The Celite was washed with MeOH and the combined organic layers were concentrated under reduced pressure to give EuK.3Ot Bu(1) was obtained as a colorless oil (95 mg; 44%).

[0105] Di-tert-butyl (((S)-5-amino-1-(tert-butoxy)-1-o (hexopentan-2-yl)carbamoyl)-L-glutamate (EuO.3OtBu) ( 2) MeOTf (248 μL, 2.27 mmol) and NEt (700 μL, 5.00 A solution of 794 mg (2.25 mmol) of 1,2-dichloroethane (3 mL) A solution of Eu.2OtBu in 1,2-dichloroethane (7 mL) was heated at 0 °C under Ar The mixture was stirred at 0°C for 30 min, and then MeOTf (124 μL, 1.14 The resulting mixture was stirred for an additional 30 min at 0° C., and then H-Orn( Z)-OtBu·HCl (807 mg, 2.25 mmol) was added in one portion to the reaction mixture. The mixture was heated at 40° C. for 3 hours. It was then cooled to room temperature and washed with H2O. The organic layer was The oil was dried over 1000 ml of SO4, filtered and concentrated under reduced pressure to give a colorless oil. Chromatography (50% EtOAC to 100% EtOAc in hexanes over 15 min) The product, tri-tert-butyl(8S,12S)-3,10-dioxo -1-phenyl-2-oxa-4,9,11-triazatetradecane-8,12,14- The tricarboxylate (EuO(Z).3OtBu) was obtained as a clear oil (950 mg ;69%). 1 H NMR (500 MHz, CDCl3) δ 7.35-7.30 (m, 5H), 5.13 (m, 3H), 5.09 (s, 2H), 4.34 (m, 2H), 3.21 (m, 2H), 2.30 (m, 2H), 2.09 (m, 1H), 1.86 (m, 2H), 1.66 -1.56 (m, 3H), 1.45 (s, 18H), 1.44 (s, 9H). ESI(+) = 608.5 [M+H] + Calculated mass: 6 07.8

[0106] EuO(Z).3OtBu (950mg, 1.56mmol) was added to EtOH (10mL ) and transferred to a round-bottom flask containing 10% palladium on carbon (12 mg). The turbid solution was stirred overnight at room temperature under an atmosphere of H2 and then filtered through Celite. Washed with MeCN and concentrated the combined organic fractions under reduced pressure. (2) was isolated as a white foam (600 mg; 81%). 1 H NMR (500 MHz, CDCl3) δ 8.20 (br s, 2H), 6.43 (d, 1H, J=7.7 Hz), 6.28 (d, 1H, J= 8.1 Hz), 4.35 (m, 2H ), 3.10 (m, 2H), 2.34 (m, 2H), 2.07 (m, 2H), 1.85 (m, 4H), 1.45 (s, 18H), 1.43 ( s, 9H). ESI(+) = 474.6 [M+H] + Calculated mass: 473.3

[0107] (S)-5-(tert-butoxy)-4-(3-((S)-1,5-di-tert- Butoxy-1,5-dioxopentan-2-yl)ureido)-5-oxopentanoic acid ( EuE.3OtBu)(3) Eu.2OtBu (200 mg, 0.57 mmol) in 1,2-dichloroethane (8 m To a solution of MeOTf (66 μL, 0.60 mmol) in 1,2-dichloro-2,4-dichloro-1,4 ... -solution in dichloroethane (1 mL) and NE in 1,2-dichloroethane (1 mL) t3 (158 μL, 1.13 mmol) was added. The resulting mixture was stirred under Ar for 30 min. The mixture was then heated to room temperature and H-Glu(OBzl)-OtBu.HCl (188 mg, 0 0.57 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 3 hours. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give a clear oil. , EuE(OBz).3OtBu (240 mg; 73%) was obtained, which was further purified It was used without 1 H NMR (500 MHz, CDCl3) δ 7.38-7.32 (m, 5H), 5.12 (d, 2H, J=3.0 Hz), 5.03 (m, 2H), 4.37 (m, 1H), 4.32 (m, 1H), 2.53-2.21 (m, 4H), 2.11 (m , 1H), 2.04 (m, 1H), 1.92 (m, 1H), 1.85 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H), 1.4 4 (s, 9H). ESI(+) = 579.6 [M+H] + Calculated mass: 578.3 Dissolve EuE(OBz).3OtBu (210 mg, 0.36 mmol) in EtOH (5 mL To a solution of 10% palladium on carbon (14 mg) was added while N2 was passed through the solution. The suspension was stirred under an atmosphere of H2 for 4 hours and then filtered through Celite. , and concentrated under reduced pressure to give EuE.3OtBu (3) as a colorless oil (178 mg; 9 9%). 1 H NMR (500 MHz, CDCl3) δ 4.37 (m, 1H), 4.29 (m, 1H), 2.40 (m, 2H), 2.2 9 (m, 2H), 2.14 (m, 1H), 2.07 (m, 1H), 1.85 (m, 2H), 1.46 (s, 9H), 1.44 (s, 9H), 1.42 (s, 9H). ESI(+) = 489.4 [M+H] + Calculated mass: 488.3

[0108] (((S)-1-carboxy-5-(4-(4-iodophenyl)butanamide)pentaerythritol) (ethyl)carbamoyl)-L-glutamic acid (RPS-005) 90 mg (185 μmol) of EuK.3OtBu(1) in CH2Cl2 (5 mL) To a solution of 4-(4-iodophenyl)butanoic acid (54 mg, 185 μmol) and E A solution of DC (34 mg, 221 μmol) in CH2Cl2 (5 mL) was added. The mixture was stirred for 10 min, and then DIPEA (38 μL, 221 μmol) was added to the reaction mixture. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with CH2Cl2 (10 mL) and diluted with 1N HCl The mixture was washed with HCl (10 mL), saturated NaHCO3 (10 mL), and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude product. Purification by column chromatography (0-100% EtOAc in hexanes) gave EuK -IPBA.3OtBu (4) was isolated as a white solid (96 mg, 68%). 1 H NMR (500 MHz, CDCl3) δ 7.54 (d, 2H, J=8.1 Hz), 6.91 (d, 2H, J=8.1 Hz), 6.67 (m, 1H ), 5.81 (d, 1H, J=8.1 Hz), 5.58 (d, 1H, J=7.7 Hz), 4.30 (m, 1H), 4.18 (m, 1H), 3 .23 (m, 1H), 3.13 (m, 1H), 2.56 (t, 2H, J=7.6 Hz), 2.29 (m, 2H), 2.18 (t, 2H, J= 7.4 Hz), 2.05 (m, 1H), 1.90 (m, 2H), 1.80 (m, 1H), 1.70 (m, 1H), 1.51-1.44 (m, 3 H), 1.41 (s, 9H), 1.38 (s, 18H), 1.28 (m, 2H). ESI(+) = 760.2 [M+H] + Calculated mass : 759.3

[0109] EuK-IPBA.3OtBu(4) (75 mg, 99 μmol) was dissolved in 2 mL of CH The mixture was dissolved in 1 mL of HCl and 2 mL of TFA and stirred for 3 hours at room temperature. The solvent was then removed under a stream of N2. The crude product was purified by preparative HPLC (15% B to 100% B). The peak corresponding to the product was collected and lyophilized to give RPS-005 as a white solid residue. Isolated (33 mg; 57%). 1 H NMR (500 MHz, DMSO) δ 7.76 (m, 1H), 7.62 (d, 2 H, J=7.7 Hz), 7.01 (d, 2H, J=7.6 Hz), 6.30 (m, 2H), 4.09 (m, 1H), 4.04 (m, 1H), 3.00 (m, 2H), 2.50 (2H), 2.26 (m, 2H), 2.04 (t, 2H, J=7.3 Hz), 1.91 (m, 1H), 1.7 5 (m, 3H), 1.64 (m, 1H), 1.53 (m, 1H), 1.38 (m, 2H), 1.27 (m, 2H). ESI(+) 592.2 = [M+H] + Calculated mass: 591.1

[0110] (((S)-1-carboxy-4-(4-(4-iodophenyl)butanamide)pentaerythritol) (ethyl)carbamoyl)-L-glutamic acid (RPS-020) 4-(p-iodophenyl)butyric acid (93 mg, 0.32 mmol) and HBTU (1 To a stirred suspension of 51 mg (0.40 mmol) in CH2Cl2 (3 mL), A solution of NEt3 (56 μL, 0.40 mmol) in CH2Cl2 (4 mL) was added, The resulting mixture was stirred at room temperature under Ar for 5 min. Then EuO.3OtBu(2) (150 The reaction mixture was terminated by adding a solution of 1 mg (0.32 mmol) of HCl in 3 mL of CH2Cl2. The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography. The product was purified by chromatography (100% hexanes to 100% EtOAc over 12 minutes). EuO-IPBA.3OtBu (5) was isolated as a pale oil (125 mg; 52%). . 1 H NMR (500 MHz, CDCl3) δ 7.59 (d, 2H, J=8.3 Hz), 6.95 (d, 2H, J=8.3 Hz), 6.2 8 (br s, 1H), 5.35 (d, 1H, J=8.2 Hz), 5.30 (d, 1H, J=7.9 Hz), 4.32 (m, 2H), 3.26 (m, 2H), 2.60 (t, 2H, J=7.7 Hz), 2.33 (m, 2H), 2.19 (t, 2H, J=7.5 Hz), 2.07 (m, 1H), 1.95 (quintet, 2H, J=7.3 Hz), 1.83 (m, 1H), 1.75 (m, 1H), 1.60 (m, 1H), 1.5 6 (m, 2H), 1.47 (s, 9H), 1.45 (s, 9H), 1.44 (s, 9H). ESI(+) = 746.5 [M+H] + .Mass Calculated value: 745.3

[0111] EuO-IPBA.3OtBu(5) (30 mg, 40 μmol) was dissolved in 1 mL of CH The mixture was dissolved in 1 mL of HCl and 1 mL of TFA and stirred overnight at room temperature. The solvent was removed under a stream of N2. The crude product was purified by preparative HPLC (15% B to 100% B). The peak corresponding to the product was collected and lyophilized to obtain RPS-020 as a white solid residue. Released (19 mg; 82%). 1H NMR (500 MHz, DMSO) δ 7.83 (t, 1H, J=5.6 Hz), 7. 65 (d, 2H, J=8.3Hz), 7.03 (d, 2H, J=8.3 Hz), 6.36 (d, 1H, J=8.2 Hz), 6.31 (d, 1H , J=8.2 Hz), 4.12 (m, 1H), 4.07 (m, 1H), 3.04 (m, 2H), 2.51 (t, 2H, J=7.7 Hz), 2 .25 (m, 2H), 2.06 (t, 2H, J=7.5 Hz), 1.95 (m, 1H), 1.81-1.66 (m, 4H), 1.53 (m, 1 H), 1.41 (m, 1H). ESI(+) = 578.2 [M+H] + ; ESI(-) = 576.3 [MH] - Calculated mass: 577.1

[0112] (((S)-1-carboxy-4-(3-(4-iodophenyl)propanamide) (butyl)carbamoyl)-L-glutamic acid (RPS-022) 3-(p-iodophenyl)propanoic acid (63 mg, 0.22 mmol) and EDC To a solution of HCl (57 mg, 0.30 mmol) in CH2Cl2 (5 mL), NEt 3 (84 μL, 0.60 mmol) was added, and the reaction mixture was stirred at room temperature under Ar for 30 min. Next, EuO.3OtBu(2) (103 mg, 0.22 mmol) was dissolved in CH2Cl2 (1 mL) was added and the reaction mixture was stirred overnight at room temperature under Ar. It was diluted with 10 mL of CH2Cl2 and washed successively with H2O and saturated NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product as a pale oil. The crude product was purified by flash chromatography (100% hexane to 100% over 20 min). % EtOAc) to give EuO-IPPA.3OtBu (6) as a clear oil. Isolated (87 mg; 53%). 1 H NMR (500 MHz, CDCl3) δ 7.57 (d, 2H, J=8.2 Hz), 6.96 (d, 2H, J=8.2 Hz), 6.61 (br s, 1H), 5.61 (d, 1H, J=8.2 Hz), 5.44 (d, 1H, J =7.8 Hz), 4.34 (m, 1H), 4.23 (m, 1H), 3.29-3.16 (m, 2H), 2.90 (t, 2H, J=7.8 Hz), 2.46 (t, 2H, J=7.8 Hz), 2.27 (m, 2H), 2.09 (m, 1H), 1.85 (m, 1H), 1.73 (m, 1H), 1.58-1.40 (m, 3H), 1.46 (s, 9H), 1.42 (s, 18H). ESI(+) = 732.4 [M+H] + . Mass calculation Value: 731.3

[0113] EuO-IPPA.3OtBu (6) (7.7 mg, 10.5 μmol) was dissolved in CHCl The mixture was dissolved in 2 (1 mL) and TFA (1 mL) and stirred overnight at room temperature. The crude residue was lyophilized to give RPS-022 as a white solid residue. The compound was obtained (2.5 mg; 42%). 1 H NMR (500 MHz, DMSO) δ 7.84 (t, 1H, J=5.6 Hz), 7.60 (d, 2H, J=8.3 Hz), 7.01 (d, 2H, J=8.3 Hz), 6.34 (d, 1H, J=8.3 Hz), 6.29 (d, 1H, J=8.3 Hz), 4.09 (m, 1H), 4.04 (m, 1H), 3.00 (m, 2H), 2.75 (t, 2H, J=7.8 Hz) , 2.32 (t, 2H, J=7.8 Hz), 2.23 (m, 2H), 1.91 (m, 1H), 1.71 (m, 1H), 1.62 (m, 1H) , 1.49 (m, 1H), 1.38 (m, 2H). ESI(+) = 564.1 [M+H] + ; 562.2 [MH] - Calculated mass: 5 63.1

[0114] (((S)-1-carboxy-4-(2-(4-iodophenyl)acetamide)pentaerythritol) (ethyl)carbamoyl)-L-glutamic acid (RPS-023) 2-(p-iodophenyl)acetic acid (26 mg, 0.10 mmol) and HBTU (5 To a stirred suspension of E uO.3OtBu(2) (50 mg, 0.11 mmol) and NEt3 (19 μL, 0 A solution of 0.13 mmol) in CH2Cl2 (0.5 mL) was added and the resulting mixture was stirred overnight The mixture was stirred at room temperature under Ar. The solvent was removed under reduced pressure and the crude residue was purified by silica chromatography. Purified by (33% EtOAc in hexanes to 100% EtOAc). -IPAA.3OtBu (7) was isolated as a clear oil (48 mg; 67%). 1 H NMR (500 MHz, MeOD) δ 7.58 (d, 2H, J=8.4 Hz), 7.02 (d, 2H, J=8.4 Hz), 4.14 (m, 1H) , 4.09 (m, 1H), 3.39 (s, 2H), 3.14 (t, 2H, J=6.7 Hz), 2.26 (m, 2H), 1.99 (m, 1H) , 1.77 (m, 1H), 1.69 (m, 1H), 1.50 (m, 3H), 1.42 (s, 9H), 1.41 (s, 18H). ESI(+) = 718.4 [M+H] + Calculated mass: 717.3

[0115] EuO-IPAA.3OtBu(7) (10mg, 14μmol) was added to CH2Cl2(1 The mixture was dissolved in 1 mL of HCl and TFA (1 mL) and stirred at room temperature for 4 hours. The crude product was then lyophilized to give RPS-023 as a white solid residue. (6.2 mg; 81%). 1 H NMR (500 MHz, DMSO) δ 8.08 (t, 1H, J=5.4 Hz), 7.64 (d, 2H, J=8.2 Hz), 7.05 (d, 2H, J=8.2 Hz), 6.32 (m, 2H), 4.08 (m, 2H), 3.34 (s, 2H), 3.03 (m, 2H), 2.23 (m, 2H), 1.91 (m, 1H), 1.72-1.62 (m, 2H), 1.51 (m, 1H), 1.41 (m, 2H). ESI(+) = 550.2 [M+H] + ; 548.2 [MH] - Calculated mass: 549.1

[0116] (3S,7S,12S)-21-(4-iodophenyl)-5,10,18-trioxa so-4,6,11,17-tetraazahenicosane-1,3,7,12-tetracarboxylic acid (RPS-025) EuE.3OtBu(3) (140 mg, 0.29 mmol) and EDC·HCl ( A solution of 60 mg (0.32 mmol) in 1,2-dichloroethane (5 mL) was heated at room temperature. The mixture was stirred under Ar for 30 min. Then, H2N-Lys(CBz)-OtBu HCl (108 m g, 0.29 mmol) and NEt3 (126 uL, 0.70 mmol) A fine suspension in chloroethane (5 mL) was added and the mixture was stirred overnight at room temperature under Ar. The reaction mixture was diluted with CH2Cl2 (5 mL) and poured into H2O (10 mL). The layers were separated and the organic layer was washed with saturated NaCl solution, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (11 min. (from 0% to 100% EtOAc in hexanes, then 100% EtOAc for 7 min) Purification yielded tetra-tert-butyl(9S,14S,18S)-3,11,16-trimethyl- Oxo-1-phenyl-2-oxa-4,10,15,17-tetraazaicosane-9 ,14,18,20-tetracarboxylate (EuEK(Z).4OtBu) was used as a transparent Isolated as an oil (94 mg; 41%). 1 H NMR (500 MHz, CDCl3) δ 7.36-7.23 (m, 6 H), 5.93 (d, 1H, J=8.4 Hz), 5.30 (d, 1H, J=8.8 Hz), 5.08 (d, 1H, J=8.7 Hz), 5.06 (s, 2H), 4.43 (m, 1H), 4.35 (m, 1H), 4.24 (m, 1H), 3.16 (m, 2H), 2.29-2.22 (m, 3H), 2.17-2.07 (m, 2H), 2.04 (m, 1H), 1.90 (m, 1H), 1.73 (m, 2H), 1.63 (m, 1H), 1.46-1.39 (m, 4H), 1.45 (s, 9H), 1.44 (s, 9H), 1.42 (s, 9H), 1.41 (s, 9H). ESI(+ ) = 807.8 [M+H] + Calculated mass: 806.5

[0117] EuEK(Z).4OtBu (37 mg, 46 μmol) was dissolved in EtOH (4 mL). Next, 10% palladium on carbon (8 mg) was added and the suspension was stirred overnight under an H2 atmosphere. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give EuEK.4OtBu. was obtained as a clear oil that solidified on standing (24 mg; 78%). 1 H NMR (500 M H z, CDCl3) δ 8.19 (br s, 2H), 7.65 (br s, 1H), 6.27 (m, 2H), 4.32 (m, 2H), 4.10 (m, 1H), 3.06 (m, 2H), 2.39 (m, 2H), 2.33 (m, 2H), 2.02 (m, 1H), 1.96 (m, 1H), 1 ,78 (m, 4H), 1.56-1.39 (m, 4H), 1.44 (s, 18H), 1.42 (s, 18H). ESI(+) = 673.7 [M+ H] + Calculated mass: 672.4

[0118] 4-(p-iodophenyl)butyric acid (580 mg, 2.0 mmol) and N-hydroxybenzoate Dissolve cis-succinimide (345 mg, 3.0 mmol) in CHCl (10 mL). The mixture was cooled to 0 °C under Ar. DCC (620 mg, 3.0 mmol) in CH2Cl2 ( A solution of 4 mL of HCl was added dropwise over 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was filtered to remove the insoluble urea by-product, and the filter cake was purified with CH2Cl The combined organic fractions were concentrated under reduced pressure and the crude product was purified by silica chromatograph. The compound was purified by elution with hexane (EtOAC:hexane=1:1) to give N-succinimidyl 4-(p -iodophenyl)butanoate was obtained as a white solid (400 mg, 52%). 1 H NMR (500 MHz, CDCl3) δ 7.61 (d, 2H, J=8.2 Hz), 6.96 (d, 2H, J=8.2 Hz), 2.85 (br s, 4H), 2.68 (t, 2H, J=7.6 Hz), 2.60 (t, 2H, J=7.3 Hz), 2.04 (quintet, 2H, J=7.4 Hz) ).

[0119] DIPEA (45 μL, 0.25 mmol) in 1,2-dichloroethane (1 mL) The solution was diluted with EuEK.4OtBu (80 mg, 0.12 mmol) and N-succinimide To a solution of diethyl 4-(p-iodophenyl)butanoate (46 mg, 0.12 mmol) The mixture was stirred overnight at room temperature under Ar. The mixture was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography. The product was purified by chromatography (20% to 100% EtOAc in hexanes). EuEK-IPBA.4OtBu (8) was isolated as a clear oil, which reacted with the and solidified (58 mg; 52%). 1 H NMR (500 MHz, CDCl3) δ 7.57 (d, 2H, J=8.2 Hz ), 7.22 (d, 1H, J=7.6 Hz), 6.92 (d, 2H, J=8.2 Hz), 5.91 (m, 2H), 5.32 (d, 1H, J= 8.8 Hz), 4.42 (m, 1H), 4.30 (m, 1H), 4.25 (m, 1H), 3.20 (m, 2H), 2.57 (t, 2H, J= 7.6 Hz), 2.32 (t, 2H, J=7.6 Hz), 2.26 (m, 1H), 2.20-2.10 (m, 5H), 2.03 (m, 1H), 1.94-1.90 (m, 3H), 1.77 (m, 2H), 1.64 (m, 1H), 1.50-1.38 (m, 4H), 1.45 (s, 18H), 1.43 (s, 9H), 1.42 (s, 9H). ESI(+) = 945.1 [M+H] + Calculated mass: 944.4

[0120] EuEK-IPBA.4OtBu (8) (1.9 mg, 2.0 μmol) was dissolved in CHCl The mixture was dissolved in 2 (0.5 mL) and TFA (0.5 mL) and stirred overnight at room temperature. After removal under a stream of N2, the crude product was diluted with H2O and purified by preparative HPLC. The fractions containing the desired product were collected and lyophilized to give RPS-025 as a white powder. Obtained as powder (1.4 mg; 97%) 1 H NMR (500 MHz, DMSO) δ 7.81 (br s, 1H), 7.6 4 (d, 2H, J=8.2 Hz), 7.02 (d, 2H, J=8.2 Hz), 6.56 (s, 1H), 6.37 (m, 2H), 4.12 (m , 3H), 3.02 (m, 2H), 2.51 (t, 2H, J=7.6 Hz), 2.28-2.17 (m, 4H), 2.05 (t, 2H, J=7 .5 Hz), 1.93 (m, 2H), 1.78-1.63 (m, 5H), 1.57 (m, 1H), 1.37 (m, 2H), 1.29 (m, 2H) ). ESI(+) = 721.1 [M+H] + Calculated mass: 720.2

[0121] (((S)-1-carboxy-5-(3-(4-iodophenyl)propanamide) (butyl)carbamoyl)-L-glutamic acid (RPS-026) 3-(p-iodophenyl)propanoic acid (85 mg, 0.308 mmol), HOAt (0.6 M in THF, 0.51 mL, 0.308 mmol) and HATU (175 mg To a solution of Eu (0.461 mmol) in DMF (1 mL) cooled to 0 °C under Ar K. A solution of 3OtBu(1) (150 mg, 0.308 mmol) in DMF (1 mL) The mixture was stirred for 10 min, and then (0.107 mL, 0.615 mmol) D The reaction mixture was stirred for 20 min at 0°C and then stirred for an additional 3 h while warming to room temperature. The mixture was diluted with EtOAc (25 mL) and diluted with 1N HCl, saturated NaHCO3 The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography (0% to 100% in hexanes). EtOAc) to isolate EuK-IPPA.3OtBu(9) as a clear oil. (163 mg, 71%). 1 H NMR (500 MHz, DMSO) δ 7.83 (m, 1H), 7.61 (d, 2H, J=8.0 Hz), 7.00 (d, 2H, J=7.9 Hz), 6.29 (d, 2H, J=6.5 Hz)), 6.20 (d, 2H, J=6.4 Hz), 4.04 (m, 1H), 3.93 (m, 1H), 2.98 (m, 2H), 2.73 (t, 2H, J = 8.2 Hz), 2.31 (t , 2H, J=8.0 Hz), 2.19 (m, 2H), 1.85 (m, 1H), 1.64 (m, 1H), 1.58 (m, 1H), 1.48 (m , 1H), 1.37 (s, 27H), 1.32 (m, 2H), 1.21 (m, 2H). ESI(+) = 746.1 [M+H] + . Mass meter Calculated value: 745.3

[0122] EuK-IPPA.3OtBu(9) (50mg, 67μmol) was added to CH2Cl2(3 The mixture was dissolved in 1 mL of HCl and TFA (3 mL) and stirred at room temperature under Ar for 3 hours. The solvent was removed under a stream of N2 and the crude product was purified by preparative HPLC. The corresponding peak was collected and lyophilized, and RPS-026 was isolated as a white solid residue. (15.5 mg, 40%). 1 H NMR (500 MHz, DMSO) δ 7.80 (m, 1H), 7.61 (d, 2H, J =7.9 Hz), 7.01 (d, 2H, J=8.0 Hz), 6.31 (m, 2H), 4.12 (m, 1H), 4.05 (m, 1H), 2.96 (m, 2H), 2.74 (t, 2H, J=8.1 Hz), 2.32 (t, 2H, J=8.0 Hz), 2.21 (m, 2H), 1.86 (m, 1H), 1.70 (m, 1H), 1.64 (m, 1H), 1.47 (m, 1H), 1.32 (m, 2H), 1.21 (m, 2H). ESI( +) = 578.0 [M+H] + Calculated mass: 577.1

[0123] (((S)-1-carboxy-5-(2-(4-iodophenyl)acetamide)pentaerythritol) (ethyl)carbamoyl)-L-glutamic acid (RPS-027) 2-(p-iodophenyl)acetic acid (81 mg, 0.308 mmol), HOAt(TH 0.6 M in F, 0.51 mL, 0.308 mmol) and HATU (175 mg, 0. To a solution of EuK.3 (461 mmol) in DMF (1 mL) cooled to 0 °C under Ar Add a solution of OtBu (1) (150 mg, 0.308 mmol) in DMF (1 mL). The mixture was stirred for 10 min, and then (0.107 mL, 0.615 mmol) DIPE A was added. The reaction mixture was stirred for 20 min at 0° C. and then warmed to room temperature for an additional 3 h. The mixture was diluted with EtOAC (25 mL) and diluted with 1N HCl, saturated NaHCO The organic layer was dried over Na2SO4, filtered, and reduced. The crude product was purified by flash chromatography (0% to 100% in hexanes). EtOAc) to give EuK-IPPA.3OtBu (10) as a yellow oil. Isolated (167 mg, 74%). 1 H NMR (500 MHz, CDCl3) δ 7.51 (d, 2H, J=8.4 Hz ), 7.09 (br s, 1H), 6.98 (d, 2H, J=8.4 Hz), 6.00 (d, 1H, J=8.4 Hz), 5.70 (d, 1H, J=7.9 Hz), 4.25 (m, 1H), 4.10 (m, 1H), 3.41 (d, 2H, J=5.4 Hz), 3.13-3.07 (m, 2H ), 2.23 (m, 2H), 1.97 (m, 1H), 1.76 (m, 1H), 1.61 (m, 1H), 1.41-1.23 (m, 3H), 1. 37 (s, 9H), 1.33 (s, 18H), 1.21 (m, 2H). ESI(+) = 722.4 [M+H] + Calculated mass: 721. 3

[0124] EuK-IPAA.3OtBu(10) (114mg, 159μmol) in CH2Cl The mixture was dissolved in 2 (0.5 mL) and TFA (0.5 mL) and stirred at room temperature under Ar for 5 h. The solvent was removed under a stream of N2 and the crude product was purified by preparative HPLC. The peak corresponding to the product was collected and lyophilized to obtain RPS-027 as a white solid residue. Released (85 mg, 95%).1 H NMR (500 MHz, DMSO) δ 12.44 (br s, 3H), 8.05 (t, 1H, J=5.5 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.07 (d, 2H, J=8.4 Hz), 6.35 (d, 1H, J=8 .3 Hz), 6.31 (d, 1H, J=8.3 Hz), 4.14-4.05 (m, 2H), 3.36 (s, 2H), 3.03 (m, 2H), 2 .33-2.21 (m, 2H), 1.95 (m, 1H), 1.63-1.57 (m, 2H), 1.49 (m, 1H), 1.41 (m, 2H), 1 .30 (m, 2H). ESI(+) = 563.9 [M+H] + ; 561.9 [MH] - Calculated mass: 563.1

[0125] Di-tert-butyl (((S)-1-(tert-butoxy)-1-oxo-6-( 4-(4-(trimethylstannyl)phenyl)butanamido)hexan-2-yl)carboxamide Bamoyl)-L-glutamate (11) EuK-IPBA.3OtBu(4) (86 mg, 113 μmol) in dioxane (2 To a solution of (SnMe3)2 (92.7 mg, 283 μmol) and PdC l2(PPh3)2 (8 mg, 11.3 μmol) was added and the mixture was stirred under Ar for 90 min. The mixture was heated to 80° C. It was then cooled to room temperature and the solvent was removed under reduced pressure. The crude residue was The mixture was dissolved in H2Cl2 (25 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography (0% to 100% EtOAc in hexanes). The product, EuK-IPBA.SnMe3(11), was isolated as a clear oil. However, it solidified on standing (18 mg; 20%). 1 H NMR (500 MHz, DMSO) δ 7.75 (m, 1H), 7.34 (d, 2H, J=7.4 Hz), 7.13 (d, 2H, J=7.6 Hz), 6.27 (m, 2H), 4.03 (m, 1H), 3.95 (m, 1H), 3.00 (m, 2H), 2.52 (2H), 2.22 (m, 2H), 2.04 (t, 2H, J=7. 4 Hz), 1.85 (m, 1H), 1.76 (quintet, 2H, J = 7.4 Hz), 1.67 (m, 1H), 1.58 (m, 1H), 1.50 (m, 1H), 1.38 (s, 27H), 1.32 (m, 2H), 1.26 (m, 2H), 0.24 (s, 9H). ESI(+) = 798.1 (100%), 796.2 (75%), 794.2 (45%) [M+H] + Calculated mass: 797.4 (100%), 795.4 ( 74.3%), 793.4 (44.6%).

[0126] Di-tert-butyl (((S)-1-(tert-butoxy)-1-oxo-5-( 4-(4-(trimethylstannyl)phenyl)butanamido)pentan-2-yl)carboxamide Bamoyl)-L-glutamate (12) EuO-IPBA.3OtBu (5) (74 mg, 9.9 μmol) in dioxane (3 To a solution of (SnMe3)2 (52 μL, 25.0 μmol) and PdCl2 (PPh3)2 (7 mg, 10.0 μmol) was added and the resulting mixture was heated to 80 °C under Ar. The reaction mixture was then cooled to room temperature and the solvent was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and filtered through Celite. The oil was purified by silica chromatography (50% to 9% in hexane). Upon purification with 0% EtOAc), a colorless oil was isolated, which then precipitated a white solid. The oil was redissolved in CH2Cl2, filtered, and concentrated under reduced pressure to give EuO-IPBA.SnM e3(12) was obtained as a colorless oil (29 mg, 37%). 1 H NMR (500 MHz, DMSO) δ 7.80 9m, 1H), 7.37 (d, 2H, J=7.9 Hz), 7.14 (d, 2H, J=8.1 Hz), 6.32 (d, 1H, J = 7 .6 Hz), 6.24 (d, 1H, J=7.6 Hz), 4.03 (m, 1H), 3.96 (m, 1H), 3.03 (m, 2H), 2.52 ( m, 2H), 2.18 (m, 2H), 2.07 (t, 2H, J=8.0 Hz), 1.86 (m, 1H), 1.77 (m, 2H), 1.66 ( 1.59 (m, 1H), 1.50 (m, 1H), 1.38 (s, 9H), 1.32 (m, 2H), 0.24 (s, 9H) I(+) = 784.4 (100%), 782.4 (70%), 780.3 (40%) [M+H] + Calculated mass: 783.4 (100%) 781.4 (74.3%), 779.4 (44.6%)

[0127] Di-tert-butyl (((S)-(1-tert-butoxy)-1-oxo-5-( 3-(4-(trimethylstannyl)phenyl)propanamido)pentan-2-yl)caprylic acid Rubamoyl)-L-glutamate (13) EuO-IPPA.3OtBu (6) (38 mg, 52 μmol) in dioxane (3 m To a solution of (SnMe3)2 (43 mg, 130 μmol) and PdCl2 (P Ph3)2 (3.7 mg, 5.2 μmol) was added and the reaction mixture was heated to 80°C for 100 min. The reaction mixture was then cooled to room temperature and the solvent was removed under reduced pressure. The product was dissolved in CH2Cl2 (12 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure. Concentration gave a brown oil, which was purified by silica chromatography (50% Et in hexanes). OAc) to give EuO-IPPA.SnMe3 (13) as a colorless oil. It solidified on standing (15 mg; 38%). 1 H NMR (500 MHz, CDCl3) δ 7.41 (d , 2H, J=7.9 Hz), 7.20 (dd, 2H, J1=12.8 Hz, J2=4.9 Hz), 6.24 (t, 1H, J=5.5 Hz), 5 .27 (d, 2H, J=8.1 Hz), 4.36-4.28 (m, 2H), 3.31 (m, 1H), 3.20 (m, 1H), 2.94 (t, 2 H, J=7.9 Hz), 2.48 (t, 2H, J=8.0 Hz), 2.25 (m, 2H), 2.08 (m, 1H), 1.85 (m, 1H), 1.74 (m, 1H), 1.59-1.46 (m, 3H), 1.45 (s, 18H), 1.44 (s, 9H), 0.27 (s, 9H). ESI( +) = 770.3 (100%), 768.2 (75%), 766.4 (50%) [M+H] + Calculated mass: 769.3 (100%), 76 7.3 (74.3%), 765.3 (44.6%)

[0128] Di-tert-butyl(((S)-1-tert-butoxy)-1-oxo-5-(2 -(4-(trimethylstannyl)phenyl)acetamido)pentan-2-yl)carba Moyl)-L-glutamate (14) EuO-IPAA.3OtBu (7) (22 mg, 31 μmol) was dissolved in dioxane (5 (SnMe3)2 (16 μL, 77 μmol) and PdCl2 (P Ph3)2 (2.2 mg, 5.1 μmol) was added sequentially, and the reaction mixture was heated to 80°C for 3 h. It was heated under Ar, then cooled to room temperature and filtered through Celite. The combined organic fractions were washed with oxane (6 mL) and CH2Cl2 (5 mL). Concentration under reduced pressure gave a pale oil. The oil was purified by silica chromatography (0% to 10% in hexanes). The product was collected and lyophilized to give EuO-IPAA. SnMe3 (14) was obtained as a white solid (8 mg; 35%). 1 H NMR (500 MHz, CDC l3) δ 8.06 (t, 1H, J=5.7 Hz), 7.39 (d, 2H, J=7.9 Hz), 7.21 (d, 2H, J=7.9 Hz), 6 .31 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=8.3 Hz), 4.04 (m, 1H), 3.98 (m, 1H), 3.31 (s, 2H), 3.02 (m, 2H), 2.29-2.19 (m, 3H), 1.87 (m, 1H), 1.67 (m, 1H), 1.63 (m, 1 H), 1.50 (m, 2H), 1.40 (s, 9H), 1.39 (s, 9H), 1.38 (s, 9H), 0.25 (s, 9H). = 756.2 (100%), 754.3 (70%), 752.4 (45%) [M+H] + Calculated mass: 755.3 (100%), 753. 3 (74.3%), 751.3 (44.6%)

[0129] Tetra-tert-butyl(3S,7S,12S)-5,10,18-trioxo-2 1-(4-(trimethylstannyl)phenyl)-4,6,11,17-tetraazahenico San-1,3,7,12-tetracarboxylate (15) EuEKIPBA.4OtBu(8) (25 mg, 26 μmol) and PdCl2 ( PPh3)2 (2.1 mg, 3.0 μmol) was dissolved in dioxane (3 mL) at room temperature. The mixture was stirred under Ar. (SnMe3)2 (25 mg, 75 μmol) was then added to the reaction mixture. The mixture was heated to 80°C and stirred under Ar for 90 min. The reaction mixture was then cooled to room temperature and The crude residue was dissolved in CH2Cl2 (5 mL) and filtered through Celite. The filtrate was concentrated and the residue was purified by silica chromatography (50% to 100% hexane). EuEK-IPBA.SnMe3 (15) was purified as a clear oil. The compound was isolated (19 mg; 73%), which solidified on standing at 0°C. 1 H NMR (500 M H z, CDCl3) δ 7.40 (d, 2H, J=7.9 Hz), 7.23 (d, 1H, J=7.7 Hz), 7.16 (dd, 2H, J1=12 .7 Hz, J2=4.9 Hz), 5.90 (d, 1H, J=8.5 Hz), 5.75 (t, 1H, J=5.5 Hz), 5.25 (d, 1H, J=9.0 Hz), 4.46 (m, 1H), 4.36 (m, 1H), 4.23 (m, 1H), 3.22 (m, 2H), 2.62 (t, 2H, J=7.6 Hz), 2.33 (t, 2H, J=7.8 Hz), 2.28 (m, 1H), 2.20-2.15 (m, 5H), 2.04 (m, 1H) , 2.00-1.91 (m, 3H), 1.73 (m, 2H), 1.65 (m, 2H), 1.47 (s, 9H), 1.46 (s, 9H), 1.4 5 (s, 9H), 1.43 (s, 9H), 1.40 (m, 2H), 0.27 (s, 9H). ESI(+) = 983.8 (100%), 981. 8 (75%), 984.9 (50%) [M+H] + Calculated mass: 982.5 (100%), 980.5 (74.3%), 983.5 (49.8%) %)

[0130] Di-tert-butyl (((S)-1-(tert-butoxy)-1-oxo-6-( 3-(4-(trimethylstannyl)phenyl)propanamido)hexan-2-yl)caprylate Rubamoyl)-L-glutamate (16) EuK-IPPA.3OtBu(9) (59 mg, 79 μmol) in dioxane (20 mL), (SnMe3)2 (65 mg, 198 μmol) and PdCl2 ( PPh3)2 (5.6 mg, 7.9 μmol) was added and the mixture was heated to 80 °C under Ar for 90 It was then cooled to room temperature and the solvent was removed under reduced pressure. The crude residue was extracted with CH The mixture was dissolved in Cl2 (25 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography (0% to 100% EtOAc in hexanes). The product, EuK-IPPA.SnMe3 (16), was purified as a clear oil. Upon isolation, it solidified on standing (51 mg; 82%). 1 H NMR (500 MHz, DMSO) δ 7.82 (m, 1H), 7.39 (d, 2H, J=8.0 Hz), 7.17 (d, 2H, J=8.1 Hz), 6.33 (d, 1H, J =5.9 Hz), 6.27 (d, 1H, J=6.1 Hz), 4.06 (m, 1H), 3.97 (m, 1H), 3.04 (m, 2H), 2.79 (t, 2H, J=7.7 Hz), 2.34 (t, 2H, J=7.8 Hz), 2.24 (m, 2H), 1.89 (m, 1H), 1.69 (m, 1H), 1.58 (m, 1H), 1.52 (m, 1H), 1.41 (s, 27H), 1.34 (m, 2H), 1.26 (m, 2H), 0.2 5 (s, 9H). (ESI(+) = 784.2 (100%), 782.2 (75%), 780.3 (45%) [M+H] + Calculated mass: 783.4 (100%), 781.4 (74.3%), 779.4 (44.6%).

[0131] Di-tert-butyl (((S)-1-(tert-butoxy)-1-oxo-6-( 2-(4-(trimethylstannyl)phenyl)acetamido)hexan-2-yl)carboxamide Bamoyl)-L-glutamate (17) EuK-IPAA.3OtBu (10) (70 mg, 96 μmol) in dioxane (2 To a solution of (SnMe3)2 (78 mg, 239 μmol) and PdCl2 in 100 mL of HCl (200 mL), (PPh3)2 (6.7 mg, 9.6 μmol) was added and the mixture was heated to 80 °C under Ar for 9 min. The mixture was heated for 10 minutes. It was then cooled to room temperature and the solvent was removed under reduced pressure. The crude residue was extracted with CH The mixture was dissolved in Cl2 (25 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure to give The crude residue was purified by flash chromatography (0% to 100% EtOAc in hexanes). The product, EuK-IPAA.SnMe3 (17), was isolated as a clear oil. However, it solidified on standing (50 mg; 69%). 1 H NMR (500 MHz, CDCl) δ 7.4 1 (d, 2H, J=7.9 Hz), 7.23 (d, 2H, J=7.9 Hz), 6.39 (m, 1H), 5.70 (d, 1H, J=8.3 Hz) ), 5.55 (d, 1H, J=7.9 Hz), 4.32 (m, 1H), 4.21 (m, 1H), 3.51 (d, 2H, J=5.1 Hz), 3 .21 (m, 1H), 3.10 (m, 1H), 2.22 (m, 2H), 2.02 (m, 1H), 1.84 (m, 1H), 1.66 (m, 1H) ), 1.49 (m, 1H), 1.42 (m, 2H), 1.41 (s, 9H), 1.40 (s, 9H), 1.39 (s, 9H), 1.30 (m , 2H), 0.24 (s, 9H). ESI(+) = 770.1 (100%), 768.2 (75%), 766.0 (45%) [M+H] + . quality Calculated values: 769.3 (100%), 767.3 (74.3%), 765.3 (44.6%).

[0132] Radiosynthesis of Exemplary Compounds. Representative synthesis sequences for certain exemplary compounds of the present technology are shown. The scheme is presented in Scheme 2 below.

[0133] [ka] Radiolabeling can be performed using the method described in Zechmann CM, Afs., incorporated herein by reference. har-Oromieh A, Armour T, et al. Radiation dose try and first therapy results with a124 I / 131 I-labeled small molecule(MIP-1095)t targeting PSMA for prostate cancer therapy y.Eur J Nucl Med Mol Imaging.2014;41:128 A modified version of the protocol described on pages 0-1292 was followed. Organotin precursors (e.g., any one of compounds 11-17) in 100 μL of 250 μg / mL EtOH mL of solution, 74–740 MBq (2–20 mCi) in 30–60 μL of aqueous NaOH solution. )Na 124 I or Na 131 15% v / v H2 was added to the vial containing I. The O2 / AcOH solution was prepared and 50 μL was immediately transferred to a reaction vial. The mixture was mixed for 2 seconds and allowed to stand at room temperature for 5 minutes. It was then diluted with 3 mL of HO and pre-activated. The sample was passed through a SOLA™ cartridge (Thermo Scientific) The cartridge was washed with HO (3 mL) and air-dried. The reaction mixture was eluted into a second vial using 1 mL of 4 M HCl / dioxane solution. The mixture was mixed for 20 seconds and allowed to stand for 40 minutes. It was then diluted with HO (9 mL) and the pre-activated Activated bonded Elut Plexa™ cartridges (Agilent Tech The cartridge was then filled with 5 mL of 20% v / v EtOH. The radiolabeled product was washed with DMSO (100 The solution was eluted with 100µL of PBS.

[0134] The radiochemical yield, radiochemical purity, and specific activity are shown in Table 1 below, where R CY = radiochemical yield, RCP = radiochemical purity, and SA = specific activity.

[0135] [Table 1] The radiochemical yields ranged from 43 to 72% for all compounds tested, and the radiochemical purity was was over 90%. For example, 131 I-RPS-027 is synthesized from its organotin precursor. The specific activity was 0.5% of the starting radiochemical yield. 124 I or 131 I The activity varied from 2 to 10 GBq / µmol. The deprotection step was time-sensitive. It was demonstrated that, at reaction times of less than 40 minutes, incomplete deprotection was observed, whereas 4 Reaction times longer than 5 min resulted in unidentified nucleotides that could not be removed during purification by solid phase extraction. The formation of an impurity occurred. 131 Instead of I 124 When I was used, the labeling yield was significantly No differences in intent were observed. 131 I-RPS-001 (elsewhere in this specification) 131 The structure of I-MIP-1095 is shown below.

[0136] [ka]

[0137] Representative Biological Assays Determination of HSA affinity. HSA was applied to HPLC-grade silica using the Schiff base method described previously. The mixture was immobilized by the method described above and packed into a microcolumn of 10 mm x 2.1 mm (inner diameter). Chen J, Hage DS. Quantitative tive studies of allosteric effects by bi ointeraction chromatography:analysis of protein binding for low-solubility drugs Anal Chem.2006:78:2672~2683, and Mats uda R, Anguizola J, Hoy KS, Hage DS.Analysi s of drug-protein interactions by high-p performance affinity chromatography:inter actions of sulfonyl urea drugs with norm al and glycated human serum albumin.Meth Please refer to pages 255-277 of ods Mol Biol.2015;1286: The protein content of these columns was approximately 60 mg HSA per gram of silica. Zheng X, Podarui M, Bi, which are incorporated herein by reference. C,Hage DS.Development of enhanced capaci ty affinity microcolumn by using a hybrid d of protein cross-linking / modification and immobilization.J.Chromatogr A.2015;1 400: pp. 82-90. A control microcolumn was prepared in the same manner. However, no HSA was added during the immobilization step. By injecting 5 μL of a sample containing approximately 50 μM of compound in HCl (pH 7.4), The retention factors for each compound were measured on both the HSA microcolumn and the control column. All samples were injected in triplicate at room temperature at 1.0 mL / min using phosphate buffer as the mobile phase. Similar injections were made with a sample containing sodium nitrate and compared with the void volume matrix. The elution of the injected compound was monitored by absorbance detection. pharrhine and L-tryptophan (i.e., Sudlow sites I and II of HSA) Estimated active HSA in the column based on injections performed using a probe for In addition to the concentration, each compound was analyzed after correcting for any observed retention on the control column. The dissociation constant (Kd) of the substance with HSA was estimated using the measured retention factor. Chen J, Hage DS. Anal. Chem.2006:78:2672-2683 (supra) and Joseph K.S., Hage DS.The effects of glycation on the binding of human serum albumin to warfar in and L-tryptophan.J Pharm Biomed Anal. 2010;53:811-818. The estimated accuracy of the Kd values ​​is ±2 ~14%.

[0138] Cell culture. The PSMA-expressing human prostate cancer cell line, LNCaP, was cultured in vitro, unless otherwise noted. Unless otherwise specified, the American Type Culture Collection. LNCaP cells were obtained from the University of California, San Diego, and culture supplies were from Invitrogen. The cells were cultured in a humidified incubator at 37°C / 5% CO2 with 10% fetal bovine serum (Hyclon e), 4mM L-glutamine, 1mM sodium pyruvate, 10mM N-2-hydroxybenzoate Hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES), 2.5 mg / m RPMI-1 supplemented with 100 μg / mL D-glucose and 50 μg / mL gentamicin The cells were maintained in 640 medium. for passaging or in 12-well plates by incubating in EDTA. The cells were removed from the flask for transfer to a standard assay plate.

[0139] In vitro IC 50 Determination of IC of non-radioactive iodine-containing ligands 50 The value is Kelly J, Amor-Coarasa A, N, incorporated herein by reference. ikolopoulou A, et al. Synthesis and pre-clinic al evaluation of a new class of high-aff inity 18 F-labeled PSMA ligands for detect tion of prostate cancer by PET imaging.E ur J Nucl Med Mol Imaging.2017;44,647~66 Binding to PSMA in LNCaP cells according to the protocol on page 1 Regarding 99m Tc-((7S,12S,16S)-1-(1-(carboxymethyl) -1H-imidazol-2-yl)-2-((1-(carboxymethyl)-1H-imidazoline-2-yl)- (2-(2-yl)methyl)-9,14-dioxo-2,8,13,15-tetraazao Technetium tricarbonyl ester of 7,12,16,18-tetracarboxylic acid methacrylate body)( 99m Screening was performed using a multi-concentration competitive binding assay against Tc-MIP-1427 Briefly, LNCaP cells were plated and cultured for 48 hours. After culturing, the cells were cultured in RPMI-1640 medium supplemented with 0.25% bovine serum albumin for approximately 5×10 5 Experiments were performed (in triplicate) to achieve a cell / well density of 1 nM. 9 9m Tc-MIP-1427 and 0.1 to 10,0 The cells were incubated for 1 hour in the presence of 100 nM of test compound. The incubation medium was removed by pipetting and 1 mL of ice-cold HEPES buffer was added. Cells were washed twice. Cells were harvested from the plates and plated in a Packard Cobra II The radioactivity was transferred to tubes for counting using a gamma counter. 50 Value , determined by nonlinear regression using GraphPad Prism software.

[0140] Inoculation of xenografted mice. All animal studies were performed by the Institutional An imal Care and Use Committee of Weill Cor. Endorsed by Nell Medicine, Humane Care and Us USPHS Policy on Laboratory Animals. The study was conducted in accordance with the guidelines set forth by the University of California, San Diego, CA. The animals were housed in an approved facility under a 12-hour light / dark The animals were housed under standard conditions in cycles. Food and water were provided ad libitum throughout the course of the study. Male inbred athymic nu / nu mice were obtained from The Jackson Laboratories. For inoculation into mice, LNCaP cells were purchased from the company Pharma. 4 × 10 in a 1:1 mixture of (BD Biosciences) 7 cells / mL Each mouse was injected with 0.25 mL of cell suspension into the left splenic flank. m 3 Mice were imaged when tumors reached 100-400 mm 3 In the range of When this occurred, biodistribution measurements were performed.

[0141] Tissue distribution studies: 2.5% v / v DMS in a volume of 0.05–0.1 mL was administered via the tail vein. A saline solution containing O was administered as a bolus injection (approximately 370 kBq (10 μCi) / mouse) Separate groups of male NCr-nu / nu mice bearing LNCaP cell xenografts administered intraperitoneally In 131 Quantitative analysis of tissue distribution of I-labeled compounds was performed in animals (n = 3–5). Mice (100-1500 mg / time point) were euthanized by CO2 asphyxiation at the indicated time points after injection. Heart, lungs, liver, spleen, pancreas, kidneys, stomach, large and small intestines (including contents), skeletal muscle, bones , and tumor-containing tissue was dissected, excised, weighed wet (Sartoriu s analytical balance), Wizard automated γ-counter (Perkin Elme r). A 1% ID / g standard was counted along with the tissue samples. Tissue time activity levels (%ID / g) expressed as a percentage of the injected dose were determined. Blood pharmacokinetics were analyzed by bivariate regression using biexponential least squares regression fits to the data. The regression method was performed using MATLAB R2015b (MathWorks) The study was carried out at the University of California, San Diego, Calif., in the US at 10:00 AM PST (Kingsville, CA).

[0142] Imaging studies. LNCaP xenograft tumor-bearing mice (2 per compound) were injected via the tail vein. through 124 I-RPS-027 7.03-7.77 MBq (190-210 μCi ) was injected intravenously as a bolus injection. 124 The specific activity of I-RPS-027 The range of 3 to 10 GBq / μmol was observed. Mice were then analyzed by μPET / CT (Inveon (trademark); Siemens Medical Solutions, Inc.) Images were taken at 1, 3, 6, 24 and 48 hours after injection. The total acquisition time was 3 0 minutes, and the CT scan was performed immediately prior to acquisition with both anatomical co-registration and attenuation correction. Data were obtained either at or immediately after the start of the experiment. ) software. Image-guided tumor uptake was calculated using the region of interest (R OI) was estimated by drawing

[0143] Representative Activities of Compounds of the Invention Exemplary in vitro study results. Table 2 below shows some exemplary formulations using PMSA and human serum albumin ("HSA"). The results of affinity studies on the compounds are shown.

[0144] [Table 2] The affinity range for PSMA was determined to be 4–40 nM, with the majority of compounds Clustered between 10 nM and 15 nM. In the same assay, RPS-001( MIP-1095) has an IC of 0.3 nM 50It was found to have Compounds bearing p-(iodophenyl)butyric acid moieties have high affinity for HSA. RPS-025 was found to have the activity (1-2 μM) of RPS-027 showed a moderate Kd of 11 μM. RPS-001, RPS-022, and RPS-026 had affinity of 1. RPS-023 (Kd = 53.2 μM) was a relatively weak parenteral It was determined that there was compatibility.

[0145] In vivo biodistribution and μPET / CT imaging. Biodistribution studies of six ligands revealed that albumin binding affinities were similar to those observed in mice. RPS-001 (K vs HSA) was shown to contribute significantly to the different pharmacokinetics. d = 20 μM) showed relatively rapid clearance from the blood (Figure 1A). The liver uptake was high (>100% ID / g) and lasted 24-96 hours after injection. R 131 I-RPS-001 activity was 65.24±22.61%ID / The tumor uptake was high, ranging from 2.12±2.47% ID / g at 96 hours. A gradual tumor washout was observed over several days (19.81 ± 1.00 at 24 hours). 6.16%ID / g vs. 10.21 ± 4.30%ID / g at 96 h) ( Figure 1A ). As a result, the tumor-to-kidney ratio increased over time. However, 24 hours after injection, the colon (2.35±1.26%ID / g) and spleen (2.41±1 Accumulated activity was observed in tumors and kidneys up to 48 hours after injection. The tissue uptake at relatively early time points was negligible in all tissues except the liver. Extrapolation was performed using previously reported data (37).

[0146] In the blood 131 Accumulation of I-RPS-005 was (for HSA, Kd = 0.89 μM), was exceptionally high, and clearance was delayed over the 96-hour observation period (Figure 1 B). At 24 hours after injection, the blood activity was 21.35±3.99%ID / g, which is 9 By 6 hours, the level had decreased to 15.57±3.98%ID / g. The incidence was 4.40±0.74%ID / g in the heart (24 hours), 8.87±0.74%ID / g in the lung (24 hours), and 1.02±0.02%ID / g in the lung (24 hours). tissues such as liver (3.41±0.56%ID / g at 24 hours) and liver (0.74%ID / g at 24 hours). This is likely due to the non-PSMA-mediated uptake observed in the tissues. 0.09±2.96%ID / g) at 24 hours after injection 131 About I-RPS-001 Although this was lower than observed, clearance was significantly slower. 9.37±1.56%ID / g at 96 hours; 10.82±2.64%ID / g at 96 hours Combined with the relatively low tumor uptake, these pharmacokinetic results were consistent with the inadequate tumor-to-background ratio.

[0147] 131 Tissue uptake of I-RPS-005 peaks within the first 24 hours. It seems like that, 131 I-RPS-020 (Kd = 2.1 μM) was also detected at early time points. Long-term retention in the blood was also observed, with a 16.5% retention rate at 1 hour after injection. The initial accumulation of 20±4.68%ID / g increased to 12.71±1.55%ID / g at 48 hours. g (Figure 2). This was associated with high off-target uptake. Of note, the lungs (6.12 ± 0.95% ID / g at 1 hour after injection) and kidneys (1 hour The uptake was 16.21±0.97% ID / g. This was followed by a peak of 22.26±2.48%ID / g at 24 hours after injection. The uptake (4.81 ± 1.27% ID / g) was as predicted by the comparison of PSMA affinity. was lower than that observed for RPS-005 over the course of 48 hours. The temperature remained stable.

[0148] in contrast, 131 I-RPS-022 (Kd = 22.9 μM) exhibits rapid hemodynamic activity. As early as 12 hours after injection, negligible activity was detected (Fig. 3). The uptake of the drug was significantly higher in the liver (12.46±1.63%ID / g) and small intestine at 1 hour after injection. (13.09±2.98%ID / g), but the clearance from each organ was Renal uptake (52.18 ± 5.35% ID / L) was achieved 1 hour after injection. g) was cleared to 2.27 ± 1.41% ID / g by 24 hours, favoring later time points. Optimal tumor-to-kidney and tumor-to-background ratios were achieved. However, tumor uptake The peak was 7.20±0.10%ID / g at 1 hour after injection and then increased by 6 hours. The concentration decreased to 3.35±1.70%ID / g.

[0149] 131 I-RPS-027 demonstrated a promising biodistribution profile over the time period studied. The activity in the blood 1 hour after injection was 3.91±0.48%ID / g. The initial uptake was 0.58±0.17%ID / g by 24 hours. , liver (6.79±0.70%ID / g; 1 h), small intestine (8.01±0.78%ID / g; 1 hour), large intestine (8.56±1.67%ID / g; 3 hours), spleen (4.13±1. 37%ID / g; 1 h) and heart (1.30±0.04%ID / g; 1 h). Clearance from these tissues was observed to be significantly higher than that from the blood. The activity of normal organs is related to blood pool activity rather than tissue uptake. The lowest activity was observed in the kidney (15.12 ± 2.82% ID / g) and tumor (9 With the exception of 0.73±1.01%ID / g), the drug was detected in tissues by 12 hours post-injection. Maximum tumor uptake (12.41 ± 0.84%ID / g; 3 h) was 131 I-RPS- Although lower than for 001, tumor uptake was 8.13 ± 2.03% at 24 hours. D / g and 72 hours, which remained high at 3.05 ± 1.30% ID / g, 18 hours after injection. yielded early and excellent tumor-to-background and tumor-to-kidney ratios (>2) .on the other hand, 131 Tumor uptake of I-RPS-027 was consistent at all time points examined. 131 I - Approximately 50% of the uptake for RPS-001, 131 I-RPS-027 The kidney concentration of 131 This was five times less than the value for I-RPS-001.

[0150] Desirable pharmacokinetics are: 131 The longer time point was observed for I-RPS-027. The activity in the blood was maintained for up to 48 hours after injection (0.20±0.06%). Although tumor-to-background ratios remained detectable (ID / g), rapid progression from the kidney was observed. It continued to increase due to clearance (1.04±0.65%ID / g at 48 hours). These in vivo findings 124 LNCaP xenografts with I-RPS-027 μPET / CT imaging of the mice revealed visually distinct tumors, kidneys, and hepatobiliary system. Initial uptake in the sera was evident at 1 hour (Figure 5), with clearance from non-target tissues. The drug resulted in highly specific tumor targeting at 24 and 48 hours after injection. .

[0151] To facilitate a better understanding of the pharmacokinetic profile of dual-binding ligands, The uptake in tumor, blood, and kidney was plotted in Figures 6A to 6C. The highest tumor uptake was 131 Observed for I-RPS-001 The rate of clearance from the tumor was similar for the three compounds with lower affinity for albumin. The level of activity in tumors was similar to that of the two ligands with the highest albumin binding. The activity of both ATP and ATP remained most constant in the ATP-dependent ... 13 1 I-RPS-005 and 131 Various compounds investigated for I-RPS-020 There was a very significant difference in the rate of blood clearance among the shows minimal blood clearance above 1000kJ / mL (Figure 6B). 131 I-RPS-001, 131 I-RPS-022 and 131 The clearance rate of I-RPS-027 was significantly higher than that of albumin. reflecting their relative affinities for 131I-RPS-022 was the most rapidly clearing It has been aligned, 131 I-RPS-027 is most slowly cleared. indicates a rapid initial distribution phase followed by a slower elimination phase. In this model, the t 1 / 2 teeth, 131 I-RPS-001, 131 I-RPS-022 and 131 I-RP For S-027, the results were 2.17 hours, 2.1 hours, and 3.15 hours, respectively. is the corresponding t for the desorption phase 1 / 2 are 20.38 hours, 17.3 hours and 21. In comparison, 131 Distribution and elimination phase of I-RPS-020 The half-lives of both compounds were 3.85 and 3,300 hours, respectively.

[0152] Absolute renal uptake of RPS-027 and RPS-022 was Renal clearance was dramatically reduced compared to RPS-001. 131 I-RPS-0 01. 131 I-RPS-022 and 131 I-RPS-027 is approximately This is described by a exponential decay (Figure 6C). 131 I-RPS-005 and 131 I-020 exhibits prolonged retention and a much flatter clearance curve. Tumor-to-kidney (T / K) and tumor-to-blood (T / B) ratios were calculated as a function of time. 13 1 The T / K ratio of I-RPS-027 reached approximately 3 by 24 hours and continued to increase with time. (Figure 7A). 131 The T / K ratio of I-RPS-001 was approximately 96 hours after injection. It doesn't reach 3 until then. 131 The T / K ratio of I-RPS-022 also increased rapidly, especially compared The increase in the IL-10 expression level at early time points (>1 at 12 hours post-injection) was due to tumor uptake. is driven by rapid renal clearance rather than 131 I-RPS-027 tumor The ratio to blood is 131 Lower than I-RPS-001 (Figure 7B) and enhanced albumin binding It mainly reflects.

[0153] 131 I-MIP-1095, 131 I-DCIBzL, and 211 Compared to At-6 do, 131 I-RPS-027 significantly increased the risk of pulmonary embolism at all time points from 1 hour to 72 hours after injection. Shows low renal uptake. 131 I-MIP-1095, 131 I-DCIBzL, and Beauty 211 For each of At-6, Hillier S, Rubino K, M aresca K, et al. 131 I]MIP-1466, a small molecu le prostate-specific membrane antigen (PS MA)inhibitor for targeted radiotherapy o f prostate cancer(PCa).J Nucl Med.2012;5 3(Suppl 1):170, Chen Y, Foss CA, Byun Y, et al. adiohalogenated prostate-specific membrane ne antigen (PSMA)-based ureas as imaging agents for prostate cancer.J Med Chem.2 008;51:7933-7943, and Kiess AP, Minn I, V aidyanathan G, et al (2S)-2-(3-(1-Carboxy-5-( 4-[211At]astatobenzamido)pentyl)ureido)- pentanedioic acid for PSMA-targeted α-pa rticle radiopharmaceutical therapy.J Nuc See Med.2016;57:1569-1575 (each of these (which is incorporated herein by reference).

[0154] In 24 hours, 131 I-MIP-1095 (elsewhere in this specification 131 I- RPS-001) and 131 20-fold difference in uptake between I-RPS-027 and I-RPS-027 In relation to the dosimetry reported for MIP-1095 in patients, 131 I - Lower renal uptake of RPS-027 resulted in a significantly lower renally absorbed dose, and reduced nephrotoxicity associated with therapeutic doses or under multiple treatment cycle regimens. It allows you to predict the risks involved. 131 The tumor-to-kidney ratio for I-RPS-027 was It exceeded 2 as early as 18 hours after injection, rose to 3 by 24 hours, and reached 7 by 72 hours. Exceeding. This is 211 Compared to the At-6, it has advantages 131 I-DCIBzL and 211 The comparative perspective between At-6 and RPS-027 is that astatination further increases the ratio. Therefore, we will limit the dosage. 211 At The irreversible nephrotoxicity of -6 is 211 At-RPS-027 is expected to solve this problem .

[0155] Although certain embodiments have been illustrated and described, those skilled in the art will understand, after reading the foregoing detailed description, The compounds or salts, pharmaceutical compositions, derivatives, prodrugs and the like of the present technology as described herein are Changes, substitutions and equivalents to compounds, metabolites, tautomers or racemic mixtures thereof and other types of modifications may be implemented. Each of the aspects and embodiments described above may be implemented in accordance with the present invention. , any such variations or modifications disclosed with respect to any or all other aspects and embodiments. Aspects may also be included therewith or incorporated therein.

[0156] The present technology is intended as merely illustrative of individual aspects of the present technology. The present invention is not limited to the specific embodiments described in the preceding paragraphs. Many modifications and variations of the teachings of the present invention may be made without departing from its spirit and scope. In addition to the methods enumerated herein, from the foregoing description, it is possible to Other, more functionally equivalent methods will be apparent to those skilled in the art. It is intended that the present technology be within the scope of the appended claims. are not limited to specific methods, reagents, compounds, compositions, labeled compounds or biological systems. It should be understood that the terms used herein may vary and may be used interchangeably. It should also be understood that the present invention is for illustrative purposes only and is not intended to be limiting. Accordingly, the specification is hereby incorporated by reference in its entirety with reference to the appended claims, definitions therein and any equivalents thereof. As an example only of the breadth, scope and spirit of the present invention, dictated solely by price. It is intended to be considered helpful.

[0157] The embodiments described herein as examples include any other embodiments not specifically disclosed herein. The presence of the component(s), without the limitation(s), and properly implemented Thus, for example, the terms "comprising" and "including" may be used interchangeably. "including," "containing," etc. are to be read expansively. In addition, the terms and phrases used herein are intended to be illustrative and not limiting. The term is used without limitation and includes any equivalent or similar of the features shown and described. Although there is no intention to use terms and expressions that would exclude those parts, various modifications are particularly It is recognized that the phrase "or" is within the scope of the claimed technology. "Consisting essentially of" refers to those components specifically recited and the basis of the claimed technology. It will be understood that the term "compound" includes additional components that do not materially affect the compound's inherent and novel characteristics. The phrase "consisting of" excludes any unspecified components.

[0158] Additionally, when a feature or aspect of the disclosure is described in Markush group terms, , one of skill in the art will appreciate that the disclosure thereby provides a method for identifying any individual member or subgroup of a Markush group. You will recognize that the disclosure also includes information about the group. Each of the narrower species and subgeneric groupings also form part of the invention. The omitted material is included in the present specification, but only if the omitted material is included in the present specification, It has a negative limitation that excludes any subject matter from the genus, whether or not it is listed in the do.

[0159] As will be appreciated by those skilled in the art, a specifically written description is provided for all purposes. In this regard, all ranges disclosed herein include all possible subranges and subranges therein. Any listed ranges are also intended to fully encompass that same range. Please state that it is at least equal to half, third, quarter, fifth, tenth, It is easy to recognize that it can be divided into other parts. By way of example, each range discussed herein may include a lower third, a middle third, and As will also be understood by those skilled in the art, All phrases such as "at," "at least," "greater than," and "less than" are used to refer to the number listed. and refers to a range that can be subsequently divided into the subranges discussed above. As defined above, ranges include each individual member.

[0160] All publications, patent applications, issued patents, and other documents (e.g., (e.g., journals, articles, and / or textbooks) are treated as if each individual publication, patent application, Any issued patent or other document specifically and entirely incorporated by reference is expressly and Each of the following is incorporated by reference as if individually set forth: Definitions contained in the accompanying text are excluded to the extent they conflict with definitions in this disclosure. Be removed.

[0161] The present technology includes the features and combinations of features set forth in the following paragraphs: Without limitation, the following paragraphs may be deemed to limit the scope of the appended claims. or all such features must necessarily be included in such a claim. It is understood that this should not be construed as requiring: A. Compounds of Formula I

[0162] [ka] or a pharmaceutically acceptable salt thereof, X 1 teeth, 124 I, 125 I, 127 I, 131 I, 211 At, or Sn(R 4 )3 and; R 1 , R 2 , and R 3 each independently represents H, methyl, benzyl, or 4-methoxybenzyl or tert-butyl; R 4 is independently at each occurrence an alkyl group; n is 1 or 2; m is 0, 1, 2, or 3). BR 1 , R 2 , and R 3 are each independently H or tert-butyl, Compound. CR 4 is independently at each occurrence methyl, ethyl, propyl, propyl, or butyl A compound of paragraph A or paragraph B. The compound of any one of paragraphs A through C, wherein when Dn is 2, then m is not 2. E. The compound of any one of paragraphs A through D, wherein the compound of Formula I is a compound of Formula Ia

[0163] [ka] or a pharmaceutically acceptable salt thereof. FX 1 but, 124 I, 125 I, 131 I, or 211 At, paragraphs A to E Either one compound. G. A composition comprising a compound of any one of paragraphs A through F and a pharmaceutically acceptable carrier. H. Pharmaceutical compositions for treating PSMA-expressing cancer, comprising: a composition comprising an effective amount of the compound of paragraph F, wherein the amount is effective to: I. Cancer is glioma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non- Small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell The pharmaceutical composition of paragraph H, wherein the cancer is prostate cancer (such as orchidectomy-resistant prostate cancer). J. Administering the compound of paragraph F to a subject suffering from a PSMA-expressing cancer. A method comprising: K. The method of paragraph J, comprising administering to a subject an effective amount of said compound. L. Cancers include glioma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non- Small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell The method of paragraph J or paragraph K, wherein the cancer is prostate cancer (such as orchidectomy-resistant prostate cancer). M. Paragraphs J-F, wherein the step of administering the compound comprises parenteral administration, preferably intravenous administration. Either one of the L ways. N. Compound of Formula II

[0164] [ka] or a pharmaceutically acceptable salt thereof, X 2 teeth, 124 I, 125 I, 127 I, 131 I, 211 At, or Sn(R 8 )3 and; R 5 , R 6 , and R 7 are each independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl; R 8 is independently at each occurrence an alkyl group; W 1 is a bond or -NH-alkylene-; p is 0, 1, 2, or 3). OR 5 , R 6 , and R 7 are each independently H or tert-butyl, compound. PR 8 is, independently at each occurrence, methyl, ethyl, propyl, propyl, or butyl. A compound of paragraph N or paragraph O. Q. The compound of any one of paragraphs N-P, wherein the compound of formula II is a compound of formula IIa

[0165] [ka] or a pharmaceutically acceptable salt thereof. RX 1 teeth, 124 I, 125 I, 131 I, or 211 At, paragraphs N to Q Either one compound. S. A composition comprising a compound of any one of paragraphs N-R and a pharmaceutically acceptable carrier. T. A pharmaceutical composition for treating a PSMA-expressing cancer, comprising: a composition comprising an effective amount of the compound of paragraph R, the effective amount being an amount effective to . U. Cancer includes glioma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non- Small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell The pharmaceutical composition of paragraph T, wherein the cancer is prostate cancer (such as orchidectomy-resistant prostate cancer). V. Administering the compound of paragraph R to a subject suffering from a PSMA-expressing cancer. A method comprising: W. The method of paragraph V, comprising administering to a subject an effective amount of said compound. X. Cancer is glioma, cervical cancer, vulvar cancer, uterine cancer, primary ovarian cancer, metastatic ovarian cancer, non- Small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell The method of paragraph V or paragraph W, wherein the cancer is prostate cancer (such as orchiectomy-resistant prostate cancer). Y. Paragraphs V-I, wherein the step of administering the compound includes parenteral administration, preferably intravenous administration. Any one of X ways. Z. Therapeutic Agent Uptake to Tumors Presenting Prostate-Specific Membrane Antigen ("PSMA") A method for enhancing a first antibody comprising a PMSA targeting moiety and a human serum albumin binding moiety comprising a radionuclide; administering a therapeutic agent to a subject having one or more cancer tumors; detecting the distribution of the first therapeutic agent in the subject; and Modifying the first therapeutic agent to provide a second therapeutic agent A method comprising: AA. The PMSA targeting moiety is a glutamate-urea-glutamate moiety or a glutamate The method of paragraph Z, comprising a tri-urea-lysine moiety. AB. Cancer is glioma, cervical cancer, vulvar cancer, uterine cancer, primary ovarian cancer, metastatic ovarian cancer, Non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma Those with cystic carcinoma or prostate cancer (such as orchiectomy-resistant prostate cancer) in paragraphs Z or AA Law. AC. Human serum albumin binding moiety 124 I-substitution, 125 I-substitution, 131 I-Placement exchange, or 211 The method of any one of paragraphs Z through AB, comprising an At-substituted phenyl moiety. AD. Human serum albumin binding moiety, 4-( 124 I)-substitution, 4-( 125 I)-Placement Exchange, 4-( 131 I)-substituted, or 4-( 211 At)-substituted phenyl moieties, Drop by one of the following methods: Z to AC. AE. The step of modifying the first therapeutic agent comprises modifying the carbohydrate chain of the human serum albumin binding moiety. The method of any one of paragraphs Z through AD, including the step of lengthening or shortening. AF. Any of paragraphs Z-AE, wherein the step of administering a first therapeutic agent includes parenteral administration. One way. AG. Administering a second therapeutic agent to a subject having one or more cancer tumors; detecting the distribution of the second therapeutic agent in the subject; The method of any one of paragraphs Z through AF, further comprising: AH. The second therapeutic agent induces a higher tumor take rate than the first therapeutic agent compared to non-tumor tissue of the subject. The method of paragraph AG showing inclusion. AI. The step of modifying the first therapeutic agent comprises modifying the first therapeutic agent with a polyalkane glycol, polyethyleneamine, or Polyvinylpyrrolidone (PEI), polyglycine, carbohydrate polymers, amino acid polymers, polyvinylpyrrolidone The donor, fatty acid, fatty acid ester group, or any combination of two or more thereof was added to human serum Any one of paragraphs Z through AH, including conjugating to an albumin binding moiety How to do it. AJ. The conjugation step comprises the steps of: conjugating a polyalkane glycol, a polyethyleneamine ( PEI), polyglycine, carbohydrate polymer, amino acid polymer, polyvinylpyrrolidone , a fatty acid, a fatty acid ester group, or a combination of any two or more thereof, the method of paragraph AI, including a step of inserting between the methylating moiety and the human serum albumin binding moiety. . AK. The conjugation step comprises the steps of: polyalkane glycol, polyethyleneamine ( PEI), polyglycine, carbohydrate polymer, amino acid polymer, polyvinylpyrrolidone , a fatty acid, a fatty acid ester group, or a combination of any two or more thereof, conjugating the human serum albumin binding moiety distal to the binding moiety; the method of paragraph AI or paragraph AJ, including.

[0166] Other embodiments are contemplated by the following claims, including all equivalents to which such claims are entitled. Specify along with the scope.

Claims

1. A compound of any of the following formulas: 【Chemical 1】 【change】

2. 2. The compound of claim 1, which is a compound of any of the following formulae: 【Chemistry 2】

3. 10. A composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.

4. 10. Use of a compound of claim 2 for the manufacture of a medicament for treating a cancer that expresses prostate-specific membrane antigen ("PSMA").

5. 5. The use of claim 4, wherein the cancer is glioma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, or prostate cancer.

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