Macrocyclic complexes of radionuclides and their use in radiotherapy of cancer

Abstract

To provide compounds and compositions including such compounds useful in targeted radiotherapy of cancer and / or mammalian tissue overexpressing prostate-specific membrane antigen ("PSMA").SOLUTION: The invention provides compounds of Formula (I) or pharmaceutically acceptable salts thereof.SELECTED DRAWING: Figure 1-1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Application No. 62 / 769,989, filed November 20, 2018. U.S. Provisional Application No. 62 / 788,700, filed January 4, 2019, and U.S. Provisional Application No. 62 / 788,700, filed January 15, 2019 This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 792,835, filed on 2006, each of which is hereby incorporated by reference. , which is incorporated herein by reference in its entirety for any and all purposes.

[0002] U.S. Government License Rights The present invention was developed using the National Institutes of Health (NIH) This product is supported by government support under license number UL1TR00457 awarded by the National Institute of Medical Sciences. The United States Government has certain rights in this invention. [Background technology]

[0003] The present technology generally relates to macrocyclic complexes of alpha-emitting radionuclides, as well as compositions containing such compounds. The present invention relates to compositions and methods of use. Summary of the Invention

[0004] In one embodiment, the compound of formula I is

[0005] [ka] [In the formula, Z 1 is H or -X 1 -W 2 and Z 2 OH or NH-W 3 and Z 3 is H or W 7 and; α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cyclo loalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH 2 CH 2 -(OCH 2 CH 2 ) w -R' (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR' (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them is , optionally, halo, -N 3 , -OR', -CH 2 CH 2 -(OCH 2 CH 2 ) y - R' (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -C H 2 CH 2 -(OCH 2 CH 2 ) z -OR' (where z is 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', - C(S)OR', -S(O)R', -SO 2 R', -SO 2 (OR'), -SO 2 NR' 2 , -P(O)(OR') 2 , -P(O)R'(OR'), -P(O)R' 2 , -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH 2 , -N=C=N-R’, - SO 2 Cl, -C(O)Cl, or substituted with one or more of an epoxide group well; W 5 and W 7 are each independently OH, NH 2 , SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl , -CH 2 CH 2 -(OCH 2 CH 2 ) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and each of them may optionally be halo, -N 3 , -OR’, -CH 2 CH 2 -(OC H 2 CH 2 )y x -R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, - C(O)OR’, -C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’ )、-SO2 NR’ 2 、 -P(O)(OR’) 2 、 -P(O)R’(OR’)、 -P(O )R’ 2 、 -CN、 -OCN、 -SCN、 -NCO、 -NCS、 -NR’ -NH 2 、 -N =C=N -R’、 -SO 2 Cl、 -C(O)Cl、 or one or more of an epoxide group may be substituted; R’ is, each occurrence, independently, H, halo, -N 3 、 C 1 ~C 6 alkyl, C 3 ~C 6 cyclo alkyl, C 2 ~C 6 alkenyl, C 5 ~C 8 cycloalkenyl, C 2 ~C 6 alkynyl 、 C 8 ~C 10 cycloalkynyl, C 5 ~C 6 aryl, heterocyclyl, or hetero aryl] or a pharmaceutically acceptable salt thereof is provided.

[0006] In related aspects, the compound of formula IA is

[0007]

Chemical formula

[0008] In further related aspects, the technology provides a compound useful for targeted radiotherapy of cancer and / or mammalian tissues that overexpress prostate-specific membrane antigen (「P SMA」) (「targeted compound」), the compound having the formula II

[0009]

Chemical Formula

[0010]

[0011] ​​​​​​In any embodiment and / or aspect disclosed herein (for simplicity, hereinafter referred to as "in any embodiment disclosed herein"), the antibody may be belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, cilentuximab, nimotuzumab, catumaxomab, or etaracizumab. In any embodiment disclosed herein, the antibody fragment may be belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, hereinafter, described as "in any embodiment disclosed herein"), an antibody may be belimumab, mo gamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, cilentuximab, nimotuzumab, catumaxomab, or etaracizumab. In any embodiment disclosed herein, an antibody fragment may be belimumab, mo gamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, cilentuximab, nimotuzumab, catumaxomab, or etaracizumab. In any embodiment disclosed herein, an antibody may be belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, cilentuximab, nimotuzumab, catumaxomab, or etaracizumab. In any embodiment disclosed herein, an antibody fragment may be belimumab, mo gamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, cilentuximab, nimotuzumab, catumaxomab, or etaracizumab. In any embodiment disclosed herein, an antibody may be belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, cilentuximab, nimotuzumab, catumaxomab, or etaracizumab. In any embodiment disclosed herein, an antibody fragment may be belimumab, mo gamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, cilentuximab, nimotuzumab, catumaxomab, or etaracizumab. In any embodiment disclosed herein, an antibody may be belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, cilentuximab, nimotuzumab, catumaxomab, or etaracizumab. In any embodiment disclosed herein, an antibody fragment may be belimumab, mo gamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, cilentuximab, nimotuzumab, catumaxomab, or etaracizumab. pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ra Murslimab, Toshitsumomab, Gemtuzumab ozogamicin, Alemtuzumab, Sixmab Mumab, Girentuximab, Nimotuzumab, Katsumaxomab, or Etaracizumab anti may contain a native binding fragment. In any embodiment disclosed herein the binding peptide may be a prostate-specific membrane antigen (「PSMA」) binding peptide, somatostatin receptor agonist, bombesin receptor agonist, separase binding compound, or may contain a binding fragment thereof.

[0012] In another aspect, the technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a compound of formula I, IA or II (or a pharmaceutically acceptable salt thereof) disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers. In a similar aspect, the technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a modified antibody, modified antibody fragment, or modified binding peptide of the technology disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers. In one aspect, a method of treating a subject is provided, the method comprising administering to the subject a targeting compound of the technology, or administering to the subject a modified antibody, modified antibody fragment, or modified binding peptide of the technology. In any embodiment disclosed herein, the subject is cancer and / or prostate-specific membrane antigen ( e.g., a pharmaceutical composition) and a medicament. In a similar aspect, the technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a modified antibody, modified antibody fragment, or modified binding peptide of the technology disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers. For example, a pharmaceutical composition) and a medicament. In a similar aspect, the technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a modified antibody, modified antibody fragment, or modified binding peptide of the technology disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers. In one aspect, a method of treating a subject is provided, the method comprising administering to the subject a targeting compound of the technology, or administering to the subject a modified antibody, modified antibody fragment, or modified binding peptide of the technology. In any embodiment disclosed herein, the subject is cancer and / or prostate-specific membrane antigen ( e.g., a pharmaceutical composition) and a medicament. In a similar aspect, the technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a modified antibody, modified antibody fragment, or modified binding peptide of the technology disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers. e.g., a pharmaceutical composition) and a medicament. In a similar aspect, the technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a modified antibody, modified antibody fragment, or modified binding peptide of the technology disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers. medicament.

[0013] In one aspect, a method of treating a subject is provided, the method comprising administering to the subject a targeting compound of the technology, or administering to the subject a modified antibody, modified antibody fragment, or modified binding peptide of the technology. In any embodiment disclosed herein, the subject is cancer and / or prostate-specific membrane antigen ( e.g., a pharmaceutical composition) and a medicament. In a similar aspect, the technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a modified antibody, modified antibody fragment, or modified binding peptide of the technology disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers. e.g., a pharmaceutical composition) and a medicament. In a similar aspect, the technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a modified antibody, modified antibody fragment, or modified binding peptide of the technology disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers. In any embodiment disclosed herein, the subject is cancer and / or prostate-specific membrane antigen ( may have problems with mammalian tissues that overexpress 「PSMA」).

[0014] In one aspect, the compound has a first domain having a blood protein binding moiety with low specific affinity for blood proteins, a second domain having a tumor targeting moiety with high affinity for tumor antigens, and a third domain having a chelator. BRIEF DESCRIPTION OF THE DRAWINGS

[0015]

Figure 1-1

Figure 1-2

Figure 2-1

Figure 2-2

Figure 3-1

Figure 3-2

Modes for Carrying Out the Invention

[0016] The following terms are used throughout as defined below.

[0017] As used herein and in the appended claims, singular articles, e.g., “a,” “an,” and “the,” and similar referents in connection with the description of these elements (particularly in connection with the following claims), are to be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. The detailed description of value ranges herein is to be construed to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Unless otherwise indicated herein or clearly contradicted by context, the singular forms of articles, e.g., Unless otherwise indicated, the shorthand references individually to each separate value falling within that range are merely intended to act as a method, and each separate value is incorporated herein as if individually listed herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. Any and all examples or exemplary language provided herein (e.g., "such as") are merely intended to better clarify embodiments and do not impose a limitation in the claims unless otherwise stated. The language in this specification should not be construed as indicating any non-claimed element as essential.

[0018] As used herein, "about" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. In the case of usage of a term that is not obvious to those skilled in the art and that indicates the context in which it is used, "about" means plus or minus 10% of a particular term; for example, "about 10 wt%" is understood to mean "9 wt% to 11 wt%". When "about" precedes a term, that term should be construed as disclosing the "about" term as well as the term not modified by "about"; for example, "about 1 0 wt%" discloses "9 wt% to 11 wt%" and also discloses "10 wt%".

[0019] Generally, reference to some elements, e.g., hydrogen or H, means including all isotopes of that element. For example, where an R group is defined to include hydrogen or H, ​​In combination, the R group also includes deuterium and tritium. Thus, compounds containing radioisotopes such as , tritium, C 14 , P 32 and S 35 etc. are within the scope of this technology . The procedures for inserting such labels into the compounds of this technology are readily apparent to those skilled in the art based on the disclosure herein .

[0020] Generally, "substituted" means an organic group (e.g., an alkyl group) as defined below, and one or more bonds to the hydrogen atoms contained therein are replaced by single bonds to non-hydrogen or non-carbon atoms. The substituents also include groups in which one or more bonds to carbon(s) or hydrogen(s) (if any) atoms are replaced by one or more bonds including double or triple bonds to heteroatoms . Thus, the substituents are substituted with one or more substituents unless otherwise specified. In some embodiments, the substituents are substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include halogen (i.e., F, Cl, Br, and I); hydroxyl; alk oxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocy clylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyl (oxo); carboxylate; ester; urethane; oxime; hydroxylamine ; alkoxyamine; aralkoxyamine; thiol; sulfide; sulfoxide; sulfone ; sulfonyl; pentafluorosulfanyl (i.e., SF ); sulfonamide; a mine; N-oxide; hydrazine; hydrazide; hydrazone; azide; amide; urea; a mine; etc. ; alkoxyamine; aralkoxyamine; thiol; sulfide; sulfoxide; sulfone ; sulfonyl; pentafluorosulfanyl (i.e., SF 5 ); sulfonamide; a mine; N-oxide; hydrazine; hydrazide; hydrazone; azide; amide; urea; a Thiazine; guanidine; enamine; imide; isocyanate; isothiocyanate; cyanate -ate; thiocyanate; imine; nitro group; nitrile (i.e., CN); etc. are included therein.

[0021] Substituted ring groups, for example, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and ring systems in which a single bond to a hydrogen atom is replaced by a single bond to a carbon atom. Thus, substituted cycloalkyl, aryl, heterocy clyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl , alkenyl, and alkynyl groups as defined below.

[0022] As used herein, C m ~C n , for example, C 1 ~C 12 , C 1 ~C 8 , or C 1 ~C 6 , when used before a group, means a group containing from m to n carbon atoms .

[0023] Alkyl groups include straight-chain and branched-chain alkyl groups having from 1 to 12 carbon atoms, usually from 1 to 10 carbon atoms, or in some embodiments, from 1 to 8, from 1 to 6, or from 1 to 4 carbon atoms. Examples of straight-chain alkyl groups include, for example, methyl, ethyl , n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n- octyl groups and the like. Examples of branched alkyl groups include, but are not limited to, i sopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopenty l, etc. groups. ​The alkyl group includes a neopentyl group and a 2,2-dimethylpropyl group. The alkyl group may or may not be substituted. A typical substituted alkyl group may be substituted one or more times with substituents such as those described above, but not limited thereto, and includes haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.

[0024] The cycloalkyl group has from 3 to 12 carbon atoms in the ring(s), or in some embodiments, from 3 to 10, from 3 to 8, or from 3 to 4, 5, or 6 carbon atoms, and includes mono-, bi- or tricyclic alkyl groups. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has from 3 to 8 ring members, and in other embodiments, the number of carbon atom rings ranges from 3 to 5, from 3 to 6, or from 3 to 7. Bicyclic and tricyclic ring systems include bridged cycloalkyl groups and fused rings such as, but not limited to, bicyclo [2.1.1]hexane, adamantyl, decalinyl, and the like. The cycloalkyl group may or may not be substituted. A substituted cycloalkyl group may be substituted one or more times with the non-hydrogen and non-carbon groups defined above. However, a substituted cycloalkyl group also includes rings substituted with the straight-chain or branched-chain alkyl groups defined above. Representative substituted cycloalkyl groups may be mono-substituted or multi-substituted with more than one substitution. ​ may be, for example, but not limited thereto, 2,2-, 2,3-, 2,4-2 ,5- or 2,6-disubstituted cyclohexyl groups, etc., which may be substituted with substituents such as those described above etc.

[0025] A cycloalkylalkyl group is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a single bond to a cycloalkyl group as defined above . In some embodiments, the cycloalkylalkyl group has 4 to 16 carbon atoms , 4 to 12 carbon atoms, and usually 4 to 10 carbon atoms. The cycloalkylalkyl group may or may not be substituted. A substituted cycloalkylalkyl group may be substituted in the alkyl, cycloalkyl or alkyl and cycloalkyl moieties of this group . Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, for example, but not limited thereto, may be mono-substituted, di-substituted or tri-substituted with substituents such as those described above .

[0026] An alkenyl group includes straight-chain and branched-chain alkyl groups as defined above, except that at least one double bond is present between two carbon atoms . The alkenyl group has 2 to 12 carbon atoms, usually 2 to 10 carbon atoms, or in some embodiments , 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments , the alkenyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to, among others, vinyl, allyl, -CH=CH(CH 3 )、 -CH=C(CH 3 ) 2 、 -C(CH 3 )=CH 2 、 -C(CH 3 )=CH(CH 3 )、 -C(CH 2 CH 3 )=CH 2 is included. The alkenyl group may or may not be substituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, and may be, for example, but not limited to, mono-substituted, di-substituted or tri-substituted with substituents such as those described above. The cycloalkenyl group includes the cycloalkyl groups defined above having at least one double bond between two carbon atoms. The cycloalkenyl group may or may not be substituted. In some embodiments, the cycloalkenyl group may have one, two or three double bonds, but does not include aromatic compounds. The cycloalkenyl group has 4 to 14 carbon atoms, or in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, and further, 5, 6, 7, or 8 carbon atoms. Examples of the cycloalkenyl group include cyclohexenyl, cyclopentenyl, cyclohexadienyl,

[0027] cyclobutadienyl, and cyclopentadienyl. The cycloalkenylalkyl group is the alkyl group defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a single bond to the cycloalkenyl group defined above. The cycloalkenylalkyl group may or may not be substituted. In some embodiments, the cycloalkenylalkyl group may have one, two or three double bonds, but does not include aromatic compounds. The cycloalkenylalkyl group has 4 to 14 carbon atoms, or in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, and further, 5, 6, 7, or 8 carbon atoms. Examples of the cycloalkenylalkyl group include cyclohexenylmethyl, cyclopentenylmethyl, cyclohexadienylmethyl, cyclobutadienylmethyl, and cyclopentadienylmethyl. Examples of the cycloalkenyl group include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl.

[0028] The cycloalkenylalkyl group is an alkyl group in which a hydrogen or carbon bond of the alkyl group is replaced by a single bond to a cycloalkenyl group as defined above. The cycloalkenylalkyl group may or may not be substituted. In some embodiments, the cycloalkenylalkyl group may have one, two or three double bonds, but does not include aromatic compounds. The cycloalkenylalkyl group has 4 to 14 carbon atoms, or in some embodiments, 5 to 14 carbon atoms, 。The substituted cycloalkenylalkyl group may be substituted with alkyl, cycloalkenyl or an alkyl and cycloalkenyl moiety of that group. The substituted cycloalkenylalkyl group may be substituted one or more times with substituents such as those described above. The substituted cycloalkenylalkyl group may be substituted one or more times with substituents such as those described above.

[0029] The alkynyl group includes the straight-chain and branched alkyl groups defined above, except that at least one triple bond is present between two carbon atoms. The alkynyl group has from 2 to 12 carbon atoms and usually from 2 to 10 carbon atoms, or in some embodiments, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms. In some embodiments, the alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to, -C≡CH, -C≡CCH 3 2 3 2 2 3 2 The alkynyl group may or may not be substituted. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, and may be mono-substituted, di-substituted or tri-substituted, for example, but not limited to, with substituents such as those described above.

[0030] An aryl group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. The aryl groups in this specification include monocyclic, bicyclic and tricyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl(heptaleny ​​​​​​​​​​​​​​​​​l), biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, i ndanyl, pentalenyl, and naphthyl groups are included. In some embodiments, the aryl group contains 6 to 14 carbons in these ring moieties, and otherwise contains 6 to 12 carbons, and further 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. The aryl group may or may not be substituted. The term "aryl group" includes groups including fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, mono-substituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those described above.

[0031] An aralkyl group is an alkyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a single bond to an aryl group as defined above. In some embodiments, the aralkyl group contains 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. The aralkyl group may or may not be substituted. Substituted aralkyl groups may be substituted in the alkyl, aryl, or alkyl and aryl moieties of such groups. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups and fused (cycloalkylaryl) alkyl groups, such as 4-indanylethyl. Representative substituted aralkyl groups are those described above. It may be substituted one or more times with substituents such as those carried.

[0032] The heterocyclyl group includes aromatic (also referred to as heteroaryl) and non-aromatic ring compounds, among which one or more are heteroatoms, for example, but not limited to only, N, O, and S. In some embodiments, the heterocy clyl group contains 1, 2, 3, or 4 heteroatoms. In some embodiments, the heter ocyclic group includes mono-, bi-, and tricyclic rings having 3 to 16 ring members, and other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. The heterocyclyl group includes aromatic, partially unsaturated, and saturated ring systems, for example, imidazo ryl, imidazolinyl, and imidazolidinyl groups. The term "heterocyclyl group" includes those containing fused aromatic and non-aromatic groups, for example, benzotriazolyl, 2,3- dihydrobenzo[1,4]dioxinyl, and benzodioxolyl, including fused ring species. This term includes bridged polycyclic ring systems containing heteroatoms, for example, but not limited to only, quinuclidinyl, etc. The heterocyclyl group may or may not be substituted. The heterocyclyl group includes, but is not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiaz olidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiaz olyl, and the like. Ril, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl , piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahyd rothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimi dinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithi nyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolin yl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizin yl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, be nzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyr idyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, pur inyl, xanthinyl, adeninyl, guaninyl, quinolinyl, i soquinolinyl, quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaz inyl, naphthyridinyl, pteridinyl, thianaphthyl, dihyd robenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzod oxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenz imidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetra hydro pyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyr idyl, and tetrahydroquinolinyl groups are included. Representative substituted heterocyclyl groups are It may be mono-substituted or polysubstituted more than once. For example, but not limited thereto, it may be 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those described above, and may be a pyridyl or morpholinyl group.

[0033] A heteroaryl group is an aromatic ring compound containing 5 or more ring members, among which one or more are heteroatoms, such as, but not limited thereto, N, O, and S. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guanylinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups, etc. The heteroaryl group may include fused ring compounds where all rings are aromatic, such as an indolyl group, or may include fused ring compounds where only one of the rings is aromatic, such as a 2,3-dihydroindolyl group. The heteroaryl group may or may not be substituted. Therefore, the term "heteroaryl group" includes fused ring compounds. Also included are heterocycles, for example, having other groups attached to one of the alkyl groups, and heteroaryl groups. Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those described above. A heteroaryl group is included. Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those described above. A heteroaryl group may be substituted one or more times with various substituents such as those described above.

[0034] A heterocyclylalkyl group is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a single bond to a heterocyclyl group as defined above. A heterocyclylalkyl group may or may not be substituted. A substituted heterocyclylalkyl group may be substituted in the alkyl, heterocyclyl, or alkyl and heterocyclyl moieties of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those described above. A heterocyclylalkyl group is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a single bond to a heterocyclyl group as defined above. A heterocyclylalkyl group may or may not be substituted. A substituted heterocyclylalkyl group may be substituted in the alkyl, heterocyclyl, or alkyl and heterocyclyl moieties of the group. A substituted heterocyclylalkyl group may be substituted in the alkyl, heterocyclyl, or alkyl and heterocyclyl moieties of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. A substituted heterocyclylalkyl group may be substituted in the alkyl, heterocyclyl, or alkyl and heterocyclyl moieties of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those described above. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those described above. A substituted heterocyclylalkyl group may be substituted one or more times with substituents such as those described above.

[0035] A heteroaralkyl group is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a single bond to a heteroaryl group as defined above. A heteroaralkyl group may or may not be substituted. A substituted heteroaralkyl group may be substituted in the alkyl, heteroaryl, or alkyl and heteroaryl moieties of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those described above. A heteroaralkyl group is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a single bond to a heteroaryl group as defined above. A heteroaralkyl group may or may not be substituted. A substituted heteroaralkyl group may be substituted in the alkyl, heteroaryl, or alkyl and heteroaryl moieties of the group. A substituted heteroaralkyl group may be substituted in the alkyl, heteroaryl, or alkyl and heteroaryl moieties of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those described above. A substituted heteroaralkyl group may be substituted in the alkyl, heteroaryl, or alkyl and heteroaryl moieties of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those described above. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those described above.

[0036] The present technology's compounds having two or more bonds (i.e., divalent, trivalent, or polyvalent) within the compound The groups described in the specification are named by using the suffix "ene". For example, a divalent alkyl group is an alkylene group, a divalent aryl group is an arylene group, a divalent hetero aryl group is a divalent heteroarylene group, and so on. Substituents having a single bonding point to the present technology's compounds are not applied using the "ene" nomenclature. Thus, for example, chloro ethyl is not referred to herein as chloroethylene. Such groups may or may not be substituted.

[0037] An alkoxy group is a hydroxyl group (-OH) in which the bond to the hydrogen atom is replaced by a single bond to a carbon atom of the above-defined substituted or unsubstituted alkyl group. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopent toxy, isohexoxy, and the like. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclo hexyloxy, and the like. An alkoxy group may or may not be substituted. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those described above.

[0038] As used herein, the terms "alkanoyl" and "alkanoyloxy" Each means a -C(O)-alkyl and an -O-C(O)-alkyl group, and in some embodiments, the alkanoyl or alkanoyloxy groups each contain 2 to 5 carbon atoms. Similarly, the terms "aroyl" and "aroyloxy" each mean a -C(O)-aryl and an -O-C(O)-aryl group, respectively.

[0039] The terms "aryloxy" and "arylalkoxy" each mean a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to an oxygen atom in an alkyl, respectively. Examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those described above.

[0040] As used herein, the term "carboxylic acid" means a compound having a -C(O)OH group. As used herein, the term "carboxylate" means a -C(O)O - group. "Protected carboxylate" means -C(O)O-G [wherein G is , a carboxylate protecting group]. Carboxylate protecting groups are well known to those skilled in the art. A comprehensive list of protecting groups for carboxylate group functional groups can be found in Protect ive Groups in Organic Synthesis, Greene, T .W.; Wuts, P.G.M., John Wiley & Sons, New Yor .k, NY, (3rd Edition, 1999), which is described therein It can be added or removed using the procedures described, and the whole of it is incorporated herein by reference for all purposes as fully as if set forth herein. Incorporate herein by reference for all purposes as set forth when described herein.

[0041] As used herein, the term "ester" means a -COOR 70 group. R 70 is an alkyl, cycloalkyl, alkene nyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group which is substituted or unsubstituted as defined herein.

[0042] The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(O)NR 71 R 72 , and -NR 71 C(O )R 72 groups. R 71 and R 72 are independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Thus, amide groups include, but are not limited to, carbamoyl groups (-C(O)NH ) and formamide groups (-NHC(O)H). In some embodiments, the amide is - 2 NR C(O)-(C alkyl) which is named "carbonylamino", and otherwise the amide is -NHC(O)-alkyl which is named "al 71 kanoylamino". 1~5

[0043] As used herein, the term "nitrile" or "cyano" means a -CN group .

[0044] The urethane group includes N- and O-urethane groups, i.e., -NR 73 C(O )OR 74 and -OC(O)NR 73 R 74 groups. R 73 and R 74 are, independently, a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R can also be H. 73

[0045] As used herein, the term "amine" (or "amino") means a -NR 75 R 76 group [wherein R 75 and R 76 are, independently, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, ara lkyl, heterocyclylalkyl or heterocyclyl group as defined herein]. In some embodiments, the amine is alkylamino, dialkylamino, arylamino, or is alkylarylamino. In other embodiments, the amine is NH 2 , methyla mino, dimethylamino, ethylamino, diethylamino, propylamino, isopropyl amino, phenylamino, or benzylamino.

[0046] The term "sulfonamide" includes S- and N-sulfonamide groups, i.e., respectively , -SO 2 ​NR 78 R 79 and -NR 78 SO 2 R 79 groups are included. R 78 and R 79 are, independently, hydrogen, or a substituted or unsubstituted alkyl, a lkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl l, or heterocyclyl group. Thus, the sulfonamide group includes, but is not limited to, the sulfamoyl group (-SO NH 2 NH 2 ). In some embodiments herein, the sulfonamide is -NHSO 2 -alkyl and is referred to as an "alkylsulfon ylamino" group.

[0047] The term "thiol" means a -SH group, the sulfide includes a -SR 80 group, the sul foxide includes a -S(O)R 81 group, the sulfone includes a -SO 2 R 82 group, and the sulfonyl includes a -SO SO 2 OR 83 group. R 80 , R 81 , R 82 , and R 8 3 are each independently a substituted or unsubstituted alkyl, cyclo alkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or hetero cycllylalkyl group as defined herein. In some embodiments, the sulfide is an alkylthio group, - S-alkyl.

[0048] The term "urea" refers to -NR 84-C(O)-NR 85 R 86 means a group. R 84 、R 85 、and R 86 groups are, independently, hydrogen, or a substituted or un substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, he terocyclic, or heterocyclic alkyl group.

[0049] The term "amidine" refers to -C(NR 87 )NR 88 R 89 and -NR 87 C(NR 8 8 )R 89 [wherein R 87 、R 88 、and R 89 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, a lkynyl, aryl aralkyl, heterocyclic or heterocyclic alkyl group as defined herein].

[0050] The term "guanidine" refers to -NR 90 C(NR 91 )NR 92 R 93 [wherein R 90 、 R 91 、R 92 and R 93 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclic or heterocyclic alkyl group as defined herein].

[0051] The term "enamine" refers to -C(R 94 )=C(R 95)NR 96 R 97 and -NR 9 4 C(R 95 )=C(R 96 )R 97 [wherein, R 94 , R 95 , R 96 and R 97 each independently means hydrogen, a substituted or unsubstituted alkyl, cyclo alkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or hetero cycloalkylalkyl group as defined herein]. As used herein, the term "halogen" or "halo" means bromine, chlorine, fluoro

[0052] rine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.

[0053] As used herein, the term "hydroxyl" means -OH or its ionized form , -O - and may mean.

[0054] The term "imide" means -C(O)NR 98 C(O)R 99 , [wherein, R 98 and R 99 each independently means hydrogen, or a substituted or unsubstituted alkyl as defined herein, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group].

[0055] The term "imine" means -CR 100 (NR 101 ) and -N(CR 100 R 101 )​ Group [wherein, R 100 and R 101 are each independently hydrogen or an alkyl, cycloalkyl, alkenyl, alkynyl, aryl alkyl, aralkyl, heterocyclyl or heterocyclylalkyl group which is substituted or unsubstituted as defined herein, provided that R and R 1 00 and R 101 are not both hydrogen at the same time].

[0056] As used herein, the term "nitro" means a -NO 2 group.

[0057] As used herein, the term "trifluoromethyl" means -CF 3 .

[0058] As used herein, the term "trifluoromethoxy" means -OCF 3 . .

[0059] The term "azide" means -N 3 .

[0060] The term "trialkylammonium" means a -N(alkyl) 3 group. The trialkylammonium group has a positive charge and thus usually has an associated anion, for example, a halogen anion and the like. .

[0061] The term "trifluoromethyldiaziride" means

[0062]

Chemical formula

[0063] The term "isocyano" means -NC.

[0064] The term "isothiocyano" means -NCS.

[0065] The term "pentafluorosulfanyl" means -SF 5 and means.

[0066] As will be understood by those skilled in the art, for any and all purposes, particularly with respect to providing a written description, all ranges disclosed herein also include any and all possible sub-ranges and combinations of those sub-ranges. Any recited range is sufficiently described and can be readily recognized as being divisible into at least equal halves, thirds, quarters, fifths, tenths, etc. of the same range. By way of non-limiting example, each range discussed herein can be readily divided into lower third, middle third and upper third. As will also be understood by those skilled in the art all languages, e.g., "up to", "at least", "more than", "less than", etc. include the recited numbers and can be followed by ranges that can be divided into the sub-ranges discussed above. Finally, as will be understood by those skilled in the art ranges include each individual member. Thus, for example, a group having from 1 to 3 atoms means a group having 1, 2, or 3 atoms. Similarly, a group having 1 to 5 atoms means a group having 1, 2, 3, 4, or 5 atoms, etc.

[0067] The pharmaceutically acceptable salts of the compounds described herein are within the scope of the present technology, retain the desired pharmacological activity and are biologically desirable (e.g., the salts are not overly toxic, (which is not allergic or irritating and is bioavailable), and includes acid or base addition salts If the compound of the present technology has a basic group such as an amino group, pharmaceutically acceptable salts are inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid, etc.), organic acids (such as alginic acid, formic acid, acetic acid, benzoic acid , gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p- toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid etc.). If the compound of the present technology has an acidic group such as a carboxylic acid group etc., this can form salts with metals such as alkali and alkaline earth metals (such as , Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (such as dicyclohexylamine, trimethylamine, triethylamine, pyridine , picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (such as arginine, lysine and ornithine). Such salts can be prepared by reacting the compound during the isolation and purification of the present compound in situ or the purified compound in the form of its free base or free acid separately with a suitable acid or base and isolating the salt thus formed in this way. Those skilled in the art will appreciate that the compounds of the present technology may exhibit tautomerism, conformational isomerism etc. can be done.

[0068] Those skilled in the art will appreciate that the compounds of the present technology may exhibit tautomerism, conformational be capable of exhibiting the phenomenon of l-isomerism, geometric isomerism and / or steric isomerism It is understood that the diagrams of the formulas within the scope of this specification and the claims may be in the form of any of the possible tautomeric, conformational isomeric, stereochemical or geometric isomeric forms of the compounds. Since only one of the possible tautomeric, conformational isomeric, stereochemical or geometric isomeric forms of the compounds can be represented, the present technology encompasses any tautomeric, conformational isomeric, stereochemical and / or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms. It should be understood that this is the case. "Tautomers" means isomeric forms of a compound that are in equilibrium with each other. The presence and concentration of the isomeric forms depend on the environment in which the compound is found and can vary, for example, depending on whether the compound is in solid form or in the form of an organic or aqueous solution. For example, in an aqueous solution, quinazolinone can exhibit the following isomeric forms, which are referred to as tautomers of each other. For example, in an aqueous solution, quinazolinone can exhibit the following isomeric forms, which are referred to as tautomers of each other. It should be understood that this is the case.

[0069] "Tautomers" means isomeric forms of a compound that are in equilibrium with each other. The presence and concentration of the isomeric forms depend on the environment in which the compound is found and can vary, for example, depending on whether the compound is in solid form or in the form of an organic or aqueous solution. For example, in an aqueous solution, quinazolinone can exhibit the following isomeric forms, which are referred to as tautomers of each other. The presence and concentration of the isomeric forms depend on the environment in which the compound is found and can vary, for example, depending on whether the compound is in solid form or in the form of an organic or aqueous solution. For example, in an aqueous solution, quinazolinone can exhibit the following isomeric forms, which are referred to as tautomers of each other. or in the form of an organic or aqueous solution. For example, in an aqueous solution, quinazolinone can exhibit the following isomeric forms, which are referred to as tautomers of each other. In an aqueous solution, quinazolinone can exhibit the following isomeric forms, which are referred to as tautomers of each other. It is understood that this is the case.

[0070]

Chemical formula

[0071]

Chemical formula

[0072] Since the representation of the compounds by structural formulas is limited, all chemical formulas of the compounds described herein represent all tautomeric forms of the compounds and are understood to be within the scope of the present technology. Since the representation of the compounds by structural formulas is limited, all chemical formulas of the compounds described herein represent all tautomeric forms of the compounds and are understood to be within the scope of the present technology. should be

[0073] Stereoisomers of the compounds (also known as optical isomers), unless a specific stereochemistry is explicitly indicated, include all chiral, diastereomeric, and racemic forms of the structure Thus, the compounds used in the present technology, as is apparent from the drawings include enriched or resolved optical isomers at any or all of the asymmetric atoms Both racemic and diastereomeric mixtures, as well as individual optical isomers, may be isolated or synthesized such that they are substantially free of their enantiomeric or diastereomeric partners, and all such stereoisomers are within the scope of the present technology

[0074] The compounds of the present technology can exist as solvates, particularly hydrates. Hydrates can be formed during the manufacture of the present compound or a composition containing the compound, or hydrates can be formed over time due to the hygroscopic nature of the present compound. The compounds of the present technology can also exist as organic solvates, including, inter alia, DMF, ether, and alcohol solvates The identification and preparation of any particular solvate are within the skill of those in the art of synthetic organic chemistry or pharmaceutical chemistry

[0075] Throughout this disclosure, various publications, patents, and published patent specifications are incorporated by reference for identification Also within the scope of this disclosure, arabic numerals are meant to refer to the cited references and the full details of the literature thereof are shown to come immediately before the claims. The disclosures of these publications, patents, and published patent specifications are incorporated herein to more fully describe the present technology ​is incorporated herein by reference into the present disclosure.

[0076] This technology Targeted radiotherapy has been carried out for a period of time using macrocyclic complexes of radionuclides, but currently the macrocyclic molecules in use (e.g., DOTA) generally form complexes with insufficient stability with radionuclides, especially those of larger sizes, such as actinium, radium, bismuth, and lead isotopes. Such instability dissociates the radionuclide from the macrocyclic molecule, thereby resulting in a lack of selectivity for the target tissue, which also brings toxicity to non-target tissues.

[0077] This technology provides new macrocyclic complexes that are substantially more stable than those of the prior art. Thus, these new complexes can substantially eliminate toxicity to non-target tissues compared to the complexes in the art and can more efficiently and advantageously target cancer cells. Furthermore, the new complexes can be advantageously generated at room temperature, in contrast to DOTA-type complexes that generally require an increase in temperature (e.g., at least 80 °C) for complex formation with radionuclides. This technology also particularly uses α-emitting radionuclides instead of β-radionuclides. α-emitting radionuclides have much higher energy and are thus substantially more powerful than β-emitting radionuclides.

[0078] Thus, in one aspect, the compound of formula I is

[0079] [Chemical formula] [In the formula, Z 1 is H or -X 1 -W 2 and Z 2 is OH or NH-W 3 and Z 3 is H or W 7 ; α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cyclo loalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH 2 CH 2 -(OCH 2 CH 2 ) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them is , optionally, halo, -N 3 , -OR’, -CH 2 CH 2 -(OCH 2 CH 2 ) y - R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -C H 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10), -SR’, -OC(O)R’, -C(O)OR’, - C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’), -SO2 NR’ 2 、 -P(O)(OR’) 2 、 -P(O)R’(OR’), -P(O)R’ 2 、 -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH 2 、 -N=C=N-R’, - SO 2 Cl, -C(O)Cl, or substituted with one or more of an epoxide group well; W 5 and W 7 are each independently OH, NH 2 、 SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl 、 -CH 2 CH 2 -(OCH 2 CH 2 ) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and each of them may optionally be halo, -N 3 、 -OR’, -CH 2 CH 2 -(OC H 2 CH 2 )y x -R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, - C(O)OR’, -C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’ )), -SO 2 NR’ 2 , -P(O)(OR’) 2 , -P(O)R’(OR’), -P(O )R’ 2 , -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH 2 , -N =C=N-R’, -SO 2 Cl, -C(O)Cl, or one or more of epoxy groups may be substituted; R’ is, each occurrence, independently, H, halo, -N 3 , C 1 ~C 6 alkyl, C 3 ~C 6 cyclo alkyl, C 2 ~C 6 alkenyl, C 5 ~C 8 cycloalkenyl, C 2 ~C 6 alkynyl , C 8 ~C 10 cycloalkynyl, C 5 ~C 6 aryl, heterocyclyl, or hetero aryl] or a pharmaceutically acceptable salt thereof is provided.

[0080] Significantly, the unbound form of formula (I) is at high radiochemical yields, for example, at least 90%, 95%, 97%, or 98% or above 90%, 95%, 97%, or 98% at room temperature (generally, 18 - 30 °C, or about 20 °C, about 25 °C, or about 30 °C or 20 °C, 25 °C, or 30 °C or below), such as α-emitting radionuclides It can be combined with a radionuclide.

[0081] In related embodiments, the compound of formula IA is

[0082] [Chemical formula] [wherein, M 1 is an α-emitting radionuclide; Z 1 is H or -X 1 -W 2 and Z 2 is OH or NH-W 3 and Z 3 is H or W 7 and α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cyclo loalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH 2 CH 2 -(OCH 2 CH 2 ) w -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them is , optionally, halo, -N 3 , -OR', -CH 2 CH 2 -(OCH 2 CH 2 ) y - R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -C H 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10), -SR’, -OC(O)R’, -C(O)OR’, - C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’), -SO 2 NR’ 2 , -P(O)(OR’) 2 , -P(O)R’(OR’), -P(O)R’ 2 , -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH 2 , -N=C=N-R’, - SO 2 Cl, -C(O)Cl, or substituted with one or more of an epoxide group well; W 5 and W 7 are each independently OH, NH 2 , SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl , -CH 2 CH 2 -(OCH 2 CH 2 ) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and each of which may optionally be halo, -N3 、 -OR’, -CH 2 CH 2 -(OC H 2 CH 2 )y x -R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, - C(O)OR’, -C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’ ) -SO 2 NR’ 2 -P(O)(OR’) 2 -P(O)R’(OR’), -P(O )R’ 2 -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH 2 -N =C=N-R’, -SO 2 Cl, -C(O)Cl, or one or more of the epoxy groups may be substituted; R’ is, each time it appears, independently, H, halo, -N 3 , C 1 ~C 6 alkyl, C 3 ~C 6 cyclo alkyl, C 2 ~C 6 alkenyl, C 5 ~C 8 cycloalkenyl, C 2 ~C 6 alkynyl , C 8 ~C 10 cycloalkynyl, C 5 ~C 6 aryl, heterocyclyl, or hetero aryl] or a pharma- ceutically acceptable salt thereof is provided.

[0083] In any embodiment disclosed herein, M 1 Actinium-225 ( 225 Ac 3+ ), Radium-223( 233 Ra 2+ ), Bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ), Terbium-14 9( 149 Tb 3+ ), Fermium-255( 255 Fm 3+ ), Thorium-227( 227 Th 4+ ), Thorium-226( 226 Th 4+ ), Astatine-211( 211 At + ), Astatine-217( 217 At + ), or uranium-230. It is possible that...

[0084] In further related aspects, the technology provides a method for the treatment of cancer and / or prostate specific membrane antigen ("P- Compounds useful for targeted radiation therapy of mammalian tissues overexpressing SMA ("targeted radiation therapy"). The compound is represented by formula II

[0085] [ka] [In the formula, M 1 is an alpha-emitting radionuclide; Z 1 is H or -L 3 -R 22and Z 2 is OH or NH-L 4 -R 24 and Z 3 is H or -L 6 -R 28 and; α is 0 or 1; X 1 is O, NH, or S; L 3 , L 4 , L 5 , or L 6 is, independently at each occurrence, a bond or a linker group; R 22 , R 24 , R 26 , and R 28 are each independently an antibody, an antibody fragment ( For example, antigen-binding fragments), binding moieties, binding peptides, binding polypeptides (e.g. , selective targeting oligopeptides containing up to 50 amino acids), binding proteins Substances, enzymes, nucleobase-containing moieties (e.g., oligonucleotides, DNA or RNA vectors) or aptamer), or lectin] or a pharma- ceutically acceptable salt thereof It is.

[0086] In any embodiment disclosed herein that is encompassed by Formula II, M 1 Actinium Mu-225( 225 Ac 3+ ), Radium-223( 233 Ra 2+ ), Bismuth-21 3( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ) , terbium-149( 149 Tb 3+ ), Fermium-255(255 Fm 3+ ), Thorium-227( 227 Th 4+ ), Thorium-226( 226 Th 4+ ), Astati N-211( 211 At + ), Astatine-217( 217 At + ), or uranium-2 It could be 30.

[0087] Representative R 22 , R 24 , R 26 , and R 28 The group, as known to those skilled in the art, can be represented as These antibodies, as well as antigen-binding fragments of such antibodies, and any This invention includes any equivalent embodiment.

[0088] [Table 1] JPEG2025087695000012.jpg243131JPEG2025087695000013.jpg116163

[0089] In any of the embodiments disclosed herein, the binding peptide is a prostate specific membrane antigen ( "PSMA" binding peptide, somatostatin receptor agonist, bombesin receptor agonist The compound may comprise a seprase-binding compound, a seprase-binding compound, or a binding fragment thereof. Exemplary PSMA binding peptides include, but are not limited to, the following structures:

[0090] [ka] [Wherein, nn is 0, 1, or 2; P 1 , P 2 , and P 3are each independently , H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl], by are included. In any embodiment herein, P 1 , P 2 , and P 3 each may be H.

[0091] Somatostatin, exemplified in Scheme A, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation through its interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin has two active forms produced by alternative cleavage of a single preproprotein. Five known somatostatin receptors: SST1 (SSTR1); SST2 (SSTR2); SST3 (SSTR3); SST4 (SSTR4); and SST5 (SSTR5) exist , all of which are G protein-coupled seven-transmembrane receptors. Exemplary somatostatin receptor agonists include somatostatin itself, lanreotide, octreotide , octotide, pasireotide, and vapreotide.

[0092]

Chemical formula

[0093] Many neuroendocrine tumors express SSTR2 and other somatostatin receptors. Long -acting somatostatin agonists (e.g., octreotide, lanreotide) are used to stimulate the SSTR2 receptor and thus further inhibit tumor growth. Zatel ​​Li MC et al. (April 2007) "Control of pituitary adrenergic encephalopathy" noma cell proliferation by somatostatin analogs, dopamine agonists and novel chim eric compounds”, European Journal of Endo crinology / European Federation of Endocri See ne Societies.156 Suppl 1:S29-35. Treotide is an octapeptide that mimics natural somatostatin, but in vivo o. Octreotide has a significantly longer half-life in tumors that produce growth hormone (Tregs). gigantism and gigantism), when surgery is contraindicated, thyroid-stimulating hormone-secreting ptosis Thyrotropinoma, carcinoid syndrome The incidence of diarrhea and flushing episodes associated with the group and the presence of vasoactive intestinal peptide-secreting tumors (VIPs) Lanreotide is used to treat diarrhea in patients with acromegaly and Used in the management of symptoms caused by neuroendocrine tumors, particularly carcinoid syndrome. Pasireotide has a stronger effect on SSTR5 than other somatostatin agonists. It is a somatostatin analogue with high affinity for the treatment of Cushing's disease and acromegaly. Vapreotide is approved for use in patients with cirrhotic liver disease and AIDS-related diarrhea. It is used to treat bleeding from esophageal varices.

[0094] Bombesin was originally isolated from the skin of the European fire-bellied frog (Bombina bombina) In addition to stimulating gastrin release from G cells, bombesin is also Activates at least three G protein-coupled receptors: BBR1, BBR2, and BBR3, and such activation includes antagonism of such receptors in the brain. Bombesin is also a tumor marker for small cell lung cancer, gastric cancer, pancreatic cancer, and neuroblastoma. Bombesin receptor agonists include, but are not limited to, BBR-1 agonists, BBR-2 agonists, and BBR-3 agonists. Seprase (or fibroblast activation protein (FAP)) is an endogenous membrane serine peptidase. In addition to gelatinase activity, seprase has a dual function in tumor progression. Seprase promotes cell invasiveness against the ECM and also supports tumor growth and proliferation. Seprase engagement compounds include seprase inhibitors.

[0095] In a further related aspect, modified antibodies, modified antibody fragments, or modified binding peptides comprising a binding resulting from conjugation of a compound of formula I or a pharmaceutically acceptable salt thereof to an antibody, antibody fragment, or binding peptide. In a related aspect, modified antibodies, modified antibody fragments, or modified binding peptides are provided that comprise a binding resulting from conjugation of a compound of formula IA or a pharmaceutically acceptable salt thereof to an antibody, antibody fragment, or binding peptide. In any of the embodiments disclosed herein, the antibody is pembrolizumab, mogamulizumab, brentuximab vedotin, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab

[0096] vedotin, or ado-trastuzumab emtansine. antibody fragment, or binding peptide. In a related aspect, modified antibodies, modified antibody fragments, or modified binding peptides are provided that comprise a binding resulting from conjugation of a compound of formula IA or a pharmaceutically acceptable salt thereof to an antibody, antibody fragment, or binding peptide. In any of the embodiments disclosed herein, the antibody is pembrolizumab, mogamulizumab, brentuximab vedotin, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, or ado-trastuzumab emtansine. vedotin, or ado-trastuzumab emtansine. In any of the embodiments disclosed herein, the antibody is pembrolizumab, mogamulizumab, brentuximab vedotin, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, or ado-trastuzumab emtansine. Bvedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab , dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, siltuximab, semipramab, nivolumab, pembrolizumab, olaratumab, atezo lizumab, abelumab, durvalumab, capromab pendetide, elotuzumab, deno sumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gem tuzumab ozogamicin, alemtuzumab, siltuximab, gilotuzumab, nimo tuzumab, catumaxomab, or etaracizumab may be included. In any embodiment disclosed in this specification, the antibody fragment is belimumab, mogamulizumab , blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab , rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, bre ntuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab em tansine, siltuximab, semipramab, nivolumab, pembrolizumab, olaratum ab, atezolizumab, abelumab, durvalumab, capromab pendetide, elotuz umab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumo mab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, gilotuzimab, nimo, catumaxomab, or the antigen-binding fragment of etaracizumab may be included. In any embodiment disclosed in this specification, the binding peptide is a prostate-specific membrane antigen ("PSMA") binding peptide, a somatostatin receptor agonist peptide, or the like. a tropsine, a bombesin receptor agonist, a separase-binding compound, or a binding fragment thereof may be included.

[0097] Examples of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology include that the binding may be a thiocyanate bond obtained; the thiocyanate bond results from the conjugation of the compound to an antibody, antibody fragment, or binding peptide and the compound is

[0098]

Chemical formula

[0099] Another example of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology includes that the binding may be a thiocyanate bond; the thiocyanate bond results from the conjugation of the compound to an antibody, antibody fragment, or binding peptide and the compound is

[0100]

Chemical formula

[0101] In any embodiment herein, the structure includes a binding resulting from the conjugation of a compound of formula III, a compound of formula III or a pharmaceutically acceptable salt thereof to an antibody, antibody fragment, or binding peptide, a modified antibody, modified antibody fragment, or modified binding peptide, a compound of formula IV, a compound of formula IV or a pharmaceutically acceptable salt thereof to an antibody, antibody fragment, or binding peptide or a modified binding peptide, a compound of formula IV, a compound of formula IV or a pharmaceutically acceptable salt thereof to an antibody, antibody fragment, or binding peptide or a modified binding peptide, a compound of formula IV, a compound of formula IV or a pharmaceutically acceptable salt thereof to an antibody, antibody fragment, or binding peptide or a modified binding peptide, a compound of formula IV, a compound of formula IV or a pharmaceutically acceptable salt thereof to an antibody, antibody fragment, or binding peptide Modified antibodies, modified antibody fragments, or modified binding peptides that may contain the resulting linkages, and

[0102]

Chemical formula

[0103]

Chemical formula

[0104]

Chemical formula

[0105] The target-directed compound of formula V is prepared by a 22 process that includes reacting a compound of formula III or IV 1 with R, and Table B provides representative examples (where n is independently, for each occurrence, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Thus, R 22 can be conjugated to the macrocyclic molecule 1 W 2 by reaction of the complementary chemical functional groups R 21 to form the linker L 3 . For example, R 22 -W 1 can contain a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A, or an antigen-binding fragment thereof; a PSMA-binding peptide, a somatostatin receptor agonist, a bombesin receptor 1 agonist, a separase-binding compound, or a binding fragment of can be obtained, and its non-limiting examples are disclosed in Table B, W 2 is the L of formula V 3 to provide W 1 can be selected to react selectively with

[0106] [Table 2] JPEG2025087695000022.jpg98158JPEG2025087695000023.jpg91158JPEG2025087695000024.jpg91158JPEG2025087695000025.jpg85158JPEG2025087695000026.jpg95158JPEG2025087695000027.jpg92158JPEG2025087695000028.jpg91158JPEG2025087695000029.jpg88159JPEG2025087695000030.jpg91158

[0107] In any embodiment herein, the structure is a conjugate of a compound of formula VI, a compound of formula VI or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide, a conjugate of a compound of formula VII, a compound of formula VII or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide, and may include a target-directed compound of formula VIII.

[0108] [Chemical formula]

[0109] ​​​​ [Chemistry]

[0110] [Chemistry]

[0111] The target-directed compound of formula VIII is prepared by a process comprising reacting a compound of formula VI or VII with R 24 -W 4 to react and Table C provides representative examples (wherein n is, each time it appears, independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Thus, R is conjugated to the macrocyclic 24 molecule R 3 and W 4 to form a linker L by the reaction of W 23 . For example, 4 R -W 24 -W 4 can contain a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A, or an antigen-binding fragment thereof; a PSMA-binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase-binding compound, or a binding fragment of any one thereof). W can contain a reactive chemical functional 4 moiety, non-limiting examples of which are disclosed in Table C, and W can be selected to selectively react with W 3 to provide the L 4 of formula VIII . W 4 can be selected to react selectively with W

[0112] [Table 3] JPEG2025087695000035.jpg125164JPEG2025087695000036.jpg98164

[0113] In any embodiment herein, the structure comprises a bond resulting from conjugation of a compound of Formula IX, a compound of Formula IX or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide, a compound of Formula X, a compound of Formula X or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide, and may include a target-directed compound of Formula XI. Therefore, the target-directed compound of Formula XI can be prepared by a process comprising reacting a compound of Formula IX or X with R -W and Table D provides representative examples (wherein n is, each occurrence, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Thus, R is a complementary chemical functional group W and W

[0114]

Chem.

[0115]

Chem.

[0116]

Chem.

[0117] The target-directed compound of Formula XI can be prepared by a process comprising reacting a compound of Formula IX or X with R 26 -W 6 and Table D provides representative examples (wherein n is, each occurrence, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). and Table D provides representative examples (wherein n is, each occurrence, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). and Table D provides representative examples (wherein n is, each occurrence, independently, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Thus, R 26 is a complementary chemical functional group W 5 and W6 By the reaction of, the macrocyclic molecule R 25 is conjugated to to form the linker L 5 For example, R 26 - W 6 may contain a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A, or an antigen-binding fragment thereof; a PSMA-binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase-binding compound, or a binding fragment of any one thereof ; a PSMA-binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase-binding compound, or a binding fragment of any one thereof ; a PSMA-binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase-binding compound, or a binding fragment of any one thereof). W contains a reactive chemical functional moiety 6 and can be obtained, non-limiting examples of which are disclosed in Table D, and W is selected to selectively react with W 5 to provide L of formula IX 5 and can be selected to react selectively with W 6 to provide L of formula IX.

[0118]

Table 4

[0119] In any embodiment herein, the structure contains a bond resulting from conjugation of a compound of formula XII, a compound of formula XII or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide, a compound of formula XIII, a compound of formula XIII or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide In any embodiment herein, the structure contains a bond resulting from conjugation of a compound of formula XII, a compound of formula XII or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide, a compound of formula XIII, a compound of formula XIII or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide In any embodiment herein, the structure contains a bond resulting from conjugation of a compound of formula XII, a compound of formula XII or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide In any embodiment herein, the structure contains a bond resulting from conjugation of a compound of formula XII, a compound of formula XII or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide It may contain a decorated binding peptide and a target-directed compound of formula XIV. be.

[0120]

Chemical formula

[0121]

Chemical formula

[0122]

Chemical formula

[0123] The target-directed compound of formula XIV can be prepared by a process comprising reacting a compound of formula XII or XIII with R 28 -W 8 and the table E provides representative examples (wherein n is, each time it appears, independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Thus, R can be conjugated to the macrocyclic molecule R by the reaction of the complementary chemical functional groups W 28 and W 7 and W 8 to form a linker L . For example 27 4 4 , R 28 -W 8 can contain a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A, or its antigen-binding fragment; a PSMA-binding peptide, a somatostatin receptor agonist , a bombesin receptor agonist, a seprase-binding compound, or a binding fragment of any one of them). W 8 8 can contain a reactive chemical functional moiety, non-limiting examples of which are disclosed in Table E, and W7 is selected to selectively react with W to provide L of formula XIV 6 and can 8 be selected to selectively react with W to provide L of formula XIV

[0124] [Table 5] JPEG2025087695000047.jpg111169JPEG2025087695000048.jpg39169

[0125] Those skilled in the art will recognize that a number of chemical conjugation strategies provide easy access to the targeted compounds of the present technology, whereby the exposed amino acid residues of the protein (e.g., antibody) undergo well-known reactions with the reactive moieties of the complementary molecule. For example, the amide coupling ring is a well-known pathway in which, for example, lysine residues on the antibody surface react with terminally activated carboxylic acid esters to form stable amide bonds. Amide coupling is usually mediated by any of several coupling reagents (e.g., HATU, EDC, DCC, HOBT, PyBOP, etc.), which are described in detail elsewhere (generally, see Eric Valeur & Mark Bradley, Amide Bond Formation: Beyond the Myth of Coupling Reagents, 38 CHEM. SOC. REV. 606 (2009)). These and other amide coupling strategies are described in a recent review by Tsuchikama. (Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation Chemistry, 45 CURRENT OPINION IN CHEMICAL BIOLOGY 63 (2009)). to the targeted compounds of the present technology, whereby the exposed amino acid residues of the protein (e.g., antibody) undergo well-known reactions with the reactive moieties of the complementary molecule Those skilled in the art will recognize that a number of chemical conjugation strategies provide easy access to the targeted compounds of the present technology, whereby the exposed amino acid residues of the protein (e.g., antibody) undergo well-known reactions with the reactive moieties of the complementary molecule. For example, the amide coupling ring is a well-known pathway in which, for example, lysine residues on the antibody surface react with terminally activated carboxylic acid esters to form stable amide bonds. Amide coupling is usually mediated by any of several coupling reagents (e.g., HATU, EDC, DCC, HOBT, PyBOP, etc.), which are described in detail elsewhere (generally, see Eric Valeur & Mark Bradley, Amide Bond Formation: Beyond the Myth of Coupling Reagents, 38 CHEM. SOC. REV. 606 (2009)). These and other amide coupling strategies are described in a recent review by Tsuchikama. (Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation Chemistry, 45 CURRENT OPINION IN CHEMICAL BIOLOGY 63 (2009)). ring is a well-known pathway in which, for example, lysine residues on the antibody surface react with terminally activated carboxylic acid esters to form stable amide bonds Amide coupling is usually mediated by any of several coupling reagents (e.g., HATU, EDC, DCC, HOBT, PyBOP, etc.), which are described in detail elsewhere (generally, see Eric Valeur & Mark Bradley, Amide Bond Formation: Beyond the Myth of Coupling Reagents, 38 CHEM. SOC. REV. 606 (2009)). These and other amide coupling strategies are described in a recent review by Tsuchikama. (Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation Chemistry, 45 CURRENT OPINION IN CHEMICAL BIOLOGY 63 (2009)). Amide coupling is usually mediated by any of several coupling reagents (e.g., HATU, EDC, DCC, HOBT, PyBOP, etc.), which are described in detail elsewhere (generally, see Eric Valeur & Mark Bradley, Amide Bond Formation: Beyond the Myth of Coupling Reagents, 38 CHEM. SOC. REV. 606 (2009)). These and other amide coupling strategies are described in a recent review by Tsuchikama. (Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation Chemistry, 45 CURRENT OPINION IN CHEMICAL BIOLOGY 63 (2009)). BOP, etc.), which are described in detail elsewhere (generally, see Eric Valeur & Mark Bradley, Amide Bond Formation: Beyond the Myth of Coupling Reagents, 38 CHEM. SOC. REV. 606 (2009)). These and other amide coupling strategies are described in a recent review by Tsuchikama. (Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation Chemistry, 45 CURRENT OPINION IN CHEMICAL BIOLOGY 63 (2009)). Eric Valeur & Mark Bradley, Amide Bond Formation: Beyond the Myth of Coupling Reagents 38 CHEM. SOC. REV. 606 (2009). These and other amide coupling strategies are described in a recent review by Tsuchikama. (Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation Chemistry, 45 CURRENT OPINION IN CHEMICAL BIOLOGY 63 (2009)). These and other amide coupling strategies are described in a recent review by Tsuchikama. (Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation Chemistry, 45 CURRENT OPINION IN CHEMICAL BIOLOGY 63 (2009)). Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation Chemistry 45 CURRENT OPINION IN CHEMICAL BIOLOGY 63 (2009). Conjugation and Linker Chemistries, 9 PROTE IN CELL 33, 36 (2018); also, for example, A.C. Lazar et al., An alysis of the Composition of Immunoconju gates Using Size-Exclusion Chromatograph y Coupled to Mass Spectrometry, 19 RAPID COMMUN. MASS SPECTROM. 1806 (2005) (see also).

[0126] Furthermore, those skilled in the art will recognize that the cysteine coupling reaction can be utilized to conjugate a moiety having a thiol-reactive end to the protein surface via the exposed thiol side chains of cysteine residues on the protein surface (e.g., antibody) (generally, see Tsuchikama & An, supra, pages 36 - 37; also, for example, Pierre Adumeau et al., Thiol-Reactive Bifunct ional Chelators for the Creation of Site -Selectively Modified Radioimmunoconjuga tes with Improved Stability, 29 BIOCONJUG ATE CHEM. 1364 (2018) (see also). Since cysteine residues are more likely to form disulfide bonds with neighboring cysteine residues under physiological conditions than to exist as free thiols, some cysteine coupling strategies rely on the selective reduction of disulfides to generate more reactive free thiols (see the same reference above). Those skilled in the art ional Chelators for the Creation of Site -Selectively Modified Radioimmunoconjuga tes with Improved Stability, 29 BIOCONJUG ATE CHEM. 1364 (2018) (see also). The cysteine residues are more likely to form disulfide bonds with neighboring cysteine residues under physiological conditions than to exist as free thiols, so some cysteine coupling strategies rely on the selective reduction of disulfides to generate more reactive free thiols (see the same reference above). Those skilled in the art ol than to exist as free thiols, so some cysteine coupling strategies rely on the selective reduction of disulfides to generate more reactive free thiols (see the same reference above). Since cysteine residues are more likely to form disulfide bonds with neighboring cysteine residues under physiological conditions than to exist as free thiols, some cysteine coupling strategies rely on the selective reduction of disulfides to generate more reactive free thiols (see the same reference above). Those skilled in the art form disulfide bonds with neighboring cysteine residues under physiological conditions than to exist as free thiols, so some cysteine coupling strategies rely on the selective reduction of disulfides to generate more reactive free thiols (see the same reference above). Those skilled in the art ect the selective reduction of disulfides to generate more reactive free thiols (see the same reference above). Those skilled in the art Cysteine ​​coupling techniques known in the art include, but are not limited to, cys-arylamines. Alkylation reactions, cysteine ​​rebridging reactions, and cys-alkylation reactions using organometallic palladium reagents Aryl couplings are included (e.g., C.R. Behrens et al., Antibodies y-Drug Conjugates(ADCs)Derived from Inte rchain Cysteine ​​Cross-Linking Demonstrat es Improved Homogeneity and Other Pharma cological properties over conventional H eterogeneous ADCs, 12 MOL.PHARM.3986(2015 ); Vinogradova et al., Organometallic Palladium Reagents for Cysteine ​​Bioconjugation, 52 6 NATURE 687 (2015); see also Tsuchikama, See also p. 37 (consolidated examples) above.

[0127] Protein conjugation strategies using unnatural amino acid side chains are also known in the art. For example, "click chemistry" is a method for the rapid synthesis of aryl esters under a wide range of reaction conditions. Providing access to conjugated proteins through selective chemical transformations Click chemistry can be carried out under aqueous conditions, regardless of the presence of unprotected functional groups. It is known that peptide conjugates can be obtained with little by-product formation. One important, but non-limiting example of a click reaction in the formation of condensed peptides is copper. The azide-alkyne 1,3-dipolar cycloaddition reaction (CuAAC) catalyzed by (I) ( Liyuan Liang & Didier Astruc, The Copper(I) -Catalysed Alkyne-Azide Cycloaddition (Cu AAC) “Click” Reaction and Its Applications : An Overview, 255 COORD. CHEM. REV. 2933 (201 1). See also, for example, Herman S. Gill & Jan Mari k, Preparation of 18 F-labeled Peptides us ing the Copper(I)-Catalyzed Azide-Alkyne 1,3-Dipolar Cycloaddition, 6 NATURE PROT OCOLS 1718 (2011). The CuAAC click reaction can be carried out in the presence of ligands that enhance the reaction rate. Such ligands can include, for example, polydentate nitrogen donors including amines (e.g., tris(triazolyl)methylamine) and pyridine (Liang & Astruc, supra, at 2934 (collective examples); P. L. Golas et al., 39 MACROMOLECULES 6451 (2006) . See also). Other widely used click reactions include, but are not limited to, thiol-ene, oxime, Diels-Alder, Michael addition, and pyridylsulfide reactions.

[0128] Copper-free (Cu-free) click methods are also useful for drugs for therapy and / or diagnosis, such as radionuclides (e.g., 18 F), chemotherapeutic agents, dyes, contrast agents, fluorescent labels, chemiluminescent labels ​For the delivery of labels, or other labels, to the protein surface, it is known in the art. The Cu-free click method may enable stable covalent bonds between target molecules and complementary molecule families. The Cu-free click chemical reaction is a non-natural amino acid side chain containing an activating moiety such as cyclooctyne (e.g., dibenzocyclooctyne (DBCO)), nitrone or azide group (e.g., David J. Donnelly et al., Synthesis and Biologic Evaluation of a Novel F-L 18 abeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression, 59 J. NUCL. MED. 529 (2018)) antibodies or antigen-binding fragments, azide, nitro reacting with a complementary molecule family presenting a corresponding or complementary reactive moiety such as ron, or cyclooctyne (e.g., DBCO). For example, if the targeting molecule contains cyclooctyne, the complementary molecule family may contain azide, nitrone, or a similar reactive moiety. If the targeting molecule contains azide or nitrone, the complementary molecule family can present a complementary cyclooctyne, alkyne, or a similar reactive moiety. The Cu-free click reaction can be carried out at room temperature in an aqueous solution in the presence of phosphate buffered saline (PBS). The complementary molecule family can be radiolabeled (e.g., with F) or conjugated to any other therapeutic and / or diagnostic agent (e.g., a chelating agent) (see ibid., page 531). The Cu-free click reaction can be carried out at room temperature in an aqueous solution in the presence of phosphate buffered saline (PBS). The complementary molecule family can be radiolabeled (e.g., with F) or conjugated to any other therapeutic and / or diagnostic agent (e.g., a chelating agent) (see ibid., page 531). The complementary molecule family can be radiolabeled (e.g., with 18 F) or conjugated to any other therapeutic and / or diagnostic agent (e.g., a chelating agent) (see ibid., page 531). F) or conjugated to any other therapeutic and / or diagnostic agent (e.g., a chelating agent) (see ibid., page 531). It can be conjugated to (see ibid., page 531).

[0129] Compounds of any embodiment and aspect in the specification of the present technology can be triple compounds. . However, such triple compounds are not limited to compositions containing Formula I, IA, or II. Thus, in one aspect, the triple compound has a relatively low but still specific affinity for serum albumin (e.g., 0.5 - 50×10 - 6 M), for example, but not limited to only those described herein, a second domain containing a chelating moiety , and a third domain containing a tumor target targeting moiety (TTT) having a relatively high affinity for a tumor antigen (e.g., 0.5 - 50×10 M) are provided. The following -9 are exemplary peptide receptors, enzymes, cell adhesion molecules, tumor associated antigens, growth factor receptors, and clusters of differentiation antigens: TTT domain: somatostatin peptide receptor - 2 (SST R2), gastrin - releasing peptide receptor, seprase (FAP - α), incretin receptor , glucose - dependent insulinotropic polypeptide receptor, VIP - 1, NPY, folate receptor, LHRH, and αvβ3, overexpressed peptide receptors, neuronal transporters (e.g., norepinephrine transporter (NET)), or other tumor - associated proteins, such as EGFR, HER - 2, VGFR, MUC - 1, CEA, MUC - 4, ED2, T F - antigen, endothelial - specific markers, neuropeptide Y, uPAR, TAG - 72, CCK analogues, VIP, bombesin, VEGFR, tumor - specific cell surface proteins, GLP - 1, CXCR4, hepsin, TMPRSS2, caspases, Alpha V beta 6, cMET are useful targets for construction. Other such targets will be apparent to those skilled in the art, ​​Compounds that combine with these can be incorporated into TTT to produce triple radiotherapy compounds. It can be done.

[0130] The following formulas L to LIV provide exemplary general structures for the triple compounds of the present technology.

[0131] [Chemical formula] [In the formula, TTT, each time it appears, is independently a somatostatin peptide receptor-2 (SSTR2 ), gastrin-releasing peptide receptor, seprase (FAP-α), incretin receptor, glucose-dependent insulinotropic polypeptide receptor, VIP-1, NPY, folate receptor, LHRH, αvβ3, overexpressed peptide receptor, neuronal transporter (for example the norepinephrine transporter (NET)), tumor-related protein (for example, EGFR, H ER-2, VGFR, MUC-1, CEA, MUC-4, ED2, TF-antigen, endothelium-specific marker, neuropeptide Y, uPAR, TAG-72, CCK analog, VIP, bombesin, VEGFR, tumor-specific cell surface protein, GLP-1, CXCR4, hepsin, TMPRSS2, caspase, Alpha V beta 6, cMET, or any combination of two or more thereof) receptor, or binding domain for any combination of two or more thereof is, X 501 each time it appears, is independently absent, O, S, or NH; L 501 each time it appears, is independently absent, -C(O)-, -C(O)-NR 4 -, -C(O)-NR 5 -C 1 ~C 12 alkylene-, -C1 ~C 12 alkylene-C(O) -, -C(O)-NR 6 -C 1 ~C 12 alkylene-C(O)-, -arylene-, -O (CH 2 CH 2 O) r -CH 2 CH 2 C(O)-, -O(CH 2 CH 2 O) rr -CH 2 CH 2 C(O)-NH-, -O(CH 2 CH 2 O) rrr -CH 2 CH 2 -, amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more of them (wherein r is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 and rr is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, and rrr is 0 , 1, 2, 3, 4, 5, 6, 7, 8, or 9) (wherein R 4 , R 5 , and R 6 are each independently H, alkyl, or aryl); Rad, each occurrence, independently, contains a radionuclide and, optionally, further can contain a moiety; L 502 is, each occurrence, independently, absent or -C(O)-, -(CH 2 CH 2 O) s -CH 2 CH 2 C(O)-, -(CH 2 CH 2 O) ss -CH 2 CH2 C(O)-NH- 、-(CH 2 CH 2 O) sss -CH 2 CH 2 -、 an amino acid, -CH(CO 2 H)-(C H 2 ) 4 -、-CH(CO 2 H)-(CH 2 ) 4 -NH-、 2, 3, 4, 5, 6, 7, 8 、 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid peptides, or any combination of two or more thereof (wherein s is 0, 1, 2 、 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1 8, or 19, and ss is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 、 12, 13, 14, 15, 16, 17, 18, or 19, and sss is 0 、 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19); Alb is, independently for each occurrence, an albumin-binding moiety; p is, independently for each occurrence, 0, 1, 2, or 3; q is, independently for each occurrence, 1 or 2].

[0132] In any of the embodiments disclosed herein, the radionuclide is 177 Lu 3+ 、 175 Lu 3+ 、 45 Sc 3+ 、 66 Ga 3+ 、 67 Ga 3+ 、 68 Ga 3+ 、 69 Ga 3+, 71 Ga 3+ , 89 Y 3+ , 86 Y 3+ , 89 Zr 4+ , 90 Y 3+ , 99m Tc +1 , 111 In 3+ , 113 In 3+ , 115 In 3+ , 139 La 3+ , 136 Ce 3+ , 138 Ce 3+ , 140 Ce 3+ , 142 Ce 3+ , 151 Eu 3+ , 153 Eu 3+ , 152 Dy 3+ , 149 Tb 3+ , 159 Tb 3+ , 154 Gd 3+ , 155 Gd 3+ , 156 Gd 3+ , 157 Gd 3+ , 158 Gd 3+ , 160 Gd 3+ , 188 Re +1 , 186 Re +1 , 213 Bi 3+ , 211 At + , 217 At + , 227 Th 4+ , 22 6 Th 4+ 、 225 Ac 3+ 、 233 Ra 2+ 、 152 Dy 3+ 、 213 Bi 3+ 、 21 2 Bi 3+ 、 211 Bi 3+ 、 212 Pb 2+ 、 212 Pb 4+ 、 255 Fm 3+ 、 or may be uranium-230. For example, the radionuclide may be any alpha-emitting radionuclide, such as for example 213 Bi 3+ 、 211 At + 、 225 Ac 3+ 、 152 Dy 3+ 、 212 Bi 3+ 、 211 Bi 3+ 、 217 At + 、 227 Th 4+ 、 226 Th 4+ 、 233 Ra 2+ 、 212 Pb 2+ 、 or 212 Pb 4+ may be.

[0133] In any embodiment disclosed herein, the triplet compounds of Formulas L-LIV may be those of Formulas LV - LIX.

[0134] [Chemical formula] JPEG2025087695000051.jpg83162 [wherein, L 503 is, independently for each occurrence, absent, -C(O)-, -C 1 ~C 12 alkylene-, -C 1 ~C 12 alkylene-C(O)-, -C 1 ~C 12 alkylene-N R 10 -, -arylene-, -(CH 2 CH 2 O) z -CH 2 CH 2 C(O)-, -(C H 2 CH 2 O) zz -CH 2 CH 2 C(O)-NH-, -(CH 2 CH 2 O) zzz -C H 2 CH 2 -, amino acid, -CH(CO 2 H)-(CH 2 ) 4 -, -CH(CO 2 H)- (CH 2 ) 4 -NH-, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 1 4, 15, 16, 17, 18, 19, or 20 amino acids, or a combination of any two or more thereof (wherein, z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 11, 12, 13, 14, 15, 16, 17, 18, or 19, zz is 0 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, and zzz is 0, 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19), and present; For each occurrence, independently, optionally, CHEL is a co-bound chelator that may include a chelated radionuclide.

[0135] The albumin-binding moiety modulates the rate of plasma clearance of the compound in the subject, thereby increasing the circulation time, the cytotoxic effect of the cytotoxin-containing domain, and / or the imaging agent-containing domain in the plasma space instead of normal organs and tissues that may express the antigen. Without being bound by theory, this component of the structure is thought to interact reversibly with serum proteins such as albumin and / or cellular elements. The affinity of this albumin-binding moiety for plasma or cellular components of blood can be configured to affect the residence time of the compound in the blood pool of the subject. In any embodiment herein, the albumin-binding moiety can be configured to bind reversibly or irreversibly to albumin in the case of plasma. In any embodiment herein, the albumin-binding moiety can be selected such that the binding affinity of the compound to human serum albumin is from about 5 μM to about 15 μM. Thereby increasing the circulation time, the cytotoxic effect of the cytotoxin-containing domain, and / or the imaging agent-containing domain in the plasma space instead of normal organs and tissues that may express the antigen. Without being bound by theory, this component of the structure is thought to interact reversibly with serum proteins such as albumin and / or cellular elements. The albumin-binding moiety modulates the rate of plasma clearance of the compound in the subject, thereby increasing the circulation time, the cytotoxic effect of the cytotoxin-containing domain, and / or the imaging agent-containing domain in the plasma space instead of normal organs and tissues that may express the antigen. Without being bound by theory, this component of the structure is thought to interact reversibly with serum proteins such as albumin and / or cellular elements. Compartmentalize the imaging ability. Without being bound by theory, this component of the structure is thought to interact reversibly with serum proteins such as albumin and / or cellular elements. This component of the structure is thought to interact reversibly with serum proteins such as albumin and / or cellular elements. The affinity of this albumin-binding moiety for plasma or cellular components of blood can be configured to affect the residence time of the compound in the blood pool of the subject. The affinity of this albumin-binding moiety for plasma or cellular components of blood can be configured to affect the residence time of the compound in the blood pool of the subject. In any embodiment herein, the albumin-binding moiety can be configured to bind reversibly or irreversibly to albumin in the case of plasma. In any embodiment herein, the albumin-binding moiety can be configured to bind reversibly or irreversibly to albumin in the case of plasma. In any embodiment herein, the albumin-binding moiety can be selected such that the binding affinity of the compound to human serum albumin is from about 5 μM to about 15 μM.

[0136] By way of example, the albumin-binding moiety of any embodiment herein can include a single-chain fatty acid, a medium-chain fatty acid, a long-chain fatty acid, myristic acid, a substituted or unsubstituted indole-2-carboxylic acid, a substituted or unsubstituted 4-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butyric acid, a substituted or unsubstituted naphthaleneacylsulfonamide, a substituted or unsubstituted diphenylcyclohexanol phosphate ester, a substituted or unsubstituted 2 a substituted or unsubstituted indole-2-carboxylic acid, a substituted or unsubstituted 4-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butyric acid, a substituted or unsubstituted naphthaleneacylsulfonamide, a substituted or unsubstituted diphenylcyclohexanol phosphate ester, a substituted or unsubstituted 2 a substituted or unsubstituted naphthaleneacylsulfonamide, a substituted or unsubstituted diphenylcyclohexanol phosphate ester, a substituted or unsubstituted 2 a substituted or unsubstituted diphenylcyclohexanol phosphate ester, a substituted or unsubstituted 2 -(4-Iodophenyl)acetic acid, substituted or unsubstituted 3-(4-iodophenyl)pro pionic acid, or substituted or unsubstituted 4-(4-iodophenyl)butyric acid may be included. Some representative examples of albumin-binding moieties that may be included in any embodiment herein are as follows:

[0137]

Chemical formula

[0138] In any embodiment herein, the triple compound is

[0139]

Chemical formula

[0140] Representative chelators useful in any embodiment of the present technology include, but are not limited to the following groups: 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) , p-SCN-Bn-DOTA (also known as 2B-DOTA-NCS), PIP-DOTA, diethylenetriaminepentaacetic acid (DTPA), PIP-DTPA, AZEP-DTPA, ethylenediaminetetraacetic acid (EDTA), triethylenetetramine-N,N,N’,N’’,N’’’,N’’’-hexa-acetic acid (TTHA), 7-[2-(bis-carboxymethylamino)-ethyl]-4,10-bis-carboxy methyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid (DEPA), 2,2’,2’’-(10-(2-(bis(carboxymethyl)amino)-5-(4-i sothiocyanatophenyl)pentyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triyl)triacetic acid (3p-C-DEPA-NCS), NETA, {4-carboxymethyl-7-[2-(carboxymethylamino)-ethyl]-perhydro -1,4,7-triazonin-1-yl}-acetic acid (NPTA), diacetylpyridine bis(benzoylhydrazone), 1,4,7,10,13,16-hexaazacyclooctadecane-N,N’,N’’,N ’’’,N’’’’,N’’’’’-hexaacetic acid (HEHA), 8-coordinate terephthalic amide ligand, siderophore, 2,2'-(4-(2-(bis(carboxymethyl)amino)-5-(4-isothiocyanato phenyl)pentyloxy)-10-(2-(bis(carboxymethyl)amino)ethyl) -1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid, N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18 -crown-6 (H 2 macropa), 6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13 -tetraoxa-7,16-diazacyclooctadecane-7-yl)methyl)-4-isothio cyanatopicolinic acid (macropa-NCS), 1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoyl(car bamonyl)methyl)cyclododecane (TCMC), S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4, 7,10-tetra(2-carbamoylmethyl)cyclododecane (S-p-SCN-Bn- TCMC), R-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4, 7,10-tetra(2-carbamoylmethyl)cyclododecane (R-p-SCN-Bn- TCMC), and 3,9-carboxymethyl-6-(2-methoxy-5-isothiocyanatophenyl)car boxymethyl-3,6,9,15-tetraazabicyclo-[9.3.1]pentadeca-1 (15),11,13-triene contains covalently bonded substituted or unsubstituted chelators.

[0141] Some elements of this exemplary group are illustrated below.

[0142]

Chemical formula

[0143] A "covalently bound" chelator means a chelator (e.g., those described above) in which one or more bonds to the hydrogen atoms contained therein are replaced by single bonds to Rad and / or the remaining atoms of the CHEL moiety, L and / or L , or a π-bond between two atoms is replaced by a single bond from one of the two atoms to Rad and / or the remaining atoms of the CHEL moiety, L 501 and / or L 502 such that the other of the two atoms contains, for example, a new bond to hydrogen (e.g., a reaction of the -NCS group within the chelator that provides a covalently bound chelator). It should be understood. from, and the other of the two atoms contains, for example, a new bond to hydrogen (e.g., a reaction of the -NCS group within the chelator that provides a covalently bound chelator). and / or the remaining atoms of the CHEL moiety, L 501 and / or L 502 It should be understood that a new bond to hydrogen is included (e.g., a reaction of the -NCS group within the chelator that provides a covalently bound chelator). -CS group reaction). ).

[0144] In any of the embodiments disclosed herein, the CHEL of the triplex compound may be a chelator as shown in the compounds of Formula I, IA , or II. For example, the triplex compound may be of Formula II (wherein R , R 22 , R 24 , and R 26 , and R 28 are each independently ),

[0145]

Chemical formula

[0146] In any of the embodiments disclosed herein, TTT is

[0147]

Chemical formula

[0148] In any embodiment herein, P 501 , P 502 and P 503 each may be H .

[0149] The triple compounds of the present technology include any deformation of three domains: for example, a domain containing a chelator, a domain containing an albumin binding group, or a domain containing a tumor target-directed moiety. The following is exemplary.

[0150]

[0151] RPS-092.

Chemical formula

[0152] ​​In any embodiment disclosed herein, RPS-92 may, in some cases, 21 3 Bi 3+ , 211 At + , 225 Ac 3+ , 152 Dy 3+ , 212 Bi 3+ , 211 Bi 3+ , 217 At + , 227 Th 4+ , 226 Th 4+ , 233 Ra 2+ , 212 P b 2+ or 212 Pb 4+ can chelate.

[0153] NTI-093 is an analog of NTI-063, and TCMC can be used as a chelator. used.

[0154] [Chemical formula]

[0155] In any embodiment disclosed herein, NTI-93 may, in some cases, 21 2 Pb 2+ or 212 Pb 4+ can chelate.

[0156] NTI-094 is an analog of NTI-072, and TCMC can be used as a chelator. used.

[0157] [Chemical formula]

[0158] In any of the embodiments disclosed herein, NTI-94, in some cases, 21 2 Pb 2+ or 212 Pb 4+ can chelate.

[0159] Next is the bromo analog of NTI-063 with a modified albumin-binding domain .

[0160]

Chemical Structure

[0161] Next is the chloro analog of NTI-063 with a modified albumin-binding domain .

[0162]

Chemical Structure

[0163] NTI-309 modifies the tumor targeting domain to target sepulase (fibroblast activation protein / FAP).

[0164]

Chemical Structure

[0165] The NTI-309 compound can include TCMC as a chelator.

[0166]

Chemical Structure

[0167] In any of the embodiments disclosed herein, NTI-309, in some cases, 2 12 Pb 2+ or 212 Pb 4+ can be chelated.

[0168] Next is a boronic acid analog of NTI-309.

[0169]

Chem.

[0170] Next is a boronic acid analog of NTI-309 using TCMC as a chelator.

[0171]

Chem.

[0172] In any of the embodiments disclosed herein, the analog may, in some cases, 212 P b 2+ or 212 Pb 4+ can be chelated.

[0173] As a further specific example, a derivative of RPS-072 (which targets PSMA itself) can be constructed, TTT has an affinity for the SSTR2 receptor using a derivative of lanreotide and this compound (A) has a molecular weight of 3537.93 and the formula C 165 H 2 35 IN 28 O 44 S 3 167 A derivative of RPS-072 that targets the GRP / bombesin receptor can be prepared, and this compound (B) has a molecular weight of 3537.93 and the formula C and 167 H 248 IN 31 O 44It has the formula of S.

[0174] [Chemical formula] JPEG2025087695000069.jpg131170

[0175] This technology also provides any one of the compounds of formula I, IA, II, the modified antibodies, modified antibody fragments, or modified binding peptides of this technology disclosed herein, or any one of the embodiments of any one of them, or the triple compounds disclosed herein, and a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a pharmaceutically acceptable carrier or one or more additives or fillers (collectively referred to as "pharmaceutically acceptable carrier" unless otherwise specified). The composition can be used in the methods and treatments described herein. The pharmaceutical composition can contain an effective amount of any embodiment of the compounds of this technology for treating cancer and / or mammalian tissues overexpressing PSMA, or an effective amount of any embodiment of the modified antibodies, modified antibody fragments, or modified binding peptides of this technology for treating cancer and / or mammalian tissues overexpressing PSMA, or an effective amount of any embodiment of the triple compounds of this technology for treating cancer and / or mammalian tissues overexpressing PSMA. In one aspect, a method of treating a subject comprising administering a targeting compound of this technology to the subject, or administering a modified antibody, modified antibody fragment, or modified binding peptide of this technology to the subject. A method is provided. In any of the embodiments disclosed herein, the subject has a problem with cancer and / or mammalian tissue that overexpresses prostate-specific membrane antigen (「PSMA」). This can be the case. In any of the embodiments herein, the administering step is for treating cancer and / or mammalian tissue that overexpresses PSMA of the compounds of the present technology, or for treating cancer and / or mammalian tissue that overexpresses PSMA of a modified antibody, modified antibody fragment, or modified binding peptide of the present technology, or for treating cancer and / or mammalian tissue that overexpresses PSMA of a triple compound of the present technology, and may include the step of administering an effective amount of any of the embodiments. The subject may have a problem with mammalian tissue that expresses somatostatin receptor, bombesin receptor, separase, or any combination of two or more thereof, and / or mammalian tissue that overexpresses PSMA. The mammalian tissue in any of the embodiments disclosed herein may include one or more of tumors that produce growth hormones, neuroendocrine tumors, pituitary tumors, vasoactive intestinal peptide-secreting tumors, small cell lung cancer of the lung, gastric cancer, pancreatic cancer, neuroblastoma, and metastatic cancer. In any of the embodiments disclosed herein, the subject may have a problem with one or more of glioma, breast cancer, adrenal cortical cancer, 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 cancer, and prostate cancer. In any of the embodiments disclosed herein, the composition (e.g., pharmaceutical composition) and / or pharmaceutical product is parenteral ​​​​​​​​​​​​​​ It can be formulated for administration. In any of the embodiments disclosed herein, the composition ( e.g., a pharmaceutical composition) and / or the medicament can be formulated for intravenous administration. In any of the embodiments disclosed herein, the administration step of the method can include parenteral administration. In any of the embodiments disclosed herein, the administration step of the method can include intravenous administration.

[0176] In any of the above embodiments, the effective amount can be determined for the subject. "Effective amount" means the amount of a compound or composition required to produce the desired effect. A non-limiting example of an effective amount includes, but is not limited to, for example, glioma, breast cancer, adrenocortical cancer, 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, and one or more treatments for prostate cancer, including amounts or dosages that provide acceptable toxicity levels and bioavailability levels for therapeutic (pharmaceutical) use. Another example of an effective amount includes, for example, glioma, breast cancer, adrenocortical cancer, 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, and one or more of prostate cancer, including amounts or dosages that can reduce the symptoms associated therewith, for example, reduce the growth and / or metastasis of prostate cancer, breast cancer, or bladder cancer. The effective amount is about 0.01 μg to about 1 mg of the compound per gram of the composition, preferably per gram of the composition can be about 0.1 μg to about 500 μg of the compound per hit. As used herein, " subject" or "patient" refers to a mammal such as a cat, dog, rodent, or primate, etc. There is. Usually, the subject is a human, preferably glioblastoma, breast cancer, adrenocortical cancer, uterine 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 (e.g., colon adenocarcinoma), primary gastric adenocarcinoma, primary colorectal adenocarcinoma , renal cell carcinoma, and a human having or suspected of having one or more problems of prostate cancer. The terms "subject" and "patient" can be used synonymously.

[0177] In any of the embodiments of the technology described herein, the pharmaceutical composition can be packaged in unit dosage form. The unit dosage form is effective in treating one or more of glioblastoma, breast cancer, adrenocortical cancer, uterine 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 (e.g., colon adenocarcinoma), primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer. Generally, the unit dosage form including the compound of the technology varies according to the considerations for the patient. Such considerations include, for example, age, protocol, condition, gender, degree of disease, contraindications, combination therapy, etc. Exemplary unit dosage forms based on these considerations can also be adjusted or corrected by a physician skilled in the art. For example, the unit dosage form for a patient containing the compound of the technology can vary from 1×10 g / kg to 1 g / kg, preferably from 1×10 g / kg to 1.0 g / kg. The dosage of the compound of the technology can also be from 0.01 mg / kg to 100 mg / kg, preferably modified by a physician skilled in the art. For example, the unit dosage form for a patient containing the compound of the technology can be from 1×10 g / kg to 1 g / kg, preferably from 1×10 -4 g / kg to 1.0 g / kg. The dosage of the compound of the technology can also be from 0.01 mg / kg to 100 mg / kg, preferably -3 ​​​​​​can vary from 0.1 mg / kg to 10 mg / kg. Suitable unit dosage forms include, but are not limited to, powders, tablets, pills, capsules, troches, suppositories, patches, nasal sprays, injections, implantable sustained-release formulations, mucoadherent films, topical varnishes, lipid complexes, etc. include, but are not limited to, powders, tablets, pills, capsules, troches, suppositories, patches, nasal sprays injections, implantable sustained-release formulations, mucoadherent films topical varnishes, lipid complexes, etc.

[0178] The pharmaceutical composition is prepared by mixing one or more of the compounds of Formulas I, IA, II, or any modified antibodies, modified antibody fragments, or modified binding peptides of the present technology, or any embodiment of the triple compounds of the present technology, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, or their solvates, with pharmaceutically acceptable carriers, additives, binders, excipients, etc., to prevent and treat cancer and / or disorders associated with mammalian tissues overexpressing PSMA. Using the compounds and compositions described herein, for example, formulations and pharmaceuticals for treating prostate cancer, breast cancer, or bladder cancer can be prepared. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The composition can be formulated for various routes of administration, for example, orally, parenterally, topically, rectally, nasally, vaginally, or by implantable reservoirs. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injections. The following dosage forms are presented by way of example and should not be construed as limiting the instant present technology of the present invention. Using the compounds and compositions described herein, formulations and pharmaceuticals for treating, for example, prostate cancer, breast cancer, or bladder cancer can be prepared. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The composition can be formulated for various routes of administration, for example, orally, parenterally, topically, rectally, nasally, vaginally, or by implantable reservoirs. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injections. The following dosage forms are presented by way of example and should not be construed as limiting the instant present technology of the present invention. The composition can be formulated for various routes of administration, for example, orally, parenterally, topically, rectally, nasally, vaginally, or by implantable reservoirs. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injections. The following dosage forms are presented by way of example and should not be construed as limiting the instant present technology of the present invention. The following dosage forms are presented by way of example and should not be construed as limiting the instant present technology of the present invention. should not be construed as limiting the instant present technology of the present invention.

[0179] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules , gel capsules, and caplets are acceptable as solid dosage forms. These may be, for example, one or more compounds of the technology of the present invention, or pharmaceutically acceptable salts or tautomers thereof, mixed with at least one additive, such as starch or other additives, and prepared. Suitable additives include sucrose, lactose , cellulose sugar, mannitol, maltitol, dex tran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth , gum arabic, gelatin, collagen, casein, albumin, synthetic or semi synthetic polymers or glycerides. In some cases, oral dosage forms may be supplemented in administration with other ingredients, such as inert excipients, or lubricants, such as magnesium stearate, or preservatives, such as parabens or sorbic acid, or antioxidants, such as ascorbic acid, tocopherol or cysteine, disintegrants, binders, thickeners, buffers , sweeteners, flavoring agents or flavoring adjuncts. Tablets and pills may be further treated with suitable coating materials known in the art.

[0180] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions , and solutions, which may contain inert excipients, such as water, etc. Pharmaceutical formulations and pharmaceuticals may be prepared as liquid suspensions or It can be done. Pharmaceutically suitable surfactants, suspending agents, and emulsifiers can be added for oral or parenteral administration. It can be added for administration.

[0181] As described above, the suspension can contain oil. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. It includes, but is not limited to, peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. The suspension formulation can also contain esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. It can also contain esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. The suspension composition can contain alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol. It can contain alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol. Ethers, such as, but not limited to, poly(ethylene glycol); petroleum hydrocarbons, such as mineral oil and petrolatum; and water can also be used in the suspension composition. It can also be used in the suspension composition. Injection dosage forms generally include aqueous suspensions or oily suspensions, which can be prepared using suitable dispersing agents or wetting agents and suspending agents. The injection form can be in the form of a solution or a suspension, and is prepared with a solvent or excipient. Acceptable solvents or vehicles include sterile water, Ringer's solution, or isotonic aqueous saline solution. Alternatively, sterile oil can be used as a solvent or suspending agent. Usually, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di-, or tri-glycerides.

[0182] Injection dosage forms generally include aqueous suspensions or oily suspensions, which can be prepared using suitable dispersing agents or wetting agents and suspending agents. The injection form can be in the form of a solution or a suspension, and is prepared with a solvent or excipient. Acceptable solvents or vehicles include sterile water, Ringer's solution, or isotonic aqueous saline solution. Alternatively, sterile oil can be used as a solvent or suspending agent. Usually, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di-, or tri-glycerides. It can be prepared using suitable dispersing agents or wetting agents and suspending agents. The injection form can be in the form of a solution or a suspension, and is prepared with a solvent or excipient. It can be in the form of a solution or a suspension, and is prepared with a solvent or excipient. Acceptable solvents or vehicles include sterile water, Ringer's solution, or isotonic aqueous saline solution. It includes sterile water, Ringer's solution, or isotonic aqueous saline solution. Alternatively, sterile oil can be used as a solvent or suspending agent. Usually, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di-, or tri-glycerides. It is non-volatile, including natural or synthetic oils, fatty acids, mono-, di-, or tri-glycerides.

[0183] For injection, the pharmaceutical formulation and / or the medicament can be a powder suitable for reconstitution with the appropriate solution described above. These examples include, but are not limited to, lyophilized, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or microparticles. For injection, the formulation can optionally contain stabilizers, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. The compounds of the present technology can be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosol formulations containing any suitable solvent, and optionally other compounds, such as, but not limited to, stabilizers, antibacterial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof.

[0184] Carriers and stabilizers vary depending on the required amount of the particular compound, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, saccharides or sugar alcohols. Aqueous and non-aqueous (e.g., in the form of a fluorocarbon propellant) aerosol formulations are commonly used for delivery of the compounds of the present technology by inhalation. In addition to these representative dosage forms described above, pharmaceutically acceptable additives and carriers are well known to those skilled in the art and are therefore included in the technology of the present invention. Such additives and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Ma The compounds of the present technology can be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosol formulations containing any suitable solvent, and optionally other compounds, such as, but not limited to, stabilizers, antibacterial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary depending on the required amount of the particular compound, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, saccharides or sugar alcohols. Aqueous and non-aqueous (e.g., in the form of a fluorocarbon propellant) aerosol formulations are commonly used for delivery of the compounds of the present technology by inhalation. In addition to these representative dosage forms described above, pharmaceutically acceptable additives and carriers are well known to those skilled in the art and are therefore included in the technology of the present invention. Such additives and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Ma

[0185] In addition to these representative dosage forms described above, pharmaceutically acceptable additives and carriers are well known to those skilled in the art and are therefore included in the technology of the present invention. Such additives and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Ma To those skilled in the art, such additives and carriers are well-known and are thus included in the technology of the present invention. Such additives and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Ma For example, "Remingtons Pharmaceutical Sciences" Ma described in ck Pub.Co., New Jersey (1991), which is hereby incorporated by reference into this specification. The composition can also include, for example, micelles or liposomes, or some other encapsulated form. is hereby incorporated by reference into this specification. The composition can also include, for example, micelles or liposomes, or some other encapsulated form.

[0186] Specific dosages can be adjusted according to the subject's disease state, age, weight, overall health, gender, and diet, dosing interval, route of administration, excretion rate, and combination of drugs. Any of the dosage forms containing an effective amount is sufficient within the scope of routine experimentation and is thus sufficient within the scope of the technology of the present invention. Specific dosages can be adjusted according to the subject's disease state, age, weight, overall health, gender, and diet, dosing interval, route of administration, excretion rate, and combination of drugs. Any of the dosage forms containing an effective amount is sufficient within the scope of routine experimentation and is thus sufficient within the scope of the technology of the present invention. Specific dosages can be adjusted according to the subject's disease state, age, weight, overall health, gender, and diet, dosing interval, route of administration, excretion rate, and combination of drugs. Any of the dosage forms containing an effective amount is sufficient within the scope of routine experimentation and is thus sufficient within the scope of the technology of the present invention. Specific dosages can be adjusted according to the subject's disease state, age, weight, overall health, gender, and diet, dosing interval, route of administration, excretion rate, and combination of drugs. Any of the dosage forms containing an effective amount is sufficient within the scope of routine experimentation and is thus sufficient within the scope of the technology of the present invention.

[0187] A variety of assays and model systems can be readily used to determine the therapeutic efficacy of the treatment according to this technology. A variety of assays and model systems can be readily used to determine the therapeutic efficacy of the treatment according to this technology.

[0188] In the case of the indicated condition, the test subject shows a 10%, 20%, 30%, 50% or more reduction, 75 to 90% or a 95% or more reduction in one or more symptoms (plural) caused by or associated with the disorder in the subject as compared to a subject treated with a placebo or other appropriate control. to 90% or a 95% or more reduction in one or more symptoms (plural) caused by or associated with the disorder in the subject as compared to a subject treated with a placebo or other appropriate control. to 90% or a 95% or more reduction in one or more symptoms (plural) caused by or associated with the disorder in the subject as compared to a subject treated with a placebo or other appropriate control.

[0189] In another aspect, the technology provides a method of treating cancer by administering to a subject having cancer an effective amount of a target-directed composition according to formula (II). Since the cancer cell target-directed agent can be selected to target any of a wide range of cancers, the cancers contemplated herein for treatment are not limited. The cancer can be essentially any type of cancer. For example, an antibody or peptide vector can target any of a wide range of cancers. In another aspect, the technology provides a method of treating cancer by administering to a subject having cancer an effective amount of a target-directed composition according to formula (II). Since the cancer cell target-directed agent can be selected to target any of a wide range of cancers, the cancers contemplated herein for treatment are not limited. The cancer can be essentially any type of cancer. For example, an antibody or peptide vector can target any of a wide range of cancers. In another aspect, the technology provides a method of treating cancer by administering to a subject having cancer an effective amount of a target-directed composition according to formula (II). Since the cancer cell target-directed agent can be selected to target any of a wide range of cancers, the cancers contemplated herein for treatment are not limited. The cancer can be essentially any type of cancer. For example, an antibody or peptide vector can target any of a wide range of cancers. In another aspect, the technology provides a method of treating cancer by administering to a subject having cancer an effective amount of a target-directed composition according to formula (II). Since the cancer cell target-directed agent can be selected to target any of a wide range of cancers, the cancers contemplated herein for treatment are not limited. The cancer can be essentially any type of cancer. For example, an antibody or peptide vector can target any of a wide range of cancers. In another aspect, the technology provides a method of treating cancer by administering to a subject having cancer an effective amount of a target-directed composition according to formula (II). Since the cancer cell target-directed agent can be selected to target any of a wide range of cancers, the cancers contemplated herein for treatment are not limited. The cancer can be essentially any type of cancer. For example, an antibody or peptide vector can target any of a wide range of cancers. can be generated for. The targeted compositions described herein are typically administered by injection into the bloodstream, but other modes of administration, such as oral or topical administration, are also considered. In some embodiments, the targeted composition is administered locally at the site where the target cells are present, i.e., in a particular tissue, organ, or body fluid (e.g., blood, cerebrospinal fluid, etc.). Any cancer that can be delivered to the target through the bloodstream is specifically contemplated herein. Some examples of applicable body sites containing cancer cells include the breast, lung, stomach, intestine, prostate, ovary, cervix, pancreas, kidney, liver, skin, lymph, bone, bladder, uterus, colon, rectum, and brain. Cancer can also include the presence of one or more carcinomas, sarcomas, lymphomas, blastomas, or teratomas (germ cell tumors). Cancer can also be in the form of leukemia. In some embodiments, the cancer is triple negative breast cancer.

[0190] As is well known in the art, the dosage of the active ingredient(s) generally depends on the disorder or condition to be treated, the degree of the disorder or condition, the method of administration, the size of the patient, and the potential side effects In different embodiments, depending on these and other factors, the appropriate dosage of the targeted composition is exactly at least, for example, at least 1 mg, 10 mg, 50 mg , 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, or 1500 mg, 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 50 0 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 m g, or more than 1500 mg, 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 9 00 mg, 1000 mg, 1200 mg, or up to or less than 1500 mg, or may be a dosage within the range limited by any of the aforementioned exemplary dosages . Further, the composition may be administered in any suitable schedule, e.g., once, twice, or three times a day or for 1, 2, 3, 4, or 5 days, or 1, 2, 3, or 4 weeks, or 1 , 2, 3, 4, 5, or 6 months, on alternate days throughout the entire treatment period, or within the time frame therein, in the indicated amounts. Alternatively, or in addition, the composition may be administered until the desired change in the disorder or condition is achieved or until a prophylactic effect is provided as may be contemplated.

[0191] The examples in this specification are provided to illustrate the benefits of the technology and to further assist those skilled in the art in preparing or using the compounds of the technology or their salts, pharmaceutical compositions, derivatives, prodrugs, or tautomers. The examples in this specification are also presented to more fully illustrate the preferred embodiments of the technology. These examples should not be construed as limiting the scope of the technology as defined by the appended claims. These examples can include or incorporate any of the aforementioned variations, aspects, or embodiments of the technology. The aforementioned variations, aspects, or embodiments can also further include or incorporate any variation of any or all of the other variations, aspects, or embodiments of the technology.

Examples

[0192] Exemplary Synthesis Procedures and Characterization Materials and Instrumentation Used. All solvents and reagents were purchased from commercial sources and used without further purification when administered. Solvents labeled "dry" were obtained after storage over 3 Å molecular sieves. Metal salts were purchased from Strem Chemicals (Newburyport, MA) and obtained in the highest purity available; Lu(ClO ) was provided as an aqueous solution containing 15.1 wt% Lu. The bifunctional ligand p-SCN- Bn-DOTA was purchased from Macrocyclics (Plano, TX). NM 4 ) 3 was purchased as a 25 wt% solution in H O (trace metal basis, Beantown Chemical, Hudson, NH). Hydrochloric acid (BDH Aristar Plus, VWR, Radnor, PA) and nitric acid (Optima, ThermoFisher Scientific, Waltham, MA) were of trace metal grade e 4 OH was 2 . Chelex 100 (sodium form, 50 - 100 mesh) and human serum used for the Ac-complex challenge assay were purchased from Sigma Aldrich (St. Louis, MO). Deionized water (≥18 MΩcm) was prepared in-house using a Millipore Direct-Q® 3UV or Elga Purelab Flex 2 water purification system . Hydrochloric acid (BDH Aristar Plus, VWR, Radnor, PA) and nitric acid (Optima, ThermoFisher Scientific, Waltham, MA) were of trace metal grade . 225 Chelex 100 (sodium form, 50 - 100 mesh) used for the Ac-complex challenge assay and human serum were purchased from Sigma Aldrich (St. Louis, MO). Deionized water (≥18 MΩcm) was prepared in-house using a Millipore Direct-Q® 3UV or Elga Purelab Flex 2 water purification system . The reactions were monitored by thin layer chromatography (TLC, Whatman UV254 aluminum plates)

[0193] plates) ​Monitored by back silica gel). H used for the analysis and purification of the compound The PLC system consists of a CBM-20A communication bus module, L C-20AP (preparative) or LC-20AT (analytical) pump, and at 270 nm SPD-20AV UV / Vis detector monitoring (Shimadzu Corporation Shimadzu Corporation, Japan). Analytical chromatography was performed at a flow rate of 1.0 mL / min using an Ultra Aqueous C18 column, 100 Å, 5 μm, 2 50 mm × 4.6 mm (Restek, Bellefonte, PA). Purification was performed at a flow rate of 14 mL / min using an Epic Polar preparative column, 120 Å, 10 μm, 25 cm × 20 mm (ES Industries, West B erlin, NJ) unless otherwise indicated. Gradient HPLC was performed using a binary mobile phase 2 containing H O (A) and MeOH ( B) or ACN (C). HPLC method A: 10% B (0 - 5 min), 10 - 100% B (5 - 25 min). Method B: 10% C (0 - 5 min), 10 - 100% C (5 - 25 min). Method C: 10% C (0 - 5 min), 10 - 100% C (5 - 40 min). Method D: 10% C (0 - 5 min), 10 - 100% C (5 - 20 min). The solvent system contained 0.1% trifluoroacetic acid (TFA) except for method C which used 0.2% TFA. NMR spectra were recorded on a Varian Inova 300 MHz, 400 MHz, 500 MHz or 600 MHz spectrometer, or a Bruker AV equipped with a broadband Prodigy cryoprobe III Recorded at ambient temperature on a HD 500 MHz spectrometer. Chemical shifts are reported in p pm. 1 H and 13 C NMR spectra were referenced to the TMS internal standard (0 ppm), the remaining solvent peaks, or the acetonitrile internal standard (D 2 O spectrum at 2.0 6 ppm). 19 F NMR spectra were referenced to the monofluorobenzene internal standard ( -113.15 ppm). The reported 1 proton resonance splittings in the H spectrum were defined as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dt = triple doublet, td = double triplet, and br = broad. IR spectroscopy was performed on a KBr pellet of the sample using a Nic olet Avatar 370 DTGS (ThermoFisher Scient ific, Waltham, MA). High-resolution mass spectra (HRMS) were recorded in positive ESI mode on an Exactive Orbitrap mass spectrometer ( ThermoFisher Scientific, Waltham, MA). UV / Visible spectra were recorded on a Cary 8454 UV-Vis (Agilent Tec hnologies, Santa Clara, CA) using a 1-cm quartz cuvette unless otherwise indicated. Elemental analysis (EA) was performed by Atlantic Microlab, Inc. (Norcross, GA) .

[0194] Synthesis and Characterization of Macropa Complexes, Macropa-NCS, and Macropa-NHC(S) NHCH 3 N,N’-Bis[(6-carboxy-2-pyridyl) Methyl]-4,13-diaza-18-crown-6(H 2 macropa·2HCl·4 H 2 O) [102,103] was purchased from EMD Millipore (Darmstadt, G ermany) or synthesized according to the literature protocol

[0104] and used to prepare 1, 7,10,16-tetraoxa-4,13-diazacyclooctadecane (7). Ceridamic acid monohydrate (1) was purchased from TCI America (Portland, O R). Dimethyl 4-chloropyridine-2,6-dicarboxylate (2), dimethyl 4-azidopyridine-2,6-dicarboxylate (3),

[0105] and 6-chloromethylpyridine-2-carboxylic acid methyl ester (8), [106 ] were prepared according to the indicated literature protocols.

[0102] Preparation of

[0195] [La(macropa)] 2+ To a suspension of H

[0196]

Chemical formula

[0197] [Lu(macropa)] + Preparation of

[0198]

Chem.

[0199] Preparation of dimethyl 4-aminopyridine-2,6-dicarboxylate (4).

[0200] [Chemical formula] Dimethyl 4-azidopyridine-2,6-dicarboxylate (3, 0.9445 g, 4. 0 mmol), 10% Pd / C (0.1419 g), and DCM:MeOH (1:1, 18 mL) were combined in a round-bottom flask. The flask was purged with an H 2 balloon, and then the reaction was vigorously stirred at room temperature for 46 h under an H atmosphere. The gray mixture was diluted with DMF (450 2 mL) and filtered through a celite layer. After filtering through a 0.22 μm nylon membrane, the filtrate was concentrated under reduced pressure at 60 °C and further dried in vacuo to give 4 as a light tan solid (0 .824 g, 98% yield). 1 H NMR (500 MHz, DMSO-d 6 ): δ = 7.36 (s, 2 H), 6.72 (s, 2 H), 3.84 (s, 6 H). 13 C{ 1 H} APT NMR (126 MHz, DMSO-d6): δ = 165 .51, 156.24, 148.05, 111.99, 52.29. IR (cm -1 ): 3409, 3339, 3230, 1726, 1639, 15 91, 1443, 1265, 996, 939, 787, 630, 543. HPLC t R = 9.369 min (Method B). HRMS (m / z) : 211.07213 [M + H] + ; Calculated value: 211.07133.​

[0201] Preparation of ethyl 4-amino-6-(hydroxymethyl)picolinate (5).

[0202] [Chemical formula] To a refluxing suspension of 4 (0.677 g, 3.22 mmol) in anhydrous EtOH (27 mL), Na BH 4 (0.1745 g, 4.61 mmol) was added portionwise over 1 h to give a pale yellow suspension which was obtained. Then, the reaction was quenched with acetone (32 mL) and concentrated under reduced pressure at 60 °C to a yellowish brown solid product. The crude product was dissolved in H 2 O (60 mL) and washed with ethyl acetate (4 × 150 mL ). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure at 40 °C . Further dried in vacuo to produce 5 as a pale yellow solid (0.310 g, 49% yield) . 1 H NMR (300 MHz, DMSO-d 6 ): δ = 7.07 (d, J = 2.1 Hz, 1H), 6.78 (m, 1H), 6.3 2 (s, 2H), 5.30 (t, J = 5.8 Hz, 1H), 4.39 (d, J = 5.6 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13 C APT NMR (126 MHz, DMSO-d 6 ) δ = 165.57, 1 62.38, 155.68, 147.25, 108.50, 107.01, 63.95, 60.61, 14.24. IR (cm -1 ): 3439, 321 7, 2974, 2917, 1717, 1643, 1600, 1465, 1396, 1378, 1239, 1135, 1022, 974, 865, 7 83. HPLC t R = 8.461 minutes (Method B). HRMS (m / z): 197.09288 [M + H] + ; Calculated value: 197.092 07.

[0203] Preparation of ethyl 4-amino-6-(chloromethyl)picolinate (6).

[0204]

Chemical formula

[0205] Methyl 6 - ((1,4,10,13 - tetraoxa - 7,16 - diazacyclooctade can - 7 - yl)methyl)picolinate (9·2TFA·1H 2 O) preparation.

[0206]

Chem.

[0207] Ethyl 4-amino-6-((16-((6-(methoxycarbonyl)pyridin-2-yl methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadeca ne-7-yl)methyl)picolinato (10) Preparation.

[0208]

Chemical formula

[0209] 4-Amino-6-((16-((6-carboxypyridin-2-yl)methyl)-1, 4,10,13-tetraoxa-7,16-diazacyclooctadecane-7-yl)methyl yl)picolinic acid (11·4TFA) Preparation.

[0210] [Chemical formula] Compound 10 (0.612 g) was dissolved in 6 M HCl (7 mL) and heated at 90 °C for 17 h. The dark brown solution containing a slight precipitate was concentrated under reduced pressure at 60 °C to a light tan solid. To this solid was added 10% MeOH / H O containing 0.1% TFA (3 mL). 2 The slight suspension was filtered, and the filtrate was purified by preparative HPLC using Method A. The pure fractions were combined, concentrated under reduced pressure at 60 °C, and then lyophilized to give an off-white solid (0.2974 g, 46% yield over 2 steps). 11 was obtained. 1 H NMR (500 MHz, DMSO-d 6 ) δ = 8.13 - 8.08 (m, 2H), 7.80 (dd, J = 7.3, 1.6 Hz, 1H), 7.64 (br s), 7.24 (d, J = 2.3 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 4.74 ( s, 2H), 4.15 (s, 2H), 3.85 (t, J = 5.0 Hz, 4H), 3.63 (t, J = 5.1 Hz, 4H), 3.57 - 3 .50 (m, 12H), 3.09 (br t, J = 5.2 Hz, 4H). 13 C{ 1 H} NMR (126 MHz, DMSO-d 6 ) δ 16 5.96, 163.37, 159.47, 158.78 - 157.98 (q, TFA), 151.93, 151.64, 148.25, 144.68, 13 9.59, 128.43, 124.96, 120.79 - 113.68 (q, TFA), 109.40, 108.96, 70.03, 69.89, 67.0 9, 65.16, 57.28, 55.85, 54.47, 53.81. 19 F NMR (470 MHz, DMSO - d 6 ) δ = -74.03. E A Measured values: C, 40.60; H, 4.29; N, 7.04. C 26 H 37 N 5 O 8· 4CF 3 COOH Calculated values: C, 40.69; H, 4.12; N, 6.98. IR (cm -1 ): 3387, 3161, 1735, 1670, 1204, 1130, 791, 722. HPLC t R = 11.974 min (Method B); 11.546 min (Method D). HRMS (m / z): 548.26883 [M + H] + ; Calculated value: 548.27149.

[0211] 6 - ((16 - ((6 - carboxypyridin - 2 - yl)methyl)-1,4,10,1 3 - tetraoxa - 7,16 - diazacyclooctadecane - 7 - yl)methyl)-4 - i sothiocyanatopicolinic acid (12, macropa - NCS) preparation.

[0212]

Chemical formula

[0108] 0 °C. Isothiocyanate 12 was obtained as a mixture of white and pale yellow solids (0.0547 g) and stored at -80 °C in a wide-mouth bottle with Drierite. The H NMR and F NMR spectra of a sample of 12 added with a known concentration of fluorobenzene 1 suggested that 12 was isolated as the tetra-TFA salt. 19 F NMR Based on calculations from the spectra, 12 was estimated to be isolated as the tetra-TFA salt. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.17 - 8.06 (m, 2H), 8.00 (s w / fine splitting, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.81 - 7.75 (d w / fine splitting, J = 7.16 Hz, 1H), 4.71 (s, 2H), 4.64 (s, 2H), 3.89 - 3.79 (m, 8H), 3.62 - 3.46 (m, 16H). 19 F NMR (470 MHz, DMSO -d 6 ) δ = -74.17. IR (cm -1 ): ~3500 - 2800, 2083, 2026, 1735, 1670, 1591, 1448, 118 ​​3, 1130, 796, 717. HPLC t R = 15.053 min (Method B); 13.885 min (Method D). HRMS (m / z): 5 90.22600 [M + H] + ; Calculated: 590.22791.

[0213] 6-((16-((6-Carboxypyridin-2-yl)methyl)-1,4,10,1 3-tetraoxa-7,16-diazacyclooctadecane-7-yl)methyl)-4-( 3-methylthioureido)picolinic acid (13, macropa-NHC(S)NHCH 3 ) Preparation.

[0214]

Chemical Structure

[0215] Macropa-(OCH 2 CH 2 )-Ph-NCS preparation. Schematic overview of the synthesis of another embodiment of Macropa-NCS with improved stability The figure is provided in Figure 3. The compound is evaluated as described below and is useful for radiolabeling their binding to antibodies, antibody fragments (e.g., antigen-binding fragments), and peptides, as well as for chelation of radionuclides and their inevitable use in the manufacture of therapeutic compounds and targeted delivery of therapeutic radiation. Detailed information on the synthesis is provided below.

[0216]

Chemical Structure

[0217]

Chemical Structure

[0218]

Chemical Structure

[0219]

Chemical formula

[0220]

Chemical formula

[0221] ​[Chemistry] Compound 7 (0.08 g, 0.1 mmol) was dissolved in 6 M aqueous HCl (5 mL) and stirred at room temperature for 2 h to 3 h. After completion of the starting material (as indicated by LCMS), the aqueous HCl solution was removed under reduced pressure, and the crude reaction mixture containing Compound 8 was used in the next step of the synthesis without further purification. solution was removed under reduced pressure, and the crude reaction mixture containing Compound 8 was used in the next step of the synthesis without further purification. solution was removed under reduced pressure, and the crude reaction mixture containing Compound 8 was used in the next step of the synthesis without further purification. and used in the next step of the synthesis.

[0222] [Chemistry] The crude deboc product was dissolved in THF: 1 M LiOH (1:1, 5 mL) and stirred until the reaction was complete. The resulting crude product was purified by prep-HPLC to give Compound 9. The crude product obtained was purified by prep-HPLC to give Compound 9. was obtained.

[0223] [Chemistry] NEt 3 (7.6 mg, 0.076 mmol) was added to a solution of Compound 9 (26 mg, 0.038 mmol) in (8:2) acetonitrile and water ( 1 mL). Next, di-2 -pyridylthiocarbonate (18 mg, 0.076 mmol) was added at room temperature and stirred vigorously for 1 h. The crude reaction mixture was purified directly by HPLC to give Compound 10 (mac ropa-(OCH CH 2 CH 2 )-Ph-NCS).

[0224] [Chemistry]

[0225] X-ray diffraction test. H suitable for X-ray diffraction 2macropa·2HCl·4H 2 Single crystals of O were , left at room temperature and then grown from a saturated H 2 O:acetone (1:5) solution. [La(H macropa)(H 2 O)]·(ClO 4 ) 2 Single crystals of were grown by vapor diffusion of THF into an acidic aqueous solution (pH approximately 2) after adding the complex. [Lu(macr opa)]·ClO ·DMF single crystals were grown by 4 vapor diffusion of Et 2 O into a DMF solution of the complex .

[0226] H 2 macropa·2HCl·4H 2 O, [La(Hmacropa)(H 2 O)] ·(ClO 4 ) 2 , and [Lu(macropa)]·ClO 4 ·DMF for X -ray diffraction data were collected on a Bruker APEX 2 CCD Kappa diffractometer (Mo Kα, λ = 0.71073 Å) at 223 K. These structures were analyzed by the intrinsic phasing method using SHE LXT , and after establishing an improved

[0109] strategy, all data were refined by full-matrix least squares using SHELXL for F

[0110] against all data. 2 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in the model at geometrically calculated positions and refined using the riding model.

[0111] All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in the model at geometrically calculated positions and refined using the riding model. ​​It was done. The hydrogen atoms bonded to nitrogen and oxygen were located by difference Fourier synthesis and subsequently refined semi-freely using distance restraints. The isotropic displacement parameters of all hydrogen atoms were fixed at 1.2 times the U value of the atoms to which they are connected (1.5 times in the case of methyl groups). In the case of [La(H macropa)(H O)]·(ClO macropa)(H 2 O)]·(ClO 4 ) 2 the partially occupied solvent molecules of water were included in the unit cell but could not be satisfactorily modeled. Therefore, this solvent was treated as a contribution to the overall scattering by diffusion using the solvent masking function in Olex2 without using the positions of specific atoms. Macropa titration of La and Lu. The pH of 10 mM 3-(N-morpholino

[0112]

[0227] )propanesulfonic acid (MOPS) buffer was adjusted to 7.4 3+ using an aqueous solution of NMe 3+ OH. The ionic strength was set at 100 mM using NMe )propanesulfonic acid (MOPS) buffer was adjusted to 7.4 4 using an aqueous solution of NMe OH. The ionic strength was set at 100 mM using NMe 4 Cl. Stock solutions of LaCl 3 · 6.8H 2 O (40 mM) and LuCl 3 ·6H 2 O (21 mM) were prepared with 1 mM HCl. A stock solution of H 2 macropa·2HCl·4H 2 O (8.8 mM) was prepared in MOPS buffer. Titration solutions containing macropa (100 μM) and MOPS buffer. Aliquots of 5 - 10 μL of the titrant were added to 3000 μL of macropa (100 μM) in MOPS. LaCl 3 or LuCl 3 were prepared in MOPS. Aliquots of 5 - 10 μL of the titrant were added to 3000 μL of macropa (100 μM) in MOPS. containing aliquots of 5 - 10 μL of the titrant were added to 3000 μL of macropa (100 μM) in MOPS. By adding to the cuvette, each metal ion titration was performed at RT. Each sample was , and equilibrated for 5 minutes each time it was added before acquiring the spectrum. The complex formation of the metal ion was monitored by the decrease in absorbance at 268 nm, which is the λ of acropa. The titrant was added until no further spectral changes were detected. max

[0228] Kinetic inertness of the La 3+ and Lu 3+ complexes of Macropa: Transchelation challenge. A stock solution of ethylenediaminetetraacetic acid (EDTA, 100 mM) was prepared in MOPS buffer (prepared as described above) by adjusting the pH of the initial suspension to 6.6 using an aqueous solution of NMe 4 OH. A stock solution of diethylenetriaminepentaacetic acid (DTPA, 125 mM ) was prepared in H O by adjusting the pH to 7.4 as described for EDTA. This solution was serially diluted with H O to produce 12.5 mM and 1.25 mM solutions of DTPA. 2 2 The preformed La and Lu

[0229] complexes of macropa were challenged with EDTA. An aliquot of the solution containing EDTA (98.7 mM) and macropa (10 3+ 0 μM) in MOPS buffer was added to each solution of the complex to initiate the challenge. The final M:macropa:EDTA ratio was approximately 1:1:20 (La) and 3+ 1:1:10 (Lu). The solutions were repeatedly analyzed by UV spectroscopy for any spectral changes over a period of 21 days. The final pH of each solution was 7.18. ​ was between 7.25.

[0230] La 3+ and the complex formed in situ between macropa and excess DT PA was further severely challenged. The aforementioned LaCl 3 and macropa stock solution containing 500 μM of the complex prepared using the solution was equilibrated for 5 minutes. Subsequently, this was divided into cuvettes and diluted with 125 mM DTPA, 12.5 mM DTPA, 1.25 m M DTPA, or MOPS to produce solutions containing 1000-, 100-, 10-, or 0 -fold excess of DTPA and 100 μM concentration of macropa. These solutions were repeatedly analyzed by UV spectroscopy over 21 days for any spectral changes. The final pH of each solution was between 7.11 and 7.42.

[0231] Macropa and DOTA's 225 Ac radiolabeling. 225 Ac and 225 Ra were produced by the fragmentation reaction of uranium carbide and separated downstream from other radionuclides by a mass separator using the Isotope Separator and Accelerator (ISAC) online isotope separation (ISOL) capabilities at TRIUMF (Vancouver, BC, Canada) and collected according to the literature protocol. arator and Accelerator) online isotope separation (ISOL) capabilities using a mass separator and separated downstream from other radionuclides by a mass separator and collected according to the literature protocol. collected. [103,104] Next, 225 Ac was passed through a DGA column [105,106 ] (branched, 50 - 100 μm, Eichrom Technologies LLC) by 225Separated from Ra and obtained in 0.05 M HNO for use in the radiolabeling experiment 3 obtained in. Aluminum-backed TLC plates (silica gel 60, F 254 , EMD Millipore, Darmstadt, Germany) were used to 225 analyze the progress of the Ac radiolabeling reaction. Silica gel (iTLC-SG, Agilent Tech nologies, Mississauga, ON, Canada)-impregnated instant thin layer chromatography paper was used for La and serum stability challenges. The TLC plates were developed and then, after at least 8 h, counted in a BioScan Autocha 3+ nger 1000 and BioScan System 200 imaging scanner equipped with WinScan software to allow the time for the daughter radionuclide to completely decay and to ensure that the measured radioactivity signal was generated by the parent Ac. The quantitative radioactivity measurements of Ac, Fr, and Bi were determined by γ-spectroscopy measurements using a high-purity germanium (HPGe 225 ) detector (Canberra GR1520, Meriden, CT) calibrated with NIST-traceable 225 Ac, 221 Fr, and 213 Bi mixed source. The dead time of the detector was maintained at less than 10% for all measurements 133 Ba and 152 . The data were analyzed using Genie2000 software (v3.4, Canberra, Mer iden, CT). The detector dead time was maintained at less than 10% for all measurements . The data were analyzed using Genie2000 software (v3.4, Canberra, Mer iden, CT).

[0232] Concentration dependence. Various concentrations of macropa and DOTA were used for 225 Ac 3+Radioactive labeling was identified, and the lowest concentration at which >95% of the radioactive label further occurred was determined. H 2 macropa· 2HCl·4H 2 O (10 -3 ~10 -8 M) and H 4 DOTA (10 -3 、10 -5 、and 10 -7 M) stock solutions were prepared in H 2 O. For each radioactive labeling reaction, ligand (10 μL) and 225 Ac (10~26 kBq, 10~30 μL) were sequentially added to NH 4 OA c buffer (pH 6, 0.15 M, 150 μL) to obtain a final ligand concentration of ma cropa of 5.3×10 -5 ~5.9×10 -10 M and 5.9 ×10 -5 ~5.9×10 -9 M for DOTA. The final pH of all labeling reactions was between 5.5 and 6. The reaction solution was maintained at ambient temperature or 80 °C. The progress of the reaction was monitored at 5 and 30 minutes by spotting 3~5 μL of the reaction solution onto a TLC plate. These plates were developed with a mobile phase of 0.4 M sodium citrate containing 10% MeOH (pH 4) and then counted. Under these conditions, 225 Ac (macropa)] + and 225 Ac (DOTA)] - remained at the baseline (R F = 0), and any unchelated 225 Ac( 225 Ac-citrate) migrated with the solvent front (R 、and moved with the solvent front (R F=1). The radiochemical yields (RCYs) were determined by integrating the peak areas under the curve in grams and dividing the counts associated with the 225 Ac-complex (R F =0) by the total counts integrated along the length of the TLC plate. Calculations were performed as follows.

[0233] Kinetic inertness of the 225 Ac complexes of Macropa and DOTA.

[0234] Overview. Stock solutions of La(NO 3 ) 3 (0.001 M or 0.1 M) were prepared in H 2 2O. NH 4 4OAc buffer (pH 6, 0.15 M, 150 μL) containing macropa (10 -5 M stock solution 10 μL; 1.0 × 10 -10 −5 moles) or DOTA (10 -3 M stock solution 10 μ L; 1.0 × 10 -8 −5 moles) and 225 225Ac (10 μL, 26 kBq) were added to radiolabeled samples containing a 50-fold molar excess of La (0.001 M or 0.1 3+ M stock solution 5 μL was added to the solutions containing macropa and DOTA, respectively). The solutions were maintained at room temperature and analyzed by iTLC at several time points over 8 days. The iT LC plates were developed using citric acid (0.05 M, pH 5) as the eluent. Under these conditions, 225Ac(macropa)] 225 and + and 225 225Ac(DOTA)] - remained at the baseline (R F = 0), and any unchelated 225 225Ac( 22 5 The Ac-citrate) moved along with the tip of the solvent, (R F = 1). The percentage of the complex remaining unchanged was determined by integrating the peak areas in the radiochromatogram and by 225 dividing the counts associated with the Ac-complex (R F = 0) by the total counts integrated along the length of the iTLC plate. It was calculated by

[0235] Transmetalation reaction with La 3+ 225 Ac(macropa)] + and 225 Ac(DOTA)] - were each prepared using 10 -5 M and 10 -3 M stock solutions (10 μL) of macropa and DOTA to obtain final ligand concentrations of 5.9 × 10 - 7 M (macropa) and 5.9 × 10 -5 M (DOTA). TLC using 0.4 M sodium citrate (pH 4) containing 1 0% MeOH as the mobile phase was used to confirm a radiochemical yield > 90%. After that, 16 0 μL of human serum (equal volume based on the labeling reaction volume) was added to each of the radiolabeled solutions. A control solution was also prepared with water substituted for the ligand . The solutions were monitored by iTLC over 8 days. The plates were developed with EDTA (50 mM, pH 5) as the eluent. Under these conditions, 225 Ac(macropa)] + and 225 Ac(DOTA)] - complexes remained at the base line in saline (R F ​​​=0), any that had been transchelated by serum 225 Ac( 225 Ac-EDTA) moved with the solvent tip (R F =1). The percentage of the complex remaining unchanged was calculated.

[0236] In vivo biodistribution of the Ac complexes of Macropa and DOTA. All 225 experiments were approved by the Institutional Animal Care Committee (IACC) of the University of British Columbia and were conducted in accordance with the Canadian Council on Animal Care Guidelines. A total of nine female C57BL / 6 mice (6 - 8 weeks old, 20 - 25 g) were used for the biodistribution study of each radiometal complex, with n = 3 at each time point. Canadian Council on Animal Care Guidelin es were used for the biodistribution study of each radiometal complex, with n = 3 at each time point.

[0237] Macropa (100 μL out of 1 mg / mL solution in NH 4 OAc) was diluted with 387 μL of NH 4 O Ac (1 M, pH 7), and then 225 Ac(NO 3 ) 3 (approximately 1 57 kBq) aliquot (203 μL) was added; the pH of this solution was adjusted to 6.5 - 7 by adding 210 μL of 1 M NaOH (trace metal grade). After 5 minutes at ambient temperature , the reaction solution was analyzed by TLC (using 0.4 M sodium citrate (pH 4) as the eluent) to confirm a radiochemical yield > 95%. The reaction was allowed to proceed overnight and the radiochemical yield was confirmed again to be > 95% the next morning. During this period, the mice were anesthetized with 2% isoflurane, and 225 [Ac(macropa)]+ Complex approximately 100 μL (10 - 15 kBq) was injected into the tail vein of each mouse. After injection, the mice were allowed to recover and move freely in the cage. Fifteen minutes, 1 hour, or 5 hours after injection, the mice were euthanized by CO 2 inhalation (n = 3 for each time point). Blood was collected by cardiac puncture and placed into appropriate test tubes for scintillation measurement. The collected tissues included heart, liver, kidney, lung, small intestine, large intestine, brain, bladder, spleen, stomach, pancreas, bone, thyroid, tail, urine, and feces. The tissues were weighed and then counted using three energy windows: 60 - 120 keV (window A), 180 - 260 keV (window B), and 400 - 480 keV (window C) with a calibrated gamma counter (Packard, Cobra II model 5002). The measurements were performed immediately after sacrifice and 7 days later; the counts were decay-corrected from the time of injection and then converted to the percentage of the injected dose per gram of tissue (%ID / g). Differences between the data were not shown; thus, the biodistribution was reported using the data obtained immediately with window A. The biodistribution studies of 5002). The measurements were performed immediately after sacrifice and 7 days later; the counts were decay-corrected from the time of injection and then converted to the percentage of the injected dose per gram of tissue (%ID / g). Differences between the data were not shown; thus, the biodistribution was reported using the data obtained immediately with window A. %ID) of the injected dose. Differences between the data were not shown; thus, the biodistribution was reported using the data obtained immediately with window A.

[0238] 225 [[Ac(DOTA)]] - and 225 [[Ac(NO 3 )]] 3 were performed as described above for [[Ac(macropa)]] with the following 225 modifications. + The biodistribution study of 22 5 [[Ac(DOTA)]] - was compared with 225 [[Ac(NO 3 )]] 3 (338 μL, 1.1 MBq) as ​DOTA (100 μg, in 20 mg / mL in H 2 O) was added to an NH 4 OAc (467 μL, 0. 15 M, pH 7) solution to prepare. The pH of the solution was adjusted to 7 using NH 4 OAc (1 50 μL, 1 M, pH 7), and the solution was heated at 85 °C for 45 minutes. R CY > 99% was confirmed by TLC as described above. 225 Ac(DOTA)] - was , diluted with saline to a final concentration of 0.05 MBq / 100 μL, and 100 μL was injected into each mouse . 225 Ac(NO 3 ) 3 (approximately 58 μL, 0.4 MBq) was diluted and 2 25 Ac(DOTA)] - was injected in the same manner as 225 Ac(DOTA)] - During the test , one mouse euthanized at the 5 h time point died immediately after injection. In the same manner, 2 25 Ac(NO 3 ) 3 , one mouse euthanized at the 1 h time point during the test died.

[0239] Hydrolysis of Macropa-NCS and p-SCN-Bn-DOTA. macrop a-NCS (Compound 12, n = 4) or p-SCN-Bn-DOTA (n = 5) approximately 1 mg was contained in a screw-cap vial, and 1 mL of a buffer solution containing 0.154 M NaCl and 0.1 M NaHCO 3 (pH 9.1) was added, which had passed through a pre-equilibrated Cation exchange column. After stirring for 1 minute, each solution was passed through a 0.2 μm PES or The samples were filtered through a PTFE membrane. Five-microliter aliquots were then transferred to the buffer at various times over a period of 46–72 h. The eluate was removed from the vial and analyzed by HPLC. Method B was used for p-SCN-Bn-DOTA using Epic Polar C 18 columns, 120 Å, 10 μm, 25 cm × 4.6 mm (ES Industries A 100-milliliter chromatograph (West Berlin, NJ) was used with a flow rate of 1 mL / min. The vials were stored at room temperature (23±1°C) away from light between 12 and 24 h. 13.8 min (corresponding to p-SCN-Bn-DOTA) or 18.417 min (corresponding to p-SCN-Bn-DOTA). The peak in was considered complete after it disappeared or had negligible integration. Linear regression of the plot of the area versus time yielded a pseudo-first order rate constant ( k obs ) was shown. 1 / 2 ) into equation t 1 / 2 =0.693 / k obs of The half-life of each compound is reported as the mean ± 1 standard deviation.

[0240] La 3+ By Macropa-NHC(S)NHCH 3 Titration of conjugates. 13 The La stock solution (0.760 mM) was prepared in ACN instead of MOPS. 3+ by macropa-NHC(S)NHCH 3 Titration of the conjugate (13) In the case of Macropa, the pH was 7.4. The amount of ACN in the sample was 3.3% by volume. A 3-minute wait after each aliquot was added allowed the samples to settle to their normal concentration. It was found that this was sufficient to reach equilibrium before the acquisition of the kinetic energy. was monitored using the increase in absorbance at 300 nm. The pH of the solution at the end of the titration was , 7.43.

[0241] La-Macropa-NHC(S)NHCH 3 Kinetic Inactivation: Transchelation Challenge. Solutions of diethylenetriaminepentaacetic acid (DTPA; 125 mM and 12.5 mM) were prepared in MOPS buffer (pH 7.4). macropa-NHC(S) NHCH 3 (126.7 μM, 16.7% by ACN volume) and LaCl 3 (12 6.2 μM) containing MOPS solutions were prepared using the aforementioned stock solutions and equilibrated for 10 minutes . Subsequently, this was divided into cuvettes and diluted with 125 mM DTPA, 12.5 mM DTP A, or MOPS to produce solutions containing 1000-, 100-, or 0-fold excess DTPA . The final concentration of macropa-NHC(S)NHCH 3 in each cuvette was 25.3 μM. These solutions were repeatedly analyzed by UV spectroscopy over 21 days for any spectral changes . The final pH of each solution was between 7.42 and 7.49. The experiment was performed 3 times.

[0242] 225 Exemplary Synthesis and Bioactivity of Ac-macropa-RPS-070.

[0243] Di-tert-butyl (((S)-1-(tert-butoxy)-6-(3-(3-eth ynylphenyl)ureido)-1-oxohexan-2-yl)carbamoyl)-L-glu tamate (214) Preparation.

[0244] [Chemical formula] Alkyne 214 was prepared by the published method

[0247] and isolated as an off-white powder. 1 H NMR (500 MHz, CDCl 3 ) δ = 7.90 (s, 1H), 7.58 (t, 1H, J = 1.7 H z), 7.51 (dd, 1H, J 1 = 8.2 Hz, J 2 = 1.3 Hz), 7.18 (t, 1H, J = 7.9 Hz), 7.05 (d, 1 H, J = 7.7 Hz), 6.38 (d, 1H, J = 7.9 Hz), 6.28 (br s, 1H), 5.77 (d, 1H, J = 6.9 Hz), 4.32 (m, 1H), 4.02 (m, 1H), 3.53 (m, 1H), 3.05 (m, 1H), 3.00 (s, 1H), 2.39 (m, 2H), 2.07 (m, 1H), 1.88 (m, 1H), 1.74 (m, 1H), 1.62 (m, 1H), 1.49 - 1.37 (m, 4 H), 1.41 (s, 18H), 1.37 (s, 9H).

[0245] Preparation of 2,5-dioxopyrrolidin-1-yl N 2 -(((9H-fluoren-9-yl)meth oxy)carbonyl)-N 6 -(tert-butoxycarbonyl)-L-lysinate(2 15).

[0246] [Chemical formula] Fmoc-L-Lys(Boc)-OH (5.0 g, 10.7 mmol) and N,N’ -Disk cinnimidyl carbonate (2.74 g, 10.7 mmol) in CH 2 Cl 2 ( 50 mL) suspension was stirred at room temperature under argon. Then, DIPEA (1.86 mL , 10.7 mmol) was added and the suspension was stirred overnight. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (0 - 100% EtOAc in hexane). Lysine 215 was isolated as a white powder (2.5 g, 41%). 1 H N MR (500 MHz, CDCl 3 ) δ = 7.76 (d, 2H, J = 7.6 Hz), 7.59 (d, 2H, J = 7.3 Hz), 7.40 (t, 2H, J = 7.4 Hz), 7.32 (t, 2H, J = 7.3 Hz), 5.46 (br s, 1H), 4.71 (m, 2H), 4 .45 (m, 2H), 4.23 (t, 1H, J = 6.6 Hz), 3.14 (br s, 2H), 2.85 (s, 4H), 2.02 (m, 1 H), 1.92 (m, 1H), 1.58 (m, 4H), 1.44 (s, 9H).

[0247] 2 -(N 2 -(((9H - Fluoren - 9 - yl)methoxy)carbonyl)-N -(tert - butoxycarbonyl)-L - lysyl)-N 6 -((benzy 6 loxy)carbonyl)-L - lysinate (216) preparation. L - Lys(Z)-OtBu·HCl (1.49 g, 4.0 mmol) in CH

[0248]

Chemical formula

[0249] 7). 7).

[0250]

Chemical formula

[0251] tert-Butyl N 2 -(N 2 -(1-Azido-3,6,9,12,15,18-hexa oxahexacosan-21-yl)-N 6 -(tert-Butoxycarbonyl)-L -lysyl)-N 6 -((Benzyloxy)carbonyl)-L-lysinate (218) was prepared .

[0252]

Chemical Structure

[0253] Di-tert-butyl (((S)-1-(tert-butoxy)-6-(3-(3-( 1-((9S,12S)-9-(tert-butoxycarbonyl)-12-(4-((t ert-butoxycarbonyl)amino)butyl)-3,11,14-trioxo-1-f enyl-2,17,20,23,26,29,32-heptaoxa-4,10,13-tri azatetratriacontan-34-yl)-1H-1,2,3-triazole-4-yl ((S)-1-(tert-Butoxy)-6-(3-(3-((1-((23S,26S)-26-(tert-Butoxycarbonyl)-23-(4-((tert-Butoxycarbonyl)amino)butyl)-33-(4-iodophenyl)-21,24,32-trioxo-3,6,9,12,15,18-hexaoxa-22,25,31-triazatritriacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)-1-oxohexan-2-yl)carbamoyl)-L-glu Preparation of Tamart (219).

[0254]

Chemical formula

[0255] Di-tert-butyl(((S)-1-(tert-butoxy)-6-(3-(3-( 1-((23S,26S)-26-(tert-butoxycarbonyl)-23-(4-( (tert-butoxycarbonyl)amino)butyl)-33-(4-iodophenyl)- 21,24,32-trioxo-3,6,9,12,15,18-hexaoxa-22, 25,31-triazatritriacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)-1-oxohexan-2-yl)carbamoyl)-L-glu ((S)-1-(tert-Butoxy)-6-(3-(3-((1-((23S,26S)-26-(tert-Butoxycarbonyl)-23-(4-((tert-Butoxycarbonyl)amino)butyl)-33-(4-iodophenyl)-21,24,32-trioxo-3,6,9,12,15,18-hexaoxa-22,25,31-triazatritriacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)-1-oxohexan-2-yl)carbamoyl)-L-glu Preparation of Tamart (220).

[0256]

Chemical formula

[0257] (((S)-1-Carboxy-5-(3-(3-(1-((23S,26S)-26- ​​Carboxy-23-(4-(3-(2-carboxy-6-((16-((6-carboxy pyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diaza cyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl) -33-(4-iodophenyl)-21,24,32-trioxo-3,6,9,12, 15,18-hexaoxa-22,25,31-triazatriacontyl)-1H- 1,2,3-triazol-4-yl)phenyl)ureido)penty)carbamoyl) -L-glutamic acid (221, macropa-RPS-070) preparation.

[0258] [Chemical formula] 220 (34 mg, 20 μmol) of CH 2 Cl 2 (2 mL) solution, TFA (0.5 m L) was added, and the reaction mixture was stirred at room temperature for 5 h. Then, it was concentrated under reduced pressure, and the crude product was diluted with H 2 O and lyophilized to obtain the free amine as the TFA salt. Mass (ESI+): 1342.5 M+H] + . Mass (ESI-): 1340.6 [M-H] - . Mass calculated value = 1341.50. The DMF (0.5 mL) solution of the amine (9 mg, 6.7 μmol) was added to the DMF (0.5 mL) solution of macropa-N CS (15 mg, 25.4 μmol). Then, D IPEA (300 μL, 1.72 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The volatile substances were removed under reduced pressure, and the crude product was purified by prep HPLC to obtain macropa-RPS-070 (221) as a white powder (5 .4 mg; 42%). Mass (ESI +): 1932.76 [M+H] + . 1931.09 [M+H] - . Calculated mass = 1931.91.

[0259] 225 Preparation of radio - synthesis of Ac - macropa - RPS - 070

[0260] Overview. All reagents were purchased from Sigma Aldrich unless otherwise indicated, and were reagent grade. Hydrochloric acid (HCl) was traceSELEC T® (>99.999%) for trace element analysis quality. Aluminum - backed silica thin - layer chromato graphy (TLC) plates were purchased from Sigma Aldrich. Stock solutions of 0.05M HCl and 1M NH 4 OAc were prepared by dilution in Milli - Q® water .

[0261] Radio - labeling procedure 225 Ac(NO 3 ) 3 (Oak Ridge National Laboratory, USA) in 0.05M HCl (17.9 MBq in 970 μL ) solution, 20 μL of a 1 mg / mL solution of macropa - RPS - 070 in DMSO was added. The pH was raised to 5 - 5.5 by adding 90 μL of 1M NH 4 OAc. The reaction mixture was left at room temperature for 20 minutes with periodic shaking. Then, 20 0 μL of the reaction solution was removed and diluted with 3.8 mL of commercially available saline (0.9% NaCl in de - H O; VWR 2 ) to obtain a solution at a concentration of 910 kBq / mL. Aliquots were removed from the final solution and spotted on aluminum - backed silica TLC plates to determine the radiochemical yield ​ done. In 0.05 M HCl 225 Ac(NO 3 ) 3 An aliquot of the solution was spotted in parallel lanes as a control. On the plate, it was developed immediately in a 10% v / v MeOH / 10 mM ED TA mobile phase and then left standing for 8 h to allow radiochemical equilibrium to be achieved. After the plate was exposed on the fluorescent surface for 3 minutes, it was visualized on a Cyclone Plus Storage Phosphor System (Perkin Elme r). The radiochemical yield was expressed as the ratio to the total activity of Ac-macropa-RPS-070 and was determined to be 98.1%. 225 Ac-macropa-RPS-070 and was determined to be 98.1%.

[0262] 225 In vivo distribution study of Ac-macropa-RPS-070.

[0263] Cell culture. The PSMA-expressing human prostate cancer cell line, LNCaP, was obtained from the American T ype Culture Collection. Cell culture supplies were from Invitrogen unless otherwise indicated. LNCaP cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (Hyclone), 4 mM O 2 L-glutamine, 1 mM sodium pyruvate, 10 mM N-2-hydroxyeth ylpiperazine-N-2-ethanesulfonic acid (HEPES), 2.5 mg / mL D-glu cose, and 50 μg / mL gentamicin in a humidified incubator at 37 °C / 5% C O. The cells were transported or transferred to a 12-well assay plate by incubating them with 0.25% trypsin / ethylenediaminetetraacetic acid (EDTA). from which they were incubated with 12-well assay plates by incubating them with​ For this purpose, it was removed from the flask.

[0264] Inoculation of xenografts into mice. All animal experiments were conducted within the facilities of Weill Cornell Medical College by the Institutional Animal Care and Us e Committee and were carried out in accordance with the guidelines described by the USPHS Policy on Hum ane Care and Use of Laboratory Animals. The animals were housed under standard conditions in an approved facility with a 12 h light / dark cycle. Food and drinking water were provided ad libitum throughout the test period. Male hairless nu / nu mice were purchased from Jackson L aboratory. For inoculation in mice, LNCaP cells were suspended at 4 ×10 7 cells / mL in a 1:1 mixture of PBS:Matrigel (BD Biosciences). Each mouse was injected with 0.25 mL of the cell suspension into the left flank. Biodistribution was performed when the tumors were in the range of 100 - 400 mm 3 .

[0265] 225 Biodistribution of Ac-macropa-RPS-070 in LNCaP xenograft mice. Fifteen mice bearing LNCaP xenograft tumors (5 per time point) were injected intravenously with a bolus injection of each ligand at 85

[0265] ~95 kBq and 100 ng (50 pmol). The mice were sacrificed by cervical dislocation at 4, 24, and 96 h after injection. Blood samples were removed and a complete biodistribution study was performed on the following organs (including contents): heart, lung, liver 225 , and performed on the small intestine, large intestine, stomach, spleen, pancreas, kidney, muscle, bone, and tumor. The tissues were weighed , and counted with a 2470 Wizard automatic gamma counter (Perkin Elmer) . Samples of 1% ID / mL were counted before and after each set of tissue samples to enable attenuation correction. The count values were corrected for attenuation and the injected activity, and the tissue uptake was expressed as a percentage of the injected dose per gram (% ID / g) . The standard error was measured at each data point.

[0266]

Table 6

[0267] Conjugation of Macropa-NCS and p-SCN-Bn DOTA to trastuzumab.

[0268] Summary. All glassware was washed overnight in 1 M HCl. Saline (0.154 M NaCl) and all buffers were passed through a PD-10 column pre-equilibrated with the appropriate buffer. Trastuzumab (Tmab, Genentech) was purified with saline as the mobile phase using a Zeba spin desalting column (2 mL or 5 mL, 40 MWCO , Thermo Scientific, Waltham, MA) according to the manufacturer's protocol. The concentration of the purified Tmab was calculated by the Lambert-Beer law using A of 1.446 mL mg 280 and ε 280 of 1. 446 mL mg -1 cm -1 . [ 107]The purified Tmab and Tmab conjugate were stored at 4°C.

[0269] Conjugation of Macropa-NCS to Tmab. Macropa-NCS (12) A stock solution containing 4.4 mg / mL was prepared in 0.1 M pH 9.1 NaHCO 3 buffer and stored at -80°C. The stability of 12 during storage was verified by analytical HPLC. The final concentrations of Tmab and 12 were, respectively 5.1 mg / mL and 0.59 mg / mL. To a portion of Tmab in saline (74 μL) such that the final concentrations were as described above, 12 (52 μL) and NaHCO 3 buffer (266 μL) were added. Macropa-NCS was estimated to be a 16-fold molar excess over Tmab based on a molecular weight of 1045.76 g / mol for 12 (tetra-TFA salt). The pH of this solution was between 8 and 9 as determined by litmus test paper. The solution was gently shaken at room temperature for 17. 5 h and then purified using a spin column.

[0270] Conjugation of p-NCS-Bn-DOTA to Tmab. p-NCS-Bn- A stock solution containing 3.05 mg / mL of DOTA was prepared in H 2 O and stored at -80°C . The final concentrations of Tmab and p-NCS-Bn-DOTA were, respectively, 5.1 mg / m L and 0.38 mg / mL (16-fold molar excess of L). To a portion of Tmab in saline (66 μL ) such that the final concentrations were as described above, p-NCS-Bn-DOTA (49 μL) and NaHCO 3 buffer (274.5 μL) were added. The pH of this solution was between 8 and 9 as determined by litmus test paper. It was between. The solution was gently shaken at room temperature for 17.5 h and then purified using a spin column. purified.

[0271] Determination of the complex protein concentration by BCA assay. Macropa-Tmab and D The concentration of the protein in the OTA-Tmab conjugate was determined using the Pierce™ BCA Protein Assay Kit (Thermo Scientific, Waltham, M A, microplate protocol). Tmab was used as a protein standard. The stock solution of the purified Tmab was diluted with saline, and the concentration of this solution (1.83 mg / mL) was determined using a NanoDrop 1000 spectrophotometer (Thermo Scien tific, Waltham, MA). The standard curve was linear over the measured concentration range (0 - 1828 μg / mL) (r 2 = 0.9966). The protein concentration of each conjugate was calculated from two independent dilutions and measured three times each, and the results were averaged to obtain a protein concentration of 4.55 7 mg / mL for macropa-Tmab and 2.839 mg / mL for DOTA-Tmab. obtained.

[0272] Analysis of the ligand-to-protein ratio by MALDI-ToF. The average number of macropa or DOTA ligands conjugated to Tmab was determined by MALDI-ToF MS / MS at Bruker autoflex speed using the procedure described elsewhere at the Alberta Proteomics and Mass Spectrometry F acility (University of Alberta, Canada). determined.

[0108] Purification​​ The generated Tmabs and their conjugates were analyzed twice, and the [M+H] mass signals obtained from the chromatograms were averaged for each compound. The ligand-to- + + protein (L:P) ratio for each conjugate was obtained by subtracting the molecular weight of the Tmab from that of the conjugate and then dividing by the mass of the bifunctional ligand. Serum stability of the Ac radiolabeled and complexed Tmab conjugates. Overview. The progress of the Ac radiolabeling reaction was monitored and serum stability was determined using instant thin layer chromatography paper impregnated with silica gel (iTLC-SG, Agilent Technologies, Mississauga, ON, Canada). The TLC plates were developed as described below and then counted in a BioScan System 200 imaging scanner equipped with BioScan Autochanger 1000 and WinScan software at least 8 h later to completely decay the time for the daughter isotope and ensure that the measured radioactivity signal was generated by the parent Ac.

[0273] Ac radiolabeling test. In a total reaction volume of 200 μL prepared with NH4OAc buffer (pH 6, 0.15 M), Ac (10 or 20 kBq, 7 - 10 μL) was added to macropa-Tmab (5.5 - 22 μL) or DOTA-Tmab (8.81 - 3 225 225

[0274] 225

[0275] 225 225 A

[0275] 225 225 4 4 225 225 Mix with 25 - 100 μg (5.2 μL), and adjust the pH to approximately 5 with NaOH. Control solution was also prepared, in which unmodified Tmab (25 μg) was substituted instead of the conjugate . The reaction solution was maintained at ambient temperature and analyzed at 5 min, 30 min, 1 h, 2 h, 3 h, and 4 h by spotting 8 μL three times on an iTLC strip. The strip was developed with a mobile phase of 0.05 M citrate (pH 5). Under these conditions Ac - macropa - Tmab and Ac - DOTA - 225 Tmab remained at the baseline of the plate (R 225 = 0), and any non - chelated Ac( F Ac - citrate) migrated with the solvent front (R 225 = 1). Radiochemical yields (RCYs) were calculated by integrating the peak area under the curve in the radiochromatogram and dividing by the total counts integrated along the length of the TLC plate 225 for the Ac - complex (R F = 0). Stability of Ac - macropa - Tmab in human serum. A solution of Ac - macropa - Tmab was prepared using 100 μg of protein. After confirmation by TLC that RCY > 95% was achieved, human serum was thawed at room temperature and a solution containing 90% serum by volume was obtained in addition to the radiolabeled immune complex. Samples were incubated at 37 °C. At various time points over 7 days, aliquots (15 - 30 μL) were removed from the samples and spotted three times on an iTLC strip. The strip was developed with ED 225 F 225

[0276] 225 Ac - macr opa - Tmab and TA buffer (pH 8). Developed using a TA (50 mM, pH 5.2) mobile phase and counted. Under these conditions 、 225 Ac-macropa-Tmab remained at the baseline (R F = 0), and any transchelation by serum 225 Ac( 225 Ac-EDTA) migrated with the solvent front (R = 1). The percentage of the complex remaining unchanged was calculated. F =1). The percentage of the complex remaining unchanged was calculated.

[0277] As an additional challenge, separate aliquots (39 μL) were also removed from the serum samples on days 1 and 7, mixed with 50 mM DTPA (pH 7, 13 μL), and challenged to dissociate any 225 Ac that was only loosely bound by the radiolabeled immune complex. The solution was incubated at 37 °C for 15 minutes, and then an aliquot (30 μL ) was spotted 3 times on an iTLC plate and developed using an EDTA (50 mM, pH 5.2) mobile phase . The percentage of the complex remaining unchanged was calculated.

[0278] 225 Ac(macropa)] + 、 225 Ac(DOTA)] - 、and 225 A c(NO 3 ) 3 in vivo biodistribution study.

[0279]

Table 7

[0280] ​

Table 8

[0281]

Table 9

[0282] 225 In vivo test of Ac-macropa-Tmab.

[0283] At the time points shown in Table 4 below, aliquots of the complex in serum were removed and analyzed directly by radio-TLC or first mixed with an excess of DTPA to remove any loosely bound Ac. The decay-corrected values shown represent the % activity with the complex at R 2 25 = 0 on the TLC plate after exposure to the EDTA mobile phase. The reported uncertainty (±1SD) arose from spotting three TLC plates at each time point. The % of unchanged complex remaining F was not significantly different (p > 0.05, two-sided t-test) between samples challenged with DTPA and those not challenged with DTPA. From these results, it is demonstrated that Ac remains strongly bound by macropa-Tmab in human serum over 7 days. 225 Ac is strongly bound by macropa-Tmab in human serum over 7 days.

[0284]

Table 10

[0285] ​​​​ Characterization of 18-Membered Macrocyclic Ligands for Ion Chelation Radium-223 ( 223 Ra) is the first therapeutic alpha (α)-emitting radionuclide approved for clinical use in cancer patients and is effective in eradicating bone metastases. To take advantage of the therapeutic potential of α-particles for soft tissue metastases, a strategy of targeted α-particle therapy (TAT) has emerged, in which a lethal α-emitting radionuclide is conjugated to a tumor-targeting vector using a bifunctional chelator to selectively deliver cytotoxic α-radiation to cancer cells. Actinium-225 ( Ac) has a 10-day long half-life that is suitable for antibody-based targeting vectors and produces four high-energy α-emissions that are extremely 225 lethal to cells, so it has been tested for use in TAT. The 12-membered tetraazamacrocyclic molecule H DOTA is currently the state of the art for chelation of Ac ions, but as the ionic radius of the metal ion increases, the thermodynamic stability of the H DOTA complex decreases, indicating that this ligand is not optimal for chelation of 4 Ac ions (the largest +3 ions in the periodic table). The macrocyclic complexes of the present technology show significant and unexpected improvements compared to known complexes, and 225 Ac bifunctional chelators improved by the present technology are exemplified in this example (H 3+ macropa and H macropa-NCS; Scheme 1). 4 D OTA complexes, and this ligand is shown to be suboptimal for chelation of 3+ Ac ions (the largest +3 ions in the periodic table). The macrocyclic complexes of the present technology show significant and unexpected improvements compared to known complexes, and in this example (H macropa and H macropa-NCS; Scheme 1), improved 2 Ac bifunctional chelators according to the present technology are exemplified. 2 According to (Scheme 1), improved Ac bifunctional chelators according to the present technology are exemplified. 225 Ac bifunctional chelators according to the present technology are exemplified.

[0286] Scheme 1. H 2macropa, H 2 macropa-NCS (「macropa- NCS」), and the structure of macropa-(OCH 2 CH 2 )-Ph-NCS.

Chemical formula

[0287] Previous tests have evaluated the thermodynamic affinity for the entire lanthanide series. macropa is selective for larger metal ions La 3+ , Ca 2+ , and Cm 3+ compared to smaller Lu , Ca 3+ , Pb 2+ , and Am 3+ ions, as shown. Selected. [24-26] Without being bound by theory, it was considered that macropa should efficiently chelate large Ac 3+ ions. Before evaluating its Ac-chelation characteristics, complex formation was evaluated in situ between macropa and cold La and Lu 3+ ions. In these tests, La 3+ ions were used as a non-radioactive surrogate for Ac because they are chemically similar despite being slightly smaller (1.03 Å, CN6). Complex formation of smaller Lu 3+ ions (0.861 Å, CN6) by macropa was investigated to explore its size selectivity. La 225 and Lu 3+ titrations were used to determine the complex formation of macropa at pH 7.4. u 3+ ions (0.861 Å, CN6) to explore its size selectivity. La 3+ and Lu 3+ titrations were used to determine the complex formation of macropa at pH 7.4. The high affinity for these metal ions was confirmed. This is in line with the stability constants (log K LaL = 14.99, log K LuL = 8.25) measured previously.

[24] in s itu of these complexes formed was investigated by challenging them with an excess of the ethylenediaminetetraacetic acid (E 3+ DTA) or diethylenetriaminepentaacetic acid (DTPA) chelators, which have a higher thermodynamic affinity for Lu 3+ and La ions than macropa. DTA) or diethylenetriaminepentaacetic acid (DTPA) chelators were used to challenge them. The Lu

[27] ions were transchelated within 1 minute even with the addition of only 10 equivalents of EDTA, while the La 3+ complex remained unchanged for 21 days in the presence of 1000 equivalents of DTPA. These results demonstrate that, despite the strong thermodynamic preference of DTPA for the transchelating of La 3+ complexes, the high level of kinetic inertness of the macrop a complexes suppresses this process on a detectable time scale. 3+ The trans chelating of La by macropa was suppressed by the high level of kinetic inertness of the macropa complexes on a detectable time scale. This was demonstrated.

[0288] The La 3+ and Lu 3+ complexes of macropa were isolated and their solid structures were elucidated by X-ray crystal structure analysis (Figs. 1A - 1D). The La 3+ and Lu 3+ ions are present in the above 18-membered macrocyclic molecule, and the two picolinate arms are located on the same side of the macrocyclic molecule. The Lu 3+ ion's coordination sphere is filled by 10 donors of macropa with both picolinate arms deprotonated; in contrast, the larger La ion has a 3+ larger The formation of an 11 - coordinated complex occurs by the uptake of inner - sphere water molecules that penetrate the cyclic molecule. Recent E XAFS experiments have demonstrated that Ac 3+ prefers a coordination number of 11 in aqueous solution. Therefore, the ability of macropa to form stable 11 - coordinated complexes is of particular importance since . [29,30]

[0289] Macropa was tested for the chelation of larger, radioactive 225 Ac 3+ ions and compared with DOTA. Both ligands (59 μM) were incubated in 0.1 5 M NH OAc buffer at pH 5.5 - 6 4 using Ac (26 kBq), and the complex formation reaction was monitored by radio - TLC after 5 minutes. Unexpectedly, macro 225 pa formed complexes with all of the Ac within just 5 minutes at RT, while DOTA was only 10% bound under these conditions. At a concentration 100 - fold lower (0.59 μM) of macro 225 pa, which has an L:M ratio of only 1800, the radiolabeling was even more complete at 5 minutes at RT . At this concentration, DOTA failed to form complexes with Ac . 225 . In summary, these tests have revealed that macropa exhibits excellent radiolabeling kinetics at ambient temperature and sub - μM ligand concentrations, under conditions where DOTA fails. .

[0290] 225 The long half - life of Ac, due to its stable complex retention in vivo, avoids off - target damage to normal tissues resulting from the release of free 225 Ac 3+ . is necessary. Furthermore, for the transmetalation reaction and transchelation, 225 it is necessary that the stability of the Ac complex is high. To determine the kinetic inertness, 225 Ac(macropa)] + was challenged with this metal ion because a high affinity of macropa for this metal ion was established. For La since 3+ a 50-fold excess of La with respect to the ligand concentration 3+ was added to a solution (0.59 μM) of macropa radiolabeled with 225 Ac at RT. Over 7 days, 225 98% of the Ac complex remained unchanged as determined by radio-TLC, indicating that a large molar equivalent of La 3+ could not replace 225 Ac 3+ . The stability of 225 A c(macropa)] + in human serum was also evaluated by radio-TLC, and it was revealed that 225 Ac 3+ remained bound to macropa for at least 8 days.

[0291] 225 Ac(macropa)] + Evaluation of the in vivo distribution of the complex 225 Ac(macropa)] + The in vivo stability of was compared with its in vivo distribution 225 of 3 Ac(NO 3 ) 225 and - Ac(DOTA)] ​​It was tested by injecting each radioactive metal complex at 10 - 50 kBq into C57BL / 6 mice via the tail vein and sacrificing them 15 minutes, 1 hour, or 5 hours later. The amount of Ac retained in each organ was quantified by gamma measurement and reported as the percentage of the injected dose per gram of tissue (% 22 5 ID / g). The results of these tests are summarized in Tables 1 - 3. The inappropriate stability of the Ac complex that leads to the loss of the radioisotope in vivo is revealed by the accumulation of 225 Ac in the mouse liver, spleen, and bone. 225 In Figure 2A, the large accumulation of unbound [11,12,3 2] Ac(NO 225 ) 3 in the liver and spleen is linked to slow blood clearance and excretion. The in - vivo distribution profile of 3 Ac(macropa)] (Figure 3B) is clearly different from that of 225 Ac (macropa)] + Ac(NO 225 ) 3 3 Ac(macropa)] 225 is rapidly removed from the mouse, and very little activity was measured in the blood every hour after injection. Most of the injected dose was excreted in the kidneys and subsequently detected in the urine, as observed in mice 15 minutes and 1 hour + after injection. The moderate uptake of Ac(macropa)] in the kidneys and bladder is demonstrated. Importantly, Ac(macropa)] 225 + 225 + 225 Ac(macropa)] + does not accumulate in any organ over the course of the test, indicating that the complex is, in vivo released free by ivo 225 Ac 3+ was shown not to release. Its in vivo distribution profile was, 225 [[Ac(DOTA)]] - similar to the in vivo distribution profile of (Figure 3C), which is, in vivo 225 Ac 3+ has been previously shown to retain. [7]

[0292] 225 [[Ac(macropa)]] + Synthesis and characterization of the TAT complex 225 [[Ac(macropa)]] + Due to the inherent stability of the complex, macropa was incorporated into the tumor targeting construct. To facilitate its conjugation for, a reactive isothiocyanate functional group was installed on one of the picolinate arms of macropa to obtain the novel bifunctional ligand macropa-NCS (Scheme 1). As exemplified in the above reference, macropa-NCS was synthesized over 8 steps and characterized by conventional techniques. In one case of a tumor targeting construct , macropa-NCS was conjugated to trastuzumab (Tmab), a monoclonal antibody approved by the FDA that targets human epidermal growth factor receptor 2 (HER2) in breast cancer and other cancers. Due to its several-week biological half-life Tmab is an ideal vector for shuttling long-lived

[33] Ac radionuclides to tumor cells. by [34,35] Ac-macropa-Tmab is in human serum at 37 °C 225 and is an ideal vector for shuttling long-lived 225 Ac radionuclides to tumor cells. ​​showed excellent stability; after 7 days, >99% of the complex remained unchanged (Table 4). Collectively, these results demonstrate the effect of macropa as a chelator for Ac in antibody constructs as well as other cancer-targeted constructs. in 225 become apparent.

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V Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, H. Puschmann , J. Appl. Crystallogr.2009, 42, 339-341. 113. J. Dilling, R. Krucken, L. Merminga, Eds., ISAC and ARIEL: The TRIUMF Radi oactive Beam Facilities and the Scientific Program, Springer, Dordrecht, Netherl ands, 2014. 114. J. R. Crawford, P. Kunz, H. Yang, P. Schaffer, T. J. Ruth, Appl. Radiat. I sot. 2017, 122, 222-228. 115. B. Zielinska, C. Apostolidis, F. Bruchertseifer, A. Morgenstern, Solvent E xtr. Ion Exch. 2007, 25, 339-349. 116. V. Radchenko, J. W. Engle, J. J. Wilson, J. R. Maassen, F. M. Nortier, W. A. Taylor, E. R. Birnbaum, L. A. Hudston, K. D. John, M. E. Fassbender, J. Chrom atogr. A 2015, 1380, 55-63. 117. M. P. Miranda-Hernandez, E. R. Valle-Gonzalez, D. Ferreira-Gomez, N. O. Pe Rez, L. F., Flores-Ortiz, E., Medina-Rivero, Anal. Bioanal. Chem. 2016, 408, 1523- 1530. 118. E. W. Price, K. J. Edwards, K. E. Carnazza, S. D. Carlin, B. M. Zeglis, M. J. Adam, C. Orvig, J. S. Lewis, Nucl. Med. 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[0294] Some embodiments have been illustrated and described, and those skilled in the art can make modifications , equivalent substitutions and other types of changes to the compounds or their salts, pharmaceutical compositions described herein, derivatives, prodrugs, metabolites, tautomers or racemic mixtures. Each of the foregoing aspects and embodiments can also include or incorporate into any or all of the other aspects and embodiments disclosed herein such variant methods or aspects.

[0295] The present technology is not limited to the specific aspects described herein, which are intended as a single illustration of individual aspects of the present technology. Many modifications and variations of the present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Within the scope of the present technology, functionally equivalent methods are, in addition to those listed herein, described above ​ will be apparent to those skilled in the art from. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that the technology is not limited to a particular method, reagent, compound, composition, labeled compound or biological system, as these can of course vary. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting. It should also be understood that the specification is to be considered exemplary only and is defined by the appended claims, the definitions herein, and any equivalents thereof, such that the breadth, scope and spirit of the technology are intended to be limited only by the appended claims, the definitions herein, and any equivalents thereof. The embodiments described herein by way of example can be practiced suitably in the absence of any one or more elements, or one or more limitations, not specifically disclosed herein. Thus, for example, terms such as "comprising", "including", "containing", etc. are to be read broadly and not limited thereto. Further, the terms and expressions used herein are for the purpose of explanation and not limitation, and are not intended to exclude any equivalents of the features shown and described or portions thereof, although various modifications are possible within the scope of the claimed technology. It is recognized that the phrase "consisting essentially of" includes additional elements that do not substantially affect the basic and novel characteristics of the elements recited in detail and the claimed technology. The phrase "consisting of" excludes any element not specified.

[0296] The embodiments exemplified herein can be carried out suitably in the absence of any one or more elements, or one or more limitations, not specifically disclosed herein. Thus, for example, terms such as "comprising", "including", "containing", etc. are to be read broadly and not limited thereto. Furthermore, the terms and expressions used herein are for the purpose of explanation and not limitation, and are not intended to exclude any equivalents of the features shown and described or portions thereof, although various modifications are possible within the scope of the claimed technology. It is recognized that the phrase "consisting essentially of" includes additional elements that do not substantially affect the basic and novel characteristics of the elements recited in detail and the claimed technology. The phrase "consisting of" excludes any element not specified. The use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, although various modifications are possible within the scope of the claimed technology. It is recognized that the phrase "consisting essentially of" includes additional elements that do not substantially affect the basic and novel characteristics of the elements recited in detail and the claimed technology. The phrase "consisting of" excludes any element not specified. It is recognized that the phrase "consisting essentially of" includes additional elements that do not substantially affect the basic and novel characteristics of the elements recited in detail and the claimed technology. The phrase "consisting of" excludes any element not specified.

[0297] Furthermore, when a feature or aspect of the present disclosure is described in terms of Markush groups, one of ordinary skill in the art will recognize that the present disclosure thereby also describes any individual member or members of the Markush group as well as subgroups. Each of the more specific groupings of species and subgenera that fall within the general disclosure also forms part of the present invention. This includes a general description of the invention and, subject to any negative limitations that conditionally or otherwise exclude any subject from that genus, is recited herein in detail, whether or not the material is cut. As will be understood by one of ordinary skill in the art, for any and all purposes, particularly in connection with showing any written

[0298] description, all ranges disclosed herein also include any and all possible subranges and combinations thereof. Any recited range can be readily recognized as being fully described and thus divisible into at least one-half, one-third, one-fourth, one-fifth, one-tenth, etc. of the same range. By way of non-limiting example, each range discussed herein can be readily divided into lower one-third, middle one-third, and upper one-third, etc. As will also be understood by one of ordinary skill in the art all language such as "up to," "at least," "greater than," "less than," etc. recites the recited number and then ranges divisible into subranges as discussed above. Finally, as will be understood by one of ordinary skill in the art, ranges include each and every individual member therein. As will be readily recognized, any recited range can be divided into at least one-half, one-third, one-fourth, one-fifth, one-tenth, etc. of the same range. By way of non-limiting example, each range discussed herein can be readily divided into lower one-third, middle one-third, and upper one-third, etc. As will also be understood by one of ordinary skill in the art all language such as "up to," "at least," "greater than," "less than," etc. recites the recited number and then ranges divisible into subranges as discussed above. Finally, as will be understood by one of ordinary skill in the art, ranges include each and every individual member therein. As will be understood by one of ordinary skill in the art, all language such as "up to," "at least," "greater than," "less than," etc. includes the recited number and then ranges divisible into subranges as discussed above and means ranges that can be divided into subranges as discussed above. Finally, as will be understood by one of ordinary skill in the art, ranges include each and every individual member therein. Therein.

[0299] All publications, patent applications, issued patents, and other documents referenced herein (such as, for example, academic journals, papers and / or textbooks) are incorporated herein by reference in their entirety into each individual patent publication, patent application, issued patent, or other document as if fully set forth herein. Definitions contained in incorporated material are excluded to the extent they contradict definitions in the present disclosure.

[0300] This technology can include, but is not limited to, the features and combinations of features recited in the (lettere d) paragraph below, it being understood that the following paragraphs are not to be construed as limiting within the scope of the appended claims and that it is not obligatory that all such features be necessarily included in such claims. A. Formula I

[0301] [Chemical formula] [wherein, Z 1 is H or -X 1 -W 2 ; Z 2 is OH or NH-W 3 ; Z 3 is H or W 7 ; α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cyclo alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH 2 CH 2-(OCH 2 CH 2 ) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them is , optionally, halo, -N 3 , -OR’, -CH 2 CH 2 -(OCH 2 CH 2 ) y - R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -C H 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10), -SR’, -OC(O)R’, -C(O)OR’, - C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’), -SO 2 NR’ 2 , -P(O)(OR’) 2 , -P(O)R’(OR’), -P(O)R’ 2 , -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH 2 , -N=C=N-R’, - SO 2 Cl, -C(O)Cl, or substituted with one or more of epoxy groups and may well; W 5 and W 7 are each independently OH, NH 2 , SH, alkyl, cycloalkyl, Alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl -CH 2 CH 2 -(OCH 2 CH 2 ) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and each of them may optionally be halo, -N -, -OR’, -CH 3 -, -CH 2 CH 2 -(OC H 2 CH 2 )y x -R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, - C(O)OR’, -C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’ )-, -SO 2 NR’ 2 -, -P(O)(OR’) 2 -, -P(O)R’(OR’), -P(O )R’ 2 -, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH 2 -, -N =C=N-R’, -SO 2 Cl, -C(O)Cl, or one or more epoxy groups may also be replaced by; R’ is, independently for each occurrence, H, halo, -N 3 , C 1 ~C 6 alkyl, C 3 ~C 6 cyclo alkyl, C 2 ~C 6 alkenyl, C 5 ~C 8 cycloalkenyl, C 2 ~C 6 alkynyl , C 8 ~C 10 cycloalkynyl, C 5 ~C 6 aryl, heterocyclyl, or hetero aryl], or a pharmaceutically acceptable salt thereof. B. Compound of formula III

[0302]

Chemical formula

[0303]

Chemical formula

[0304]

Chemical formula

[0305]

Chemical formula

[0306] [Chemical formula] The compound of paragraph A, or a pharmaceutically acceptable salt thereof, which is a compound of . G. Formula IA

[0307] [Chemical formula] [wherein, M 1 is an α-emitting radionuclide; Z 1 is H or -X 1 -W 2 and Z 2 is OH or NH-W 3 and Z 3 is H or W 7 and α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cyclo loalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH 2 CH 2 -(OCH 2 CH 2 ) w -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR' (wherein, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them is , optionally, halo, -N 3 , -OR’, -CH 2 CH 2 -(OCH 2 CH 2 ) y - R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -C H 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10), -SR’, -OC(O)R’, -C(O)OR’, - C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’), -SO 2 NR’ 2 , -P(O)(OR’) 2 , -P(O)R’(OR’), -P(O)R’ 2 , -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH 2 , -N=C=N-R’, - SO 2 Cl, -C(O)Cl, or substituted with one or more of an epoxide group even well; W 5 and W 7 are each independently OH, NH 2 , SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl , -CH 2 CH 2 -(OCH 2 CH 2 ) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2 CH 2 -(OCH 2 CH 2 ) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may, in some cases, be halo, -N 3 , -OR’, -CH 2 CH 2 -(OC H 2 CH 2 )y x -R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, - C(O)OR’, -C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’ ) -SO 2 NR’ 2 , -P(O)(OR’) 2 , -P(O)R’(OR’), -P(O )R’ 2 , -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH 2 , -N =C=N-R’, -SO 2 Cl, -C(O)Cl, or one or more of epoxy groups may be substituted; R’ is, each time it appears, independently, H, halo, -N 3 , C 1 ~C 6 alkyl, C 3 ~C 6 cyclo alkyl, C 2 ~C 6 alkenyl, C 5 ~C 8Cycloalkenyl, C 2 ~C 6 alkynyl , C 8 ~C 10 cycloalkynyl, C 5 ~C 6 aryl, heterocyclyl, or hetero aryl] compound, or a pharmaceutically acceptable salt thereof. H. M 1 is actinium-225( 225 Ac 3+ ), radium-223( 233 R a 2+ ), bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149( 149 Tb 3+ ), fermium-2 55( 255 Fm 3+ ), thorium-227( 227 Th 4+ ), thorium-226( 2 26 Th 4+ ), astatine-211( 211 At + ), astatine-217( 217 A t + ), or uranium-230, the compound of paragraph G. I. The compound of formula I is of formula IV

[0308]

Chemical formula

[0309]

Chem.

[0310]

Chemical formula

[0311] [Chemical formula] [wherein, M 4 is an α-emitting radionuclide] the compound, or a pharmaceutically acceptable salt thereof, the compound of paragraph G or paragraph H. P. M 4 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 R a 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-2 55 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 2 26 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 A t + ), or uranium-230, the compound of paragraph O. Q. The compound of formula IA is of formula XIII

[0312] [Chemical formula] [wherein, M 5is a compound of an α-emitting radionuclide, or a pharmaceutically acceptable salt thereof compound of paragraph G or paragraph H R. M 5 is actinium-225( 225 Ac 3+ ), radium-223( 233 R a 2+ ), bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149( 149 Tb 3+ ), fermium-2 55( 255 Fm 3+ ), thorium-227( 227 Th 4+ ), thorium-226( 2 26 Th 4+ ), astatine-211( 211 At + ), astatine-217( 217 A t + ), or uranium-230, the compound of paragraph Q S. Formula II

[0313]

Chemical formula

[0314]

Chemical formula

[0315] [Chemical formula] [wherein M 3 is an alpha-emitting radionuclide], or a pharmaceutically acceptable salt thereof, which is a targeting compound of any one of paragraphs S to U. Y. M 3 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 R a 2+ ), bismuth-213 ( 213 Bi 3+) Lead-212( 212 Pb 2+ and / or 212 Pb 4+ ) Terbium-149( 149 Tb 3+ ) Fermium-2 55( 255 Fm 3+ ) Thorium-227( 227 Th 4+ ) Thorium-226( 2 26 Th 4+ ) Astatine-211( 211 At + ) Astatine-217( 217 A t + ) or Uranium-230, a target-directed compound of Paragraph X. Z. A target-directed compound of Formula II is a compound of Formula XI

[0316] [wherein M is an α-emitting radionuclide], or a pharmaceutically acceptable salt thereof, a target-directed compound of any one of Paragraphs S to U. 4 is an α-emitting radionuclide], or a pharmaceutically acceptable salt thereof, a target-directed compound of any one of Paragraphs S to U. salt thereof, a target-directed compound of any one of Paragraphs S to U. AA. M 4 is Actinium-225( 225 Ac 3+ ) Radium-223( 233 Ra 2+ ) Bismuth-213( 213 Bi 3+ ) Lead-212( 212 Pb 2+ and / or 212 Pb 4+ ) Terbium-149( 149 Tb 3+ ) Fermium- 255( 255 Fm 3+ ) Thorium-227(227 Th 4+ )、 thorium-226 ( 226 Th 4+ )、 astatine-211 ( 211 At + )、 astatine-217 ( 217 At + )、 or uranium-230, the targeting compound of paragraph Z. AB. The targeting compound of formula II is of formula XIV

[0317]

Chemical formula

[0318]

Chem.

[0319]

Chemical formula

[0320]

Chemical formula

[0321] [Chemical formula] a compound of any one of paragraphs AD - AG, or a pharmaceutically acceptable salt thereof one modified antibody, modified antibody fragment, or modified binding peptide. AK. The compound of formula I is of formula IX

[0322] [Chemical formula] a compound of any one of paragraphs AD - AG, or a pharmaceutically acceptable salt thereof one modified antibody, modified antibody fragment, or modified binding peptide. AL. The compound of formula I is of formula XII

[0323] [Chemical formula] a compound of any one of paragraphs AD - AG, or a pharmaceutically acceptable salt thereof one modified antibody, modified antibody fragment, or modified binding peptide. AM. Formula IA

[0324] [Chemical formula] [wherein, M 1 is an alpha - emitting radionuclide; Z 1 is H or -X 1 -W 2 and Z 2 is OH or NH - W 3 and Z 3 is H or W 7 and α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cyclo loalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH 2 CH 2 -(OCH 2 CH 2 ) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them is , optionally, halo, -N 3 , -OR’, -CH 2 CH 2 -(OCH 2 CH 2 ) y - R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -C H 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10), -SR’, -OC(O)R’, -C(O)OR’, - C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’), -SO 2 NR’ 2 , -P(O)(OR’) 2 , -P(O)R’(OR’), -P(O)R’ 2 , -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH 2 , -N=C=N-R’, - SO 2 Cl, -C(O)Cl, or substituted with one or more of epoxy groups well; W 5 and W 7 are each independently OH, NH 2 , SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl , -CH 2 CH 2 -(OCH 2 CH 2 ) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and each of them may optionally be halo, -N 3 , -OR’, -CH 2 CH 2 -(OC H 2 CH 2 )y x -R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH 2 CH 2 -(OCH 2 CH 2 ) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, - C(O)OR’, -C(S)OR’, -S(O)R’, -SO 2 R’, -SO 2 (OR’ )、-SO2 NR’ 2 、 -P(O)(OR’) 2 、 -P(O)R’(OR’)、 -P(O )R’ 2 、 -CN、 -OCN、 -SCN、 -NCO、 -NCS、 -NR’-NH 2 、 -N =C=N-R’、 -SO 2 Cl、 -C(O)Cl、 or one or more of an epoxide group may be substituted therewith; R’ is, each occurrence independently, H, halo, -N 3 、 C 1 ~C 6 alkyl, C 3 ~C 6 cyclo alkyl, C 2 ~C 6 alkenyl, C 5 ~C 8 cycloalkenyl, C 2 ~C 6 alkynyl 、 C 8 ~C 10 cycloalkynyl, C 5 ~C 6 aryl, heterocyclyl, or hetero aryl, of a compound, or a pharmaceutically acceptable salt thereof, an antibody, antibody fragment to, or a bond resulting from conjugation to a binding peptide, a modified antibody 、 a modified antibody fragment, or a modified binding peptide. AN.M 1 is actinium-225( 225 Ac 3+ )、 radium-223( 233 Ra 2+ )、 bismuth-213( 213 Bi 3+ )、 lead-212( 212 Pb 2+ and / or 212 Pb 4+ )、 terbium-149( 149 Tb3+ ) fermium- 255( 255 Fm 3+ ) thorium-227( 227 Th 4+ ) thorium-226( 226 Th 4+ ) astatine-211( 211 At + ) astatine-217( 217 At + ) or uranium-230, a modified antibody, modified antibody fragment, or modified binding peptide of paragraph AM. fragment, or modified binding peptide. AO. The antibody is pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semapimod, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, gilotrif, nimotuzumab, catumaxomab, or etrolizumab, a modified antibody, modified antibody fragment, or modified binding peptide of paragraph AM or paragraph AN. AP. The antibody fragment is pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semapimod, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, gilotrif, nimotuzumab, catumaxomab, or etrolizumab, a modified antibody, modified antibody fragment, or modified binding peptide of paragraph AM or paragraph AN. AP. The antibody fragment is pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semapimod, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, gilotrif, nimotuzumab, catumaxomab, or AP. The antibody fragment is pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semapimod, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, gilotrif, nimotuzumab, catumaxomab, or etrolizumab, a modified antibody, modified antibody fragment, or modified binding peptide of paragraph AM or paragraph AN. AP. The antibody fragment is pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semapimod, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, gilotrif, nimotuzumab, catumaxomab, or etrolizumab, a modified antibody, modified antibody fragment, or modified binding peptide of paragraph AM or paragraph AN. AP. The antibody fragment is pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semapimod, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, gilotrif, nimotuzumab, catumaxomab, or etrolizumab, a modified antibody, modified antibody fragment, or modified binding peptide of paragraph AM or paragraph AN. AP. The antibody fragment is pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semapimod, nivolumab, pembrolizumab, orlaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, gilotrif, nimotuzumab, catumaxomab, or etrolizumab, a modified antibody, modified antibody fragment, or modified binding peptide of paragraph AM or paragraph AN. Ozogamicin, Moxetumomab Pasudotox, Brentuximab Vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab Emtansine, Siltuximab, Gemtuzumab Ozogamicin, Alemtuzumab, Sixatumumab, Girentuximab, Nimotuzumab, Catumaxomab, or an antigen-binding fragment of Etaracizumab, of any one of paragraphs AM to AO, a modified antibody, a modified antibody fragment, or a modified binding peptide. Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab Emtansine, Siltuximab, Gemtuzumab Ozogamicin, Alemtuzumab, Sixatumumab, Girentuximab, Nimotuzumab, Catumaxomab, or an antigen-binding fragment of Etaracizumab, of any one of paragraphs AM to AO, a modified antibody, a modified antibody fragment, or a modified binding peptide. , Pertuzumab, Trastuzumab, Trastuzumab Emtansine, Siltuximab, Gemtuzumab Ozogamicin, Alemtuzumab, Sixatumumab, Girentuximab, Nimotuzumab, Catumaxomab, or an antigen-binding fragment of Etaracizumab, of any one of paragraphs AM to AO, a modified antibody, a modified antibody fragment, or a modified binding peptide. Gemtuzumab Ozogamicin, Alemtuzumab, Sixatumumab, Girentuximab, Nimotuzumab, Catumaxomab, or an antigen-binding fragment of Etaracizumab, of any one of paragraphs AM to AO, a modified antibody, a modified antibody fragment, or a modified binding peptide. , Durvalumab, Capromab Pendetide, Erituximab, Denosumab, Ziv-aflibercept, Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab Ozogamicin, Alemtuzumab, Sixatumumab, Girentuximab, Nimotuzumab, Catumaxomab, or an antigen-binding fragment of Etaracizumab, of any one of paragraphs AM to AO, a modified antibody, a modified antibody fragment, or a modified binding peptide. , Bevacizumab, Ramucirumab, Tositumomab, Gemtuzumab Ozogamicin, Alemtuzumab, Sixatumumab, Girentuximab, Nimotuzumab, Catumaxomab, or an antigen-binding fragment of Etaracizumab, of any one of paragraphs AM to AO, a modified antibody, a modified antibody fragment, or a modified binding peptide. , Alemtuzumab, Sixatumumab, Girentuximab, Nimotuzumab, Catumaxomab, or an antigen-binding fragment of Etaracizumab, of any one of paragraphs AM to AO, a modified antibody, a modified antibody fragment, or a modified binding peptide. or an antigen-binding fragment of Etaracizumab, of any one of paragraphs AM to AO, a modified antibody, a modified antibody fragment, or a modified binding peptide. or an antigen-binding fragment of Etaracizumab, of any one of paragraphs AM to AO, a modified antibody, a modified antibody fragment, or a modified binding peptide. AQ. The binding peptide is a prostate-specific membrane antigen ("PSMA") binding peptide, somatostatin receptor agonist, bombesin receptor agonist, separase binding compound, or a binding fragment thereof, of any one of paragraphs AM to AP, a modified antibody, a modified antibody fragment, or a modified binding peptide. , bombesin receptor agonist, separase binding compound, or a binding fragment thereof, of any one of paragraphs AM to AP, a modified antibody, a modified antibody fragment, or a modified binding peptide. , of any one of paragraphs AM to AP, a modified antibody, a modified antibody fragment, or a modified binding peptide. , a modified antibody fragment, or a modified binding peptide. AR. The compound of formula I is a compound of formula IV

[0325] [Chemical formula] [wherein, M 2 is an alpha-emitting radionuclide], or a pharmaceutically acceptable salt thereof, of any one of paragraphs AM to AQ, a modified antibody, a modified antibody fragment, or a modified binding peptide. , a modified antibody fragment, or a modified binding peptide. AS. M 2 is actinium-225 (​​225 Ac 3+ )、radium-223( 233 Ra 2+ )、bismuth-213( 213 Bi 3+ )、lead-212( 212 Pb 2+ and / or 212 Pb 4+ )、terbium-149( 149 Tb 3+ )、fermium- 255( 255 Fm 3+ )、thorium-227( 227 Th 4+ )、thorium-226( 226 Th 4+ )、astatine-211( 211 At + )、astatine-217( 217 At + )、or uranium-230, a modified antibody, modified antibody f ragment, or modified binding peptide. AT. The binding may be a thiocyanate bond; the thiocyanate bond results from conjugation of the compound to an antibody, antibody fragment, or binding peptide; the compound is

[0326]

Chem.

[0327] [wherein, M is an α-emitting radionuclide], or a pharmaceutically acceptable 3 salt thereof, the modified antibody of any one of paragraphs AM~AQ, the modified antibody frag ment, or the modified binding peptide. AW. M 3 is actinium-225( 225 Ac 3+ )、radium-223( 233 Ra 2+ )、bismuth-213( 213 Bi 3+ )、lead-212( 212 Pb 2+ and / or 212 Pb 4+ )、terbium-149( 149 Tb​3+ )、 fermium- 255( 255 Fm 3+ )、 thorium-227( 227 Th 4+ )、 thorium-226( 226 Th 4+ )、 astatine-211( 211 At + )、 astatine-217( 217 At + )、 or uranium-230, a modified antibody of paragraph AV, a modified antibody frag ment, or a modified binding peptide. AX. A compound of formula IA is a compound of formula X

[0328]

Chemical formula

[0329] [wherein, M [wherein, M 5 is an alpha-emitting radionuclide], or a pharmaceutically acceptable salt thereof, a modified antibody, a modified antibody fragment of any one of paragraphs AM to AQ, or a modified binding peptide. BA. M 5 is actinium-225( 225 Ac 3+ ), radium-223( 233 Ra 2+ ), bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149( 149 Tb 3+ ), fermium- 255( 255 Fm 3+ ), thorium-227( 227 Th 4+ ), thorium-226( 226 Th 4+ ), astatine-211( 211 At + ), astatine-217( 217 At +), or uranium-230, fragments, or modified binding peptides. BB. A composition comprising a pharma- ceutically acceptable carrier and any one of the compounds of paragraphs A-R. thing. BC. A pharma- ceutically acceptable carrier and a targeting compound of any one of paragraphs S through AC. or a pharma- ceutically acceptable carrier, and any one of paragraphs AD through BA. Compositions containing modified antibodies, modified antibody fragments, or modified binding peptides Composition. BD. Cancer and / or prostate-specific membrane antigen ("PSMA")-positive subjects A pharmaceutical composition useful for targeted radiation therapy of mammalian tissue overexpressing a medicament comprising a pharma- ceutical composition ... and any one of the compounds of paragraphs S through AC, or any one of paragraphs AD through BA. Any one of the modified antibodies, modified antibody fragments, or modified binding peptides A pharmaceutical composition comprising tide. BE. Methods for treating cancer and / or mammalian tissue that overexpresses PSMA An effective amount of a compound or a cancer and / or mammalian tissue that overexpresses PSMA. and an effective amount of a modified antibody, modified antibody fragment, or modified The pharmaceutical composition of paragraph BD, comprising a binding peptide. BF. The subject is a patient who has a tumor that is associated with a somatostatin receptor, a bombesin receptor, a seprase receptor, or a combination thereof. Mammalian tissues expressing any combination of two or more of the above and / or overexpressing PSMA The pharmaceutical composition of paragraph BD or paragraph BE, wherein the pharmaceutical composition has a mammalian tissue problem. BG. The subject is a tumor producing growth hormone, a neuroendocrine tumor, a pituitary tumor, a vasoactive tumor, One or more of neuroendocrine peptide-secreting tumors, small cell lung cancer, gastric cancer, pancreatic cancer, and neuroblastoma A pharmaceutical composition according to any one of paragraphs BD to BF, having the problem. BH. A pharmaceutical composition according to any one of paragraphs BD to BG, wherein the subject has one or more problems of glioma, breast cancer, adrenocortical cancer, 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 One or more problems of primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer A pharmaceutical composition according to any one of paragraphs BD to BG, having the problem. BI. A pharmaceutical composition according to any one of paragraphs BD to BH, formulated for intravenous administration and optionally containing sterile water, Ringer's solution, or isotonic saline A pharmaceutical composition according to any one of paragraphs BD to BH, formulated for intravenous administration and optionally containing sterile water, Ringer's solution, or isotonic saline BJ. A pharmaceutical composition according to any one of paragraphs BD to BI, wherein the effective amount of the compound is about 0.01 μg to about 10 mg of the compound per gram of the pharmaceutical composition A pharmaceutical composition according to any one of paragraphs BD to BI, wherein the effective amount of the compound is about 0.01 μg to about 10 mg of the compound per gram of the pharmaceutical composition BK. A pharmaceutical composition according to any one of paragraphs BD to BJ, provided in an injectable dosage form BL. A method of treating a subject, comprising administering to the subject a targeting compound according to any one of paragraphs S to AC, or administering a modified antibody according to any one of paragraphs AD to BA A method of treating a subject, comprising administering to the subject a targeting compound according to any one of paragraphs S to AC, or administering a modified antibody according to any one of paragraphs AD to BA A method of treating a subject, comprising administering to the subject a targeting compound according to any one of paragraphs S to AC, or administering a modified antibody according to any one of paragraphs AD to BA, a modified antibody fragment, or a modified binding peptide A method of treating a subject, comprising administering to the subject a targeting compound according to any one of paragraphs S to AC, or administering a modified antibody according to any one of paragraphs AD to BA, a modified antibody fragment, or a modified binding peptide BM. The method according to paragraph BL, wherein the subject has a problem of cancer and / or mammalian tissue that overexpresses prostate-specific membrane antigen ("PSMA") The method according to paragraph BL, wherein the subject has a problem of cancer and / or mammalian tissue that overexpresses prostate-specific membrane antigen ("PSMA") BN. The method according to paragraph BM, comprising administering an effective amount of a compound for treating cancer and / or mammalian tissue that overexpresses PSMA, or an effective amount of a modified antibody, a modified antibody fragment, or a modified binding peptide for treating cancer and / or mammalian tissue that overexpresses PSMA The method according to paragraph BM, comprising administering an effective amount of a compound for treating cancer and / or mammalian tissue that overexpresses PSMA, or an effective amount of a modified antibody, a modified antibody fragment, or a modified binding peptide for treating cancer and / or mammalian tissue that overexpresses PSMA The method according to paragraph BM, comprising administering an effective amount of a compound for treating cancer and / or mammalian tissue that overexpresses PSMA, or an effective amount of a modified antibody, a modified antibody fragment, or a modified binding peptide for treating cancer and / or mammalian tissue that overexpresses PSMA The method according to paragraph BM, comprising administering an effective amount of a compound for treating cancer and / or mammalian tissue that overexpresses PSMA, or an effective amount of a modified antibody, a modified antibody fragment, or a modified binding peptide for treating cancer and / or mammalian tissue that overexpresses PSMA BO. When administered to a subject, the subject has a problem with mammalian tissue that expresses somatostatin receptor, bombesin receptor, sep lase, or a combination of any two or more thereof, and / or mammalian tissue that overexpresses prostate-specific membrane antigen ("PSMA"), by any one of the methods of paragraphs BL to BN. BP. When the mammalian tissue includes one or more of a tumor that produces growth hormone, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, small cell lung cancer, gastric cancer, pancreatic cancer, neuroblastoma, and metastatic cancer, by any one of the methods of paragraphs BL to BO. BQ. When the subject has a problem with one or more of glioma, breast cancer, adrenal cortical cancer, 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, and prostate cancer, by any one of the methods of paragraphs BL to BP. BR. When the administration step includes parenteral administration, by any one of the methods of paragraphs BL to BQ . BS. When the administration step includes intravenous administration, by any one of the methods of paragraphs BL to BR . BT. When the effective amount is about 0.1 μg to about 50 μg per kilogram of the subject's body weight, by any one of the methods of paragraphs BL to BS. BU. A compound comprising a first domain having a blood protein-binding moiety with low specific affinity for blood proteins, a second domain having a tumor-targeting moiety with high affinity for tumor antigens , and a third domain having a chelator. BV. When the tumor antigen is PSMA, bombesin, somatostatin receptor, or sep lase, the compound of paragraph BU. BW. The blood protein binding portion is approximately 0.5-50×10 -6 About M albumin and the tumor targeting moiety has a specific affinity of about 0.5-50×10 -9 Tumor antigens of M The compound of paragraph BU or paragraph BV having a specific affinity for BX. The following structure

[0330] [ka] or a pharma- ceutically acceptable salt thereof. BY. 213 Bi 3+ , 211 At + , 225 Ac 3+ , 152 Dy 3+ , 212 Bi 3+ , 211 Bi 3+ , 217 At + , 227 Th 4+ , 226 Th 4+ , 233 Ra 2 + , 212 Pb 2+ ,or 212 Pb 4+ chelating, including compounds of paragraph BX composition. BZ. A method of treating a subject, comprising administering to the subject the composition of paragraph BY. How to do it. CA. Subject has cancer and / or prostate specific membrane antigen ("PSMA") overexpression The method of paragraph BZ, wherein the mammalian tissue is CB. Useful compounds for treating cancer and / or mammalian tissues that overexpress PSMA The method of paragraph CA, comprising the step of administering a composition of the dosage. CC. The method of any one of paragraphs BZ to CB, wherein the subject has a problem with mammalian tissue that overexpresses prostate-specific membrane antigen ("PSMA"). The method of any one of paragraphs BZ to CB, wherein the subject has a problem with mammalian tissue that overexpresses prostate-specific membrane antigen ("PSMA"). CD. The method of any one of paragraphs BZ to CC, wherein the mammalian tissue comprises one or more of a tumor that produces growth hormone, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, small cell lung cancer, gastric cancer, pancreatic cancer, neuroblastoma, and metastatic cancer. The method of any one of paragraphs BZ to CC, wherein the mammalian tissue comprises one or more of a tumor that produces growth hormone, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, small cell lung cancer, gastric cancer, pancreatic cancer, neuroblastoma, and metastatic cancer. The method of any one of paragraphs BZ to CC, wherein the mammalian tissue comprises one or more of a tumor that produces growth hormone, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, small cell lung cancer, gastric cancer, pancreatic cancer, neuroblastoma, and metastatic cancer. CE. The method of any one of paragraphs BZ to CD, wherein the subject has a problem with one or more of glioma, breast cancer, adrenocortical cancer, 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 cancer, and prostate cancer. The method of any one of paragraphs BZ to CD, wherein the subject has a problem with one or more of glioma, breast cancer, adrenocortical cancer, 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 cancer, and prostate cancer. The method of any one of paragraphs BZ to CD, wherein the subject has a problem with one or more of glioma, breast cancer, adrenocortical cancer, 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 cancer, and prostate cancer. The method of any one of paragraphs BZ to CD, wherein the subject has a problem with one or more of glioma, breast cancer, adrenocortical cancer, 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 cancer, and prostate cancer. CF. The method of any one of paragraphs BZ to CE, wherein the step of administering comprises parenteral administration. CG. The method of any one of paragraphs BZ to CF, wherein the step of administering comprises intravenous administration. CH. The method of any one of paragraphs BZ to CG, wherein the effective amount is about 0.1 μg to about 50 μg per kilogram of the subject's body weight. The method of any one of paragraphs BZ to CG, wherein the effective amount is about 0.1 μg to about 50 μg per kilogram of the subject's body weight.

[0331] Other embodiments are described in the following claims, along with the full scope of equivalents to which such claims are entitled. ​

Claims

1. Formula I 【Chemistry 1】 [In the formula, Z １ is H or -X １ -W ２ and Z ２ is OH or NH-W ３ and Z ３ is H or W ７ and a is 0 or 1; X １ is O, NH, or S; W ２ and W. ３ are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH ２ CH ２ - (OCH ２ CH ２ ) ｗ -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH ２ CH ２ - (OCH ２ CH ２ ) ｘ -OR' (in the formula, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which is , optionally halo, -N ３ , -OR', -CH ２ CH ２ - (OCH ２ CH ２ ) ｙ - R', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; H ２ CH ２ -(OCH ２ CH ２ ) ｚ -OR' (wherein z is 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10), —SR′, —OC(O)R′, —C(O)OR′, — C(S)OR’、-S(O)R’、-SO ２ R’、-SO ２ (OR’)、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’)、-P(O)R’ ２ 、-CN、 -OCN、-SCN、-NCO、-NCS、-NR’-NH ２ 、-N=C=N-R’、- SO ２ may be substituted with one or more of Cl, —C(O)Cl, or epoxide groups; often; W ５ and W. ７ are each independently OH, NH ２ , SH, alkyl, cycloalkyl, Alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl Ru, -CH ２ CH ２ - (OCH ２ CH ２ ) ｗ -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH ２ CH ２ - (OCH ２ CH ２ ) ｘ -OR', where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each of which is optionally selected from halo, -N ３ , —OR′, —CH ２ CH ２ - (OC H ２ CH ２ ) y ｘ -R', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH ２ CH ２ - (OCH ２ CH ２ ) ｚ -OR' (wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', - C(O)OR’、-C(S)OR’、-S(O)R’、-SO ２ R’、-SO ２ (OR’ )、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’)、-P(O )R’ ２ 、-CN、-OCN、-SCN、-NCO、-NCS、-NR’-NH ２ 、-N =C=NR', -SO ２ one or more of Cl, -C(O)Cl, or epoxide groups may be substituted with; R' at each occurrence is independently H, halo, -N ３ , C １ ~C ６ Alkyl, C ３ ~C ６ Cyclo Alkyl, C ２ ~C ６ Alkenyl, C ５ ~C ８ Cycloalkenyl, C ２ ~C ６ Alkynyl , C ８ ~C １０ Cycloalkynyl, C ５ ~C ６ Aryl, heterocyclyl, or hetero aryl], or a pharma- ceutically acceptable salt thereof.

2. Formula III 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof. 【Request 3】 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

4. The compound of formula I is represented by formula VI 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

5. The compound of formula I is of formula IX 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

6. The compound of formula I is represented by formula XII 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

7. Formula IA 【Chemistry 7】 [In the formula, M １ is an alpha-emitting radionuclide; Z １ is H or -X １ -W ２ and Z ２ is OH or NH-W ３ and Z ３ is H or W ７ and a is 0 or 1; X １ is O, NH, or S; W ２ and W. ３ are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH ２ CH ２ - (OCH ２ CH ２ ) ｗ -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH ２ CH ２ - (OCH ２ CH ２ ) ｘ -OR' (in the formula, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which is , optionally halo, -N ３ , —OR′, —CH ２ CH ２ - (OCH ２ CH ２ ) ｙ - R', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; H ２ CH ２ -(OCH ２ CH ２ ) ｚ -OR' (wherein z is 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10), —SR′, —OC(O)R′, —C(O)OR′, — C(S)OR’、-S(O)R’、-SO ２ R’、-SO ２ (OR’)、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’)、-P(O)R’ ２ 、-CN、 -OCN、-SCN、-NCO、-NCS、-NR’-NH ２ 、-N=C=N-R’、- SO ２ may be substituted with one or more of Cl, —C(O)Cl, or epoxide groups; often; W ５ and W. ７ are each independently OH, NH ２ , SH, alkyl, cycloalkyl, Alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl Ru, -CH ２ CH ２ - (OCH ２ CH ２ ) ｗ -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH ２ CH ２ - (OCH ２ CH ２ ) ｘ -OR', where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each of which is optionally selected from halo, -N ３ , —OR′, —CH ２ CH ２ - (OC H ２ CH ２ ) y ｘ -R', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH ２ CH ２ - (OCH ２ CH ２ ) ｚ -OR' (wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', - C(O)OR’、-C(S)OR’、-S(O)R’、-SO ２ R’、-SO ２ (OR’ )、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’)、-P(O )R’ ２ 、-CN、-OCN、-SCN、-NCO、-NCS、-NR’-NH ２ 、-N =C=NR', -SO ２ one or more of Cl, -C(O)Cl, or epoxide groups may be substituted with; R' at each occurrence is independently H, halo, -N ３ , C １ ~C ６ Alkyl, C ３ ~C ６ Cyclo Alkyl, C ２ ~C ６ Alkenyl, C ５ ~C ８ Cycloalkenyl, C ２ ~C ６ Alkynyl , C ８ ~C １０ Cycloalkynyl, C ５ ~C ６ Aryl, heterocyclyl, or hetero aryl], or a pharma- ceutically acceptable salt thereof.

8. M １ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ 8. The compound of claim 7, wherein said compound is uranium-230.

9. The compound of formula I is represented by formula IV 【Chemistry 8】 [In the formula, M ２ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof.

9. The compound of claim 7 or claim 8, which is a salt.

10. M ２ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ 10. The compound of claim 9, wherein said compound is uranium-230.

11. 【Chemical 9】 or a pharma- ceutically acceptable salt thereof.

12. M ２ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230.

13. The compound of formula IA is represented by formula VIII 【Chemistry 10】 [In the formula, M ３ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof.

9. A compound according to claim 7 or claim 8, which is a salt.

14. M ３ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230.

15. The compound of formula IA is represented by formula X 【Chemistry 11】 [In the formula, M ４ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof.

9. The compound of claim 7 or claim 8, which is a salt.

16. M ４ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230.

17. The compound of formula IA is represented by formula XIII 【Chemistry 12】 [In the formula, M ５ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof.

9. The compound of claim 7 or claim 8, which is a salt.

18. M ５ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230.

19. Formula II 【Chemistry 13】 [In the formula, M １ is an alpha-emitting radionuclide; Z １ is H or -L ３ -R ２２ and Z ２ is OH or NH-L ４ -R ２４ and Z ３ is H or -L ６ -R ２８ and a is 0 or 1; X １ is O, NH, or S; L ３ , L ４ , L ５ , or L ６ is, independently at each occurrence, a bond or a linker group; R ２２ , R ２４ , R ２６ , and R ２８ each independently represents an antibody, an antibody fragment ( For example, an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (e.g. , selective targeting oligopeptides containing up to 50 amino acids), binding proteins Substances, enzymes, nucleobase-containing moieties (e.g., oligonucleotides, DNA or RNA vectors) or aptamers, or lectins, or and a commercially acceptable salt thereof.

20. M １ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ 20. The targeting compound of claim 19, which is uranium-230.

21. R ２２ , R ２４ , R ２６ , and R ２８ However, belimumab and mogamulizumab were independently Mab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, Lentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab , panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab e Mutansine, siltuximab, cemiplimab, nivolumab, pembrolizumab, olarrativ Mab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotzumab Zumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tocit Momab, gemtuzumab ozogamicin, alemtuzumab, cixutumumab, girentzi cimatinib, nimotuzumab, catumaxomab, etaracizumab, or any of their antigen-binding fragments Segment, prostate specific membrane antigen ("PSMA") binding peptide, somatostatin receptor agonist agonists, bombesin receptor agonists, seprase binding compounds, or any of them 21. A targeting compound according to claim 19 or claim 20 comprising a binding fragment.

22. The targeting compound of formula II is represented by formula V 【Chemistry 14】 [In the formula, M ２ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof. The targeting compound of any one of claims 19 to 21, which is a salt.

23. M ２ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230.

24. The targeting compound of formula II is represented by formula VIII 【Chemistry 15】 [In the formula, M ３ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof. The targeting compound of any one of claims 19 to 21, which is a salt.

25. M ３ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230.

26. The targeting compound of formula II is represented by formula XI 【Chemistry 16】 [In the formula, M ４ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof. The targeting compound of any one of claims 19 to 21, which is a salt.

27. M ４ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230.

28. The targeting compound of formula II is represented by formula XIV 【Chemistry 17】 [In the formula, M ５ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof. The targeting compound of any one of claims 19 to 21, which is a salt.

29. M ５ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230.

30. Formula I 【Chemistry 18】 [In the formula, Z １ is H or -X １ -W ２ and Z ２ is OH or NH-W ３ and Z ３ is H or W ７ and a is 0 or 1; X １ is O, NH, or S; W ２ and W. ３ are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH ２ CH ２ - (OCH ２ CH ２ ) ｗ -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH ２ CH ２ - (OCH ２ CH ２ ) ｘ -OR' (in the formula, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which is , optionally halo, -N ３ , —OR′, —CH ２ CH ２ - (OCH ２ CH ２ ) ｙ - R', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; H ２ CH ２ -(OCH ２ CH ２ ) ｚ -OR' (wherein z is 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10), —SR′, —OC(O)R′, —C(O)OR′, — C(S)OR’、-S(O)R’、-SO ２ R’、-SO ２ (OR’)、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’)、-P(O)R’ ２ 、-CN、 -OCN、-SCN、-NCO、-NCS、-NR’-NH ２ 、-N=C=N-R’、- SO ２ may be substituted with one or more of Cl, —C(O)Cl, or epoxide groups; often; W ５ and W. ７ are each independently OH, NH ２ , SH, alkyl, cycloalkyl, Alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl Ru, -CH ２ CH ２ - (OCH ２ CH ２ ) ｗ -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH ２ CH ２ - (OCH ２ CH ２ ) ｘ -OR', where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each of which is optionally selected from halo, -N ３ , —OR′, —CH ２ CH ２ - (OC H ２ CH ２ ) y ｘ -R', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH ２ CH ２ - (OCH ２ CH ２ ) ｚ -OR' (wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', - C(O)OR’、-C(S)OR’、-S(O)R’、-SO ２ R’、-SO ２ (OR’ )、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’)、-P(O )R’ ２ 、-CN、-OCN、-SCN、-NCO、-NCS、-NR’-NH ２ 、-N =C=NR', -SO ２ one or more of Cl, -C(O)Cl, or epoxide groups may be substituted with; R' at each occurrence is independently H, halo, -N ３ , C １ ~C ６ Alkyl, C ３ ~C ６ Cyclo Alkyl, C ２ ~C ６ Alkenyl, C ５ ~C ８ Cycloalkenyl, C ２ ~C ６ Alkynyl , C ８ ~C １０ Cycloalkynyl, C ５ ~C ６ Aryl, heterocyclyl, or hetero or a pharma- ceutically acceptable salt thereof, or a modified antibody, comprising a bond resulting from conjugation to a binding peptide. , a modified antibody fragment, or a modified binding peptide.

31. The antibodies are belimumab, mogamulizumab, blinatumomab, and ibritumomab tiuxeta. , obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, Moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab Mab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, Rastuzumab, trastuzumab emtansine, siltuximab, cemiplimab, nivolumab Mab, pembrolizumab, olaratumab, atezolizumab, avelumab, durvalumab , capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, benign prostatic hyperplasia Basizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab tuzumab, cixutumumab, girentuximab, nimotuzumab, catumaxomab, or etat The modified antibody or modified antibody fragment of claim 30, comprising racizumab. or a modified binding peptide.

32. Antibody fragments include belimumab, mogamulizumab, blinatumomab, and ibritumomab. Tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozo gamycin, moxetumomab pasudotox, brentuximab vedotin, daratumumab ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pelvic Tuzumab, trastuzumab, trastuzumab emtansine, siltuximab, cempril Mab, nivolumab, pembrolizumab, olaratumab, atezolizumab, avelumab, de Urvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-Afribe Rucept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin , alemtuzumab, cixutumumab, girentuximab, nimotuzumab, catumaxomab or an antigen-binding fragment of etaracizumab. A modified antibody, modified antibody fragment, or modified binding peptide as described.

33. The binding peptide is a prostate specific membrane antigen ("PSMA") binding peptide, somatostatin Receptor agonists, bombesin receptor agonists, seprase binding compounds, or combinations thereof The modified antibody according to any one of claims 30 to 32, comprising a fused fragment. modified antibody fragments, or modified binding peptides.

34. The compound of formula I is represented by formula III 【Chemistry 19】 or a pharma- ceutically acceptable salt thereof. A modified antibody, modified antibody fragment, or modified binding peptide as described.

35. The bond may be a thiocyanate bond; the thiocyanate bond may be an anti- resulting from conjugation to a ribozyme, antibody fragment, or binding peptide; 、 【Chemistry 20】 or a pharma- ceutically acceptable salt thereof. modified antibodies, modified antibody fragments, or modified binding peptides.

36. The compound of formula I is represented by formula VI 【Chemistry 21】 or a pharma- ceutically acceptable salt thereof. A modified antibody, modified antibody fragment, or modified binding peptide as described.

37. The compound of formula I is of formula IX 【Chemical 22】 or a pharma- ceutically acceptable salt thereof. A modified antibody, modified antibody fragment, or modified binding peptide as described.

38. The compound of formula I is represented by formula XII 【Chemistry 23】 or a pharma- ceutically acceptable salt thereof. A modified antibody, modified antibody fragment, or modified binding peptide as described.

39. Formula IA 【Chemistry 24】 [In the formula, M １ is an alpha-emitting radionuclide; Z １ is H or -X １ -W ２ and Z ２ is OH or NH-W ３ and Z ３ is H or W ７ and a is 0 or 1; X １ is O, NH, or S; W ２ and W. ３ are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH ２ CH ２ - (OCH ２ CH ２ ) ｗ -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH ２ CH ２ - (OCH ２ CH ２ ) ｘ -OR' (in the formula, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which is , optionally halo, -N ３ , —OR′, —CH ２ CH ２ - (OCH ２ CH ２ ) ｙ - R', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; H ２ CH ２ -(OCH ２ CH ２ ) ｚ -OR' (wherein z is 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10), —SR′, —OC(O)R′, —C(O)OR′, — C(S)OR’、-S(O)R’、-SO ２ R’、-SO ２ (OR’)、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’)、-P(O)R’ ２ 、-CN、 -OCN、-SCN、-NCO、-NCS、-NR’-NH ２ 、-N=C=N-R’、- SO ２ may be substituted with one or more of Cl, —C(O)Cl, or epoxide groups; often; W ５ and W. ７ are each independently OH, NH ２ , SH, alkyl, cycloalkyl, Alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl Ru, -CH ２ CH ２ - (OCH ２ CH ２ ) ｗ -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH ２ CH ２ - (OCH ２ CH ２ ) ｘ -OR', where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each of which is optionally selected from halo, -N ３ , -OR', -CH ２ CH ２ - (OC H ２ CH ２ ) y ｘ -R', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH ２ CH ２ - (OCH ２ CH ２ ) ｚ -OR' (wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', - C(O)OR’、-C(S)OR’、-S(O)R’、-SO ２ R’、-SO ２ (OR’ )、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’)、-P(O )R’ ２ 、-CN、-OCN、-SCN、-NCO、-NCS、-NR’-NH ２ 、-N =C=NR', -SO ２ one or more of Cl, -C(O)Cl, or epoxide groups may be substituted with; R' at each occurrence is independently H, halo, -N ３ , C １ ~C ６ Alkyl, C ３ ~C ６ Cyclo Alkyl, C ２ ~C ６ Alkenyl, C ５ ~C ８ Cycloalkenyl, C ２ ~C ６ Alkynyl , C ８ ~C １０ Cycloalkynyl, C ５ ~C ６ Aryl, heterocyclyl, or hetero or a pharma- ceutically acceptable salt thereof, or a modified antibody, comprising a bond resulting from conjugation to a binding peptide. , a modified antibody fragment, or a modified binding peptide.

40. M １ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ 40. The modified antibody of claim 39, which is uranium-230. Fragments, or modified binding peptides.

41. The antibodies are belimumab, mogamulizumab, blinatumomab, and ibritumomab tiuxeta. , obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, Moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab Mab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, Rastuzumab, trastuzumab emtansine, siltuximab, cemiplimab, nivolumab Mab, pembrolizumab, olaratumab, atezolizumab, avelumab, durvalumab , capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, benign prostatic hyperplasia Basizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab tuzumab, cixutumumab, girentuximab, nimotuzumab, catumaxomab, or etat The modified antibody of claim 39 or claim 40, comprising racizumab. a polypeptide fragment, or a modified binding peptide.

42. Antibody fragments include belimumab, mogamulizumab, blinatumomab, and ibritumomab. Tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozo gamycin, moxetumomab pasudotox, brentuximab vedotin, daratumumab ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pelvic Tuzumab, trastuzumab, trastuzumab emtansine, siltuximab, cempril Mab, nivolumab, pembrolizumab, olaratumab, atezolizumab, avelumab, de Urvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-Afribe Rucept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin , alemtuzumab, cixutumumab, girentuximab, nimotuzumab, catumaxomab or an antigen-binding fragment of etaracizumab. The modified antibody, modified antibody fragment, or modified binding peptide according to any one of claims 1 to 5. Do.

43. The binding peptide is a prostate specific membrane antigen ("PSMA") binding peptide, somatostatin Receptor agonists, bombesin receptor agonists, seprase binding compounds, or combinations thereof The modified antibody according to any one of claims 39 to 42, comprising a fused fragment. modified antibody fragments, or modified binding peptides.

44. The compound of formula I is represented by formula IV 【Chemistry 25】 [In the formula, M ２ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof. The modified antibody or modified antibody fragment according to any one of claims 39 to 43, which is a salt. fragments, or modified binding peptides.

45. M ２ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230. Fragments, or modified binding peptides.

46. The bond may be a thiocyanate bond; the thiocyanate bond may be an anti- resulting from conjugation to a ribozyme, antibody fragment, or binding peptide; 、 【Chemistry 26】 or a pharma- ceutically acceptable salt thereof. or modified binding peptides.

47. M ２ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230. Fragments, or modified binding peptides.

48. The compound of formula IA is represented by formula VIII 【Chemistry 27】 [In the formula, M ３ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof. The modified antibody or modified antibody fragment according to any one of claims 39 to 43, which is a salt. fragments, or modified binding peptides.

49. M ３ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230. Fragments, or modified binding peptides.

50. The compound of formula IA is represented by formula X 【Chemistry 28】 [In the formula, M ４ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof. The modified antibody or modified antibody fragment according to any one of claims 39 to 43, which is a salt. fragments, or modified binding peptides.

51. M ４ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230. Fragments, or modified binding peptides.

52. The compound of formula IA is represented by formula XIII 【Chemical Formula 29】 [In the formula, M ５ is an alpha-emitting radionuclide], or a pharma- ceutically acceptable derivative thereof. The modified antibody or modified antibody fragment according to any one of claims 39 to 43, which is a salt. fragments, or modified binding peptides.

53. M ５ However, actinium-225 ( ２２５ A.C. ３＋ ), Radium-223 ( ２３３ Ra ２ ＋ ), Bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ And / If Kuha ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), Fermium-255 ( ２５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), or uranium-230. Fragments, or modified binding peptides.

54. A pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound according to any one of claims 1 to 18. composition.

55. A pharma- ceutically acceptable carrier and a targeting agent according to any one of claims 19 to 29. or a pharma- ceutically acceptable carrier and any one of claims 30 to 53. The modified antibody, modified antibody fragment, or modified binding peptide according to any one of claims 1 to 5. A composition comprising a chid.

56. Cancer and / or overexpression of prostate specific membrane antigen ("PSMA") in a subject A pharmaceutical composition useful for targeted radiation therapy of mammalian tissue comprising a pharma- ceutical composition comprising a pharma- ceutical acceptable carrier. and a compound according to any one of claims 19 to 29 or claims 30 to 53. The modified antibody, modified antibody fragment, or modified A pharmaceutical composition comprising the selected binding peptide.

57. Effective amount for treating cancer and / or mammalian tissue that overexpresses PSMA or a compound of formula (I) for treating cancer and / or mammalian tissue that overexpresses PSMA. and an effective amount of the modified antibody, modified antibody fragment, or modified 57. The pharmaceutical composition of claim 56, comprising a binding peptide.

58. The subject is a somatostatin receptor, a bombesin receptor, a seprase, or any of them. Mammalian tissue expressing one or a combination of two or more of PSMA, and / or mammalian tissue overexpressing PSMA.

58. The pharmaceutical composition of claim 56 or claim 57, which has a problem with mammalian tissue.

59. The subjects are tumors that produce growth hormone, neuroendocrine tumors, pituitary tumors, vasoactive intestinal tumors, and One or more of the following problems may be considered: peptide-secreting tumors, small cell lung cancer, gastric cancer, pancreatic cancer, and neuroblastoma The pharmaceutical composition according to any one of claims 56 to 58, comprising

60. The subjects were glioma, breast cancer, adrenal cortical cancer, 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 Patients with one or more of the following problems: gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer The pharmaceutical composition according to any one of claims 56 to 59.

61. Formulated for intravenous administration, in some cases with sterile water, Ringer's solution, or isotonic saline. The pharmaceutical composition according to any one of claims 56 to 60, comprising

62. The effective amount of the compound is from about 0.01 μg to about 10 mg of compound per gram of pharmaceutical composition. The pharmaceutical composition according to any one of claims 57 to 61.

63. 63. The pharmaceutical composition of any one of claims 56 to 62, provided in an injectable dosage form.

64. A method of treating a subject, comprising administering to a subject a targeting agent according to any one of claims 19 to 29. or a modification according to any one of claims 30 to 53. The method comprises administering the modified antibody, modified antibody fragment, or modified binding peptide to the subject. The method includes the steps:

65. The subject is diagnosed with cancer and / or a prostate cancer that overexpresses prostate specific membrane antigen ("PSMA").

65. The method of claim 64 having a problem with dairy tissue.

66. Effective amount for treating cancer and / or mammalian tissue that overexpresses PSMA or a compound of formula (I) for treating cancer and / or mammalian tissue that overexpresses PSMA. and an effective amount of the modified antibody, modified antibody fragment, or modified 66. The method of claim 65, comprising administering a binding peptide.

67. The subject is a somatostatin receptor, a bombesin receptor, a seprase, or any of them. Mammalian tissue expressing a combination of two or more of the above, and / or prostate specific membrane antigen ("P-specific membrane antigen").

67. The method according to claim 64, wherein the patient has a problem of mammalian tissue overexpressing SMAS ("SMA"). The method according to claim 5.

68. Mammalian tissues include growth hormone-producing tumors, neuroendocrine tumors, pituitary tumors, and vascular tumors. intestinal peptide-secreting tumors, small cell carcinoma of the lung, gastric cancer, pancreatic cancer, neuroblastoma, and metastatic The method of any one of claims 64 to 67, comprising one or more of the following:

69. The subjects were glioma, breast cancer, adrenal cortical cancer, 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 Patients with one or more of the following problems: gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer The method according to any one of claims 64 to 68,

70. The method of any one of claims 64 to 69, wherein the administering step comprises parenteral administration. Law.

71. The method of any one of claims 64 to 70, wherein the administering step comprises intravenous administration. Law.

72. 7. The method of claim 6, wherein the effective amount is from about 0.1 μg to about 50 μg per kilogram of the subject's body weight.

6. The method according to any one of claims 6 to 71.

73. A first domain having a blood protein binding portion with low specific affinity for blood proteins. a second domain having a tumor targeting moiety with high affinity for a tumor antigen; and and a third domain having a chelator.

74. The tumor antigen is PSMA, bombesin, somatostatin receptor, or seprase.

74. The compound of claim 73.

75. The blood protein binding moiety is about 0.5 to 50×10 －６ Specificity of albumin in M The affinity and tumor targeting moiety is about 0.5-50×10 －９ Regarding tumor antigens of M The compound of claim 73, having a specific affinity of

76. The following structure 【Chemistry 30】 or a pharma- ceutically acceptable salt thereof.

77. ２１３ Bi ３＋ , ２１１ At ＋ , ２２５ Ac ３＋ , １５２ Dy ３＋ , ２１２ Bi ３＋ , ２１１ Yes ３＋ 、 ２１７ At ＋ 、 ２２７ Th ４＋ 、 ２２６ Th ４＋ 、 ２３３ Ra ２＋ 、 ２ １２ Pb ２＋ ,or ２１２ Pb ４＋ 77. The compound according to claim 76, A composition comprising:

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