Macrocyclic complexes of α-emitting radionuclides and their use in targeted radiotherapy of cancer

Abstract

To provide macrocyclic complex-containing compositions comprising radionuclides that are less toxic to non-targeted tissue and useful for targeted radiotherapy of cancer.SOLUTION: Provided herein are compositions comprising compounds represented by the formula in the figure or pharmaceutically acceptable salts thereof. In the formula, M is an α-emitting radionuclide.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 478,945, filed March 30, 2017. No. 6,313,633, filed on Dec. 13, 2003, and the entire disclosure of which is hereby incorporated by reference for any and all purposes. Enter.

[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 composition of formula I is

[0005] [ka] [wherein M is an α-emitting radionuclide, A 1 is a nitrogen atom (N) or CR 1 Represents ;A 2 is a nitrogen atom (N) or CR 2 A 3 is a nitrogen atom (N) or CR 3 of Representation; A 4 is a nitrogen atom (N) or CR 4 A 5 is a nitrogen atom (N) or CR 5 A6 is a nitrogen atom (N) or CR 6 A 7 is a nitrogen atom (N) or CR 7 A 8 is a nitrogen atom (N) or CR 8 A 9 is a nitrogen atom (N) Or CR 9 A 10 is a nitrogen atom (N) or CR 10 where A represents 1 , A 2 , A 3 , A 4 , and A 5 up to three of A may be nitrogen atoms; 6 , A 7 , A 8 , A 9 , and A 10 up to three of R may be nitrogen atoms; 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is H, alkyl, cycloalkyl, alkene, aryl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, haloaryl B, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCH2CH2) y -OR', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR' , -NR'C(S)NR', ​​-S(O)R', -SO2R', -SO2(OR'), -S O2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2 , -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R' , -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and epoxide groups. are each independently selected and optionally include halo, -(OCH2CH2) x -R', -( OCH2CH2) y -OR', -OR', -SR', -OC(O)R', -C(O)OR ', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O )R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C( S)NR', ​​-S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, - CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N= C=N-R', -SO2Cl, -C(O)Cl, and epoxide groups are -(CH2) n a linker (wherein n is 1, 2, or 3) that connects the carbon atom to which it is attached; or directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 One or two pairs of groups are interconnected to form 5 to 10 forming a 6-membered substituted or unsubstituted carbocyclic or nitrogen-containing ring; each occurrence of R' is In particular, H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C 5~C6 cycloalkenyl, C2~C6 alkynyl, C5~C6 aryl, heterocyclyl or heteroaryl, or two R' groups attached to the same atom are bonded to each other. joined to form a 3- to 6-membered ring], or a pharma- ceutically acceptable salt thereof.

[0006] L in formula (I) 1 and L 2 The group is -(CH2) p - a linker independently selected from and p has a value of 1, 2, or 3. The subscripts r and s in formula (I) are independently When r is 0 or s is 0, then L 1 or L 2 are absent, thereby providing a gap between each aromatic ring and the macrocycle. This results in direct binding.

[0007] In one aspect, a targeting composition is provided that is represented by formula (II):

[0008] [ka]

[0009] In formula (II), A 1 ~A 10 , M, L 1 , L 2 , r, and s are R 1 ~R 10 Of at least one of which is or contains a selective cancer cell targeting group. Each of the above terms has the same meaning as provided herein for any embodiment.

[0010] In another aspect, a method for producing a composition according to formula (I) and / or formula (II) is provided. will be done.

[0011] In another aspect, the present technology also provides compounds of formula II (or pharmaceutical or a pharma- ceutically acceptable salt thereof) and a pharma- ceutically acceptable carrier or one or more excipients or or a composition (e.g., a pharmaceutical composition) comprising one of the embodiments of the filler. and medicines.

[0012] In another aspect, the present technology provides a method for administering an effective amount of a targeting composition according to formula (II) to a subject having cancer. The present invention provides a method for treating cancer by administering to a subject having cancer. [Brief description of the drawings]

[0013] [Figure 1A] Figure 1A shows the X-ray crystal structure of [La(Hmacropa)(HO)]·(ClO) (Figure 1A, side view). Ellipsoids are drawn at the 50% probability level. Counteranions and hydrogen atoms attached to carbon are omitted for clarity. [Figure 1B] Figure 1B shows the X-ray crystal structure of [La(Hmacropa)(HO)]·(ClO) (Figure 1B, top view). Ellipses are drawn at the 50% probability level. The counteranion and hydrogen atoms attached to the carbon are omitted for clarity. [Figure 1C] Figure 1C shows the X-ray crystal structure of [Lu(macropa)]·ClO4·DMF (side view). Ellipsoids are drawn at the 50% probability level. Counteranions and hydrogen atoms attached to carbons are omitted for clarity. [Figure 1D] Figure 1D shows the X-ray crystal structure of [Lu(macropa)]·ClO4·DMF (Figure 1D, top view). Ellipses are drawn at the 50% probability level. Counteranions and hydrogen atoms attached to carbon are omitted for clarity. [Figure 2A] FIG. 2A shows the biodistribution of Ac(NO) to select organs after intravenous injection in mice. Adult C57BL / 6 mice were sacrificed 15 min, 1 h, or 5 h after injection. Values ​​for each time point are shown as the mean %ID / g ± 1 SD. [Figure 2B] Figure 2B shows the biodistribution of [225Ac(macropa)]+ (Figure 2B) to select organs after intravenous injection in mice. Adult C57BL / 6 mice were sacrificed 15 min, 1 h, or 5 h after injection. Values ​​for each time point are shown as the mean %ID / g ± 1SD. [Figure 2C] Figure 2C shows the biodistribution of [225Ac(DOTA)]- (Figure 2C) to select organs after intravenous injection in mice. Adult C57BL / 6 mice were sacrificed 15 min, 1 h, or 5 h after injection. Values ​​for each time point are shown as the mean %ID / g ± 1SD. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The following terms are used throughout as defined below:

[0015] As used in this specification and the appended claims, the singular articles, e.g. For example, "a" and "an" and "the" and the related terms used to describe these elements. Similar referents, particularly in relation to the following claims, include the singular and plural forms. , unless otherwise indicated herein or clearly contradicted by context, The recitation of ranges of values ​​herein should be construed as inclusive. Unless otherwise indicated in the specification, the shorthand notation refers individually to each separate value falling within the range. It is merely intended to serve as a method, and each separate value is not necessarily individually recited herein. All methods described herein are incorporated herein by reference in their entirety. Unless otherwise indicated in or otherwise clearly contradicted by context, Any and all of the methods provided herein may be used in any suitable order. The use of examples or exemplary language (e.g., "such as") may help to better clarify the embodiments. The present invention is intended to be merely illustrative and not restrictive in any way, and unless otherwise stated, the scope of the claims is not intended to be limiting. No language in the specification should be construed as construed to represent any non-claimed element in its entirety. The present disclosure should not be construed as indicative of any limitation or limitation of the present invention.

[0016] As used herein, "about" is understood by those of ordinary skill in the art and is understood to be within the meaning of the text as used. To some extent, it depends on the context. When used, "about" means up to plus or minus 10% of a particular term. do.

[0017] In general, a reference to some element, e.g., hydrogen or H, refers to all equivalents of that element. For example, if an R group is defined to include hydrogen, i.e., H, In this case, the R group also includes deuterium and tritium. Thus, radioisotopes, e.g. , Tritium, C 14 , P 32 and S 35 Compounds including, but not limited to, are within the scope of the present technology. Procedures for inserting such labels into compounds of the present technology can be developed based on the disclosure herein. This will be readily apparent to one skilled in the art.

[0018] In general, "substituted" refers to an organic group (e.g., an alkyl group) as defined below. means that one or more bonds to a hydrogen atom contained therein may be replaced by a non-hydrogen or non-carbon The substituents may also include a carbon(s) or hydrogen atom. One or more bonds to the atom(s) include a double or triple bond to a heteroatom. This includes groups that are replaced by one or more bonds, such as Unless otherwise specified, groups are substituted with one or more substituents. In embodiments, the substituent is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include halogen (i.e., F, Cl, Br, and I); hydroxyl; koxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclo heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; aryl(oxo);carboxylate;ester;urethane;oxime;hydroxylamine ;Alkoxyamines;Aralkoxyamines;Thiols;Sulfides;Sulfoxides;Sulfones ;sulfonyl; pentafluorosulfanyl (i.e., SF5), sulfonamide; a amine;N-oxide;hydrazine;hydrazide;hydrazone;azide;amide;urea;a imide; isocyanate; isothiocyanate; cyanide thiocyanate; imine; nitro group; nitrile (i.e., CN); etc. do.

[0019] Substituted ring groups, such as substituted cycloalkyl, aryl, heterocyclyl and A heteroaryl group also includes an aryl group in which a single bond to a hydrogen atom is replaced by a single bond to a carbon atom. Thus, substituted cycloalkyl, aryl, heterocyclic, The aryl and heteroaryl groups may also be substituted or unsubstituted alkyl, as defined below. , alkenyl, and alkynyl groups.

[0020] As used herein, C m ~C n For example, C1~C 12 , C1-C8, or C1-C6, when used before a group, means a group containing m to n carbon atoms .

[0021] Alkyl groups have from 1 to 12 carbon atoms, usually from 1 to 10 carbons or In some embodiments, linear alkyl groups having 1 to 8, 1 to 6, or 1 to 4 carbon atoms. and branched chain alkyl groups. Examples of straight chain alkyl groups include, for example, methyl, ethyl, , n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n- Examples of branched alkyl groups include, but are not limited to, groups such as isopropyl, octyl, and the like. isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl The alkyl groups include substituted, ethyl, butyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups include those groups described above. The aryl groups may be substituted one or more times, such as, but not limited to, fluoroalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, amino Noalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl , carboxyalkyl, and the like.

[0022] Cycloalkyl groups have from 3 to 12 carbon atoms or any number of carbon atoms in the ring or rings. In some embodiments, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 The exemplary monocyclic cycloalkyl groups include mono-, bi- or tricyclic alkyl groups having carbon atoms. Alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohex ... These include cycloalkyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In one embodiment, the cycloalkyl group has 3 to 8 ring members, and in another embodiment, the cycloalkyl group has 3 to 8 ring members. The number of child rings ranges from 3 to 5, 3 to 6, or 3 to 7. Bicyclic and Tricyclic Ring Systems Included are bridged cycloalkyl groups and fused rings, such as, but not limited to, bicycloalkyl groups. [2.1.1] Hexane, adamantyl, decalinyl, etc. Cycloalkyl groups may be substituted or unsubstituted. Substituted cycloalkyl groups are as defined above. The alkyl group may be substituted one or more times with non-hydrogen and non-carbon groups. The substituted cycloalkyl groups also include those substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups include rings which are monosubstituted or more than one substituted. For example, but not limited to, 2,2-, 2,3-, 2,4-2 , 5- or 2,6-disubstituted cyclohexyl groups, etc., which are described above. The aryl group may be substituted with a substituent such as those mentioned above.

[0023] Cycloalkylalkyl groups are those in which the hydrogen or carbon bond of the alkyl group is as defined above. an alkyl group as defined above, which is replaced by a single bond to a cycloalkyl group; In some embodiments, the cycloalkylalkyl group has 4 to 16 carbon atoms. , having from 4 to 12 carbon atoms, usually from 4 to 10 carbon atoms. The alkylalkyl group may be substituted or unsubstituted. The alkyl group is an alkyl, cycloalkyl or alkyl and cycloalkyl portion of the group. Representative substituted cycloalkylalkyl groups are monosubstituted. They may be substituted once or more than once, for example, but not limited to, those listed above. The alkyl group may be mono-, di- or trisubstituted with substituents such as those listed above.

[0024] An alkenyl group must have at least one double bond between two carbon atoms. The alkenyl group includes straight and branched chain alkyl groups as defined above, except for those having 2 or more carbon atoms. 1 to 12 carbon atoms, typically 2 to 10 carbons or, in some embodiments, , 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In the formula, the alkenyl group has one, two, or three carbon-carbon double bonds. Examples include , including, but not limited to, vinyl, allyl, -CH=CH(CH 3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH 3) and -C(CH2CH3)=CH2. The alkenyl group may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or more than one substituted. may be substituted, for example, but not limited to, those listed above. It may be mono-, di- or trisubstituted with substituents.

[0025] Cycloalkenyl groups include those having at least one double bond between two carbon atoms, Cycloalkenyl groups include cycloalkyl groups as defined above. Cycloalkenyl groups can be substituted or unsubstituted. In some embodiments, the cycloalkenyl group is one, two, or three substituted. or three double bonds, but does not include aromatic compounds. 4 to 14 carbon atoms, or, in some embodiments, 5 to 14 carbon atoms; having from 5 to 10 carbon atoms, and further having 5, 6, 7, or 8 carbon atoms. Examples of alkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, Cyclobutadienyl, and cyclopentadienyl.

[0026] Cycloalkenylalkyl groups are those in which the hydrogen or carbon bond of the alkyl group is as defined above. an alkyl group as defined above, which is replaced by a single bond to a cycloalkenyl group; The cycloalkenylalkyl group may be substituted or unsubstituted. Substituted cycloalkenylalkyl groups are alkyl, cycloalkenyl or alkyl groups of the group. The cycloalkenyl and cycloalkenyl moieties may be substituted. Representative substituted cycloalkenyls include The alkyl group may be substituted one or more times with substituents such as those described above. Good too.

[0027] An alkynyl group must have at least one triple bond between two carbon atoms. The alkynyl group includes straight and branched chain alkyl groups as defined above, except for alkynyl groups having 2 or more carbon atoms. 1 to 12 carbon atoms, typically 2 to 10 carbons or, in some embodiments, , 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In the formula, alkynyl groups have one, two, or three carbon-carbon triple bonds. Examples include , among others, but not limited to, -C≡CH, -C≡CCH3, -CH 2C≡CCH3, -C≡CCH2CH(CH2CH3)2. Alkynyl groups include It may be substituted or unsubstituted. Representative substituted alkynyl groups are monosubstituted It may be substituted once or more than once, for example, but not limited to, any of the groups described above. The aryl group may be mono-, di- or trisubstituted with substituents such as those shown below.

[0028] An aryl group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Aryl groups include monocyclic, bicyclic and tricyclic ring systems. Thus, aryl groups include , including but not limited to phenyl, azulenyl, heptaleny l), biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, isopropyl In some embodiments, aryl, aryl- ... The aryl groups contain 6 to 14 carbons in these ring portions and 6 to 12 in others. In some embodiments, the aryl group contains 6 to 10 carbon atoms. The aryl group may be substituted or unsubstituted. The term "aryl group" includes fused rings, e.g., fused aromatic-aliphatic ring systems (e.g., indium, Representative substituted aryl groups include groups such as aryl, aryloxy ... For example, monosubstituted aryl groups include Including, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or na It includes butyl groups, which may be substituted with substituents such as those described above.

[0029] An aralkyl group is an alkyl group in which a hydrogen or carbon bond is bonded to an aryl group as defined above. In some embodiments, the alkyl group is an alkyl group as defined above, which is replaced by a single bond. In embodiments, the aralkyl group has from 7 to 16 carbon atoms, from 7 to 14 carbon atoms, or contains 7 to 10 carbon atoms. Aralkyl groups may be substituted or unsubstituted. The substituted aralkyl group may be an alkyl, aryl or alkyl and aryl group. Representative aralkyl groups include, but are not limited to, However, benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl Representative substituted aralkyl groups include those described above. The alkyl groups may be substituted one or more times with substituents such as those listed above.

[0030] Heterocyclyl groups include aromatic groups containing three or more ring members (also called heteroaryls). and non-aromatic ring compounds, one or more of which contain a heteroatom, e.g., Examples include, but are not limited to, N, O, and S. In some embodiments, heterocyclic The acrylic group contains 1, 2, 3, or 4 heteroatoms. Cyclyl groups include 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. Heterocyclyl groups include aromatic, partially unsaturated and saturated ring systems, e.g. imidazo The term "heterocyclyl group" includes heteroaryl, imidazolinyl and imidazolidinyl groups. include those containing fused aromatic and non-aromatic groups, e.g., benzotriazolyl, 2,3- Dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl The term includes bridged polycyclic ring systems containing heteroatoms, e.g., Heterocyclyl groups include, but are not limited to, quinuclidyl and the like. Heterocyclyl groups include, but are not limited to, aryl, aryls ... Diazolidinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl Lysinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl , thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, Pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl aryl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl , piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydropyranyl Rothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimi dihydropyridyl, dihydrodithiyl dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl Indolyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, Benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, Benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzyl Benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, nyl, xanthinyl, adenyl, guanyl, quinolinyl, isopropyl Quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazide nyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydridinyl dihydrobenzothiazinil, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodi Oxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenz Imidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetra Hydropyrazolopyridyl, Tetrahydroimidazopyridyl, Tetrahydrotriazolopyridyl Representative substituted heterocyclyl groups include: It may be mono-substituted or more than mono-substituted, for example, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted or with various substituents, e.g., as described above It may be a disubstituted pyridyl or morpholinyl group such as those described.

[0031] Heteroaryl groups are aromatic ring compounds containing five or more ring members, of which at least one The one or more heteroatoms include, but are not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, Triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, Ranyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazo aryl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolo Pyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzo Thiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, Thianaphthyl, purinyl, xanthinyl, adenyl, guanyl, quinolinyl, isoxyl These include quinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused rings in which all rings are aromatic, e.g., indolyl groups. These include cyclic compounds in which only one of the rings is aromatic, e.g., 2,3-dihydroindo Heteroaryl groups may be substituted or unsubstituted. Thus, the term "heteroaryl group" includes fused ring compounds. Heterocyclic rings having other groups attached to one of the ring members, e.g., alkyl groups. Representative substituted heteroaryl groups include those described above. The alkyl groups may be substituted one or more times with a variety of substituents.

[0032] Heterocyclylalkyl groups are those in which the hydrogen or carbon bond of the alkyl group is as defined above. an alkyl group as defined above, which is replaced by a single bond to a heterocyclyl group; The heterocyclylalkyl group may be substituted or unsubstituted. Heterocyclylalkyl groups are alkyl, heterocyclyl or the alkyl and The heterocyclyl moiety may be optionally substituted. Representative heterocyclylalkyl groups Examples of such compounds include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, ethyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofurafine Representative substituents include indol-2-yl-ethyl, indol-2-yl-propyl, and indol-2-yl-ethyl. Heterocyclylalkyl groups may be substituted one or more times with substituents such as those described above. It may be replaced.

[0033] Heteroaralkyl groups are groups in which the hydrogen or carbon bond of the alkyl group is replaced by a heteroaryl group as defined above. An alkyl group as defined above replaced by a single bond to an aryl group. A heteroaralkyl group may be substituted or unsubstituted. The alkyl group is an alkyl, heteroaryl or alkyl and heteroaryl portion of the group. Representative substituted heteroaralkyl groups are described above. The substituents may be substituted one or more times with substituents such as:

[0034] The present invention relates to compounds having two or more points of attachment (i.e., divalent, trivalent, or polyvalent) within the compounds of the present technology. Radicals described in the specification are named using the suffix "ene." For example, a divalent alkyl group is The divalent alkyl group is an alkylene group, the divalent aryl group is an arylene group, and the divalent heteroaryl group is an The aryl group is a divalent heteroarylene group, etc. A single point of attachment to the compound of the present technology. Substituents with the "ene" nomenclature are not applicable. Thus, for example, chloro Ethyl is not referred to herein as a chloroethylene. Such groups are substituted and may also be unsubstituted.

[0035] An alkoxy group is an alkyl group in which the bond to the hydrogen atom is a substituted or unsubstituted alkyl group as defined above. A hydroxyl group (-OH) is replaced by a single bond to a carbon atom of Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, etc. Examples of branched alkoxy groups include Examples include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy Examples of cycloalkoxy groups include, but are not limited to, cycloalkoxy, cyclohexoxy, and the like. However, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclo Alkoxy groups may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times with a substituent such as those described above. It may be substituted multiple times.

[0036] As used herein, the terms "alkanoyl" and "alkanoyloxy" refer to They can refer to -C(O)-alkyl and -OC(O)-alkyl groups, respectively. In some embodiments, each of the alkanoyl or alkanoyloxy groups is aryloxy groups. Similarly, the terms "aryloyl" and "aryloyloxy groups" "C(O)-aryl" refers to the groups -C(O)-aryl and -OC(O)-aryl, respectively.

[0037] The terms "aryloxy" and "arylalkoxy" each refer to an aryl group bonded to an oxygen atom. Substituted or unsubstituted aryl groups and alkyl groups bonded to oxygen atoms or unsubstituted aralkyl groups. Examples include, but are not limited to, phenoxy. Representative substituted aryloxy and aryloxy groups include aryloxy, naphthyloxy, and benzyloxy. and arylalkoxy groups may be substituted one or more times with substituents such as those described above. It may be replaced.

[0038] As used herein, the term "carboxylic acid" refers to a compound having a -C(O)OH group. As used herein, the term "carboxylate" refers to -C(O)O - "Protected carboxylate" refers to the group -C(O)OG, where G is Carboxylate protecting groups are well known to those skilled in the art. A comprehensive list of protecting groups for the carboxylate functional group is available at Protect. ive Groups in Organic Synthesis, Greene,T. .W.;Wuts, PGM, John Wiley&Sons, New York , NY, (3rd ed., 1999), which is incorporated herein by reference. and may be added or removed using procedures described in the present specification and in their entirety and as fully set forth herein. No. 6,313,936, filed on Dec. 13, 2003, and incorporated by reference herein for all purposes as if written.

[0039] As used herein, the term "ester" refers to an ester of -COOR 70 R 70 is a substituted or unsubstituted alkyl, cycloalkyl, alkoxy ... Nyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl It is a aryl group.

[0040] 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 R 71 and R 72 are independently hydrogen or Substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl aryl, aralkyl, heterocyclylalkyl or heterocyclyl group. Amide groups include, but are not limited to, carbamoyl groups (-C(O)NH2) and phosphatidyl groups. In some embodiments, the amide is - NR 71 C(O)-(C 1~5 alkyl), which is also called "carbonylamino". In others, the amide is -NHC(O)-alkyl, which is also referred to as "alkyl." It is named "canoylamino".

[0041] As used herein, the term "nitrile" or "cyano" refers to the group -CN. do.

[0042] The urethane group includes N- and O-urethane groups, i.e., -NR 73 C(O ) OR 74 and -OC(O)NR 73 R 74 R 73 and R 74 is In particular, substituted or unsubstituted alkyl, alkenyl, alkynyl, Cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl R is a cyclic group. 73 can also be H.

[0043] As used herein, the term "amine" (or "amino") refers to -NR 75 R 76 The group [wherein, R 75 and R 76 are independently hydrogen or a substitution as defined herein. or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arabinanyl, alkyl, heterocyclylalkyl or heterocyclyl group. In this embodiment, the amine is an alkylamino, a dialkylamino, an arylamino, or In another embodiment, the amine is NH, methyla Amino, dimethylamino, ethylamino, diethylamino, propylamino, isopropyl amino, phenylamino, or benzylamino.

[0044] The term "sulfonamide" includes S- and N-sulfonamide groups, i.e., , -SO2NR 78 R 79 and -NR 78 SO2R 79 R 78 and R 79 are independently hydrogen, or substituted or unsubstituted alkyl, a, or aryl as defined herein. Alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl Therefore, the sulfonamide group has In some embodiments, the aryl group is a sulphamoyl group (-SO2NH2), but is not limited to this. In one embodiment, the sulfonamide is -NHSO2-alkyl, and the term "alkylsulfonamide" is used herein. These are referred to as "arylamino" groups.

[0045] The term "thiol" refers to the -SH group and the sulfide to the -SR group. 80 It contains a sul Hoxide has -S(O)R 81 groups, and sulfones include -SOR 82 Groups included , for sulfonyl, -SO2OR 83 Contains: R 80 , R 81 , R 82 , and R 8 3 each independently represents a substituted or unsubstituted alkyl, cyclo, Alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl or hete In some embodiments, the sulfide is an alkylthio group, - It is S-alkyl.

[0046] The term "urea" refers to -NR 84 -C(O)-NR 85 R 86 R 84 , R 85 , and R 86 The groups are independently hydrogen or a substituted or unsubstituted aryl group as defined herein. Substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, hexafluoroalkyl, It is a terecyclyl, or heterocyclylalkyl group.

[0047] The term "amidine" refers to -C(NR 87 )NR 88 R 89 and -NR 87 C(NR 8 8 )R 89 [In the formula, R 87 , R 88 , and R 89 are each independently hydrogen or Substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aliphatic, aryl, aryl- ... aryl, aralkyl, heterocyclyl or heterocyclylalkyl group. It means [to be].

[0048] The term "guanidine" refers to -NR 90 C(NR 91 )NR 92 R 93 [In the formula, R 90 , R91 , R 92 and R 93 are each independently hydrogen or as defined herein. Substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group.

[0049] The term "enamine" refers to a -C(R 94 )=C(R 95 )NR 96 R 97 and -NR 9 4 C(R 95 )=C(R 96 )R 97 [In the formula, R 94 , R 95 , R 96 and R 97 teeth, each independently represents hydrogen, substituted or unsubstituted alkyl, cycloalkyl ... Alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl or hete is a cycloalkyl group.

[0050] As used herein, the term "halogen" or "halo" refers to bromine, chlorine, fluorine, In some embodiments, the halogen is fluorine. In an embodiment, the halogen is chlorine or bromine.

[0051] As used herein, the term "hydroxyl" refers to -OH or its ionized form. , -O - It can mean:

[0052] The term "imide" refers to -C(O)NR 98 C(O)R 99 , [where R 98 and R 99 each independently represents hydrogen or a substituted or unsubstituted alkyl group as defined herein; aryl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl or a heterocyclylalkyl group.

[0053] The term "imine" refers to -CR 100 (NR 101 ) and -N(CR 100 R 101 ) The group [wherein, R 100 and R 101 are each independently hydrogen or as defined herein. substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aryl is an aralkyl, heterocyclyl, or heterocyclylalkyl group, where R 1 00 and R 101 means that neither is hydrogen at the same time.

[0054] As used herein, the term "nitro" refers to the group --NO.

[0055] As used herein, the term "trifluoromethyl" means --CF.sub.3.

[0056] As used herein, the term "trifluoromethoxy" means -OCF3. do.

[0057] The term "azido" refers to --N3.

[0058] The term "trialkylammonium" refers to the -N(alkyl)3 group. The alkyl ammonium group carries a positive charge and therefore usually has an associated anion, e.g. It has an aryl anion, etc.

[0059] The term "trifluoromethyl diaziride" means

[0060] [ka] means...

[0061] The term "isocyano" means --NC.

[0062] The term "isothiocyano" refers to --NCS.

[0063] The term "pentafluorosulfanyl" means -SF5.

[0064] As will be appreciated by those skilled in the art, for any and all purposes, specifically, In providing a descriptive description, all ranges disclosed herein also include any and all Any description of the present invention is intended to include all possible subranges and combinations of such subranges. The ranges listed must be fully described and the same ranges must be divided into at least equal halves, thirds, or quarters. It is easy to recognize that it can be divided into 1, 5, 10, etc. As a non-limiting example, each range discussed herein may include a lower third, a middle third, and the upper third. As will also be appreciated by those skilled in the art, , all languages, e.g. "up to", "at least", "greater than", "less than", etc. is a range that can be included in the recited numbers and subsequently divided into the subranges discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1 to 3 atoms refers to a group containing 1, 2, or 3 atoms. Similarly, a group having 1 to 5 atoms means a group having 1, 2, 3, 4, or It means a group having 5 atoms, etc.

[0065] Pharmaceutically acceptable salts of the compounds described herein are within the scope of the art and may be used to prepare any desired compound. retain pharmacological activity and are biologically desirable (e.g., the salts are not excessively toxic, are not allergenic or irritating and are bioavailable, including acid or base addition salts When the compound of the present technology has a basic group, such as an amino group, it is pharma- ceutically acceptable. The salts that can be obtained are those formed from inorganic acids (e.g., hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginic acid, formic acid, acetic acid, benzoic acid, etc. , 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 (e.g., aspartic acid and glutamic acid etc.) The compounds of the present technology may be formed by an acidic group, e.g., a carboxylic acid groups, this may include metals, such as alkali and alkaline earth metals (e.g. , Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine , picoline, ethanolamine, diethanolamine, triethanolamine) or salts It is capable of forming salts with basic amino acids (e.g., arginine, lysine and ornithine). Such salts can be prepared in situ during the isolation and purification of the compounds or by the formation of their free bases. or the compound purified in the form of a free acid is reacted separately with an appropriate acid or base, respectively. and isolating the salt thus formed. can be done.

[0066] Those skilled in the art will appreciate that the compounds of the present technology may exhibit tautomerism, conformational isomerism, l isomerism), which can exhibit the phenomenon of geometric and / or stereoisomerism It is understood that the formula drawings in this specification and claims are intended to be illustrative and not restrictive. Represents only one of the isomeric, conformational, stereochemical or geometric isomeric forms The present technology can thus have one or more of the utilities described herein. Any tautomeric, stereoisomeric, stereochemical and / or geometrical variations of the compounds It should be understood that the present invention encompasses various forms of the active ingredient, as well as mixtures of these various different forms. It is.

[0067] "Tautomers" means isomeric forms of a compound that are in equilibrium with each other. The presence and concentration of the form depends on the environment in which the compound is found, e.g. or in the form of an organic or aqueous solution. In solution, quinazolinones can exhibit the following isomeric forms, which are tautomeric with each other: It is called the sex body

[0068] [ka] . As another example, guanidine can exhibit the following isomeric forms in protic organic solutions: They are also called tautomers of each other.

[0069] [ka] .

[0070] Because of the limitations of structural formulas in representing compounds, all of the compounds described herein are It is understood that the formula represents all tautomeric forms of the compound and are within the scope of the art. It should be.

[0071] Stereoisomers (also known as optical isomers) of a compound have a particular stereochemistry. Unless expressly indicated, all chiral, diastereomeric, and racemic forms of a structure are Therefore, the compounds used in the present technology include those as shown in the drawings. and enriched or resolved optical isomers at any or all asymmetric atoms. Both racemic and diastereomeric mixtures, as well as individual optical isomers, are included. , isolated substantially free of their enantiomeric or diastereomeric partners.

[0043] Stereoisomers can be prepared or synthesized and all of these stereoisomers are within the scope of the present technology.

[0072] The compounds of the present technology can exist as solvates, in particular hydrates. Hydrates that may be formed during the preparation of the compounds or compositions containing the compounds include The hygroscopic nature of the compound can cause the formation of hygroscopic compounds over time. Among others, organic solvates, including DMF, ether, and alcohol solvates. The identification and preparation of any particular solvate may be accomplished by a synthetic organic chemistry. It is within the skill of one in the art of biology or medicinal chemistry to perform this procedure.

[0073] Throughout this disclosure, various publications, patents and published patent specifications are cited by an identifying citation. Within the scope of this disclosure, Arabic numerals also refer to the referenced citations. The full bibliographic details of which are set forth immediately preceding the claims. The disclosures of the publications, patents and published patent specifications are incorporated herein by reference in their entirety to more fully describe the present technology. , which is hereby incorporated by reference into this disclosure.

[0074] This technology Targeted radiation therapy has been practiced for some time using macrocyclic complexes of radionuclides. Currently used macrocycles (e.g., DOTA) are generally suitable for the synthesis of radionuclides, especially the larger Radionuclides of various sizes, such as actinium, radium, bismuth, and lead isotopes This instability leads to the formation of complexes with the macrocycle that are poorly stable. This dissociates the nuclide, resulting in a lack of selectivity for the target tissue, which also Resulting in toxicity to target tissue.

[0075] The present technology provides new macrocyclic complexes that are substantially more stable than those of the prior art. Thus, these new complexes are substantially less toxic to non-target tissues than the complexes of the art. In addition, the new complex can be used to advantageously target cancer cells more efficiently rather than selectively. The body will tolerate an increase in temperature (e.g., at least 80°C) due to complexation with radionuclides. In contrast to commonly required DOTA-type complexes, they can advantageously be formed at room temperature. The present technique also specifically uses alpha-emitting radionuclides instead of beta-emitting nuclides. emitting radionuclides are much more energetic and therefore more practical than β-emitting radionuclides. Qualitatively strong.

[0076] Thus, in one embodiment, the composition of formula I comprises:

[0077] [ka] wherein M is an alpha-emitting radionuclide, or a pharma- ceutically acceptable salt thereof. Exemplary alpha-emitting radionuclides include, but are not limited to, 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-2 27( 227 Th 4+ ), Thorium-226( 226 Th 4+ ), Astatine-211( 211 At + ), Astatine-217( 217 At + ), and uranium-230 do.

[0078] In formula I, A 1 is a nitrogen atom (N) or CR 1 A 2 is a nitrogen atom (N) or CR 2 A 3 is a nitrogen atom (N) or CR 3 A 4 is a nitrogen atom (N) Or CR 4A 5 is a nitrogen atom (N) or CR 5 A 6 is a nitrogen atom (N ) or CR 6 A 7 is a nitrogen atom (N) or CR 7 A 8 is a nitrogen atom (N) or CR 8 A 9 is a nitrogen atom (N) or CR 9 A 10 is nitrogen Atom (N) or CR 10 where A represents 1 , A 2 , A 3 , A 4 , and A 5 Of Up to three may be nitrogen atoms, A 6 , A 7 , A 8 , A 9 , and A 10 3 or less of can be a nitrogen atom. The A groups are independently selected so that the composition can be symmetrical or asymmetrical. In the case of an asymmetric system, for example, one of the aromatic rings may have only one ring carbon atom. and the other aromatic ring may have 1, 2, or 3 ring nitrogen atoms. or, for example, one of the aromatic rings can have a monocyclic nitrogen atom; The other aromatic ring may have two or three ring nitrogen atoms. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 (hereinafter, "R group") is H, alkyl, aryl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic Acryl, heteroaryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is , 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCH2CH2) y -OR', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R ', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R ', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO2R' , -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'( OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -N CS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)C and an epoxide group, and optionally a halo, -OR' , -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR', -OC (O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S) NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C (O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO2R', -SO2(O R'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P (O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR' -NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and epoxide The oxide group is -(CH2) n- a linker, wherein n is 1, 2, or 3 and each independently connects to the carbon atom to which it is attached; or 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 One or two of the groups The pairs are interconnected to form a 5- to 6-membered substituted or unsubstituted carbocyclic or nitrogen-containing ring. R' at each occurrence is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5 ~C6 aryl, poly(ethylene glycol), heterocyclyl, or heteroaryl or two R' groups attached to the same atom are interconnected to form a 3- to 6-membered ring. The heteroatom-containing functional group (i.e., the "functional group") can be, for example, hydrophilic or hydrophobic. It functions to modify the aqueous solution and has reactive functionalities (e.g., for binding to cell targeting agents). By acting as a functional group or by complexing with radionuclides Some examples of functional groups include alkylnyl, halogen, Atoms (e.g., F, Cl, Br, or I), -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCH 2CH2) y -OR', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. ), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C( O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R' , -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P (O)R'(OR'), -P(O)R'2, -NO2, -CN, -C(O)R', -C( S)R', -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N3, -N=C=N-R', -SO2Cl, -C(O)Cl, and epoxide groups, or Any one or more of the above functional groups may be included in any embodiment herein. The or plural may be excluded or required to be present.

[0079] L in formula (I) 1 and L 2 The group is -(CH2) p - [wherein p is 1, 2, or 3] The subscripts r and s in formula (I) are independently selected from the group consisting of is independently 0 or 1. If r is 0 or s is 0, then L 1 or L 2 are absent, thereby allowing each aromatic ring and macrocyclic molecule This results in a direct bond between

[0080] In any embodiment herein, this is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 and at least one of a halogen atom; ';-(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9 , or 10);-(OCH2CH2) y -OR' (wherein y is 1, 2, 3, 4 , 5, 6, 7, 8, 9, or 10), -SR';-OC(O)R';-C(O) OR';-C(S)OR';-C(O)NR'R';-C(S)NR'R';-NR'C (O)R';-NR'C(S)R';-NR'R';-NR'C(O)NR';-NR' C(S)NR';-S(O)R';-SO2R';-SO2(OR');-SO2NR' 2;-P(O)(OR')2;-P(O)R'(OR');-P(O)R'2;-NO2 and CN, or a subset thereof (referred to herein as "first In any embodiment herein, this is referred to as a "set of functional groups" of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 At least one of -C(O)R';-C(S)R';-OCN;-SCN;-NCO;- NCS;-NR'-NR'R';-N3;-N=C=N-R';-SO2Cl;-C(O )Cl; and an epoxide group, or a subset thereof (as defined herein). In any embodiment herein, the functional groups are referred to as a "second set of functional groups." This is R 1 , R 2 , R 3 , R 4 , and R 5 At least one of 1 and / or R 6 , R 7 , R 8 , R 9 , and R 10 At least one of the first In any embodiment herein, this is selected from the functional groups R 1 , R 2 , R 3 , R 4 , and R 5 and / or R 6 , R 7 , R 8 , R 9 , and R 10 At least one of is selected from a second set of functional groups. In any embodiment herein, this is R 1 , R 2 , R 3 , R 4 , and R 5 of At least one of the following may be true: 6 , R 7 , R 8 , R 9 , and R 10 of at least one of which is selected from a first set of functional groups, R 1 , R 2 , R 3 , R 4 , and R 5 At least one of and / or R 6 , R 7 , R 8 , R 9 , and R 10 At least one of is selected from a second set of functional groups.

[0081] A 1 , A 2 , A 3 , A 4 , and A 5is not a nitrogen atom and / or A 6 , A 7 , A 8 , A 9 , and A 10 It is possible that A is not a nitrogen atom. For example, 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 It doesn't have to be all nitrogen. The composition preferably has the formula Ia

[0082] [ka] or a pharma- ceutically acceptable salt thereof.

[0083] In any embodiment herein, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 At least one of the groups may be a nitrogen atom. In any embodiment herein, A 1 , A 2 , A 3 , A 4 , and A 5 A small number of At least one is a nitrogen atom, and A 6 , A 7 , A 8 , A 9 , and A 10 At least one of One of the atoms may be a nitrogen atom. For example, this is A 1 Or A5 oh and / or A 6 Or A 10 can be a nitrogen atom. The structure is a subclass of compositions having a single nitrogen atom in each aromatic ring.

[0084] [ka] or a pharma- ceutically acceptable salt thereof.

[0085] In any embodiment herein, any of the above structures may be used as a functional group or Specifically, the present specification also refers to "a first set of functional groups" and "a second set of functional groups," respectively. At least one of the indicated R groups from a first or second set of functional groups designated For example, in formula (Ib), R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 At least one of the following may not be H. In any embodiment herein, any of the above structures may include a first set of functional groups. As the functional group, take at least one of the R groups shown, and as the second set of functional groups, take at least one of the R groups shown For example, in formula (Ib), R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 At least one of the first set functional groups and R 2 , R3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 At least one of It is possible that one is a second set of functional groups. In the formula, at least one of the R groups and / or other aromatic rings is / are present in one of the aromatic rings. At least one of the R groups in the aromatic ring may be a first set functional group. For example, in formula (Ib), R 2 , R 3 , R 4 , and R 5 At least one of and / or R 7 , R 8 , R 9 , and R 10 At least one of the first set In any embodiment herein, one of the aromatic rings may be a substituted or unsubstituted functional group. At least one of the R groups and / or at least one of the R groups on the other aromatic ring For example, in formula (Ib), R 2 , R 3 , R 4 , and R 5 At least one of and / or R 7 , R 8 , R 9 , and R 10 At least one of the functional groups may be a second set. In any of the embodiments, at least one of the R groups in one of the aromatic rings and At least one of the R groups on the aromatic ring and / or the other aromatic ring is a first set functional group. and at least one of the R groups in one of the aromatic rings and / or the other aromatic At least one of the R groups in the aromatic ring may be a functional group of the second set. For example, in formula (Ib), R 2 , R 3 , R 4 , and R 5 At least one of and / or R 7 , R 8 , R 9 , and R 10 At least one of the first set R 2 , R 3 , R 4 , and R 5 At least one of and / or is R 7 , R 8 , R 9 , and R 10 At least one of the functional groups is a second set. It is possible.

[0086] In any embodiment herein, A1, A2, A3, A4, A5, A6, A7, A8 At least two of A, A, and A may be nitrogen atoms. In any embodiment herein, A 1 , A 2 , A 3 , A 4 , and A 5 At least 2 are nitrogen atoms and / or A 6 , A 7 , A 8 , A 9 , and A 10 Few of them At least two may be nitrogen atoms. , A 1 , A 2 , A 3 , A 4 , and A 5 Two of the atoms are nitrogen atoms, and A 6 , A7 , A 8 , A 9 , and A 10 It is possible that two of the atoms are nitrogen atoms. The structure is a subclass or pharma- ceutically acceptable compound having two nitrogen atoms in each aromatic ring. Examples of acceptable salts are:

[0087] [ka] .

[0088] In any embodiment herein of formula (Ie) and (If), R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 At least one of the first set functional groups It is possible that the first set of functional groups may be either the first set or the second set of functional groups. This means that any of the above structures may be used as the first set of functional groups, among the R groups shown. At least one of the R groups shown as the second set of functional groups and at least one of the R groups shown as the third set of functional groups. For example, in formula (Ie), R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 may be a first set functional group, and R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 At least one of the functional groups may be a second set of functional groups. In any embodiment herein, at least one of the R groups in one of the aromatic rings may be At least one of the R groups in at least one of the aromatic rings is a first cyclic ring. For example, in formula (Ie), R 2 , R 3 , and R 4 At least one of and / or R 7 , R 8 , and R 9 At least one of In any embodiment herein, the aromatic ring may be a first set functional group. At least one of the R groups in one of the aromatic rings and / or the R groups in the other aromatic rings It is possible that at least one of the functional groups is of the second set. For example, In formula (Ie), R 2 , R 3 , and R 4 At least one of and / or R 7 , R 8 , and R 9 At least one of the functional groups may be of the second set. In any embodiment, this is the case where at least one of the R groups is present in one of the aromatic rings. At least one of the R groups on the other aromatic ring is selected from the first set functional group, at least one of the R groups in one of the aromatic rings and / or at least one of the R groups on the other aromatic ring is a functional group of the second set. For example, in formula (Ie), R 2 , R 3 , and R 4 At least one of Also one and / or R 7 , R 8 , and R 9 At least one of the first set of officers It can be a functional group, R 2 , R 3 , and R 4 At least one of and / or R 7 , R 8 , and R 9 At least one of the functional groups may be of a second set. For example, for the formula (If), 2 , R 3 , and R 4 " An example of "R 2 , R 4 ,oh YobiR 5 " and "R 7 , R 8 , and R 9 " An example of "R 7 , R 9 , and R 10 " can be provided by replacing

[0089] In any embodiment herein, A in formula (I) 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 At least three of the atoms are nitrogen atoms. For example, A 1 , A 2 , A 3 , A 4 , and A 5 At least three of them are nitrogen is an elementary atom and / or A 6 , A 7 , A 8 , A 9 , and A 10 At least 3 of Each of the aromatic rings may be a nitrogen atom. The following subgeneric structures have three nitrogen atoms in each aromatic ring: Sub-classes of composition

[0090] [ka] or a pharma- ceutically acceptable salt thereof.

[0091] In any embodiment herein of formula (Ig), R 2 , R 4 , R 7 , and R 9 brain At least one of them can be a first set functional group or a second set functional group. In any embodiment herein of g), R 2 , R 4 , R 7 , and R 9 A small number of At least one R 2 , R 4 , R 7 , and R 9 It is possible that the second set of functional groups may be the functional groups of the present invention. In any embodiment herein, R 2 and R 4 and / or R 7 and R 9 At least one of the first set functional groups may be In any embodiment herein of formula (Ig), R 2 and R 4 At least one of Also one and / or R 7 and R 9 At least one of the functional groups is from the second set. In any embodiment herein of formula (Ig), this may be R 2 and R 4At least one of and / or R 7 and R 9 At least one of The other is the first set functional group, R 2 and R 4 At least one of and / or Or R 7 and R 9 At least one of the functional groups is a second set. could be.

[0092] In any embodiment herein, in at least one of the aromatic rings in formula (I), At least one of the A groups has a first set functional group attached thereto as an R group. In any embodiment herein, the carbon atom of the aromatic ring may be a first set having at least one of the A groups attached thereto as an R group; For example, the carbon atom of formula (I), (Ia), or in (Ib), A 2 and / or A 7 (In other words, A 4 and / or A 9 ) can be a carbon atom having a first set functional group attached thereto. As another example, A 1 and / or A 6 (In other words, A 5 and / or A 10 ) is a carbon atom In some cases, the carbon atom may have a first set of functional groups attached thereto. The following subgeneric structures are The aforementioned composition

[0093] [ka] JPEG2025066780000012.jpg245165 or some exemplary pharma- ceutically acceptable salt thereof.

[0094] This structure also corresponds to the following exemplary structure:

[0095] [ka] Asymmetric in the selection of functional groups such as those provided in or pharma- ceutically acceptable salts thereof. It could be.

[0096] In any embodiment herein, in at least one of the aromatic rings in formula (I), At least one of the A groups has a second set of functional groups attached thereto as an R group. In any embodiment herein, the aromatic ring may be a carbon atom. At least one of the A groups in each of the groups has a second set of A groups attached thereto as an R group. or only one of the aromatic rings is a carbon atom bearing a functional group of at least one In any embodiment herein, the compound may include a second set of functional groups. , the second set of functional groups is, in particular, A 2 , A 3 , or A 4 to, or A 7 , A 8 if KuhaA 9 More specifically, 3 Or A 8 It is possible that the object is located at the following A subgeneric structure is the aforementioned composition containing at least one second set of functional groups.

[0097] [ka] JPEG2025066780000015.jpg113160 or some exemplary pharma- ceutically acceptable salts thereof.

[0098] In any embodiment herein, any of the above structures in an aromatic ring may be At least one of the R groups can be a first set functional group. In any embodiment herein, the first set of functional groups may be present in the same compound containing the second set of functional groups. It is possible that it is in the ring.

[0099] In any embodiment herein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 one or two pairs of immediately adjacent groups of the groups are interconnected, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 As mentioned above A 4- to 6-membered carbocyclic ring optionally substituted with one or more groups as defined above. or forms a nitrogen-containing ring, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 The interconnection of the groups is A 1 , A 2 , A3 , A 4 , and A 5 In the formula (I) and / or A provides a fused ring system containing the ring shown. 6 , A 7 , A 8 , A 9 , and A 10 It is possible that this results in a fused ring system comprising the ring shown in formula (I) which comprises:

[0100] In any embodiment herein, these structures include the depicted aromatic ring containing the A group. It may be that the ring system includes at least one fused ring system including at least one of Exemplary subgeneric structures of such structures are as follows:

[0101] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0102] In formula (Iv), A 1 , A 4 , A 5 , A 6 , A 9 , A 10 , L 1 , L 2 , r, s, and and M are as set forth in any embodiment herein; R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently H, alkyl, cycloalkyl, aryl, alkenyl, cycloalkenyl, alkynyl, aryl, halo, -OR', -(OCHCH 2) x -R', where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. , -(OCH2CH2) y -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9 , or 10), -SR', -OC(O)R', -C(O)OR', -C(S)O R', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR' C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S (O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR ')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', - selected from the group consisting of SO2Cl, -C(O)Cl, and an epoxide group, The following are examples of halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y -OR ', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)N R'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -N R'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO 2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O) R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO , -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C( O)Cl, and the epoxide group is -(CH2) n - a linker, wherein n is 1, 2, or or 3] to the carbon atom to which it is attached; R' is , each occurrence independently, H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 Alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl , heterocyclyl, or heteroaryl. 15 and R 16 The groups can optionally be interconnected to form a second fused ring. This may be the same or different from the first fused ring. In this state, R 11 , R 12 , R 13 , and R 14 are not further interconnected, this is a bicyclic It is possible to leave the fused rings as fused ring systems; however, in any embodiment herein is R 11 , R 12 , R 13 , and R 14 The two adjacent groups between are interconnected. , whereby a tricyclic fused ring system can be formed.

[0103] In any embodiment herein of formula (Iv), R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 At least one of -C(O)R';-C(S)R';- OCN;-SCN;-NCO;-NCS;-NR'-NR'R';-N3;-N=C=N -R'; -SO2Cl; -C(O)Cl; and an epoxide group. In any embodiment herein of formula (Iv), R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 At least one of the following is a halogen atom; OR';-(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8 , 9, or 10), -(OCH2CH2) y -OR' (wherein y is 1, 2, 3 , 4, 5, 6, 7, 8, 9, or 10), -SR';-OC(O)R';-C( O)OR';-C(S)OR';-C(O)NR'R';-C(S)NR'R';-NR 'C(O)R';-NR'C(S)R';-NR'R';-NR'C(O)NR';-N R'C(S)NR';-S(O)R';-SO2R';-SO2(OR');-SO2N R'2;-P(O)(OR')2;-P(O)R'(OR');-P(O)R'2;-N It is possible that the alkyl group is a group selected from: -O2; and -CN.

[0104] In any embodiment herein, these structures include the depicted aromatic ring containing the A group. It is possible that the structure includes two fused ring systems each containing The subgenera structure is as follows:

[0105] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0106] In formula (Iw), A 1 , A 4 , A 5 , A 6 , A 9 , A 10 , L 1 , L 2 , r, s, and and M are as defined above; R 11 , R 12 , R 13 , R 14 , R 17, R 1 8 , R 19 , and R 20 are independently H, alkyl, cycloalkyl, alkenyl, cycloalkyl, Chloroalkenyl, alkynyl, aryl, halo, -OR', -(OCH2CH2) x -R ' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OC H2CH2) y -OR', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 1 0), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C (O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R ', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R' , -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, - P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl , —C(O)Cl, and an epoxide group, and optionally , -OR', -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR ', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO2R', - SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR '), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS , -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group is -(CH2) n - a linker, wherein n is 1, 2, or 3; each occurrence of R' is independently linked to the carbon atom to which it is attached by , independently, H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl , C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl, heterocyclic It is aryl, or heteroaryl.

[0107] In any embodiment herein of formula (Iw), A 1 , A 4 , A 5 , A 6 , A 9 ,oh Yobi A 10 At least one of the groups represented by formula (I-) may be a nitrogen atom. In any embodiment herein of w), A 1 , A 4 , and A 5 At least one of one (i.e., one, two, or all) of the A 6 , A 9 , and A 10 At least one (i.e., one, two, or all) of An exemplary subgeneric structure of such a structure is as follows:

[0108] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0109] In another aspect, the present technology provides compositions useful for targeted radiotherapy of cancer. The compound has in its structure a selective cancer cell targeting group that selectively directs the compound to cancer cells. The compound targets (i.e., selectively binds to) cancer cells by comprising Except that at least one of the R groups includes a selective cancer cell targeting group. Thus, the composition may conveniently be represented by formula (I): The targeting group can be any group known in the art that is capable of selectively targeting cancer cells. By way of example, a selective cancer cell targeting group may be a receptor specific to cancer cells. The cancer cell targeting group is linked by a peptide bond. The present invention can be applied to any embodiment of the present invention. The selective cancer cell targeting moiety may be a cancer targeting antibody, antibody fragment, or up to 50 Selective targeting oligopeptides containing amino acids, enzymes, nucleobase-containing moieties (e.g. For example, an oligonucleotide, a DNA or RNA vector, or an aptamer, or In any embodiment herein, the cancer cell targeting lectin may be included. Either of the activators is attached to one of the aromatic rings of the macrocyclic composition by a reactive functional group. and binding or adsorption onto particles (e.g., nanoparticles or microparticles). It is possible.

[0110] The targeting composition has the formula (II)

[0111] [ka] It is represented by:

[0112] In formula (II), A 1 ~A10 , M, L 1 , L 2 , r, and s are at least one of the R groups. Friend 1 (R 1 ~R 10 ) is or contains a selective cancer cell targeting moiety. The same meaning is shown for any embodiment in this specification, except for the above. any one of the selective cancer cell targeting groups set forth above, including particles containing a group In particular, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 At least one of the molecules comprises a selective cancer cell targeting group or an Alkylene, -O-, -S-, -(OCH2CH2) z - (wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -C(O)-, -OC(O)-, -C(O) O-, -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S (O)-, -SO2-, -S(O)2O-, -SO2NR'-, -P(O)(OR')- , -P(O)(R')-, -C(NR')-, -OC(NR')-, -SC(NR')- , a selective cancer cell targeting group linked to the carbon atom to which it is attached. and in some cases -O-, -S-, -(OCH2CH2) z -, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O)NR'-, -C(S)N R', -NR'C(O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO2-, -S(O)2O-, -SO2NR' -, -P(O)(OR')-, -P(O)(R')-, -C(NR')-, -OC(NR -S-C(NR')- and -SC(NR')- are each independently C1-C3 alkylene. is attached to the carbon atom. Thus, in formula (II), the R group (R 1 ~R 10 At least one of the groups is or contains a selective cancer cell targeting group. The formula (I) includes the same number of subgeneric structures as those of the formula (I), except that the formula (II) includes the same number of subgeneric structures as those of the formula (I). A similar series is shown in each of these subgeneric formulas with the R group (R 1 ~R 10 ) By requiring at least one of the following, formulas (Ia) to (Ix) are derived, and the selected Thus, the sub-genus of structures under formula (II) includes a compound represented by the formula (II) Analogously to formulas (II-a) to (II-x), formulas (II-a) to (II-x) can be defined as can.

[0113] In another aspect, a method of producing a composition according to Formula (I) and Formula (II) is provided. In such a method, the aromatic ring is free of alpha-emitting radionuclide M, except that the aromatic ring is free of alpha-emitting radionuclide M. By attaching the macrocyclic moiety to the compound shown in formula (I) or formula (II) by methods well known in the art, A ligand portion can then be generated that corresponds to the structure of interest. The radionuclide is attached by methods known in the art. An aromatic ring is attached to the macrocyclic moiety. If the functional group, e.g., R 1 ~R 10 Any of the information provided about Usually present on an aromatic ring, often in a protected form; in some cases, The ring is R 1 ~R 10 Prior to functionalization with any of the functional groups provided for To produce a composition under formula (II), a small amount of Compositions under formula (I) containing at least one reactive functional group are capable of selectively targeting cancer cells. The aromatic ring attached to the macrocyclic moiety via the reactive functional group is reacted with a tertiary functional group to selectively bond the aromatic ring to the macrocyclic moiety. For example, isocyanate or isothiocyanate can be attached to the carboxyl group to target specific cancer cells. The aryl reactive functional group may be included on at least one aromatic ring of the composition of formula (I). The resulting functionalized composition reacts with the amino and isogroups in the amino acid-containing targeting agent. Reacting the cyanate or isothiocyanate groups to form a targeting composition of formula (II) Thus, the amino acid is added to the amino acid-containing targeting agent. The -containing targeting agent is attached to the macrocyclic complex by a urea or thiourea bond. Many other modes of attachment with the bond are possible depending on the reactive functional group used. The attachment of the selective cancer cell targeting group can be achieved by the free or conjugated form of formula (I) Significantly, the unbound form of formula (I) can be carried out in a highly radiochemical state. For example, at least 90%, 95%, 97%, or 98% yield or 90% yield; Over 95%, 97%, or 98% at room temperature (generally 18-30°C or about 20°C). ℃, about 25℃, or about 30℃ or below 20℃, 25℃, or 30℃) It can be combined with a radioactive nuclide.

[0114] The targeting composition according to formula (II) is prepared by reaction of the reactive functional group with a targeting agent. Because it contains an attached targeting agent, the targeted composition according to formula (II) generally comprises substantially Alternatively, a reactive functional group, such as one used to attach a targeting agent at a first location, may be used. Thus, in any embodiment herein, the target according to formula (II) The targeting composition has the same structure as above, except that the reactive functional groups are found in a second set of functional groups. Under formula (I), R 1 ~R 10 The group may include any of the groups described for.

[0115] The present technology also provides compounds of formula II disclosed herein (or a pharma- ceutically acceptable derivative thereof). a salt of) and a pharma- ceutically acceptable carrier or one or more excipients or fillers ( Unless otherwise specified, collectively referred to as "pharmaceutically acceptable carriers" in the embodiments of the present invention. Compositions (e.g., pharmaceutical compositions) and medicaments comprising any one of the above are provided. The compositions can be used in the methods and treatments described herein. an effective amount of any one of the embodiments of the compounds of the present technology disclosed herein In any of the above embodiments, the effective amount can include An "effective amount" can be defined as the amount of a compound or compound required to produce a desired effect. By effective amounts is meant an amount of the composition. Non-limiting examples of effective amounts include, but are not limited to, For therapeutic (medical) uses, including, for example, the treatment of prostate cancer, breast cancer, or bladder cancer The amount or dose that results in an acceptable level of toxicity and bioavailability is determined. Other examples of effective amounts include, for example, those for treating symptoms associated with prostate cancer, breast cancer, or bladder cancer. Reducing symptoms, e.g., reducing the growth and / or metastasis of prostate, breast, or bladder cancer An effective amount includes an amount or dose that can reduce the amount of the compound by about 0.0 g / g of the composition. From about 1 μg to about 1 mg, preferably from about 0.1 μg to about 500 μg of compound per gram of composition. As used herein, a "subject" or "patient" refers to a mammal, e.g. For example, a cat, a dog, a rodent or a primate. Typically, the subject is a human, preferably a human. or have non-small cell lung cancer, bladder cancer, or colon cancer (e.g., colon adenocarcinoma) A human subject is a person who is or is suspected of being affected by a disease. The terms "subject" and "patient" are used interchangeably. There can be.

[0116] In any of the embodiments of the technology described herein, the pharmaceutical composition is in unit dosage form. The unit dosage form can be packaged as a single unit for the treatment of non-small cell lung cancer, bladder cancer, or colon cancer (colon Generally, the unit dosage form containing the compound of the present technology is effective in treating cancers such as adenocarcinoma. Varies depending on patient considerations, such as age, protocol, condition, and sex. These include the type of treatment, severity of disease, contraindications, and concomitant therapies. The dosage form may also be adjusted or modified by a physician skilled in the art. The unit dosage form for a patient containing the compound of the present technology is 1×10 -4 g / kg~1g / kg, Preferably, 1 x 10 -3 The compound of the present invention can vary from 1.0 g / kg to 1.0 g / kg. The dosage is also from 0.01 mg / kg to 100 mg / kg, preferably from 0.1 mg / kg to Suitable unit dosage forms include, but are not limited to, powders, Tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injections, implants Sustained release formulations, mucoadherent films, topical varnishes, lipids Complexes and the like are included.

[0117] The pharmaceutical compositions include one or more compounds of formula II, pharma- ceutically acceptable salts thereof, The stereoisomers, tautomers thereof, or solvates thereof are each independently selected from the group consisting of phenyl, ... The composition may be prepared by mixing with a carrier, additive, binder, excipient, etc., to treat cancer (e.g., prostate cancer). In one embodiment, the method can prevent and treat disorders associated with cancer of the bladder, breast, or adenocarcinoma. The compounds and compositions described herein can be used to treat, for example, prostate cancer, breast cancer, or Compositions and medicaments for treating bladder cancer can be prepared. Such compositions include, for example, For example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, etc. The compositions may be in the form of a suspension or solution. The compositions may be administered, for example, orally, parenterally, topically, rectally, or intravenously. Formulated for various routes of administration: nasally, vaginally, or via an implantable reservoir Parenteral or systemic administration can include, but is not limited to, subcutaneous, intravenous, The following dosage forms are given by way of example and are not intended to be limiting unless otherwise specified. Interpreted as limiting instant present technology You shouldn't.

[0118] For oral, buccal, and sublingual administration: powders, suspensions, granules, tablets, pills, and capsules Tablets, gel capsules, and caplets are acceptable solid dosage forms. For example, one or more compounds of the present technology, or a pharma- ceutically acceptable salt thereof. Or the tautomers are combined with at least one additive, such as starch or other additives. The mixture can be prepared by mixing. Suitable additives include sucrose, lactose, etc. , cellulose sugar, mannitol, maltitol, decanitol Cystran, starch, agar, alginate, chitin, chitosan, pectin, tragacan gum arabic, gelatin, collagen, casein, albumin, synthetic or semi Synthetic polymers or glycerides. In some cases, oral dosage forms may be formulated to aid in administration. Other ingredients that may be added include 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, disintegrant, binder, thickener, buffer Tablets and pills may contain sweetening, flavoring or perfuming agents. The coating may be further treated with suitable coating materials known in the art.

[0119] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, syrups, elixirs, suspensions, and the like. and in the form of a solution, which may contain an inert excipient such as water. Pharmaceutical formulations and medicaments can be prepared in sterile liquids, such as, but not limited to, oils, Prepared as a liquid suspension or solution using water, alcohol, and combinations thereof Pharmaceutically suitable surfactants, suspending agents, and emulsifying agents can be used for oral or parenteral administration. It can be added to the grant.

[0120] As mentioned above, the suspension may include oil. Such oils may include, but are not limited to, but includes peanut oil, sesame oil, cottonseed oil, corn oil and olive oil Suspension formulations also include esters of fatty acids, e.g., ethyl oleate, isopropyl myristate, It may also contain propyl, fatty acid glycerides and acetylated fatty acid glycerides. The suspension formulation may be prepared by dissolving in an alcohol, such as, but not limited to, ethanol, isopropyl alcohol, or the like. Propyl alcohol, hexadecyl alcohol, glycerol and propylene glycol Ethers, such as, but not limited to, poly(ethylene glycol) coal), petroleum hydrocarbons, such as mineral oil and petrolatum; and water are also used in suspension formulations. It can also be used in a mixture.

[0121] Injectable dosage forms generally include aqueous or oily suspensions, which are suitable for dispersion. Injectable forms can be prepared using a liquid phase or a wetting agent and a suspending agent. The solvent may be in the form of a liquid or suspension, prepared with a solvent or excipient. Vehicles included sterile water, Ringer's solution, or isotonic saline. Alternatively, sterile oil can be used as a solvent. Typically, the oil or fatty acid is a natural or They are non-volatile, including synthetic oils, fatty acids, mono-, di-, or tri-glycerides.

[0122] For injection, the pharmaceutical formulation and / or drug product is suitable for reconstitution with a suitable solution as described above. Examples of these include, but are not limited to, freeze-dried, rotary dried or or spray dried powders, amorphous powders, granules, precipitates, or particulates. In this case, the formulation may contain stabilizers, pH adjusters, surfactants, bioavailability modifiers and and combinations thereof, as the case may be.

[0123] The compounds of the present technology can be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations of the present invention may be in the form of a solution, spray, dry powder, or any suitable solvent. aerosol formulations, optionally with other compounds, such as, but not limited to, stabilizers agents, antibacterial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers and Carriers and stabilizers vary depending on the requirements of a particular compound. However, non-ionic surfactants (Tween, Pluronic, or polyethylene) are usually used. glycol), harmless proteins such as serum albumin, sorbitan esters, and oleic acid. acids, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols Aqueous and non-aqueous (e.g., in the form of fluorocarbon propellants) aerosols are suitable for inhalation. are commonly used for delivery of the compounds of the present technology.

[0124] In addition to these representative dosage forms described above, pharma- ceutically acceptable excipients and carriers are known to those skilled in the art. Such additives and carriers are well known in the art and are therefore included in the technology of the present invention. For example, "Remingtons Pharmaceutical Sciences" Ma ck Pub. Co., New Jersey (1991), which The compositions may also be used in the form of, for example, micelles or liposomes. , or some other encapsulated form.

[0125] The particular dose will depend on the disease state, age, weight, general health, sex, and diet of the subject. This can be adjusted according to the dosage, administration interval, administration route, excretion rate, and drug combination. Any of the above dosage forms containing an effective amount will be sufficient within the bounds of routine experimentation. and is therefore well within the scope of the present invention.

[0126] Various assays and model systems have been developed to determine the therapeutic efficacy of treatment with this technology. It can be easily used.

[0127] For the indicated conditions, test subjects were treated with placebo or other appropriate control. A disorder caused by or associated with a disorder in a subject compared to a subject is a 10%, 20%, 30%, 50% or greater reduction in one or more symptoms, 75 It shows a reduction of up to 90%, or 95% or more.

[0128] In another aspect, the present technology provides a method for administering an effective amount of a targeting composition according to formula (II) to a subject having cancer. The present invention provides a method for treating cancer by administering a cancer cell targeting agent to a subject having a cancer. can be selected to target any of a wide range of cancers, The cancers contemplated herein are not limited. Cancers can be essentially any type of cancer. For example, antibodies or peptide vectors could be used to target any of a wide range of cancers. The targeting compositions described herein can be produced for delivery to the bloodstream. The drug is administered by injection, but other modes of administration, such as oral or topical administration, are also possible. In some embodiments, the targeting composition is administered locally to target cells. At the site of presence, i.e., in a particular tissue, organ, or body fluid (e.g., blood, Any drug that can be delivered to the target via the bloodstream can be administered. Any cancer of the type described herein is specifically contemplated. Some examples include the breasts, lungs, stomach, intestines, prostate, ovaries, cervix, pancreas, kidneys, liver, skin, These include lymphatic, bone, bladder, uterus, colon, rectum, and brain. Cancers can also be classified as one or more of the following: Include the presence of multiple carcinomas, sarcomas, lymphomas, blastomas, or teratomas (germ cell tumors) The cancer may also be in the form of leukemia. In some embodiments, the cancer is It is a tumor-negative breast cancer.

[0129] As is well known in the art, the dosage of the active ingredient(s) is generally determined according to the disorder being treated. or condition, the severity of the disorder or condition, the method of administration, the size of the patient, and potential side effects. In different embodiments, depending on these and other factors, the targeting composition A suitable dose is at least, e.g., at least 1 mg, 10 mg, 50 mg , 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700 mg, 800mg, 900mg, 1000mg, 1200mg, or 1500mg, 1mg, 10mg, 50mg, 100mg, 200mg, 300mg, 400mg, 50 0mg, 600mg, 700mg, 800mg, 900mg, 1000mg, 1200m g or more than 1500 mg, 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 9 up to or below 00mg, 1000mg, 1200mg, or 1500mg, or a dose within a range bounded by any of the exemplary doses set forth above. Additionally, the compositions can be administered on any suitable schedule, for example, once, twice or three times daily. once or for 1, 2, 3, 4, or 5 days, or for 1, 2, 3, or 4 weeks, or , on alternate days for the entire treatment period of 2, 3, 4, 5, or 6 months, or any time frame in between Alternatively, or in addition, the compositions can be administered in the amounts indicated within the range of 0.1 to 1.5 mg / kg. or until a desired change in condition is achieved, or a prophylactic effect is provided. It can be administered at any time.

[0130] The examples herein are provided to illustrate the benefits of the technology and to illustrate the compounds of the technology or their or to prepare salts, pharmaceutical compositions, derivatives, prodrugs, or tautomeric forms of The present disclosure is provided to further assist those skilled in the art in the use of the present disclosure. The examples in are also presented to more fully illustrate preferred embodiments of the present technology. shall be construed to limit the scope of the present technology as defined by the appended claims. These examples include any variations, aspects or embodiments of the technology described above. Any of the above variations, aspects or embodiments may be included or incorporated in the present invention. The present invention also relates to any or all other variations, aspects or embodiments of the present technology. It may include or incorporate variants. EXAMPLES

[0131] Exemplary synthetic procedures and characterization Materials and Equipment. All solvents and reagents were purchased from commercial sources unless otherwise indicated. Solvents designated "dry" were prepared using the same method as in Example 1 and were used without further purification when administered. The metal salts were obtained after filtering and storing. Lu(ClO4)3 was purchased from It was provided as an aqueous solution containing 15.1 wt% Lu. The bifunctional ligand p-SCN- Bn-DOTA was purchased from Macrocyclics (Plano, TX). e4OH was dissolved in a 25 wt% solution (based on trace metals) in HO at Beantown Che Hydrochloric acid (BDH Aristar P lus, VWR, Radnor, PA) and nitric acid (Optima, ThermoFis Herman Scientific, Waltham, MA) is trace metals grade. there were. 225 Chelex 100 (NaCl) was used for the Ac-complex challenge assay. Tritium form, 50-100 mesh) and human serum were obtained from Sigma Aldrich Deionized water (≧18 MΩ cm) was purchased from MilliporeSigma (St. Louis, MO). ipore Direct-Q® 3UV or Elga Purelab F Prepared on-site using the lex 2 water purification system.

[0132] The reaction was analyzed by thin layer chromatography (TLC, Whatman UV254 aluminum). The H used for the analysis and purification of the compounds was monitored by a silica gel column. The PLC system is a CBM-20A communication bus module, L C-20AP (for preparative use) or LC-20AT (for analytical use) pump, and 270 nm SPD-20AV UV / Vis detector monitoring (Inc. Analytical chromatography was performed at a flow rate of 100 s, unless otherwise indicated. Ultra Aqueous C18 column, 100Å, 5μm, 2 at 1.0mL / min This was done using a 50 mm × 4.6 mm (Restek, Bellefonte, PA). Purification was performed on an Epic Polar preparative column at a flow rate of 14 mL / min unless otherwise indicated. 120Å, 10μm, 25cm x 20mm (ES Industries, West B The gradient HPLC method was performed using HO (A) and MeOH (B). B) or ACN (C) containing binary mobile phase HPLC method A: 10% B (0-5 min), 10-100% B (5-25 minutes). Method B: 10%C (0-5 minutes), 10-100%C (5-25 minutes). direction Method C: 10%C (0~5 minutes), 10~100%C (5~40 minutes). Method D: 10%C(0 10-100% C (5-5 min), 10-100% C (5-20 min). The solvent system was Method C using 0.2% TFA. Except for , contained 0.1% trifluoroacetic acid (TFA). NMR spectra were rian Inova 300MHz, 400MHz, 500MHz or 600MHz Spectrometer or Bruker AV with broadband Prodigy cryoprobe The chemical shifts were recorded on a 300 MHz NMR spectrometer at ambient temperature. I will report in pm. 1 H and 13 C NMR spectra were measured using TMS as the internal standard (0 ppm). , remaining solvent peaks, or acetonitrile internal standard (2.0 in the D2O spectrum) 6 ppm). 19F NMR spectra were analyzed using the monofluorobenzene internal standard ( -113.15 ppm) reported. 1 Proton resonances in the H spectrum Splitting is: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dt=triplet The IR spectroscopy was performed using the Nic olet Avatar 370 DTGS(ThermoFisher Scient The analysis was performed on KBr pellets of the samples using a HPLC HPLC system (Faculty of Science, Waltham, MA). High resolution mass spectra (HRMS) were obtained using an Exactive Orbitrap mass spectrometer ( ThermoFisher Scientific, Waltham, MA) The UV / visible spectra were recorded in ESI mode. A Cary 8454 UV-Vis (Agilent Technology) was used with a glass cuvette. The analytical data were recorded on a 350 nm NMR spectrometer (Humanities, Santa Clara, CA). by Atlantic Microlab, Inc. (Norcross, GA). went.

[0133] Macropa complexes, Macropa-NCS, and Macropa-NHC(S) Synthesis and characterization of NHCH3.N,N'-bis[(6-carboxy-2-pyridyl) Methyl]-4,13-diaza-18-crown-6(H2macropa·2HCl·4 H2O) [102,103] The product was purchased from EMD Millipore (Darmstadt, Germany). Purchased from ERMANY or according to literature protocol

[0104] 1, synthesized by Prepared using 7,10,16-tetraoxa-4,13-diazacyclooctadecane (7) Chelidamic acid monohydrate (1) was obtained from TCI America (Portland, ON). Dimethyl 4-chloropyridine-2,6-dicarboxylate (2), purchased from R&D Laboratories.

[0105] Dimethyl 4-azidopyridine-2,6-dicarboxylate (3), [106 ] and 6-chloromethylpyridine-2-carboxylic acid methyl ester (8),

[0102] was prepared according to the literature protocol indicated.

[0134] [La(macropa)] 2+ Preparation of.

[0135] [ka] H2macropa·2HCl·4H2O (0.0233 g, 0.034 mmol) A suspension of 2-propanol (0.6 mL) was added to a solution of triethylamine (20 μL, 0.143 m The pale gold solution was heated under reflux for 25 min, after which La(C lO4)3 6H2O (0.0209 g, 0.038 mmol) of 2-propanol (0 A precipitate formed immediately. The cream-colored suspension was stirred for further The mixture was stirred under reflux for another 1.5 h, cooled and centrifuged. The supernatant was removed and the pellet was diluted with 2-Propylene glycol. The solution was washed with 2-propanol (2 × 1 mL), then air-dried on filter paper and diluted with 0.64 mL of 2-propanol. The title complex was obtained as a light tan solid (0.0177g) containing equivalents. 1 H NMR (50 0 MHz, D2O, pD ≒ 9) δ= 7.87 (t, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.3 9 (d, J = 7.6 Hz, 2H), 5.21 (d, J = 15.7 Hz, 2H), 4.44 (t, J = 11.6 Hz, 2H), 4.0 9 (t, J = 11.2 Hz, 4H), 4.01 (t, J = 10.4 Hz, 2H), 3.74 (d, J = 9.9 Hz, 2H), 3.6 5-3.60 (m, 4H), 3.58-3.47 (m, 4H), 3.44 (d, J = 10.8 Hz, 2H), 2.75 (td, J = 13.1 , 2.7 Hz, 2H), 2.56 (d, J = 13.9 Hz, 2H), 2.38 (d, J = 14.0 Hz, 2H). 13 C{ 1 H}AP T NMR (126 MHz, D2O, pD ≒ 9) δ= 172.62, 158.70, 150.19, 140.94, 126.89, 122.32 , 71.88, 70.12, 69.20, 68.05, 60.14, 56.08, 54.01. EA test value: C, 35.16; H, 4.73; N, 5.91.C 26 H 35 Calculated value of LaN4O8·2ClO4·2H2O·0.64iPrOH: C, 35.53; H, 4.71; N, 5 .94. IR (cm -1 ): 3443, 2913, 1630, 1596, 1461, 1370, 1265, 1083, 948, 839, 770, 678, 617, 513. HPLC R = 18.104 min (Method A). HRMS (m / z): 669.14289, 335.07519; [ C 26 H 34 LaN4O8] + および[C 26 H 35 LaN4O8] 2+Calculated values ​​are: 669.14346, 335.07537 respectively.

[0136] [Lu (macropa)] + Preparation of.

[0137] [ka] H2macropa·2HCl·4H2O (0.0730 g, 0.108 mmol) A suspension of 2-propanol (2 mL) was added to the solution containing triethylamine (61.5 μL, 0.441 m The pale gold solution was heated under reflux for 25 min, after which Lu(C Lu) in 2-propanol (1.8 A precipitate formed immediately. The mixture was stirred at reflux for 1 h. Afterwards, the cream-colored suspension was ground for 20 h at RT and then centrifuged. The supernatant was removed. The pellet was washed with 2-propanol (2 × 2 mL) and then air-dried on filter paper. , a light tan solid containing the remaining 2-propanol and triethylamine salt (0. The title complex was obtained as 0.605 g). 1 H NMR (600 MHz, D2O, pD ≒ 7-8) δ= 7.85 (t, J = 7.7 Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 4.68 (d, J = 16.3 Hz, 2H), 4.56 (td, J = 11.2, 1.7 Hz, 2H), 4.42-4.38 (m, 2H), 4.23-4.19 (m , 6H), 4.07 (d, J = 16.3 Hz, 2H), 3.96-3.87 (m, 2H), 3.71-3.63 (m, 4H), 3.38 (td , J = 10.0, 4.7 Hz, 2H), 3.00 (m, 2H), 2.93 (d, J = 13.1 Hz, 2H), 2.52 (dt, J = 14.8, 4.5 Hz, 2H). 13 C{ 1 H} APT NMR (126 MHz, D2O, pD ≒ 7-8) δ= 172.13, 158.67 , 148.98, 141.81, 127.38, 122.83, 75.33, 73.12, 71.97, 71.70, 64.65, 57.37, 55.0 8. IR (cm -1 ): 3400, 1639, 1396, 1274, 1091, 913, 770, 678, 622. HPLC t R = Stable Not (Method A). HRMS (m / z): 705.17772; [C 26 H 34 LuN4O8] + Calculated value: 705.17788.

[0138] Preparation of dimethyl 4-aminopyridine-2,6-dicarboxylate (4).

[0139] [ka] Dimethyl 4-azidopyridine-2,6-dicarboxylate (3, 0.9445g, 4 0.0 mmol), 10% Pd / C (0.1419 g), and DCM:MeOH (1:1 , 18 mL) were combined in a round-bottom flask. After purging the flask with a balloon of H The reaction was stirred vigorously under H2 atmosphere at room temperature for 46 h. The grey mixture was diluted with DMF (45 The mixture was diluted with 0.0 mL of ethyl acetate and filtered through a layer of Celite. After that, the filtrate was concentrated under reduced pressure at 60° C. and further dried in vacuum to give a light yellowish brown solid ( 4 was obtained as 0.824 g, 98% yield. 1 H NMR (500 MHz, DMSO-d6): 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= 1 65.51, 156.24, 148.05, 111.99, 52.29.IR (cm -1 ): 3409, 3339, 3230, 1726, 1639, 1591, 1443, 1265, 996, 939, 787, 630, 543. HPLC R = 9.369 minutes (Method B). HRMS (m / z): 211.07213 [M + H] + ; Calculated value: 211.07133.

[0140] Preparation of ethyl 4-amino-6-(hydroxymethyl)picolinate (5).

[0141] [ka] A suspension of 4 (0.677 g, 3.22 mmol) in anhydrous EtOH (27 mL) was refluxed with Add aBH4 (0.1745 g, 4.61 mmol) in small portions for 1 h to give a pale yellow suspension. The reaction was then quenched with acetone (32 mL) and heated at 60 °C under reduced pressure to give a tan solid. The crude product was dissolved in H2O (60 mL) and extracted with ethyl acetate (4 × 150 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure at 40 °C. Further drying in vacuum afforded 5 as a pale yellow solid (0.310 g, 49% yield). Successful. 1H NMR (300 MHz, DMSO-d6): δ= 7.07 (d, J = 2.1 Hz, 1H), 6.78 (m, 1H), 6 .32 (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-d6) δ= 165.57, 162.38, 155.68, 147.25, 108.50, 107.01, 63.95, 60.61, 14.24.IR (cm -1 ): 3439, 3 217, 2974, 2917, 1717, 1643, 1600, 1465, 1396, 1378, 1239, 1135, 1022, 974, 865, 783. HPLC R = 8.461 min (Method B). HRMS (m / z): 197.09288 [M + H] + ; Calculated value: 197.0 9207.

[0142] Preparation of ethyl 4-amino-6-(chloromethyl)picolinate (6).

[0143] [ka] A mixture of thionyl chloride (2.5 mL) and 5 (0.301 g, 1.53 mmol) The mixture was stirred in an ice bath for 1 h and then at RT for 30 min. The mixture was concentrated under reduced pressure at 40 °C to an oily residue. The residue was diluted with saturated aqueous NaHCO3 (12 mL). The mixture was neutralized with ethyl acetate (75 mL) and then extracted with ethyl acetate (2 mL). ), dried over sodium sulfate, concentrated under reduced pressure at 40 °C, and further dried in vacuum. as an amber wax (0.287 g, 80% yield, corrected for residual ethyl acetate) I got 6. 1 H NMR (500 MHz, DMSO-d6) δ= 7.18 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 2 .1 Hz, 1H), 6.62 (br s, 2H), 4.62 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13 C{ 1 H} APT NMR (126 MHz, DMSO-d6) δ= 164.75, 156.42, 156.19, 1 47.17, 109.79, 109.50, 60.97, 46.47, 14.15.IR (cm -1 ): 3452, 3322, 3209, 2978, 2922, 1726, 1639, 1604, 1513, 1465, 1378, 1248, 1126, 1026, 983, 861, 783, 752, 700. HPLC R = 12.364 minutes (Method B). HRMS (m / z): 215.05903 [M + H] + ; Calculated value: 215.0 5818.

[0144] Methyl 6-((1,4,10,13-tetraoxa-7,16-diazacyclooctade Preparation of (can-7-yl)methyl)picolinate (9·2TFA·1H2O).

[0145] [ka] 1,7,10,16-Tetraoxa- 4,13-Diazacyclooctadecane (7, 1.9688 g, 7.5 mmol) and di A clear and colorless solution of isopropylethylamine (0.8354 g, 6.5 mmol) was The solution was cooled to 37°C for 2 h. The solution of 6 (0.9255 g, 5.0 mmol) in dry ACN (125 mL) was The flask was then fitted with a condenser and a drying tube. The slightly yellow solution was heated under reflux for 42 h. A fine, white precipitate was subsequently formed. The resulting dark gold solution was concentrated under reduced pressure at 60° C. to an amber oil. The crude oil was diluted with 0. 10% MeOH / H2O containing 1% TFA (10 mL) was added. A slight suspension was formed. It was filtered and the filtrate was purified by preparative HPLC (Method A). The pure fractions were combined and purified under reduced pressure. The mixture was concentrated at 60° C. under reduced pressure and then freeze-dried to give 9 (1.6 ml) as a pale orange solid. Obtained 350g, 50% yield. 1 H NMR (500 MHz, DMSO-d6) δ= 8.75 (br s, 2H), 8.1 7-8.06 (m, 2H), 7.83 (dd, J = 7.4, 1.5 Hz, 1H), 4.68 (br s, 2H), 3.91 (s, 3H), 3 .85 (br t, J = 5.1 Hz, 4H), 3.69 (t, J = 5.1 Hz, 4H), 3.59 (br s, 8H), 3.50 (br s, 4H), 3.23 (br t, J = 5.1 Hz, 4H). 13 C{ 1 H} APT NMR (126 MHz, DMSO-d6) δ 164. 68, 158.78-157.98 (q, TFA), 151.44, 147.13, 139.01, 128.63, 124.87, 120.08-113.0 1 (q, TFA), 69.33, 69.00, 65.31, 64.60, 56.43, 53.29, 52.67, 46.32. 19 F NMR (47 0 MHz, DMSO-d6) δ= -73.84. EA measured values: C, 43.88; H, 5.29; N, 6.28. C 20 H 33 N3O 6· Calculated for 2CF3COOH·1H2O: C, 43.84; H, 5.67; N, 6.39. HPLC t R = 12.372 minutes (Method B). HRMS (m / z): 412.24568 [M + H] + ; Calculated value: 412.24421.

[0146] Ethyl 4-amino-6-((16-((6-(methoxycarbonyl)pyridine-2-yl (methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadeca Preparation of (benzo-7-yl)methyl)picolinate (10).

[0147] [ka] In a round-bottom flask equipped with a condenser and drying tube, add 9 (0.4210 g, 0.64 (0.3400 g, 3.2 mmol), Na2CO3 (0.3400 g, 3.2 mmol), and dry ACN (1 The pale yellow suspension was heated to reflux for 15 min, after which 6 (0.0 mL) was added. .1508 g, 0.70 mmol, corrected for remaining ethyl acetate) in dry ACN (3. The mixture was heated under reflux for 44 h and then The orange filtrate was concentrated under reduced pressure at 60°C to give an orange-brown oil (0.612 g). This was used in the next step without further purification. HRMS(m / z): 59 0.32021[M+H] + ;Calc:590.31844.

[0148] 4-Amino-6-((16-((6-carboxypyridin-2-yl)methyl)-1, 4,10,13-Tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl Preparation of picolinic acid (11·4TFA).

[0149] [ka] Compound 10 (0.612 g) was dissolved in 6 M HCl (7 mL) and heated at 90°C for 17 h. The orange-brown solution, containing a small amount of precipitate, was heated to 60°C under reduced pressure to give a light yellow-brown solution. The solid was concentrated to a solid. The solid was diluted with 10% MeOH containing 0.1% TFA (3 mL). / H2O was added. The slight suspension was filtered and the filtrate was subjected to preparative HPLC using method A. The pure fractions were combined and concentrated under reduced pressure at 60° C., then lyophilized to give 1 as an off-white solid (0.2974 g, 46% yield over two steps) I got 1. 1 H NMR (500 MHz, DMSO-d6) 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-d6) δ 165.96, 163.37, 159.47, 158.78-157.98 (q, TFA), 151.93, 151.64, 148.25, 144.68, 139.59, 128.43, 124.96, 120.79-113.68 (q, TFA), 109.40, 108.96, 70.03, 69.89, 67 .09, 65.16, 57.28, 55.85, 54.47, 53.81. 19 F NMR (470 MHz, DMSO-d6) δ= -74.03. EA Actual Values: C, 40.60; H, 4.29; N, 7.04. C 26 H 37 N5O 8· Calculated for 4CF3COOH: 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 minutes (Method B); 11.546 minutes (Method D). HRMS (m / z): 548.26883 [M + H] + ; Calculated value : 548.27149.

[0150] 6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,1 3-Tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)-4-iso Preparation of sothiocyanatopicolinic acid (12, macropa-NCS).

[0151] [ka] 11 (0.1598 g, 0.16 mmol) and Na2CO3 (0.2540 g, 2 A white suspension of 1.4 mmol) was heated under reflux in acetone (10 mL) for 30 min. Then, CSCl2 (CSCl2 305 μL, 85%, Acros Organics) was added. The resulting orange suspension was heated under reflux for 3 h and then at 30 °C. The solid was concentrated under reduced pressure at 37° C. to a pale orange solid. The solid was washed with 0.2% TFA (8 mL total ) in small portions, filtered, and purified using method C for preparative H It was immediately purified by PLC.

[0108] Pure fractions were combined and concentrated under reduced pressure at RT. The organic solvent was removed and then freeze-dried. The fractions that could not be immediately concentrated were The isothiocyanate 12 was obtained as a white and pale yellow solid (0.054 7 g) and stored in a Drierite jar at -80°C. of 12 samples spiked with fluorobenzene at 1 H NMR and 19 F.N.M. Based on the R spectrum, it was estimated that 12 was isolated as the tetra-TFA salt. It was. 1 H NMR (400 MHz, DMSO-d6) δ= 8.17-8.06 (m, 2H), 8.00 (sw / fine splitting, 1H) , 7.84 (d, J = 1.5 Hz, 1H), 7.81-7.75 (dw / 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, DM SO-d6) δ= -74.17. IR (cm-1 ): about 3500-2800, 2083, 2026, 1735, 1670, 1591, 1448, 1 183, 1130, 796, 717. HPLC R = 15.053 min (Method B); 13.885 min (Method D). HRMS (m / z): 590.22600 [M+H] + ; Calculated value: 590.22791.

[0152] 6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,1 3-Tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)-4-( 3-Methylthioureido)picolinic acid (13, macropa-NHC(S)NHCH3 ) Preparation of

[0153] [ka] Compound 12 was synthesized from 0.0873 g (0.01 g) of 11, except that the purification step was omitted. 087 mmol) as previously described. Alternatively, the crude solid was directly dissolved in THF. 2M methylamine in 4mL was added. The color became tan-orange. The suspension of nge) was stirred at RT for 2 h and then concentrated under reduced pressure at RT to a pale pink solid. The solid was dissolved in 10% ACN / H2O containing 0.2% TFA (2 mL) and It was filtered and purified by preparative HPLC using method C. The pure fractions were combined and purified under reduced pressure. The mixture was concentrated at 50° C. to remove the organic solvent, and then freeze-dried. The dark gold solid was recrystallized from ACN with Et2O. The suspension was centrifuged. The pellet was washed with EtO (2 × 1.5 mL) and dried in vacuum to give a tan powder. The final product was 13 (0.0166 g, 22% unoptimized yield from 11). ). 1 H NMR (600 MHz, DMSO-d6) δ= 10.56 (s, 1H), 8.64 (br s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 8.13-8.02 (m, 2H), 7.81-7.73 (d, J = 7.40 Hz, 1H), 4.74-4.48 (m, 4 H), 3.82 (br s, 8H), 3.57 (br s, 8H), 3.54-3.25 (m, 8 H), 2.97 (d, J = 4.4 Hz, 4 H). 13 C{ 1 H} NMR (126 MHz, DMSO-d6) δ 180.71, 165.44, 165.39, 158.77-157.95 (q, TFA), 151.04, 150.96, 149.79, 147.95, 147.71, 139.22, 127.76, 124.55, 119.68-11 2.66 (q, TFA), 116.45, 114.85, 69.36, 64.52, 64.50, 57.00, 56.75, 53.42, 53.37, 31.02. 19 F NMR (470 MHz, DMSO-d6) δ = -74.49. EA found: C, 44.66; H, 5.36; N, 9.83.C 28 H 40 N6O8S · 2CF3COOH · Calculated for 1H2O: C, 44.34; H, 5.12; N, 9.70. HPLC t R = 14.067 minutes (Method B). HRMS (m / z): 621.26799 [M + H] + ; Calculated value: 621.27011.

[0154] X-ray diffraction test. A single crystal of H2macropa 2HCl 4H2O suitable for X-ray diffraction was prepared. After standing at room temperature, it was grown from a saturated solution of [La(H A single crystal of )]·(ClO4)2 was acidified after adding the complex. The crystals were grown by vapor diffusion of THF into aqueous solutions (pH approximately 2) containing [Lu(macr opa)]·ClO4·DMF, and vapor-diffusion of Et2O into a DMF solution of the complex. This allowed it to grow.

[0155] H2macropa·2HCl·4H2O, [La(Hmacropa)(H2O)] X for (ClO4)2 and [Lu(macropa)]·ClO4·DMF Diffraction data were collected using a Bruker APEX 2 CCD Kappa detector at 223K. The structures were collected on a diffractometer (Mo Kα, λ = 0.71073 Å). LXT

[0109] Analyzed and improved by the intrinsic phasing method using After establishing the strategy, SHELXL

[0110] Full matrix least squares method using F for all data using atrix least squares 2 Against It was refined.

[0111] All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were refined geometrically. The model was then refined using a riding model. The hydrogen atoms attached to the nitrogen and oxygen are placed in a difference Fourier synthesis, followed by distance control. The isotropic displacement parameters of all hydrogen atoms were refined semi-freely using the fixed it to 1.2 times the U value of the atom to which it is linked (1.5 times for methyl groups). [La(H macropa)(H2O)]·(ClO4)2, the solvent fraction partially occupied by water The child was included in the unit cell, but could not be modeled satisfactorily. Solvents can be identified by the solvent masking function in Olex2 without using specific atom positions. It was treated as a diffuse contribution to the overall scattering.

[0112]

[0156] La by Macropa 3+ and Lu 3+ Titration. 10mM 3-(N-morpholino ) The pH of the propane sulfonic acid (MOPS) buffer was adjusted to 7.4 using an aqueous solution of NMe4OH. The ionic strength was set at 100 mM with NMe4Cl. Stock solutions of 6.8H2O (40 mM) and LuCl3 6H2O (21 mM) were diluted to 1 mM A stock solution of H2macropa 2HCl 4H2O (8.8 mM) was prepared using From these stock solutions, macropa (100 μM) and Titration solutions containing LaCl3 or LuCl3 were prepared in MOPS. Recoat 5-10 μL containing 3000 μL of macropa (100 μM) in MOPS. Each metal ion titration was carried out at RT by adding each sample to a cuvette containing Each addition was allowed to equilibrate for 5 min before acquiring spectra. Metal ion complexation was monitored using acropa λ max The drop in absorbance at 268 nm was monitored. The reagent was added until no further change in the spectrum was detected.

[0157] Macropa La 3+ and Lu 3+ Kinetic inertness of complexes: Transchelation. Challenge: A stock solution of ethylenediaminetetraacetic acid (EDTA, 100 mM) was diluted with NMe4OH The pH of the initial suspension was adjusted to 6.6 using aqueous solution (prepared as above). The solution was prepared in MOPS buffer. Diethylenetriaminepentaacetic acid (DTPA, 125 mM ) stock solution was prepared by adjusting the pH to 7.4 as described for EDTA. The solution was prepared in HO. This solution was serially diluted with HO to give 12.5 mM and and 1.25 mM solutions were made.

[0158] macropa preformed La 3+ and Lu 3+ The complex was converted to chalcone by EDTA. The mixture was incubated with EDTA (98.7 mM) and macropa (10 The challenge was performed by adding an aliquot of a solution containing 0 μM of 10 ... The final M:macropa:EDTA ratio was approximately 1:1:20 (La) and The solutions were monitored for any spectral changes for 21 days. The final pH of each solution ranged from 7.18 to 1.25. The average daily average was between 7.25 and 7.50.

[0159] La 3+ The complex formed in situ between and macropa was analyzed by addition of excess DT Using PA, we took on a more rigorous challenge. A solution containing 500 μM of the complex was prepared with the solution and allowed to equilibrate for 5 min. This was divided into cuvettes, containing 125 mM DTPA, 12.5 mM DTPA, and 1.25 mM Dilute with M DTPA or MOPS to 1000-, 100-, 10-, or 0 A solution containing 1-fold excess of DTPA and a 100 μM concentration of macropa was created. These solutions were monitored by UV spectroscopy over a period of 21 days for any spectral changes. The final pH of each solution was between 7.11 and 7.42.

[0160] Macropa and DOTA 225 Ac radiolabel.

[0161] overview. 225 Ac and 225 Ra is produced by spallation reaction of uranium carbide, and TRI Isotope separator and accelerator at UMF, Vancouver, BC, Canada. (ISAC: Isotope Separator and Accelerator) Using the online isotope separation (ISOL) capability, the mass separator separates the radionuclides from the other radionuclides. The flow was separated and collected according to literature protocols. [103,104] Next, 225 A c is the DGA column [105,106] (branched, 50~100μm, Eichrom T by echnologies LLC 225 Separated from Ra, The elution was performed using 0.05M HNO3 for use in aluminium-backed TLC plates ( Silica gel 60, F 254 , EMD Millipore, Darmstadt, Ger Using "many"), 225 The progress of the Ac radiolabeling reaction was analyzed. C-SG, Agilent Technologies, Mississauga, ON Instant thin-layer chromatography paper impregnated with La 3+ Oh The TLC plates were developed and then incubated for at least 8 h. In addition, BioScan Autochanger 1000 and WinScan software The daughters were counted in a BioScan 200 imaging scanner equipped with Allow time for the isotope to decay completely and the measured radioactive signal is 225 Ac It was guaranteed to be generated by 225 Ac, 221 Fr, and 213 Quantitative determination of Bi Radioactivity measurements using NIST-traceable mixtures 133 Ba and 152 Calibrated with Eu source A high-purity germanium (HPGe) detector (Canberra GR1520, Me The results were determined by gamma spectrometry using a CT (combined CT) detector. The data was analyzed using Genie2000 software ( v3.4, Canberra, Meriden, CT) were used for the analyses.

[0162] Concentration dependence. Various concentrations of macropa and DOTA were 225 Ac 3+ Radioactivity sign The lowest concentration at which >95% radiolabeling still occurred was determined. 2HCl 4H2O(10 -3 ~10 -8 M) and H4DOTA (10 -3 , 10 -5 , and 10 -7 Stock solutions of ligand (M) were prepared in H2O. (10 μL) and 225 Ac (10-26 kBq, 10-30 μL) c buffer (pH 6, 0.15 M, 150 μL) was added sequentially to obtain the final ligand concentration, 5.3×10 for cropa -5 ~5.9×10 -10 5.9 for M and DOTA ×10 -5 ~5.9×10 -9 The final pH of all labeling reactions was 5.5 to 100 mM. The reaction time was between 10 min and 6 min. The reaction solution was maintained at ambient temperature or at 80° C. The progress of the reaction was monitored by TL At the 5 and 30 minute time points, 3–5 μL of the reaction solution was spotted onto the C plate. The plates were incubated in 0.4 M sodium citrate containing 10% MeOH for 1 h at 4 °C. The mixture was developed with a mobile phase of 1000 mM NaCl (pH 4) and then counted. 225 Ac(macropa)] + and 225 Ac(DOTA)] - is the baseline (R F =0) and does not undergo any chelation 225 Ac( 225 Ac-citrate) , which moved with the solvent front (R F Radiochemical yields (RCYs) were calculated by radiochromatography. by integrating the area under the peak in grams and 225 Ac-complex (R F =0) by dividing the counts associated with the total counts integrated along the length of the TLC plate. Calculated.

[0163] Macropa and DOTA 225 Kinetic inactivity of Ac complexes.

[0164] Summary. A stock solution of La(NO3)3 (0.001M or 0.1M) was prepared in H2O. Macropa (10 -5M stock solution 10μL; 1.0×10 -10 mole) or DOTA(10 -3 M stock solution 10μ L;1.0×10 -8 moles) and 225 Radioactive material containing Ac (10 μL, 26 kBq) The radiolabeled sample was treated with a 50-fold molar excess of La 3+ (0.001M or 0.1 5 μL of M stock solution was added to the solutions containing macropa and DOTA, respectively). The solutions were kept at room temperature and analyzed by iTLC at several time points over a period of 8 days. The LC plate was developed using citric acid (0.05 M, pH 5) as the eluent. Under these conditions, 225 Ac(macropa)] + and 225 Ac(DOTA)] - remains at baseline (R F =0), any non-chelated 225 Ac( 22 5 Ac-citrate) moved with the solvent front (R F = 1). Complexes that remain unchanged The percent of the compound was determined by integrating the area under the peak in the radiochromatogram. Call 225 Ac-complex (R F = 0) along the length of the iTLC plate. Calculated by dividing by the total integrated counts.

[0165] La 3+ Transmetallation reaction by [ 225 Ac(macropa)] + and 225 Ac(DOTA)] - 10 for macropa and DOTA, respectively. -5 M and 10-3 Prepare the final ligand concentration of 5.9 x 10 using 10 µL of M stock solution. - 7 M (macropa) and 5.9 × 10 -5 M(DOTA) was obtained. TLC using 0.4 M sodium citrate (pH 4) containing 0% MeOH showed After confirming that the radiochemical yield was >90%, human serum (equivalent volume based on the labeling reaction volume) was added to 16 0 μL was added to each of the radiolabeled solutions. Control solutions were also prepared, containing water as ligand. The solution was monitored by iTLC over a period of 8 days. was developed with EDTA (50 mM, pH 5) as the eluent. Under these conditions, [ 225 Ac(macropa)] + and 225 Ac(DOTA)] - The complex is Stay in Sline (R F = 0), any transchelated by serum 225 Ac( 225 Ac-EDTA) moved with the solvent front (R F =1). Remains unchanged The percentage of complexes that are

[0166] Macropa and DOTA 225 In vivo biodistribution of Ac complexes. Experiments were performed in accordance with the Institutional Animal Care and Use Committee (IACC) of the University of British Columbia. Approved by the National Animal Care Committee. Canadian Council on Animal Care Guidelin A total of nine female C57BL / 6 mice (6–8 weeks old, 20–25 g) were used. was used for biodistribution studies of each radioactive metal complex, with n=3 for each time point.

[0167] Macropa (100 μL of a 1 mg / mL solution in NH4OAc) was added to NH4O Dilute with 387 μL of Ac (1M, pH 7) and then 225 Ac(NO3)3 (approximately 1 An aliquot (203 μL) of 57 kBq was added; the pH of this solution was adjusted with 1 M NaOH ( The pH was adjusted to 6.5-7 by adding 210 μL of trace metal grade ammonium nitrate. After 5 min at RT, the reaction solution was analyzed by TLC (eluent: 0.4 M sodium citrate (pH 4) The reaction was allowed to proceed overnight. The radiochemical yield was again confirmed to be >95% the following morning. The subjects were anesthetized with 2% isoflurane. 225 Ac(macropa)] + Complexes: about 100 1 μL (10-15 kBq) was injected into the tail vein of each mouse. After injection, the mice were allowed to recover. The mice were allowed to move freely in their cages and were then monitored for CO2 inhalation 15 min, 1 h, or 5 h after injection. All animals were euthanized by infusion (n=3 per time point). Blood was collected by cardiac puncture and scintillation was performed. The tissues collected included heart, liver, kidney, and lung. , small intestine, large intestine, brain, bladder, spleen, stomach, pancreas, bone, thyroid, tail, urine, and feces. The tissue was weighed and then irradiated in three energy windows: 60–120 keV ( 180-260keV (window A), 180-260keV (window B), and 400-480keV (window C). A calibrated gamma counter (Packard, Cobra II model) was used. Counts were made by a 5002 (5002) scale. Measurements were made immediately after sacrifice and 7 days later; counts were is the decay corrected for time of injection, then the injected dose per gram of tissue (%ID / g) The data were converted to percentages of the total number of immunized subjects (%ID). No differences were shown; therefore, biodistribution was calculated using the Data obtained immediately using Window A was used and reported.

[0168] [ 225 Ac(DOTA)] - and 225 The biodistribution test of Ac(NO3)3 was carried out as follows: The fix is: 225 Ac(macropa)] + The above was carried out as described above. 22 5 Ac(DOTA) - of, 225 Ac(NO3)3 (338μL, 1.1MBq), D OTA (100 μg, 20 mg / mL in HO) with NH4OAc (467 μL, 0.1 The pH of the solution was adjusted by adding NH4OAc (15 The pH was adjusted to 7 with 0.0 μL of 1M HCl (pH 7) and the solution was heated at 85° C. for 45 min. Y>99% was confirmed by TLC as previously described. 225 Ac(DOTA)] - of, Dilute with saline to a final concentration of 0.05MBq / 100μL, and inject 100μL into each mouse. He shot. 225 Ac(NO3)3 (approximately 58 μL, 0.4 MBq) was diluted and 22 5 Ac(DOTA)] - The injection was done in the same manner as above. 225 Ac(DOTA)] - Test in progress 5 One mouse was euthanized at 1 h and died immediately after injection. 22 5One mouse died during the Ac(NO3)3 test that was euthanized at 1 h.

[0169] Hydrolysis of Macropa-NCS and p-SCN-Bn-DOTA. a-NCS (compound 12, n = 4) or p-SCN-Bn-DOTA (n = 5) approximately Screw-capped vial containing 1 mg of 0.154M NaCl Add 1 mL of 0.1 M NaHCO3 buffer (pH 9.1), which is the pre-equilibrated calcium carbonate. After stirring for 1 min, 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.

[0170] La 3+Titration of Macropa-NHC(S)NHCH3 conjugate with 13 The La stock solution (0.760 mM) was prepared in ACN instead of MOPS. 3+ Titration of macropa-NHC(S)NHCH3 conjugate (13) with 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. The increase in absorbance at 300 nm was monitored. The pH of the solution at the end of the titration was , 7.43.

[0171] Kinetic inactivation of La-Macropa-NHC(S)NHCH3: Transchelation Challenge: Diethylenetriaminepentaacetic acid (DTPA; 125 mM and 12.5 mM) A solution of macropa-NHC(S) was prepared in MOPS buffer (pH 7.4). NHCH3 (126.7 μM, 16.7% by volume of ACN) and LaCl3 (12 A MOPS solution containing 6.2 μM of EDTA was prepared using the above stock solution and allowed to equilibrate for 10 min. This was then divided into cuvettes containing 125 mM DTPA, 12.5 mM DTP, A, or MOPS to give a 1000-, 100-, or 0-fold excess of DTPA. A solution containing macropa-NHC(S)NHCH3 was prepared in each cuvette. The final concentration was 25.3 μM. These solutions were analyzed for any spectral changes. The final pH of each solution was measured by UV spectroscopy over a 21 day period. The mean mean β-amino acid concentration (β-amino acid concentration) was 7.42 to 7.49. Experiments were performed in triplicate.

[0172] Conjugation of Macropa-NCS and p-SCN-Bn DOTA to trastuzumab Juguetion.

[0173] Summary. All glassware was washed overnight in 1M HCl. Saline (0.154M NaCl) and all buffers were prepared using Chelex-10 pre-equilibrated with the appropriate buffer. Trastuzumab (Tmab, Genentech) was purified according to the manufacturer's instructions. Following the protocol, use a Zeba spin desalting column (2 mL or 5 mL, 40 MWCO (Thermo Scientific, Waltham, MA) was used as the mobile phase. The concentration of purified Tmab was adjusted to 100 mM NaCl. 280 and ε 280 1. 446mLmg -1 cm -1 The calculation was performed using the Beer-Lambert law. [ 107] Purified Tmab and Tmab conjugates were stored at 4°C.

[0174] Conjugation of Macropa-NCS to Tmab. macropa-NCS (12) A stock solution containing 4.4 mg / mL was diluted with 0.1 The 12 M NaHCO3 buffer was prepared and stored at -80°C. The stability was verified by analytical HPLC. The final concentrations of Tmab and 12 were T in saline (74 μL) at 5.1 mg / mL and 0.59 mg / mL To a portion of the mab was added 12 (52 μL) and NaHCO3 buffer (266 μL). Macropa-NCS has a molecular weight of 1045.76g for 12 (tetra-TFA salt). It was estimated that there was a 16-fold molar excess over Tmab on a / mol basis. The pH of this solution was between 8 and 9 by litmus paper. The solution was heated to 17. The mixture was gently rocked for 5 h and then purified using a spin column.

[0175] Conjugation of p-NCS-Bn-DOTA to Tmab. A stock solution containing 3.05 mg / mL of DOTA was prepared in HO and stored at -80°C. The final concentrations of Tmab and p-NCS-Bn-DOTA were 5.1 mg / m Add 66 µL of saline solution (0.38 mg / mL) to give a final concentration of 0.38 mg / mL (16-fold molar excess over L) ) was added to a portion of Tmab in 100 mL of 100 mL of p-NCS-Bn-DOTA (49 μL) and NaHCO3 Buffer solution (274.5 μL) was added. The pH of this solution was between 8 and 9 by litmus paper. The solution was gently rocked at room temperature for 17.5 h and then purified using a spin column. It was purified by

[0176] Determination of complex protein concentration by BCA assay. Macropa-Tmab and D The concentration of protein in the OTA-Tmab conjugate was measured using Pierce™ BCA Protein assay kit (Thermo Scientific, Waltham, MA) A, microplate protocol). Tmab was used as a protein standard. The purified Tmab stock solution was diluted with saline, and this solution (1.83 mg The concentration (μg / mL) was measured using a NanoDrop 1000 spectrophotometer (Thermo Scientific) The standard curve was determined using a tific (Waltham, MA) standard curve. The results were linear over the range (0 to 1828 μg / mL) (r 2=0.9966). The protein concentration of the conjugate was calculated from two independent dilutions, each measured in triplicate. These results were averaged to give a protein concentration of 4.55 for macropa-Tmab. Protein concentration for 7mg / mL and DOTA-Tmab 2.839mg / mL obtained.

[0177] Ligand-to-protein ratio analysis by MALDI-ToF. The average number of macropa or DOTA ligands obtained was determined using a procedure described elsewhere. berta Proteomics and Mass Spectrometry F Acility (University of Alberta, Canada) and Bruker Autoflex The results were determined by MALDI-ToF MS / MS at 100 kHz and 100 kHz.

[0108] purification The Tmab and its conjugates were analyzed in duplicate and the chromatograms obtained were [M+H] + Mass signals were averaged for each compound. The protein (L:P) ratio was calculated by subtracting the molecular weight of the Tmab from the molecular weight of the conjugate, followed by The mass of the difunctional ligand was calculated by dividing the mass of the difunctional ligand by the mass of the difunctional ligand.

[0178] Tmab conjugate 225 Ac radiolabeling and serum stability of the complexes.

[0179] Overview. Silica gel-impregnated instant thin-layer chromatography paper (iTLC-S G, Agilent Technologies, Mississauga, ON, Ca. Using nada), 225 Monitor the progress of the Ac radiolabeling reaction and determine serum stability The TLC plates were developed as described below and then run on a BioScan Autoch. BioScan S equipped with anger 1000 and WinScan software The cells were counted after at least 8 hours in a system 200 imaging scanner. , the time for the daughter isotope is completely decayed, and the measured radioactive signal is 225 A c.

[0180] 225 Ac radiolabeling test. Made in NH4OAc buffer (pH 6, 0.15M) In a total reaction volume of 200 μL, 225 Ac (10 or 20 kBq, 7 to 10 μL) was added to the acropa-Tmab (5.5-22 μL) or DOTA-Tmab (8.81-3 5.2 μL) and mixed with 25-100 μg of PBS, and the pH was adjusted to approximately 5 with NaOH. A control solution was also prepared in which unmodified Tmab (25 μg) was added to the conjugate. The reaction solution was kept at ambient temperature and analyzed by iTLC stripes. Spot 8 μL three times for 5 min, 30 min, 1 h, 2 h, 3 h, and 4 h. The stripes were developed with a mobile phase of 0.05 M citric acid (pH 5). Under these conditions, 225 Ac-macropa-Tmab and 225 Ac-DOTA- Tmab was plated (R F =0) baseline and any unchelated 225 Ac( 225 Ac-citrate) moved with the solvent front (R F =1). Radiation Chemical yields (RCYs) were calculated by integrating the areas under the peaks in the radiochromatograms. 225 Ac-complex (R F = 0) was integrated along the length of the TLC plate to obtain the total count. This was calculated by dividing by 1.

[0181] In human serum 225 Stability of Ac-macropa-Tmab. 225 Ac-macr A solution of opa-Tmab was prepared using 100 μg of protein. RCY>95% After confirmation by TLC that the antibody had been successfully identified, the human serum was thawed to room temperature and then incubated with radiolabeled immunosorbent. In addition to the immunocomplex, a solution containing 90% serum by volume was obtained. The samples were incubated at 37°C for 1 h. At various time points over a 7-day period, aliquots (15–30 μL) were The samples were then removed from the iTLC samples and spotted three times on an iTLC stripe. The mixture was developed and counted using a TA (50 mM, pH 5.2) mobile phase. , 225 Ac-macropa-Tmab remained at baseline (R F =0), serum Any transchelated by 225 Ac( 225 Ac-EDTA) is a solvent Moved with the tip (R F = 1). The percentage of the complex that remained unchanged was calculated.

[0182] As an additional challenge, separate aliquots (39 μL) were added to serum on days 1 and 7. The sample was also removed and mixed with 50 mM DTPA (pH 7, 13 μL) and radioisotope Any of the chromosomes that were only loosely bound by the immune complex 225 Cha so that Ac dissociates The solution was incubated at 37°C for 15 min and then aliquoted (30 μL ) was spotted in triplicate on an iTLC plate, and the mobile phase was EDTA (50 mM, pH 5.2). The percentage of the complex that remained unchanged was calculated.

[0183] [ 225 Ac(macropa)] + , [ 225 Ac(DOTA)] - , and 225 A In vivo biodistribution study of c(NO3)3.

[0184] Table 1. After intravenous injection in mice 225 Organ distribution of Ac complexes. Adult C57BL / 6 mice were cultured in a 30-well plate. 225 A c(macropa)] + , [ 225 Ac(DOTA)] - ,or 225 Injection with Ac(NO3)3, 15 min, 1 h, or 5 h later The values ​​for each time point were calculated using energy window A (60-120 keV) as %ID / g(n =3). [Table 1] JPEG2025066780000031.jpg139168

[0185] Table 2. After intravenous injection in mice 225 Organ distribution of Ac complexes. Adult C57BL / 6 mice were cultured in a 30-well plate. 225 A c(macropa)] + , [ 225 Ac(DOTA)] - ,or 225 Injection with Ac(NO3)3, 15 min, 1 h, or 5 h later The values ​​for each time point were calculated using the energy window B (180-260 keV) as %ID / g( The results were obtained as n=3). [Table 2] JPEG2025066780000033.jpg138168

[0186] Table 3. After intravenous injection in mice 225 Organ distribution of Ac complexes. Adult C57BL / 6 mice were cultured in a 30-well plate. 225 Ac(macropa)] + , [ 225 Ac(DOTA)] - ,or 225 Injection with Ac(NO3)3, 15 min, 1 h, or 5 h later The values ​​for each time point were calculated using the energy window C (400-480 keV) as %ID / g( The results were obtained as n=3). [Table 3] JPEG2025066780000035.jpg140169

[0187] 225 In vivo study of Ac-macropa-Tmab.

[0188] At the time points indicated in Table 4 below, aliquots of the complexes in serum were removed and analyzed by radio-TLC. Any loosely bound DTPA was analyzed directly or by first mixing with an excess of DTPA. 2 25 The decay-corrected values ​​shown are the decay-corrected values ​​of the TLC plates after exposure to EDTA mobile phase. R on T F The percent activity represents the percent activity with complex at 0.05%. The reported uncertainties (±1 SD) are Each time point was derived from spotting three TLC plates. The percentage of samples that were challenged with DTPA compared to samples that were not challenged with DTPA is There were no significant differences in the samples with 100% CI (p>0.05, two-tailed t-test). twist, 225 Ac was inhibited by macropa-Tmab in human serum over a period of 7 days. It is demonstrated that it remains strongly bound.

[0189] Table 4. Human serum concentrations at 37°C 225 Stability of Ac-macropa-Tmab complex (unchanged complex remains) %. [Table 4]

[0190] Characterization of 18-membered macrocyclic ligands for ion chelation. Radium-223( 223 Ra) is the first drug approved for clinical use in cancer patients. No. 1 therapeutic alpha (α)-emitting radionuclide and is effective in eradicating bone metastases. To exploit the therapeutic potential of alpha particles for soft tissue metastases, targeted alpha particle therapy (TAT) A strategy has been uncovered in which lethal α-emitting radionuclides are catalyzed by the addition of bifunctional chiral nuclides. conjugated to tumor targeting vectors using a cytotoxic α-radiation Selectively delivered to cancer cells. Actinium-225( 225 Ac) are antibody-based Its long half-life of 10 days is compatible with targeting vectors and is highly effective against cells. It produces four types of high-energy alpha emissions that are lethal, and so is being tested for use in TAT. The 12-membered tetraazamacrocycle H4DOTA is currently 225 Ac 3+ Ion The current state of the art for chelation is that when the ionic radius of the metal ion increases, H4D The thermodynamic stability of the OTA complex is reduced, and this ligand is 3+ Ions (in the periodic table) It has been shown that the chelation of the ions (maximum +3 ions in the total ion pool) is not optimal. The cyclic complexes provide significant and unexpected improvements over known complexes. In this example (H2macropa and H2macropa-NCS; Scheme 1), Therefore, the improved 225 An example is an Ac2-functional chelator.

[0191] [ka]

[0192] Previous studies have assessed the thermodynamic affinities for the entire lanthanide series macropa, but the smaller Lu 3+ , Ca 2+ , and Cm 3+ Compared to ions, The larger metal ion La 3+ , Pb 2+ , and Am 3+ It has been shown that It was done. [24-26] Without wishing to be bound by theory, macropa is a large Ac 3+ It was thought that it should be able to efficiently chelate Ac-ions. Before evaluating the catalytic properties, the complex formation was confirmed by cold precipitation of macropa and La. 3+ and Lu 3+ stomach In these studies, La 3+ A little bit Although smaller, it is chemically similar (1.03 Å, CN6). 225 Ac 3+ macropa was used as a non-radioactive surrogate for the smaller L. macropa. u 3+ The complexation of the ion (0.861 Å, CN6) was investigated to explore its size-selectivity. We conducted a survey to find out more. 3+ and Lu 3+ By titration, macropa at pH 7.4 The high affinity of these metal ions for β-acetylglucosamine was confirmed, which is consistent with the previously determined stability constants (logarithm K LaL =14.99, logarithm K LuL =8.25).

[24] in s The kinetic inactivity of these complexes formed with itu was confirmed by Lu 3+ and La 3+ To Aeon The thermodynamic affinity of ethylenediaminetetraacetic acid (EDA) is higher than that of macropa. These were then chelated using diethylenetriaminepentaacetic acid (DTPA) or diethylenetriaminepentaacetic acid (DTA) chelators. The study was carried out by conducting a survey.

[27] Lu 3+ Ion is only 10 equivalents of EDTA The addition of La resulted in transchelation within 1 minute. 3+ The complex is DTPA1000 These results indicate that the La 3+ No. Despite the strong thermodynamic preference of DTPA for lanthanide chelation, macrop The high level of kinetic inactivity of the a-complex inhibits this process on detectable time scales. It has been demonstrated that this is the case.

[0193] macropa La 3+ and Lu 3+ The complexes were isolated and their solid-state structures were characterized by X-ray diffraction. The crystal structure was analyzed (Figures 1A-1D). 3+ and Lu 3+ The ions are It is an 18-membered macrocycle, with the two picolinate arms located on the same side of the macrocycle. Lu 3+The coordination sphere of the ion is ma with both picolinate arms deprotonated. cropa was filled by 10 donors; in contrast, the larger La 3+ Ions are large The incorporation of water molecules into the inner sphere of the ring molecule results in the formation of an 11-coordinate complex. XAFS study revealed that Ac 3+ It has been demonstrated that a coordination number of 11 is preferred in aqueous solution. The ability of macropa to form stable 11-coordinate complexes is particularly important because do. [29,30]

[0194] Macropa is a larger, radioactive 225 Ac 3+ Chelation of ions Both ligands (59 μM) were administered at 0.1 μM at pH 5.5–6. In 5M NH4OAc buffer 225 Incubate with Ac (26 kBq) and complex The macromolecular formation reaction was monitored by radio-TLC after 5 min. pa was found to be in all 100% CI 0.01-0.25 after only 5 min at 225 DOTA forms a complex with Ac. Only 10% of the protein was bound under the conditions of L:M ratio of 1800. At a concentration 100-fold lower than that of pa (0.59 μM), radiolabeling was more complete in 5 min at RT. At this concentration, DOTA: 225 It failed to form a complex with Ac. In summary, these studies demonstrate that macropa is able to function at ambient and submicromolar liga The results show that the ELISA kit shows excellent radiolabeling kinetics at high concentrations, even under conditions where DOTA fails. is doing.

[0195] 225The long half-life of Ac is due to its stable complex retention in vivo, resulting in the release of of 225 Ac 3+ Avoid off-target damage to normal tissue resulting from release of Furthermore, the transmetallation and transchelation reactions 225 The high stability of the Ac complex is essential. To determine the kinetic inactivity, 225 Ac(macropa)] + The high affinity of macropa for this metal ion was confirmed. Since it was established, La 3+ The challenge was performed with 50-fold excess of La 3+ , RT macropa 225 Ac was added to the radiolabeled solution (0.59 μM). Over a period of seven days, 225 98% of the Ac complex remained unchanged by radio-TLC. A large molar equivalent of La 3+ teeth, 225 Ac 3+ This shows that the [ 225 A c(macropa)] + The stability of was also evaluated by radio-TLC. 225 Ac 3+ remained bound by macropa for at least 8 days. It became.

[0196] [ 225 Ac(macropa)] + Evaluation of biodistribution of the complex [ 225 Ac(macropa)] + The in vivo stability of The cloth, 225Ac(NO3)3 and [ 225 Ac(DOTA)] - Compared with the distribution in the body The test was carried out by injecting 10 to 50 kBq of each radioactive metal complex into C57BL / 6 mice. The animals were injected via the tail vein and sacrificed 15 min, 1 h, or 5 h later. 22 5 The amount of Ac was quantified by gamma counting and expressed as the percent of injected dose per gram of tissue (% The results of these studies are summarized in Tables 1-3. resulting in the loss of radioisotopes in 225 The inadequate stability of Ac complexes in mice In the liver, spleen, and bones 225 This is revealed by accumulation of Ac. [11,12,3 2] In Figure 2A, the unbound 225 Large accumulations of Ac(NO3)3 in the liver and spleen In conjunction with the accumulation, slow blood clearance and excretion are demonstrated. 225 Ac (Macropa)] + The biodistribution profile of (Figure 3B) was 225 Ac(NO3)3 The distribution profile in the body is clearly different from that of 225 Ac(macropa)] + Is, Ma The compound was rapidly eliminated from the mice, and very little activity was measured in the blood every hour after injection. The majority of the administered dose was excreted by the kidney and was subsequently detected in the urine at 15 min and 1 h after injection. Later, it was observed in mice [ 225 Ac(macropa)] + Medium kidney and Importantly, the study also demonstrated uptake of the urinary bladder. 225 Ac(macropa)] + did not accumulate in any organs over the time course of the study, and the complex Ivo and free 225 Ac 3+ Its biodistribution profile teeth,[ 225 Ac(DOTA)] - The biodistribution profile of , in vivo 225 Ac 3+ It has been shown previously to hold. [7]

[0197] [ 225 Ac(macropa)] + Synthesis and characterization of TAT complexes [ 225 Ac(macropa)] + Due to the inherent stability of the complex, macropa , which was incorporated into a tumor-targeting construct to facilitate its conjugation. To do this, we attached a reactive isothiocyanate functional group to the picolinate arm of macropa. The novel bifunctional ligand macropa-NCS (Scheme 1) was installed in one of the As illustrated in the above reference, macropa-NCS was obtained over eight steps. The tumor targeting constructs were synthesized and characterized by conventional techniques. Together, macropa-NCS inhibits the expression of human epidermal growth factor receptor α (EGFR) in breast and other cancers. HER2 is an FDA-approved monoclonal antibody that targets HER2. Conjugated to rastuzumab (Tmab).

[33] With a biological half-life of several weeks What? [34,35] , Tmab is a long-lived 225 Shuttling Ac radionuclides to tumor cells It is an ideal vector. 225Ac-macropa-Tmab was incubated in human serum at 37°C. The complexes showed excellent stability in water; after 7 days, >99% of the complexes remained unchanged (Table 4). Taken together, these results support the development of antibody constructs as well as other cancer-targeting constructs. Instruct 225 The effectiveness of macropa as a chelator for Ac has been demonstrated. It becomes.

[0198] References 7. MR McDevitt, D. Ma, LT Lai, J. Simon, P. Borchardt, RK Frank, K. Wu , V. Pellegrini, MJ Curcio, M. Miederer, et al., Science 2001, 294, 1537. 11. IA Davis, KA Glowienka, RA Boll, KA Deal, MW Brechbiel, M.S. tabin, PN Bochsler, S. Mirzadeh, SJ Kennel, Nucl. Med. Biol. 1999, 26, 581 . 12. KA Deal, IA Davis, S. Mirzadeh, SJ Kennel, MW Brechbiel, J. Med Chem. 1999, 42, 2988. 24. A. Roca-Sabio, M. Mato-Iglesias, D. Esteban-Gomez, E. Toth, A. de Blas, C. Platas-Iglesias, T. Rodriguez-Blas, J. Am. Chem. Soc. 2009, 131, 3331. 25. R. Ferreiros-Martinez, D. Esteban-Gomez, E. Toth, A. de Blas, C. Platas-Igl esias, T. Rodriguez-Blas, Inorg. Chem. 2011, 50, 3772. 26. MP Jensen, R. Chiarizia, IA Shkrob, JS Ulicki, BD Spindler, D. J. Murphy, M. Hossain, A. Roca-Sabio, C. Platas-Iglesias, A. de Blas, et al., In org. Chem. 2014, 53, 6003. 27. A. E. Martell, R. M. Smith, Critical Stability Constants: Vol. 1, Plenum Pr ess, New York; London, 1974. 29. M.G. Ferrier, E.R. Batista, J.M. Berg, E.R. Birnbaum, J.N. Cross, J.W. . Engle, H. S. La Pierre, S. A. Kozimor, J. S. Lezama Pacheco, B. W. Stein, et a l., Nat. Comm. 2016, 7, 12312. 30. M.G. Ferrier, B.W. Stein, E.R. Batista, J.M. Berg, E.R. Birnbaum, J.W. . Engle, KD John, SA Kozimor, JS Lezama Pacheco, LN Redman, ACS Cent . Sci. 2017, 3, 176. 32. GJ Beyer, R Bergmann, K Schomacker, F Rosch, G Schafer, EV Kulikov , AF Novgorodov, Isot. Isot. Approx. Heal. Stud. 1990, 26, 111. 33. MM Moasser, Oncogene2007, 26, 6469. 34. B. Leyland-Jones, K. Gelmon, J.-P. Ayoub, A. Arnold, S. Verma, R. Dias,P. Ghahramani , J. Clin . Oncol. 2003, 21, 3965. 35. D. Leveque, L. Gigou, JP Bergerat, Curr. Clin. Pharmacol. 2008, 3, 51. 37. AP Kozikowski, F. Nan, P. Conti, J. Zhang, E. Ramadan, T. Bzdega, B. Wro blewska, JH Neale, S. Pshenichkin, JT Wroblewski, J. Med. Chem. 2001, 44, 298. 38. KP Maresca, SM Hillier, FJ Femia, D. Keith, J. Barone, JL Joyal , CN Zimmerman, AP Kozikowski, JA Barrett, WC Eckelman, et al., J. M wheat. Chem. 2009, 52, 347. 39. SM Hillier, KP Maresca, FJ Femia, JC Marquis, CA Foss, N. Ng uyen, CN Zimmerman, JA Barrett, WC Eckelman, MG Pomper, et al., Canc er Res. 2009, 69, 6932. 40. JA Barrett, RE Coleman, SJ Goldsmith, S. Vallabhajosula, NA Pet ry, S. Cho, T. Armor, J. B. Stubbs, K. P. Maresca, M. G. Stabin, et al., J. Nucl . Med. 2013, 54, 380. 41. J. Kelly, A. Amor-Coarasa, A. Nikolopoulou, D. Kim, C. Williams Jr., S. Pon nala, JW Babich, Eur. J. Nucl. Med. Mol. Imaging 2017, 44, 647. 42. A. Ghosh, W. D. W. Heston, J. Cell. Biochem. 2004, 91, 528. 43. MS Dennis, M. Zhang, Y. Gloria Meng, M. Kadkhodayan, D. Kirchhofer, D. C ombs, LA Damico, J. Biol. Chem. 2002, 277, 35035. 44. CE Dumelin, S. Trussel, F. Buller, E. Trachsel, F. Bootz, Y. Zhang, L. M annocci, SC Beck, M. Drumea-Mirancea, MW Seeliger, et al., Angew. Chem. In t. Ed. 2008, 47, 3196. 102. M. Mato-Iglesias, A. Roca-Sabio, Z. Palinkas, D. Esteban-Gomez, C. Platas- Iglesias, E. Toth, A. de Blas, T. Rodriguez-Blas, Inorg. Chem. 2008, 47, 7840-78 51. 103. A. Roca-Sabio, M. Mato-Iglesias, D. Esteban-Gomez, E. Toth, A. de Blas,J. Platas-Iglesias, T. Rodriguez-Blas, J. Am. Chem. Soc. 2009, 131, 3331-3341. 104. VJ Gatto, GW Gokel, J. Am. Chem. Soc. 1984, 106, 8240-8244. 105. ER Neil, MA Fox, R. Pal, L.-O. Palsson, BA O'Sullivan, D. Parker , Dalton Trans. 2015, 44, 14937-14951. 106. ZEA Chamas, X. Guo, J.-L. Canet, A. Gautier, D. Boyer, R. Mahiou, Dal Trans tone. 2010, 39, 7091-7097. 108. DT Corson, CF Meares, Bioconjug. Chem. 2000, 11, 292-299. 109. GM Sheldrick, Acta Crystallogr. Sect. A 2015, 71, 3-8. 110. GM Sheldrick, Acta Crystallogr. Sect. A 2008, 64, 112-122. 111. P. Muller, Crystallogr. Freeze. 2009, 15, 57-83. 112. O. V Dolomanov, LJ Bourhis, RJ Gildea, JAK 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. JR Crawford, P. Kunz, H. Yang, P. Schaffer, TJ Ruth, Appl. Radiate. I silly. 2017, 122, 222-228. 115. B. Zielinska, J. Apostolidis, F. Bruchertseifer, A. Morgenstern, Solvent E xtr. Ion Exch. 2007, 25, 339-349. 116. V. Radchenko, JW Engle, JJ Wilson, JR Maassen, FM Nortier,W. A. Taylor, ER Birnbaum, LA Hudston, KD John, ME Fassbender, J. Chrom atogr. A 2015, 1380, 55-63. 117. MP Miranda-Hernandez, ER Valle-Gonzalez, D. Ferreira-Gomez, NO Pe rez, LF Flores-Ortiz, E. Medina-Rivero, Anal. Bioanal. Chem. 2016, 408, 1523- 1530. 118. EW Price, KJ Edwards, KE Carnazza, SD Carlin, BM Zeglis, M. J. Adam, C. Orvig, JS Lewis, Nucl. Med. Biol. 2016, 43, 566-576. 119. J. Kelly, A. Amor-Coarasa, A. Nikolopoulou, D. Kim, C. Williams, S. Ponnal a, JW Babich, Eur. J. Nucl. Med. Mol. Imaging 2017, 44, 647-661.

[0199] Several embodiments have been illustrated and described, and those skilled in the art will appreciate that, after reading the foregoing specification, , equivalent substitutions and the compounds of the present technology or their salts, pharmaceutical compositions , derivatives, prodrugs, metabolites, tautomers or other types of compounds into racemic mixtures. Modifications may be made. Each of the above aspects and embodiments may also be used in conjunction with other aspects and embodiments. to include such variations or embodiments disclosed with respect to any or all of You can also include it there.

[0200] The present technology is not limited with respect to the specific embodiments described herein, including, but not limited to, It is intended as a single illustration of an individual aspect of the present technology. Many modifications and variations of the present technology are possible. As will be apparent to those skilled in the art, this can be done without departing from its spirit and scope. Within the scope of the art, functionally equivalent methods include those described above in addition to those enumerated herein. Such modifications and variations are intended to fall within the scope of the appended claims. It is intended that the present technology may include, but is not limited to, certain methods, reagents, compounds, compositions, labeled compounds or biological It should be understood that the present invention is not limited to a particular system, which may of course vary. The terminology used in the specification is for the purpose of describing particular embodiments only and is not intended to be limiting. It should also be understood that this specification is not intended to The present invention is set forth solely in the appended claims, the definitions herein, and any equivalents thereof. The breadth, scope and spirit of the present technology are to be considered exemplary only. It is intended that:

[0201] The embodiments illustratively described herein may be used in any one of the above embodiments not specifically disclosed herein. or may be suitably practiced in the absence of one or more elements, limitation or limitations. Thus, for example, the terms "comprising," "including," "containing" and "containing" are used broadly and are not limited to Furthermore, the terms and expressions used in this specification are , are used for purposes of illustration and not for purposes of limitation, and are shown and Use of such terms and expressions to exclude any equivalent of the described features or parts thereof Although not intended for use herein, various modifications are possible within the scope of the claimed technology. It is further recognized that the phrase "consisting essentially of" includes those elements and and additional elements that do not materially affect the basic and novel characteristics of the claimed technology. It is understood that the term "consisting of" excludes any element not specified.

[0202] Furthermore, when features or aspects of the disclosure are described in Markush group terms, it will be understood by those of skill in the art that is intended to provide a basis for the present disclosure, which is to provide a basis for the present disclosure. I am aware that subgroups will also be described. Each of the narrower species and subgeneric groupings also form part of the invention. A general description of the invention is included, with no condition or negative exclusion of any subject from the genus. By way of specific limitation, cut materials or not are specifically recited herein.

[0203] As will be appreciated by those skilled in the art, for any and all purposes, specifically, In providing a description of the invention, all ranges disclosed herein also include any and all Any enumerated ranges and combinations of such ranges are also included. The ranges specified must be fully described and must be divided by at least half, third, or quarter of the same range. It can be easily recognized that it is possible to divide it into five parts, ten parts, etc. As a non-limiting example, each range discussed herein may include a lower third, a middle third, and As will also be appreciated by those skilled in the art, the upper third can be easily divided into two parts. ,All languages, e.g., "up to", "at least", "greater than", "less than" etc. includes the enumerated numbers, which can then be divided into subranges as discussed above. Finally, as will be understood by one of ordinary skill in the art, a range may include any combination of each individual member. - is included.

[0204] All publications, patent applications, issued patents, and other documents referenced herein are incorporated by reference in their entirety. (e.g., journal articles, papers and / or textbooks) for each individual patent publication, patent application, The above patents, or other documents are incorporated by reference in their entirety in detail and individually. The following terms are incorporated by reference herein as if set forth in the accompanying drawings: are excluded to the extent that they conflict with definitions in this disclosure.

[0205] The present technology includes, but is not limited to, the following alphabetical d) may include the features and combinations of features listed in paragraph d, to which the following paragraphs are appended: It is understood that the appended claims should not be construed as limiting the scope of the invention. It is understood that not all such features are necessarily included in the scope of such a claim. is mandatory. A. Formula I

[0206] [ka] [In the formula, M is an alpha-emitting radionuclide; A 1 is N or CR 1 and; A 2 is N or CR 2 and; A 3 is N or CR 3 and; A 4 is N or CR 4 and; A 5 is N or CR 5 and; A 6 is N or CR 6 and; A 7 is N or CR 7 and; A8 is N or CR 8 and; A 9 is N or CR 9 and; A 10 is N or CR 10 where A 1 , A 2 , A 3 , A 4 , and A 5 brain The three or fewer are N, and A 6 , A 7 , A 8 , A 9 , and A 10 Of these, 3 or less are N and; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are respectively independently, H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -( OCH2CH2) y -OR', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or is 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S )R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O) R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2 , -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SC N, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2 Cl, -C(O)Cl, and an epoxide group, and optionally halo, -O R', -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR', - OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C( S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR 'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO2R', -SO2 (OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -N R'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and The epoxide group is -(CH2) n - a linker, wherein n is 1, 2, or 3; Thus, each is independently linked to the carbon atom to which it is attached; or directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 One or two pairs of groups are interconnected to form a 5- to 6-membered substituted or unsubstituted carbon atom. forming a monocyclic or nitrogen-containing ring; R' at each occurrence is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2 ~C6 alkenyl, C5~C6 cycloalkenyl, C2~C6 alkynyl, C5~C6 a aryl, heterocyclyl, or heteroaryl, or two aryls attached to the same atom; the R' groups are interconnected to form a 3- to 6-membered ring; L 1 and L 2 are each independently -(CH2) p - (wherein p is 1, 2, or 3) , which is a value of; r is 0 or 1; s is 0 or 1] or a pharma- ceutically acceptable salt thereof. B.A. 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 Of The composition of paragraph A, wherein at least one is N. C.A. 1 , A 2 , A 3 , A 4 , and A 5 At least one of is N, and A 6 , A 7 , A 8 , A 9 , and A 10 At least one of the following is N: Paragraph A or Paragraph B Composition B. D.A. 1 , A 2 , A 3 , A 4 , and A 5 Compositions of paragraph A or B, except N . E.A. 6 , A 7 , A 8 , A 9 , and A 10Composition of paragraph A or paragraph B that is not N thing. F. The composition of formula I is represented by formula Ia

[0207] [ka] or a pharma- ceutically acceptable salt thereof. One composition. G.R. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 Of At least one of -C(O)R', -C(S)R', -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N3, -N=C=N-R', -SO2Cl, -C( O) Cl, and an epoxide group, Composition of one. H.R. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 Of At least one of halo, -OR', -(OCH2CH2) x -R', -(OCH2CH 2) y -OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S )R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O) R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2 , -P(O)R'(OR'), -P(O)R'2, -NO2, and -CN; The composition of any one of paragraphs A through F, wherein I. Any one of paragraphs A through H, in which at least one of r and s is 1. Composition of one. J. Any one of paragraphs A through J, in which at least one of r and s is 0. Composition of one. K. The composition of formula I is represented by formula Ib

[0208] [ka] or a pharma- ceutically acceptable salt thereof. L.R. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 Of the bases One or two pairs of immediately adjacent groups are interconnected and have 4 to 6 substituted or unsubstituted The composition of any one of paragraphs A through K, wherein the compound forms a 3-membered carbocyclic or nitrogen-containing ring. M. The composition of formula I is represented by the formula Iv

[0209] [ka] [In the formula, R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently H, Al alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCH2CH2) y -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C (O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -N R'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​- NR'C(S)NR', ​​-S(O)R', -SO2R', -SO2(OR'), -SO2 NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, - NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', - Consists of N, -N=C=N-R', -SO2Cl, -C(O)Cl, and epoxide groups. and optionally selected from the group consisting of halo, -OR', -(OCH2CH2) x -R', - (OCH2CH2) y -OR', -SR', -OC(O)R', -C(O)OR', -C (S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR ', -S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O )(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, - OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N- R', -SO2Cl, -C(O)Cl, and epoxide groups are -(CH2) n -linker - (where n is 1, 2, or 3) to the carbon atom to which it is attached. Each is independently connected; R' at each occurrence is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2 ~C6 alkenyl, C5~C6 cycloalkenyl, C2~C6 alkynyl, C5~C6 a aryl, heterocyclyl, or heteroaryl] or a pharma- ceutically acceptable thereof. The composition of any one of paragraphs A-C, G-J, and L which is a salt composition. N. The composition of formula I is represented by the formula Iw

[0210] [ka] [In the formula, R 11 , R 12 , R 13 , R 14 , R 17 , R 18 , R 19 , and R 20 teeth, Each independently represents H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkoxy ... Quinyl, aryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCH2CH2) y -OR ', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR' , -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', - C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', - NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO2R', -S O2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR' ), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and epoxide groups, optionally selected from the group consisting of halo, -OR', -(OC H2CH2) x -R', -(OCH2CH2) y -OR', -SR', -OC(O)R' , -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R' , -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR ', -NR'C(S)NR', ​​-S(O)R', -SO2R', -SO2(OR'), - SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R' 2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R ', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and epoxide groups are , -(CH2) n - a linker, where n is 1, 2, or 3, are each independently linked to the carbon atom to which they are attached; R' at each occurrence is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2 ~C6 alkenyl, C5~C6 cycloalkenyl, C2~C6 alkynyl, C5~C6 a aryl, heterocyclyl, or heteroaryl] or a pharma- ceutically acceptable thereof. The composition of any one of paragraphs A-C, GJ, and L which is a salt composition. O. The composition comprises a compound of formula Ix

[0211] [ka] or a pharma- ceutically acceptable salt thereof. Any one of the compositions. P.M. is actinium-225( 225 Ac 3+ ), Radium-223( 233 Ra 2+ ), Bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 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 + ), and uranium-230. Q. The composition comprises a compound of Formula II

[0212] [ka] [wherein M is an α-emitting radionuclide; A 1 is N or CR 1 and; A 2 is N or CR 2 and; A 3 is N or CR 3 and; A 4 is N or CR 4 and; A5 is N or CR 5 and; A 6 is N or CR 6 and; A 7 is N or CR 7 and; A 8 is N or CR 8 and; A 9 is N or CR 9 and; A 10 is N or CR 10 where A 1 , A 2 , A 3 , A 4 , and A 5 brain The three or fewer are N, and A 6 , A 7 , A 8 , A 9 , and A 10 Of these, 3 or less are N and; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 At least one of One is a selective cancer cell targeting group, or an alkylene, -O-, -(OCH2 CH2) z - where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. , -S-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O )NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'- , -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO2-, -S(O )2O-, -SO2NR'-, -P(O)(OR')-, -P(O)(R')-, -C( -OC(NR')-, -SC(NR')-, -OC(NR')-, -SC(NR')-, A selective cancer cell targeting group linked to a nitrogen atom, optionally including -O-, -( OCH2CH2) z -, -S-, -C(O)-, -OC(O)-, -C(O)O-, -C (S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C (S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO2-, -S(O)2O-, -SO2NR'-, -P(O)(OR')-, -P(O )(R')-, -C(NR')-, -OC(NR')-, -SC(NR')- are C1~ each independently linked to the carbon atom to which it is attached by a C alkylene; Remaining R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 Is that Each independently represents H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH2CH2 ) x -R', where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; -(OCH2CH2) y -OR', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR ', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C (S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S( O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR' )2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, - SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -S and an epoxide group, optionally selected from halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR' , -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', - C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', - NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO2R', -S O2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR' ), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group is -(CH2) n a linker, wherein n, at each occurrence, is independently 1, 2, or 3) to the carbon atom to which it is attached; or directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 One or two pairs of groups are interconnected to form a 5- to 6-membered substituted or unsubstituted Forms a carbocyclic or nitrogen-containing ring; R' at each occurrence is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2 ~C6 alkenyl, C5~C6 cycloalkenyl, C2~C6 alkynyl, C5~C6 a aryl, heterocyclyl, or heteroaryl, or two aryls attached to the same atom; the R' groups are interconnected to form a 3- to 6-membered ring; L 1 and L 2 are each independently -(CH2) p - (wherein p is 1, 2, or 3) , which is a value of; r is 0 or 1; and s is 0 or 1; means a pharma- ceutically acceptable salt thereof. R. The selective cancer cell targeting group is an amino acid linked by a peptide bond. The composition of paragraph Q, comprising a carboxylic acid. S. The selective cancer cell targeting group is a cancer targeting antibody or antibody fragment. The composition of paragraph Q or paragraph R. T. The selective cancer cell targeting group is an oligopeptide containing up to 50 amino acids. The composition of paragraph Q or paragraph R, which is a petite. U. Formula II

[0213] [ka] [In the formula, M is an alpha-emitting radionuclide; A 1 is N or CR 1 and; A 2 is N or CR 2 and; A 3 is N or CR 3and; A 4 is N or CR 4 and; A 5 is N or CR 5 and; A 6 is N or CR 6 and; A 7 is N or CR 7 and; A 8 is N or CR 8 and; A 9 is N or CR 9 and; A 10 is N or CR 10 where A 1 , A 2 , A 3 , A 4 , and A 5 brain The three or fewer are N, and A 6 , A 7 , A 8 , A 9 , and A 10 Of these, 3 or less are N and; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 At least one of One is a selective cancer cell targeting group, or an alkylene, -O-, -(OCH2 CH2) z -, -S-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O -, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)- , -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO2 -, -S(O)2O-, -SO2NR'-, -P(O)(OR')-, -P(O)(R' )-, -C(NR')-, -OC(NR')-, -SC(NR')-, a selective cancer cell targeting group linked to the carbon atom to which it is attached, and optionally For -O-, -(OCH2CH2) z -, -S-, -C(O)-, -OC(O)-, - C(O)O-, -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C( O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N -, -S(O)-, -SO2-, -S(O)2O-, -SO2NR'-, -P(O)(O R')-, -P(O)(R')-, -C(NR')-, -OC(NR')-, -SC(N R')- is independently connected to the carbon atom to which it is attached by a C1-C3 alkylene. linked to; Remaining R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 Is that Each independently represents H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH2CH2 ) x -R', where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; -(OCH2CH2) y -OR', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR ', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C (S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S( O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR' )2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, - SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -S and an epoxide group, optionally selected from halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR' , -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', - C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', - NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO2R', -S O2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR' ), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group is -(CH2) n - a linker, where n is 1, 2, or 3 ) each independently connected to the carbon atom to which it is attached; Or, the directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10One or two pairs of groups are interconnected to form a 5- to 6-membered substituted or unsubstituted Forms a carbocyclic or nitrogen-containing ring; R' at each occurrence is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2 ~C6 alkenyl, C5~C6 cycloalkenyl, C2~C6 alkynyl, C5~C6 a aryl, heterocyclyl, or heteroaryl, or two aryls attached to the same atom; the R' groups are interconnected to form a 3- to 6-membered ring; L 1 and L 2 are each independently -(CH2) p - (wherein p is 1, 2, or 3) , which is a value of; r is 0 or 1; and s is 0 or 1] or a pharma- ceutical acceptable salt thereof, 23. A method of treating cancer in a subject comprising administering to a subject having cancer. V. The selective cancer cell targeting group is an amino acid linked by a peptide bond. The process of paragraph U, comprising the step of: W. The selective cancer cell targeting group is a cancer targeting antibody or antibody fragment. (c) the method of paragraph U or paragraph V, X. The selective cancer cell targeting group is an oligopeptide containing up to 50 amino acids. The method of paragraph U or paragraph V, which is a petite. Y.M. 225 Ac 3+ ), Radium-223( 233 Ra 2+ ), Bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 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 + ), and uranium-230. or the method of any one of paragraphs U to X. Z. A composition comprising a pharma- ceutically acceptable carrier and a combination of any one of paragraphs A-T. Composition.

[0214] Other embodiments are intended to be within the full scope of equivalents to which such claims are entitled. , as set forth in the following claims.

Claims

1. Formula I 【Chemistry 1】 wherein M is an α-emitting radionuclide; A １ is N or CR １ and A ２ is N or CR ２ and A ３ is N or CR ３ and A ４ is N or CR ４ and A ５ is N or CR ５ and A ６ is N or CR ６ and A ７ is N or CR ７ and A ８ is N or CR ８ and A ９ is N or CR ９ and A １０ is N or CR １０ where A １ , A ２ , A ３ , A ４ , and A ５ brain The three or less are N, and A ６ , A ７ , A ８ , A ９ , and A １０ Of these, 3 or less are N and R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ are each In particular, H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, a Aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH ２ CH ２ ) ｘ - R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(O CH ２ CH ２ ) ｙ -OR', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', - C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S) R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-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 、-NO ２ 、-CN、-OCN、-SCN 、-NCO、-NCS、-NR’-NR’R’、-N、-N=C=N-R’、-SO ２ C , —C(O)Cl, and an epoxide group, and optionally selected from halo, —OR '、-(OCH ２ CH ２ ) ｘ -R'、-(OCH ２ CH ２ ) ｙ -OR'、-SR'、-O C(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S )NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR' C(O)NR’、-NR’C(S)NR’、-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 、-NO ２ 、-CN、-OCN、-SCN、-NCO、-NCS、-NR '-NR'R', -N, -N=C=NR', -SO ２ Cl, -C(O)Cl, and E The oxide group is -(CH ２ ) ｎ - a linker (wherein n is 1, 2, or 3) each independently linked to the carbon atom to which it is attached; or directly adjacent R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ One or two pairs of groups are interconnected to form a 5- to 6-membered substituted or unsubstituted carbon atom. forming a monocyclic or nitrogen-containing ring; R′, at each occurrence, is independently H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ２ ~C ６ Alkenyl, C ５ ~C ６ Cycloalkenyl, C ２ ~C ６ Alkynyl, C ５ ~C ６ a A aryl, heterocyclyl, or heteroaryl, or two attached to the same atom are interconnected to form a 3 to 6 membered ring; L １ and L ２ Each independently represents -(CH ２ ) ｐ - (wherein p is 1, 2, or 3) , where r is 0 or 1; and s is 0 or 1] or a pharma- ceutically acceptable salt thereof.

2. A １ , A ２ , A ３ , A ４ , A ５ , A ６ , A ７ , A ８ , A ９ , and A １０ A small number of The composition of claim 1 , wherein at least one is a nitrogen atom.

3. A １ , A ２ , A ３ , A ４ , and A ５ At least one of A is a nitrogen atom; ６ , A ７ , A ８ , A ９ , and A １０ At least one of the groups is a nitrogen atom. Item 2. The composition according to item 1.

4. A １ , A ２ , A ３ , A ４ , and A ５ is not a nitrogen atom, and / or A ６ , A ７ , A ８ , A ９ , and A １０ The composition of claim 1 , wherein is not a nitrogen atom.

5. The composition of formula I has the formula I-a 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

6. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ A small number of At least one of -C(O)R', -C(S)R', -OCN, -SCN, -NCO, -N CS、-NR’-NR’R’、-N ３ 、-N=C=N-R’、-SO ２ Cl、-C(O) 2. The composition of claim 1, wherein the aryl group is a group selected from the group consisting of aryl, aryl, aryl and epoxide groups.

7. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ A small number of At least one of halo, -OR', -(OCH ２ CH ２ ) ｘ -R', -(OCH ２ CH ２ ) ｙ -OR’、-SR’、-OC(O)R’、-C(O)OR’、-C(S)OR’、-C (O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R ', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-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 , -NO ２ and a group selected from -CN 2. The composition of claim 1 ,

8. The composition of claim 1 , wherein at least one of r and s is 1.

9. The composition of claim 1 , wherein at least one of r and s is 0.

10. A １ , A ２ , A ３ , A ４ , and A ５ At least one of is N, and A ６ , A ７ , A ８ , A ９ , and A １０ is N. composition.

11. The composition of formula I has the formula I-b 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

12. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ Of the base, the direct One or two pairs of adjacent groups are interconnected to form a substituted or unsubstituted 4- to 6-membered The composition of claim 1 which forms a carbocyclic or nitrogen-containing ring.

13. The composition of formula I is represented by the formula I-v 【Chemistry 4】 [In the formula, R １１ , R １２ , R １３ , R １４ , R １５ , and R １６ are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl , halo, -OR', -(OCH ２ CH ２ ) ｘ -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCH ２ CH ２ ) ｙ -OR', where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R ', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R ', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)N R’、-NR’C(S)NR’、-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 、-NO ２ 、-CN、-OCN、-SCN、-NCO、-NCS、-NR’-NR’ R', -N, -N=C=NR', -SO ２ Cl, -C(O)Cl, and epoxide groups and optionally selected from the group consisting of halo, -OR', -(OCH ２ CH ２ ) ｘ - R'、-(OCH ２ CH ２ ) ｙ -OR、' -SR'、-OC(O)R'、-C(O)O R', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C( O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C (S)NR’、-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 、-NO ２ 、 -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N =C=NR', -SO ２ Cl, -C(O)Cl, and epoxide groups are -(CH ２ ) ｎ the carbon to which it is attached by a linker, where n is 1, 2, or 3 are each independently linked to an atom; R′, at each occurrence, is independently H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ２ ~C ６ Alkenyl, C ５ ~C ６ Cycloalkenyl, C ２ ~C ６ Alkynyl, C ５ ~C ６ a aryl, heterocyclyl, or heteroaryl] or a pharma- ceutically acceptable form thereof. The composition of claim 1 which is a salt composition.

14. R １１ , R １２ , R １３ , R １４ , R １５ , and R １６ At least one of -C(O)R', -C(S)R', -OCN, -SCN, -NCO, -NCS, -NR' -NR'R', -N ３ , -N=C=NR', -SO ２ Cl, -C(O)Cl, and E 14. The composition of claim 13, wherein the radical is selected from the group consisting of epoxide radicals.

15. R １１ , R １２ , R １３ , R １４ , R １５ , and R １６ At least one of ハロ、-OR'、-(OCH ２ CH ２ ) ｘ -R'、-(OCH ２ CH ２ ) ｙ -OR'、- SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R ', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R ’、-NR’C(O)NR’、-NR’C(S)NR’、-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 , -NO ２ and -CN.

14. The composition described in 13.

16. The composition of formula I has the formula I-w 【Chemistry 5】 [In the formula, R １１ , R １２ , R １３ , R １４ , R １７ , R １８ , R １９ , and R ２０ are respectively independently, H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Aryl, halo, -OR', -(OCH ２ CH ２ ) ｘ -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCH ２ CH ２ ) ｙ -OR' (in the formula , y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC (O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S) NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C (O)NR’、-NR’C(S)NR’、-S(O)R’、-SO ２ R’、-SO ２ (O R’)、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’)、-P (O)R’ ２ 、-NO ２ 、-CN、-OCN、-SCN、-NCO、-NCS、-NR’ -NR'R', -N, -N=C=NR', -SO ２ Cl, -C(O)Cl, and epoxide oxide groups, and optionally halo, -OR', -(OCH ２ CH ２ ) ｘ -R'、-(OCH ２ CH ２ ) ｙ -OR'、-SR'、-OC(O)R'、-C( O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR 'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-N R’C(S)NR’、-S(O)R’、-SO ２ R’、-SO ２ (OR’)、-SO ２ N R’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’)、-P(O)R’ ２ 、-N O ２ / , -N=C=NR', -SO ２ Cl, -C(O)Cl, and epoxide groups are -(C H ２ ) ｎ - a linker, where n is 1, 2, or 3, to which it is attached each independently connected to a carbon atom of R' is, for each occurrence, independently, H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ２ ~C ６ Alkenyl, C ５ ~C ６ Cycloalkenyl, C ２ ~C ６ Alkynyl, C ５ ~C ６ a aryl, heterocyclyl, or heteroaryl] or a pharma- ceutically acceptable form thereof. The composition of claim 1 which is a salt composition.

17. R １１ , R １２ , R １３ , R １４ , R １７ , R １８ , R １９ , and R ２０ A small number of At least one of -C(O)R', -C(S)R', -OCN, -SCN, -NCO, - NCS、-NR’ -NR’R’、-N ３ 、-N=C=N-R’、-SO ２ Cl、-C( 17. The composition of claim 16, wherein O) is a group selected from Cl, and an epoxide group.

18. R １１ , R １２ , R １３ , R １４ , R １７ , R １８ , R １９ , and R ２０ A small number of At least one of halo, -OR', -(OCH ２ CH ２ ) ｘ -R', -(OCH ２ CH ２ ) ｙ -OR’、-SR’、-OC(O)R’、-C(O)OR’、-C(S)OR’、- C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S) R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-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 , -NO ２ and -CN. The composition of claim 16 , wherein the R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -R 10 -

19. A １ , A ４ , and A ５ At least one of A is a nitrogen atom; ６ , A ９ ,oh Call A １０ The composition of claim 16, wherein at least one of is a nitrogen atom.

20. The composition of formula I-w is represented by the formula I-x 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

21. M is actinium-225 ( ２２５ A.C. 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 ( ２ ５５ Fm ３＋ ), Thorium-227 ( ２２７ Th ４＋ ), Thorium-226 ( ２２６ Th ４＋ ), Astatine-211 ( ２１１ At ＋ ), Astatine-217 ( ２１７ At ＋ ), and uranium-230.

22. Formula II 【Chemistry 7】 wherein M is an α-emitting radionuclide; A １ is N or CR １ and A ２ is N or CR ２ and A ３ is N or CR ３ and A ４ is N or CR ４ and A ５ is N or CR ５ and A ６ is N or CR ６ and A ７ is N or CR ７ and A ８ is N or CR ８ and A ９ is N or CR ９ and A １０ is N or CR １０ where A １ , A ２ , A ３ , A ４ , and A ５ brain The three or less are N, and A ６ , A ７ , A ８ , A ９ , and A １０ Of these, 3 or less are N and R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ At least one of One is a selective cancer cell targeting group, or an alkylene, -O-, -(OCH ２ CH ２ ) ｚ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. , -S-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O )NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'- 、-NR’C(O)N-、-NR’C(S)N-、-S(O)-、-SO ２ -、-S(O ) ２ O-、-SO ２ NR’-、-P(O)(OR’)-、-P(O)(R’)-、-C( -NR')-, -OC(NR')-, -SC(NR')- to which it is attached A selective cancer cell targeting group linked to an atom, optionally -O-, -(OCH ２ CH ２ ) ｚ -、-S-、-C(O)-、-OC(O)-、-C(O)O-、 -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR 'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O) -、-SO ２ -、-S(O) ２ O-、-SO ２ NR’-、-P(O)(OR’)-、-P (O)(R')-, -C(NR')-, -OC(NR')-, and -SC(NR')- are C １ ~C ３ each independently linked to the carbon atom to which it is attached by an alkylene; The remaining R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ Is that Each independently represents H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH ２ CH ２ ) ｘ -R', where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; - (OCH ２ CH ２ ) ｙ -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), —SR′, —OC(O)R′, —C(O)OR′, —C(S)OR ', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C (S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-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 、-NO ２ 、-CN、-OCN、- SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=NR', -S O ２ Cl, —C(O)Cl, and an epoxide group, and optionally halo, -OR'、-(OCH ２ CH ２ ) ｘ -R'、-(OCH ２ CH ２ ) ｙ -OR'、-SR' , -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', - C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', - NR’C(O)NR’、-NR’C(S)NR’、-S(O)R’、-SO ２ R’、-S O ２ (OR’)、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’ )、-P(O)R’ ２ 、-NO ２ 、-CN、-OCN、-SCN、-NCO、-NCS、 -NR’-NR’R’、-N、-N=C=N-R’、-SO ２ C-、-C(O)C-、* and the epoxide group is -(CH ２ ) ｎ - a linker, where n is 1, 2 or 3 ) each independently linked to the carbon atom to which it is attached; or directly adjacent R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ One or two pairs of groups are interconnected to form a 5- to 6-membered substituted or unsubstituted carbon atom. forming a monocyclic or nitrogen-containing ring; R′, at each occurrence, is independently H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ２ ~C ６ Alkenyl, C ５ ~C ６ Cycloalkenyl, C ２ ~C ６ Alkynyl, C ５ ~C ６ a aryl, heterocyclyl, or heteroaryl, or two aryls attached to the same atom; the R′ groups are interconnected to form a 3- to 6-membered ring; L １ and L ２ Each independently represents -(CH ２ ) ｐ - (wherein p is 1, 2, or 3) , where r is 0 or 1; and s is 0 or 1], or a pharma- ceutically acceptable salt thereof. A composition useful in radiation therapy.

23. The selective cancer cell targeting group is an amino acid linked by a peptide bond. The composition of claim 22, comprising:

24. The selective cancer cell targeting moiety is a cancer targeting antibody or antibody fragment. The composition of claim 23.

25. The selective cancer cell targeting group is an oligopeptide containing up to 50 amino acids. The composition of claim 23 .

26. Formula II 【Chemistry 8】 wherein M is an α-emitting radionuclide; A １ is N or CR １ and A ２ is N or CR ２ and A ３ is N or CR ３ and A ４ is N or CR ４ and A ５ is N or CR ５ and A ６ is N or CR ６ and A ７ is N or CR ７ and A ８ is N or CR ８ and A ９ is N or CR ９ and A １０ is N or CR １０ where A １ , A ２ , A ３ , A ４ , and A ５ brain The three or less are N, and A ６ , A ７ , A ８ , A ９ , and A １０ Of these, 3 or less are N and R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ At least one of One is a selective cancer cell targeting group, or an alkylene, -O-, -(OCH ２ CH ２ ) ｚ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. , -S-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O )NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'- 、-NR’C(O)N-、-NR’C(S)N-、-S(O)-、-SO ２ -、-S(O ) ２ O-、-SO ２ NR’-、-P(O)(OR’)-、-P(O)(R’)-、-C( -NR')-, -OC(NR')-, -SC(NR')- to which it is attached A selective cancer cell targeting group linked to an atom, optionally -O-, -(OCH ２ CH ２ ) ｚ -、-S-、-C(O)-、-OC(O)-、-C(O)O-、 -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR 'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O) -、-SO ２ -、-S(O) ２ O-、-SO ２ NR’-、-P(O)(OR’)-、-P (O)(R')-, -C(NR')-, -OC(NR')-, and -SC(NR')- are C １ ~C ３ each independently linked to the carbon atom to which it is attached by an alkylene; The remaining R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ Is that Each independently represents H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH ２ CH ２ ) ｘ -R', where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; - (OCH ２ CH ２ ) ｙ -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), —SR′, —OC(O)R′, —C(O)OR′, —C(S)OR ', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C (S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-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 、-NO ２ 、-CN、-OCN、- SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=NR', -S O ２ Cl, —C(O)Cl, and an epoxide group, and optionally halo, -OR'、-(OCH ２ CH ２ ) ｘ -R'、-(OCH ２ CH ２ ) ｙ -OR'、-SR' , -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', - C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', - NR’C(O)NR’、-NR’C(S)NR’、-S(O)R’、-SO ２ R’、-S O ２ (OR’)、-SO ２ NR’ ２ 、-P(O)(OR’) ２ 、-P(O)R’(OR’ )、-P(O)R’ ２ 、-NO ２ 、-CN、-OCN、-SCN、-NCO、-NCS、 -NR’-NR’R’、-N、-N=C=N-R’、-SO ２ C-、-C(O)C-、* and the epoxide group is -(CH ２ ) ｎ - a linker, where n is 1, 2 or 3 ) each independently linked to the carbon atom to which it is attached; or directly adjacent R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ One or two pairs of groups are interconnected to form a 5- to 6-membered substituted or unsubstituted carbon atom. forming a monocyclic or nitrogen-containing ring; R′, at each occurrence, is independently H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ２ ~C ６ Alkenyl, C ５ ~C ６ Cycloalkenyl, C ２ ~C ６ Alkynyl, C ５ ~C ６ a aryl, heterocyclyl, or heteroaryl, or two aryls attached to the same atom; the R′ groups are interconnected to form a 3- to 6-membered ring; L １ and L ２ Each independently represents -(CH ２ ) ｐ - (wherein p is 1, 2, or 3) , where r is 0 or 1; and s is 0 or 1], or a pharma- ceutically acceptable salt thereof, 23. A method of treating cancer in a subject comprising administering to a subject having cancer.

27. The selective cancer cell targeting group is an amino acid linked by a peptide bond.

27. The method of claim 26, comprising:

28. The selective cancer cell targeting moiety is a cancer targeting antibody or antibody fragment. The method of claim 27 .

29. The selective cancer cell targeting group is an oligopeptide containing up to 50 amino acids.

28. The method of claim 27,

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