Follicle-stimulating hormone receptor (FSHR)-targeted therapeutic agents and uses thereof

Abstract

Described herein are radiotherapeutic agents that target tumor cells that express the follicle-stimulating hormone receptor (FSHR), and their use in the treatment and / or diagnosis of cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 378,484, filed October 5, 2022, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION Described herein are radiotherapeutic agents that target tumor cells that express the follicle-stimulating hormone receptor (FSHR), and methods for using such radiotherapeutic agents to treat, diagnose, or both, cancer. [Background technology]

[0003] Neoplasms are abnormal cell growths that cause enormous medical burdens to humans, including morbidity and mortality. Neoplasms include benign or noncancerous neoplasms (e.g., adenomas) that do not exhibit malignant characteristics and generally have little potential to become dangerous. Malignant neoplasms exhibit characteristics such as gene mutations, loss of normal function, rapid division, and the ability to metastasize (invasion) to other tissues, as well as neoplasms with uncertain or unknown behavior. Malignant neoplasms (i.e., cancerous solid tumors) are the leading cause of death in industrialized countries. Noncancerous neoplasms, including benign adenomas, can also cause significant morbidity and mortality. While standard treatments can achieve remarkable results in tumor growth inhibition and even tumor elimination, the applied drugs exhibit only limited selectivity for malignant tissue over healthy tissue, and their severe side effects limit their efficacy and use. Specific targeting of neoplastic cells without affecting healthy tissue is a major goal for effective solid tumor treatment.

[0004] As one of the three major classes of cell surface receptors, G protein-coupled receptors (GPCRs) are often overexpressed in tumor cells and are considered promising targets for selective tumor therapy. FSHR is a GPCR that is mainly expressed in the ovaries and testes. Targeting tumors with small molecule FSHR-targeting ligands and delivering radionuclides provides a novel approach for the treatment and diagnosis of various cancers, including but not limited to ovarian cancer, prostate cancer, breast cancer, testicular cancer, lung cancer, liver adenocarcinoma, colon adenocarcinoma, gastric adenocarcinoma, kidney cancer, or bladder cancer. Summary of the Invention

[0005] Described herein are radiopharmaceuticals for use in diagnosing and / or treating tumors. The present disclosure provides an alternative and improved method for treating tumors by targeting tumors that overexpress the follicle-stimulating hormone receptor (FSHR). In some embodiments, the radiopharmaceuticals disclosed herein are useful for treating tumors that overexpress FSHR. In some other embodiments, the radiopharmaceuticals disclosed herein are useful for identifying tissues or organs containing tumors that overexpress FSHR in a subject. The radiopharmaceuticals disclosed herein are also useful for in vivo imaging of a subject for the presence and distribution of tumors that overexpress FSHR in the subject.

[0006] In one aspect of the present specification, a compound of formula (A)

[0007] [ka] or a pharmaceutically acceptable salt thereof, wherein R is -L A -L B -R 6 , -L A -(L B -R 6 )2, or -L A -(L B -R 6 )3, L Ais a linker or is absent, L B is a linker or is absent, R 6 is a chelating moiety or a radionuclide complex thereof; Z is C1-C6 alkylene, C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR 10 -, -NR 10 C(=O)-, -NR 10 -, -O-, -S-, -S(=O)-, -SO2-, -NR 10 C(=O)NR 10 - or -CR 10 =NO-, R 10 are each independently H or unsubstituted C1-C4 alkyl; The ligand is a small molecule modulator of the follicle-stimulating hormone receptor (FSHR), y is 1, 2, or 3; The compounds, or pharmaceutically acceptable salts thereof, are described.

[0008] In some embodiments, R is -L B -R 6In some embodiments, the ligand is a small molecule agonist of FSHR. In some embodiments, the ligand is a small molecule antagonist of FSHR. In some embodiments, the ligand comprises a thiazolidinone (TZD), a diketopiperazine, a hexahydroquinoline, a thienopyrimidine, a piperidine carboxamide, an actyltryptophanol, a pyrrolobenzodiazepine, an aminoalkylamide, an isoxazolyl-thiazolyl, a dihydropyrrolo[2,1-a]isoquinoline, a dihydroimidazo[5,1-A]isoquinoline, a dihydrobenzoindazole, a fused tricyclic imidazole, a fused tricyclic pyrazole, a 1,4-dihydrochromeno[4,3-c]pyrazole, or a dihydro-1H-benzo[g]indole. In some embodiments, the ligand comprises dihydropyrrolo[2,1-a]isoquinoline, dihydroimidazo[5,1-A]isoquinoline, dihydrobenzoindazole, 1,4-dihydrochromeno[4,3-c]pyrazole, or dihydro-1H-benzo[g]indole. In some embodiments, the ligand comprises naphthalenesulfonic acid, (bis)sulfonic acid, (bis)benzamide, tetrahydroquinoline (THQ), benzamide, naphthalenesulfonic acid, or tetrahydroquinoline. In some embodiments, the fused tricyclic imidazole is dihydrobenzo-imidazole. In some embodiments, the fused tricyclic imidazole is dihydrobenzo-pyrazole.

[0009] In another aspect herein, a compound of formula (B)

[0010] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is H, F, Cl, Br, or I, W is O or -CH2-; V 1 is C or N, V 2 is C, CR 8 , or N, V 3 is CR8 or N, R 2 and R 3 are each independently substituted or unsubstituted alkyl; Or R 2 and R 3 together with the nitrogen to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl; R 4 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 5 is H, F, Cl, Br, or I, Y 1 and Y 2 are each independently CR 9 or N, Z is C1-C6 alkylene, -C(=O)NR 10 -, -NR 10 C(=O)-, -NR 10 -, -O-, -S-, -S(=O)-, -SO2-, -NR 10 C(=O)NR 10 - or -CR 10 =NO-, R is -L 1 -R 6 , -CH-(L 1 -R 6 )2, substituted or unsubstituted C1-C 10 Alkylene-CH-(L 1 -R 6 )2, substituted or unsubstituted 2- to 10-membered heteroalkylene-CH-(L 1 -R 6 )2, -N-(L 1 -R 6 )2, substituted or unsubstituted C1-C 10 Alkylene-N(L 1 -R 6 )2, substituted or unsubstituted 2- to 10-membered heteroalkylene-N(L 1 -R 6 )2, or -(CH2CH2O) q -CH2CH2N(L 1 -R 6 )2, q is 1, 2, 3, 4, 5, or 6; L 1 is a linker or is absent, R 6 is a chelating moiety or a radionuclide complex thereof; R 7 are independently H or substituted or unsubstituted alkyl; R 8 are each independently H, -N(R 11 )2, F, Cl, Br, I, or -OR 11 and R 9 are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, —CN, —N(R 12 )2, or -OR 12 and R 10 are each independently H or unsubstituted C1-C4 alkyl; R 11 are each independently H or unsubstituted C1-C4 alkyl; R 12 are each independently H or unsubstituted C1-C4 alkyl; The compounds, or pharmaceutically acceptable salts thereof, are described.

[0011] In some embodiments, the compound of Formula (B) has the structure:

[0012] [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the nitrogen to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl, and a substituted heterocycloalkyl may be formed by one or more R 2a and one or more R 2b is replaced by R 2a and R2b are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, -C(=O)R 2c , -CN, -NH2, or -OH, and R 2c is a substituted or unsubstituted C-C alkyl or a substituted or unsubstituted C-C cycloalkyl. In some embodiments, a heterocycloalkyl is a heterocyclic group having one R 2a and one R 2b In some embodiments, R 2a and R 2b are each —CH3. In some embodiments, R 2a is H and R 2b is -C(=O)R 2c and R 2c is CH, CHCH, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 2b teeth,

[0013] [ka] is.

[0014] In some embodiments, the compound of Formula (B) has the structure:

[0015] [ka] or a pharmaceutically acceptable salt thereof, wherein R 4 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, and a substituted aryl is a substituted or unsubstituted heteroaryl, and a substituted aryl is a substituted or unsubstituted heteroaryl, and a substituted aryl is a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted hetero ... 4a , 1 R 4b , and one R 4c is replaced by R 4a , R 4b , and R 4care each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, -CN, -NH2, or -OH, and a substituted aryl is selected from the group consisting of one R 4d and one R 4e is replaced by R 4d and R 4e are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2-6 membered heteroalkyl, -CN, -NH2, or -OH. 4a and R 4b are each independently F, Cl, Br, I, or -CH3, and R 4c is H. In some embodiments, R 4d and R 4e is H.

[0016] In another aspect herein, a compound of formula (I)

[0017] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is H, F, Cl, Br, or I, W is O or -CH2-; V 1 is C or N, V 2 is C, CR 8 , or N, V 3 is CR 8 or N, R 2 and R 3 are each independently substituted or unsubstituted alkyl; Or R 2 and R 3 together with the nitrogen to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl; R 4 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 5 is H, F, Cl, Br, or I, Y 1 and Y 2 are each independently CR 9 or N, Z is C1-C6 alkylene, -C(=O)NR 10 -, -NR 10 C(=O)-, -NR 10 -, -O-, -S-, -S(=O)-, -SO2-, -NR 10 C(=O)NR 10 - or -CR 10 =NO-, L 1 is a linker or is absent, R 6 is a chelating moiety or a radionuclide complex thereof; R 7 is H or substituted or unsubstituted alkyl, R 8 are H and -N(R 11 )2, F, Cl, Br, I, or -OR 11 and R 9 are each H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, —CN, —N(R 12 )2, or -OR 12 and R 10 are each independently H or unsubstituted C1-C4 alkyl; R 11 are each independently H or unsubstituted C1-C4 alkyl; R 12 are each independently H or unsubstituted C1-C4 alkyl; The compounds, or pharmaceutically acceptable salts thereof, are described.

[0018] In some embodiments, the compound of Formula (I) has the structure:

[0019] [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the nitrogen to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl, and a substituted heterocycloalkyl may be formed by one or more R 2a and one or more R 2b is replaced by R 2a and R 2b are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, -C(=O)R 2c , -CN, -NH2, or -OH, and R 2c is a substituted or unsubstituted C-C alkyl or a substituted or unsubstituted C-C cycloalkyl. In some embodiments, a heterocycloalkyl is a heterocyclic group having one R 2a and one R 2b In some embodiments, R 2a and R 2b are each —CH3. In some embodiments, R 2a is H and R 2b is -C(=O)R 2c and R 2c is CH, CHCH, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 2b teeth,

[0020] [ka] is.

[0021] In some embodiments, the compound of Formula (I) has the structure:

[0022] [ka] or a pharmaceutically acceptable salt thereof, wherein R 4 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, and a substituted aryl is a substituted or unsubstituted heteroaryl, and a substituted aryl is a substituted or unsubstituted heteroaryl, and a substituted aryl is a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted hetero ... 4a , 1 R 4b , and one R 4c is replaced by R 4a , R 4b , and R 4c are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, -CN, -NH2, or -OH, and a substituted aryl is selected from the group consisting of one R 4d and one R 4e is replaced by R 4d and R 4e are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2-6 membered heteroalkyl, -CN, -NH2, or -OH. 4a and R 4b are each independently F, Cl, Br, I, or -CH3, and R 4c is H. In some embodiments, R 4d and R 4e is H.

[0023] In some embodiments, the compound of Formula (I) has the formula (Ia):

[0024] [ka] or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound of formula (I) has formula (Ib):

[0026] [ka] or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the compound of Formula (I) has the formula (Ic):

[0028] [ka] or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the compound of formula (I) has the formula (Id):

[0030] [ka] or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the compound of Formula (I) has the structure:

[0032] [ka] or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, R 6These include 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,7-diacetinoic acid (DO2A), α,α',α'',α'''-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM), 1, 4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA), 2,2',2''-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bn-DOTA), p-hydroxy-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-OH-Bn-DOTA), 6,6'-(((pyridine-2,6 -diylbis(methylene))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4pypa), H4pypa-benzyl, 6,6',6'',6''''-(((pyridine-2,6-diylbis(methylene))-bis(azanetriyl))-tetrakis(methylene))-tetrapicolinic acid (H4py4pa), H4py4pa-benzyl, 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), 6,6'-((1,4,10,13-tetraoxa-7, 16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (macropa), 2,2',2'',2''''-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown), 6,6'-((ethane-1,2-diylbis((carboxymethyl)-azanediyl))bis(methylene))dipicolinic acid (H4octapa), H4octapa-benzyl, and 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid (TTHA), or a radionuclide complex thereof.

[0034] In some embodiments, R 6 teeth,

[0035] [ka] or a radionuclide complex thereof.

[0036] In some embodiments, L 1 -L 2 -, -L 3 -, -L 4 -, -L 5 -, -L 6 -, -L 7 -, -L 2 -L 3 -, -L 2 -L 4 -, -L 2 -L 7 -, -L 4 -L 6 -, -L 4 -L 7 -, -L 6 -L 7 -, -L 2 -L 4 -L 7 -, -L 2 -L 5 -L 7 -, -L 2 -L 6 -L 7 -, -L 3 -L 4 -L 7 -, -L 4 -L 5 -L 7 -, or -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 - and L 2 is absent or is a substituted or unsubstituted C1-C 20Alkylene, substituted or unsubstituted C1-C 20 Alkylene-NR 13 -, substituted or unsubstituted C1-C 20 Alkylene-C(=O)-, substituted or unsubstituted C1-C 20 Alkylene-C(=O)NR 13 -, substituted or unsubstituted C1-C 20 Alkylene-NR 13 C(=O)-, substituted or unsubstituted 2- to 20-membered heteroalkylene, -(CH2CH2O) z -, -(OCH2CH2) z -, -(CH2CH2O) w -CH2CH2-, -CH2CH2NR 13 -(CH2CH2O) w -, -(CH2CH2O) w -CH2CH2NR 13 -, -CH2CH2NR 13 C(=O)-(CH2CH2O) w -, -(CH2CH2O) w -CH2CH2NR 13 C(=O)-, -CH2CH2C(=O)NR 13 -(CH2CH2O) w -, -CH2CH2NR 13 C(=O)CH2-(OCH2CH2) w - or -(CH2CH2O) w -CH2CH2C(=O)NR 13 -, w is 1, 2, 3, 4, 5, or 6, z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and L 3 is a peptide formed from a non-existent, natural or unnatural amino acid, or two or more independently selected natural and unnatural amino acids, wherein, when two or more amino acids are present, the N atom of the amide linking said amino acids is optionally substituted with C1-C6 alkyl; and L 4 is absent or a substituted or unsubstituted 2- to 10-membered heteroalkylene, -CH2-(OCH2CH2) v -, -(CH2CH2O) v -CH2CH2-, -(CH2CH2O) vCH2CH2NR 14 C(=O)(CH2CH2O) v CH2CH2-, -(CH2CH2O) v CH2CH2C(=O)NR 14 (CH2CH2O) v CH2CH2-, -C(=O)CH2CH2, -CH2CH2C(=O)-, or independently -OH, -NR 14 2. -CO2R 14 , -O(CH2CH2O) u -CH3, -NR 14 (CH2CH2O) u -CH3, -NR 14 C(=O)(CH2CH2O) u -CH3 or -CH2OCH2CH2CO2R 14 wherein v is 1, 2, 3, 4, 5, or 6, u is 1, 2, 3, 4, 5, or 6, and L 5 is absent or -O-, -S-, -S(=O)-, -S(=O)2-, -NR 15 -, -CH(=NH)-, -CH(=N-NH)-, -CCH3(=NH)-, -CCH3(=N-NH)-, -C(=O)NR 15 -, -NR 15 C(=O), -NR 15 C(=O)O-, -NR 15 C(=O)NR 15 - or -OC(=O)NR 15 - and L 6 does not exist or -L 8 -L 9 -L 10 - and L 8 does not exist or -(CH2) t -, -NR w -, -NR w -(CH2) t -, -(CH2) t -C(=O)-, -C(=O)-(CH2) t -, -(CH2) t -NR w -, -(CH2) t -NR wC(=O)-, -(CH2) t -C(=O)NR w -, -CH(NHR w )-(CH2) t -C(=O)-, -NR w C(=O)-(CH2) t - and -C(=O)NR w -(CH2) t where t is 0, 1, 2, or 3, and L 10 does not exist or -(CH2) r -, -NR w -, -NR w -(CH2) r -, -(CH2) r -C(=O)-, -C(=O)-(CH2) r -, -(CH2) r -NR w -, -(CH2) r -NR w C(=O)-, -(CH2) r -C(=O)NR w -, -CH(NHR w )-(CH2) r -C(=O)-, -NR w C(=O)-(CH2) r - and -C(=O)NR w -(CH2) r and r is 0, 1, 2, or 3; R w are each independently H, C1-C6 alkyl, C1-C6 alkyl-CO2H, -(CH2CH2O) s -CH3, -C(=O)-(CH2CH2O) s -CH3, or -(CH2CH2O) s -CH2CH2CO2H, s is 1, 2, 3, 4, 5, or 6, and L 9 is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 13 , R 14 , and R 15 are each independently selected from H or unsubstituted C1-C4 alkyl; L 7is absent, -NH-, -N(CH3)-, -O-NH-, or substituted or unsubstituted N-heterocycloalkylene, or -O-NH=(substituted or unsubstituted N-heterocycloalkylene).

[0037] In some embodiments, the radionuclide of the radionuclide complex is a lanthanide or actinide. In some embodiments, the radionuclide of the radionuclide complex is actinium, bismuth, cesium, cobalt, copper, dysprosium, erbium, gold, indium, iridium, gallium, lead, lutetium, manganese, palladium, platinum, radium, rhenium, samarium, strontium, technetium, ytterbium, yttrium, or zirconium. In some embodiments, the radionuclide of the radionuclide complex is a diagnostic or therapeutic radionuclide. In some embodiments, the radionuclide of the radionuclide complex is an Auger electron-emitting radionuclide, an α-emitting radionuclide, a β-emitting radionuclide, or a γ-emitting radionuclide. In some embodiments, the radionuclide of the radionuclide complex is 111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 70-gallium ( 70 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu), or 177-lutetium ( 177 Lu).

[0038] Also described herein are pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration.

[0039]

[0010] In another aspect herein, methods for treating cancer are described, the methods comprising administering to a mammal having cancer an effective amount of a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer comprises a tumor, and the tumor overexpresses follicle-stimulating hormone receptor (FSHR). In some embodiments, the cancer is ovarian cancer, prostate cancer, breast cancer, testicular cancer, lung cancer, liver adenocarcinoma, colon adenocarcinoma, gastric adenocarcinoma, kidney cancer, or bladder cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver adenocarcinoma. In some embodiments, the cancer is colon adenocarcinoma. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is bladder cancer.

[0040] In another aspect herein, described is a method for treating a tumor in a mammal with a radionuclide, comprising administering to the mammal a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof. In some embodiments, the mammal is diagnosed with ovarian cancer. In some embodiments, the mammal is diagnosed with prostate cancer, breast cancer, or testicular cancer.

[0041] In another aspect herein, described is a method for targeted delivery of a radionuclide to a tumor in a mammal, the method comprising administering to a mammal having the tumor a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof, wherein the tumor overexpresses the follicle-stimulating hormone receptor (FSHR).

[0042]

[0013] In another aspect herein, a method for identifying a tissue or organ in a mammal having a tumor that expresses a follicle-stimulating hormone receptor (FSHR) is provided, comprising administering to the mammal a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof, and performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI), wherein R 6 is a chelating moiety-diagnostic radionuclide complex.

[0043]

[0010] In yet another aspect herein, a method for performing in vivo diagnostic imaging of a tissue or organ in a mammal having a tumor that expresses a follicle-stimulating hormone receptor (FSHR), comprising administering to the mammal a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I), Formula (B), or Formula (A)), or a pharmaceutically acceptable salt thereof, and performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI), wherein R 6 is a chelating moiety-diagnostic radionuclide complex.

[0044] In any of the embodiments disclosed herein, the mammal is a human.

[0045] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be noted, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0046] Cancer, a disease in which some cells undergo genetic changes in the regulation of growth and replication, leading to uncontrolled growth and spread, is one of the major causes of cancer worldwide. Common types of cancer include solid tumors (cancers that typically arise in organs), carcinomas (cancers arising in the skin or tissues lining organs), sarcomas (cancers of connective tissue such as bone), leukemia (cancers of the bone marrow), and lymphomas and myelomas (cancers of the immune system). Neoplasms are abnormal cell growths that result in solid tumors that can be benign (i.e., exhibit no harmful characteristics and are unlikely to pose a risk overall, such as adenomas), malignant (i.e., exhibit characteristics such as genetic mutations, loss of normal function, rapid division, and the ability to metastasize (invasion) to other tissues), and of uncertain or unknown behavior. State-of-the-art treatment for neoplasms is accomplished through a combination of surgery, chemotherapy, and radiation therapy. While surgery can be curative under some conditions, it often requires multiple interventions, as well as the combination of radiation and chemotherapy. Chemotherapy has proven to be a powerful weapon against cancer in many cases. However, further optimization is needed. Chemotherapy is typically administered through the systemic administration of potent cytotoxic drugs. However, these compounds lack tumor selectivity and therefore also kill healthy cells in the body. The resulting nonspecific toxicity accounts for the severe side effects of chemotherapy, as cancer cells are not specifically targeted over other cells. Radiation therapy is the use of high-energy radiation to kill cells. The radiation source can be external beam radiation (applied using an external source), internal radiation (placement of a radioactive material near target cells), or systemic administration of radioactive material. Like chemotherapy, many radiation therapy options lack the tumor cell signature required to achieve the ultimate goal of targeted tumor treatment using drug molecules or radionuclides.

[0047] Described herein are radiopharmaceuticals that deliver radionuclides selectively to malignant cells that overexpress FSHR.

[0048] Follicle-stimulating hormone (FSH) is a central hormone in mammalian reproductive biology. It promotes mature spermatogenesis in men and follicular maturation in women. The FSH receptor (FSHR) is a glycosylated transmembrane protein belonging to the G protein-coupled receptor (GPCR) family. In adult humans and animals, low levels of FSHR are expressed exclusively in endothelial cells of the ovaries and testes. Immunostaining has demonstrated that FSHR is overexpressed in the blood vessels of various solid tumors, including prostate, breast, lung, and ovarian cancers. In contrast, healthy, nonmalignant, inflammatory tissues are consistently FSHR-negative. These findings suggest that this receptor may be a potential target for cancer detection, image-guided cancer surgery, and selective tumor killing by radionuclide conjugates.

[0049] GPCRs are generally poorly antigenic, making them difficult to target with antibody-based strategies. The large size of antibodies can affect homogeneous uptake but may not allow for deep penetration into solid tumors. Furthermore, antibodies can present challenges during production, including batch-to-batch variability.

[0050] Peptides are inherently sensitive to proteolytic enzymes, and peptidases present in most tissues can rapidly degrade peptides into multiple fragments that lack any significant affinity for the intended receptor. Furthermore, peptides can generate unwanted immunogenic responses that complicate late-stage development by masking therapeutic efficacy and affecting safety evaluation.

[0051] When peptide ligands are linked to radionuclide payloads, the resulting conjugates often rapidly degrade in plasma, producing cytotoxic or radioactive peptide fragments that can nonspecifically bind to both tumors and normal tissues. Premature decay of such peptide-radionuclide conjugates reduces the amount of radionuclide payload distributed to targeted tumors, resulting in reduced treatment efficacy and possibly increased toxicity. Furthermore, peptides are highly likely to be excreted exclusively via the kidney, limiting their scope of application. The significant renal absorption of some peptide-based therapeutics limits their routine use.

[0052] High-affinity small molecule ligands that bind to GPCRs have been described, and they are cell-permeable, allowing them to access receptor populations in the endoplasmic reticulum and endosomes. Due to the low molecular weight of small molecules, vascular and tumor penetration should be improved compared to high molecular weight conjugates based on peptides and antibodies. In many instances, the affinity of small molecule ligands exceeds that of FDA-approved antibodies by several orders of magnitude.

[0053] Follicle-stimulating hormone receptor (FSHR) The follicle-stimulating hormone receptor (FSHR) is a G protein-coupled receptor expressed on the ovaries and testes. FSHR is a glycosylated transmembrane protein with an extracellular region that recognizes and binds to its endogenous hormone, follicle-stimulating hormone (FSH). FSH is an important hormone in mammalian reproductive systems. It is produced primarily in the anterior pituitary gland, and its target organs are receptors on the ovaries and testes. In women, FSH stimulates follicular maturation and estrogen production by aromatizing androgens. In men, FSH stimulates Sertoli cell proliferation in the immature testes and maintains normal spermatogenesis in adults.

[0054] In adult humans and animals, FSHR is known to be expressed only in testicular Sertoli cells and ovarian granulosa cells, and at lower levels in endothelial cells of the ovary and testis. In the testis, FSHR mediates the translocation of FSH across the blood-testicular endothelial barrier by the process of receptor-mediated transcytosis.

[0055] ovarian cancer Ovarian cancer is classified histologically and genetically as type I or type II. Type I cancers have lower histological grades and include endometrial carcinoma, mucinous carcinoma, and clear cell carcinoma. Type II cancers have higher histological grades and include serous carcinoma and carcinosarcoma.

[0056] The most common type of ovarian cancer is epithelial ovarian cancer, accounting for over 95% of cases. There are five main subtypes of ovarian cancer, of which high-grade serous adenocarcinoma (HGSC) is the most common. Other ovarian cancer subtypes include low-grade serous carcinoma, clear cell carcinoma, endometrioid carcinoma, and mucinous carcinoma. Less common types of ovarian cancer include germ cell tumors and sex cord-stromal tumors.

[0057] Ovarian cancer is staged using the FIGO staging system, which uses information obtained after surgery, which may include a complete abdominal hysterectomy through a midline abdominal incision, removal of both ovaries and fallopian tubes (usually), omentum, pelvic (peritoneal) washings, evaluation of retroperitoneal lymph nodes (including pelvic and para-aortic lymph nodes), appendectomy for suspected mucinous tumors, and pelvic / peritoneal biopsies for cytopathology. Even stage I cancers must be completely resected because approximately 30% of ovarian cancers considered confined to the ovary will microscopically metastasize. Twenty-two percent of cancers estimated to be stage I are observed to develop lymphatic metastases. AJCC (American Joint Committee on Cancer) stages are the same as FIGO stages. The AJCC staging system describes the extent of the primary tumor (T), the absence or presence of nearby lymph node (N) metastases, and the absence or presence of distant metastases (M). The most common stage at diagnosis is stage IIIc, accounting for over 70% of diagnoses.

[0058] Tumors can form in the ovaries. Types of treatments used to treat ovarian tumors include surgery, radiation therapy, and chemotherapy. Surgery to remove the ovaries (oophorectomy) and fallopian tubes (salpingectomy) or both (salpingo-oophorectomy) is often used to treat ovarian cancer. Occasionally, surgery is performed to remove nearby lymph nodes and other tissues where the cancer has spread. Radiation therapy uses high-energy X-rays or other types of radiation to kill cancer cells or prevent them from growing. There are two types of radiation therapy: external radiation therapy uses a machine outside the body to direct radiation toward the area of ​​the body that has cancer. Internal radiation therapy uses radioactive material sealed in needles, seeds, wires, or catheters that are placed directly on or near the cancer. Additionally, targeted radiopharmaceuticals can deliver targeted radiation to the tumor site. Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells by killing them or stopping them from dividing.

[0059] Therefore, there is still a need for treatment options for ovarian tumors, such as epithelial ovarian tumors.This paper describes a radiopharmaceutical that targets the delivery of radionuclides to ovarian tumors that overexpress FSHR.Targeted therapy usually causes less harm to normal cells than chemotherapy or radiotherapy.

[0060] prostate cancer Prostate cancer is cancer of the prostate gland, a gland in the male reproductive system that surrounds the urethra and lies just below the bladder. Prostate cancer is one of the most common types of cancer. Nearly all prostate cancers are adenocarcinomas, which develop from glandular epithelial cells (the cells that produce the prostate fluid that is added to semen). Although very rare, other types of cancer that can arise from the prostate include small cell carcinoma, neuroendocrine tumors (excluding small cell carcinoma), transitional cell carcinoma, and sarcoma. Many prostate cancers grow slowly and are confined to the prostate, but may not cause serious harm there. However, some types of prostate cancer grow slowly and may require minimal or no treatment, while others are aggressive and can spread rapidly.

[0061] Prostate cancer is staged using the TNM system, developed by the AJCC. The three key components of the TNM system include T (tumor), which describes the size, location, and depth of growth of the tumor into tissue; N (node), which indicates whether cancer cells have spread to nearby lymph nodes or the channels connecting those lymph nodes; and M (metastasis), which refers to whether cancer cells have spread to distant organs or tissues. Prostate cancer stages range from 1 to 4.

[0062] Tumors can originate in the prostate gland, and recommended treatments can vary widely. Low-grade prostate cancer may not require immediate treatment. For some, treatment may not be necessary. Instead, doctors may recommend observation (sometimes called watchful waiting) or active surveillance. Surgery is a common option used to attempt to cure prostate cancer when it is not thought to have spread outside the prostate. The main type of prostate cancer surgery is radical prostatectomy. In this surgery, the surgeon removes the entire prostate gland as well as some of the surrounding tissue, including the seminal vesicles. Other treatment options for prostate cancer include radiation therapy, cryotherapy, hormone therapy, chemotherapy, immunotherapy, and targeted therapy. Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or prevent them from growing. Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells by killing them or stopping them from dividing.

[0063] Therefore, there is still a need for treatment options for prostate tumors, such as epithelial prostate tumors.This paper describes a radiopharmaceutical that targets the delivery of radionuclides to prostate tumors that overexpress FSHR.Targeted therapy usually causes less harm to normal cells than chemotherapy or radiotherapy.

[0064] testicular cancer Testicular cancer begins in the testicles (testicles), located inside the scrotum, a loose, skin-like sac located just below the penis. The testicles produce male hormones and sperm for reproduction. Compared to other types of cancer, testicular cancer is rare. However, testicular cancer is the most common cancer in American men between the ages of 15 and 35.

[0065] Types of testicular cancer include germ cell tumors, intraductal germ cell neoplasia (carcinoma in situ of the testis (CIS)), and stromal tumors.

[0066] The main types of germ cell tumors are seminomas and nonseminomas. Seminomas tend to grow and spread more slowly than nonseminomas. The two main subtypes of seminoma tumors are classic (or typical) seminoma and spermatocytic seminoma. Nonseminoma tumors usually occur in men between their early teens and late 30s. The four main types of nonseminoma tumors are embryonal tumors, yolk sac carcinoma, choriocarcinoma, and teratoma. Most tumors are a combination of different types (sometimes containing seminoma cells), but this does not change the treatment of most nonseminoma cancers.

[0067] Gonadal stromal tumors can arise from the supportive and hormone-producing tissue, or stroma, of the testicles. They account for less than 5% of adult testicular tumors but 20% of pediatric testicular tumors. The main types are Leydig cell tumors and Sertoli cell tumors. Most Leydig and Sertoli tumors are benign.

[0068] Testicular cancer stages are designated by Roman numerals ranging from 0 to 3, with the lowest stage indicating cancer limited to the area around the testicles. Depending on the type and stage of testicular cancer, a patient may receive one or a combination of several treatments. Treatments for testicular cancer include surgery, radiation therapy, chemotherapy and high-dose chemotherapy, and stem cell transplantation.

[0069] Therefore, there is still a need for treatment options for testicular tumors such as embryonal carcinoma.This paper describes a radiopharmaceutical that targets the delivery of radionuclides to testicular tumors that overexpress FSHR.Targeted therapy usually causes less harm to normal cells than chemotherapy or radiotherapy.

[0070] Solid tumors: benign and / or malignant neoplasms (cancer) In one embodiment, the compounds of Formula (I), Formula (B), or Formula (A) are used to treat benign and / or malignant neoplasms (solid tumors), which comprise cells that overexpress FSHR on the cell surface.

[0071] As used herein, the term "neoplasm" refers to an abnormal growth of cells that can proliferate in an uncontrolled manner and have the capacity to metastasize (spread).

[0072] Neoplasms include solid tumors at any stage, with or without metastasis, adenomas, carcinomas, sarcomas, leukemias, and lymphomas.

[0073] A solid tumor is an abnormal mass of tissue that usually does not contain cysts or areas of fluid. Solid tumors can be benign (non-cancerous) or malignant (cancerous). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) do not generally form solid tumors.

[0074] Solid tumors are cancers that typically arise from organs such as the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, ovaries, pancreas or other endocrine organs (thyroid), and prostate.

[0075] In some embodiments, compounds of Formula (I), Formula (B), or Formula (A) are used to treat adenomas. Adenomas are non-cancerous tumors that arise from gland-like cells in epithelial tissue (thin layers of tissue that cover organs, glands, and other structures in the body). Adenomas can grow from many glandular organs, including the adrenal glands, pituitary gland, thyroid gland, and prostate gland. Even if benign, they can cause serious health complications by compressing other structures (mass effect) and by producing large amounts of hormones in an unregulated, non-feedback-dependent manner (causing paraneoplastic syndromes). Over time, adenomas can transform and become harmful, at which point they are called adenocarcinomas.

[0076] Adenomas can occur in the colon (e.g., adenomatous polyps that tend to become harmful and result in colon cancer), kidney (e.g., renal adenomas can be precursor lesions to renal cancer), adrenal glands (e.g., adrenal adenomas; some secrete hormones such as cortisol, which causes Cushing's syndrome, aldosterone, which causes Conn's syndrome, or androgens, which cause hyperandrogenism), thyroid gland (e.g., goiter), pituitary gland (e.g., prolactinoma, Cushing's syndrome, and acromegaly). They may also be found in the pituitary adenomas (e.g., hypertrophy of the pituitary gland), parathyroid glands (e.g., parathyroid adenomas may secrete inappropriately high amounts of parathyroid hormone, thereby causing primary hyperparathyroidism), liver (e.g., hepatocellular adenoma), breast (e.g., fibroadenocarcinoma), appendix (e.g., cystadenoma), bronchi (e.g., bronchial adenomas may cause carcinoid syndrome, a paraneoplastic syndrome), prostate (e.g., prostatic adenoma), sebaceous glands (e.g., sebaceous adenoma), and salivary glands.

[0077] Metastasis is the spread of malignant cells to new areas of the body, often via the lymphatic system or bloodstream. A metastatic tumor is one that has spread from its primary site, i.e., where it first began, to different areas of the body. A metastatic tumor contains malignant cells that express cell surface FSHR.

[0078] Tumors that form from spread cells are called secondary tumors. Tumors may spread to areas near the primary site (called regional metastasis) or to distant parts of the body (called distant metastasis).

[0079] In some embodiments, the tumor to be treated comprises tumor cells that express FSHR, and the tumor is a primary or metastatic tumor. In some embodiments, the tumor to be treated comprises tumor cells that express FSHR, and the tumor is a primary or metastatic tumor of ovarian origin. In some embodiments, the tumor to be treated comprises tumor cells that express FSHR, and the tumor is a primary or metastatic tumor of prostate origin. In some embodiments, the tumor to be treated comprises tumor cells that express FSHR, and the tumor is a primary or metastatic tumor of testicular origin.

[0080] In some embodiments, compounds of Formula (I), Formula (A), or Formula (B) are used to treat carcinoma. Carcinomas include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma (a type of skin cancer), squamous cell carcinoma (various tissues), bladder carcinoma including transitional cell carcinoma (malignant neoplasm of the bladder), bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, renal cell carcinoma, intraductal or bile duct carcinoma, choriocarcinoma, seminoma, embryonal tumor, Wilms' tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, bone carcinoma, carcinoma of the epithelium, and nasopharyngeal carcinoma.

[0081] In some embodiments, compounds of Formula (I), Formula (A), or Formula (B) are used to treat sarcomas, including, but not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[0082] Solid tumors include, but are not limited to, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, medullary hemangioma, melanoma, neuroblastoma, and retinoblastoma. Benign solid tumors include adenomas.

[0083] Primary and metastatic tumors include, for example, lung cancer (including, but not limited to, lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, non-small cell carcinoma, small cell carcinoma, and mesothelioma), breast cancer (including, but not limited to, ductal carcinoma, lobular carcinoma, inflammatory breast carcinoma, clear cell carcinoma, and mucinous carcinoma), colorectal cancer (including, but not limited to, colon carcinoma and rectal carcinoma), anal cancer, pancreatic cancer (including, but not limited to, pancreatic adenocarcinoma, islet cell carcinoma, and neuroendocrine tumors), prostate cancer, ovarian cancer (including, but not limited to, serous tumors, endometrioid tumors, and epithelial or surface epithelial-stromal tumors of the ovary, including, but not limited to, mucinous cystadenocarcinoma and sex cord-stromal tumors), liver and bile duct cancer (including, but not limited to, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and hemangioma). Cancers of the stomach (including but not limited to gastric adenocarcinoma, gastrointestinal stromal tumor), multiple myeloma, testicular cancer, germ cell tumors, neuroendocrine tumors, cervical cancer, carcinomas of the stomach, esophageal cancer (including but not limited to esophageal adenocarcinoma and squamous cell carcinoma), non-Hodgkin's lymphoma, bladder cancer, carcinomas of the uterus (including but not limited to endometrial adenocarcinoma, uterine serous carcinoma, uterine clear cell carcinoma, uterine sarcoma, and leiomyosarcoma, mixed Mullerian tumor), gliomas, glioblastomas, medulloblastomas, and other tumors of the brain, kidney cancer (including but not limited to renal cell carcinoma, clear cell carcinoma, Wilms' tumor), cancers of the head and neck (including but not limited to squamous cell carcinoma), cancers of the stomach (including but not limited to gastric adenocarcinoma, gastrointestinal stromal tumor), multiple myeloma, testicular cancer, germ cell tumors, neuroendocrine tumors, cervical cancer, carcinoid tumors of the gastrointestinal tract, breast, and other organs, and signet ring cell carcinoma.

[0084] Representative follicle-stimulating hormone receptor (FSHR)-targeting ligands In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) has an affinity for FSHR that is at least 10 times, at least 50 times, at least 100 times, at least 200 times, at least 500 times, or at least 1000 times higher than its affinity for other non-target receptors. In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) is selective for FSHR compared to any one of other glycoprotein hormone receptors, including luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG). In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) has an affinity for FSHR that is at least 10 times, at least 50 times, at least 100 times, at least 200 times, at least 500 times, or at least 1000 times higher than its affinity for any one of LH, TSH, and hCG.

[0085] In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) preferentially accumulates in tumor tissues expressing the targeted FSHR. In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) preferentially accumulates in tissues or organs containing tumor cells expressing FSHR compared to tissues or organs lacking tumor cells expressing FSHR. In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) preferentially accumulates at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or more than 5-fold in tissues or organs containing tumor cells expressing FSHR compared to tissues or organs lacking tumor cells expressing FSHR. In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) preferentially accumulates in tissues or organs containing tumor cells expressing FSHR compared to healthy tissues or organs lacking tumor cells expressing FSHR at low levels. In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) preferentially accumulates at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or more than 5-fold in tissues or organs containing tumor cells that express FSHR compared to healthy tissues or organs lacking tumor cells that express FSHR at low levels. The compound may accumulate in certain tissues and organs involved in the metabolism and / or excretion of therapeutic agents, including, but not limited to, the kidney and liver.

[0086] In one embodiment, the FSHR targeting ligand has the formula (A):

[0087] [ka] or a pharmaceutically acceptable salt thereof, wherein R is -L A -L B -R 6 , -L A -(L B -R 6 )2, or -L A -(L B -R 6 )3, L Ais a linker or is absent, L B is a linker or is absent, R 6 is a chelating moiety or a radionuclide complex thereof; Z is C1-C6 alkylene, C1-C6 alkylene-O-, -O-C1-C6 alkylene-, -C(=O)NR 10 -, -NR 10 C(=O)-, -NR 10 -, -O-, -S-, -S(=O)-, -SO2-, -NR 10 C(=O)NR 10 - or -CR 10 =NO-, R 10 are each independently H or unsubstituted C1-C4 alkyl; The ligand is a small molecule modulator of the follicle-stimulating hormone receptor (FSHR), y is 1, 2, or 3.

[0088] In some embodiments, R is -L B -R 6 is.

[0089] In some embodiments, the ligand is a small molecule agonist of FSHR. In some embodiments, the ligand is a small molecule antagonist of FSHR.

[0090] In some embodiments, the ligand comprises a thiazolidinone (TZD), a diketopiperazine, a hexahydroquinoline, a thienopyrimidine, a piperidine carboxamide, an actyltryptophanol, a pyrrolobenzodiazepine, an aminoalkylamide, an isoxazolyl-thiazolyl, a dihydropyrrolo[2,1-a]isoquinoline, a dihydroimidazo[5,1-A]isoquinoline, a dihydrobenzoindazole, a fused tricyclic imidazole, a fused tricyclic pyrazole, a 1,4-dihydrochromeno[4,3-c]pyrazole, or a dihydro-1H-benzo[g]indole. In some embodiments, the ligand comprises dihydropyrrolo[2,1-a]isoquinoline, dihydroimidazo[5,1-A]isoquinoline, dihydrobenzoindazole, 1,4-dihydrochromeno[4,3-c]pyrazole, or dihydro-1H-benzo[g]indole. In some embodiments, the ligand comprises naphthalenesulfonic acid, (bis)sulfonic acid, (bis)benzamide, tetrahydroquinoline (THQ), benzamide, naphthalenesulfonic acid, or tetrahydroquinoline. In some embodiments, the fused tricyclic imidazole is dihydrobenzo-imidazole. In some embodiments, the fused tricyclic imidazole is dihydrobenzo-pyrazole.

[0091] In some embodiments, the compound has the structure of formula (B), or a pharmaceutically acceptable salt thereof.

[0092] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is H, F, Cl, Br, or I, W is O or -CH2-; V 1 is C or N, V 2 is C, CR 8 , or N, V 3 is CR 8or N, R 2 and R 3 are each independently substituted or unsubstituted alkyl; Or R 2 and R 3 together with the nitrogen to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl; R 4 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 5 is H, F, Cl, Br, or I, Y 1 and Y 2 are each independently CR 9 or N, Z is C1-C6 alkylene, -C(=O)NR 10 -, -NR 10 C(=O)-, -NR 10 -, -O-, -S-, -S(=O)-, -SO2-, -NR 10 C(=O)NR 10 - or -CR 10 =NO-, R is -L 1 -R 6 , -CH-(L 1 -R 6 )2, substituted or unsubstituted C1-C 10 Alkylene-CH-(L 1 -R 6 )2, substituted or unsubstituted 2- to 10-membered heteroalkylene-CH-(L 1 -R 6 )2, -N-(L 1 -R 6 )2, substituted or unsubstituted C1-C 10 Alkylene-N(L 1 -R 6 )2, substituted or unsubstituted 2- to 10-membered heteroalkylene-N(L 1 -R 6 )2, or -(CH2CH2O) q -CH2CH2N(L 1 -R 6 )2, q is 1, 2, 3, 4, 5, or 6; L 1 is a linker or is absent, R 6 is a chelating moiety or a radionuclide complex thereof; R 7 is H or substituted or unsubstituted alkyl, R 8 are each independently H, -N(R 11 )2, F, Cl, Br, I, or -OR 11 and R 9 are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, —CN, —N(R 12 )2, or -OR 12 and R 10 are each independently H or unsubstituted C1-C4 alkyl; R 11 are each independently H or unsubstituted C1-C4 alkyl; R 12 are each independently H or unsubstituted C1-C4 alkyl; The compounds, or pharmaceutically acceptable salts thereof, are described.

[0093] In some embodiments, the compound has formula (I):

[0094] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is H, F, Cl, Br, or I, W is O or -CH2-; V 1 is C or N, V 2 is C, CR 8 , or N, V3 is CR 8 or N, R 2 and R 3 are each independently substituted or unsubstituted alkyl; Or R 2 and R 3 together with the nitrogen to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl; R 4 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 5 is H, F, Cl, Br, or I, Y 1 and Y 2 are each independently CR 9 or N, Z is C1-C6 alkylene, -C(=O)NR 10 -, -NR 10 C(=O)-, -NR 10 -, -O-, -S-, -S(=O)-, -SO2-, -NR 10 C(=O)NR 10 - or -CR 10 =NO-, L 1 is a linker or is absent, R 6 is a chelating moiety or a radionuclide complex thereof; R 7 is H or substituted or unsubstituted alkyl, R 8 are each independently H, -N(R 11 )2, F, Cl, Br, I, or -OR 11 and R 9 are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, —CN, —N(R 12 )2, or -OR 12 and R 10are each independently H or unsubstituted C1-C4 alkyl; R 11 are each independently H or unsubstituted C1-C4 alkyl; R 12 are each independently H or unsubstituted C1-C4 alkyl.

[0095] In some embodiments, the compound of Formula (I) has the formula (Ia):

[0096] [ka] or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the compound of formula (I) has formula (Ib):

[0098] [ka] or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the compound of Formula (I) has the formula (Ic):

[0100] [ka] or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the compound of formula (I) has the formula (Id):

[0102] [ka] or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, R 1 is H, F, or Cl. In some embodiments, R 1is H or F. In some embodiments, R 1 is H. In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I.

[0104] In some embodiments, R 5 is H or F. In some embodiments, R 5 is H. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is I.

[0105] In some embodiments, Y 1 and Y 2 is CR 9 In some embodiments, Y 1 is N and Y 2 is CR 9 In some embodiments, Y 1 is CR 9 and Y 2 is N. In some embodiments, Y 1 is N and Y 2 is N. In some embodiments, Y 1 and Y 2 is CH. In some embodiments, Y 1 is N and Y 2 is CH. In some embodiments, Y 1 is CH and Y 2 is N. In some embodiments, Y 1 is N and Y 2 is N.

[0106] In some embodiments, R 7 is C1-C4 alkyl. In some embodiments, R 7 is -CH3. In some embodiments, R7 is -CH2CH3. In some embodiments, R 7 is H.

[0107] In some embodiments, R 9 are each independently H, halogen, —CH, or —CF. In some embodiments, R 9 is H. In some embodiments, R 9 is a halogen. In some embodiments, R 9 is F. In some embodiments, R 9 is Cl. In some embodiments, R 9 is Br. In some embodiments, R 9 is I. In some embodiments, R 9 is unsubstituted C1-C4 alkyl. In some embodiments, R 9 is -CH3. In some embodiments, R 9 is —CF. In some embodiments, R 9 is a substituted or unsubstituted 2-6 membered heteroalkyl. In some embodiments, R 9 is -CN. In some embodiments, R 9 is -N(R 12 )2. In some embodiments, R 9 is -NH. In some embodiments, R 9 -OR 12 In some embodiments, R 9 is -OH.

[0108] In some embodiments, R 10 is H. In some embodiments, R 10 is -CH3.

[0109] In some embodiments, R 11 is H. In some embodiments, R 11 is -CH3.

[0110] In some embodiments, R 12 is H. In some embodiments, R 12is -CH3.

[0111] In some embodiments, R 13 is H. In some embodiments, R 13 is -CH3.

[0112] In some embodiments, R 14 is H. In some embodiments, R 14 is -CH3.

[0113] In some embodiments, R 15 is H. In some embodiments, R 15 is -CH3.

[0114] In some embodiments, the compound of Formula (I) has the structure:

[0115] [ka] or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the compound of Formula (I) has the structure:

[0117] [ka] or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the compound of Formula (I) has the structure:

[0119] [ka] or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, R 2 and R 3 are each independently substituted or unsubstituted alkyl. In some embodiments, R 2is -CH3 and R 3 is t-butyl.

[0121] In some embodiments, R 2 and R 3 together with the nitrogen to which they are attached form a substituted or unsubstituted 5-6 membered heterocycloalkyl. In the foregoing embodiment, the 5-6 membered heterocycloalkyl is independently selected from H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2-6 membered heteroalkyl, —C(═O)R 2c , -CN, -NH, or -OH; R 2c is a substituted or unsubstituted C1-C4 alkyl or a substituted or unsubstituted C3-C6 cycloalkyl. 2 and R 3 together with the nitrogen to which they are attached form a substituted or unsubstituted 7-membered heterocycloalkyl. In the foregoing embodiment, the 7-membered heterocycloalkyl is independently selected from H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2-6 membered heteroalkyl, —C(═O)R 2c , -CN, -NH, or -OH; R 2c is a substituted or unsubstituted C1-C4 alkyl or a substituted or unsubstituted C3-C6 cycloalkyl. 2 and R 3 along with the nitrogen to which they are attached,

[0122] [ka] wherein R 2a and R 2b are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, -C(=O)R2c , -CN, -NH2, or -OH, and R 2c is a substituted or unsubstituted C1-C4 alkyl or a substituted or unsubstituted C3-C6 cycloalkyl. 2 and R 3 along with the nitrogen to which they are attached,

[0123] [ka] wherein R 2a and R 2b are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2-6 membered heteroalkyl, -CN, -NH2, or -OH. 2 and R 3 along with the nitrogen to which they are attached,

[0124] [ka] wherein R 2a and R 2b are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, -C(=O)R 2c , -CN, -NH2, or -OH, and R 2c is a substituted or unsubstituted C1-C4 alkyl or a substituted or unsubstituted C3-C6 cycloalkyl.

[0125] In some embodiments, R 2a and R 2b are each —CH3. In some embodiments, R 2a is H and R 2b is -C(=O)R 2c and R 2cis CH, CHCH, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 2b teeth,

[0126] [ka] is.

[0127] In some embodiments, R 2c is unsubstituted C1-C4 alkyl. In some embodiments, R 2c is unsubstituted C-C cycloalkyl. In some embodiments, R 2c is -CH3, -CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 2c is -CH3. In some embodiments, R 2c is -CH2CH3. In some embodiments, R 2c is cyclopropyl. In some embodiments, R 2c is cyclobutyl. In some embodiments, R 2c is cyclopentyl. In some embodiments, R 2c is cyclohexyl.

[0128] In some embodiments, R 2 and R 3 along with the nitrogen to which they are attached,

[0129] [ka] In some embodiments, R 2 and R 3 along with the nitrogen to which they are attached,

[0130] [ka] Form.

[0131] In some embodiments, R4 is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0132] In some embodiments, R 4 is substituted or unsubstituted pyridinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted furazanyl.

[0133] In some embodiments, R 4 teeth,

[0134] [ka] where R 4a , R 4b , R 4c , R 4d , and R 4e are each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2-6 membered heteroalkyl, -CN, -NH2, or -OH. 4 teeth,

[0135] [ka] where R 4a , R 4b , R 4c , R 4d , and R 4eare each independently H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, —CN, —NH2, or —OH.

[0136] In some embodiments, R 4a and R 4b are each independently F, Cl, Br, I, or -CH3, and R 4c is H. In some embodiments, R 4a and R 4b are Cl and R 4c is H.

[0137] In some embodiments, R 4d and R 4e is H.

[0138] In some embodiments, R 4 teeth,

[0139] [ka] In some embodiments, R 4 teeth,

[0140] [ka] In some embodiments, R 4 teeth,

[0141] [ka] is.

[0142] In some embodiments, Z is C1-C6 alkylene. In some embodiments, Z is -CH2-. In some embodiments, Z is -CH2CH2-.

[0143] In some embodiments, Z is -C(=O)NH-, -NHC(=O)-, -O-, or -NHC(=O)NH-. In some embodiments, Z is -NHC(=O)- or -NHC(=O)NH-. In some embodiments, Z is C1-C6 alkylene. In some embodiments, Z is -C(=O)NR 10 In some embodiments, Z is -C(=O)NH-. In some embodiments, Z is -NR 10 In some embodiments, Z is -NHC(=O)-. In some embodiments, Z is -NR 10 In some embodiments, Z is -. In some embodiments, Z is -NH-. In some embodiments, Z is -O-. In some embodiments, Z is -S-. In some embodiments, Z is -S(=O)-. In some embodiments, Z is -SO2-. In some embodiments, Z is -NR 10 C(=O)NR 10 In some embodiments, Z is -NHC(=O)NH-. In some embodiments, Z is -CR 10 In some embodiments, Z is -CH=NO-.

[0144] In some embodiments, R 8 is H. In some embodiments, R 8 is -N(R 11 )2. In some embodiments, R 8 is -NH. In some embodiments, R 8 is F. In some embodiments, R 8 is Cl. In some embodiments, R 8 is Br. In some embodiments, R 8 is I. In some embodiments, R 8 -OR 11 In some embodiments, R 8 is -OH.

[0145] In some embodiments, R 6 is Cyclen, DO2A, DO3A, HP-DO3A, DO3A-Nprop, DO3AP, DO3APPrA , DO3AP ABn , DO3AM nBu , BT-DO3A, DOTA, DOTAGA, DOTA(GA)2, DOTAM, DOTA-4AMP, DOTMA, DOTP, CB-DO2A, DOTPA, DOTMP, DOTAMAP, TRITA, L py , cyclam, TETA, CB-Cyclam, CB-TE2A, TE2A, NOTA, NODAGA, NODA-MPAA, TACN, TACN-TM, NOTP, Sarcophagine (Sar), DiAmSar, SarAr, AmBaSar, cis-DO2A2P, trans-DO2A2P, DOTEP, p-NO2-Bn-DOTA, BAT, DO3TMP- Monoamide, CHX-A''-DTPA, c-DEPA, PCTA, p-NO2-Bn-PCTA, TRAP, TRAPH, TRAP-OH, TRAP-Ph, NOPO, AAZTA, DATAM, HEHA, PEPA, DTA, EDTMP, DTPMP, NTA, EDTA, DTPA, CyDTPA, DFO, DFO*, deferiprone, TTHA, HBED, HBED-CC, HBED-CC The chelating moiety is selected from the group consisting of TFP, H4pypa, H4py4pa, CP256, THP, YM103, t-Bu-calix[4]arene-tetracarboxylic acid, CHX-A″-DTPA, H6phospha, p-NH2-Bn-CHXA″-DTPA, DEDPA, H4octox, H4octapa, H4CHXoctapa, HYNIC, macropa, crown, macropid, HOPO, bis(2-mercaptoacetamide), bis(aminothiolate), or SBTG2DAP.

[0146] In some embodiments, R 6These are 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,7-diacetanoic acid (DO2A), α,α',α'',α'''-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM), 1 ,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA), 2,2',2''-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bn-DOTA), p-hydroxy-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-OH-Bn-DOTA), 6,6'-(((pyridine-2, 6-Diylbis(methylene))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4pypa), H4pypa-benzyl, 6,6',6'',6''''-(((pyridine-2,6-diylbis(methylene))-bis(azanetriyl))-tetrakis(methylene))-tetrapicolinic acid (H4py4pa), H4py4pa-benzyl, 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), 6,6'-((1,4,10,13-tetraoxa- 7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (macropa), 2,2',2'',2''''-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown), 6,6'-((ethane-1,2-diylbis((carboxymethyl)-azanediyl))bis(methylene))dipicolinic acid (H4octapa), H4octapa-benzyl, 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid (TTHA), or a radionuclide complex thereof.

[0147] In some embodiments, R 6These are 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,7-diacetanoic acid (DO2A), α,α',α'',α'''-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,1 0-Tetraazacyclododecane (DOTAM), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA), 2,2',2''-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, 6,6'-(((pyridine-2,6-diylbis(methylene))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4pypa), 6,6',6 '',6'''-(((pyridine-2,6-diylbis(methylene))bis(azanetriyl))-tetrakis(methylene))-tetrapicolinic acid (H4py4pa), 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (macropa), 2,2',2'',2'''-(1, In some embodiments, R is a chelating moiety selected from the group consisting of 10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown), 6,6'-((ethane-1,2-diylbis((carboxymethyl)-azanediyl))bis(methylene))dipicolinic acid (H4octapa), 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid (TTHA), or radionuclide complexes thereof. 6 is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a radionuclide complex thereof. 6is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) or a radionuclide complex thereof. 6 is 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A) or a radionuclide complex thereof. 6 is α,α',α'',α'''-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) or a radionuclide complex thereof. In some embodiments, R 6 is 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM) or a radionuclide complex thereof. 6 is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA) or a radionuclide complex thereof. 6 is 2,2',2''-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid or a radionuclide complex thereof. In some embodiments, R 6 is 6,6'-(((pyridine-2,6-diylbis(methylene))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4pypa) or a radionuclide complex thereof. In some embodiments, R 6 is 6,6',6'',6'''-(((pyridine-2,6-diylbis(methylene))bis(azanetriyl))-tetrakis(methylene))-tetrapicolinic acid (H4py4pa) or a radionuclide complex thereof. In some embodiments, R 6 is 2,2′,2″-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA). In some embodiments, R 6 is 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (macropa). In some embodiments, R 6is 2,2',2'',2'''-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown). In some embodiments, R 6 is 6,6'-((ethane-1,2-diylbis((carboxymethyl)-azanediyl))bis(methylene))dipicolinic acid (H4octapa) or a radionuclide complex thereof. In some embodiments, R 6 is 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid (TTHA) or its radionuclide complex.

[0148] In some embodiments, R 6 is a chelating moiety selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), or radionuclide complexes thereof.

[0149] In some embodiments, R 6 teeth,

[0150] [ka] or a radionuclide complex thereof.

[0151] In some embodiments, R 6 teeth,

[0152] [ka] or a radionuclide complex thereof.

[0153] In some embodiments, R 6 teeth,

[0154] [ka] or a radionuclide complex thereof.

[0155] In some embodiments, R 6 teeth,

[0156] [ka] or a radionuclide complex thereof.

[0157] In some embodiments, R 6 teeth,

[0158] [ka] or a radionuclide complex thereof.

[0159] In some embodiments, R 6 teeth,

[0160] [ka] or a radionuclide complex thereof.

[0161] Radionuclide complexes Radiopharmaceuticals are becoming very useful tools for physicians to diagnose, stage, treat, and monitor the progression of several diseases, especially cancer. The main difference between radiopharmaceuticals and other pharmaceutical drugs is that radiopharmaceuticals contain a radionuclide. The nuclear decay properties of the radionuclide determine whether the radiopharmaceutical is used clinically as a diagnostic or therapeutic agent. Diagnostic radiopharmaceuticals require a radionuclide that emits either gamma (γ) rays or positrons (β+), which subsequently annihilate with a nearby electron to produce two 511 keV annihilation photons emitted approximately 180° apart from each other. Gamma-emitting radionuclides (e.g., 99m Tc, 111 In, 201 Tl) are useful for single-photon emission computed tomography (SPECT), while positron-emitting radionuclides, e.g.18 F, 89 Zr, 68 Ga) are useful for positron emission tomography (PET).

[0162] In contrast, therapeutic radiopharmaceuticals require radionuclides that emit particulate radiation, such as alpha (α) particles, beta (β) particles, or Auger electrons, which interact strongly with target tissue (e.g., cancerous tumors) resulting in widespread localized ionization, which can damage chemical bonds in DNA molecules and potentially induce cytotoxicity.

[0163] In most nuclear medicine applications, it is desirable to pair a diagnostic radiopharmaceutical with a therapeutic radiopharmaceutical. This concept is commonly known as "theranostics." As a first step in the theranostics concept, a targeted molecule labeled with a diagnostic radionuclide is used to perform quantitative imaging of tumor imaging biomarkers by either positron emission tomography (PET) or single-photon emission computed tomography (SPECT). As a second step, it has been demonstrated that a tumor-destroying absorbed dose of radiation can be delivered to tumors or metastases by administering the same or a similar targeted molecule labeled with a therapeutic radionuclide.

[0164] In some embodiments, the chemical and pharmacokinetic behavior of diagnostic and therapeutic radiopharmaceuticals is matched. In some embodiments, the diagnostic and therapeutic radionuclides are chemically identical pairs of radioisotopes (also known as "matched pairs"). An example of a matched pair in theranostic radiopharmaceutical applications is 123 I / 131 I pair, in this case 123 I-labeled compounds are used in diagnostics, 131 I-labeled compounds are used in therapy. Other theranostic matching pairs, especially 44 Sc / 47 Sc, 64 Cu / 67 Cu, 72 As / 77 As,86 Y / 90 Y, and 203 Pb / 212 Alternatively, radionuclide pairs of different elements can be used for theranostic radiopharmaceutical development if their chemical properties are very similar (e.g., 99m Tc / 186 / 188 Re), there are no significant differences between diagnostic and therapeutic analogs in terms of pharmacokinetic behavior. Another example is 68 Ga / 177 Lu pair, in this case 68 Ga is used for diagnosis, 177 Lu is used in the treatment. For example, gastroenteropancreatic endocrine tumors express high amounts of sst2 receptors, which 68 Ga sst2 ligand conjugate ([ 68 Ga]Ga-DOTA-TATE (NETSPOT™) or [ 68 Diagnosis with ]Ga]Ga-DOTA-TOC (DOTA-(D-Phe1,Tyr3)-Octreotide, SomaKit TOC®) and subsequent internal radiotherapy 177 Lu sst2 ligand conjugate ([ 177 For purposes of treatment with [Lu]Lu-DOTA-TATE), somatostatin receptors can be targeted by somatostatin receptor scintigraphy.

[0165] Chelating moieties used in the formation of metal (radionuclide) complexes The compounds described herein comprise at least one R 6 group, R 6 is a chelating moiety capable of chelating a radionuclide (Z') or a radionuclide complex thereof. In some embodiments, any suitable group or atom of a chelator is used to connect to an FSHR targeting ligand via an optional linker.

[0166] In some embodiments, the chelator is capable of binding to the radioactive atom. In some embodiments, the binding is direct, e.g., the chelator undergoes hydrogen bonding or electrostatic interactions with the radioactive atom. In some embodiments, the binding is indirect, e.g., the chelator binds to a molecule that includes the radioactive atom. In some embodiments, the chelator is a macrocycle.

[0167] In some embodiments, the chelator comprises one or more amine groups. In some embodiments, the metal chelator comprises two or more amine groups. In some embodiments, the chelator comprises three or more amine groups. In some embodiments, the chelator comprises four or more amine groups. In some embodiments, the chelator comprises four or more N atoms, four or more carboxylic acid groups, or a combination thereof. In some embodiments, the chelator does not contain S. In some embodiments, the chelator comprises a ring. In some embodiments, the ring comprises O and / or N atoms. In some embodiments, the chelator is a ring containing three or more N atoms, three or more carboxylic acid groups, or a combination thereof. In some embodiments, the chelator is a multidentate, bidentate, or monodentate ligand. Multidentate ligands range in the number of atoms used to bind to the metal atom or ion. EDTA, a hexadentate ligand, is an example of a multidentate ligand, with six donor atoms with electron pairs available to bind to the central metal atom or ion. Bidentate ligands have two donor atoms that allow them to bond to a central metal atom or ion at two points. Ethylenediamine (en) and oxalate (ox) are examples of bidentate ligands.

[0168] In some embodiments, the chelating agents described herein comprise a cyclic chelating agent or an acyclic chelating agent. In some embodiments, the chelating agents described herein comprise a cyclic chelating agent. In some embodiments, the chelating agents described herein comprise an acyclic chelating agent.

[0169] In some embodiments, the chelating agents described herein include cyclen, DO2A, DO3A, HP-DO3A, DO3A-Nprop, DO3AP, DO3AP PrA , DO3AP ABn , DO3AM nBu , BT-DO3A, DOTA, DOTAGA, DOTA(GA)2, DOTAM, DOTA-4AMP, DOTMA, DOTP, CB-DO2A, DOTPA, DOTMP, DOTAMAP, TRITA, L py , cyclam, TETA, CB-Cyclam, CB-TE2A, TE2A, NOTA, NODAGA, NODA-MPAA, TACN, TACN-TM, NOTP, Sarcophagin (Sar), DiAmSar, SarAr, AmBaSar, cis-DO2A2P, trans-DO2A2P, DOTEP, p-NO2-Bn-DOTA, BAT, DO3TMP-monoamide, C HX-A''-DTPA, c-DEPA, PCTA, p-NO2-Bn-PCTA, TRAP, TRAPH, TRAP-OH, TRAP-Ph, NOPO, AAZTA, DATAM, HEHA, PEPA, DTA, EDTMP, DTPMP, NTA, EDTA, DTPA, CyDTPA, DFO, DFO*, deferiprone, TTHA, HBED, HBED-CC, HBED-CC Including TFP, H4pypa, H4py4pa, CP256, THP, YM103, t-Bu-calix[4]arene-tetracarboxylic acid, CHX-A''-DTPA, H6phospha, p-NH2-Bn-CHXA''-DTPA, DEDPA, H4octox, H4octapa, H4CHXoctapa, HYNIC, macropa, crown, macropid, HOPO, bis(2-mercaptoacetamide), bis(aminothiolate), or SBTG2DAP.

[0170] In some embodiments, the chelating agents described herein include DOTA, DOTAGA, DOTA(GA), NOTA, NODAGA, TRITA, TETA, DOTA-MA, HP-DO3A, DOTMA, DOTA-pNB, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP, DOTBzP, DOTA-monoamide, BAT, DO3TMP-monoamide, and CHX-A''-DTPA.

[0171] In some embodiments, the chelating agents described herein include DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, and BOPA.

[0172] In some embodiments, the chelating agents described herein include DOTA, DOTAGA, DOTA(GA)2, DOTP, DOTMA, DOTAM, DTPA, NTA, EDTA, DO3A, DO2A, NOC, NOTA, TETA, TACN, DiAmSar, CB-Cyclam, CB-TE2A, DOTA-4AMP, or NOTP.

[0173] In some embodiments, the chelating agents described herein are HP-DO3A, BT-DO3A, DO3A-Nprop, DO3AP, DO2A2P, DOA3P, DOTP, DOTPMB, DOTAMAE, DOTAMAP, DO3AM Bu , DOTMA, TCE-DOTA, DEPA, PCTA, p-NO2-Bn-PCTA, p-NO2-Bn-DOTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, TRAP, AAZTA, DATA m , THP, HEHA, HBED, or HBED-CC TFP.

[0174] In some embodiments, the chelating agent described herein is selected from the group consisting of DOTA, NOTA, NODAGA, DOTAGA, HBED, HBED-CC TFP, H2DEPDPA, DFO-B, deferiprone, CP256, YM103, TETA, CB-TE2A, TE2A, Sar, DiAmSar, TRAPH, TRAP-Pr, TRAP-OH, TRAP-Ph, NOPO, DEADPA, PCTA, EDTA, PEPA, HEHA, DTPA, EDTMP, AAZTA, DO3AP, DO3AP PrA , DO3AP ABn , or DOTAM.

[0175] In some embodiments, the chelators described herein are or include DOTA, HBED-CC, DOTAGA, DOTA(GA)2, NOTA, and DOTAM. In some embodiments, the chelators described herein are or include NODAGA, NOTA, DOTAGA, DOTA(GA)2, TRAP, NOPO, NCTA, DFO, DTPA, and HYNIC.

[0176] In some embodiments, the chelator comprises a macrocycle, e.g., a macrocycle containing O and / or N atoms, DOTA, HBED-CC, DOTAGA, DOTA(GA)2, NOTA, DOTAM, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTPA, TETA, DO3A, PCTA, or desferrioxane.

[0177] In some embodiments, the metal chelators described herein have the structure:

[0178] [ka]

[0179] [ka]

[0180] [ka]

[0181] [ka]

[0182] [ka]

[0183] [ka]

[0184] [ka] Contains one of the following.

[0185] In some embodiments, the chelating moiety R 6 comprises a radionuclide and DOTA. In some embodiments, the chelating moiety R 6 comprises a radionuclide and a DOTA derivative. In some embodiments, the chelating moiety comprises two independent chelators, at least one or both of which is DOTA.

[0186] In some embodiments, the chelating moiety comprises a radionuclide and a chelator configured to bind to the radionuclide (Z'), and the chelator comprises DOTA, DOTP, DOTMA, DOTAM, DTPA, NOTA, NTA, NODAGA, EDTA, DO3A, DO2A, NOC, TETA, CB-TE2A, DiAmSar, CB-Cyclam, DOTA-4AMP, H4pypa, H4octox, H4octapa, p-NO2-Bn-neunpa, or NOTP.

[0187] In some embodiments, the metal chelators described herein include macropa or crown. In some embodiments, the metal chelators described herein include macropa. In some embodiments, the metal chelators described herein include crown. In some embodiments, the metal chelators described herein include

[0188] [ka] Includes:

[0189] In some embodiments, the metal chelators described herein are

[0190] [ka] Includes:

[0191] In some embodiments, R 6These include 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,7-diacetinoic acid (DO2A), α,α',α'',α'''-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM), 1, 4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA), 2,2',2''-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bn-DOTA), p-hydroxy-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-OH-Bn-DOTA), 6,6'-(((pyridine-2,6 -diylbis(methylene))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4pypa), H4pypa-benzyl, 6,6',6'',6''''-(((pyridine-2,6-diylbis(methylene))-bis(azanetriyl))-tetrakis(methylene))-tetrapicolinic acid (H4py4pa), H4py4pa-benzyl, 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), 6,6'-((1,4,10,13-tetraoxa-7, 16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (macropa), 2,2',2'',2''''-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown), 6,6'-((ethane-1,2-diylbis((carboxymethyl)-azanediyl))bis(methylene))dipicolinic acid (H4octapa), H4octapa-benzyl, and 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,In some embodiments, R, is a chelating moiety selected from the group consisting of 12-tetraazattetradecanedioic acid (TTHA), or a radionuclide complex thereof. 6 is a chelating moiety selected from the group consisting of DOTA and DO3A, or radionuclide complexes thereof.

[0192] In some embodiments, R 6 teeth,

[0193] [ka] or a radionuclide complex thereof. 6 teeth,

[0194] [ka] or a radionuclide complex thereof. In some embodiments, R 6 teeth,

[0195] [ka] or a radionuclide complex thereof.

[0196] In some embodiments, R 6 teeth,

[0197] [ka] or a radionuclide complex thereof. In some embodiments, R 6 teeth,

[0198] [ka] or a radionuclide complex thereof.

[0199] In some embodiments, R 6 teeth,

[0200] [ka] where Z' is a diagnostic or therapeutic radionuclide.

[0201] In some embodiments, R 6 teeth,

[0202] [ka] where Z' is a diagnostic or therapeutic radionuclide.

[0203] In some embodiments, Z' is an Auger electron-emitting radionuclide, an α-emitting radionuclide, a β-emitting radionuclide, or a γ-emitting radionuclide. In some embodiments, Z' is 111-indium ( 111 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 99m-technetium ( 99m Tc), or 195m-Platinum ( 195m In some embodiments, Z' is an Auger electron emitting radionuclide that is 225-actinium (Pt). 225 Ac), 213-Bismuth ( 213 Bi), 223-radium ( 223 Ra), or 212-lead ( 212 In some embodiments, Z' is an α-emitting radionuclide that is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), iodine-131( 131 I), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 64-Copper( 64 Cu), 67-copper ( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Kin ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium (165 Dy), 99m-Technetium ( 99m Tc), 89-zirconium ( 89 Zr), and h52-manganese ( 52 In some embodiments, Z' is a β-emitting radionuclide that is 60-cobalt ( 60 Co), 103-palladium ( 103 Pd), 137-Cesium ( 137 Cs), 169-ytterbium ( 169 Yb), 192-iridium ( 192 Ir), or 226-radium ( 226 Ra) is a gamma-emitting radionuclide.

[0204] In some embodiments, R 6 comprises a radionuclide (Z') and a chelator configured to bind to the radionuclide (Z'), wherein the radionuclide is suitable for positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI). In some embodiments, the radionuclide is copper-64 ( 64 Cu), Gallium-68( 68 Ga), 111-Indium ( 111 In), or technetium-99m ( 99m Tc).

[0205] Metals (radionuclides) In some embodiments, Z' is an Auger electron-emitting radionuclide. In some embodiments, Z' is an α-emitting radionuclide. In some embodiments, Z' is a β-emitting radionuclide. In some embodiments, Z' is a γ-emitting radionuclide. In some embodiments, the type of radionuclide used in a non-peptide targeted therapy compound can be tailored to the specific type of cancer, the type of targeting moiety (e.g., a non-peptide ligand), etc. A radionuclide undergoing α decay releases an α particle (a helium ion with a +2 charge) from its nucleus. As a result of α decay, the daughter nuclide has two fewer protons and two fewer neutrons than the parent nuclide. This means that the number of protons is reduced by two and the number of neutrons is reduced by four in α decay. A radionuclide undergoing β decay releases a β particle (an electron) from its nucleus. During β decay, one of the neutrons is transformed into a proton and an electron. The proton remains in the nucleus, while the electron is released as the β particle. This means that in beta decay, the nucleus loses a neutron but gains a proton. In gamma decay, a nucleus in an excited (high-energy) state emits a gamma ray and changes to a lower-energy state. The number of protons and neutrons remains the same during gamma decay. The emission of a gamma ray is often accompanied by the emission of an alpha particle and a beta particle.

[0206] Auger electrons (AE) are very low energy electrons emitted by radionuclides that decay by electron capture (EC) (e.g., 111 In, 67 Ga, 99m Tc, 195m Pt, 125 I, and 123 I). This energy is deposited over distances of nanometers to micrometers, resulting in a high linear energy transfer that is effective in causing lethal damage to cancer cells. Therefore, AE-emitting radiotherapeutic agents have great potential for cancer treatment.

[0207] Beta particles are electrons emitted from the nucleus. These typically have a long range in tissue (about 1-5 mm) and are the most frequently used.

[0208] Alpha particles are helium nuclei (two protons and two neutrons) emitted from the nuclei of radioactive atoms. They can travel 50–100 μm in tissue, depending on the energy emitted. They are positively charged and orders of magnitude greater than electrons. The amount of energy deposited per path length of an alpha particle (termed "linear energy transfer") is approximately 400 times greater than that of an electron. This results in substantially more damage along the path than that caused by an electron. The trajectory of an alpha particle results in a large number of complex and largely irreparable DNA double-strand breaks. The absorbed dose required to achieve cytotoxicity is related to the number of alpha particles traversing the cell nucleus. On this basis, cytotoxicity can be achieved with 1–20 alpha particles traversing the cell nucleus. The resulting high potency, combined with the short range of alpha particles (which reduces normal organ toxicity), has generated significant interest in the development of alpha particle-emitting drugs. Typically used alpha particle emitters include bismuth-212, lead-212, bismuth-213, actinium-225, radium-223, and thorium-227.

[0209] In some embodiments, Z' is a diagnostic or therapeutic radionuclide.

[0210] [Table 1]

[0211] In some embodiments, Z' is an Auger electron emitting radionuclide. In some embodiments, Z' is 111-indium ( 111 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 99m-technetium ( 99m Tc), or 195m-Platinum ( 195m Pt) is an Auger electron-emitting radionuclide.

[0212] In some embodiments, Z' is an α-emitting radionuclide. In some embodiments, Z' is 225-actinium ( 225Ac), 213-Bismuth ( 213 Bi), 223-radium ( 223 Ra), or 212-lead ( 212 Pb) is an α-emitting radionuclide.

[0213] In some embodiments, Z' is a β-emitting radionuclide. In some embodiments, Z' is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 64-Copper( 64 Cu), 67-copper ( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Kin ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium ( 165 Dy), 99m-Technetium ( 99m Tc), 89-zirconium ( 89 Zr), or 52-manganese ( 52 Mn) is a β-emitting radionuclide.

[0214] In some embodiments, Z' is a γ-emitting radionuclide. In some embodiments, Z' is 60-cobalt ( 60 Co), 103-palladium ( 103 Pd), 137-Cesium ( 137 Cs), 169-ytterbium ( 169 Yb), 192-iridium ( 192 Ir), or 226-radium ( 226 Ra) is a gamma-emitting radionuclide.

[0215] In some embodiments, Z' is 111-indium ( 111 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 99m-technetium ( 99m Tc), or 195m-Platinum ( 195mZ' is an Auger electron emitting radionuclide that is 225-actinium (Pt) or Z' is 225-actinium ( 225 Ac), 213-Bismuth ( 213 Bi), 223-radium ( 223 Ra), or 212-lead ( 212 Pb), or Z' is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 64-Copper( 64 Cu), 67-copper ( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Kin ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium ( 165 Dy), 99m-Technetium ( 99m Tc), 89-zirconium ( 89 Zr), or 52-manganese ( 52 Mn), and Z' is 60-Cobalt ( 60 Co), 103-palladium ( 103 Pd), 137-Cesium ( 137 Cs), 169-ytterbium ( 169 Yb), 192-iridium ( 192 Ir), or 226-radium ( 226 Ra) is a gamma-emitting radionuclide.

[0216] In some embodiments, Z' is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 67-Copper( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Kin ( 198 Au), 169-Erbium (169 Er), 165-dysprosium ( 165 Dy), or technetium-99m ( 99m Tc).

[0217] In some embodiments, Z' is 94 Tc, 90 In, 111 In, 67 Ga, 68 Ga, 86 Y, 90 Y, 177 Lu, 161 Tb, 186 Re, 188 Re, 64 Cu, 67 Cu, 55 Co, 57 Co, 43 Sc, 44 Sc, 47 Sc, 225 Ac, 213 Bi, 212 Bi, 212 Pb, 227 Th, 153 Sm, 166 Ho, 152 Gd, 153 Gd, 157 Gd, and 166 Dy.

[0218] In some embodiments, Z' is 67 Cu, 64 Cu, 90 Y, 109 Pd, 111 Ag, 149 Pm, 153 Sm, 166 Ho, 99m Tc, 67 Ga, 68 Ga, 111 In, 90 Y, 177 Lu, 186 Re, 188 Re, 197 Au, 198 Au, 199 Au, 105 Rh, 165 Ho, 161Tb, 149 Pm, 44 Sc, 47 Sc, 70 As, 71 As, 72 As, 74 As, 76 As, 77 As, 212 Pb, 212 Bi, 213 Bi, 225 Ac, 117m Sn, 67 Ga, 201 Tl, 160 Gd, 148 Nd, and 89 Sr.

[0219] In some embodiments, Z' is 68 Ga, 43 Sc, 44 Sc, 47 Sc, 177 Lu, 161 Tb, 225 Ac, 213 Bi, 212 Bi, or 212 In some embodiments, Z' is 67 Ga, 99m Tc, 111 In, or 201 It is Tl.

[0220] Exemplary Chelators and Radionuclide Complexes Radionuclides are used in single photon emission computed tomography (SPECT, e.g. 67 Ga, 99m Tc, 111 In, 177 Lu) and positron emission tomography (PET, e.g., 68 Ga, 64 Cu, 44 Sc, 86 Y, 89 Zr) as well as for other diagnostic imaging techniques, as well as for therapeutic applications (e.g. 47 Sc, 114 mIn, 177 Lu, 90 Y, 212 / 213 Bi, 212Pb, 225 Ac, 186 / 188 They have useful release properties that allow them to be used for radiometals (Re). The fundamental component of radiometal-based radiopharmaceuticals is a chelator, i.e., a ligand system that binds to the radiometal ion in a tight and stable coordination complex so that it can be appropriately directed to the desired molecular target in vivo. The art provides guidance for selecting the optimal match between chelator and radiometal for a particular application (see, for example, Price et al., "Matching chelators to radiometals for radiopharmaceuticals," Chem. Soc. Rev., 2014, 43, pp. 260-290).

[0221] In some embodiments, R 6 is a chelating moiety selected from the group consisting of DOTA, DO3A, DO2A, DOTMA, DOTAM, DOTPA, Bn-DOTA, p-OH-Bn-DOTA, H4pypa, H4pypa-benzyl, H4py4pa, H4py4pa-benzyl, H4octapa, H4octapa-benzyl, and TTHA, or radionuclide complexes thereof.

[0222] In some embodiments, R 6 teeth,

[0223] [ka] where Z' is a diagnostic or therapeutic radionuclide.

[0224] In some embodiments, the radionuclide (Z') is 111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 70-gallium ( 70 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu), or 177-lutetium (177 Lu).

[0225] In some embodiments, the radionuclide (Z') is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 186-rhenium ( 186 Re), 188-rhenium ( 188 Re), 67-Copper( 67 Cu), 153-Samarium ( 153 Sm), 89-strontium ( 89 Sr), 198-Kin ( 198 Au), 169-Erbium ( 169 Er), 165-dysprosium ( 165 Dy), or technetium-99m ( 99m Tc).

[0226] Emission tomography In some embodiments, R 6 comprises a chelated radionuclide suitable for positron emission tomography (PET) analysis or single photon emission computed tomography (SPECT). 6 comprises a chelated radionuclide suitable for single photon emission computed tomography (SPECT). 6 comprises a chelated radionuclide suitable for positron emission tomography (PET) analysis. In some embodiments, R 6 comprises a chelated radionuclide suitable for positron emission tomography imaging, positron emission tomography including computed tomography imaging, or positron emission tomography including magnetic resonance imaging (MRI).

[0227] In some embodiments, R 6is a chelating moiety selected from the group consisting of DOTA, DO3A, DO2A, DOTMA, DOTAM, DOTPA, Bn-DOTA, p-OH-Bn-DOTA, H4pypa, H4pypa-benzyl, H4py4pa, H4py4pa-benzyl, H4octapa, H4octapa-benzyl, and TTHA, or radionuclide complexes thereof. In some embodiments, the radionuclide is copper-64 (64Cu), gallium-68 ( 68 Ga), or technetium-99m ( 99m Tc).

[0228] In some embodiments, the conjugates described herein are designed to have a defined elimination profile. The elimination profile can be designed by adjusting the sequence and length of the non-peptide ligand, the properties of the linker, the type of radionuclide, etc. In some embodiments, the conjugate has an elimination half-life of about 5 minutes to about 12 hours. In some embodiments, the conjugate has an elimination half-life of about 10 minutes to about 8 hours. In some embodiments, the conjugate has an elimination half-life of at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, or at least about 8 hours. In some embodiments, the conjugate has an elimination half-life of at most about 15 minutes, at most about 30 minutes, at most about 1 hour, at most about 2 hours, at most about 3 hours, at most about 4 hours, at most about 5 hours, at most about 6 hours, or at most about 8 hours. In some embodiments, the elimination half-life is determined in mice. In some embodiments, the elimination half-life is determined in humans.

[0229] The conjugates described herein can have an elimination half-life in tumor and non-tumor tissues of a subject. The elimination half-life in a tumor can be the same as or different from (longer or shorter than) the elimination half-life in a non-tumor tissue. In some embodiments, the elimination half-life of the conjugate in a tumor is from about 15 minutes to about 1 day. In some embodiments, the elimination half-life of the conjugate in a tumor is at least 1.1 times, at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 2.0 times, at least 2.5 times, at least 3.0 times, at least 4.0 times, or at least 5.0 times the elimination half-life of the conjugate in a non-tumor tissue of the subject.

[0230] As used herein, "elimination half-life" may refer to the time from maximum concentration to half maximum concentration after administration. In some embodiments, the elimination half-life is determined after intravenous administration. In some embodiments, the elimination half-life is measured as the biological half-life, which is the half-life of the pharmaceutical in a biological system. In some embodiments, the elimination half-life is measured as the effective half-life, which is the half-life of the radiopharmaceutical in a biological system taking into account the half-life of the radionuclide.

[0231] Prediction of response and toxicity is essential for the rational implementation of cancer treatment. The biological effects of radionuclide therapy are mediated by a well-defined physical quantity, the absorbed dose (D), defined as the energy absorbed per unit mass of tissue.

[0232] Radiation dosimetry is the measurement, calculation, and assessment of the amount of ionizing radiation absorbed by an object, usually the human body, and may also be thought of as the ability to perform real-time equivalent pharmacodynamic testing on treated patients. This can be applied internally due to inhaled radioactive material or externally due to radiation from a radioactive source. Dosimetry analysis may be performed as part of a patient treatment to calculate the absorbed dose to tumor versus normal organs, and from there, the likelihood of treatment success.

[0233] The conjugates described herein have a time-integrated activity coefficient defined for tumor or non-tumor tissue of interest.

[0234] [ka] The a value of (a) can be determined using methods known in the art. In some embodiments, the a value of the conjugate in the tumor is from about 10 minutes to about 1 day. The a value of the conjugate in the tumor can be the same as the a value of the conjugate in the non-tumor tissue of the subject. The a value of the conjugate in the tumor can be longer or shorter than the a value of the conjugate in the non-tumor tissue of the subject. In some embodiments, the a value of the conjugate in the tumor is at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 2.0-fold, at least 2.5-fold, at least 3.0-fold, at least 4.0-fold, or at least 5.0-fold the a value of the conjugate in the non-tumor tissue of the subject.

[0235] The conjugates described herein can have an a value in an organ of a subject. In some embodiments, the conjugate has an a value of up to 24 hours in the kidney of a subject. In some embodiments, the a value of the conjugate in the kidney of a subject is up to 18 hours, 15 hours, 12 hours, 10 hours, 8 hours, 6 hours, or 5 hours. In some embodiments, the a value of the conjugate in the kidney of a subject is from about 30 minutes to about 24 hours. In some embodiments, the a value of the conjugate in the kidney of a subject is from about 2 to 24 hours. In some embodiments, the a value of the conjugate in the kidney of a subject is longer than about 24 hours. In some embodiments, the a value of the conjugate in the liver of a subject is up to 24 hours. In some embodiments, the a value of the conjugate in the liver of a subject is up to 18 hours, 15 hours, 12 hours, 10 hours, 8 hours, 6 hours, or 5 hours. In some embodiments, the a value of the conjugate in the liver of a subject is from about 30 minutes to about 24 hours. In some embodiments, the a value of the conjugate in the liver of a subject is from about 2 to 24 hours. In some embodiments, the a value of the conjugate in the liver of the subject is greater than about 24 hours.

[0236] Linker In some embodiments, the linker has a defined length, thereby providing a link between the follicle-stimulating hormone receptor (FSHR) targeting ligand and the chelating moiety or its radionuclide complex (R 6 ) while allowing for an appropriate distance between them.

[0237] In some embodiments, the linker is flexible. In some embodiments, the linker is rigid.

[0238] In some embodiments, the linker comprises a linear structure. In some embodiments, the linker comprises a non-linear structure. In some embodiments, the linker comprises a branched structure. In some embodiments, the linker comprises a cyclic structure.

[0239] In some embodiments, the linker comprises one or more linear structures, one or more non-linear structures, one or more branched structures, one or more cyclic structures, one or more flexible portions, one or more rigid portions, or a combination thereof.

[0240] In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. In some embodiments, one or more amino acids of the linker are unnatural amino acids.

[0241] In some instances, the linker comprises a peptide bond. The peptide bond may comprise an L-amino acid and / or a D-amino acid. In some embodiments, D-amino acids are preferred to minimize immune and non-specific cleavage by background peptidases or proteases. The cellular uptake of oligo-D-arginine sequences is known to be equal to or better than that of oligo-L-arginine.

[0242] In some embodiments, the linker is 1 to 100 atoms, 1 to 50 atoms, 1 to 30 atoms, 1 to 20 atoms, 1 to 15 atoms, 1 to 10 atoms, or 1 to 5 atoms in length. In some embodiments, the linker is 1 to 10 atoms in length. In some embodiments, the linker is 1 to 20 atoms in length.

[0243] In some embodiments, a linker can comprise flexible and / or rigid regions. Exemplary flexible linker regions include those comprising Gly and Ser residues ("GS" linkers), glycine residues, alkylene chains, PEG chains, etc. Exemplary rigid linker regions include those comprising alpha-helix-forming sequences, proline-rich sequences, and regions rich in double and / or triple bonds.

[0244] In some embodiments, the cleavable linker comprises one or more of substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and substituted or unsubstituted heteroarylene.

[0245] In some embodiments, the linker comprises a click chemistry residue. In some embodiments, the linker is coupled to the non-peptide ligand, the metal chelator, or both via click chemistry. For example, in some embodiments, the non-peptide ligand comprises an azide group that reacts with an alkyne moiety of the linker. For another example, in some embodiments, the non-peptide ligand comprises an alkyne group that reacts with the azide of the linker. The metal chelator and the linker can be coupled in a similar manner. In some embodiments, the linker comprises an azide moiety, an alkyne moiety, or both. In some embodiments, the linker comprises a triazole moiety.

[0246] In some embodiments, L 1 -L 2 -, -L 3 -, -L 4 -, -L 5 -, -L 6 -, -L 7 -, -L 2 -L 3 -, -L 2 -L 4 -, -L 2 -L 7 -, -L 4 -L 6 -, -L 4 -L 7 -, -L 6 -L 7 -, -L 2 -L 4 -L 7 -, -L 2 -L 5 -L 7 -, -L 2 -L 6 -L 7 -, -L 3 -L 4 -L 7-, -L 4 -L 5 -L 7 - or -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 - or a combination thereof, L 2 is absent or is a substituted or unsubstituted C1-C 20 Alkylene, substituted or unsubstituted C1-C 20 Alkylene-NR 13 -, substituted or unsubstituted C1-C 20 Alkylene-C(=O)-, substituted or unsubstituted C1-C 20 Alkylene-C(=O)NH-, substituted or unsubstituted C1-C 20 Alkylene-NR 13 C(=O)-, substituted or unsubstituted 2- to 20-membered heteroalkylene, -(CH2CH2O) z -, -(OCH2CH2) z -, -(CH2CH2O) w -CH2CH2-, -CH2CH2NR 13 -(CH2CH2O) w -, -(CH2CH2O) w -CH2CH2NR 13 -, -CH2CH2NR 13 C(=O)-(CH2CH2O) w , -(CH2CH2O) w -CH2CH2NR 13 C(=O)-, -CH2CH2C(=O)NR 13 -(CH2CH2O) w -, -CH2CH2NR 13 C(=O)CH2-(OCH2CH2) w , or -(CH2CH2O) w -CH2CH2C(=O)NH-, w is 1, 2, 3, 4, 5, or 6, z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and L 3is a peptide formed from a non-existent, natural or unnatural amino acid, or two or more independently selected natural and unnatural amino acids, where, when two or more amino acids are present, the N atom of the amide linking the amino acids is optionally substituted with C1-C6 alkyl; and L 4 is absent or a substituted or unsubstituted 2- to 10-membered heteroalkylene, -CH2-(OCH2CH2) v -, -(CH2CH2O) v -CH2CH2-, -(CH2CH2O) v CH2CH2NR 14 C(=O)(CH2CH2O) v CH2CH2-, -(CH2CH2O) v CH2CH2C(=O)NR 14 (CH2CH2O) v CH2CH2-, -C(=O)CH2CH2, -CH2CH2C(=O)-, or independently -OH, -NR 14 2. -CO2R 14 , -O(CH2CH2O) u -CH3, -NR 14 (CH2CH2O) u -CH3, -NR 14 C(=O)(CH2CH2O) u -CH3 or -CH2OCH2CH2CO2R 14 wherein each instance of v is independently 1, 2, 3, 4, 5, or 6; u is 1, 2, 3, 4, 5, or 6; and L 5 is absent or -O-, -S-, -S(=O)-, -S(=O)2, -NR 15 -, -CH(=NH)-, -CH(=N-NH)-, -CCH3(=NH)-, -CCH3(=N-NH)-, -C(=O)NR 15 -, -NR 15 C(=O), -NR 15 C(=O)O-, -NR 15 C(=O)NR 15 - or -OC(=O)NR 15 - and L 6 does not exist or -L8 -L 9 -L 10 - and L 8 does not exist or -(CH2) t -, -NR w -, -NR w -(CH2) t -, -(CH2) t -C(=O)-, -C(=O)-(CH2) t -, -(CH2) t -NR w -, -(CH2) t -NR w C(=O)-, -(CH2) t -C(=O)NR w -, -CH(NHR w )-(CH2) t -C(=O)-, -NR w C(=O)-(CH2) t - and -C(=O)NR w -(CH2) t where t is 0, 1, 2, or 3, and L 10 does not exist or -(CH2) r -, -NR w -, -NR w -(CH2) r -, -(CH2) r -C(=O)-, -C(=O)-(CH2) r -, -(CH2) r -NR w -, -(CH2) r -NR w C(=O)-, -(CH2) r -C(=O)NR w -, -CH(NHR w )-(CH2) r -C(=O)-, -NR w C(=O)-(CH2) r - and -C(=O)NR w -(CH2) r and r is 0, 1, 2, or 3; R w are each independently H, C1-C6 alkyl, C1-C6 alkyl-CO2H, -(CH2CH2O) s -CH3, -C(=O)-(CH2CH2O)s -CH3, or -(CH2CH2O) s -CH2CH2CO2H, s is 1, 2, 3, 4, 5, or 6, and L 9 is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R 13 , R 14 , and R 15 are each independently selected from H or unsubstituted C1-C4 alkyl; L 7 is absent, -NH-, -N(CH3)-, -O-NH-, or substituted or unsubstituted N-heterocycloalkylene, or -O-NH=(substituted or unsubstituted N-heterocycloalkylene).

[0247] In some embodiments, L 1 -L 2 -, -L 3 -, -L 4 -, -L 5 -, -L 6 -, -L 7 -, -L 2 -L 3 -, -L 2 -L 4 -, -L 2 -L 6 -, -L 2 -L 7 -, -L 4 -L 6 -, -L 4 -L 7 -, -L 6 -L 7 -, -L 2 -L 4 -L 7 -, -L 2 -L 5 -L 7 -, -L 2 -L 6 -L 7 -, -L 3 -L 4 -L 7 -, -L 3 -L 5 -L 7 - or -L2 -L 3 -L 4 -L 5 -L 6 -L 7 - or a combination thereof, L 2 is absent or is a substituted or unsubstituted C1-C 20 Alkylene, substituted or unsubstituted C1-C 20 Alkylene-NH-, substituted or unsubstituted C1-C 20 Alkylene-C(=O)-, substituted or unsubstituted C1-C 20 Alkylene-C(=O)NH-, substituted or unsubstituted C1-C 20 Alkylene -NHC(=O)-, substituted or unsubstituted 2- to 20-membered heteroalkylene, -(CH2CH2O) z -, -(OCH2CH2) z -, -(CH2CH2O) w -CH2CH2-, -CH2CH2NH-(CH2CH2O) w -, -(CH2CH2O) w -CH2CH2NH-, -CH2CH2NHC(=O)-(CH2CH2O) w , -(CH2CH2O) w -CH2CH2NHC(=O)-, -CH2CH2C(=O)NH-(CH2CH2O) w -, -CH2CH2NHC(=O)CH2-(OCH2CH2) w , or -(CH2CH2O) w -CH2CH2C(=O)NH-, and L 3 is a peptide formed from a non-existent, natural or unnatural amino acid, or one or more independently selected natural and unnatural amino acids, wherein, when more than one amino acid is present, the N atom of the amide linking the amino acid is optionally substituted with C1-C6 alkyl; and L 4 is -CH2-(OCH2CH2) v -, -(CH2CH2O) v -CH2CH2-, -(CH2CH2O) v CH2CH2NHC(=O)(CH2CH2O) v CH2CH2-, -(CH2CH2O) vCH2CH2C(=O)NH(CH2CH2O) v CH2CH2-, -C(=O)CH2CH2, -CH2CH2C(=O)-, or independently -OH, -NH2, -CO2H, -O(CH2CH2O) u -CH3, -NH(CH2CH2O) u -CH3, -NHC(=O)(CH2CH2O) u C1-C6 alkylene optionally substituted with one or two groups selected from -CH3, and -CH2OCH2CH2CO2H; L 5 is absent, -C(=O)NH-, or -NHC(=O)-, and L 6 does not exist or -L 8 -L 9 -L 10 - and L 8 does not exist or -(CH2) t -, -NR w -(CH2) t -, -(CH2) t -C(=O)-, -C(=O)-(CH2) t -, -(CH2) t -NR w -, -(CH2) t -NR w C(=O)-, -(CH2) t -C(=O)NR w -, -CH(NHR w )-(CH2) t -C(=O)-, -NR w C(=O)-(CH2) t - and -C(=O)NR w -(CH2) t - and L 10 is absent or -(CH2) r and r is 0, 1, 2, or 3; R w are each independently H, C1-C6 alkyl, C1-C6 alkylCO2H, -(CH2CH2O)-CH3, -C(=O)-(CH2CH2O) s -CH3, or -(CH2CH2O) s -CH2CH2CO2H, L 9is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; L 7 is absent, -NH-, -N(CH3)-, -O-NH-, substituted or unsubstituted N-heterocycloalkylene, or -O-NH=(substituted or unsubstituted N-heterocycloalkylene).

[0248] In some embodiments, L 1 -L 2 -or-L 2 -L 7 In some embodiments, L 1 -L 2 In some embodiments, L 1 -L 2 -L 7 -It is.

[0249] In some embodiments, L 1 -L 3 -or-L 2 -L 3 In some embodiments, L 1 -L 3 In some embodiments, L 1 -L 2 -L 3 -It is.

[0250] In some embodiments, L 2 is a substituted or unsubstituted C1-C6 alkylene-C(=O)-, and L 3 is a peptide formed from one or more independently selected natural or unnatural amino acids.

[0251] In some embodiments, L 2 In some embodiments, L 2 is -CH- or -CHCH-. In some embodiments, L 2 is -CH-. In some embodiments, L 2 is a substituted or unsubstituted C1-C 20Alkylene-NH-, substituted or unsubstituted C1-C 20 Alkylene-C(=O)-, substituted or unsubstituted C1-C 20 Alkylene-C(=O)NH- or substituted or unsubstituted C-C 20 In some embodiments, L is alkylene-NHC(=O)-. 2 is -(CH2CH2O) w -CH2CH2-, -(CH2CH2O) w -CH2CH2NH-, -CH2CH2NHC(=O)-(CH2CH2O) w -, -(CH2CH2O) w -CH2CH2NHC(=O)-, -CH2CH2C(=O)NH-(CH2CH2O) w - or -CH2CH2NHC(=O)CH2-(OCH2CH2) w In some embodiments, —(CHCHO) w -CH2CH2- or -(CH2CH2O) w In some embodiments, L 2 is a substituted or unsubstituted C1-C 20 In some embodiments, L is alkylene-NH-. 2 is a substituted or unsubstituted C1-C 20 In some embodiments, L is alkylene-C(=O)-. 2 is a substituted or unsubstituted C1-C 20 In some embodiments, L is alkylene -C(=O)NH-. 2 is a substituted or unsubstituted C1-C 20 In some embodiments, L is alkylene-NHC(=O)-. 2 is -(CH2CH2O) w In some embodiments, L 2 is -(CH2CH2O) w In some embodiments, L 2 is -CH2CH2NHC(=O)-(CH2CH2O) w In some embodiments, L 2 is -(CH2CH2O) wIn some embodiments, L 2 is -CH2CH2C(=O)NH-(CH2CH2O) w In some embodiments, L 2 is -CH2CH2NHC(=O)CH2-(OCH2CH2) w -It is.

[0252] In some embodiments, L 3 In some embodiments, L 3 is a peptide formed from natural amino acids, unnatural amino acids, or two or more independently selected amino acids selected from the group consisting of alanine (Ala), arginine (Arg), asparagine (Asn), aspartate (Asp), cysteine ​​(Cys), cysteic acid, glutamine (Gln), glutamate (Glu), glycine (Gly), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), sarcosine, tyrosine (Tyr), and valine (Val), wherein, when two or more amino acids are present, the N atom of the amide linking the amino acids is optionally substituted with —CH3. In some embodiments, the peptide is formed from one or more independently selected L-amino acids. In some embodiments, the peptide is formed from one or more independently selected D-amino acids. In some embodiments, the peptide is formed from one or more independently selected L-amino acids and one or more independently selected D-amino acids.

[0253] In some embodiments, L 3 is cysteic acid. In some embodiments, L 3 is aspartic acid. In some embodiments, L 3 is glutamic acid. In some embodiments, L 3 is sarcosine. In some embodiments, L 3 is di-sarcosine. In some embodiments, L 3 is penta-sarcosine.

[0254] In some embodiments, L 3 is a peptide that is Ala-Lys-Ser-Asn-Asn-Ser-Ala-NH2, Ala-Ser-Asn-Lys-Asn-Ser-Ala-NH2, Ala-Ser-Asn-Asn-Ser-Lys-Ala-NH2, Ala-Arg-Arg-Lys-Glu-Glu-Glu-NH2, or Ala-Glu-Ala-Lys-Glu-Ala-NH2. 3 is a peptide that is Ala-Lys-Ser-Asn-Asn-Ser-Ala-NH2. 3 is a peptide that is Ala-Ser-Asn-Lys-Asn-Ser-Ala-NH2. 3 is a peptide that is Ala-Ser-Asn-Asn-Ser-Lys-Ala-NH2. 3 is a peptide that is Ala-Arg-Arg-Lys-Glu-Glu-Glu-NH2. 3 is a peptide that is Ala-Glu-Ala-Lys-Glu-Ala-NH2.

[0255] In some embodiments, L 4 In some embodiments, L 4 is a substituted or unsubstituted 2-10 membered heteroalkylene. 4 is -CH2-(OCH2CH2) v In some embodiments, L 4 is -(CH2CH2O) v In some embodiments, L 4 is -(CH2CH2O) v CH2CH2NHC(=O)(CH2CH2O) v CHCH-, and in some embodiments, L 4 is -(CH2CH2O) v CH2CH2C(=O)NH(CH2CH2O) v In some embodiments, L4 is —C(═O)CH2CH2. In some embodiments, L 4 is —CH2CH2C(═O)—. In some embodiments, L 4 are independently -OH, -NH2, -CO2H, -O(CH2CH2O) u -CH3, -NH(CH2CH2O) u -CH3, -NHC(=O)(CH2CH2O) u In some embodiments, L is a C1-C6 alkylene optionally substituted with one or two groups selected from: -CH3, -CH2OCH2CH2CO2H, or -CH2OCH2CH2CO2H. 4 is a C-C alkylene optionally substituted with one or two groups independently selected from -OH, -NH, -COH, or -CHOCHCHCOH. In some embodiments, L 4 is unsubstituted C1-C6 alkylene.

[0256] In some embodiments, L 5 In some embodiments, L 5 is —O—. In some embodiments, L 5 is -S-. In some embodiments, L 5 is -S(=O)-. In some embodiments, L 5 is -S(=O)2. In some embodiments, L 5 In some embodiments, L 5 is —CH(═NH)—. In some embodiments, L 5 is -CH(=N-NH)-. In some embodiments, L 5 is —CCH3(═NH)—. In some embodiments, L 5 is -CCH3(=N-NH)-. In some embodiments, L 5 is —C(═O)NH— or —NHC(═O)—. In some embodiments, L 5 is —C(═O)NH—. In some embodiments, L 5 is —NHC(═O)—. In some embodiments, L 5is —NHC(═O)O—. In some embodiments, L 5 is —NHC(═O)NH—. In some embodiments, L 5 is -OC(=O)NH-.

[0257] In some embodiments, L 9 is a substituted or unsubstituted cycloalkylene. 9 is a substituted or unsubstituted C4-C8 cycloalkylene. 9 is a substituted or unsubstituted heterocycloalkylene, and in some embodiments, L 9 is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 9 is azetidinylene, pyrrolidinylene, piperidinylene, or piperazinylene. 9 is a monosaccharide. In some embodiments, R 9 teeth,

[0258] [ka] In some embodiments, L 9 is a 7-12 membered spirocyclic heterocycloalkylene. In some embodiments, R 9 teeth,

[0259] [ka] In some embodiments, R 9 teeth,

[0260] [ka] In some embodiments, L 9 is a substituted or unsubstituted arylene. In some embodiments, R 9 is phenylene. In some embodiments, R 9 teeth,

[0261] [ka] In some embodiments, L 9 is a substituted or unsubstituted heteroarylene.

[0262] In some embodiments, L 8 In some embodiments, L 8 is -(CH2) t -, -(CH2) t -C(=O)NR w - or -CH(NHR w )-(CH2) t In some embodiments, L 8 is -(CH2) t In some embodiments, L 8 is -NR w In some embodiments, L 8 is -NR w -(CH2) t In some embodiments, L 8 is -(CH2) t In some embodiments, L 8 is -C(=O)-(CH2) t In some embodiments, L 8 is -(CH2) t -NR w In some embodiments, L 8 is -(CH2) t -NR w In some embodiments, L 8 is -(CH2) t -C(=O)NR w In some embodiments, L 8 is -CH(NHR w )-(CH2) t In some embodiments, L 8 is -NR w C(=O)-(CH2) t In some embodiments, L 8 is -C(=O)NRw -(CH2) t -It is.

[0263] In some embodiments, L 10 does not exist or -(CH2) r -, -NR w -(CH2) r - or -C(=O)-(CH2) r In some embodiments, L 10 is absent or -(CH2) r In some embodiments, L 10 In some embodiments, L 10 is -(CH2) r In some embodiments, L 10 is -NR w In some embodiments, L 10 is -NR w -(CH2) r In some embodiments, L 10 is -(CH2) r In some embodiments, L 10 is -C(=O)-(CH2) r In some embodiments, L 10 is -(CH2) r -NR w In some embodiments, L 10 is -(CH2) r -NR w In some embodiments, L 10 is -(CH2) r -C(=O)NR w In some embodiments, L 10 is -CH(NHR w )-(CH2) r In some embodiments, L 10 is -NR w C(=O)-(CH2) r In some embodiments, L 10 is -C(=O)NR w -(CH2) r -It is.

[0264] In some embodiments, L 6 In some embodiments, L 6 -L 8 -L 9 -L 10 -That is.

[0265] In some embodiments, L 7 In some embodiments, L 7 In some embodiments, L 7 is —N(CH)—. In some embodiments, L 7 is —O—NH—. In some embodiments, L 7 is a substituted or unsubstituted N-heterocycloalkylene. 7 is a substituted or unsubstituted N-heterocycloalkylene, and the N-heterocycloalkylene is connected to an adjacent group (e.g., -L) via a nitrogen atom of the N-heterocycloalkylene. 6 -or-R 6 ) (e.g.,

[0266] [ka] In some embodiments, L 7 is an unsubstituted N-heterocycloalkylene. 7 teeth,

[0267] [ka] In some embodiments, L 7 teeth,

[0268] [ka] In some embodiments, L 7 teeth,

[0269] [ka] In some embodiments, L 7 teeth,

[0270] [ka] is.

[0271] In some embodiments, L 1 -L 2 - and L 2 is -(CH2CH2O) w -CH2CH2NH, and w is 1, 2, 3, 4, 5, or 6. In some embodiments, L 1 -L 2 - and L 2 is -(CH2CH2O) w -CH2CH2NH, and w is 1, 2, 3, 4, 5, or 6.

[0272] In some embodiments, L 1 -L 3 - and L 3 is a natural amino acid, an unnatural amino acid, or a peptide.

[0273] In some embodiments, L 1 -L 6 - and L 6 -L 8 -L 9 -L 10 - and L 8 is -(CH2) t -C(=O)NR w - and L 9 is a substituted or unsubstituted heterocycloalkylene, and R 10 is absent and t is 1, 2, or 3. In some embodiments, L 9 is azetidine, pyrrolidine, piperidine, or piperazine. w is C1-C6 alkyl-CO2H. In some embodiments, R w is -(CH2CH2O)s -CH2CH2CO2H.

[0274] In some embodiments, L 1 -L 7 - and L 7 is a substituted or unsubstituted N-heterocycloalkylene.

[0275] In some embodiments, L 1 -L 2 -L 3 - and L 2 is a substituted or unsubstituted C1-C6 alkylene-NH-, a substituted or unsubstituted C1-C6 alkylene-C(=O)-, a substituted or unsubstituted C1-C6 alkylene-NH-, or -(CH2CH2O) w -CH2CH2NH-, and L 3 is a natural or unnatural amino acid, or a peptide. 3 is a peptide.

[0276] In some embodiments, L 1 -L 2 -L 4 - and L 2 is -(CH2CH2O) w -CH2CH2NHC(=O)-, and L 4 is unsubstituted C1-C6 alkylene.

[0277] In some embodiments, L 1 -L 2 -L 7 - and L 2 represents a substituted or unsubstituted C1-C6 alkylene-, a substituted or unsubstituted C1-C6 alkylene-C(=O)NH-, -(CH2CH2O) w -CH2CH2-, and L 7 is -NH-, -O-NH, or a substituted or unsubstituted N-heterocycloalkylene.

[0278] In some embodiments, L 1 -L 2 -L7 - and L 2 is -(CH2CH2O) w -CH2CH2-, and L 7 is -NH-.

[0279] In some embodiments, L 1 -L 4 -L 6 - and L 4 is C1-C6 alkylene optionally substituted with one or two groups independently selected from -OH or -NH2; L 6 -L 8 -L 9 -L 10 - and L 8 is -(CH2) t -C(=O)NR w - and R w is H and L 9 is a substituted or unsubstituted heterocycloalkylene; L 10 does not exist.

[0280] In some embodiments, L 1 -L 4 -L 7 - and L 4 is C1-C6 alkylene optionally substituted with one or two groups independently selected from -OH or -NH2; L 7 is -NH-.

[0281] In some embodiments, L 1 -L 6 -L 7 - and L 6 -L 8 -L 9 -L 10 - and L 8 is absent or -CH(NHR w )-(CH2) t -C(=O)- or -(CH2) t -C(=O)NR w - and L 9 is a substituted or unsubstituted heterocycloalkylene; L 10does not exist or -(CH2) r - or -C(=O)-(CH2) r - and L 7 is —NH— or substituted or unsubstituted N-heterocycloalkylene. In some embodiments, R w is -C(=O)-(CH2CH2O) s -CH3 or -(CH2CH2O) s -CH2CH2CO2H.

[0282] In some embodiments, L 1 -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted C1-C6 alkylene -NHC(=O)-, -(CH2CH2O) z - or -CH2CH2NHC(=O)-(CH2CH2O) w and L 4 is —CH—(OCHCH) optionally substituted with one or two groups independently selected from —OH, —NH, or —CHOCHCHCOH v - or C1-C6 alkylene, and L 7 is -NH- or a substituted or unsubstituted N-heterocycloalkylene.

[0283] In some embodiments, L 1 -L 2 -L 7 - and L 2 is a substituted or unsubstituted C1-C6 alkylene, and L 7 where -ON=(substituted or unsubstituted N-heterocycloalkylene).

[0284] In some embodiments, L 1 -L 2 -L 6 -L 7 - and L 2is a substituted or unsubstituted C1-C6 alkylene-NH-, a substituted or unsubstituted C1-C6 alkylene-NHC(=O)-, a substituted or unsubstituted C1-C6 alkylene-C(=O)NH, or -(CH2CH2O) w -CH2CH2NHC(=O)-, and L 6 -L 8 -L 9 -L 10 - and L 8 is absent or -(CH2) t and L 9 is a substituted or unsubstituted heterocycloalkylene; L 10 does not exist or -(CH2) r -, or -NR w -(CH2) r - and L 7 is -NH-.

[0285] In some embodiments, L 1 L 3 -L 4 -L 7 - and L 3 is a peptide in which the N atom of the amide linking the amino acid is replaced with -CH3, and L 4 is -C(=O)CH2CH2-, and L 7 is -NH-.

[0286] In some embodiments, L 1 L 4 -L 5 -L 7 - and L 4 is C1-C6 alkylene optionally substituted with one or two groups independently selected from -OH or -NH2; L 5 is -C(=O)NH-, and L 7 is a substituted or unsubstituted N-heterocycloalkylene. In some embodiments, R is —(CHCHO) u -CH2CH2N(L 1 -R 6 )2-. In some embodiments, R is -CH-(L 1 R6 )2. In some embodiments, L 1 L 2 and L 2 is -(CH2CH2O) w -CH2CH2NH- and w is 3. In some embodiments, L 1 L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted C1-C 20 alkylene-NHC(=O)-, and L 4 is C1-C6 alkylene, and L 7 is NH.

[0287] In some embodiments, Z is —C(═O)NH— and L 1 -L 2 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —C(═O)NH— and L 1 -L 2 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —C(═O)NH— and L 1 -L 2 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)— and L 1 -L 2 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)— and L 1 -L 2 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)— and L 1 -L2 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)NH— and L 1 -L 2 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)NH— and L 1 -L 2 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)NH— and L 1 -L 2 - and L 2 is -(CH2CH2O) w -CH2CH2NH and w is 6.

[0288] In some embodiments, Z is —C(═O)NH— and L 1 -L 2 -L 7 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —CHCH— and w is 2. In some embodiments, Z is —C(═O)NH— and L 1 -L 2 -L 7 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —C(═O)NH— and L 1 -L 2 -L 7 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)— and L 1 -L 2 -L 7 - and L 2 is -(CH2CH2O)w In some embodiments, Z is —NHC(═O)— and L 1 -L 2 -L 7 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)— and L 1 -L 2 -L 7 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)NH— and L 1 -L 2 -L 7 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)NH— and L 1 -L 2 -L 7 - and L 2 is -(CH2CH2O) w In some embodiments, Z is —NHC(═O)NH— and L 1 -L 2 -L 7 - and L 2 is -(CH2CH2O) w -CH2CH2- and w is 6.

[0289] In some embodiments, Z is —NHC(═O)— and L 1 -L 2 -L 7 - and L 2 is a substituted or unsubstituted C1-C 20 alkylene -C(=O)NH-, and L 7 is N-heterocycloalkylene.

[0290] In some embodiments, Z is —NHC(═O)NH—, and L 1-L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted C1-C 20 alkylene-NHC(=O)-, and L 4 is a C1-C6 alkylene substituted with two -OH groups, and L 7 is -NH-.

[0291] In some embodiments, Z is —NHC(═O)— and L 1 -L 6 - and L 6 -L 8 -L 9 -L 10 - and L 8 is -(CH2) t -C(=O)NR w - and R w is -(CH2CH2O) s -CH2CH2CO2H, s is 2, and L 9 is a substituted or unsubstituted heterocycloalkylene; L 10 does not exist.

[0292] In some embodiments, Z is —NHC(═O)NH—, and L 1 -L 2 -L 4 -L 7 - and L 2 is a substituted or unsubstituted C1-C 20 alkylene-NHC(=O)-, and L 4 is a C1-C6 alkylene substituted with one -NH2, and L 7 is -NH-.

[0293] In some embodiments, Z is —NHC(═O)— and L 1 -L 2 -L 4 -L 7 - and L 2 is -(CH2CH2O) w -CH2CH2NHC(=O)-, w is 2, and L 6 -L8 -L 9 -L 10 - and L 8 does not exist, and L 9 is a substituted or unsubstituted heterocycloalkylene; L 10 (CH2) r where r is 1 and L 7 is -NH-.

[0294] In some embodiments, Z is —NHC(═O)— and L 1 -L 3 -L 4 -L 7 - and L 3 is a peptide in which the N atom of the amide linking the amino acid is replaced with -CH3 and L 4 is -C(=O)CH2CH2-, and L 7 is —NH—. In some embodiments, L 3 is penta-sarcosine.

[0295] In some embodiments, Z is —NHC(═O)— and L 1 -L 2 -L 3 - and L 2 is -(CH2CH2O) w -CH2CH2NH-, w is 4, and L 3 is an amino acid. In some embodiments, L 3 is L-cysteic acid.

[0296] In some embodiments, L 1 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-,

[0297] [ka]

[0298] [ka]

[0299] [ka]

[0300] [ka] is.

[0301] In some embodiments, L 1 teeth,

[0302] [ka]

[0303] [ka]

[0304] [ka]

[0305] [ka]

[0306] [ka]

[0307] [ka] is.

[0308] In some embodiments, L 1 is -CH-. In some embodiments, L 1 teeth,

[0309] [ka] In some embodiments, L 1 teeth,

[0310] [ka] In some embodiments, L 1 teeth,

[0311] [ka] In some embodiments, L 1 teeth,

[0312] [ka] In some embodiments, L 1 teeth,

[0313] [ka] In some embodiments, L 1 teeth,

[0314] [ka] In some embodiments, L 1 teeth,

[0315] [ka] In some embodiments, L 1 teeth,

[0316] [ka] In some embodiments, L 1 teeth,

[0317] [ka] In some embodiments, L 1 teeth,

[0318] [ka] In some embodiments, L 1 teeth,

[0319] [ka] In some embodiments, L 1 teeth,

[0320] [ka] In some embodiments, L 1 teeth,

[0321] [ka] In some embodiments, L 1 teeth,

[0322] [ka] In some embodiments, L 1 teeth,

[0323] [ka] In some embodiments, L 1 teeth,

[0324] [ka] In some embodiments, L 1 teeth,

[0325] [ka] In some embodiments, L 1 teeth,

[0326] [ka] In some embodiments, L 1 teeth,

[0327] [ka] In some embodiments, L 1 teeth,

[0328] [ka] In some embodiments, L 1 teeth,

[0329] [ka] In some embodiments, L 1 teeth,

[0330] [ka] In some embodiments, L 1 teeth,

[0331] [ka] In some embodiments, L 1 teeth,

[0332] [ka] In some embodiments, L 1 teeth,

[0333] [ka] In some embodiments, L 1 teeth,

[0334] [ka] In some embodiments, L 1 teeth,

[0335] [ka] In some embodiments, L 1 teeth,

[0336] [ka] In some embodiments, L 1 teeth,

[0337] [ka] In some embodiments, L 1 teeth,

[0338] [ka] In some embodiments, L 1 teeth,

[0339] [ka] In some embodiments, L 1 teeth,

[0340] [ka] In some embodiments, L 1 teeth,

[0341] [ka] In some embodiments, L 1 teeth,

[0342] [ka] In some embodiments, L 1 teeth,

[0343] [ka] In some embodiments, L 1 teeth,

[0344] [ka] In some embodiments, L 1 teeth,

[0345] [ka] In some embodiments, L 1 teeth,

[0346] [ka] In some embodiments, L 1 teeth,

[0347] [ka] In some embodiments, L 1 teeth,

[0348] [ka] In some embodiments, L 1 teeth,

[0349] [ka] In some embodiments, L 1 teeth,

[0350] [ka] In some embodiments, L 1 teeth,

[0351] [ka] In some embodiments, L 1 teeth,

[0352] [ka] In some embodiments, L 1 teeth,

[0353] [ka] In some embodiments, L 1 teeth,

[0354] [ka] In some embodiments, L 1 teeth,

[0355] [ka] In some embodiments, L 1 teeth,

[0356] [ka] In some embodiments, L 1 teeth,

[0357] [ka] In some embodiments, L 1 teeth,

[0358] [ka] In some embodiments, L 1 teeth,

[0359] [ka] In some embodiments, L 1 teeth,

[0360] [ka] In some embodiments, L 1 teeth,

[0361] [ka] In some embodiments, L 1 teeth,

[0362] [ka] In some embodiments, L 1 teeth,

[0363] [ka] In some embodiments, L 1 teeth,

[0364] [ka] In some embodiments, L 1 teeth,

[0365] [ka] In some embodiments, L 1 teeth,

[0366] [ka] In some embodiments, L 1 teeth,

[0367] [ka] In some embodiments, L 1 teeth,

[0368] [ka] In some embodiments, L 1 teeth,

[0369] [ka] In some embodiments, L 1 teeth,

[0370] [ka] In some embodiments, L 1 teeth,

[0371] [ka] In some embodiments, L 1 teeth,

[0372] [ka] In some embodiments, L 1 teeth,

[0373] [ka] In some embodiments, L 1 teeth,

[0374] [ka] In some embodiments, L 1 teeth,

[0375] [ka] In some embodiments, L 1 teeth,

[0376] [ka] In some embodiments, L 1 teeth,

[0377] [ka] In some embodiments, L 1 teeth,

[0378] [ka] In some embodiments, L 1 teeth,

[0379] [ka] In some embodiments, L 1 teeth,

[0380] [ka] In some embodiments, L 1 teeth,

[0381] [ka] In some embodiments, L 1 teeth,

[0382] [ka] In some embodiments, L 1 teeth,

[0383] [ka] In some embodiments, L 1 teeth,

[0384] [ka] In some embodiments, L 1 teeth,

[0385] [ka] In some embodiments, L 1 teeth,

[0386] [ka] In some embodiments, L 1 teeth,

[0387] [ka] In some embodiments, L 1 teeth,

[0388] [ka] In some embodiments, L 1 teeth,

[0389] [ka] In some embodiments, L 1 teeth,

[0390] [ka] In some embodiments, L 1 teeth,

[0391] [ka] In some embodiments, L 1 teeth,

[0392] [ka] In some embodiments, L 1 teeth,

[0393] [ka] In some embodiments, L 1 teeth,

[0394] [ka] In some embodiments, L 1 teeth,

[0395] [ka] In some embodiments, L 1 teeth,

[0396] [ka] In some embodiments, L 1 teeth,

[0397] [ka] In some embodiments, L 1 teeth,

[0398] [ka] In some embodiments, L 1 teeth,

[0399] [ka] In some embodiments, L 1 teeth,

[0400] [ka] In some embodiments, L 1 teeth,

[0401] [ka] In some embodiments, L 1 teeth,

[0402] [ka] In some embodiments, L 1 teeth,

[0403] [ka] In some embodiments, L 1 teeth,

[0404] [ka] In some embodiments, L 1 teeth,

[0405] [ka] In some embodiments, L 1 teeth,

[0406] [ka] In some embodiments, L 1 teeth,

[0407] [ka] In some embodiments, L 1 teeth,

[0408] [ka] In some embodiments, L 1 teeth,

[0409] [ka] In some embodiments, L 1 teeth,

[0410] [ka] In some embodiments, L 1 teeth,

[0411] [ka] In some embodiments, L 1 teeth,

[0412] [ka] In some embodiments, L 1 teeth,

[0413] [ka] In some embodiments, L 1 teeth,

[0414] [ka] In some embodiments, L 1 teeth,

[0415] [ka] In some embodiments, L 1 teeth,

[0416] [ka] In some embodiments, L 1 teeth,

[0417] [ka] In some embodiments, L 1 teeth,

[0418] [ka] In some embodiments, L 1 teeth,

[0419] [ka] In some embodiments, L 1 teeth,

[0420] [ka] In some embodiments, L 1 teeth,

[0421] [ka] In some embodiments, L 1 teeth,

[0422] [ka] In some embodiments, L 1 teeth,

[0423] [ka] In some embodiments, L 1 teeth,

[0424] [ka] In some embodiments, L 1 teeth,

[0425] [ka] In some embodiments, L 1 teeth,

[0426] [ka] In some embodiments, L 1 teeth,

[0427] [ka] In some embodiments, L 1 teeth,

[0428] [ka] In some embodiments, L 1 teeth,

[0429] [ka] In some embodiments, L 1 teeth,

[0430] [ka] In some embodiments, L 1 teeth,

[0431] [ka] In some embodiments, L 1 teeth,

[0432] [ka] In some embodiments, L 1 teeth,

[0433] [ka] is.

[0434] In some embodiments, -L 1 -R 6 is -CH2-R 6 , -CH2CH2-R 6 ,

[0435] [ka]

[0436] [ka]

[0437] [ka] is.

[0438] In some embodiments, R is

[0439] [ka] is.

[0440] In some embodiments, R is

[0441] [ka] is.

[0442] In some embodiments, R is

[0443] [ka] is.

[0444] Representative Linkers and Chelating Moieties In some embodiments, -L 1 -R 6 teeth,

[0445] [ka]

[0446] [ka]

[0447] [ka]

[0448] [ka]

[0449] [ka]

[0450] [ka]

[0451] [ka]

[0452] [ka] is.

[0453] In some embodiments, -L 1 -R 6 teeth,

[0454] [ka]

[0455] [ka]

[0456] [ka]

[0457] [ka]

[0458] [ka]

[0459] [ka] and R 6 teeth,

[0460] [ka] is.

[0461] In some embodiments, R is

[0462] [ka] is.

[0463] Representative compounds In some embodiments, the compound of Formula (I) has the structure:

[0464] [ka]

[0465] [ka]

[0466] [ka]

[0467] [ka]

[0468] [ka]

[0469] [ka]

[0470] [ka]

[0471] [ka]

[0472]

change

[0473]

change

[0474]

change

[0475]

change

[0476]

change

[0477]

change

[0478]

change

[0479]

change

[0480]

change

[0481]

change

[0482]

change

[0483]

change

[0484]

change

[0485]

change

[0486]

change

[0487]

change

[0488]

change

[0489]

change

[0490]

change

[0491]

change

[0492]

change

[0493] [ka]

[0494] [ka]

[0495] [ka]

[0496] [ka] or a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

[0497] In some embodiments, the compound of Formula (I) is Compound 1, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 2, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 3, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 4, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 5, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 6, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 7, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

[0498] In some embodiments, the compound of Formula (I) is Compound 8, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 9, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 10, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 11, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 12, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 14, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 15, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 16, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 17, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 18, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 18, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 19, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 20, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 21, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 22, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 23, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (I) is compound 24, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (I) is compound 25, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.In some embodiments, the compound of Formula (I) is Compound 26, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 27, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 28, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 29, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 30, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 31, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 32, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 33, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 34, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 36, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 37, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 38, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 39, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 40, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 41, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 42, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 43, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 44, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.In some embodiments, the compound of Formula (I) is Compound 45, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 46, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 47, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 48, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 49, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 50, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 51, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 52, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 53, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 54, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 55, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 56, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 57, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 58, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 59, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 60, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 61, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 62, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.In some embodiments, the compound of Formula (I) is Compound 63, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 64, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 65, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 66, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 67, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 68, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 69, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 70, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 71, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 72, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 73, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 74, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 75, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 76, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 77, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 78, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 79, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 80, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.In some embodiments, the compound of Formula (I) is Compound 81, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 82, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 83, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 84, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 85, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 86, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 87, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 88, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 89, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 90, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 91, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 92, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 93, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 94, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 95, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 96, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (I) is compound 97, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of formula (I) is compound 98, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.In some embodiments, the compound of Formula (I) is Compound 99, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 100, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 101, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 101, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 102, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 103, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (I) is Compound 104, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

[0499] In some embodiments, the compound of Formula (B) has the structure:

[0500] [ka] or a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

[0501] In some embodiments, the compound of Formula (B) is Compound 13, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof. In some embodiments, the compound of Formula (B) is Compound 35, a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

[0502] All combinations of the groups described above for the various variables are contemplated herein. Throughout this specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0503] Compound synthesis The compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with the methods described herein.

[0504] Unless otherwise specified, conventional mass spectroscopy, NMR, HPLC are utilized.

[0505] The compounds are prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be utilized, including variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions.

[0506] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts.In addition, the compounds described herein can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water and ethanol.The solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0507] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are useful in solid dosage forms because they are typically more soluble than non-ionic species and dissolve rapidly in gastric and intestinal fluids. Furthermore, their solubility is often pH-dependent, allowing for selective dissolution in one or another part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Furthermore, salt-forming molecules can be in equilibrium with neutral forms, thereby modulating passage through biological membranes.

[0508] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), Formula (B), or Formula (A) with an acid. In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), and glutamic acid. These include, but are not limited to, conic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0509] In some embodiments, the compound of Formula (I), Formula (B), or Formula (A) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt, or phosphate salt.

[0510] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), Formula (B), or Formula (A) with a base. In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) is acidic and is reacted with a base. In such situations, the acidic proton of a compound of Formula (I), Formula (B), or Formula (A) is replaced with a metal ion, such as a lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, the compounds described herein cooperate with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0511] It should be understood that a reference to a pharmaceutically acceptable salt includes solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are formed during the crystallization process using a pharmaceutically acceptable solvent, such as water or ethanol. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein are advantageously prepared or formed during the processes described herein. Furthermore, the compounds provided herein optionally exist in solvated as well as unsolvated forms.

[0512] In some embodiments, a moiety on an organic radical (eg, alkyl group, aromatic ring) of a compound of Formula (I), Formula (B), or Formula (A) is deuterated.

[0513] In some embodiments, compounds of Formula (I), Formula (B), or Formula (A) have one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. In some embodiments, compounds of Formula (I), Formula (B), or Formula (A) exist in the R configuration. In some embodiments, compounds of Formula (I), Formula (B), or Formula (A) exist in the S configuration. The compounds presented herein include all enantiomeric, atropisomeric, and epimeric forms, as well as the appropriate mixtures thereof. The compounds and methods presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof.

[0514] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers on chiral chromatographic columns, or separation of diastereomers on either non-chiral or chiral chromatographic columns, or crystallization and recrystallization in an appropriate solvent or solvent mixture. In certain embodiments, compounds of Formula (I), Formula (B), or Formula (A) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or diastereomeric salts and separation by recrystallization or chromatography, or any combination thereof. "Enantiomers, Racemates and Resolutions" by Jean Jacques, Andre Collet, and Samuel H. Wilen, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0515] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful in some situations because they are easier to administer than the parent drug. They are, for example, bioavailable by oral administration, whereas the parent drug is not. Additionally, or alternatively, prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the design of the prodrug improves effective water solubility. See, for example, Design of Prodrugs, edited by Bundgaard, A., Elsevier, 1985 and Method in Enzymology, edited by Widder, K. et al., Academic, 1985, Vol. 42, pp. 309-396; "Design and Application of Prodrugs" by Bundgaard, H., A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, 1991, Chapter 5, pp. 113-191; and "Advanced Drug Delivery Review" by Bundgaard, H., 1992, 8, pp. 1-38, each of which is incorporated herein by reference.

[0516] A "metabolite" of a compound disclosed herein is a derivative of that compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the totality of processes (including, but not limited to, hydrolysis and enzyme-catalyzed reactions) by which a particular substance is transformed by an organism. Thus, enzymes may induce specific structural changes in a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified by either administering the compound to a host and analyzing multiple tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0517] Pharmaceutical Composition In some embodiments, the compound described herein is formulated into pharmaceutical compositions. Pharmaceutical compositions are conventionally formulated with one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Suitable formulations depend on the selected route of administration. Summary information on pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, New York, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for disclosure.

[0518] In some embodiments, the compound described herein is administered alone or in pharmaceutical compositions with pharmaceutically acceptable carriers, excipients or diluents.The administration of the compound and composition described herein can be achieved by any method that allows compound to be delivered to the site of action.These methods include but are not limited to parenteral delivery (including injection or infusion and subcutaneous).

[0519] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Preparations for injection may be provided in unit dosage form, e.g., in ampoules or multi-dose containers, to which a preservative may be added. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The composition may be provided in unit-dose or multi-dose containers, e.g., sealed ampoules or vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, e.g., saline or pyrogen-free distilled water, immediately prior to use.

[0520] Treatment method In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (B), or Formula (A), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (I), Formula (B), or Formula (A), or a pharmaceutically acceptable salt or solvate thereof, is administered in a pharmaceutical composition. In some embodiments, the subject has cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the subject has a non-cancerous tumor. In some embodiments, the subject has an adenoma.

[0521] In some embodiments, treatment is sufficient to reduce or inhibit tumor growth, reduce the number or size of metastatic lesions, reduce tumor burden, reduce primary tumor burden, reduce invasiveness, prolong survival, or maintain or improve quality of life in a subject, or a combination thereof.

[0522] In some embodiments, provided herein is a method for killing tumor cells, the method comprising contacting tumor cells with a compound of Formula (I), Formula (B), or Formula (A), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, emits many alpha particles by spontaneous radioactive decay. In some embodiments, the emitted alpha particles are sufficient to kill the tumor cells. In some embodiments, the emitted alpha particles are sufficient to stop cell growth. In some embodiments, the tumor cells are malignant tumor cells. In some embodiments, the tumor cells are benign tumor cells. In some embodiments, the method comprises killing tumor cells with a beta particle-emitting radionuclide. In some embodiments, the method comprises killing tumor cells with an alpha particle-emitting radionuclide. In some embodiments, the method comprises killing tumor cells with a gamma particle-emitting radionuclide.

[0523] In one aspect herein, methods and compositions for treating cancer are provided.

[0524] In one aspect herein, methods and compositions for treating adenoma are provided.

[0525] In one aspect herein, methods and compositions for treating carcinoma are provided.

[0526] In one aspect herein, there is provided a method for identifying tissues or organs in a mammal that overexpress FSHR, the method comprising: (i) administering to the mammal a compound of Formula (I), Formula (B), or Formula (A); and (ii) performing single photon emission computed tomography (SPECT) or positron emission tomography (PET) analysis on the mammal. In some embodiments, the method comprises: (i) administering to the mammal a compound of Formula (I), Formula (B), or Formula (A); and (ii) performing positron emission tomography (PET) analysis on the mammal.

[0527] In some embodiments, the mammal has been diagnosed with ovarian cancer. In some embodiments, the tissue that overexpresses FSHR in the mammal is a tumor.

[0528] In some embodiments, the compounds of Formula (I), Formula (B), or Formula (A) disclosed herein are used in a method for imaging a subject in vivo. In some embodiments, the method includes (i) administering a compound of Formula (I), Formula (B), or Formula (A) to a mammal, (ii) waiting a sufficient time for the compound of Formula (I), Formula (B), or Formula (A) to accumulate at the tissue or cell site to be imaged, and (iii) imaging the cell or tissue using a non-invasive imaging technique.

[0529] In some embodiments, the non-invasive imaging technique is single photon emission computed tomography (SPECT) or positron emission tomography (PET) analysis. In some embodiments, the non-invasive imaging technique is single photon emission computed tomography (SPECT). In some embodiments, the non-invasive imaging technique is selected from positron emission tomography imaging or positron emission tomography including computed tomography imaging, and positron emission tomography including magnetic resonance imaging (MRI).

[0530] Dosage and Treatment Regimen In one embodiment, a compound of Formula (I), Formula (B), or Formula (A), or a pharmaceutically acceptable salt thereof, is used in the preparation of a medicament for treating a tumor in a mammal. A method for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0531] In certain embodiments, compositions containing the compounds described herein are administered for diagnostic and / or therapeutic treatments.

[0532] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the specific conjugate, the specific cancer or tumor being treated (and its severity), the identity (e.g., weight, sex) of the subject or host requiring treatment, and the like, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the specific conjugate being administered, the route of administration, the disease being treated, and the subject or host being treated. Optimal dosages are generally determined using experimental models and / or clinical trials. Optimal dosages depend on the subject's body type, weight, or blood volume.

[0533] The toxicity and therapeutic efficacy of such treatment regimens are discussed in detail below. 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies is used to formulate a therapeutically effective daily dose range and / or therapeutically effective unit dose for use in mammals, including humans.

[0534] The dosage of the compound of Formula (I), Formula (B), or Formula (A), or a pharmaceutically acceptable salt thereof, and / or pharmaceutical composition is sufficient to deliver a therapeutically effective dose to a particular subject. In some embodiments, the dosage of the compound of Formula (I), Formula (B), or Formula (A) is between about 0.1 pg and about 50 mg per kilogram of body weight, between 1 μg and about 50 mg per kilogram of body weight, or between about 0.1 and about 10 mg per kg of body weight. Therapeutically effective dosages can also be determined at the discretion of a physician. By way of example only, the dosage of the compound of Formula (I), Formula (B), or Formula (A), or a pharmaceutically acceptable salt thereof, described herein in the methods for treating a disease described herein, is between about 0.001 mg and about 1 mg per kg of subject body weight per administration. In some embodiments, the dose of a compound of Formula (I), Formula (B), or Formula (A) described herein or a pharmaceutically acceptable salt thereof in the described methods is about 0.001 mg to about 1000 mg per administration to the subject being treated. In some embodiments, the compound of Formula (I), Formula (B), or Formula (A) described herein or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.01 mg to about 500 mg, about 0.01 mg to about 100 mg, or about 0.01 mg to about 50 mg.

[0535] In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) described herein, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 0.01 picomole to about 1 mole, about 0.1 picomole to about 0.1 mole, about 1 nanomolar to about 0.1 mole, or about 0.01 micromolar to about 0.1 millimolar.

[0536] In some embodiments, a compound of Formula (I), Formula (B), or Formula (A) described herein, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 0.01 Gbq to about 1000 Gbq, about 0.5 Gbq to about 100 Gbq, or about 1 Gbq to about 50 Gbq.

[0537] In some embodiments, the dose is administered once daily, 1 to 3 times weekly, 1 to 4 times monthly, or 1 to 12 times yearly.

[0538] In any of the foregoing aspects, in a further embodiment, an effective amount of a compound of Formula (I), Formula (B), or Formula (A), or a pharmaceutically acceptable salt thereof, is (a) administered systemically to the mammal, and / or (b) administered intravenously to the mammal, and / or (c) administered by injection to the mammal.

[0539] In certain instances, it will be appropriate to administer a compound of Formula (I), Formula (B), or Formula (A), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0540] Specific Terms Unless otherwise specified, the following terms used in this application have the definitions provided below. Use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0541] As used herein and in the appended claims, singular forms such as "a," "an," and "the," and similar referents, where an element is described (particularly in the context of the claims below), should be construed to encompass both the singular and the plural, unless otherwise stated herein or clearly contradicted by context. The listing of ranges of values ​​herein is intended to serve merely as a shorthand method for referring to each separate value falling within the range, unless otherwise stated herein, and each separate value is incorporated herein as if it were individually listed herein. All methods described herein can be performed in any suitable order unless otherwise stated herein or clearly contradicted by context.

[0542] As used herein, "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to those of ordinary skill in the art, "about" will mean up to plus or minus 10% of the particular term, given the context in which it is used.

[0543] As discussed herein, a "small molecule" is a low molecular weight organic compound having a molecular weight of less than 1000 daltons but not containing more than three consecutive amino acid moieties. In some embodiments, the molecular weight of a small molecule is 900 daltons or less. In some embodiments, the molecular weight of a small molecule is 800 daltons or less. In some embodiments, the molecular weight of a small molecule is 700 daltons or less. In some embodiments, the molecular weight of a small molecule is 600 daltons or less.

[0544] As used herein, C1-C x is C1-C2, C1-C3...C1-C x By way of example only, a group designated as "C1-C6" indicates that there are from 1 to 6 carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0545] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group may be branched or straight-chain. In some embodiments, an "alkyl" group may contain 1 to 10 carbon atoms, i.e., C1-C6. 10The term "alkyl" includes alkyl. Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range. For example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also covers occurrences of the term "alkyl" without any numerical range specified. In some embodiments, alkyl is C1-C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl. In some embodiments, the alkyl group is an "alkenyl" or "alkynyl" group.

[0546] An "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups mentioned above can be an alkylene by abstraction of another hydrogen atom from the alkyl. In some embodiments, the alkylene is a C1-C6 alkylene. In other embodiments, the alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-.

[0547] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0548] The term "alkenyl" refers to a species of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which can be the same or different. In some embodiments, each R is independently H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0549] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0550] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. In some embodiments, "heteroalkyl" groups have 2 to 10 atoms in their backbone, which includes a combination of carbon atoms and heteroatoms (e.g., N, O, S), i.e., 2-10 membered heteroalkyls. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a 2-8 membered heteroalkyl.

[0551] A "heteroalkylene" group refers to a divalent alkyl radical derived from heteroalkyl, including, but not limited to, -CH-CH-O-CH-CH- and -CH-O-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(=O)O- represents both -C(=O)O- and -OC(=O)-. Furthermore, the formula -C(=O)NH- represents both -C(=O)NH- and -NHC(=O)-.

[0552] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, this term distinguishes carbocycle from "heterocyclic" or "heterocycle" rings, which have at least one atom other than carbon in the backbone of the ring. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0553] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, an aryl is phenyl or naphthyl. In some embodiments, an aryl is phenyl. In some embodiments, an aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a C6-C 10 Aryl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0554] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical in which each of the atoms forming the ring (i.e., the skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged cycloalkyl. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is to a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 12 ring atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicycle[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C4 cycloalkyl. In some embodiments, the cycloalkyl is a C5-C6 cycloalkyl.

[0555] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0556] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0557] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 12 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 12 atoms in their ring system, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups may be C-bonded (i.e., C-linked) or N-bonded, where possible. For example, pyrrole-derived groups include pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, imidazole-derived groups include imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0558] The term "heteroaryl," or alternatively "heteroaromatic," refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1 O atom. In some embodiments, the heteroaryl contains 1 S atom in the ring. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5 membered heteroaryl. In some embodiments, the monocyclic heteroaryl is a 6 membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a 10 membered heteroaryl.

[0559] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a 3- to 12-membered heterocycloalkyl. In another aspect, a heterocycloalkyl is a 5- to 10-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3- or 4-membered ring. In some embodiments, a heterocycloalkyl contains 1-4 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0560] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby allowing a bond to be formed between the remaining specified groups.

[0561] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded in or attached to a molecule.

[0562] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, and —S(═O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CHF, -CF, -OCH, -OCHF, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0563] The term "modulate," as used herein, means to interact with a target directly or indirectly to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0564] The term "modulator," as used herein, refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0565] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological effect. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion). Those of skill in the art are familiar with administration techniques that can be used with the compounds and methods described herein.

[0566] "Co-administration" and like terms, as used herein, are intended to encompass the administration of selected therapeutic agents to a single patient and include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0567] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or compound administered such that one or more of the symptoms of the disease or disorder being treated are alleviated to some extent. This result may include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount," in therapeutic applications, is the quantity of a composition comprising a compound disclosed herein that is required to result in a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0568] The terms "enhance" or "enhancing," as used herein, means to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0569] The terms "article of manufacture" and "kit" are used synonymously.

[0570] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of any of the following mammalian classes: humans, non-human primates such as chimpanzees, other apes, and monkey species; farm animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0571] "Treat," "treating," or "treatment," as used herein, includes alleviating, reducing, or relieving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., preventing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or prophylactically and / or therapeutically arresting a symptom of a disease or condition. In some embodiments, "treating," as used herein, includes alleviating, reducing, or relieving at least one symptom of a disease or condition, preventing additional symptoms, preventing the onset or progression of a disease or condition, causing regression of a disease or condition, or arresting a symptom of a disease or condition. For example, in some embodiments, treating includes arresting the growth of tumor cells expressing FSHR, reducing the size of tumor cells, reducing the abundance of tumor cells, or reducing the distribution of tumor cells within a mammal. [Example]

[0572] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. Abbreviation AcOH: acetic acid, FA: formic acid, PivOH: pivalic acid, TFA: trifluoroacetic acid, ACN or MeCN or CH3CN: acetonitrile, BocO: di-tert-butyl carbonate, H2O: water, Brine: saturated NaCl solution, MeOH: methanol, EtOH: ethanol, t-BuOH: t-butanol, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC: N,N'-dicyclohexylcarbodiimide, EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, DCM: dichloromethane, DCE: dichloroethane, DIEA or DIPEA: N,N-diisopropylethylamine, TEA: triethylamine, DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide, DMSO: dimethyl sulfoxide, DOTA-tris(t-Bu) ester NHS ester: 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, ELSD: evaporative light scattering detector; Et2O: diethyl ether, PE: petroleum ether, THF: tetrahydrofuran, EtOAc or EA: ethyl acetate, FDPP: pentafluorophenyl diphenylphosphinate, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, HBTU: N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, HOBt: hydroxybenzotriazole, HCl: Hydrochloric acid or hydrochloride, InCl3: indium trichloride, LuCl3: ruthenium(III) chloride, K2CO3: potassium carbonate, Na2CO3: sodium carbonate, LCMS: liquid chromatography mass spectrometry, MS: mass spectrometry, LDA: lithium diisopropylamide; MPLC: Medium Pressure Liquid Chromatography; NaOH: sodium hydroxide, Na2SO4: sodium sulfate, NaHSO4: sodium hydrogen sulfate, NBS: N-bromosuccinimide, NH4Cl: ammonium chloride, NMI: N-methylimidazole; NMM: N-methylmorpholine, NMP: N-methyl-2-pyrrolidine, Pd(dppf)Cl2: 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride, Pd(PPh3)4: Palladium-tetrakis(triphenylphosphine), Prep-HPLC: preparative high performance liquid chromatography; PyBop: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, TCFH: chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate; TIPS: triisopropylsilane, TMSI: trimethylsilyl iodide, PhSiH3: phenylsilane, rt: room temperature, h or hr: hour, hrs: hour, min: minute, mg: milligram, kg: kilogram, mL or ml: milliliter, Eq: equivalent, mmol: millimole, mol: mole, UV: Ultraviolet light

[0573] Basic analysis methods: Preparative HPLC using DAC: The crude product was purified by DAC-HPLC: column, YMC-C18, 150-250 nm, 10 μm; mobile phase, water (0.05% TFA) and ACN (25% ACN, up to 65% in 8 min); total flow rate, 120 mL / min; detector, UV 220 nm.

[0574] LC-MS analysis was performed on a Shimadzu LCMS-2020 series instrument equipped with a binary pump LC-20ADXR, a micro vacuum degasser, a standard autosampler SIL-20AC XR, a thermostatic column compartment CTO-20AC, and a variable wavelength detector SPD-M20A. Data were analyzed using Shimadzu LabSolutions stand-alone workstation software. The HPLC solvent consisted of 0.05% ammonia in HO (mobile phase A) and acetonitrile (mobile phase B). Conditions: An Ascentis Express C18 (2.6 μm, 3.0 × 50 mm) column was used at a flow rate of 1.2 mL / min. 1 H NMR spectra were recorded using an AVANCE III HD 300 MHz. Unless otherwise specified, chemical shifts are reported as δ (ppm) relative to TMS4Si (in DMSO-d6) as an internal standard using an Instrument model (Bruker TopSpin).

[0575] Compound synthesis Example 1: 2,2′,2″-(10-(1-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 1)

[0576] [ka]

[0577] Step 1: A 500 mL round-bottom flask was charged with a mixture of 3-chloropropanoic acid (52 g, 1.2 Eq, 0.48 mol) in 100 mL of water, followed by the addition of a saturated solution of sodium bicarbonate (81 g, 2.4 Eq, 0.96 mol). The mixture was stirred at room temperature for 5 minutes. 3-Methoxyphenol (50 g, 1 Eq, 0.40 mol) was added to a saturated solution of sodium hydroxide (39 g, 2.4 Eq, 0.98 mol), and the resulting mixture was added to the first mixture. The reaction mixture was stirred at 100° C. for 3 hours. The mixture was adjusted to pH=5 with 2 N HCl and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by MPLC under the following conditions: silica gel column 330 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 40 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 3-(3-methoxyphenoxy)propanoic acid (12.5 g, 57 mmol, 14%, 90% purity) as a yellow oil. MS: Calculated for C 10 H 12 O4:196.07,found[M+H] + :197.2,199.2.

[0578] Step 2: A 500 mL round-bottom flask was charged with a mixture of 3-(3-methoxyphenoxy)propanoic acid (12.5 g, 1 eq, 63.7 mmol), trifluoromethanesulfonic acid (19.1 g, 2.00 eq, 127 mmol), 2,2,2-trifluoroacetic anhydride (16.1 g, 1.20 eq, 76.7 mmol), and DCM (120 mL). The reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with 100 mL of ice water and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (2 x 100 mL), brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC using the following conditions: a 330 g silica gel column, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 40 mL / min, and wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 7-methoxychroman-4-one (7.7 g, 39 mmol, 61%, 90% purity) as a yellow oil. MS: Calculated for C 10 H 10 O3:178.06,found[M+H] + :179.2,181.2.

[0579] Step 3: A 250 mL round-bottom flask was charged with a mixture of 7-methoxychroman-4-one (8.0 g, 1 Eq, 45 mmol), silicon dioxide (800 mg, 0.30 Eq, 13.3 mmol), EtO (96 mL), and MeCN (32 mL). To this mixture was added 1-bromopyrrolidine-2,5-dione (9.60 g, 1.2 Eq, 53.9 mmol). The reaction mixture was stirred at 25 °C for 3.5 h. The crude product was purified by MPLC under the following conditions: silica gel column 120 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 80 mL / min, wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 6-bromo-7-methoxychroman-4-one (9.5 g, 37 mmol, 82%) as a pale yellow solid. MS:Calc'd for C 10 H9BrO3: 255.97, found [M+H] + :257.0,259.0.

[0580] Step 4: A 500 mL three-necked flask was charged with 6-bromo-7-methoxychroman-4-one (9.5 g, 1 Eq, 37 mmol) in THF (190 mL) at 25° C. under an inert nitrogen atmosphere. The mixture was cooled to −78° C., and then lithium diisopropylamide in THF (4.7 g, 22 mL, 2 mol, 1.2 Eq, 44 mmol) was added at −78° C. The mixture was stirred at −78° C. for 1 hour. Diethyl oxalate (8.1 g, 1.5 Eq, 55 mmol) in THF (8 mL) was then added dropwise to the reaction mixture at −78° C. The resulting mixture was stirred at 0° C. for 1 hour. The resulting mixture was quenched by the addition of a saturated solution of NH4Cl (100 mL) and adjusted to pH=6 by the addition of saturated NaHSO4. The solution was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine (2 x 200 mL). A large amount of solid precipitated in the organic layer, which was filtered, and the cake was washed with EA and then dried under vacuum. The solid gave ethyl (Z)-2-(6-bromo-7-methoxy-4-oxochroman-3-ylidene)-2-hydroxyacetate (8.0 g, 22 mmol, 61%) as a yellow solid. MS: Calculated for C 14 H 13 BrO6:355.99,found[M+H] + :356.9,358.9.

[0581] Step 5: To a solution of ethyl (Z)-2-(6-bromo-7-methoxy-4-oxochroman-3-ylidene)-2-hydroxyacetate (9.3 g, 1 Eq, 26 mmol) in t-BuOH (20 mL) and AcOH (300 mL), (3,5-dichlorophenyl)hydrazine hydrochloride (5.0 g, 0.90 Eq, 23 mmol) was added at room temperature under N. The mixture was stirred at 100 °C for 4 hours. The mixture was then concentrated in vacuo. The residue was dissolved in EtOAc (800 mL), washed with water (200 mL), brine (100 mL), and a saturated solution of anhydrous sodium sulfate, and then concentrated in vacuo. The residue was triturated with 200 mL of PE to give ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (8.0 g, 14 mmol, 56%, 90% purity) as an off-white solid, which was used in the next step without further purification. MS: Calculated for C 20 H 15 BrCl2N2O4: 495.96, found [M+H] + :497.0,499.0.

[0582] Step 6: A 100 mL round-bottom flask was charged with a mixture of ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (2.55 g, 1 eq, 5.12 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.1 g, 0.98 eq, 5.0 mmol), 1,1′-bis(di-t-butylphosphino)ferrocenepalladium dichloride (137 mg, 0.0411 eq, 210 μmol), KCO (2.12 g, 3.00 eq, 15.3 mmol), 1,4-dioxane (77 mL), and water (7.7 mL) under an inert nitrogen atmosphere. The reaction mixture was stirred at 60° C. for 3 hours. The resulting mixture was extracted with DCM (50 mL x 3), dried over anhydrous NaSO, concentrated, and purified by MPLC under the following conditions: silica gel column 40 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 40 mL / min; wavelength: 254 nm. This gave ethyl 8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (1.74 g, 3.1 mmol, 60%, 90% purity) as a yellow solid. MS: Calculated for C 26 H 21 Cl2N3O4: 509.09, found [M+H] + :510.1,512.1.

[0583] Step 7: A 40 mL vial was charged with a mixture of TEA (327 mg, 450 μL, 3.00 Eq, 3.23 mmol) and ethyl 8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate in THF (6 mL). A solution of triphosgene (256 mg, 0.801 Eq, 863 μmol) in THF (1 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was used directly in the next step without further purification. MS: Calculated for C 27 H 19Cl2N3O5: 535.07, found [M+H] + :536.2,538.2.

[0584] Step 8: An 8 mL vial was charged with a mixture of ethyl 1-(3,5-dichlorophenyl)-8-(3-isocyanatophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (1 Eq) in THF (3 mL), followed by the addition of tert-butyl (20-amino-3,6,9,12,15,18-hexaoxaicosyl)carbamate (2 Eq). The reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure. The mixture was directly purified by preparative HPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 5% ACN to 98% in 6 min, 98% ACN to 98% in 2 min); total flow rate, 70 mL / min; detector, UV 220 nm. Lyophilization of the collected fractions gave ethyl 1-(3,5-dichlorophenyl)-8-(3-(3-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-yl)ureido)phenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (610 mg, 0.57 mmol, 90% purity) as a colorless oil. MS: Calculated for C 46 H 59 Cl2N5O 13 :959.35,found[M+H] + :960.2,962.0.

[0585] Step 9: A 40 mL vial was charged with a mixture of ethyl 1-(3,5-dichlorophenyl)-8-(3-(3-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-yl)ureido)phenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (610 mg, 1 Eq, 635 μmol), LiOH (152 mg, 10.0 Eq, 6.35 mmol), THF (6 mL), and water (2 mL). The reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure to remove most of the THF, and the residue was diluted with water (50 mL), and then the pH was adjusted to 6.0 by adding saturated NaHSO solution. The resulting solid was filtered to give 1-(3,5-dichlorophenyl)-8-(3-(3-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-yl)ureido)phenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid (380 mg, 0.37 mmol, 58%, 90% purity) as a pale yellow solid, which was used directly in the next step without further purification. MS: Calculated for C 44 H 55 Cl2N5O 13 :931.32,found[M+H] + :932.5,934.5.

[0586] Step 10: A 40 mL vial was charged with a mixture of 1-(3,5-dichlorophenyl)-8-(3-(3-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-yl)ureido)phenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid (380 mg, 1 Eq, 407 μmol), HATU (186 mg, 1.20 Eq, 489 μmol), DIEA (158 mg, 213 μL, 3.00 Eq, 1.22 mmol), and DMF (4 mL). The reaction mixture was stirred at 25 °C for 10 min, then N,2-dimethylpropan-2-amine (71 mg, 2.0 eq, 0.81 mmol) was added, and the reaction mixture was stirred for an additional 1 h at 25 °C. The mixture was directly purified by preparative HPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 5% ACN to 98% in 6 min, 98% ACN to 98% in 2 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were lyophilized to give tert-butyl (1-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azadocosan-22-yl)carbamate (260 mg, 0.23 mmol, 57%, 90% purity) as a colorless oil. MS: Calculated for C 49 H 66 Cl2N6O 12 :1000.41,found[M+H] + :1001.3,1003.3.

[0587] Step 11: To an 8 mL vial was added a mixture of tert-butyl (1-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azadocosan-22-yl)carbamate (250 mg, 1 Eq, 250 μmol) and DCM (5 mL), and zinc bromide (281 mg, 66.5 μL, 5.00 Eq, 1.25 mmol) was added. The reaction mixture was stirred at 25° C. for 1.5 hours. The resulting mixture was concentrated, and DMF was added (1 mL). The mixture was then purified by preparative PLC using the following conditions: column: WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase: water (0.1% FA) and ACN (5% ACN in 1 min, 5% ACN in 5 min, 10% ACN in 6 min, 98% ACN in 1 min, 98% ACN in 98%); total flow rate: 70 mL / min; detector: UV 220 nm. This gave 8-(3-(3-(20-amino-3,6,9,12,15,18-hexaoxaicosyl)ureido)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide 2,2,2-trifluoroacetate (250 mg, 0.22 mmol, 89%, 90% purity) as a colorless oil. MS: Calculated for C 44 H 58 Cl2N6O 10 :900.36,found[M+H] + :901.4,903.4.

[0588] [ka]

[0589] Step 12: A 40 mL vial was charged with a mixture of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (5.0 g, 1 Eq, 8.7 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (3.3 g, 1.0 Eq, 8.7 mmol), and ACN (20 mL). The reaction mixture was stirred at 25° C. for 60 minutes, then 1-hydroxypyrrolidine-2,5-dione (1.0 g, 1.0 Eq, 8.7 mmol) was added, and the reaction mixture was stirred at 25° C. for an additional 12 hours. The mixture was concentrated under reduced pressure. The crude product was purified by MPLC under the following conditions: C18 120 g, ACN / HO system, ACN ratio from 0% to 85% in 20 min, flow rate: 70 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give tri-tert-butyl 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (5.0 g, 4.5 mmol, 51%, 60% purity) as a white solid. Calculated for C 32 H 55 N5O 10 :669.39,found[M+H] + :670.3.

[0590] Step 13: A 50 mL round-bottom flask was charged with a mixture of tri-tert-butyl 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (5.0 g, 1 Eq, 7.5 mmol) and DCM (20 mL), to which TFA (10 mL) was added. The reaction mixture was stirred at 25° C. for 4 hours. The mixture was concentrated under reduced pressure. The crude product was precipitated with diethyl ether to give 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (4.0 g, 6.8 mmol, 85% purity, 91% yield) as a white solid. Calc'd for C 20 H 31 N5O 10 :501.21,found[M+H] + :502.4.

[0591] [ka]

[0592] Step 14: In a 25 mL round-bottom flask, add 8-(3-(3-(20-amino-3,6,9,12,15,18-hexaoxaicosyl)ureido)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (250 mg, 1 Eq, 2 A mixture of 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (278 mg, 2.00 Eq, 554 μmol) was added, followed by the addition of DIEA (180 mg, 243 μL, 5.02 Eq, 1.39 mmol). The resulting mixture was stirred at 25 °C for 1 hour. The crude product was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% FA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(1-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (160 mg, 0.11 mmol, 39% yield, 95% purity) as a white solid. Calculated for C. 62 H 85 Cl2F3O 19 :1286.54,found[M+H] + :1287.5,1289.5.

[0593] Example 2: 2,2′,2″-(10-(1-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 2)

[0594] [ka]

[0595] Step 1: A 50 mL round-bottom flask was charged with ethyl 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (2.0 g, 1 Eq, 4.0 mmol), EtOH (30 mL), LiOH (960 mg, 10 Eq, 40.1 mmol), and HO (10 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove most of the EtOH, and the residue was then diluted with water (30 mL), and the pH was adjusted to 6.0 by adding saturated NaHSO solution. The precipitated solid was collected by filtration and washed with EA to give 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid (1.8 g, 3.8 mmol, 95%) as a white solid. Calculated for C 18 H 11 BrCl2N2O4: 467.93, found [M+H] + :469.0,471.0.

[0596] Step 2: A 100 mL round-bottom flask was charged with 8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid (1.8 g, 1 Eq, 3.8 mmol), HATU (1.8 g, 1.2 Eq, 4.7 mmol), and DMF (20 mL). The reaction mixture was stirred at 20 °C for 10 min, and then N,2-dimethylpropan-2-amine (0.55 g, 1.6 Eq, 6.3 mmol) was added, and the reaction mixture was stirred at 20 °C for an additional 2 h. The mixture was diluted with 50 mL of water and extracted with EtOAc (3 x 50 mL). The combined organic layers were then washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC under the following conditions: silica gel column 40 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 50 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 8-bromo-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (1.7 g, 3.2 mmol, 82%) as a white solid. Calculated for C. 23 H 22 BrCl2N3O3: 537.02, found [M+H] + :538.0,540.0.

[0597] Step 3: A 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere was charged with 8-bromo-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (1.7 g, 1 Eq, 3.2 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.70 g, 1.0 Eq, 3.2 mmol), KCO (1.32 g, 3.0 Eq, 9.55 mmol), 1,4-dioxane (20 mL), HO (2 mL), and 1,1′-bis(di-t-butylphosphino)ferrocenepalladium dichloride (0.2 g, 0.1 Eq, 0.3 mmol). The reaction mixture was stirred at 100°C for 4 hours, and then the reaction mixture was concentrated under reduced pressure. The crude product was purified by MPLC under the following conditions: silica gel column 80g, PE / EtOAc system, 0% to 85% EtOAc in 25 min, flow rate: 55 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 8-(3-aminophenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (1.2 g, 2.2 mmol, 69%) as a pale yellow solid. Calculated for C 29 H 28 Cl2N4O3: 550.15, found [M+H] + :551.2,553.2.

[0598] Step 4: A 40 mL vial was charged with bis(trichloromethyl)carbonate (250 mg, 0.801 Eq, 843 μmol), THF (6 mL), and triethylamine (480 mg, 4.51 Eq, 4.74 mmol), to which was added a solution of 8-(3-aminophenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (580 mg, 1 Eq, 1.05 mmol) in THF (2 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. LCMS showed 80% product. The reaction solution was used in the next step without purification. Calculated for C 30 H 26 Cl2N4O4: 576.13, found [M+H] + :577.2,579.2.

[0599] Step 5: A 40 mL vial was charged with N-(tert-butyl)-1-(3,5-dichlorophenyl)-8-(3-isocyanatophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (600 mg, 1 Eq, 1.04 mmol) in THF (8 mL), to which was added a solution of tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (550 mg, 1.57 Eq, 1.63 mmol) in THF (2 mL) dropwise at 0° C. The reaction mixture was stirred at 20° C. for 1 hour. The crude mixture was concentrated under reduced pressure and then purified by preparative HPLC using the following conditions: column, WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase, water (0.1% FA) and ACN (5% ACN to 5% ACN in 1 min, 25% ACN to 90% in 8 min, 95% ACN to 95% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure and lyophilized to give tert-butyl (1-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14-tetraoxa-2-azahexadecan-16-yl)carbamate (800 mg, 875 μmol, 84.2%) as a white solid. Calculated for C 45 H 58 Cl2N6O 10 :912.36,found[M+H] + :913.2,915.2.

[0600] Step 6: An 8 mL vial was charged with tert-butyl (1-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14-tetraoxa-2-azahexadecan-16-yl)carbamate (800 mg, 1 Eq, 875 μmol), DCM (15 mL), tris(propan-2-yl)silane (800 mg, 1.04 mL, 5.77 Eq, 5.05 mmol), and zinc bromide (980 mg, 232 μL, 4.97 Eq, 4.35 mmol). The reaction mixture was stirred at 20 °C for 2 h, then additional zinc bromide (980 mg, 232 μL, 4.97 Eq, 4.35 mmol) was added, and the reaction mixture was stirred at 20 °C for an additional 2 h. The mixture was concentrated under reduced pressure, and then 10 mL of DMF was added. The crude product was purified by preparative HPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20-40 μm; mobile phase, water (0.1% FA) and ACN (5% ACN to 5% ACN in 1 min, 25% ACN to 80% in 8 min, 90% ACN to 90% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure to remove most of the acetonitrile. The residue was diluted with water (20 mL), and the pH was adjusted to 7.0 by adding saturated NaHCO solution, and the product was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 8-(3-(3-(14-amino-3,6,9,12-tetraoxatetradecyl)ureido)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (520 mg, 639 μmol, 73.0%) as a white solid. Calculated for C 40 H 50 Cl2N6O8:812.31,found [M+H] + :813.3,815.3.

[0601] Step 7: In an 8 mL vial, add 8-(3-(3-(14-amino-3,6,9,12-tetraoxatetradecyl)ureido)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (320 mg, 1 Eq, 393 μmol), D MF (3 mL), DIEA (250 mg, 337 μL, 4.92 Eq, 1.93 mmol), and 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (400 mg, 2.03 Eq, 798 μmol) were added. The reaction mixture was stirred at 25 °C for 1 h. The crude product was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.1% FA); Mobile phase B: ACN; Gradient: 20% B to 55% B in 10 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(1-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (220 mg, 177 μmol, 44.9%) as a white solid. Calculated for C 40 H 50 Cl2N6O8: 1198.49, found [M+H-FA] + :1199.8,1201.8.

[0602] Example 3: 2,2',2''-(10-(24-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-2,24-dioxo-6,9,12,15,18,21-hexaoxa-3-azatetracosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 3)

[0603] [ka]

[0604] Step 1: A 40 mL vial was charged with a mixture of 2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-onic acid (oic acid) (200 mg, 1.52 Eq, 441 μmol), N-ethyl-N-isopropylpropan-2-amine (120 mg, 3.20 Eq, 928 μmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (150 mg, 1.36 Eq, 394 μmol) and DMF (1 mL). The reaction mixture was stirred at 20 °C for 10 min, then 8-(3-aminophenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (160 mg, 1 eq, 290 μmol) was added, and the reaction mixture was stirred for an additional 1 h at 25 °C. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20-40 μm; mobile phase, water (0.05% TFA) and ACN (5% ACN in 1 min, 30% ACN in 6 min, 98% ACN in 3 min, 98% ACN in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure to give tert-butyl (21-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-21-oxo-3,6,9,12,15,18-hexaoxaheneicosyl)carbamate (180 mg, 182 μmol, 62.9%) as a yellow oil. Calculated for C 49 H 65 Cl2N5O 12 :985.40,found[M+H] + :986.4,988.3.

[0605] Step 2: A 50 mL round-bottom flask was charged with a mixture of tert-butyl (21-((3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-21-oxo-3,6,9,12,15,18-hexaoxaheneicosyl)carbamate (170 mg, 1 Eq, 172 μmol), zinc(II) bromide (400 mg, 10.3 Eq, 1.78 mmol), and DCM (4 mL). The reaction mixture was stirred at 25° C. for 16 h, and then 5 mL of DMF was added. The mixture was purified directly by MPLC under the following conditions: column, WelFlash™, C18 120 g, Spherical 20–40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm, to give 8-(3-(1-amino-3,6,9,12,15,18-hexaoxaheneicosan-21-amido)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (60 mg, 68 μmol, 39%) as a yellow oil. Calculated for C. 44 H 57 Cl2N5O 10 :885.34,found[M+H] + :886.4,888.4.

[0606] Step 3: A 2 mL vial was charged with a mixture of 8-(3-(1-amino-3,6,9,12,15,18-hexaoxaheneicosan-21-amido)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (5 mg, 1 Eq, 6 μmol), 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (5 mg, 2 Eq, 0.01 mmol), DIEA (3 mg, 4 μL, 4 Eq, 0.02 mmol), and DMF (0.01 mL). The reaction mixture was stirred at 60°C for 1 hour. The crude product was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150mm 5um; Mobile phase A: Water (0.05% TFA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give the product (9.9 mg, 7.1 μmol, 12%). Calc'd for C 62 H 83 Cl2F3N9O 18 :1368.52,found[M+H-TFA] + :1272.5,1274.5.

[0607] Example 4: 2,2',2''-(10-(1-(3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 4)

[0608] [ka]

[0609] [ka]

[0610] Step 1: A 40 mL vial purged and maintained under an inert nitrogen atmosphere was charged with a mixture of 8-bromo-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (Step 2 of Example 2; 350 mg, 1 Eq, 649 μmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (160 mg, 0.994 Eq, 645 μmol), potassium carbonate (270 mg, 3.01 Eq, 1.95 mmol), 1,1′-bis(di-t-butylphosphino)ferrocenepalladium dichloride (20 mg, 1 Eq, 649 μmol), 1,4-dioxane (4 mL), and water (0.4 mL). The reaction mixture was stirred at 80°C for 1 hour. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 120g, Spherical 20-40µm; mobile phase, water (0.05% TFA) and ACN (5% ACN to 5% ACN in 1 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70mL / min; detector, UV 220. Purification afforded 3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)benzoic acid (212mg, 365µmol, 56.3%) as a yellow solid. Calculated for C 30 H 27 Cl2N3O5:579.13,found[M+H] + :580.1,582.1.

[0611] Step 2: An 8 mL vial was charged with a mixture of 3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)benzoic acid (200 mg, 1 Eq, 345 μmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (160 mg, 1.22 Eq, 421 μmol), DIEA (130 mg, 175 μL, 2.92 Eq, 1.01 mmol), and DMF (2 mL). The reaction mixture was stirred at 20 °C for 10 min, then tert-butyl (20-amino-3,6,9,12,15,18-hexaoxaicosyl)carbamate (200 mg, 1.37 eq, 471 μmol) was added, and the reaction mixture was stirred for an additional 1 h at 25 °C. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20-40 μm; mobile phase, water (0.05% TFA) and ACN (5% ACN in 1 min, 30% ACN in 6 min, 98% ACN in 3 min, 98% ACN in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure to give tert-butyl (1-(3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azadocosan-22-yl)carbamate (260 mg, 263 μmol, 76.5%) as a yellow oil. Calculated for C 49 H 65 Cl2N5O 12 :985.40,found[M+H] + :986.3,988.3.

[0612] Step 3: An 8 mL vial was charged with a mixture of tert-butyl (1-(3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azadocosan-22-yl)carbamate (255 mg, 1 Eq, 258 μmol), zinc(II) bromide (580 mg, 9.97 Eq, 2.58 mmol), and DCM (5 mL). The reaction mixture was stirred at 25° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to remove most of the DCM, and then ACN (3 mL) was added. The solid ZnBr was removed by filtration, and the remaining residue was then diluted with water (50 mL), extracted with DCM (7 x 50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 8-(3-((20-amino-3,6,9,12,15,18-hexaoxaicosyl)carbamoyl)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (180 mg, 203 μmol, 78.6%) as a pale yellow solid, which was used directly in the next step without further purification. Calculated for C 44 H 57 Cl2N5O 10 :885.35,found[M+H] + :886.3,888.3.

[0613] Step 4: An 8 mL vial was charged with a mixture of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (170 mg, 1.55 Eq, 297 μmol), DIEA (80 mg, 0.11 mL, 3.2 Eq, 0.62 mmol), 2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (90 mg, 1.3 Eq, 0.25 mmol), and DMF (2 mL). The reaction mixture was stirred at 20° C. for 10 minutes, then 8-(3-((20-amino-3,6,9,12,15,18-hexaoxaicosyl)carbamoyl)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (170 mg, 1 Eq, 192 μmol) was added and the reaction mixture was stirred at 25° C. for an additional 1 hour. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Purification afforded tri-tert-butyl 2,2',2''-(10-(1-(3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, zinc salt(II) (80 mg, 53 μmol, 28%) as a pale yellow solid. Product 2: Calculated for C 72 H 107 Cl2N9O 17 Zn 2+ :1503.64,found[(M+Zn 2+ ) / 2+H] + :753.2.

[0614] Step 5: An 8 mL vial was charged with a mixture of tri-tert-butyl 2,2′,2″-(10-(1-(3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, zinc salt (II) (70 mg, 1 Eq, 46 μmol), lithium hydroxide (33 mg, 30 Eq, 1.4 mmol), MeOH (0.3 mL), and water (0.3 mL). The reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH, and then the residue was diluted with water (50 mL). The crude product was purified by preparative HPLC under the following conditions: column: SunFire prep OBD 19*150 mm 5 um; mobile phase A: water (0.05% TFA); mobile phase B: ACN; gradient: 25% B to 65% B in 8 min; flow rate: 20 mL / min; wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(1-(3-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) (4.6 mg, 3.3 μmol, 7.1%) as a white solid. Calculated for C 62 H 84 Cl2F3N9O 19 :1385.52,found[(M+H-TFA] + :1272.7,1274.7.

[0615] Example 5: 2,2′,2″-(10-(1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 5)

[0616] [ka]

[0617] Step 1: In a 40 mL vial maintained under an inert nitrogen atmosphere, 8-bromo-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (Step 2 of Example 2; 700 mg, 1 Eq, 1.30 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2 A mixture of (-dioxaborolan-2-yl)aniline (256 mg, 0.900 eq, 1.17 mmol), K2CO3 (538 mg, 3.00 eq, 3.89 mmol), 1,1'-bis(di-t-butylphosphino)ferrocenepalladium dichloride (85 mg, 0.10 eq, 0.13 mmol), 1,4-dioxane (7 mL), and water (0.7 mL) was added. The reaction mixture was stirred at 80 °C for 1 h. The mixture was concentrated, and the crude product was purified by MPLC under the following conditions: silica gel column 40 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 40 mL / min; wavelength: 254 nm. Purification gave 8-(4-aminophenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (600 mg, 1.09 mmol, 83.8%) as a yellow solid. Calculated for C 29 H 28 Cl2N4O3: 550.15, found [M+H] +:551.2,553.2.

[0618] Step 2: A 40 mL vial was charged with a mixture of 8-(4-aminophenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (320 mg, 1 Eq, 580 μmol) and TEA (120 mg, 165 μL, 2.04 Eq, 1.19 mmol) in THF (3 mL), to which triphosgene (138 mg, 0.801 Eq, 465 μmol) in THF (1 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The resulting mixture was used directly in the next step without further purification.

[0619] Step 3: An 8 mL vial was charged with a mixture of 8-(4-aminophenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (320 mg, 1 Eq, 580 μmol) and THF (1 mL), and tert-butyl (20-amino-3,6,9,12,15,18-hexaoxaicosyl)carbamate (176 mg, 1.50 Eq, 415 μmol) was added. The reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure. The collected fractions were lyophilized. This resulted in tert-butyl (1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azadocosan-22-yl)carbamate (200 mg, 0.18 mmol, 65%, 90% purity) as a colorless oil. Calculated for C 49 H 66 Cl2N6O 12 :1000.41,found[M+H] + :1001.5,1003.5.

[0620] Step 4: An 8 mL vial was charged with a mixture of tert-butyl (1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azadocosan-22-yl)carbamate (190 mg, 1 Eq, 190 μmol) in DCM (5 mL), to which zinc(II) bromide (427 mg, 10.0 Eq, 1.90 mmol) was added. The reaction mixture was stirred at 25° C. for 1.5 hours. The resulting mixture was concentrated, MeCN was added, and the solution was sonicated for 2 minutes, then filtered, and the filtrate was concentrated. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 8-(4-(3-(20-amino-3,6,9,12,15,18-hexaoxaicosyl)ureido)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (160 mg, 177 μmol, 93.6%) as an off-white solid. Calc'd for C 44 H 58 Cl2N6O 10 :900.36,found[M+H] + :901.2,903.2.

[0621] Step 5: An 8 mL vial was charged with a mixture of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (80 mg, 0.84 Eq, 0.14 mmol) in DMF (0.5 mL), followed by the addition of N-ethyl-N-isopropylpropan-2-amine (160 mg, 7.44 Eq, 1.24 mmol) and 2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (48 mg, 0.80 Eq, 0.13 mmol). The mixture was stirred at 25° C. for 10 minutes. To this mixture was added 8-(4-(3-(20-amino-3,6,9,12,15,18-hexaoxaicosyl)ureido)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (160 mg, 177 μmol, 93.6%). The resulting mixture was stirred at 25° C. for 1 hour. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 5% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were lyophilized to give tri-tert-butyl 2,2',2''-(10-(1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (150 mg, 93 μmol, 56%, 90% purity) as a white solid. Calculated for C 72 H 108 Cl2N 10 O 17 :1454.73,found[M / 2+H] + :728.3.

[0622] Step 6: An 8 mL vial was charged with a mixture of tri-tert-butyl 2,2′,2″-(10-(1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (90 mg, 1 Eq, 62 μmol) in MeOH (2.4 mL) and HO (0.8 mL), followed by the addition of lithium hydroxide (30 mg, 20 Eq, 1.3 mmol). The resulting mixture was stirred at 80°C for 1 hour. The crude product was purified by preparative HPLC under the following conditions: column: SunFire prep OBD 19*150mm 5um; mobile phase A: water (0.1% FA); mobile phase B: ACN; gradient: 25% B to 65% B in 8 min; flow rate: 20 mL / min; wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (25.6 mg, 18 μmol, 29%, 95% purity) as a white solid. Calculated for C. 61 H 86 Cl2N 10 O 19 :1332.54,found[M+H-FA] + :1286.5,1288.5.

[0623] Example 6: 2,2′,2″-(10-(1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 6)

[0624] [ka]

[0625] Step 1: An 8 mL vial was charged with a mixture of N-(tert-butyl)-1-(3,5-dichlorophenyl)-8-(4-isocyanatophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (150 mg, 1 Eq, 260 μmol) and THF (1 mL), and tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (175 mg, 2.00 Eq, 520 μmol) was added. The reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure. The collected fractions were lyophilized. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 5% ACN to 98% in 6 min, 98% ACN to 98% in 2 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were lyophilized to give tert-butyl (1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14-tetraoxa-2-azahexadecan-16-yl)carbamate (160 mg, 0.16 mmol, 61%, 90% purity) as a white solid. Calculated for C 45 H58 Cl2N6O 10 :912.36,found[M+H] + :913.4,915.4.

[0626] Step 2: An 8 mL vial was charged with a mixture of tert-butyl (1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14-tetraoxa-2-azahexadecan-16-yl)carbamate (160 mg, 1 Eq, 175 μmol) and DCM (2 mL), to which was added ZnBr (400 mg, 10.1 Eq, 1.78 mmol). The reaction mixture was stirred at 25 °C for 1.5 h. The resulting mixture was concentrated, MeCN was added, the solution was sonicated for 2 min, filtered, and the filtrate was concentrated. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL), then the combined organic layers were washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give tert-butyl (1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14-tetraoxa-2-azahexadecan-16-yl)carbamate (160 mg, 0.16 mmol, 61%, 90% purity) as a white solid. Calc'd for C 40 H 50 Cl2N6O8:812.31,found [M+H] + :813.4,815.4.

[0627] Step 3: An 8 mL vial was charged with a mixture of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (100 mg, 1.09 Eq, 175 μmol) in DMF (2 mL), followed by the addition of N,N,N,N-tetramethyl-o-(n-succinimidyl)uronium hexafluorophosphate (70 mg, 1.2 Eq, 0.19 mmol) and DIEA (88 mg, 0.12 mL, 4.3 Eq, 0.68 mmol). The mixture was stirred at 25° C. for 10 minutes. To this mixture was added 8-(4-(3-(14-amino-3,6,9,12-tetraoxatetradecyl)ureido)phenyl)-N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide (130 mg, 1 eq, 160 μmol). The resulting mixture was stirred at 25 °C for 1 h. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 120 g, spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 5% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were lyophilized to give tri-tert-butyl 2,2',2''-(10-(1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (130 mg, 85 μmol, 54%, 90% purity) as a white solid. Calculated for C 68 H 100 Cl2N 10 O 15 :1366.67,found[M+H] + :1367.3,1369.3.

[0628] Step 4: An 8 mL vial was charged with a mixture of tri-tert-butyl 2,2′,2″-(10-(1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (130 mg, 1 Eq, 95.0 μmol), MeOH (1.5 mL), and water (0.5 mL), followed by the addition of LiOH (23 mg, 10 Eq, 0.96 mmol). The resulting mixture was stirred at 80° C. for 1 hour. The crude product was purified by preparative HPLC using the following conditions: column: SunFire prep OBD 19*150mm 5um; mobile phase A: water (0.1% FA); mobile phase B: ACN; gradient: 25% B to 65% B in 8 min; flow rate: 20 mL / min; wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(1-((4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (22 mg, 17 μmol, 18%, 95% purity) as a white solid. Calculated for C 57 H 78 Cl2N 10 O 17 :1244.49,found[M+H-FA] + :1199.6,1201.6.

[0629] Example 7: 2,2',2''-(10-(1-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 7)

[0630] [ka]

[0631] Step 1: A 40 mL vial was charged with a mixture of ethyl 1-(3,5-dichlorophenyl)-8-(3-isocyanatophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (525 mg, 1 Eq, 979 μmol) and THF (5 mL), and tert-butyl (20-amino-3,6,9,12,15,18-hexaoxaicosyl)carbamate (416 mg, 1.00 Eq, 980 μmol) was added. The reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure. The mixture was directly purified by preparative HPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 5% ACN to 98% in 6 min, 98% ACN to 98% in 2 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were lyophilized to give ethyl 1-(3,5-dichlorophenyl)-8-(3-(3-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-yl)ureido)phenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (300 mg, 312 μmol, 31.9%) as a colorless oil. Calculated for C. 46 H 59 Cl2N5O 13:959.35,found[M+H] + :960.2,962.0.

[0632] Step 2: A 40 mL vial was charged with a mixture of ethyl 1-(3,5-dichlorophenyl)-8-(3-(3-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-yl)ureido)phenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (300 mg, 1 Eq, 312 μmol), lithium hydroxide (23 mg, 3.1 Eq, 0.96 mmol), THF (1.5 mL), and water (0.3 mL). The reaction mixture was stirred at 25° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to remove most of the THF, and then the residue was diluted with water (1 mL). The pH of the solution was adjusted to 6.0 by adding saturated NaHSO solution. The precipitated solid was filtered to give 1-(3,5-dichlorophenyl)-8-(3-(3-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-yl)ureido)phenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid (200 mg, 0.19 mmol, 62%, 90% purity) as a pale yellow solid, which was used directly in the next step without further purification. Calc'd for C 44 H 55 Cl2N5O 13 :931.32,found[M+H] + :932.4,934.4.

[0633] Step 3: In an 8 mL vial, add 1-(3,5-dichlorophenyl)-8-(3-(3-(2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-yl)ureido)phenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid (100 mg, 1 Eq, 107 μm A mixture of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (50 mg, 1.2 Eq, 0.13 mmol), N-ethyl-N-isopropylpropan-2-amine (42 mg, 3.0 Eq, 0.32 mmol), and DMF (1 mL) was added to the reaction mixture. The reaction mixture was stirred at 25° C. for 10 minutes, and then 3,3-dimethylmorpholine (19 mg, 1.5 Eq, 0.16 mmol) was added, and the reaction mixture was stirred at 25° C. for an additional hour. The mixture was directly purified by preparative HPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 5% ACN to 98% in 6 min, 98% ACN to 98% in 2 min); total flow rate, 70 mL / min; detector, UV 220 nm. Concentration of the collected fractions gave tert-butyl (1-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azadocosan-22-yl)carbamate (90 mg, 87 μmol, 82%) as a colorless oil. Calculated for C 50 H 66 Cl2N6O 13 :1028.41,found[M+H] + :1029.4,1031.4.

[0634] Step 4: An 8 mL vial was charged with a mixture of tert-butyl (1-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14,17,20-hexaoxa-2-azadocosan-22-yl)carbamate (82 mg, 1 Eq, 80 μmol), DCM (1 mL), and TFA (0.1 mL). The reaction mixture was stirred at 25° C. for 20 minutes. The resulting mixture was concentrated, DMF (1 mL) was added, and the solution was then purified by preparative PLC using the following conditions: column: WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase: water (0.1% FA) and ACN (5% ACN in 1 min, 5% ACN in 5 min, 10% ACN in 6 min, 98% ACN in 1 min, 98% ACN in 98%); total flow rate: 70 mL / min; detector: UV 220 nm. Purification gave 1-(20-amino-3,6,9,12,15,18-hexaoxaicosyl)-3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)urea (80 mg, 77 μmol, 97%, 90% purity) as a colorless oil. Calc'd for C 45 H 58 Cl2N6O 11 :928.35,found[M+H] + :929.5,931.5.

[0635] Step 5: In a 25 mL round-bottom flask, add 1-(20-amino-3,6,9,12,15,18-hexaoxaicosyl)-3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)urea (80 mg, 1 Eq A mixture of 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (86 mg, 2.0 Eq, 0.17 mmol) was added, followed by the addition of DIEA (56 mg, 75 μL, 5.0 Eq, 0.43 mmol). The resulting mixture was stirred at 25 °C for 1 hour. The crude product was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% TFA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(1-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazapentacosan-25-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) (54.8 mg, 35.7 μmol, 42%, 93.3% purity) as a white solid. Calculated for C. 63 H 85 Cl2F3N 10 O 20 :1428.52,found[M+H-TFA] + :1315.6,1317.6.

[0636] Example 8: 2,2',2''-(10-(1-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 8)

[0637] [ka]

[0638] Step 1: A 40 mL vial was charged with a mixture of (1-(3,5-dichlorophenyl)-8-(3-isocyanatophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (1 eq) and THF (2.0 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated and purified by MPLC using the following conditions: column, C18 120 g; mobile phase, water (0.1% FA) and ACN (30% ACN to 98% in 8 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure and dried to give tert-butyl (1-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14-tetraoxa-2-azahexadecan-16-yl)carbamate (165 mg, 175 μmol) as a yellow oil. Calc'd for C 46 H 58 Cl2N6O 11 :940.35,found[M+H] + :941.4.

[0639] Step 2: An 8 mL vial was charged with a mixture of tert-butyl (1-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1-oxo-5,8,11,14-tetraoxa-2-azahexadecan-16-yl)carbamate (155 mg, 1 Eq, 165 μmol) and DCM (1.0 mL), and TFA (0.1 mL) was added. The reaction mixture was stirred at 25° C. for 30 minutes. The mixture was concentrated under reduced pressure to give 1-(14-amino-3,6,9,12-tetraoxatetradecyl)-3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)urea 2,2,2-trifluoroacetate (76 mg, 80 μmol, 48%) as a yellow oil. Calc'd for C 43 H 51 Cl2F3N6O 11 :954.29,found[M+H-TFA] + :841.2.

[0640] Step 3: In an 8 mL vial, add 1-(14-amino-3,6,9,12-tetraoxatetradecyl)-3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)urea (76 mg, 1 Eq, 90 μmol) and DIE A mixture of A (76 mg, 0.10 mL, 6.5 Eq, 0.59 mmol), 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (132 mg, 2.9 Eq, 263 μmol), and DMF (1.0 mL) was added. The reaction mixture was stirred at 25 °C for 2 h. The crude product was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% FA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(1-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazanonadecan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (59.2 mg, 46.5 μmol, 51%) as an off-white solid. Calculated for C. 58 H 78 Cl2N 10 O 18 :1272.48,found[M+H-FA] + :1227.6.

[0641] Example 9: 2,2',2''-(10-(2-(4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)carbamoyl)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 9)

[0642] [ka]

[0643] Step 1: A 40 mL vial was charged with a mixture of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (1.2 g, 1.2 Eq, 2.1 mmol), 2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (0.75 g, 1.2 Eq, 2.1 mmol), N-ethyl-N-isopropylpropan-2-amine (0.68 g, 3.0 Eq, 5.3 mmol), and THF (10 mL). The reaction mixture was stirred at 25 °C for 1 h, and then piperidine-4-carboxylic acid (0.45 g, 2.0 Eq, 3.5 mmol), sodium bicarbonate (0.32 g, 2.2 Eq, 3.8 mmol), HO (2 mL), and THF (2 mL) were added. The resulting mixture was stirred at 25 °C for an additional 16 h. The combined solution was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% NH3HO); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 70 mL / min; Wavelength: 220 nm; ELSD was used as the monitoring method. The collected fractions were lyophilized to give 1-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl)piperidine-4-carboxylic acid (525 mg, 768 μmol, 44%) as a white solid. Calculated for C34 H 61 N5O9:683.45,found[M+H] + :684.5.

[0644] Step 2: An 8 mL vial was charged with a mixture of 1-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl)piperidine-4-carboxylic acid (354 mg, 3.00 Eq, 518 μmol), HATU (210 mg, 3.20 Eq, 552 μmol), DIEA (134 mg, 181 μL, 6.01 Eq, 1.04 mmol), and DMF (1.0 mL). The reaction mixture was stirred at 20 °C for 10 min, then (8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (100 mg, 1 eq, 173 μmol) was added, and the reaction mixture was stirred for an additional 2 h at 25 °C. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN in 1 min, 30% ACN in 6 min, 98% ACN in 3 min, 98% ACN in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Purification gave tri-tert-butyl 2,2',2''-(10-(2-(4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)carbamoyl)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (125 mg, 100 μmol, 58.2%) as a yellow oil. Calc'd for C 64 H 87 Cl2N9O 12 :1243.58,found[M+H] + :1244.7.

[0645] Step 3: An 8 mL vial was charged with a mixture of tri-tert-butyl 2,2′,2″-(10-(2-(4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)carbamoyl)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (118 mg, 1 Eq, 94.8 μmol), iodotrimethylsilane solution (114 mg, 80.6 μL, 6.01 Eq, 570 μmol), and DCM (1.0 mL). The reaction mixture was stirred at 25° C. for 2 hours. The crude product was purified by preparative HPLC using the following conditions: column: SunFire prep OBD 19*150mm 5um; mobile phase A: water (0.05% FA); mobile phase B: ACN; gradient: 25% B to 65% B in 8 min; flow rate: 20 mL / min; wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(2-(4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)carbamoyl)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (19.4 mg, 17.3 μmol, 18.2%) as an off-white solid. Calculated for C 53 H 65 Cl2N9O 14 :1121.40,found[M+H-FA] + :1076.5.

[0646] Example 10: 2,2',2''-(10-(1-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,6,13-trioxo-9-oxa-2,5,12-triazatetradecan-14-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 10)

[0647] [ka]

[0648] Step 1: A 40 mL vial was charged with a mixture of (1-(3,5-dichlorophenyl)-8-(3-isocyanatophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (790 mg, 1 Eq, 1.30 mmol) and THF (8 mL), and tert-butyl (2-aminoethyl)carbamate (420 mg, 2.01 Eq, 2.62 mmol) was added. The reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150mm 5um; Mobile phase A: Water (0.05% TFA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give tert-butyl (2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)carbamate (660 mg, 862 μmol, 66.1%) as a white solid. Calc'd for C 38 H 42 Cl2N6O7:764.25,found [M+H-FA] + :765.2,767.2.

[0649] Step 2: A 40 mL round-bottom flask was charged with a mixture of tert-butyl (2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)carbamate (660 mg, 1 Eq, 862 μmol), DCM (8 mL), and TFA (0.4 mL). The reaction mixture was stirred at 25° C. for 1 h. The collected fractions were concentrated under reduced pressure to give 1-(2-aminoethyl)-3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)urea (600 mg, 901 μmol, 105%) as a yellow oil. Calculated for C 33 H 44 Cl2N6O5:664.20,found[M+H] + :665.2,667.2.

[0650] Step 3: An 8 mL vial was charged with a mixture of 1-(2-aminoethyl)-3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)urea (100 mg, 1 Eq, 150 μmol), 3-(2-((tert-butoxycarbonyl)amino)ethoxy)propanoic acid (85 mg, 2.4 Eq, 0.36 mmol), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (105 mg, 2.49 Eq, 374 μmol), 1-methylimidazole (N-) (74 mg, 71 μL, 6.0 Eq, 0.90 mmol), and DMF (1 mL). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% FA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give tert-butyl (2-(3-((2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)amino)-3-oxopropoxy)ethyl)carbamate (63 mg, 72 μmol, 48%) as a white solid. Calc'd for C 43 H 51 Cl2N7O9:879.31,found [M+H] + :880.3,882.3.

[0651] Step 4: An 8 mL vial was charged with a mixture of tert-butyl (2-(3-((2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)amino)-3-oxopropoxy)ethyl)carbamate (65 mg, 1 Eq, 74 μmol) and DCM (2 mL), to which TFA (0.1 mL) was added. The reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150mm 5um; Mobile phase A: Water (0.05% FA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give 3-(2-aminoethoxy)-N-(2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)propanamide (52 mg, 67 μmol, 90%) as a white solid. Calc'd for C 38 H 43 Cl2N7O7:779.26,found [M+H] + :780.3,782.3.

[0652] Step 5: An 8 mL vial was charged with a mixture of 3-(2-aminoethoxy)-N-(2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)propanamide (52 mg, 1 Eq, 67 μmol) and DIEA (75 mg, 0.10 mL, 8.7 Eq, 0.58 mmol), to which was added 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (75 mg, 2.2 Eq, 0.15 mmol). The reaction mixture was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column: SunFire prep OBD 19*150mm 5um; mobile phase A: water (0.05% FA); mobile phase B: ACN; gradient: 25% B to 65% B in 8 min; flow rate: 20 mL / min; wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(1-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-1,6,13-trioxo-9-oxa-2,5,12-triazatetradecan-14-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (14.3 mg, 11.8 μmol, 18%) as a white solid. Calculated for C 55 H 71 Cl2N 11 O 16 :1211.45,found[M+H-FA] + :1166.5,1168.5.

[0653] Example 11: 2,2′,2″-(10-(2-(4-(4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 11)

[0654] [ka]

[0655] Step 1: A 250 mL vial was charged with a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (10 g, 1 Eq, 50 mmol), dihydrofuran-2,5-dione (1.2 g, 0.24 Eq, 12 mmol), DMAP (0.30 g, 0.049 Eq, 2.5 mmol), and DCM (40 mL). The reaction mixture was stirred at 25° C. for 2 hours, and then an aqueous solution of sodium bicarbonate (200 mL) was added. The aqueous layer was extracted with EtOAc (3×200 mL), the pH of the aqueous layer was adjusted to 3 by the addition of 2 N HCl solution, and the aqueous layer was then extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-4-oxobutanoic acid (8.0 g, 27 mmol, 53%) as a white solid. Calc'd for C 14 H 24 N2O5:300.16,found[M+H] + :301.3.

[0656] Step 2: A 40 mL vial was charged with a mixture of 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-4-oxobutanoic acid (1.0 g, 1 Eq, 3.3 mmol) and 4 M HCl in dioxane (20 mL). The reaction mixture was stirred at 25 °C for 1 h. Aqueous NaHCO3 was added to the mixture to adjust the pH to 9, and then concentrated under reduced pressure to give 4-oxo-4-(piperidin-4-ylamino)butanoic acid (0.85 g, 3.4 mmol, 100%, 79% purity) as a white solid. Calculated for CH 16 N2O3:300.11,found[M+H] + :201.1.

[0657] Step 3: A 40 mL vial was charged with a mixture of 4-oxo-4-(piperidin-4-ylamino)butanoic acid (813 mg, 3.00 Eq, 4.06 mmol), 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (0.775 g, 1 Eq, 1.35 mmol), HBTU (616 mg, 1.20 Eq, 1.62 mmol), DMAP (10 mg, 0.060 Eq, 82 μmol), and DMF (10 mL). The reaction mixture was stirred at 25° C. for 4 hours. The combined solution was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150mm 5um; Mobile phase A: water (0.05% NH3HO); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 70 mL / min; Wavelength: 220 nm; ELSD was used as the monitoring method. The collected fractions were lyophilized to give 4-oxo-4-((1-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl)piperidin-4-yl)amino)butanoic acid (490 mg, 649 μmol, 48.0%) as a white solid. Calculated for C. 37 H 66 NO 10 :754.48,found[M+H] + :755.5.

[0658] Step 4: An 8 mL vial was charged with a mixture of 4-oxo-4-((1-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl)piperidin-4-yl)amino)butanoic acid (100 mg, 1 Eq, 132 μmol) and DMF (1 mL), to which was added HATU (80 mg, 1.6 Eq, 0.21 mmol) and DIEA (55 mg, 74 μL, 3.2 Eq, 0.43 mmol). The reaction mixture was stirred at 23 °C for 30 min, and then (8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (70 mg, 0.91 Eq, 0.12 mmol) was added. The reaction mixture was stirred at 23 °C for 2 h. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 2 min, 30% ACN to 98% in 10 min, 98% ACN to 98% in 1 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated to give tri-tert-butyl 2,2',2''-(10-(2-(4-(4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (150 mg, 114 μmol, 86.0%) as a yellow solid. Calculated for C 67 H 92 Cl2N 10 O 13 :1314.62,found[M+H] + :1315.5,1317.5.

[0659] Step 5: An 8 mL vial was charged with a mixture of tri-tert-butyl 2,2′,2″-(10-(2-(4-(4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (150 mg, 1 Eq, 114 μmol), TMSI (140 mg, 95.2 μL, 6.14 Eq, 700 μmol), and DCM (1.5 mL). The reaction mixture was stirred at 20° C. for 1 hour. The crude product was purified by preparative HPLC under the following conditions: column: SunFire prep OBD 19*150mm 5um; mobile phase A: water (0.05% FA); mobile phase B: ACN; gradient: 25% B to 65% B in 10 min; flow rate: 20 mL / min; wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(2-(4-(4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (49.2 mg, 41.2 μmol, 36.2%) as a white solid. Calculated for C 56 H 70 Cl2N 10 O 15 :1192.44,found[M+H-FA] + :1147.5,1149.5.

[0660] Example 12: (R)-2,2′,2″-(10-(2-(4-(2-amino-4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 12)

[0661] [ka]

[0662] Step 1: A 250 mL round-bottom flask was charged with 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (2.0 g, 1 Eq, 3.5 mmol), DMF (20 mL), DIEA (1.8 g, 2.4 mL, 4.0 Eq, 14 mmol), and N,N,N,N-tetramethyl-o-(n-succinimidyl)uronium hexafluorophosphate (1.7 g, 1.4 Eq, 4.7 mmol). The reaction mixture was stirred at 25° C. for 5 minutes, then tert-butyl piperidin-4-ylcarbamate (1.1 g, 1.6 Eq, 5.5 mmol) was added, and the reaction mixture was stirred at 25° C. for an additional 1 hour. The reaction mixture was purified by MPLC using the following conditions: column, C18 120 g; mobile phase, water (0.1% FA) and ACN (30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Collected fractions were concentrated under reduced pressure and dried to give tri-tert-butyl 2,2',2''-(10-(2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (2.0 g, 2.6 mmol, 76%) as a yellow solid. Calculated for C 38 H 70 N6O9:754.52,found[M+H]+ :755.5.

[0663] Step 2: A 100 mL round-bottom flask was charged with tri-tert-butyl 2,2′,2″-(10-(2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (1.5 g, 1 Eq, 2.0 mmol), DCM (15 mL), and TFA (3 mL). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give tri-tert-butyl 2,2',2''-(10-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate 2,2,2-trifluoroacetate (1.5 g, 1.6 mmol, 79%, 80% purity) as a yellow oil. Calc'd for C 35 H 63 F3N6O9:768.46,found[M+H-TFA] + :655.5.

[0664] Step 3: A 100 mL round-bottom flask was charged with (R)-2-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutanoic acid (0.53 g, 1.4 Eq, 2.1 mmol), DMF (15 mL), and DIEA (1.0 g, 1.3 mL, 5.0 Eq, 7.7 mmol), and to this was added HATU (0.81 g, 1.4 Eq, 2.1 mmol). The mixture was stirred at 25°C for 20 min, then tri-tert-butyl 2,2',2''-(10-(2-(4-aminopiperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate 2,2,2-trifluoroacetate (1.5 g, 80% wt, 1 Eq, 1.6 mmol) was added. The reaction mixture was stirred at 25°C for an additional 1 h. The reaction mixture was purified by MPLC using the following conditions: column, C18 120 g; mobile phase, water (0.1% FA) and ACN (30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure and dried to give tri-tert-butyl 2,2',2''-(10-(2-(4-(2-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-triacetate (880 mg, 995 μmol, 64%) as a yellow solid. Calc'd for C 43 H 77 N7O 12 :883.56,found[M+H] + :884.6.

[0665] Step 4: A 40 mL vial was charged with a mixture of tri-tert-butyl 2,2′,2″-(10-(2-(4-(2-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) (R)-triacetate (880 mg, 1 Eq, 995 μmol), MeOH (10 mL), LiOH (50 mg, 2.1 Eq, 2.1 mmol), and HO (2 mL). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH, and the residue was diluted with water (30 mL), and the pH was adjusted to 6.0 by adding saturated NaHSO solution. The solution was extracted with DCM (3 x 50 mL), dried over anhydrous NaSO and concentrated under reduced pressure to give (R)-3-((tert-butoxycarbonyl)amino)-4-oxo-4-((1-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl)piperidin-4-yl)amino)butanoic acid (700 mg, 805 µmol, 80.8%) as a pale yellow solid, which was used directly in the next step without further purification. Calc'd for C 42 H 75 N7O 12 :869.55,found[M+H] + :870.5.

[0666] Step 5: An 8 mL vial was charged with a mixture of (R)-3-((tert-butoxycarbonyl)amino)-4-oxo-4-((1-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl)piperidin-4-yl)amino)butanoic acid (100 mg, 1 Eq, 115 μmol) in DCM (1 mL), and (8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (67 mg, 1.0 Eq, 0.12 mmol) and DMAP (7 mg, 0.5 Eq, 0.06 mmol) were added. The reaction was stirred at 0°C, then DCC (36 mg, 1.5 Eq, 0.17 mmol) was added. The resulting mixture was stirred at 0°C to 25°C for 2 hours. The crude product was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150mm 5um; Mobile phase A: Water (0.05% TFA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give tri-tert-butyl 2,2',2''-(10-(2-(4-(2-((tert-butoxycarbonyl)amino)-4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-triacetate (60 mg, 42 μmol, 36%) as a pale yellow oil. Calculated for C 72 H 101 Cl2N 11 O 15 :1429.69,found[M+H] + :1430.9,1432.9.

[0667] Step 6: An 8 mL vial was charged with a mixture of tri-tert-butyl 2,2′,2″-(10-(2-(4-(2-((tert-butoxycarbonyl)amino)-4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-triacetate (60 mg, 1 Eq, 42 μmol) in DCM (1 mL). The reaction was cooled to 0°C with stirring, and then iodotrimethylsilane (50 mg, 6.0 Eq, 0.25 mmol) was added. The resulting mixture was stirred at 0°C to 25°C for 1 hour. To the reaction mixture was added a 1N aqueous solution of NaOH (0.25 mL) and a saturated solution of NaHCO3 at 0°C. The resulting mixture was concentrated and purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% TFA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give (R)-2,2',2''-(10-(2-(4-(2-amino-4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-2,2,2-trifluoroacetic acid (1 / 1) (6.8 mg, 5.1 μmol, 12%, 96% purity) as a white solid. Calculated for C 57 H 70 Cl2F3N 11 O 15 :1275.44,found[M+H-TFA] + :1162.4,1164.4.

[0668] Example 13: (Compound 13)

[0669] [ka]

[0670] Step 1: A 40 mL vial was charged with a mixture of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (1.15 g, 2.30 Eq, 2.01 mmol), N-ethyl-N-isopropylpropan-2-amine (565 mg, 5.00 Eq, 4.37 mmol), 2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (785 mg, 2.50 Eq, 2.19 mmol), and DMF (5 mL). The mixture was stirred at 25 °C for 1 h, then 1-amino-12-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3,6,9,15,18,21-hexaoxa-12-azatetracosan-24-onic acid (500 mg, 1 Eq, 875 μmol) was added. The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase, water (0.1% TFA) and ACN (20% ACN to 65% in 7 min); total flow rate, 20 mL / min; detector, UV 220 nm. The pure fractions were lyophilized to give 2,2,2-trifluoroacetic acid-2-oxo-15-(2-oxo-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-6,9,12-trioxa-3-azatetradecan-14-yl)-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-6,9,12,18,21,24-hexaoxa-3,15-diazaheptacosan-27-onic acid (1 / 1) (750 mg, 0.41 mmol, 47%, 98% purity) as a colorless oil. Calc'd for C 83 H 154 F3N11 O 27 :1794.10,found[M+H-TFA] + :1681.2.

[0671] Step 2: In a 40 mL vial, add 2-oxo-15-(2-oxo-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-6,9,12-trioxa-3-azatetradecan-14-yl)-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-6,9,12-trioxa-3-azatetradecan-14-yl)-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-6,9,12-trioxa-3-azatetradecan-14-yl)-1,4,7,10-tris(2-(tert-butoxy)-2-oxoethyl ... A mixture of (8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (35 mg, 1.0 Eq, 60 μmol) was added to the mixture, followed by HATU (82 mg, 3.6 Eq, 0.22 mmol) and DIEA (46 mg, 62 μL, 6.0 Eq, 0.36 mmol). The mixture was stirred at 25° C. for 10 minutes. To this mixture was added (8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (35 mg, 1.0 Eq, 60 μmol). The resulting mixture was stirred at 25° C. for 2 hours. The crude product was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150mm 5um; Mobile phase A: Water (0.05% TFA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give the product (140 mg, 56 μmol, 94%, 90% purity) as a pale yellow oil. Calc'd for C 111 H 179 Cl2N 15 O 28 :2240.24,found[M / 2+H] + :1121.9,1123.9.

[0672] Step 3: An 8 mL vial was charged with the product from Step 2 (70 mg, 1 Eq, 31 μmol) and DCM (1 mL), to which was added iodotrimethylsilane (120 mg, 19 Eq, 600 μmol). The reaction mixture was stirred at 0°C to 25°C for 2 hours. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% TFA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to afford the title compound (14.6 mg, 5.83 μmol, 19%, 94.1% purity) as an off-white solid. Calc'd for C 89 H 132 Cl2F3N 15 O 30 :2017.86,found[M+H-TFA] + :1904.8,1906.8.

[0673] Example 14: 2,2',2''-(10-(2-(((3R,5R)-7-((2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)amino)-3,5-dihydroxy-7-oxoheptyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 14)

[0674] [ka]

[0675] Step 1: A 100 mL round-bottom flask was charged with a mixture of tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (2 g, 1 Eq, 7 mmol), TEA (2 g, 3 mL, 3 Eq, 0.02 mol), BocO (2 g, 3 mL, 1.5 Eq, 0.01 mol), and DCM (20 mL). The reaction mixture was stirred at 25 °C for 1 h. The mixture was purified by MPLC using the following conditions: silica gel column 40 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 40 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give tert-butyl 2-((4R,6R)-6-(2-((tert-butoxycarbonyl)amino)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (2.34 g, 6.27 mmol, 90%) as a yellow oil. Calc'd for C 19 H 35 NO6:373.25,found[M+H] + :374.2.

[0676] Step 2: A 40 mL round-bottom flask was charged with a mixture of tert-butyl 2-((4R,6R)-6-(2-((tert-butoxycarbonyl)amino)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (2.34 g, 1 Eq, 6.27 mmol), LiOH (3.00 g, 20 Eq, 125 mmol), HO (2 g, 2 mL, 2e+1 Eq, 0.1 mol), and MeOH (6 mL). The reaction mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL), then the combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous NaSO and concentrated under reduced pressure to give 2-((4R,6R)-6-(2-((tert-butoxycarbonyl)amino)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid (1.37 g, 4.32 mmol, 68.9%) as a yellow oil. Calc'd for C 15 H 27 NO6:317.18,found[M+H] +:318.2.

[0677] Step 3: An 8 mL vial was charged with a mixture of 2-((4R,6R)-6-(2-((tert-butoxycarbonyl)amino)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid (175 mg, 2.45 Eq, 551 μmol), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (190 mg, 3.00 Eq, 677 μmol), 1-methylimidazole (N-) (92 mg, 89 μL, 5.0 Eq, 1.1 mmol), and DMF (1.5 mL). The reaction mixture was stirred at 20° C. for 10 minutes, then 1-(2-aminoethyl)-3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)urea (see Example 10, Step 2, 150 mg, 1 Eq, 225 μmol) was added, and the reaction mixture was stirred for another hour at 25° C. The crude mixture was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% FA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 minutes; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give tert-butyl (2-((4R,6R)-6-(2-((2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)amino)-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)ethyl)carbamate (60 mg, 62 μmol, 28%) as a white solid. Calculated for C 48 H 59 Cl2N7O 10 :963.37,found[M+H] + :964.4,966.4.

[0678] Step 4: A 40 mL round-bottom flask was charged with a mixture of tert-butyl (2-((4R,6R)-6-(2-((2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)amino)-2-oxoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)ethyl)carbamate (60 mg, 1 Eq, 62 μmol), TFA (0.1 mL), and DCM (2 mL). The reaction mixture was stirred at 25° C. for 20 minutes. This resulted in (3R,5R)-7-amino-N-(2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)-3,5-dihydroxyheptanamide (43 mg, 52 μmol, 84%) as a yellow oil. Calculated for C 40 H 47 Cl2N7O8:823.29,found [M+H] + :824.3,826.3.

[0679] Step 5: In an 8 mL vial, add (3R,5R)-7-amino-N-(2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)-3,5-dihydroxyheptanamide (65 mg, 1 Eq, 79 μmol) and N-ethyl A mixture of ethyl-N-isopropylpropan-2-amine (80 mg, 7.9 Eq, 0.62 mmol), 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (80 mg, 2.0 Eq, 0.16 mmol), and DMF (1 mL) was added. The reaction mixture was stirred at 25 °C for 3 hours. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% FA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(2-(((3R,5R)-7-((2-(3-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)ureido)ethyl)amino)-3,5-dihydroxy-7-oxoheptyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (18.9 mg, 15.6 μmol, 20%) as a white solid. Calculated for C 56 H 73 Cl2N 11 O 15 :1209.47,found[M+H] + :1210.5,1212.5.

[0680] Example 15: 2,2',2''-(10-(2-(4-(N-(2-(2-(2-carboxyethoxy)ethoxy)ethyl)-4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 15)

[0681] [ka]

[0682] Step 1: A 500 mL round-bottom flask was charged with a mixture of tert-butyl 4-oxopiperidine-1-carboxylate (2.3 g, 1 eq, 12 mmol), tert-butyl 3-(2-(2-aminoethoxy)ethoxy)propanoate (3.5 g, 1.3 eq, 15 mmol), and DCE (25 mL). The reaction mixture was stirred at 20 °C for 50 min, and then sodium cyanoborohydride (2.15 g, 2.02 mL, 3.0 eq, 34.2 mmol) was added, and the reaction mixture was stirred at 25 °C for an additional 3 days. The crude product was purified by MPLC under the following conditions: silica gel column 120 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 90 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give tert-butyl 4-((2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethyl)amino)piperidine-1-carboxylate (2.2 g, 5.3 mmol, 46%) as a yellow oil. Calc'd for C 21 H 40 N2O6:416.29,found[M+H] + :417.5.

[0683] Step 2: A 40 mL vial was charged with a mixture of tert-butyl 4-((2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethyl)amino)piperidine-1-carboxylate (1.0 g, 1 Eq, 2.4 mmol), dihydrofuran-2,5-dione (0.5 g, 2 Eq, 5 mmol), DMAP (0.9 g, 3 Eq, 7 mmol), and ClCHCHCl (15 mL). The reaction mixture was stirred at 25 °C for 24 h. The mixture was diluted with 100 mL of water and extracted with EtOAc (3 x 150 mL), then the combined organic layers were washed with water (2 x 150 mL), brine (150 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by MPLC under the following conditions: silica gel column 80 g, PE / EtOAc system, 0% to 85% EtOAc in 15 min, flow rate: 70 mL / min; wavelength: 254 nm. The collected fractions were concentrated under reduced pressure to give 13-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,2-dimethyl-4,14-dioxo-3,7,10-trioxa-13-azaheptadecan-17-onic acid (920 mg, 1.78 mmol, 74%) as a yellow oil. Calculated for C 25 H 44 N2O9:516.30,found[M+H] + :517.5.

[0684] Step 3: A 40 mL vial was charged with a mixture of 13-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,2-dimethyl-4,14-dioxo-3,7,10-trioxa-13-azaheptadecan-17-onic acid (1.0 g, 1 Eq, 1.9 mmol), ZnBr (2 g, 5 Eq, 9 mmol), and DCM (10 mL). The reaction mixture was stirred at 25 °C for 16 h. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Collected fractions were concentrated under reduced pressure to give 2,2-dimethyl-4,14-dioxo-13-(piperidin-4-yl)-3,7,10-trioxa-13-azaheptadecan-17-one-formic acid (1 / 1) (440 mg, 951 μmol, 49%) as a yellow oil. Calculated for C. 21 H 38 N2O9:462.57,found[M+H-FA] + :417.5.

[0685] Step 4: A 40 mL vial was charged with a mixture of 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (817 mg, 1.50 Eq, 1.43 mmol), HBTU (722 mg, 2.00 Eq, 1.90 mmol), DIEA (615 mg, 829 μL, 5.00 Eq, 4.76 mmol), and DMF (5 mL). The reaction mixture was stirred at 25° C. for 10 minutes, then 2,2-dimethyl-4,14-dioxo-13-(piperidin-4-yl)-3,7,10-trioxa-13-azaheptadecan-17-onic acid-formic acid (1 / 1) (440 mg, 1 Eq, 951 μmol) was added, and the reaction mixture was stirred for another hour at 25° C. The crude product was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% NH 3 .HO); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 minutes; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give 2,2-dimethyl-4,14-dioxo-13-(1-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl)piperidin-4-yl)-3,7,10-trioxa-13-azaheptadecan-17-onic acid (250 mg, 257 μmol, 27.1%) as a yellow oil. Calculated for C 48 H 86 NO 14 :970.60,found[M+H] + :972.2.

[0686] Step 5: An 8 mL vial was charged with a mixture of 2,2-dimethyl-4,14-dioxo-13-(1-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl)piperidin-4-yl)-3,7,10-trioxa-13-azaheptadecan-17-onic acid (120 mg, 1 Eq, 124 μmol), 1-methyl-1H-imidazole (30.4 mg, 3.00 Eq, 370 μmol), N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (69.3 mg, 2.00 Eq, 247 μmol), and DCM (1.5 mL). The reaction mixture was stirred at 20 °C for 10 min, then (8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (107 mg, 1.49 eq, 185 μmol) was added, and the reaction mixture was stirred for another 1 h at 25 °C. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20-40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN in 1 min, 30% ACN in 6 min, 98% ACN in 3 min, 98% ACN in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were concentrated under reduced pressure to give tri-tert-butyl 2,2',2''-(10-(2-(4-(N-(2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethyl)-4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate formate (95 mg, 60 μmol, 49%) as a yellow oil. Calc'd for C 79 H 114 Cl2N 10 O 19:1576.76,found[M+H-FA] + :1533.7.

[0687] Step 6: In an 8 mL vial, add tri-tert-butyl 2,2',2''-(10-(2-(4-(N-(2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethyl)-4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-8 A mixture of (-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate formate (60 mg, 1 eq, 38 μmol) and ACN (0.5 mL) was added, and TMS-I (63 mg, 43 μL, 8.3 eq, 0.31 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% FA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(2-(4-(N-(2-(2-(2-carboxyethoxy)ethoxy)ethyl)-4-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-4-oxobutanamido)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (20.2 mg, 14.9 μmol, 39%) as a white solid. Calculated for C 63 H 82 Cl2N 10 O 19 :1352.51,found[M+H-FA] + :1307.6.

[0688] Example 16: 2,2',2''-(10-(24-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-2,24-dioxo-6,9,12,15,18,21-hexaoxa-3-azatetracosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 16)

[0689] [ka]

[0690] Step 1: An 8 mL vial was charged with a mixture of 2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azahexacosan-26-onic acid (95 mg, 1.2 eq, 0.21 mmol), HATU (146 mg, 2.23 eq, 384 μmol), DIEA (68 mg, 92 μL, 3.0 eq, 0.53 mmol), and DMF (1 mL). The reaction mixture was stirred at 20 °C for 10 min, and then (8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (100 mg, 1 eq, 173 μmol) was added, and the reaction mixture was stirred at 25 °C for an additional 2 h. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Purification gave tert-butyl (21-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-21-oxo-3,6,9,12,15,18-hexaoxaheneicosyl)carbamate (115 mg, 113 μmol, 65.7%) as a yellow oil. Calc'd for C 50 H 65 Cl2N5O 13 :1013.40,found[M+H] + :1014.2.

[0691] Step 2: An 8 mL vial was charged with a mixture of tert-butyl (21-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-21-oxo-3,6,9,12,15,18-hexaoxaheneicosyl)carbamate (105 mg, 1 Eq, 103 μmol) and DCM (1.0 mL), and TFA (0.1 mL) was added. The reaction mixture was stirred at 25° C. for 30 minutes. The mixture was concentrated under reduced pressure to give 1-amino-N-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)-3,6,9,12,15,18-hexaoxaheneicosan-21-amide 2,2,2-trifluoroacetate as a yellow oil. Calc'd for C 47 H 58 Cl2F3N5O 13 :1027.34,found[M+H-TFA] + :914.2.

[0692] Step 3: In a 100 mL vial, add 1-amino-N-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)-3,6,9,12,15,18-hexaoxaheneicosan-21-amide (52 mg, 1 Eq, 57 μmol A mixture of 2,2',2''-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (88 mg, 3.1 Eq, 0.18 mmol), DIEA (46 mg, 62 μL, 6.3 Eq, 0.36 mmol), and DMF (1.0 mL) was added. The reaction mixture was stirred at 25 °C for 2 h. The crude product was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% FA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(24-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-2,24-dioxo-6,9,12,15,18,21-hexaoxa-3-azatetracosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (34.7 mg, 25.8 μmol, 45%) as an off-white solid. Calculated for C 62 H 85 Cl2N9O 20 :1345.53,found[M+H-FA] + :1300.8.

[0693] Example 17: 2,2',2''-(10-(18-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-2,18-dioxo-6,9,12,15-tetraoxa-3-azaoctadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 17)

[0694] [ka]

[0695] Step 1: A 40 mL vial was charged with a mixture of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-onic acid (126 mg, 2.00 Eq, 345 μmol), HATU (144 mg, 2.19 Eq, 379 μmol), DIEA (134 mg, 181 μL, 6.01 Eq, 1.04 mmol), and DMF (1.0 mL). The reaction mixture was stirred at 20° C. for 10 minutes, and then (8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (100 mg, 1 Eq, 173 μmol) was added, and the reaction mixture was stirred at 25° C. for an additional 2 hours. The mixture was directly purified by MPLC using the following conditions: column, WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Purification afforded tert-butyl (15-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate (135 mg, 146 μmol, 84.4%) as a yellow oil. Calc'd for C 46 H 57 Cl2N5O 11 :925.34,found[M+H] + :926.2.

[0696] Step 2: An 8 mL vial was charged with a mixture of tert-butyl (15-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate (125 mg, 1 Eq, 135 μmol) and DCM (2.0 mL), and TFA (0.1 mL) was added. The reaction mixture was stirred at 25° C. for 40 minutes. The mixture was diluted with water (2 mL) and extracted with EtOAc (3 x 2 mL), then the combined organic layers were washed with water (2 x 2 mL) and brine (2 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 1-amino-N-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)-3,6,9,12-tetraoxapentadecan-15-amide (110 mg, 133 μmol, 98.7%) as a white solid. Calc'd for C 41 H 49 Cl2N5O9:825.29,found [M+H] + :826.3.

[0697] Step 3: An 8 mL vial was charged with a mixture of 2,2′,2″-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (206 mg, 3.09 Eq, 411 μmol), DIEA (103 mg, 139 μL, 5.99 Eq, 797 μmol), and DMF (1.0 mL). The reaction mixture was stirred at 20 °C for 10 min, then 1-amino-N-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)-3,6,9,12-tetraoxapentadecan-15-amide (110 mg, 1 Eq, 133 μmol) was added and the reaction mixture was stirred for another 2 h at 25 °C. The crude product was purified by preparative HPLC under the following conditions: Column: SunFire prep OBD 19*150 mm 5 μm; Mobile phase A: water (0.05% FA); Mobile phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL / min; Wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(18-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-2,18-dioxo-6,9,12,15-tetraoxa-3-azaoctadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (37.8 mg, 30.0 μmol, 22.6%) as an off-white solid. Calculated for C 58 H 77 Cl2N9O 18 :1257.48,found[M+H-FA] + :1212.6.

[0698] Example 18: 2,2',2''-(10-(15-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-2,15-dioxo-6,9,12-trioxa-3-azapentadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 18)

[0699] [ka]

[0700] Step 1: An 8 mL vial was charged with a mixture of (8-(3-aminophenyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3-dimethylmorpholino)methanone (100 mg, 1 eq, 173 μmol), HATU (102 mg, 1.55 eq, 268 μmol), DIEA (76.8 mg, 104 μL, 3.44 eq, 594 μmol), and DMF (1.0 mL). The reaction mixture was stirred at 20° C. for 10 minutes, and then 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecan-17-onic acid (112 mg, 2.02 eq, 349 μmol) was added, and the reaction mixture was stirred at 25° C. for an additional 2 hours. The mixture was directly purified by MPLC under the following conditions: column, WelFlash™, C18 120 g, spherical 20–40 μm; mobile phase, water (0.05% FA) and ACN (5% ACN to 5% ACN in 1 min, 30% ACN to 98% in 6 min, 98% ACN to 98% in 3 min); total flow rate, 70 mL / min; detector, UV 220 nm. Purification gave tert-butyl (2-(2-(2-(3-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-3-oxopropoxy)ethoxy)ethoxy)ethyl)carbamate (105 mg, 119 μmol, 68.9%) as a yellow oil. Calc'd for C 44 H 53 Cl2N5O 10 :881.32,found[M+H] + :882.2.

[0701] Step 2: An 8 mL vial was charged with a mixture of tert-butyl (2-(2-(2-(3-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-3-oxopropoxy)ethoxy)ethoxy)ethyl)carbamate (95 mg, 1 Eq, 0.11 mmol) and DCM (2.0 mL), and to this was added TFA (0.1 mL). The mixture was concentrated under reduced pressure to give 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)propanamide 2,2,2-trifluoroacetate (63 mg, 70 μmol, 65%) as a yellow oil. Calc'd for C 41 H 46 Cl2F3N5O 10 :895.26,found[M+H-TFA] + :782.1.

[0702] Step 3: An 8 mL vial was charged with a mixture of 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)propanamide (58 mg, 1 Eq, 74 μmol), DIEA (67 mg, 90 μL, 7.0 Eq, 0.52 mmol), and DMF (1.0 mL). The reaction mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column: SunFire prep OBD 19*150mm 5um; mobile phase A: water (0.05% FA); mobile phase B: ACN; gradient: 25% B to 65% B in 8 min; flow rate: 20 mL / min; wavelength: 220 nm. The collected fractions were lyophilized to give 2,2',2''-(10-(15-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-2,15-dioxo-6,9,12-trioxa-3-azapentadecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid-formic acid (1 / 1) (35.0 mg, 28.8 μmol, 39%) as an off-white solid. Calculated for C. 56 H 73 Cl2N9O 17 :1213.45,found[M+H-FA] + :1168.5.

[0703] Example 19: 2,2',2''-(10-(2-((2-(2-(3-((3-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)phenyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound 19)

[0704] [ka]

[0705] Step 1: An 8 mL vial was charged with a mixture of 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatetradecan-14-onic acid (98.6 mg, 2.06 eq, 356 μmol), HATU (145 mg, 2.21 eq, 381 μmol), DIEA (69 mg, 93 μL, 3.1 eq, 0.53 mmol), and DMF (1.0 mL). The reaction mixt...

Claims

1. Formula (A) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R is L Ａ -L Ｂ -R ６ , -L Ａ - (L Ｂ -R ６ ) ２ , or -L Ａ - (L Ｂ -R ６ ) ３ and L Ａ is a linker or is absent, L Ｂ is a linker or is absent, R ６ is a chelating moiety or a radionuclide complex thereof; Z is C １ -C ６ Alkylene, C １ -C ６ Alkylene-O-, -O-C １ -C ６ Alkylene-, —C(═O)NR １０ -, -NR １０ C(=O)-, -NR １０ -, -O-, -S-, -S(=O)-, -SO ２ -, -NR １０ C(=O)NR １０ - or -CR １０ = NO-, R １０ are each independently H or unsubstituted C １ -C ４ is alkyl, the ligand is a small molecule modulator of the follicle-stimulating hormone receptor (FSHR); y is 1, 2, or 3; The compound, or a pharmaceutically acceptable salt thereof.

2. R is L Ｂ -R ６ 2. The compound of claim 1, wherein:

3. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the ligand is a small molecule agonist of FSHR.

4. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the ligand is a small molecule antagonist of FSHR.

5. 5. The compound of any one of claims 1 to 4, wherein the ligand comprises a thiazolidinone (TZD), a diketopiperazine, a hexahydroquinoline, a thienopyrimidine, a piperidine carboxamide, an actyltryptophanol, a pyrrolobenzodiazepine, an aminoalkylamide, an isoxazolyl-thiazolyl, a dihydropyrrolo[2,1-a]isoquinoline, a dihydroimidazo[5,1-A]isoquinoline, a dihydrobenzoindazole, a fused tricyclic imidazole, a fused tricyclic pyrazole, a 1,4-dihydrochromeno[4,3-c]pyrazole, or a dihydro-1H-benzo[g]indole, or a pharmaceutically acceptable salt thereof.

6. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the ligand comprises dihydropyrrolo[2,1-a]isoquinoline, dihydroimidazo[5,1-A]isoquinoline, dihydrobenzoindazole, 1,4-dihydrochromeno[4,3-c]pyrazole, or dihydro-1H-benzo[g]indole.

7. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the ligand comprises naphthalenesulfonic acid, (bis)sulfonic acid, (bis)benzamide, tetrahydroquinoline (THQ), benzamide, naphthalenesulfonic acid, or tetrahydroquinoline.

8. 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein said fused tricyclic imidazole is a dihydrobenzimidazole.

9. 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein said fused tricyclic imidazole is a dihydrobenzo-pyrazole.

10. The compound of formula (A) is a compound of formula (B) 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein: R １ is H, F, Cl, Br, or I, W is O or —CH ２ - and V １ is C or N, V ２ is C, CR ８ , or N, V ３ is CR ８ or N, R ２ and R ３ are each independently substituted or unsubstituted alkyl; Or R ２ and R ３ together with the nitrogen to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl; R ４ is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R ５ is H, F, Cl, Br, or I, Y １ and Y ２ are each independently CR ９ or N, Z is C １ -C ６ Alkylene, —C(═O)NR １０ -, -NR １０ C(=O)-, -NR １０ -, -O-, -S-, -S(=O)-, -SO ２ -, -NR １０ C(=O)NR １０ - or -CR １０ = NO-, R is -L １ -R ６ , —CH—(L １ -R ６ ) ２ , substituted or unsubstituted C １ -C １０ Alkylene-CH-(L １ -R ６ ) ２ , substituted or unsubstituted 2- to 10-membered heteroalkylene -CH-(L １ -R ６ ) ２ , -N-(L １ -R ６ ) ２ , substituted or unsubstituted C １ -C １０ Alkylene-N(L １ -R ６ ) ２ , substituted or unsubstituted 2- to 10-membered heteroalkylene-N(L １ -R ６ ) ２ , or -(CH ２ CH ２ O) ｑ -CH ２ CH ２ N (L １ -R ６ ) ２ and q is 1, 2, 3, 4, 5, or 6; L １ is a linker or is absent, R ６ is a chelating moiety or a radionuclide complex thereof; R ７ is H or substituted or unsubstituted alkyl; R ８ are each independently H, —N(R １１ ) ２ , F, Cl, Br, I, or —OR １１ and R ９ are each independently H, halogen, substituted or unsubstituted C １ -C ４ Alkyl, substituted or unsubstituted C １ -C ４ fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, —CN, —N(R １２ ) ２ , or -OR １２ and R １０ are each independently H or unsubstituted C １ -C ４ is alkyl, R １１ are each independently H or unsubstituted C １ -C ４ is alkyl, R １２ are each independently H or unsubstituted C １ -C ４ is alkyl, 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

11. The compound is represented by formula (I) 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, wherein: R １ is H, F, Cl, Br, or I, W is O or CH ２ and V １ is C or N, V ２ is C, CR ８ , or N, V ３ is CR ８ or N, R ２ and R ３ are each independently substituted or unsubstituted alkyl; Or R ２ and R ３ together with the nitrogen to which they are attached form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl; R ４ is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R ５ is H, F, Cl, Br, or I, Y １ and Y ２ are each independently CR ９ or N, Z is C １ -C ６ Alkylene, —C(═O)NR １０ -, -NR １０ C(=O)-, -NR １０ -, -O-, -S-, -S(=O)-, -SO ２ -, -NR １０ C(=O)NR １０ - or -CR １０ = NO-, L １ is a linker or is absent, R ６ is a chelating moiety or a radionuclide complex thereof; R ７ is H or substituted or unsubstituted alkyl; R ８ are each independently H, —N(R １１ ) ２ ,F,Cl,Br,I,-OR １１ and R ９ are each H, halogen, substituted or unsubstituted C １ -C ４ Alkyl, substituted or unsubstituted C １ -C ４ fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, —CN, —N(R １２ ) ２ , or -OR １２ and R １０ are each independently H or unsubstituted C １ -C ４ is alkyl, R １１ are each independently H or unsubstituted C １ -C ４ is alkyl, R １２ are each independently H or unsubstituted C １ -C ４ is alkyl, 11. A compound according to claim 1 or 10, or a pharmaceutically acceptable salt thereof.

12. The compound of formula (I) is of formula (Ia) 【Chemistry 4】 12. The compound of claim 11 having the structure: or a pharmaceutically acceptable salt thereof.

13. The compound of formula (I) is of formula (Ib) 【Chemistry 5】 12. The compound of claim 11 having the structure: or a pharmaceutically acceptable salt thereof.

14. R １ The compound of any one of claims 10 to 13, or a pharmaceutically acceptable salt thereof, wherein is H, F, or Cl.

15. R ５ The compound according to any one of claims 10 to 14, or a pharmaceutically acceptable salt thereof, wherein is H or F.

16. R ９ are each independently H, halogen, or —CH ３ , or -CF ３ 16. The compound according to any one of claims 10 to 15, wherein:

17. Y １ and Y ２ 16. The compound of any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, wherein is CH.

18. Y １ is N and Y ２ 16. The compound of any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, wherein is CH.

19. Y １ is CH and Y ２ The compound of any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, wherein is N.

20. Y １ is N and Y ２ The compound of any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, wherein is N.

21. R ７ Ga-CH ３ 21. The compound according to any one of claims 10 to 20, wherein:

22. R １０ The compound of any one of claims 10 to 21, or a pharmaceutically acceptable salt thereof, wherein is H.

23. R １０ Ga-CH ３ 22. The compound according to any one of claims 10 to 21, wherein:

24. The compound has the following structure: 【Chemistry 6】 12. The compound of claim 1, 10, or 11, having one of: or a pharmaceutically acceptable salt thereof.

25. The compound has the following structure: 【Chemistry 7】 12. The compound of claim 1, 10, or 11, having one of: or a pharmaceutically acceptable salt thereof.

26. R ２ Ga-CH ３ and R ３ 26. The compound of any one of claims 10 to 25, or a pharmaceutically acceptable salt thereof, wherein is t-butyl.

27. R ２ and R ３ But along with the nitrogen to which they are connected, 【Chemistry 8】 wherein R ２ａ and R ２ｂ are each independently H, halogen, substituted or unsubstituted C １ -C ４ Alkyl, substituted or unsubstituted C １ -C ４ fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, —C(═O)R ２ｃ , -CN, -NH ２ or —OH, and R ２ｃ is a substituted or unsubstituted C １ -C ４ Alkyl or substituted or unsubstituted C ３ -C ６ 26. The compound of any one of claims 10 to 25, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

28. R ２ａ and R ２ｂ are -CH ３ 26. The compound of claim 25, wherein:

29. R ２ and R ３ But along with the nitrogen to which they are connected, 【Chemistry 9】 26. The compound of any one of claims 10 to 25, or a pharmaceutically acceptable salt thereof, which forms:

30. R ４ 30. The compound of any one of claims 10 to 29, or a pharmaceutically acceptable salt thereof, wherein is substituted or unsubstituted phenyl or substituted or unsubstituted 5- to 6-membered heteroaryl.

31. R ４ is substituted or unsubstituted pyridinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, and substituted or unsubstituted furazanyl, or a pharmaceutically acceptable salt thereof.

32. R ４ but, 【Chemistry 10】 wherein R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , and R ４ｅ are each independently H, halogen, substituted or unsubstituted C １ -C ４ Alkyl, substituted or unsubstituted C １ -C ４ Fluoroalkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, —CN, —NH ２ 30. The compound of any one of claims 10 to 29, or a pharmaceutically acceptable salt thereof, wherein:

33. R ４ａ and R ４ｂ are each independently F, Cl, Br, I, or —CH ３ and R ４ｃ 33. The compound of claim 32, wherein is H, or a pharmaceutically acceptable salt thereof.

34. R ４ｄ and R ４ｅ 33. The compound of claim 32, wherein is H, or a pharmaceutically acceptable salt thereof.

35. R ４ but, 【Chemistry 11】 30. The compound of any one of claims 1 to 29, wherein:

36. 36. The compound of any one of claims 1 to 35, wherein Z is -C(=O)NH-, -NHC(=O)-, -O-, or -NHC(=O)NH-, or a pharmaceutically acceptable salt thereof.

37. 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein Z is -NHC(=O)- or -NHC(=O)NH-.

38. R ８ 38. The compound of any one of claims 10 to 37, or a pharmaceutically acceptable salt thereof, wherein each is H.

39. R ６ However, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,7-diacetate (DO2A), α,α',α'',α'''-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM), 1,4,7,10-tetraazacyclododecane-1,4,7 ,10-tetrapropionic acid (DOTPA), 2,2',2''-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bn-DOTA), p-hydroxy-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-OH-Bn-DOTA), 6,6'-(((pyridine-2,6-diylbis(methylene))bis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H ４ pypa), H ４ pypa-benzyl, 6,6',6'',6'''-(((pyridine-2,6-diylbis(methylene))-bis(azanetriyl))tetrakis(methylene))-tetrapicolinic acid (H ４ py4pa), H ４ Py4pa-benzyl, 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), 6,6'-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (macropa), 2,2',2'',2'''-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown), 6,6'-((ethane-1,2-diylbis((carboxymethyl)-azanediyl))bis(methylene))-dipicolinic acid (H ４ octapa), H ４ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein the chelating moiety is selected from the group consisting of octapa-benzyl, and 3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid (TTHA), or a radionuclide complex thereof.

40. R ６ 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein is a chelating moiety selected from the group consisting of DOTA and DO3A, or radionuclide complexes thereof.

41. R ６ but, 【Chemistry 12】 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, which is a chelating moiety selected from the group consisting of: or a radionuclide complex thereof.

42. R ６ but, 【Chemistry 13】 39. The compound of any one of claims 1 to 38, which is or a radionuclide complex thereof, or a pharmaceutically acceptable salt thereof.

43. R ６ but, 【Chemistry 14】 or a radionuclide complex thereof, or a pharmaceutically acceptable salt thereof.

44. L Ｂ L １ 10. The compound of any one of claims 1 to 9, wherein:

45. L １ が、-L ２ -、-L ３ -、-L ４ -、-L ５ -、-L ６ -、-L ７ -、-L ２ -L ３ -、-L ２ -L ４ -、-L ２ -L ７ -、-L ４ -L ６ -、-L ４ -L ７ -、-L ６ -L ７ -、-L ２ -L ４ -L ７ -、-L ２ -L ５ -L ７ -、-L ２ -L ６ -L ７ -、-L ３ -L ４ -L ７ -、-L ４ -L ５ -L ７ -、または-L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -であり、 L ２ is absent or is substituted or unsubstituted C １ -C ２０ Alkylene, substituted or unsubstituted C １ -C ２０ Alkylene -NR １３ -, substituted or unsubstituted C １ -C ２０ Alkylene-C(=O)-, substituted or unsubstituted C １ -C ２０ Alkylene -C(=O)NR １３ -, substituted or unsubstituted C １ -C ２０ Alkylene -NR １３ C(═O)—, substituted or unsubstituted 2- to 20-membered heteroalkylene, —(CH ２ CH ２ O) ｚ -, -(OCH ２ CH ２ ) ｚ -, -(CH ２ CH ２ O) ｗ -CH ２ CH ２ -, -CH ２ CH ２ NR １３ - (CH ２ CH ２ O) ｗ -, -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NR １３ -, -CH ２ CH ２ NR １３ C(=O)-(CH ２ CH ２ O) ｗ , -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NR １３ C(=O)-, -CH ２ CH ２ C(=O)NR １３ - (CH ２ CH ２ O) ｗ -, -CH ２ CH ２ NR １３ C(=O)CH ２ -(OCH ２ CH ２ ) ｗ , or -(CH ２ CH ２ O) ｗ -CH ２ CH ２ C(=O)NR １３ - and w is 1, 2, 3, 4, 5, or 6; z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; L ３ is a peptide formed from an absent, natural or unnatural amino acid, or two or more independently selected natural and unnatural amino acids, and when two or more amino acids are present, the N atom of the amide linking said amino acids is C １ -C ６ optionally substituted with alkyl; L ４ is absent, substituted or unsubstituted 2- to 10-membered heteroalkylene, —CH ２ -(OCH ２ CH ２ ) ｖ -, -(CH ２ CH ２ O) ｖ -CH ２ CH ２ -, -(CH ２ CH ２ O) ｖ CH ２ CH ２ N.R. １４ C(=O)(CH ２ CH ２ O) ｖ CH ２ CH ２ -, -(CH ２ CH ２ O) ｖ CH ２ CH ２ C(=O)NR １４ (CH ２ CH ２ O) ｖ CH ２ CH ２ -, -C(=O)CH ２ CH ２ , -CH ２ CH ２ C(═O)—, or independently —OH, —NR １４ ２ , -CO ２ R １４ , -O(CH ２ CH ２ O) ｕ -CH ３ , -NR １４ (CH ２ CH ２ O) ｕ -CH ３ , -NR １４ C(=O)(CH ２ CH ２ O) ｕ -CH ３ , or -CH ２ OCH ２ CH ２ CO ２ R １４ C optionally substituted with one or two groups selected from １ -C ６ is alkylene, v is 1, 2, 3, 4, 5, or 6; u is 1, 2, 3, 4, 5, or 6; L ５ does not exist or -O-, -S-, -S(=O)-, -S(=O) ２ -, -NR １５ -, -CH(=NH)-, -CH(=N-NH)-, -CCH ３ (=NH)-,-CCH ３ (=N-NH)-, -C(=O)NR １５ -, -NR １５ C(=O), -NR １５ C(=O)O-, -NR １５ C(=O)NR １５ - or -OC(=O)NR １５ - and L ６ does not exist or -L ８ -L ９ -L １０ - and L ８ does not exist or -(CH ２ ) ｔ -, -NR ｗ -, -NR ｗ - (CH ２ ) ｔ -, -(CH ２ ) ｔ -C(=O)-, -C(=O)-(CH ２ ) ｔ -, -(CH ２ ) ｔ -NR ｗ -, -(CH ２ ) ｔ -NR ｗ C(=O)-,-(CH ２ ) ｔ -C(=O)NR ｗ -, -CH(NHR ｗ )-(CH ２ ) ｔ -C(=O)-, -NR ｗ C(=O)-(CH ２ ) ｔ -, and -C(=O)NR ｗ - (CH ２ ) ｔ - and t is 0, 1, 2, or 3; L １０ does not exist or -(CH ２ ) ｒ -, -NR ｗ -, -NR ｗ - (CH ２ ) ｒ -, -(CH ２ ) ｒ -C(=O)-, -C(=O)-(CH ２ ) ｒ -, -(CH ２ ) ｒ -NR ｗ -, -(CH ２ ) ｒ -NR ｗ C(=O)-,-(CH ２ ) ｒ -C(=O)NR ｗ -, -CH(NHR ｗ )-(CH ２ ) ｒ -C(=O)-, -NR ｗ C(=O)-(CH ２ ) ｒ -, and -C(=O)NR ｗ - (CH ２ ) ｒ - and r is 0, 1, 2, or 3; R ｗ are independently H, C １ -C ６ Alkyl, C １ -C ６ Alkyl-CO ２ H, -(CH ２ CH ２ O) ｓ -CH ３ , -C(=O)-(CH ２ CH ２ O) ｓ -CH ３ , or -(CH ２ CH ２ O) ｓ -CH ２ CH ２ CO ２ H, s is 1, 2, 3, 4, 5, or 6; L ９ is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; R １３ , R １４ , and R １５ are each independently H or unsubstituted C １ -C ４ alkyl, L ７ does not exist or -NH-, -N(CH ３ )-, —O—NH-, substituted or unsubstituted N-heterocycloalkylene, or —O—NH═(substituted or unsubstituted N-heterocycloalkylene); 45. The compound of any one of claims 10 to 44, or a pharmaceutically acceptable salt thereof.

46. L １ が、-L ２ -、-L ３ -、-L ４ -、-L ５ -、-L ６ -、-L ７ -、-L ２ -L ３ -、-L ２ -L ４ -、-L ２ -L ６ -、-L ２ -L ７ -、-L ４ -L ６ -、-L ４ -L ７ -、-L ６ -L ７ -、-L ２ -L ４ -L ７ -、-L ２ -L ５ -L ７ -、-L ２ -L ６ -L ７ -、-L ３ -L ４ -L ７ -、-L ３ -L ５ -L ７ -、または-L ２ -L ３ -L ４ -L ５ -L ６ -L ７ -であり、 L ２ is absent or is substituted or unsubstituted C １ -C ２０ Alkylene, substituted or unsubstituted C １ -C ２０ Alkylene-NH-, substituted or unsubstituted C １ -C ２０ Alkylene-C(=O)-, substituted or unsubstituted C １ -C ２０ Alkylene -C(=O)NH-, substituted or unsubstituted C １ -C ２０ Alkylene-NHC(=O)-, substituted or unsubstituted 2- to 20-membered heteroalkylene, -(CH ２ CH ２ O) ｚ -, -(OCH ２ CH ２ ) ｚ -, -(CH ２ CH ２ O) ｗ -CH ２ CH ２ -, -CH ２ CH ２ NH-(CH ２ CH ２ O) ｗ -, -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NH-, -CH ２ CH ２ NHC(=O)-(CH ２ CH ２ O) ｗ , -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NHC(=O)-,-CH ２ CH ２ C(=O)NH-(CH ２ CH ２ O) ｗ -, -CH ２ CH ２ NHC(=O)CH ２ -(OCH ２ CH ２ ) ｗ , or -(CH ２ CH ２ O) ｗ -CH ２ CH ２ C(═O)NH—, L ３ is a peptide formed from an absent, natural or unnatural amino acid, or one or more independently selected natural and unnatural amino acids, and when more than one amino acid is present, the N atom of the amide linking said amino acids is C １ -C ６ optionally substituted with alkyl; L ４ But -CH ２ -(OCH ２ CH ２ ) ｖ -, -(CH ２ CH ２ O) ｖ -CH ２ CH ２ -, -(CH ２ CH ２ O) ｖ CH ２ CH ２ NHC(=O)(CH ２ CH ２ O) ｖ CH ２ CH ２ -, -(CH ２ CH ２ O) ｖ CH ２ CH ２ C(=O)NH(CH ２ CH ２ O) ｖ CH ２ CH ２ -, -C(=O)CH ２ CH ２ , -CH ２ CH ２ C(=O)-, or independently -OH, -NH ２ , -CO ２ H, —O(CH ２ CH ２ O) ｕ -CH ３ , -NH(CH ２ CH ２ O) ｕ -CH ３ , -NHC(=O)(CH ２ CH ２ O) ｕ -CH ３ , and -CH ２ OCH ２ CH ２ CO ２ C optionally substituted with 1 or 2 groups selected from H １ -C ６ is alkylene, L ５ is absent, —C(═O)NH—, or —NHC(═O)—; L ６ does not exist or -L ８ -L ９ -L １０ - and L ８ does not exist or -(CH ２ ) ｔ -, -NR ｗ - (CH ２ ) ｔ -, -(CH ２ ) ｔ -C(=O)-, -C(=O)-(CH ２ ) ｔ -, -(CH ２ ) ｔ -NR ｗ -, -(CH ２ ) ｔ -NR ｗ C(=O)-,-(CH ２ ) ｔ -C(=O)NR ｗ -, -CH(NHR ｗ )-(CH ２ ) ｔ -C(=O)-, -NR ｗ C(=O)-(CH ２ ) ｔ -, and -C(=O)NR ｗ - (CH ２ ) ｔ - and L １０ does not exist or -(CH ２ ) ｒ -, -NR ｗ - (CH ２ ) ｒ - or -C(=O)-(CH ２ ) ｒ - and r is 0, 1, 2, or 3; R ｗ are independently H, C １ -C ６ Alkyl, C １ -C ６ Alkyl CO ２ H, -(CH ２ CH ２ O) —CH ３ , -C(=O)-(CH ２ CH ２ O) ｓ -CH ３ , or -(CH ２ CH ２ O) ｓ -CH ２ CH ２ CO ２ H, L ９ is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; L ７ does not exist or -NH-, -N(CH ３ )-, —O—NH-, substituted or unsubstituted N-heterocycloalkylene, or —O—NH═(substituted or unsubstituted N-heterocycloalkylene); 45. The compound of any one of claims 10 to 44, or a pharmaceutically acceptable salt thereof.

47. L １ But, -L ２ - or -L ２ -L ７ 47. The compound of claim 45 or 46, or a pharmaceutically acceptable salt thereof, wherein:

48. L １ But, -L ３ - or -L ２ -L ３ 47. The compound of claim 45 or 46, or a pharmaceutically acceptable salt thereof, wherein:

49. L ２ is a substituted or unsubstituted C １ -C ６ alkylene —C(═O)—, and L ３ 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein is a peptide formed from one or more independently selected natural or unnatural amino acids.

50. L ２ 49. The compound of any one of claims 45 to 48, or a pharmaceutically acceptable salt thereof, wherein is absent.

51. L ２ But -CH ２ - or -CH ２ CH ２ 49. The compound of any one of claims 45 to 48, or a pharmaceutically acceptable salt thereof, wherein:

52. L ２ is a substituted or unsubstituted C １ -C ２０ Alkylene-NH-, substituted or unsubstituted C １ -C ２０ Alkylene-C(=O)-, substituted or unsubstituted C １ -C ２０ Alkylene -C(=O)NH- or substituted or unsubstituted C １ -C ２０ The compound of any one of claims 45 to 48, which is alkylene-NHC(=O)-, or a pharmaceutically acceptable salt thereof.

53. L ２ But -(CH ２ CH ２ O) ｗ -CH ２ CH ２ -, -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NH-, -CH ２ CH ２ NHC(=O)-(CH ２ CH ２ O) ｗ -, -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NHC(=O)-,-CH ２ CH ２ C(=O)NH-(CH ２ CH ２ O) ｗ - or -CH ２ CH ２ NHC(=O)CH ２ -(OCH ２ CH ２ ) ｗ 49. The compound of any one of claims 45 to 48, or a pharmaceutically acceptable salt thereof, wherein:

54. L ２ But -(CH ２ CH ２ O) ｗ -CH ２ CH ２ - or - (CH ２ CH ２ O) ｗ -CH ２ CH ２ 49. The compound of any one of claims 45 to 48, or a pharmaceutically acceptable salt thereof, which is NH-.

55. L ３ 55. The compound of any one of claims 45 to 54, or a pharmaceutically acceptable salt thereof, wherein is absent.

56. L ３ is a natural amino acid, an unnatural amino acid, or alanine (Ala), Ala(SO ３ and valine (Val), wherein when two or more amino acids are present, the N atom of the amide linked to said amino acids is -CH. ３ 55. The compound of any one of claims 45 to 54, or a pharmaceutically acceptable salt thereof, optionally substituted with:

57. L ３ is Ala-Lys-Ser-Asn-Asn-Ser-Ala-NH ２ ,Ala-Ser-Asn-Lys-Asn-Ser-Ala-NH ２ ,Ala-Ser-Asn-Asn-Ser-Lys-Ala-NH ２ ,Ala-Arg-Arg-Lys-Glu-Glu-Glu-NH ２ or Ala-Glu-Ala-Lys-Glu-Ala-NH ２ 55. The compound of any one of claims 45 to 54, which is a peptide which is: or a pharmaceutically acceptable salt thereof.

58. L ４ 58. The compound of any one of claims 45 to 57, or a pharmaceutically acceptable salt thereof, wherein is absent.

59. L ４ -C(=O)CH ２ CH ２ 58. The compound of any one of claims 45 to 57, or a pharmaceutically acceptable salt or solvate thereof, wherein

60. L ４ is unsubstituted C １ -C ６ 58. The compound of any one of claims 45 to 57, or a pharmaceutically acceptable salt thereof, which is alkylene.

61. L ４ are independently —OH, —NH ２ , -CO ２ H, or -CH ２ OCH ２ CH ２ CO ２ C substituted with 1 or 2 groups selected from H １ -C ６ 58. The compound of any one of claims 45 to 57, or a pharmaceutically acceptable salt thereof, which is alkylene.

62. L ５ 62. The compound of any one of claims 45 to 61, or a pharmaceutically acceptable salt thereof, wherein is absent.

63. L ５ 62. The compound of any one of claims 45 to 61, or a pharmaceutically acceptable salt or solvate thereof, wherein is -C(=O)NH-.

64. L ５ 62. The compound of any one of claims 45 to 61, or a pharmaceutically acceptable salt or solvate thereof, wherein is -NHC(=O)-.

65. L ９ is a substituted or unsubstituted C ４ -C ８ 65. The compound of any one of claims 45 to 64, or a pharmaceutically acceptable salt thereof, which is cycloalkylene.

66. L ９ 65. The compound of any one of claims 45 to 64, or a pharmaceutically acceptable salt thereof, wherein is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene.

67. L ９ 65. The compound of any one of claims 45 to 64, or a pharmaceutically acceptable salt thereof, wherein is azetidinylene, pyrrolidinylene, piperidinylene, or piperazinylene.

68. L ９ 65. The compound of any one of claims 45 to 64, or a pharmaceutically acceptable salt thereof, wherein is a monosaccharide.

69. L ９ but, 【Chemistry 15】 65. The compound of any one of claims 45 to 64, wherein:

70. L ９ 65. The compound of any one of claims 45 to 64, or a pharmaceutically acceptable salt thereof, wherein is a 7-12 membered spirocyclic heterocycloalkylene.

71. L ９ but, 【Chemistry 16】 65. The compound of any one of claims 45 to 64, wherein:

72. L ９ but, 【Chemistry 17】 65. The compound of any one of claims 45 to 64, wherein:

73. L ８ 73. The compound of any one of claims 45 to 72, or a pharmaceutically acceptable salt thereof, wherein is absent.

74. L ８ But -(CH ２ ) ｔ -, -(CH ２ ) ｔ -C(=O)NR ｗ -, or -CH(NHR ｗ )-(CH ２ ) ｔ 73. The compound of any one of claims 45 to 72, or a pharmaceutically acceptable salt thereof, which is -C(=O)-.

75. L １０ 75. The compound of any one of claims 45 to 74, or a pharmaceutically acceptable salt thereof, wherein is absent.

76. L １０ But -(CH ２ ) ｒ -, -NR ｗ - (CH ２ ) ｒ - or -C(=O)-(CH ２ ) ｒ 75. The compound of any one of claims 45 to 74, or a pharmaceutically acceptable salt thereof, wherein:

77. 77. The compound of claim 76, or a pharmaceutically acceptable salt thereof, wherein r is 1.

78. L ７ 78. The compound of any one of claims 45 to 77, or a pharmaceutically acceptable salt thereof, wherein is absent.

79. L ７ 78. The compound of any one of claims 45 to 77, or a pharmaceutically acceptable salt thereof, wherein is -NH-.

80. L ７ 78. The compound of any one of claims 45 to 77, or a pharmaceutically acceptable salt thereof, wherein is a substituted or unsubstituted N-heterocycloalkylene.

81. L ７ but, 【Chemistry 18】 78. The compound of any one of claims 45 to 77, wherein:

82. L １ Ga-L ２ - and L ２ But -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NH— and w is 1, 2, 3, 4, 5, or 6; 47. A compound according to any one of claims 45 or 46, or a pharmaceutically acceptable salt thereof.

83. L １ Ga-L ３ - and L ３ is a natural amino acid, an unnatural amino acid, or a peptide; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

84. L １ Ga-L ６ - and L ６ But, -L ８ -L ９ -L １０ - and L ８ But -(CH ２ ) ｔ -C(=O)NR ｗ - and L ９ is a substituted or unsubstituted heterocycloalkylene, and R １０ is absent and t is 1, 2, or 3; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

85. L ９ 85. The compound of claim 84, or a pharmaceutically acceptable salt thereof, wherein is azetidine, pyrrolidine, piperidine, or piperazine.

86. R ｗ But C １ -C ６ Alkyl-CO ２ 86. The compound of claim 84 or 85, wherein R is H, or a pharmaceutically acceptable salt thereof.

87. R ｗ But -(CH ２ CH ２ O) ｓ -CH ２ CH ２ CO ２ 86. The compound of claim 84 or 85, wherein R is H, or a pharmaceutically acceptable salt thereof.

88. L １ But, -L ７ - and L ７ 47. The compound of claim 45 or 46, or a pharmaceutically acceptable salt thereof, wherein is a substituted or unsubstituted N-heterocycloalkylene.

89. L １ But, -L ２ -L ３ - and L ２ is a substituted or unsubstituted C １ -C ６ Alkylene-NH-, substituted or unsubstituted C １ -C ６ Alkylene-C(=O)-, substituted or unsubstituted C １ -C ６ Alkylene -NH-, or -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NH-, L ３ is a natural or unnatural amino acid, or a peptide; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

90. L ３ 90. The compound of claim 89, or a pharmaceutically acceptable salt thereof, wherein is a peptide.

91. L １ But, -L ２ -L ４ - and L ２ But -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NHC(═O)—, L ４ is unsubstituted C １ -C ６ is alkylene, 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

92. L １ But, -L ２ -L ７ - and L ２ is a substituted or unsubstituted C １ -C ６ Alkylene-, substituted or unsubstituted C １ -C ６ Alkylene -C(=O)NH-, -(CH ２ CH ２ O) ｗ -CH ２ CH ２ - and L ７ is —NH—, —O—NH, or a substituted or unsubstituted N-heterocycloalkylene; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

93. L １ But, -L ２ -L ７ - and L ２ But -(CH ２ CH ２ O) ｗ -CH ２ CH ２ - and L ７ is —NH—; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

94. L １ But, -L ４ -L ６ - and L ４ are independently —OH or —NH ２ C optionally substituted with one or two groups selected from １ -C ６ is alkylene, L ６ But, -L ８ -L ９ -L １０ - and L ８ But -(CH ２ ) ｔ -C(=O)NR ｗ - and R ｗ is H and L ９ is a substituted or unsubstituted heterocycloalkylene; L １０ does not exist, 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

95. L １ But, -L ４ -L ７ - and L ４ are independently —OH or —NH ２ C optionally substituted with one or two groups selected from １ -C ６ is alkylene, L ７ is —NH—; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

96. L １ But, -L ６ -L ７ - and L ６ But, -L ８ -L ９ -L １０ - and L ８ is not present or -CH(NHR ｗ )-(CH ２ ) ｔ -C(=O)-, or -(CH ２ ) ｔ -C(=O)NR ｗ - and L ９ is a substituted or unsubstituted heterocycloalkylene; L １０ does not exist or -(CH ２ ) ｒ - or -C(=O)-(CH ２ ) ｒ - and L ７ is —NH— or substituted or unsubstituted N-heterocycloalkylene; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

97. R ｗ is -C(=O)-(CH ２ CH ２ O) ｓ -CH ３ or -(CH ２ CH ２ O) ｓ -CH ２ CH ２ CO ２ H, or a pharmaceutically acceptable salt thereof.

98. L １ But, -L ２ -L ４ -L ７ - and L ２ is a substituted or unsubstituted C １ -C ６ Alkylene -NHC(=O)-, -(CH ２ CH ２ O) ｚ - or -CH ２ CH ２ NHC(=O)-(CH ２ CH ２ O) ｗ and L ４ are independently —OH, —NH ２ , or -CH ２ OCH ２ CH ２ CO ２ -CH optionally substituted with one or two groups selected from H ２ -(OCH ２ CH ２ ) ｖ - or C １ -C ６ is alkylene, L ７ is —NH— or substituted or unsubstituted N-heterocycloalkylene; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

99. L １ But, -L ２ -L ７ - and L ２ is a substituted or unsubstituted C １ -C ６ is alkylene, L ７ is -O-N=(substituted or unsubstituted N-heterocycloalkylene); 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

100. L １ But, -L ２ -L ６ -L ７ - and L ２ is a substituted or unsubstituted C １ -C ６ Alkylene-NH-, substituted or unsubstituted C １ -C ６ Alkylene-NHC(=O)-, substituted or unsubstituted C １ -C ６ Alkylene -C(=O)NH, or -(CH ２ CH ２ O) ｗ -CH ２ CH ２ NHC(═O)—, L ６ But, -L ８ -L ９ -L １０ - and L ８ is not present or -(CH ２ ) ｔ and L ９ is a substituted or unsubstituted heterocycloalkylene; L １０ does not exist or -(CH ２ ) ｒ - or -NR ｗ - (CH ２ ) ｒ - and L ７ is —NH—; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

101. L １ But, L ３ -L ４ -L ７ - and L ３ is a peptide, and in this case, the N atom of the amide linked to the amino acid is -CH ３ is replaced by L ４ is -C(=O)CH ２ CH ２ - and L ７ is —NH—; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

102. L １ But, L ４ -L ５ -L ７ - and L ４ are independently —OH or —NH ２ C optionally substituted with one or two groups selected from １ -C ６ is alkylene, L ５ is —C(═O)NH—, L ７ is a substituted or unsubstituted N-heterocycloalkylene; 47. A compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof.

103. R is -(CH ２ CH ２ O) ｕ -CH ２ CH ２ N (L １ -R ６ ) ２ 11. The compound of claim 10, wherein: -, or a pharmaceutically acceptable salt thereof.

104. R is -CH-(L １ R ６ ) ２ 11. The compound of claim 10, wherein:

105. L １ L ２ and L ２ But -(CH ２ CH ２ O) ｗ -CH ２ CH ２ 104. The compound of claim 103, or a pharmaceutically acceptable salt thereof, wherein w is 3;

106. L １ But, L ２ -L ４ -L ７ and L ２ is a substituted or unsubstituted C １ -C ２０ alkylene-NHC(═O)—, L ４ is C １ -C ６ is alkylene, L ７ is NH, 105. The compound of claim 104, or a pharmaceutically acceptable salt thereof.

107. L １ But -CH ２ -, 【Chemistry 19】 【Chemistry 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical Formula 26】 【Chemical 27】 82. The compound of any one of claims 10 to 81, wherein:

108. -L １ -R ６ が、-CH ２ -R ６ 、-CH ２ CH ２ -R ６ 、 【Chemical Formula 28】 【Chemical 29】 【Chemistry 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 44. The compound of any one of claims 11 to 43, wherein:

109. R is, 【Chemical 37】 11. The compound of claim 10, wherein:

110. -L １ -R ６ but, 【Chemical 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemical Formula 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 wherein R ６ teeth 【Chemistry 48】 82. The compound of any one of claims 10 to 81, wherein:

111. R is, 【Chemistry 49】 11. The compound of claim 10, wherein:

112. The compound of formula (I) has the following structure: 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemical 54】 【Chemistry 55】 【Chemical 56】 【Chemical 57】 【Chemistry 58】 【Chemical Formula 59】 【Chemistry 60】 【Hua 61】 【Hua 62】 【Chemistry 63】 【Hua 64】 【Chemistry 65】 【Hua 66】 【Hua 67】 【Chemistry 68】 or a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

113. The compound of formula (B) has the following structure: 【Chemical Formula 69】 or a pharmaceutically acceptable salt thereof, or a radionuclide complex thereof.

114. 114. The compound of any one of claims 1 to 113, or a pharmaceutically acceptable salt thereof, wherein the radionuclide of the radionuclide complex is a lanthanide or an actinide.

115. 114. The compound of any one of claims 1 to 113, or a pharmaceutically acceptable salt thereof, wherein the radionuclide of the radionuclide complex is actinium, bismuth, cesium, cobalt, copper, dysprosium, erbium, gold, indium, iridium, gallium, lead, lutetium, manganese, palladium, platinum, radium, rhenium, samarium, strontium, technetium, ytterbium, yttrium, or zirconium.

116. 114. The compound of any one of claims 1 to 113, or a pharmaceutically acceptable salt thereof, wherein the radionuclide of the radionuclide complex is a diagnostic or therapeutic radionuclide.

117. 114. The compound of any one of claims 1 to 113, or a pharmaceutically acceptable salt thereof, wherein the radionuclide of said radionuclide complex is an Auger electron-emitting radionuclide, an α-emitting radionuclide, a β-emitting radionuclide, or a γ-emitting radionuclide.

118. the radionuclide of the radionuclide complex is 111-Indium ( １１１ In), 67-gallium ( ６７ Ga), 68-gallium ( ６８ Ga), 99m-technetium ( ９９ｍ Tc), or 195m-Platinum ( １９５ｍ an Auger electron emitting radionuclide, which is 225-Actinium ( ２２５ Ac), 213-bismuth ( ２１３ Bi), 223-radium ( ２２３ Ra), or 212-lead ( ２１２ α-emitting radionuclide, which is 90-Yttrium ( ９０ Y), 177-lutetium ( １７７ Lu), 186-rhenium ( １８６ Re), 188-rhenium ( １８８ Re), 64-copper ( ６４ Cu), 67-copper ( ６７ Cu), 153-samarium ( １５３ Sm), 89-strontium ( ８９ Sr), 198-Fri ( １９８ Au), 169-erbium ( １６９ Er), 165-dysprosium ( １６５ Dy), 99m-technetium ( ９９ｍ Tc), 89-zirconium ( ８９ Zr), or 52-manganese ( ５２ Mn), or 60-Cobalt ( ６０ Co), 103-palladium ( １０３ Pd), 137-Cesium ( １３７ Cs), 169-ytterbium ( １６９ Yb), 192-iridium ( １９２ Ir), or 226-radium ( ２２６ Ra) a gamma-emitting radionuclide 114. The compound of any one of claims 1 to 113, wherein:

119. The radionuclide of the radionuclide complex is 111-indium ( １１１ In), 115-indium ( １１５ In), 67-gallium ( ６７ Ga), 68-gallium ( ６８ Ga), 70-gallium ( ７０ Ga), 225-actinium ( ２２５ Ac), 175-lutetium ( １７５ Lu), or 177-lutetium ( １７７ 114. The compound of any one of claims 1 to 113, or a pharmaceutically acceptable salt thereof, wherein:

120. 120. A pharmaceutical composition comprising a compound according to any one of claims 1 to 119, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

121. 121. The pharmaceutical composition of claim 120, formulated for administration to a mammal by intravenous administration.

122. 120. A method of treating cancer, comprising administering to a mammal having cancer an effective amount of a compound of any one of claims 1 to 119, or a pharmaceutically acceptable salt thereof.

123. 123. The method of claim 122, wherein the cancer comprises a tumor, and the tumor overexpresses the follicle-stimulating hormone receptor (FSHR).

124. 124. The method of claim 122 or 123, wherein the cancer is ovarian cancer, prostate cancer, breast cancer, testicular cancer, lung cancer, liver adenocarcinoma, colon adenocarcinoma, gastric adenocarcinoma, kidney cancer, or bladder cancer.

125. 124. The method of claim 122 or 123, wherein the cancer is ovarian cancer.

126. 124. The method of claim 122 or 123, wherein the cancer is prostate cancer.

127. 124. The method of claim 122 or 123, wherein the cancer is testicular cancer.

128. 120. A method of killing tumors in a mammal which overexpress the follicle stimulating hormone receptor (FSHR), comprising administering to said mammal a compound of any one of claims 1 to 119, or a pharmaceutically acceptable salt thereof, wherein the compound of any one of claims 1 to 119, or a pharmaceutically acceptable salt thereof, comprises a therapeutic radionuclide.

129. 129. The method of claim 128, wherein the mammal has been diagnosed with ovarian cancer, prostate cancer, breast cancer, testicular cancer, lung cancer, liver adenocarcinoma, colon adenocarcinoma, gastric adenocarcinoma, kidney cancer, or bladder cancer.

130. 129. The method of claim 128, wherein the mammal has been diagnosed with ovarian cancer.

131. 129. The method of claim 128, wherein the mammal has been diagnosed with prostate cancer.

132. 129. The method of claim 128, wherein the mammal has been diagnosed with testicular cancer.

133. 120. A method of identifying tumors in a mammal which express the follicle stimulating hormone receptor (FSHR), comprising administering to said mammal a compound of any one of claims 1 to 119, or a pharmaceutically acceptable salt thereof, and performing positron emission tomography (PET) analysis, single photon emission tomography (SPECT), or magnetic resonance imaging (MRI), wherein the compound of any one of claims 1 to 119, or a pharmaceutically acceptable salt thereof, comprises a diagnostic radionuclide.

134. 120. A method of performing in vivo diagnostic imaging of tissues or organs associated with tumors expressing the follicle stimulating hormone receptor (FSHR) in a mammal, comprising administering to said mammal a compound of any one of claims 1 to 119, or a pharmaceutically acceptable salt thereof, and performing positron emission tomography (PET) analysis, single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI), wherein the compound of any one of claims 1 to 119, or a pharmaceutically acceptable salt thereof, comprises a diagnostic radionuclide.

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