Compositions targeting neurotensin receptor and uses thereof

Abstract

The disclosure features neurotensin receptor 1 (NTSR1) targeting compounds, radiolabeled NTSR1 targeting compounds, and their use in in vivo medical imaging applications for imaging tissues or tumors expressing NTSR1, or in radiotherapy for treatment of a disease or condition in which NTSR1 is expressed or overexpressed.

Description

COMPOSITIONS TARGETING NEUROTENSIN RECEPTOR AND USES THEREOFFIELD

[0001] The present disclosure relates to the fields of medical imaging and radiotherapy and, in particular, to compounds that may be radiolabeled for imaging or treating cancers expressing neurotensin receptor.BACKGROUND

[0002] Neurotensin is a 13-amino acid neuropeptide that functions as a neurotransmitter and a hormone in the nervous system and in peripheral tissues. Neurotensin receptor belongs to the family of guanine nucleotide-binding regulatory protein-coupled receptors. Studies reveal that the expression level of neurotensin receptors closely associates with disease progression.

[0003] As one of the three receptor subtypes, neurotensin receptor 1 (NTSR1) has been associated with several oncogenic effects such as proliferation, survival, migration, invasion, and neoangiogenesis. NTSR1 has been demonstrated to be overexpressed in cancers such as pancreatic ductal adenocarcinoma, Ewing’s sarcoma, and small cell lung cancer.Accordingly, NTSR1 has become a promising target for diagnostic and therapeutic purposes in the oncology field.

[0004] Targeting NTSR1 using radiopharmaceuticals comprising a radionuclide, specifically small molecule-based binders, has gained popularity in recent years. There are several NTSR1-targeting radioligands showing improved and favorable in vivo biodistribution in preclinical models, now advancing to clinical studies.

[0005] There remains a need for NTSR1 -targeting radiopharmaceuticals with enhanced efficacy and safety profiles.SUMMARY

[0006] The present disclosure relates generally to certain compounds targeting neurotensin receptor, e.g., neurotensin receptor 1 (NTSR1), that may be radiolabeled for in vivo medical imaging of cancer, as well as for radiotherapeutic treatments.

[0007] In one aspect, this disclosure covers compounds of the general Formula A or Formula B (below), that are antagonists of NTSR1:wherein:Ring A is an optionally substituted 5- to 6-membered heteroaryl;Ring B is optionally substituted phenyl, optionally substituted chromanyl, or optionally substituted naphthyl;Ring C is optionally substituted quinolinyl, optionally substituted N-oxide quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinolone, optionally substituted isoquinolinone, optionally substituted tetrahydroquinolinyl, optionally substituted dihydroquinolinone, optionally substituted phenyl, or optionally substituted pyridyl;L is a linker, optionally comprising one or more charge-modifying groups;X is a chelator optionally chelated with a radionuclide;p is 0 or 1; andW is a natural or unnatural amino acid;provided that:when p is 1, then V is O; andwhen p is 0, then V is tethered to Ring A to form an optionally substituted 5- to 6-membered heteroaryl fused to Ring A;or a pharmaceutically acceptable salt or solvate thereof.

[0008] The above compounds of Formula A or Formula B, when labelled with the appropriate diagnostic or therapeutic radionuclide, are useful for the in vivo imaging or therapy of subjects with diseases or disorders characterized by aberrant / ectopic expression of NTSR1.

[0009] In another aspect, this disclosure covers pharmaceutical compositions for diagnostic or therapeutic use, comprising one of the above-described compounds and a pharmaceutical excipient. Also provided are pharmaceutical compositions including a compound of Table 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0010] Also covered by this disclosure is a method for imaging a tissue or cancer expressing or overexpressing NTSR1 in a patient, wherein the method comprises administering to the patient in need thereof a compound set forth above, or a relevant pharmaceutical composition, with a radionuclide suitable for in vivo imaging.

[0011] Still within the scope of this disclosure is a method for treating cancer expressing or overexpressing NTSR1 in a patient, wherein the method comprises administering to the patient in need thereof a compound set forth above, or a relevant pharmaceutical composition, with a radionuclide suitable for radiotherapeutic treatment. Examples of the cancer include, but are not limited to, pancreatic ductal adenocarcinoma, small cell lung cancer, non-small cell lung cancer, breast cancer, bladder cancer, colorectal cancer, cervical cancer, gastrointestinal stromal tumors, head and neck cancer, meningioma, Ewing's sarcoma, pleural mesothelioma, prostate cancer, pancreatic cancer, uterine leiomyoma, and cutaneous T-cell lymphoma.

[0012] Further aspects of the invention will become apparent from consideration of the ensuing description of preferred embodiments of this invention. A person skilled in the art will realize that other embodiments of the invention are possible and that the details of the invention can be modified in a number of respects, all without departing from the inventive concept. Thus, the following descriptions and examples are to be regarded as illustrative in nature and not restrictive.DETAILED DESCRIPTION

[0013] In a broad aspect, the invention relates to neurotensin receptor 1 (NTSR1) targeting compounds that are optionally radiolabeled, and their use in in vivo medical imaging applications for imaging tissues or tumors expressing NTSR1, or in radiotherapy for treatment of a disease or condition in which NTSR1 is expressed, particularly for imaging tissues or tumors, and / or treatment of a disease or condition where NTSR1 is aberrantly expressed,ectopically expressed, or overexpressed. Accordingly, in certain embodiments, the invention relates to radio-labelled NTSR1 targeting compounds comprising a compound that selectively binds to NTSR1 and a radiolabel (interchangeably used with radionuclide or radioisotope) suitable for in vivo imaging or radiotherapy, and to precursors of such NTSR1 targeting compounds that may subsequently be radio-labelled.

[0014] In one aspect, the invention relates to NTSR1 targeting compounds, and radiolabeled compositions containing the compounds, for use as imaging probes, which selectively bind to NTSR1 and are suitable for in vivo imaging, for example positron emission tomography (PET) or single photon emission computed tomography (SPECT) based imaging, of patients having a disease or disorder in which NTSR1 is expressed, for example, cancer.

[0015] In another broad aspect, the invention relates to NTSR1 targeting compounds, and radiolabeled compositions containing the compounds, which selectively bind to NTSR1 and are suitable for the treatment of patients having a disease or disorder in which NTSR1 is expressed, for example, cancer.

[0016] Certain embodiments relate to unlabeled precursors of the above compounds and compositions, which can subsequently be radio-labelled and used as probes or therapeutic compositions. The radiolabel, radionuclide, radioisotope, or radiometal may be introduced, for example, by incorporating a radiolabel by readily available synthetic procedures, such as “click” chemistry, or via a chelating moiety comprised by the precursor which can chelate to a suitable radiolabel, radionuclide, radioisotope, or radiometal.

[0017] Based on the data provided in the Examples, the NTSR1 targeting compounds show high contrast, rapid renal clearance, minimal non-target organ uptake, and high tumour to normal tissue ratios, which properties make these compounds well-suited for use as diagnostic imaging agents and for radiotherapy applications.Definitions

[0018] As used herein and throughout the disclosure, the singular forms “a” and “an” include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a plurality of such compounds and equivalents thereof known to those skilled in the art, and so forth.

[0019] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can refer to a range of ± 20% of a given value.

[0020] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certainembodiments.

[0021] The term “alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, n-pentyl, t-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-10 alkyl” or “C1-C10 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms. In some embodiments, the alkyl or heteroalkyl group may contain, e.g., 1-50, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C50, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, the alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4).

[0022] The term “alkylene” refers to a straight or branched divalent hydrocarbon chain. Examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH2CH(CH3)CH2- The term “heteroalkylene” refers to a straight or branched divalent hydrocarbon chain in which one or more skeletal atoms of the hydrocarbon chain are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. In some embodiments, an alkylene or heteroalkylene may contain, e.g., 1-50, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1 -6, 1-4, or 1 -2 carbon atoms (e.g., C1-C50, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C2).

[0023] The term “alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds. Examples of alkenyl include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. The double bond in an alkenyl may be in either the cis or trans configuration and should be understood to include both isomers. Whenever it appears herein, a numerical range such as “C2-6 alkenyl” or “C2-C6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0024] The term “alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds. Examples of alkynyl include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiy nyl, and the like.

[0025] The term “alkylamino” refers to a radical of the formula -NHR or -NRR’, where R and R’ are, independently, an alkyl radical as defined. Examples of alkylamino include, but are not limited to, -NHMe, -NHEt, -NHPr', -N(Me)2, and -NMeEt.

[0026] The term “alkoxy” refers to a radical of the formula -OR where R is an alkyl radicalas defined. Examples of alkoxy include, but are not limited to, -OMe, -OEt, and -OBu‘.

[0027] The term “aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Examples of aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminopentyl.

[0028] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. An aryl can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems.

[0029] The term “carbocycle” refers to a ring system that contains only carbon atoms within the ring. A carbocycle can comprise 3 to 8 carbon atoms. A carbocycle can comprise one or more rings, wherein each ring can be saturated, partially saturated, or unsaturated. A carbocycle can be an aryl (e.g., phenyl) or a cycloalkyl (e.g., cyclohexyl), as defined below, or a combination thereof. As used herein, a carbocycle can be fused with an aryl or a heteroaryl, as defined below, or another carbocycle, to form a fused bicyclic system.

[0030] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls can be saturated or partially unsaturated. Cycloalkyls can also be spirocyclic or bridged compounds. In addition, cycloalkyls can be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.O

[0031] The term “carbamoyl” refers to a moiety comprising the structure ofH2N

[0032] The term “halo” or “halogen” refers to bromo, chloro, fluoro, or iodo.

[0033] The term “ haloalky I” refers to an alkyl radical, as defined above, that is substituted by one or more halogens. Examples of haloalkyl include, but are not limited to, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. A haloalkyl can comprise one or more halo atoms. For example, “fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0034] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. Examples of heteroalkyl include, but are not limited to, -CH2-O-CH2-, -CH2-NH-CH2-, -CH2-N(alkyl)-CH2-, -OCH2CH2O-, and -OCH2CH2OCH2CH2O-.

[0035] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one hetero ring atom, e.g., a heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atom in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, imidazolinyl, imidazolidinyl, morpholinyl, piperidinyl, and piperazinyl.

[0036] The term “heteroaryl” refers to a ring system radical comprising carbon atom(s) and one or more ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl is monocyclic, bicyclic or polycyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, and indazole. A heteroaryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems.

[0037] The terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms (e.g., oxygen, sulfur, nitrogen, phosphorus, or silicon). When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in r=N p-NH3,4-dihydro-2H-pyrrolyl -e), NH (as in pyrrolidinyl - ), NR (as in N- Rsubstituted 2- pyrrolidinyl - O- / c) or+NR (as in N-substituted 1 -pyrrolidinyl -). As used herein, a heterocycle can be fused with an aryl, cycloalkyl, heteroaryl, or another heterocycle, to form a fused bicyclic system.

[0038] The terms “alkenylene” and “alkynylene,” as used herein, refer to divalent groups having a specified size. In some embodiments, an alkenylene or alkynylene may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Alkenylene and / or alkynylene includes straight-chain and branched-chain forms, as well as combinations of these. The divalency of an alkenylene or alkynylene group does not include the optional substituents on the alkenylene or alkynylene group.

[0039] The term “cycloalkylene,” as used herein, refers to a divalent cyclic group linking together two parts of a compound. For example, one carbon within the cycloalkylene group may be linked to one part of the compound, while another carbon within the cycloalkylene group may be linked to another part of the compound. A cycloalkylene group may include saturated or unsaturated non-aromatic cyclic groups. A cycloalkylene may have, e.g., three to twenty carbons in the cyclic portion of the cycloalkylene (e.g., a C3-C7, Cs-Cs, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkylene). When the cycloalkylene group includes at least one carboncarbon double bond, the cycloalkylene group can be referred to as a “cycloalkenylene” group. A cycloalkenylene may have, e.g., four to twenty carbons in the cyclic portion of the cycloalkenylene (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenylene). When the cycloalkylene group includes at least one carbon-carbon triple bond, the cycloalkylene group can be referred to as a “cycloalkynylene” group. A cycloalkynylene may have, e.g., four to twenty carbons in the cyclic portion of the cycloalkynylene (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C14, C4-C16, C4-C18, or C8-C20 cycloalkynylene). A cycloalkylene group can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. Heterocycloalkylene refers to a cycloalkylene group including one or more, e.g., 1-4, 1-3, 1, 2, 3, or 4, heteroatoms, e.g., N, O, and S. Examples of cycloalkylenes include, but are not limited to, cyclopropylene and cyclobutylene. A tetrahydrofuran may be considered as a heterocycloalkylene.

[0040] The term “arylene,” as used herein, refers to a multivalent (e.g., divalent or trivalent) aryl group linking together multiple (e.g., two or three) parts of a compound. For example, one carbon within the arylene group may be linked to one part of the compound, while another carbon within the arylene group may be linked to another part of the compound. An arylene may have, e.g., five to fifteen carbons in the aryl portion of the arylene (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C11, C5-C12, C5-C13, C5-C14, orC5-C15 arylene). An arylene group can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. Heteroarylene refers to an aromatic group including one or more, e.g., 1-4, 1-3, 1, 2, 3, or 4, heteroatoms, e.g., N, O, and S. A heteroarylene group may have, e.g., two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C11, C2-C12, C2-C13, C2-C14, or C2-C15 heteroarylene).

[0041] The term “optionally substituted,” as used herein, refers to having 0, 1, or more substituents, such as 0-25, 0-20, 0-10, or 0-5 substituents. Alkyl, heteroalkyl, alkoxyl, carbocycle, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, aminoalkyl, adamantyl, pyrazolyl, pyrazolopyridinyl, pyrazolo-oxazolyl fused ring, phenyl, chromanyl, naphthyl, quinolinyl, N-oxide quinolinyl, isoquinolinyl, quinolone, isoquinolinone, tetrahydroquinolinyl, dihydroquinolinone, phenyl, and pyridyl may be substituted with alkyl, halogen, alkenyl, alkynyl, aryl, alkaryl, acyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkaryl, halogen, oxo, cyano, nitro, amino, alkylamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, ureido, amidinyl, oximo, benzyl, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, ON, CFs, OCFs, SiRs, and NO2, wherein each R is, independently, H, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, or heteroaryl. In some embodiments, a substituent is further substituted as described herein. For example, a Ci alkyl group, i.e., methyl, may be substituted with oxo to form a formyl group and further substituted with -OH or -NHR to form a carboxyl group or an amido group. An optionally substituted group or moiety refers to a group or moiety (e.g., any one of the groups or moieties described above) in which one of the atoms (e.g., a hydrogen atom) is optionally replaced with another substituent. For example, an optionally substituted alkyl may be an optionally substituted methyl, in which a hydrogen atom of the methyl group is replaced by, e.g., OH. As another example, a substituent on a heteroalkyl or its divalent counterpart, heteroalkylene, may replace a hydrogen on a carbon or a hydrogen on a heteroatom such as N. For example, the hydrogen atom in the group -R-NH-R- may be substituted with an alkamide substituent, e.g., -R-N[(CH2C(O)N(CH3)2]-R.

[0042] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0043] As used herein, the term “pyrazolyl” refers to a pyrazole radical. A non-limiting example of “pyrazolyl” may include the following structure in Ring A of Formula A or Formula B as defined herein:wherein the wavy bonds indicate attachment points to Ring B and Ring C; U is H, halo, C1-3 alkyl, or C1-3 haloalkyl, and the variables are defined in Formula A or Formula B.

[0044] As used herein, the term “pyrazolopyridinyl” refers to a pyrazolopyridine radical. A non-limiting example of “pyrazolopyridinyl” may include the following structure in Ring A of Formula A or Formula B as defined herein:wherein the pyrazolopyridinyl is optionally substituted (as defined herein), the wavy bonds indicate attachment points to Ring B and Ring C, and the variables are defined in Formula A or Formula B.

[0045] As used herein, the term “pyrazolo-oxazolyl fused ring” refers to a pyrazole fused to an oxazole, wherein the fused ring is a radical. A non-limiting example of “pyrazolo-oxazolyl fused ring” may include the following structure in Ring A of Formula A or Formula B as defined herein:wherein the wavy bonds indicate attachment points to Ring B and Ring C, and the variables are defined in Formula A or Formula B.

[0046] As used herein, the term “chromanyl” refers to a chromane radical. A nonlimiting example of “chromanyl” may include the following structure in Ring B of Formula A as defined herein:wherein the chromanyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, and Ring A can be attached to any available carbon atom in the fused ring. Alternatively, a non-limiting example of “chromanyl” may include the following structure in Ring B of Formula B as defined herein:wherein the chromanyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, Ring A and L-X are attached to any available carbon atom in the fused ring provided that Ring A and L-X are not attached to the same carbon atom, and the variables are defined in Formula A or Formula B.

[0047] As used herein, the term “naphthyl” refers to a naphthalene radical. A nonlimiting example of “naphthyl” may include the following structure in Ring B of Formula A as defined herein:wherein the naphthyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, and Ring A can be attached to any available carbon atom in the fused ring. Alternatively, a non-limiting example of “naphthyl” may include the following structure in Ring B of Formula B as defined herein:Ring AL(Xwherein the naphthyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, Ring A and L-X are attached to any available carbon atom in the fused ring provided that Ring A and L-X are not attached to the same carbon atom; and wherein the variables are defined in Formula A or Formula B.

[0048] As used herein, the term “quinoliny I” refers to a quinoline radical. A nonlimiting example of “quinolinyl” may include the following structure in Ring C of Formula A as defined herein:wherein the quinolinyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, Ring A and L-X are attached to any available carbon atom in the fused ring provided that Ring A and L-X are not attached to the same carbon atom, and the variables are defined in Formula A or Formula B.Alternatively, a non-limiting example of “quinolinyl” may include the following structure in Ring C of Formula B as defined herein:wherein the quinolinyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, and Ring A can be attached to any available carbon atom in the fused ring.

[0049] As used herein, the term “N-oxide quinolinyl” refers to an N-oxide quinoline radical. A non-limiting example of “N-oxide quinolinyl” may include the following structure in Ring C of Formula A as defined herein:wherein the N-oxide quinolinyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, Ring A and L-X are attached to any available carbon atom in the fused ring provided that Ring A and L-X are not attached to the same carbon atom, and the variables are defined in Formula A or Formula B. Alternatively, a non-limiting example of “N-oxide quinolinyl” may include the following structure in Ring C of Formula B as defined herein:Owherein the N-oxide quinolinyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, and Ring A can be attached to any available carbon atom in the fused ring.

[0050] As used herein, the term “ isoquinoliny I” refers to an isoquinoline radical. A non-limiting example of “isoquinolinyl” may include the following structure in Ring C of Formula A as defined herein:wherein the isoquinolinyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, Ring A and L-X are attached to any available carbon atom in the fused ring provided that Ring A and L-X are not attached to the same carbon atom, and the variables are defined in Formula A or Formula B.Alternatively, a non-limiting example of “isoquinolinyl” may include the following structure in Ring C of Formula B as defined herein:wherein the isoquinolinyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, and Ring A can be attached to any available carbon atom in the fused ring.

[0051] As used herein, the term “quinolone” refers to a quinolone radical. A nonlimiting example of “quinolone” may include the following structure in Ring C of Formula A as defined herein:Ring ApHXwherein the quinolone is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, Ring A and L-X are attached to any available carbon or nitrogen atom in the fused ring provided that Ring A and L-X are not attached to the same carbon or nitrogen atom, and the variables are defined in Formula A or Formula B. Alternatively, a non-limiting example of “quinolone” may include the following structure in Ring C of Formula B as defined herein:zHwherein the quinolone is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, and Ring A can be attached to any available carbon or nitrogen atom in the fused ring.

[0052] As used herein, the term “isoquinolinone” refers to an isoquinolinone radical. A non-limiting example of “isoquinolinone” may include the following structure in Ring C of Formula A as defined herein:wherein the isoquinolinone is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, Ring A and L-X are attached to any available carbon or nitrogen atom in the fused ring provided that Ring A and L-X are not attached to the same carbon or nitrogen atom, and the variables are defined in Formula A or Formula B. Alternatively, a non-limiting example of “isoquinolinone” may include the following structure in Ring C of Formula B as defined herein:wherein the isoquinolinone is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, and Ring A can be attached to any available carbon or nitrogen atom in the fused ring.

[0053] As used herein, the term “tetrahydroquinolinyl” refers to a tetrahydroquinoline radical. A non-limiting example of “tetrahydroquinolinyl” may include the following structure in Ring C of Formula A as defined herein:wherein the tetrahydroquinolinyl is optionally substituted (as defined herein), the wavy bond indicates the attachment point to Ring A, Ring A and L-X are attached to any available carbon or nitrogen atom in the fused ring provided that Ring A and L-X are notatached to the same carbon or nitrogen atom, and the variables are defined in Formula A or Formula B. Alternatively, a non-limiting example of “tetrahydroquinolinyl” may include the following structure in Ring C of Formula B as defined herein:Hwherein the tetrahydroquinolinyl is optionally substituted (as defined herein), the wavy bond indicates the atachment point to Ring A, and Ring A can be attached to any available carbon or nitrogen atom in the fused ring.

[0054] As used herein, the term “dihydroquinolinone” refers to a tetrahydroquinoline radical. A non-limiting example of “dihydroquinolinone” may include the following structure in Ring C of Formula A as defined herein:Ring AoXH^Xwherein the dihydroquinolinone is optionally substituted (as defined herein), the wavy bond indicates the atachment point to Ring A, Ring A and L-X are attached to any available carbon or nitrogen atom in the fused ring provided that Ring A and L-X are not atached to the same carbon or nitrogen atom, and the variables are defined in Formula A or Formula B. Alternatively, a non-limiting example of “dihydroquinolinone” may include the following structure in Ring C of Formula B as defined herein:Hwherein the dihydroquinolinone is optionally substituted (as defined herein), the wavy bond indicates the atachment point to Ring A, and Ring A can be attached to any available carbon or nitrogen atom in the fused ring.

[0055] The term “oxo,” as used herein, refers to a substituent having the structure =0, where there is a double bond between an atom and an oxygen atom.

[0056] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. Accordingly, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in asubject. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer. As used herein, “treating” includes the concepts of “alleviating”, which refers to lessening the frequency of occurrence or recurrence, or the severity, of any symptoms or other ill effects related to a disorder and / or the associated side effects. The term “treating” also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease.

[0057] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder can refer to a compound that in a statistical sample, reduces the occurrences of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0058] The term “therapeutically effective amount” as used herein refers to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. A therapeutically effective amount of the composition may vary depending on factors such as the individual’s condition, age, sex, and weight, and the ability ofthe protein to elicit the desired response ofthe individual. A therapeutically effective amount can also be an amount that exceeds any toxic or deleterious effect ofthe composition that would have a beneficial effect on the treatment.

[0059] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means an alkyl, as defined above, that is either substituted or unsubstituted. Further, an optionally substituted group may be un- substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0060] As used herein, the term “substituent” means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein isassumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances, one or more substituents having a double bond (e.g., “oxo” or “=O”) as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure. A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended forthose substituents.

[0061] The term “unsubstituted” means that the specified group bears no substituents.

[0062] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds being within the scope of the present disclosure.

[0063] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. For example, referring to Formula I, W includes both D- and L- forms, when applicable, of the corresponding amino acid.

[0064] The term “amino acid” is used in its broadest meaning, and it embraces not only natural amino acids but also derivatives thereof and artificial amino acids. For example, the term “amino acid” also encompasses unnatural amino acids.

[0065] The term “natural amino acid” refers to the 20 naturally occurring amino acids that are identified throughout by the conventional three- or one-letter abbreviations indicated in Table 1 below, which are as generally accepted in the art and recommended by the IUPAC-IUB commission in biochemical nomenclature.Table 1. Amino acid codesName 3-Letter 1 -Letter Name 3-Letter 1 -Letter Code Code Code Code Alanine Ala A Leucine Leu L Arginine Arg R Lysine Lys K Asparagine Asn N Methionine Met M Aspartic Acid Asp D Phenylalanine Phe F Cysteine Cys C Proline Pro P Glutamic Acid Glu E Serine Ser S Glutamine Gin Q Threonine Thr T Glycine Gly G Tryptophan Trp W Histidine His H Tyrosine Tyr Y Isoleucine lie I Valine Vai V

[0066] The term “unnatural amino acid,” interchangeably used with “non-natural amino acid” or “synthetic amino acid”, as used herein, may be any molecule that falls under the general definition of an amino acid, i.e., that comprises an amino group and a carboxyl group, but that is other than the 20 natural amino acids set forth in Table 1. Thus, non-natural amino acids are preferably obtained by chemical synthesis.

[0067] Ranges provided herein are understood to be shorthand for all the values within the range. For example, a range of 1 to 20 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0068] As used herein, Ci-X(or Ci-Cx) refers to the number of carbons in the range of 1 to x, which includes C1-2, C1-3... Ci-X. For example, a group designated as “C1-5” indicates that there are one to five carbon atoms in the moiety, i.e. groups comprising 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, or 5 carbon atoms. Thus, by way of example only, “C1-4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group ca n be m et h y l, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.Accordingly, as used herein, C1-50 alkyl includes, but is not limited to, Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, Cs alkyl, C7 alkyl, Cs alkyl, Cg alkyl, C10 alkyl, On alkyl, C12 alkyl, C13 alkyl, C14 alkyl, C15 alkyl, Cie alkyl, C17 alkyl, Cis alkyl, C19 alkyl, C20 alkyl, C30 alkyl, C40 alkyl, C50 alkyl, C1-10 alkyl, C1-20 alkyl, C1-30 alkyl, C1-40 alkyl, and any combination therebetween.

[0069] The term “subject” or “patient” refers to both human and non-human primates, including, but not limited to, mammals, birds and fish, and encompasses domestic, farm, zoo, laboratory and wild animals, such as, for example, cows, pigs, horses, goats, sheep and other hoofed animals; dogs; cats; chickens; ducks; non-human primates; guinea pigs; rabbits; ferrets; rats; hamsters and mice.

[0070] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of the ordinary skills in the art to which this invention belongs.Compounds and Radioligands

[0071] As set forth above, this disclosure covers compounds of Formula A or Formula B (below), that are antagonists of NTSR1:, W.wwherein:Ring A is an optionally substituted 5- to 6-membered heteroaryl;Ring B is optionally substituted phenyl, optionally substituted chromanyl, or optionally substituted naphthyl;Ring C is optionally substituted quinolinyl, optionally substituted N-oxide quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinolone, optionally substituted isoquinolinone, optionally substituted tetrahydroquinolinyl, optionally substituted dihydroquinolinone, optionally substituted phenyl, or optionally substituted pyridyl;L is a linker, optionally comprising one or more charge-modifying groups;X is a chelator optionally chelated with a radionuclide;p is 0 or 1; andW is a natural or unnatural amino acid;provided that:when p is 1, then V is O; andwhen p is 0, then V is tethered to Ring A to form an optionally substituted 5- to 6-membered heteroaryl fused to Ring A;or a pharmaceutically acceptable salt or solvate thereof.

[0072] In some embodiments, Ring A is optionally substituted pyrazolyl, optionally substituted py razolopy ridiny I, or optionally substituted pyrazolo-oxazolyl fused ring.

[0073] In some embodiments, Ring A ishaloalkyl.

[0074] Ring A; wherein Ring B is optionally substituted.

[0075] In some embodiments of Formula A, Ring B is:

[0076] In some embodiments of Formula B, RingB is, wherein Ring B is optionally substituted.

[0077] In some embodiments of Formula B, RingB is

[0078] In some embodiments, Ring C is optionally substituted quinolinyl, optionally substituted N-oxide quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinolone, optionally substituted isoquinolinone, optionally substituted tetrahydroquinolinyl, or optionally substituted dihydroquinolinone.

[0079] In some embodiments, Ring C is optionally substituted isoquinolinone (e.g., quinolin-2(1H)-one). In some embodiments, Ring C is 7-chloroquinolin-2(1H)-one.

[0080] In some embodiments, Ring C is substituted with halo. In other embodiments, Ring C is substituted with chloro.

[0081] In some embodiments, Ring C is substituted with oxo.

[0082] In some embodiments, Ring C is substituted with halo and oxo. In some embodiments, Ring C is substituted with chloro and oxo.

[0083] Ring C is optionally substituted.Ring ARing A

[0084] In some embodiments of Formula B, Ring C iswherein Ring C is optionally substituted.Ring AL /

[0085] In some embodiments of Formula A, Ring Cis XX is attached to any available carbon or nitrogen atom in Ring C. In some embodiments, halo is chloro or bromo.Ring A

[0086] In some embodiments of Formula B, Ring Cis, wherein L-X, if present, is attached to any available carbon or nitrogen atom in Ring C. In some embodiments, halo is chloro or bromo.Ring A

[0087] In some embodiments of Formula A, Ring Cis Xembodiments, halo is chloro or bromo.Ring A

[0088] In some embodiments of Formula B,

[0089] In some embodiments, Ring C is

[0090] In some embodiments, the compound comprises the structure of Formula A-l:(A-l),wherein:A is CH, CH2, or N;B is C, C=O, CH, CH2, or N;D is C, C=O, N, or N+-O-(N-oxide);E is C or CRC;F is CR4;wherein indicates a single bond or a double bond and at least one of A, B, and D is N;each of R1, R2, R3, R4, Ra, Rb, Rc, Rd, and Re, independently, is H, halo, hydroxy, CN, amino, amido, carbamoyl, carboxylic acid, ester, optionally substituted C1-3alkyl, optionally substituted C1-3haloalkyl, optionally substituted C3-6cycloalkyl, optionally substituted C1-3alkoxy, or optionally substituted C1-3aminoalkyl; orR1 and R2 are tethered to form an optionally substituted carbocycle or optionally substituted heterocycle;L is a linker, optionally comprising one or more charge-modifying groups, wherein * indicates an attachment point that attaches the linker to B, D, E, or F;X is a chelator optionally chelated with a radionuclide;U is H, halo, C1-3 alkyl, or C1-3 haloalkyl;V is O; orU and V are tethered to form an optionally substituted 5- to 6-membered heteroaryl; andW is an optionally substituted natural or unnatural amino acid.

[0091] In some embodiments, the compound comprises the structure of Formula A-l I:(A-II),wherein:A is CH;B is C=O;D is N;E is CRC;F is CR4;each of R1, R2, R3, R4, Ra, Rb, Rc, Rd, and Re, independently, is H, halo, C1-3alkoxy, or C1-3alkyl; orR1 and R2 are tethered to form an optionally substituted carbocycle or optionally substituted heterocycle;L is a linker, optionally comprising one or more charge-modifying groups;X is a chelator optionally chelated with a radionuclide;U is H, halo, C1-3 alkyl, or C1-3 haloalkyl;V is O; orU and V are tethered to form an optionally substituted 5- to 6-membered heteroaryl; andW is an optionally substituted natural or unnatural amino acid.

[0092] In some embodiments, the compound comprises the structure of Formula I:wherein:A is CH, CH2, or N;B is C, CH, CH2, or N;D is C or N;E is C or CRC;wherein = indicates a single bond or a double bond and at least one of A, B, and D is N;each of R1, R2, R3, R4, Ra, Rb, Rc, Rd, and Re, independently, is H, halo, hydroxy, CN, amino, amido, carbamoyl, carboxylic acid, ester, C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, C1-3alkoxy, or C1-3aminoalkyl; or R1and R2are tethered to form an optionally substituted carbocycle or heterocycle;L is a linker, optionally comprising one or more charge-modifying groups at either end of the linker, wherein * indicates an attachment point that attaches the linker to B, D, or E;X is a chelator optionally chelated with a radionuclide;U is H, halo, C1-3 alkyl, or C1-3 haloalkyl;V is O; orU and V are tethered to form an optionally substituted 5- or 6-membered heteroaryl; andW is a natural or unnatural amino acid.

[0093] In some embodiments of Formula I, the compound is optionally substituted with oxo (e.g., B is C=O).

[0094] In some embodiments of Formula I, U is H, halo, or C1-3 alkyl (e.g., Me), and V is O.

[0095] In some embodiments of Formula I, U is H and V is O.

[0096] In some embodiments of Formula I, U is halo (e.g., F) or C1-3 alkyl (e.g., Me), and V is O.

[0097] In some embodiments, each of Ra, Rb, Rc, Rd, and Re, independently, is H, halo, C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, C1-3alkoxy, or C1-3aminoalkyl. In some embodiments, each of Ra, Rb, Rc, Rd, and Re, independently, is H, halo, C1-3alkyl, or C3-6cycloalkyl. In some embodiments, each of Ra, Rb, Rc, Rd, and Re, independently, is H, halo (e.g., F or Cl), or C1-3alkyl (e.g., methyl or isopropyl). In some embodiments, each of Ra, Rb, Rc, Rd, and Re, independently, is H or C1-3alkyl (e.g., methyl or isopropyl). In some embodiments, each of Ra, Rb, Rc, Rd, and Reis H.

[0098] In some embodiments, each of R1and R3is OMe, R2is H, and R4is H or halo (e.g., F or Cl).

[0099] In some embodiments, each of R1and R3is OMe, each of R2and R4is H, and W is 2-amino-2-adamantane carboxylic acid. In some embodiments, each of R1and R3is OMe, R2is H, R4is Cl, and W is 2-amino-2-adamantane carboxylic acid.

[0100] In some embodiments, R1and R2are tethered to form an optionally substituted carbocycle (e.g., phenyl), R3is OMe, R4is H or Cl, and W is 2-amino-2-adamantane carboxylic acid.

[0101] In some embodiments, R1and R2are tethered to form an optionally substituted heterocycle (e.g., tetrahydropyran), R3is OMe, R4is H or Cl, and W is 2-amino-2-adamantane carboxylic acid.

[0102] In some embodiments of Formula I, the linker is attached to B, each of Ra, Rb, Rc, Rd, and Reis H, U is H, V is O, and the compounds are represented by Formula I-a:(I-a),wherein each variable is as defined in Formula I. Exemplary compounds in these embodiments can have the following formulas:

[0103] In some embodiments of Formula I, the linker is attached to D, each of Ra, Rb, Rc, Rd, and Reis H, U is H, V is O, and the compounds are represented by Formula I-b, Formula I-c, or Formula I-d:(I-c),(I-d),wherein each variable is defined in Formula I. Exemplary compounds in these embodiments can have the following formulas:

[0104] In some embodiments of Formula I, the linker is attached to E, each of Ra, Rb, Rd, and Reis H, U is H, V is O, and the compounds are represented by Formula I-e:(I-e),wherein each variable is defined in Formula I. Exemplary compounds in these embodiments can have the following formula:X'L

[0105] In some embodiments of Formula I, the compound comprises the structure of Formula l-f:(I-f)wherein each variable is defined in Formula I. Exemplary compounds in these embodiments can have the following formulas:

[0106] In some embodiments of Formula A-I, Formula A-II, Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-d, Formula I-e, or Formula I-f, each of R1and R3is OMe, R2is H, and R4is H or halo (e.g., chloro).

[0107] In some embodiments, the compound comprises the structure of Formula II:wherein:A is CH, CH2, or N;B is C, C=O, CH, CH2, or N;D is C, C=O, N, or N+-O-(N-oxide);E is C or CRC;F is CR4;wherein indicates a single bond or a double bond and at least one of A, B, and D is N;each of R2, R3, R4, Ra, Rb, Rc, Rd, and Re, independently, is H, halo, hydroxy, CN, amino, amido, carbamoyl, carboxylic acid, ester, optionally substituted C1-3alkyl, optionally substituted C1-3haloalkyl, optionally substituted C3-6cycloalkyl, optionally substituted C1-3alkoxy, or optionally substituted C1-3aminoalkyl; orR1 and R2 are tethered to form an optionally substituted carbocycle or optionally substituted heterocycle;L is a linker, optionally comprising one or more charge-modifying groups;X is a chelator optionally chelated with a radionuclide;U is H, halo, C1-3 alkyl, or C1-3 haloalkyl;V is O; orU and V are tethered to form an optionally substituted 5- to 6-membered heteroaryl; andW is an optionally substituted natural or unnatural amino acid.

[0108] In some embodiments, the compound comprises the structure of Formula ll-a:R4(II-a).

[0109] In some embodiments, R3 is OMe and R4 is halo.

[0110] In some embodiments, the compound comprises the structure of Formula II-b:

[0111] In some embodiments, 4 is halo.

[0112] In some embodiments of Formula A-l, Formula A-l I, Formula I, Formula l-a, Formula l-b, Formula l-c, Formula l-d, Formula l-e, Formula l-f, Formula II, Formula II-a, or Formula II-b, R4is halo (e.g., chloro).

[0113] In some embodiments, the compound comprises the structure of Formula (III):wherein:G is N or CRf;H is N, C, or CRg;J is N, C, or CRj;wherein no more than two N atoms are assigned to G, H, and J;each of Ri, R2, Rs, Re, Rf, Rg, Rh, Ri, and Rjindependently, is H, halo, hydroxy, CN, amino, amido, carbamoyl, carboxylic acid, ester, C1-6 alkyl, C3-6 cycloalkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 aminoalkyl; orR1 and R2 are tethered to form an optionally substituted carbocycle or optionally substituted heterocycle;Rs is H, optionally substituted aryl, or optionally substituted heteroaryl;L is a linker, optionally comprising one or more charge-modifying groups at either end of the linker, wherein * indicates an attachment point that attaches the linker to H or J;X is a chelator optionally chelated with a radionuclide;U is H, halo, C1-3 alkyl, or C1-3 haloalkyl;V is O; orU and V are tethered to form an optionally substituted 5- or 6-membered heteroaryl; andW is a natural or unnatural amino acid.

[0114] In some embodiments of Formula III, each of Ra, Rb, Rc, and Rd, independently, is H, halo, C1-3 alkyl, C1-3 haloalkyl, Cs-e cycloalkyl, C1-3 alkoxy, or C1-3 aminoalkyl. In some embodiments, each of Ra, Rb, Rc, and Rd, independently, is H, halo, C1-3 alkyl, or Cs-e cycloalkyl. In some embodiments, each of Ra, Rb, Rc, and Rd, independently, is H, halo (e.g., F or Cl), or C1-3 alkyl (e.g., methyl or isopropyl). In some embodiments, each of Ra, Rb, Rc, and Rd, independently, is H or C1-3 alkyl (e.g., methyl or isopropyl). In some embodiments, each of Ra, Rb, Rc, and Rdis H.

[0115] In some embodiments of Formula III, U is H, halo, or C1-3 alkyl (e.g., Me), and V is O.

[0116] In some embodiments of Formula III, U is H and V is O.

[0117] In some embodiments of Formula III, U is halo (e.g., F) or C1-3 alkyl (e.g., Me), and V is O.

[0118] In some embodiments of Formula III, each of R1 and Rs is OMe, R2 is H, and R4 is H or halo (e.g., F or Cl).

[0119] In some embodiments of Formula III, each of R1 and Rs is OMe, each of R2 and R4 is H, and W is 2-amino-2-adamantane carboxylic acid. In some embodiments, each of R1 and Rs is OMe, R2 is H, R4 is Cl, and W is 2-amino-2-adamantane carboxylic acid.

[0120] In some embodiments of Formula III, U is H, V is O, G is CRfand H is CRg, and the compounds are represented by Formula lll-a:(III-a),wherein each variable is as defined above. In certain embodiments, each of Rf, Rg, Rh, and Riis H. Exemplary compounds in these embodiments can have the following formulas:

[0121] In some embodiments of Formula III, U is H, V is O, G is N and H is CRb, and the compounds are represented by Formula lll-b:(III-b),wherein each variable is as defined above. In certain embodiments, each of Rh, Ri, and Rgis H. Exemplary compounds in these embodiments can have the following formulas:

[0122] In some embodiments of Formula III, U is H, V is O, G is CRfand H is N, and the compounds are represented by Formula lll-c:wherein each variable is as defined above. In certain embodiments, each of Rf, Rh, and Riis H. Exemplary compounds in these embodiments can have the following formulas:

[0123] In some embodiments of Formula III, the compound comprises the structure of Formula lll-d:(III-d),wherein:R1 and R3 are C1-3 alkoxy; R5 is optionally substituted aryl or optionally substituted heteroaryl; and R6 is C1-6 alkyl.

[0124] In some embodiments, Rs is heteroaryl comprising at least one N, optionally substituted with C1.3 alkyl, or C1.3 alkoxy.In some embodiments, Rs is phenyl optionally substituted with C1-3 alkyl or C1-3 alkoxy.

[0125] In some embodiments of Formula III, the compound comprises the structure of Formula lll-e:

[0126] In some embodiments of Formula III, the compound comprises the structure of Formula lll-f:X(III-f)wherein:R1 and R3 are C1-3 alkoxy; and R6 is C1-6 alkyl.

[0127] In some embodiments of Formula A-l, Formula A-l I, Formula I, Formula II, and Formula III, U and V are tethered to form an optionally substituted 5- or 6-membered heteroaryl, with exemplary partial structures shown below:

[0128] In some embodiments, W is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic acid, 2-amino-2-(adamantan-1-yl)acetic acid, 2-amino-2-(3-hydroxyadamantan-1-yl)acetic acid, cyclohexylglycine, and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid, wherein the backbone of each amino acid is optionally substituted with hydroxy, halo, alkoxy, or amino.

[0129] In some embodiments, W is 2-amino-2-adamantane carboxylic acid, 2-amino-2-(adamantan-l-yl)acetic acid, or 2-amino-2-(3-hydroxyadamantan-1-yl)acetic acid, with their structures shown below:2-amino-2-adamantane carboxylic acid2-amino-2-(adamantan-1-yl)acetic acid (both D- and L- forms)HO HOH O or H O2-amino-2-(3-hydroxyadamantan-1-yl)acetic acid (both D- and L- forms).

[0130] In some embodiments, W is 2-amino-2-adamantane carboxylic acid.

[0131] In some embodiments, Ri is OMe; R2, Rd, and Reare H; Rs is optionally substituted C1.3 alkoxy; and W is 2-amino-2-adamantane carboxylic acid, with an exemplary partial structure shown below:

[0132] In some embodiments, Ri and R2 are tethered to form an optionally substituted carbocycle (e.g., phenyl), Rs is OMe, and W is 2-amino-2-adamantane carboxylic acid, with an exemplary partial structure shown below:

[0133] In some embodiments, R1 and R2 are tethered to form an optionally substituted heterocycle (e.g., tetrahydropyran), Rs is OMe, and W is 2-amino-2-adamantane carboxylic acid, with an exemplary partial structure shown below:

[0134] In some embodiments, R1 is OMe and Rs is OH.

[0135] In some embodiments, R1and R2are tethered to form an optionally substituted carbocycle (e.g., phenyl), R3is OMe, R4is H or Cl, and W is 2-amino-2-adamantane carboxylic acid.

[0136] In some embodiments, R1and R2are tethered to form an optionally substituted heterocycle (e.g., tetrahydropyran), R3is OMe, R4is H or Cl, and W is 2-amino-2-adamantane carboxylic acid.

[0137] In some embodiments, the linker is described by Formula L:J1-(Q1)g-(T1)h-(Q2)i-(T2)j-( Q3)k-(T3)|-( Q4)m-(T4)n-( Q5)o- J2Formula Lwherein J1is a bond attached to Ring C of Formula A or to Ring B of Formula B; J2is a bond attached to X (the chelator); each of Q1, Q2, Q3, Q4, and Q5is, independently, optionally substituted C1-C40 alkylene, optionally substituted C1-C40 heteroalkylene, optionally substituted C1-C40 alkoxylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C2-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted Cs-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; each of T1, T2, T3, T4is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, imino, or oximo; R' is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C2-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; each of g, h, i, j, k, I, m, n, and 0 is, independently, 0, 1, or 2; and each of Q1, Q2, Q3, Q4, and Q5is, independently, optionally substituted with one or more charge-modifying groups. In some embodiments, each of g, h, i, j, k, I, m, n, and 0 is, independently, 0 or 1.

[0138] In some embodiments, the linker is optionally substituted with a polyethylene glycol (PEG). A PEG has a repeating unit structure (-CH2CH2O-)n, wherein n is an integer from 2 to 100. A polyethylene glycol may be selected any one of PEG2 to PEG100 (e.g., PEG2, PEG3, PEG4, PEG5, PEG5-PEG10, PEG10-PEG20, PEG20-PEG30, PEG30-PEG40, PEG50-PEG60, PEG60-PEG70, PEG70-PEG80, PEG80-PEG90, or PEG90-PEG100).

[0139] In some embodiments, the linker L is typically C1-50 alkylene (e.g., C1-10 alkylene, C1-20 alkylene, C1-30 alkylene, or C1-40 alkylene) wherein one or more carbons are each, independently, replaced with O, S, NR, or C=O, wherein R is H or C1-3 alkyl. In some embodiments, C1-50 alkylene is optionally substituted with halogen, amino, nitrile, nitro, hydroxy, oxo (=O), alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycle, and the like.

[0140] In some embodiments, the linker is optionally substituted C1-50 alkyl, wherein one or o; / more carbons are each, independently, replaced with O, S, NRx, O, C=O, or, wherein Rxis H, C1-3 alkyl, or CH2COOH.

[0141] In some embodiments, the linker is C1-10 alkylene wherein one or more carbons are each, independently, replaced with O, NRX, or C=O, wherein Rxis H or CH3.

[0142] In some embodiments, the linker is:wherein each X is as defined above.

[0143] In some embodiments, the linker further comprises one or more (e.g., one to two, one to three, or one to four, e.g., one, two, three, or four) charge-modifying groups at either end ofthe linker. As used herein, the term “charge-modifying group” refers to a chemical groupcomprising a moiety that can attract a proton to form a positive charge (e.g., a tertiary amine) or lose a proton to form a negative charge (e.g., a carboxylic acid).

[0144] In some embodiments, the charge-modifying group is an amino acid unit formed from a natural or unnatural amino acid. Examples of such charge-modifying group include, but arenot limited to, 4-amino-1-carboxymethyl-piperidine (ACMP), 2-aminohexanedioic acid (Aad), glutamic acid (Glu), and aspartic acid (Asp):HO

[0145] In some embodiments, the linker comprises one or more charge-modifying groups selected from the group consisting of 4-amino-1-carboxymethyl-piperidine (ACMP), 2-aminohexanedioic acid (Aad), aspartic acid (Asp), and glutamic acid (Glu). Examples of the linker comprising a charge-modifying group include, but are not limited to, the following:wherein each X is as defined above.

[0146] According to certain embodiments, the chelator that is incorporated into the NTSR1 targeting compounds may be a radiometal chelating agent that is chelated to a radiolabel (interchangeably used with radionuclide, radiometal, or radioisotope), or it may be a chemical group covalently bound to a radiolabel. In one embodiment, the NTSR1 targeting compound comprises an unlabeled chelatorthat is bound to the NTSR1 targeting compound, where the unlabeled chelator is one that can be subsequently labelled with a desired radionuclide, such as an unlabeled radiometal chelating agent that is capable of chelating radiometals, a moiety configured for19F / 18F exchange, or a boronate precursor that is capable of conversion to an18F-labelled trifluoroborate. The exact group selected for incorporation into the NTSR1 targeting compound will depend on the radiolabel to be used and can be readily determined by one skilled in the art.

[0147] Examples of radiometal chelating agents or chelators include, but are not limited to, 1,4,7, 10-tetraazacyclotetradecane-1,4,7, 10-tetraacetic acid (DOT A), 1,4,7,10-tetraazacyclododececane,1 -(glutaric acid)-4, 7, 10-triacetic acid (DOT AGA), 1,4,7-triazacyclononane-triacetic acid (NOTA), 1,4,7-triazacyclononane-1-glutaric acid-4, 7-diacetic acid (NODAGA), 1,8-N, N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane (TE2A), 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 11, 13-triene-3,6,9-triacetic acid (PCT A), 1 -substituted 1,4,7,-tricarboxymethyl-1,4,7,10-teraazacyclododecane triacetic acid (DO3A), DEDPA (6,6’-[1,2-ethanediylbis(iminomethylene)]bis(2-pyridinecarboxylic acid) and 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), ethylenediaminetetraacetic acid (EDTA), diethylenetriamine pentaacetic acid (DTPA), NODASA, CB-DO2A, 3p-C-DEPA, TCMC, DO3A, DTPA and DTPA analogues optionally selected from CHX-A”-DTPA and 1B4M-DTPA; TETA; NOPO; Me-3,2-HOPO, CB-TE1A1P, CB-TE2P, MM-TE2A, DM-TE2A, sarcophagine and sarcophagine derivatives optionally selected from SarAr, SarAr-NCS, diamSar, AmBaSar, and BaBaSar, TRAP, AAZTA, DATA and DATA derivatives, H2-macropa or a derivative thereof, H2dedpa, H4octapa, H4py4pa, H4Pypa, H2azapa, H5decapa, and other picolinic acid derivatives, H4CHXoctapa, H4neunpa-p-Bn-NO2, CP256, PCTA, {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid (NET A), C-NETA, C-NE3TA, HBED, HBED-CC, BCPA, CP256, YM103, desferrioxamine (DFO) and DFO derivatives, H6phospa, a trithiol chelate, mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1,2-ethylenediylbis-L-cysteine diethyl ester, methylenediphosphonate, N, N’-bis(2-hydroxy-5-sulfobenzyl)-ethylenediamine-N, N — diacetic acid (SHBED), hexamethylpropyleneamineoxime, hexakis(methoxy isobutyl isonitrile), and 2,2',2",2"'-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (CROWN) and derivatives thereof, CROWN Amide, PYTA, PY3A, PYTA-GA, PYTA-PE, and macropa-NCS.

[0148] In one embodiment, the radiometal chelating group or chelator is DOTA, DOTAGA, AAZTA, HBED-CC, H2-macropa, or CROWN.

[0149] In some embodiments, the chelator is DOTA, DOTAGA, CROWN, NOTA, NODAGA, or MACROPA.

[0150] In some embodiments, the chelator is DOTA, DOTAGA, or CROWN.

[0151] In some embodiments, the compound disclosed herein includes a chelator selected from Table 2.Table 2: Exemplary radiometal chelators and exemplary radiometalsChelator Radiometal<□ Cu-64 / 67OH Ga-67 / 68\ / \. OHrNIn-111HO 1 J O Lu-177Y-86 / 90HO^( Bi-203 / 212 / 213O Pb-212DOT A, 1,4, 7, 10-tetraazacyclododecane- Ac-2251,4,7,10-tetraacetic acid Gd-159Yb-175Ho-166As-211Sc-44 / 47Pm-149Pr-142Sn-117mSm-153Tb-149 / 152 / 155 / 161 Er-165Ra-223 / 224Th-227HO O^. OH Same radiometals as >=° Y DOTA0 L J oJL. N NfHO^^ X — t >0^OH DOT AGA, 1,4,7, 10-tetraazacyclododececane-1 -(glutaricacid)-4, 7, 10-triacetic acid / \. OH Cu-64 / 67HO I 1 J °A N\ — / CB-D02A, 4, 10-bis(carboxymethyl)-1,4,7,10- tetraazabicyclo[5.5.2]tetradecaneChelator Radiometal O Pb-212 y— NH2RN NCTH2N 1 J oH2N— (0TCMC, 1,4,7, 10-tetrakis(carbamoylmethyl)- 1, 4, 7, 10-tetraazacyclododecaneQ. HO ^0 Bi-212 / 213 orN N"l AHH? l J N^OHI N N / n. _ _\ — / ^-\_O^ J^X^NO23p-C-DEPACK ^OH Cu-64 / 67 ^0 ^X^NH2H0L JL JL Ji-A0p-NH2-Bn-Oxo-DO3AHO^O Cu-64 / 67 " N r< YH° I J oI N N y0OHTETA, 1,4,8, 11-tetraazacyclotetradecane- 1,4,8,11-tetraacetic acidChelator Radiometal Cu-64 / 67. OHN Y HO r A J0CB-TE2A, 4,11-bis-(carboxymethyl)-1,4,8,11- tetraazabicyclo[6.6.2]-hexadecaneCu-64 / 67 / OHN. IK Yo f \ J0HY U CB-TE1A1POH Cu-64 / 67 N^P-0H0C \ D °H0Y OCB-TE2PCu-64 / 67 \ / OH / N KVHO r j °1 HITMM-TE2ACu-64 / 67 \ / \ / OH / N < VHO r j °DM-TE2AChelator Radiometal H / - \ H Cu-64 / 67 AN, — ^NAH2N— O~NH2N N— 'H 'HDiamsarH / - \ H Cu-64 / 67 r-N, —. NAZ-N NA\H H / H' 'hSarcophagine0 Cu-64 / 67 Ga-68 AHIn-1110CN30Sc-44 / 47., Jk / N NC AHO OH NOTA, 1,4,7-triazacyclononane-1,4,7-triacetic acidO Cu-64 / 67 AH Ga-68NIn-111 o ^~" ^ OSc-44 / 47 HO^^-T^^OHHO^ X)NODAGA, 1,4,7-triazacyclononane,1-glutaric acid-4, 7-acetic acidCu-64 / 67 V o Ga-68H0^J AH In-111 Lu-177c A°H0AAZTAChelator Radiometal Cu-64 / 67oY° o Ga-68 J AH In-111 NJA0DATA0 Cu-64 / 67 AH Ga-68 Lu-1770CN3 Y-86 / 90 HO^NU^N^fOHBi-213 °<yJ 0Pb-212 OH NET A, {4-[2-(bis-carboxymethylamino)-ethyl]- -carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid^^N°2 Cu-64 / 67 r j Ga-68 Lu-177 A HO^0Y-86 / 90 Bi-213 H° Pb-212 HO^VSHO^ XD3p-C-NE3TAAu-198 / 199 N N.JL 1^^N^SH HS^'" N^''"'H HHxTSEChelator Radiometal Rh-105 On oC 1NH2H2NP2N2Ph2In-111 °^0H^ V Sc-44 / 47 o N N N— ' PLu-177 FoJ MHO 1 OH Y-86 / 90 OHSn-117m DTPA, diethylenetriaminepentaacetic acidPd-109 In-111 O^OH^QHOyoLu-177 o N N N^p Y-86 / 90 M Bi-212 / 213 HO T OH OH CHX-AOO-DTPA, 2-(p-isothiocyanatobenzyl)cyclohexyl- diethylenetriaminepentaacetic acidCu-64 / 67 / A YAN\AOAOH HOAQH2dedpa, 1,2-[[6-(carboxy)-pyridin-2-yl]- methylamino]ethaneCu-64 / 67 CON^Y-\Nrf p YAN\=YOAOH HOAOH2azapa, N, N’-[1-benzyl-1,2,3-triazole-4-yl]methyl- N, N’-[6-(carboxy)pyridin-2-yl]-1,2-diaminoethaneChelator Radiometal HO / OHIn-111 Lu-177 C^^I / Y-86 / 90 / A " SN\-=^ Ac-225O^OH HO-%H4octapaHO OH Ac-225 cx "* "^ if^ln\ nn ynNr7r^N N^SiOH OHH4py4paHO OH HOSOH Ac-225 V-x / — \A r- N N^yO / A YAN\-=VO^OHH° <0H6phospaIn-111 V QH“ Ac-225 NN^\t>(T 'V*N N\===jCA°HhoAH4CHXoctapaIn-111 °^0H^ v° Lu-177 N N N— ' / =\Ac-225 \ / — / o-^X— V #z=N 1 N— (O=< OH )=0OH HOH5decapaChelator Radiometal ^Hy In-111 j. *— N N N— ' / =\ Lu-177 Ac-225 )=N \0-( / =0OH f J HONO2H4neunpa-p-Bn-NO2In-111 Ga-68HOY° AKO,- o33s. J O A OH^''AjHSHBED, N, N’-bis(2-hydroxy-5-sulfobenzyl)- ethylenediamine-N, N’-diacetic acid0 In-111 VoH0 <r >=\N - C N-)\ / -OHHO~ \A oA O= _?(7 OHOH BPCACu-64 / 67 0A N; AOHHOA0OH PCTA, 3,6,9, 15-tetraazabicyclo[9.3.1 ]- pentadeca-1 (15), 11,13-triene-3, 6, 9, -triacetic acidChelator Radiometal Ac-225r° %y0>CrHO^OH2-MACROPA (N, N’-bis[(6-carboxy-2-pyridil)methyl]- 4, 13-diaza-18-crown-6)Ac-225N^"sHOyAAo I^N^]<° %y0>CrHO^OMACROPA-NCS (6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13- tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)-4- isothiocyanatopicolinic acid)Chelator Radiometal ^x ^NCS Ac-225 rjx J xH0lO A Or0HTAA j^NNCA^N N^SiULo oJUOH OHH4py4pa-phenyl-NCSHO^O Ac-225 Tb-155 °YJN> Tb-161 OHC J 0 Th-227 r ^°hO^OHCROWNHOx^° Ac-225 Tb-155 °Y>rN Tb-161 OHI 1 o Th-227O^ XDH HO" X)CROWNGAH2N^O La-135 Tb-155 °y-NrNH2N Lu-177 1 I oA Pb-203 J" L^O JNH? Bi-213 O^NH2Ac-225 CROWN AmideChelator Radiometal O^O H Tc-99m Tc-94mHN'NH2HYNICOp^OH Tc-99m Tc-94m NH HN.H2N ^NH2N4 (6-carboxy-1,4,7,11 -tetraazaundecane)Ga-68 °H^OH°HO^ \ / ^OHHBED-CCH H Th-227 / L. OH HCX ^k( T T j]CT l\T1 1Me-3,2-HOPO (3-hydroxy- / \ / -methyl-2-pyridinone)Ga-68, 0 X 0 OH1 it O^NH n JL o< IHJHIT0H\ 1o >o| HNif XII0H0Chelator Radiometal 0 Ga-68 HO^JXx,o H y y,N J 'I H d r0 0l \ — / \ / °iHN\, NH I1 \ X / OHHO. A. N nTN Jk A.J JiYM103HO^° Pb-203 Q^ - i - J Pb-212V " YJI< \ _ / NH2QA°HPb Specific Chelator (PSC)OH 225-AcN> nI x°r^Nn 1O^OH k^OOH PY3AChelator RadiometalOH 225-AcHO^OT JL0f k^JUO^OHOH PYTA-GAOH 225-AcO^^ HO^ON\<NII 1r k^N^AAO^OH k^o TOHO^OHPYTA-PE

[0152] In some embodiments, the compound of Formula (A) or Formula (B) is selected from the following compounds listed in Table 3.Table 3. Compounds of the inventionCompound Structure\ o o < AZ\fl~\ Z^Jk. X^OH\ 7~ -fl |J N JJ f). / \ N~JN '. H 0 II O 'vK J— / — U / ? RD09-005 HO^ ^N4 RD09-005 \ ]OHN-\=4 0kNv_yN(_70HHN— \ > <-N >-NHHN— 40Compound StructureRD09-006Yo \==\ N N / C ^0 RD09-006HX0 9 y f y-f n Y \=( VN 00 ^=4RD09-014 / O'AHON"\==J / —N] V / ^A \ RD09-014 °^OH <^0H0X0 9 Y < TW " Y \=( ^N'N 00 ^=4 / O'Y RD09-096 RD09-096^^c>0 NHo'^y c\ ry~NxrN>0=\ — 'N — 'OH < ^0H0 / °O-ZI Y \=( VNRD09-015r"0RD09-015 O—-Z r'Sui\ I N— \ / N-~^ ^oCompound StructureJ VRD09-097 J RD09-097✓°hr x>° / / N — <)o oN-N 0HN-A jr\RD09-155ClJNRD09-155V AC "hHO2*00 / 0RD09-098 RD09-098AV 1N—\\=( ^N-N 0RD09-118xr^ RD09-118HON / NCACompound StructurewvORD09-017HO RD09-017HNOH <z0H. — ( A^Z-X ^OH qY fRD09-100 RD09-1003NHns \=( ^N-N 0>-ORD09-025< RD09-025 / -n1 j°XH <^OHyr \=< ^N'N 04(N--D RD09-016RD09-016h° r 1 JN / Os£0O^OHCompound StructureQ-°RD09-147 I I YVNHN-Z'Uy?H< L D < A°H0 \. N^ IRD09-147 BrH°-< 0Cr°I JQ RD09-137°\ '—NrA / ' " ’ I D Au- / N-. f\_ N J \ ClHO^ Jo RD09-137r^ v-o / ° / \— x RD09-148< 1A <0 °^OHHOy- / ° RD09-148 cioxo 9<y \=( V^H0 RD09-158 / 0C > h\s=<y—O Y| RD09-158 OH rr-N1 ^° r-'.0 N. [J \OHC J 00^^?k _“r 01Compound Structure\_ }o o W' — ( N-NH0°=\ / A\ ClRD09-138 / N"\ RD09-138°^N-HJ?NSk J OH✓Nj-°HC\ °RD09-117 HO _-N \ J D |NHN— l< ' / N N \ \ > I I) ^~OH 'N J L I] 0 J < / N\ / 0HRD09-117OAOHcP'° f'W V°H(O^^'N ^N-Z^ RD09-151d^OHOH ( s »o<^N< / n'7RD09-151HO-^oRD09-039 / NRD09-039O^ / °>xKf^O\ 1 N’“\Mi )( MHOyJ HO7^00Compound Structureoo / — \y— OH Z~N OH<k s oHO rN NC \Y \ P tzvXx, OH RD09-064—N\ S ^3 — Oi °HO- 2 RD09-064 S rN°zO N" X"s> S=<Cl OH1 JN >HQ ( V l\L ) J nL _ 1 | Z KT )S / A _ / 12^ OH RD09-075O>°H s ySo RD09-075 ^o Xi JL <N1RD09-164 {31?Hv vRD09-164 „ / -;NNLXN. AN °=< < > ' S > N' / yaOH ' / =\ / Q-°n J,1 Br' AP rz> RD09-173 T> N 1 VJ '^N''^°Y SSI 'Z'< ®HQ r NNxr > X.>4 J O RD09-173 L jl o^OHClQ-°Br J^\ Z,0rZA!! °Y<yN'N HN-Z^ Oi N., N. -N. 1 RD09-174 rj°Y0H?UNN~) o AN< A0HRD09-174O^OH

[0153] Suitable radiolabels or radionuclides for incorporation into the NTSR1 targeting compounds include any selected from the group consisting of18F,123l,131l,44Sc,47Sc,61Cu,64Cu,67Cu,67Ga,68Ga,72As,77As,86Y,90Y,89Zr,90Nb,94mTc,99mTc,105Rh,109Pd,111In,114mIn,117mSn,137Cs,141Cs,141Ce,142Pr,149Pm,149Tb,152Tb,155Tb,161Tb,153Sm,159Gd,165Er,166Ho,175Yb,177Lu,186Re,188Re,198Au,199Au,211At,203Pb,212Pb,212Bi,213Bi,223Ra,224Ra,225Ac, and227Th. The exact radiolabel selected for incorporation into the NTSR1 targeting compound will be dependent on the nature of the chelating agent or chemical group present in the compound for radiolabel attachment and the intended use of the final compound. For example,18F,123l,99mTc,111In,203Pb,68Ga,64Cu,86Y, and44Sc are suitable for PET and / or SPECT imaging, and64Cu,67Cu,90Y,212Pb,213Bi,177Lu,225Ac,186Re and188Re are suitable for radiotherapy applications. Selection of an appropriate label taking these factors into account can be readily made by one skilled in the art. One skilled in the art will also appreciate the certain radioisotopes may require modification to facilitate their incorporation into the NTSR1 targeting compounds and / or for stabilization. For example,18F may be used in the form of18F-AI to allowfor chelation by a chelating group on the NTSR1 targeting compound. Likewise,186Re and188Re may be used in the form of Re(CO)3.

[0154] In some embodiments, the compound of the invention is chelated to68Ga,111In,177Lu, or225Ac.

[0155] The radio-labelled NTSR1 targeting compounds according to the invention may be prepared by standard synthetic chemistry procedures from commercially available starting materials. Provided below is an exemplary, non-limiting synthetic scheme that can be followed to synthesize certain NTSR1 targeting compounds covered by this disclosure:Scheme 1Synthesis of compounds of Formula I, wherein U is halo or C1-3 alkyl, and V is O:Condensation1. Saponification2. H2N-W Amide CouplingDeprotectionScheme 2Synthesis of compounds of Formula I, wherein U and V are tethered to form an optionally substituted 5- or 6-membered heteroaryl:SaponificationAmide CouplingMitsunobu or Alkylation or CouplingDeprotectionAlkylationScheme 3Synthesis of compounds of Formula II, wherein U is H and V is O:Bromination HO"L'PG11. Reduction Mitsunobu 2. Diazotization or Alkylation 3. ReductionScheme 4Synthesis of compounds of Formula II, wherein U is halo or C1-3 alkyl, and V is O:CondensationSuO-X AlkylationScheme 5Synthesis of compounds of Formula II, wherein U and V are tethered to form an optionally substituted 5- or 6-membered heteroaryl:1. Diazotization Iodination 2. ReductionCondensationPG2Y-R7Deprotection Stille or Suzuki Cross-CouplingSuO-X Alkylation

[0156] In certain embodiments, the invention relates to conjugates of the above-described NTSR1 targeting compounds, in which the compound is conjugated to one or more additional chemical or biochemical moieties that provide additional functionality to the NTSR1 targeting compounds, for example, increased stability, improved bioavailability or improved pharmacokinetics and / or that assist in delivery of the compound to the appropriate tissue(s) or organ(s). Conjugates include NTSR1 targeting compounds fused to one or more biological moieties as well as NTSR1 targeting compounds in which the amino-terminus and / or carboxyterminus and / or one or more amino acid side chain has been derivatized with a suitable chemical substituent group for conjugation to one or more chemical or biological moieties. Examples of such chemical or biological moieties include, but are not limited to, various carriers, lipophilic moieties, antibodies and other biological ligands, liposomes, polymericmatrices, non-polymeric matrices, particles such as gold particles, microdevices and nanodevices, and nano-scale semiconductor materials.

[0157] In certain embodiments, the NTSR1 targeting compounds of any formula disclosed herein may possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with a number of organic and inorganic bases, or organic and inorganic acids, to form pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” as used herein, refers to a salt of a sequence or compound of Formula A or Formula B, which is substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compound of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.

[0158] Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulphonic acid, methanesulphonic acid, oxalic acid, p-bromophenylsulphonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulphate, pyrosulphate, bisulphate, sulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulphonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulphonate, propanesulphonate, naphthalene-1 -sulfonate, napththalene-2-sulfonate, mandelate and the like. Pharmaceutically acceptable acid addition salts of particular interest are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulphonic acid.

[0159] Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, lower alkenyl, substituted lower alkenyl, lower alky nyl, substituted lower alkynyl, or aralkyl moiety.

[0160] Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Bases useful in preparing pharmaceutically acceptable salts thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

[0161] One skilled in the art will understand that the particular counterion forming a part of a pharmaceutically acceptable salt is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contributeundesired qualities to the salt as a whole.

[0162] In some embodiments, the present invention further encompasses pharmaceutically acceptable solvates of a NTSR1 targeting compound of Formula A or Formula B. The compounds of any formula disclosed herein can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate or acetonitrilate.Pharmaceutical Compositions

[0163] The NTSR1 targeting compounds are typically formulated for administration to a patient, either before or after incorporation of a radiolabel. Certain embodiments of the invention thus relate to pharmaceutical compositions comprising one or more of the radio-labelled NTSR1 targeting compounds, or unlabeled NTSR1 targeting compounds, and a pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients.

[0164] The pharmaceutical compositions comprising the NTSR1 targeting compounds are typically formulated for parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intra-articular, intravenous, intraperitoneal, intramuscular, intravascular, intrasternal, intrathecal injection or infusion techniques.

[0165] In certain embodiments, the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or a suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Adjuvants such as local anaesthetics, preservatives and buffering agents can also be included in the injectable solution or suspension.

[0166] Other pharmaceutical compositions and methods of preparing pharmaceutical compositions are known in the art and are described, for example, in “Remington: The Science and Practice of Pharmacy" (formerly “Remingtons Pharmaceutical Sciences’’)', Gennaro, A., Lippincott, Williams & Wilkins, Philadelphia, PA (2000).UsesIn certain embodiments, the invention relates to the use of the radio-labelled NTSR1 targeting compounds in in vivo medical imaging applications or in radiotherapy in patients having adisease or disorder associated with expression, aberrant expression, ectopic expression, or overexpression of NTSR1. In pathologies, NTSR1 is expressed in malignancies. Accordingly, radiolabeled NTSR1 targeting compounds can be used both for diagnosis and therapy.According to certain embodiments, for diagnostic applications, a single-photon (such as99mTc) or positron-emitting (such as68Ga,18F,44Sc,64Cu,61Cu,86Y, or111In) radioisotope is attached to the NTSR1 targeting compound, allowing non-invasive imaging of the abnormal expression of these receptors. In other embodiments, such as for therapeutic applications, including cancer treatment, a radioisotope that delivers a high radiation dose (such as177Lu,90Y,212Pb,225Ac, or64Cu) can be attached to the NTSR1 targeting compound, and deliver targeted radiotherapy to the cells.Diagnostic Applications

[0167] Certain embodiments relate to diagnostic applications of the radio-labelled NTSR1 targeting compounds for imaging a cancer or tissue in which NTSR1 is expressed, aberrantly expressed, ectopically expressed, or overexpressed, for example, in oncology.

[0168] Overexpression of NTSR1 has been demonstrated in many malignancies, including ductal pancreatic adenocarcinoma, small cell lung cancer, non-small cell lung cancer, breast cancer, bladder cancer, colorectal cancer, cervical cancer, gastrointestinal stromal tumors, head and neck cancer, meningioma, Ewing's sarcoma, pleural mesothelioma, prostate cancer, pancreatic cancer, uterine leiomyoma, and cutaneous T-cell lymphoma. NTSR1 activation has been shown to potentiate malignant behaviors by inducing cell proliferation, migration, and angiogenesis. Certain embodiments of the invention thus contemplate that the radio-labelled NTSR1 targeting compounds could be used as imaging probes for cancers of ductal pancreatic adenocarcinoma, small cell lung cancer, non-small cell lung cancer, breast cancer, bladder cancer, colorectal cancer, and cervical cancer, including for use in early diagnosis of solid malignancies that express NTSR1, as imaging agents to confirm the diagnostic of malignancy, or to guide focal ablative treatment if the disease is localized. According to certain embodiments, the NTSR1 targeting compounds could also be used to monitor response to therapy, by providing an independent assessment of the residual cellular content of a tumor known to overexpress NTSR1. According to further embodiments, the NTSR1 targeting compounds can be used for endoradiotherapy targeting cells expressing NTSR1, by radiolabelling the compound with a radioisotope, usually a p- or a-particle emitter, to deliver a high local dose of radiation to lesions, to inflict DNA damage and inducing cellular death.Unlike external beam radiation therapy, in certain embodiments this systemic treatment can be effective even in the treatment of metastases.

[0169] Radio-labelled NTSR1 targeting compounds of this disclosure can show high contrast, rapid renal clearance, minimal non-target organ uptake, and high tumour to normal tissue ratios, which properties make these compounds well-suited for use as imaging agents forcancer diagnosis, including diagnosis of early-stage cancer. In particular, certain NTSR1 targeting compounds according to embodiments of the invention exhibit relatively low renal retention, and relatively high ratio of tumor: kidney uptake, facilitating safe and effective use of the compounds in diagnostic and radiotherapeutic treatments.

[0170] In some embodiments of the invention, it is contemplated that the radio-labelled NTSR1 targeting compounds may be used as PET / SPECT imaging probes to assist with precise localization of primary or recurrent cancer in order to guide and assist with focal ablative therapies.

[0171] In some embodiments, the invention contemplates that the radio-labelled NTSR1 targeting compounds could be used to monitor response to therapy, by providing an independent assessment of the residual cellular content of a tumour known to overexpress NTSR1. Overexpression of NTSR1 may be an indicator of angiogenesis in tumours, as blocking of NTSR1 activation is known to have antiangiogenic activity.

[0172] There is some evidence that NTSR1 antagonists might cause growth inhibition in some cancers. In certain embodiments, NTSR1 expression and receptor blockage could be detected by imaging with the radio-labelled NTSR1 targeting compounds, which could then act as a predictive biomarker for treatment success.

[0173] In some embodiments, the use of the radio-labelled NTSR1 targeting compounds in multimodality imaging of cancers is contemplated, for example, combined functional imaging and anatomical imaging, such as PET / CT or SPECT / CT. Multimodality imaging may be useful in situations in which a cancer is present, but the uptake of imaging agent is low.Therapeutic Applications

[0174] Certain embodiments relate to therapeutic applications of the radio-labelled NTSR1 targeting compounds in cancer. Cancers that are NTSR1 positive could be amenable to treatment by radionuclide therapy. In such applications, the radio-labelled NTSR1 targeting compound would incorporate a radioisotope that delivers a high local dose of radiation.Therapeutic radioisotopes include but are not restricted to177Lu,90Y,212Pb,225Ac, and64Cu. A dose of the compound calculated to deliver an effective radiation dose to the tumour, while avoiding or minimizing normal organ damage, is administered to the patient. The accumulated radioactivity in the tumour can lead to cell death and tumour regression. In certain cases, this type of systemic therapy can be effective even in the metastatic setting.Pharmaceutical Packs or Kits

[0175] Certain embodiments of the invention relate to pharmaceutical packs or kits containing one or more NTSR1 targeting compounds, for example, therapeutic or diagnostic packs or kits. The compounds may be provided radio-labelled or as precursors suitable for radiolabelling, in which case the kit may optionally include additional reagents for radio-labellingthe compounds.

[0176] In certain embodiments, one or more of the components of the kit can be lyophilized and the kit can additionally contain a suitable solvent for reconstitution of the lyophilized components. Individual components of the kit would typically be packaged in separate containers and, associated with such containers, can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, for use or sale for human or animal administration.

[0177] In certain embodiments, the compound(s) are provided in the kit in the form of pharmaceutical compositions suitable for administration to a subject. In this case, if desired, the container may itself be an inhalant, syringe, pipette, eye dropper, or other such like apparatus, from which the composition may be administered to the subject.

[0178] NTSR1 targeting compounds according to general Formulas I herein can be synthesized according to conventional methods known to those of ordinary skill in the art. Exemplary, non-limiting procedures are provided in the Examples below.

[0179] It is contemplated that any embodiment discussed herein can be implemented with respect to any method, use or composition of the invention, and vice versa. Furthermore, compositions and kits of the invention can be used to achieve methods and uses of the invention.

[0180] To gain a better understanding of the invention described herein, the following examples are set forth. It will be understood that these examples are intended to describe illustrative embodiments of the invention and are not intended to limit the scope of the invention in any way.EXAMPLESExample 1: Synthesis of exemplary NTSR1 targeting compoundsExperimental procedures

[0181] The general procedures for the chemical synthesis of target molecules and their complexes are described below. The final synthesized molecules were evaluated in vitro using in vitro binding assays (as described in the “In vitro binding assays” section) and in vivo (as described in the “In vivo evaluation” section).Chemical synthesisGeneral methods

[0182] Chemicals and solid-phase resins were procured from commercial sources and used without further purification. Normal phase column chromatography was performed using an automated Buchi Pure chromatography system. The column cartridges used for separationswere purchased from Santai - SepaFlash™ (4 g, 12 g, 25 g, and 40 g) or SepaFlash™ HP (4 g, 12 g, 25 g, and 40 g). Purification and quality control of precursors and nonradioactive metal-complexed compounds were performed on C18 Sep-Pak, Agilent, Waters or Biotage HPLC, UPLC and LCMS systems. HPLC columns used were preparative columns (Luna 5 pm C18(2) 100 A, LC Column 150 x 21.2 mm), (Luna 5 pm C18(2) 100 A, LC Column 50 x 30 mm), (Aeris 5 pm PEPTIDE XB-C18 100 A, LC Column 250 x 21.2 mm), semipreparative columns (Luna C18, 5 pm particle size, 100 A pore size, 250 * 10 mm), (Aeris 3.6 pm PEPTIDE XB-C18 100 A, LC Column 250 x 4.6 mm) and analytical columns (Luna C18, 5 pm particle size, 100 A pore size, 250 x 4.6 mm), (Kinetex 2.6 pm PS C18 100 A, LC Column 100 x 3 mm), (Kinetex 2.6 pm C18 100 A, LC Column 100 x 3 mm) or (Kinetex 5 pm XB-C18 100 A, LC Column 150 x 4.6 mm) purchased from Phenomenex. Other columns used were CORTECS UPLC, Acquity, X-Select CSH, X-Bridge BEH from Waters. The collected HPLC eluates containing the desired peptides were lyophilized using a Labconco FreeZone 4.5 Plus freeze drier. Mass analyses were performed using an Agilent InfinityLab Pro iQ mass spectrometer.General procedure for the synthesis of cold, nonradioactive metal complexes

[0183] The precursors (1 eq., 5-10 mg) and Ga(NOs)3 (2-5 eq.), CuCl2 / Cu(NO3)2 (2-5 eq.), InCIs (2-5 eq.), LuCIs (2-5 eq.) or LaCIs (5 eq.) were dissolved in 0.1 M aq. NaOAc and MeCN (2.5:1, DMSO was added when solubility was low). The reaction mixtures were heated to 90 °C for 30 min for DOTA and DOTAGA chelators (except for CROWN, wherein complexation with LaCIs was performed at RT), at which point most reactions were complete (monitored by LCMS). The reaction mixtures were then diluted with H2O / MeCN and directly purified by HPLC or C18 Sep-Pak (0.1% TFA in H2O / MeCN) to afford the cold (nonradioactive) metal complexes. Isolated amounts ranged from 0.5-10 mg, and purities (HPLC) were between 95% and 99%.RadiolabelingGeneral methods of radiolabeling with177Lu

[0184] Generally, a small aliquot of the precursor (1-5 pL, 1-3 nmol) was dissolved in the reaction buffer / solution with a known pH (4-7) containing a radioprotectant (e.g., gentisate, ascorbate, ethanol). To the solution was added a known amount / activity of [177Lu]LuCl3. Then, the reaction was allowed to proceed at 20-95 °C for 15-20 min. At this point, the reaction was cooled and diluted with the formulation buffer. For analysis, the reaction mixtures and / or formulated solutions were analyzed using radio-TLC (ITLC) and radio-HPLC. Generally, iTLCs were run on silicic acid (SA) paper plates, with 0.1 M sodium citrate (pH 4-5; 5% MeOH) as the eluent and other optional solvents as needed. The developed plates were analyzed using a radio-TLC reading instrument. HPLC analyses were performed using a suitable C18 column, with different combinations of H2O and MeCN (both with 0.1% TFA) as the eluent. The eluting components were visualized by UV (DAD) and radio-detection flow monitors. In all cases, theradiochemical purity of the radiolabeled compound was assessed and confirmed to be >90% at the end of synthesis (EOS) and at some later timepoints (e.g., 3 h at room temperature or after overnight storage at -20°C followed by 3 h at room temperature). Table 4 summarizes exemplary compounds radiolabeled with177Lu.Table 4. Examples of radiolabeling with177LuRCP by RCP by RCP by RCP byActivity TLC at HPLC at Compound Time / Temp TLC at HPLC at(MBq) Stability Stability EOS EOSTimepoint Timepoint RD09-049 50 99% 99% 99% 99% RD09-040 50 95°C / 20 min 99% 99% 99% 99% RD09-060 50 99% 99% 99% 99%General methods of radiolabeling with225Ac

[0185] Generally, a small aliquot of the precursor (1-10 L, 1-10 nmol) was dissolved in the reaction buffer / solution with a known pH (4-9) containing a radioprotectant (e.g., gentisate, ascorbate, ethanol). To the solution was added a known amount / activity of [225Ac]AcCl3 or [225AC]AC(NC>3)3. Then, the reaction was allowed to proceed at 20-95 °C for 15-20 min. At this point, the reaction was cooled (if needed) and diluted with the formulation buffer. For analysis, the reaction mixtures and / or formulated solutions were analyzed using radio-TLC (iTLC) and radio-HPLC. Generally, iTLCs were run on SA paper plates, with 0.1 M sodium citrate (pH 4-5; 5% MeOH) as the eluent and other optional solvents as needed. The developed plates were then analyzed using a radio-TLC reading instrument. HPLC analyses were performed using a suitable C18 column, with different combinations of H2O and MeCN (both with 0.1% TFA) as the eluent. The eluting components were visualized by UV (DAD) and fraction collection / gamma counting for radioactive reconstructions. Following fraction collection, all samples from the HPLC were allowed to equilibrate for >6 h, then analyzed in a gamma counting instrument for subsequent measurements. In all cases, the radiochemical purity of the radiolabeled compound was assessed and confirmed to be >90% at the end of synthesis (EOS) and at some later timepoints (e.g., 3 h at room temperature or after overnight storage at -20°C followed by 3 h at room temperature). Table 5 summarizes exemplary compounds radiolabeled with225Ac.Table 5. Examples of radiolabeling with225AcRCP by RCP by RCP by RCP byActivity TLC at HPLC at Compound Time / Temp TLC at HPLC at(MBq) Stability Stability EOS EOSTimepoint Timepoint RD09-049 1.0 95°C / 20 min 99% 99% 99% 99% RD09-040 0.7 95°C / 20 min 99% 98% 99% 98% RD09-063 0.7 25°C / 20 min 99% 99% 99% 99% RD09-102 0.7 95°C / 20 min 94% 86% 91% 86% RD09-150 0.7 95°C / 15 min 98% 95% 98% 95%General methods of radiolabeling with64Cu

[0186] Generally, a small aliquot of the precursor (1-5 pL, 1-3 nmol) was dissolved in the reaction buffer / solution with a known pH (4-7) containing a radioprotectant (e.g., gentisate, ascorbate, ethanol). To the solution was added a known amount / activity of [64Cu]CuCl2. Then, the reaction was allowed to proceed at 20-95 °C for 15-20 min. At this point, the reaction was cooled (if needed) and diluted with the formulation buffer. For analysis, the reaction mixtures and / or formulated solutions were analyzed using radio-TLC (iTLC) and radio-HPLC. Generally, iTLCs were run on silicic acid (SA) paper plates, with 0.05 M EDTA (pH 5.5) as the eluent and other optional solvents as needed. The developed plates were analyzed using a radio-TLC reading instrument. HPLC analyses were performed using a suitable C18 column, with different combinations of H2O and MeCN (both with 0.1% TFA) as the eluent. The eluting components were visualized by UV (DAD) and radio-detection flow monitors. In all cases, the radiochemical purity of the radiolabeled compound was assessed and confirmed to be >90% at the end of synthesis (EOS) and at some later timepoints (e.g., 3 h at room temperature or after overnight storage at -20°C followed by 3 h at room temperature). Table 6 summarizes exemplary compounds radiolabeled with64Cu.Table 6. Example of radiolabeling with64CuRCP by RCP by RCP by RCP byActivity TLC at HPLC at Compound Time / Temp TLC at HPLC at(MBq) Stability Stability EOS EOSTimepoint Timepoint RD09-085 30 75°C / 15 min 99% 99% 99% 98%General methods of radiolabeling with111In

[0187] Generally, a small aliquot of the precursor (1-5 pL, 1-3 nmol) was dissolved in the reaction buffer / solution with a known pH (4-7) containing a radioprotectant (e.g., gentisate,ascorbate, ethanol). To the solution was added a known amount / activity of [111In]InCl3. Then, the reaction was allowed to proceed at 20-95 °C for 15-20 min. At this point, the reaction was cooled (if needed) and diluted with formulation buffer. For analysis, the reaction mixtures and / or formulated solutions were analyzed using radio-TLC (iTLC) and radio-HPLC. Generally, iTLCs were run on silicic acid (SA) paper plates, with 0.1 M sodium citrate (pH 4-5; 5% MeOH) as the eluent and other optional solvents as needed. The developed plates were analyzed using a radio-TLC reading instrument. HPLC analyses were performed using a suitable C18 column, with different combinations of H2O and MeCN (both with 0.1% TFA) as the eluent. The eluting components were visualized by UV (DAD) and radio-detection flow monitors. In all cases, the radiochemical purity of the radiolabeled compound was assessed and confirmed to be >90% at the end of synthesis (EOS) and at some later timepoints (e.g., 3 h at room temperature or after overnight storage at -20°C followed by 3 h at room temperature). Table 7 summarizes exemplary compounds radiolabeled with111In.Table 7. Examples of radiolabeling with111InRCP by RCP by RCP by RCP byActivity TLC at HPLC at Compound Time / Temp TLC at HPLC at(MBq) Stability Stability EOS EOSTimepoint Timepoint RD09-049 25 98% 99% - - RD09-049 200 95°C / 15 min 99% 99% 99% 99% RD09-040 50 99% 99% 99% 99%Synthesis of target moleculesSynthesis of RD09-006Step 12Step 1

[0188] Sodium methoxide (12.2 mL, 0.5 M in MeOH, 1.10 eq., 6.10 mmol) was added to a mixture of 1 (1.00 g, 1.00 eq., 5.55 mmol) and 2 (819 mg, 1.25 eq., 6.94 mmol) at RT under nitrogen. The mixture was heated to 70 °C and stirred for 18 h. The mixture was cooled to RT, which formed an off-white precipitate. The precipitate was filtered, washed with MeOH (3 x 5.00 mL), and dried to provide product 3 (1.07 g, 4.02 mmol, 72.4%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 57.14 (t, J = 8.3 Hz, 1H), 6.57 (d, J = 8.3 Hz, 2H), 5.50 (s, 1H), 3.65 (s, 6H), 3.58 (s, 3H). Note: rotamers were present. LRMS: m / z calculated C13H14O6 [M+H]+267.1, found 267.0.Step 2

[0189] Acetic acid (10.0 mL) was added to a mixture of 3 (1.07 g, 1.00 eq., 4.02 mmol) and 4 (1.17 g, 1.50 eq., 6.03 mmol) at RT under air. The mixture was heated to 65 °C and stirred overnight. The mixture was cooled to RT and diluted with H2O (50.0 mL), which formed a brown precipitate. The brown precipitate was filtered, washed with H2O (3 x 50.0 mL), and purified by flash chromatography (Silica gel, 25 g cartridge) with hexanes and EtOAc (0-40%) to provide product 5 (739 mg, 1.74 mmol, 43.4%) as an orange solid. LRMS: m / z calculated C22H18CIN3O4 [M+H]+424.1, found 424.0.Step 3Step 3

[0190] Lithium hydroxide monohydrate (341 mg, 5.00 eq., 8.13 mmol) was added to a mixture of 5 (689 mg, 1.00 eq., 1.63 mmol) in THF (5.00 mL) and H2O (5.00 mL) at RT under air. The mixture was stirred for 2 h and the THF was evaporated under reduced pressure. Theaqueous residue was diluted with 3 M aq. HCI (20.0 ml_), and EtOAc (20.0 ml_). The biphasic mixture was stirred for 10 min, which formed a precipitate. The precipitate was filtered, washed with H2O (3 x 20.0 ml_), EtOAc (3 x 5.00 ml_), and dried to provide product 6 (598 mg, 1.46 mmol, 89.8%) as an orange-brown solid.1H-NMR (400 MHz, Acetone-de) 58.88 (d, J = 4.7 Hz, 1H), 8.17 (d, J = 2.2 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.68 (dd, J = 9.1, 2.1 Hz, 1H), 7.31 -7.24 (m, 2H), 7.05 (s, 1H), 6.56 (d, J = 8.4 Hz, 2H), 3.47 (s, 6H). LRMS: m / z calculated C21H16CIN3O4 [M+H]+410.1, found 410.1.Step 4

[0191] HATU (832 mg, 1.50 eq., 2.19 mmol) was added to a mixture of 6 (598 mg, 1.00 eq., 1.46 mmol) and DIPEA (1.27 ml_, 5.00 eq., 7.30 mmol) in anhydrous DMF (10.0 ml_) at RT under nitrogen. The mixture was stirred for 15 min and then 7 (403 mg, 1.10 eq., 1.61 mmol) was added. The mixture was stirred for 72 h at RT and then diluted with brine (40.0 ml_), which formed a brown precipitate. The precipitate was filtered, washed with H2O (3 x 20.0 ml_), dried, and purified by flash chromatography (Silica gel, 40 g cartridge) with hexanes and EtOAc (0-60%) to provide product 8 (627 mg, 975 mol, 66.8%) as an off-white solid.1H-NMR (400 MHz, CDCIs) 58.76 (d, J = 4.6 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.49 (dd, J = 9.0, 2.1 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 7.11 (s, 1H), 7.08 (s, 1H), 7.04 (d, J = 4.6 Hz, 1H), 6.39 (d, J = 8.4 Hz, 2H), 3.38 (s, 6H), 2.66 (s, 2H), 2.13 (d, J = 13.2 Hz, 2H), 2.08 - 2.00 (m, 2H), 1.91 - 1.64 (m, 8H), 1.51 (s, 9H). LRMS: m / z calculated C36H39CIN4O5 [M+H]+643.3, found 643.3.

[0192] Cpd 9 (55.6 mg, 3.00 eq., 233 µmol) in anhydrous 1,4-dioxane (2.00 mL) was added to a mixture of 8 (50.0 mg, 1.00 eq., 77.7 pmol), Brettphos-Pd-G3 (21.1 mg, 0.30 eq., 23.3 pmol), and Brettphos (14.6 mg, 0.35 eq., 27.2 mol) at RT under nitrogen. The mixture was stirred for 1 min and then LiHMDS (233 L, 1.0 M in THF, 3.00 eq., 233 mol) was added. The mixture was heated to 80 °C, stirred for 3 h, quenched with H2O (4.00 ml_), and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 12 g cartridge) with a gradient of 1:0:0 Hexanes: EtOAc: MeOH to 4:5:1 Hexanes: EtOAc: MeOH to provide product 10 (35.1 mg, 35 mol, 45%) as a yellow solid. LRMS: m / z calculated C48H56N6O8[M+H]+845.4, found 845.4.Step 6

[0193] A balloon filled with H2 (1 atm) was placed into a mixture of 10 (35.1 mg, 1.00 eq., 35.3 mol) and Pd / C (7.51 mg, 10% wt, 0.20 eq., 7.06 mol) in anhydrous MeOH (2.0 ml_) at RT. The mixture was stirred for 24 h, filtered, washed with MeOH (3 x 5.0 ml_), and concentrated under reduced pressure to provide product 11 (25.7 mg, 31 mol, 87%) as a yellow oil. LRMS: m / z calculated C40H50N6O6[M+H]+711.4, found 711.4.Step 7Step 7

[0194] DOTA-OSu (12) (27.3 mg, 1.50 eq., 35.9 pmol) was added to a mixture of 11 (20.0 mg, 85% wt, 1.00 eq., 23.9 pmol) and DIPEA (41.7 pL, 10.0 eq., 239 pmol) in anhydrous DMF (2.00 ml_) at RT under nitrogen. The mixture was stirred for 72 h and then concentrated under reduced pressure to provide the mono-tBu-protected material, which was used immediately in the next step. LRMS: m / z calculated C56H76N10O13[M+H]+1097.6, found 1097.6. TIS (100 pL, 20.4 eq., 488 pmol) was added to a mixture of the mono-tBu-protected material in anhydrous DCM (1.00 ml_) at RT under nitrogen. The mixture was stirred for 5 min then TFA (900 pL) was added. The stirring continued for 24 h and the reaction was concentrated under reduced pressure. The crude product was purified by HPLC with an isocratic gradient of 66% H2O and 34% MeCN (0.1% TFA) and lyophilized to provide product RD09-006 (10.0 mg, 5.6 pmol, 23%) as a yellow solid.1H-NMR (400 MHz, DMSO-de) 58.65 (d, J = 5.4 Hz, 1H), 8.52 (s, 1H), 7.60 (s, 1H), 7.53 (d, J = 9.3 Hz, 1H), 7.27 (t, J = 8.4 Hz, 1H), 7.15 (d, J = 9.4 Hz, 1H), 6.97 (d, J = 5.4 Hz, 1H), 6.94 (s, 1H), 6.87 (d, J = 2.2 Hz, 1H), 6.57 (d, J = 8.5 Hz, 2H), 4.00 (s, 2H), 3.85 (s, 2H), 3.65 (t, J = 5.5 Hz, 2H), 3.59 (s, 6H), 3.51 (t, J = 6.0 Hz, 2H), 3.48 (s, 6H), 3.36 - 3.26 (m, 11 H), 3.08 (s, 8H), 2.58 (s, 2H), 2.05 (dd, J = 39.5, 12.9 Hz, 4H), 1.70 (td, J = 38.5, 14.6 Hz, 8H). Note: acid and TFA salt protons in exchange with residual H2O signal.19F-NMR (377 MHz, DMSO-de) 5 -74.33. LRMS: m / z calculated C52H68N10O13 [M+H]+1041.5, found 1041.6.Synthesis of RD09-005Step 1

[0195] Cpd 14 (83.8 mg, 1.00 eq., 103 mol) was added to a mixture of 13 (20.0 mg, 1.00 eq., 103 mol) and DIPEA (89.5 L, 5.00 eq., 514 pmol) in anhydrous DMSO (2.00 ml_) at RT under nitrogen. The mixture was stirred for 72 h and then purified by HPLC with H2O and MeCN (5-50%, 0.1% TFA) and lyophilized to provide product 15 (24.2 mg, 18.9 pmol, 18.4%) as a white solid. LRMS: m / z calculated C35H64N6O9 [M+H]+713.5, found 713.4.Step 2

[0196] DIPEA (39.4 pL, 12.0 eq., 226 pmol) was added to a solution of 15 (24.2 mg, 1.00 eq., 18.9 pmol) in anhydrous DMF (2.00 ml_) at RT under nitrogen. The mixture was stirred for 30 min and then HATU (10.8 mg, 1.50 eq., 28.3 pmol) was added. The mixture was stirred for 30 min and then a solution of 11 (16.7 mg, 1.25 eq., 23.5 pmol) in anhydrous DMF (1.00 ml_) was added. The mixture was stirred for 24 h and concentrated under reduced pressure to provide the tetra-tBu-protected intermediate, which was used immediately in the next step. LRMS: m / z calculated C75H112N12O14 [M+H]+1405.8, found 1406.0. TIS (100 pL, 25.9 eq., 488 pmol) and TFA (2.0 ml_) were added to the protected intermediate at RT under nitrogen. The mixture was heated to 80 °C, stirred for 2 h, and concentrated under reduced pressure. The crude product was purified by HPLC with an isocratic gradient of 69% H2O and 31% MeCN (0.1% TFA) and lyophilized to provide product RD09-005 (22.9 mg, 11 pmol, 60%) as a yellow solid.1H-NMR (400 MHz, DMSO-de) 58.69 (s, 1H), 8.62 (d, J = 5.0 Hz, 1H), 8.50 (s, 1H), 7.56 (s, 1H), 7.47 (d, J = 9.3 Hz, 1H), 7.25 (t, J = 8.4 Hz, 1H), 7.15 - 7.08 (m, 1H), 6.92 (d, J = 6.8 Hz, 2H), 6.83 (d, J = 2.2 Hz, 1H), 6.70 - 6.41 (m, 4H), 4.06 - 3.54 (m, 29H), 3.47 (s, 6H), 3.33 -2.86 (m, 20H), 2.58 (s, 2H), 2.10 (d, J = 12.7 Hz, 2H), 1.98 (t, J = 15.3 Hz, 4H), 1.85 - 1.65 (m, 8H), 1.60 (d, J = 12.6 Hz, 2H).19F-NMR (377 MHz, DMSO-de) 5 -74.15. LRMS: m / z calculated C59H80N12O14 [M+H]+1181.6, found 1181.9.Synthesis of RD09-014

[0197] Hydrazine hydrate (1.22 ml_, 65% wt, 1.50 eq., 16.3 mmol) was added to a mixture of 3 (2.90 g, 1.00 eq., 10.9 mmol) and acetic acid (30.0 ml_) at RT under air. The mixture was heated to 65 °C and stirred for 18 h. The mixture was cooled to RT, which formed a white precipitate. The precipitate was filtered, washed with H2O (3 x 25.0 ml_), and dried to provide product 16 (2.54 g, 9.68 mmol, 88.9%) as a white solid. LRMS: m / z calculated C13H14N2O4 [M+H]+263.1, found 263.1.Step 2

[0198] Lithium hydroxide monohydrate (1.84 g, 5.00 eq., 43.8 mmol) was added to a mixture of 16 (2.30 g, 1.00 eq., 8.77 mmol) in THF (10.0 mL) and H2O (10.0 mL) at RT under air. The mixture was heated to 70 °C and stirred for 3 h. The mixture was cooled to RT and acidified with 3 M aq. HCI (40.0 mL), which formed a white precipitate. The precipitate was filtered, washed with 3 M aq. HCI (20.0 mL), H2O (20.0 mL), MeCN (3 x 10.0 mL), and dried to provide product 17 (1.78 g, 7.17 mmol, 81.8%) as a white solid. LRMS: m / z calculated C12H12N2O4 [M+H]+249.1, found 249.1.Step 3

[0199] DIPEA (2.46 mL, 5.00 eq., 14.1 mmol) was added to a mixture of 17 (700 mg, 1.00 eq., 2.82 mmol) in DMF (10.0 mL) at RT under nitrogen. The mixture was stirred for 15 min and then HATU (1.61 g, 1.50 eq., 4.23 mmol) was added. The mixture was stirred for 30 min and then 7 (744 mg, 1.05 eq., 2.96 mmol) was added. The reaction was stirred for 72 h and quenched with H2O (30.0 mL) and brine (10.0 mL), which yielded an off-white precipitate. The precipitate was filtered, washed with water (3 x 20.0 mL), and dried. The aqueous layers were combined and extracted with EtOAc (30.0 mL). The organic EtOAc layer and precipitate were combined and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 24 g cartridge) with DCM and EtOAc (0-20%) to provide product 18 (843 mg, 1.6 mmol, 56%) as a white solid. LRMS: m / z calculated C27H35N3O5 [M+H]+482.3, found 482.4.Step 4Cl

[0200] A mixture of 18 (150 mg, 1.00 eq., 280 pmol), K2CO3 (77.5 mg, 2.00 eq., 561 pmol), and 19 (58.3 mg, 1.05 eq., 294 mol) in anhydrous DMSO (2.00 ml_) was heated to 120 °C and stirred for 24 h under nitrogen. The mixture was then heated to 155 °C and stirred for an additional 6 h. The mixture was cooled to RT and diluted with H2O (10.0 mL), brine (10.0 mL), and EtOAc (20.0 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (20.0 ml_). The combined organic layers were washed with brine (40.0 ml_), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (C18, 48 g cartridge) with H2O and MeOH + 0.1% TFA (50-90%) and lyophilized to provide product 20 (75.0 mg, 0.10 mmol, 37%) as an off-white solid. LRMS: m / z calculated C36H39CIN4O5 [M+H]+643.3, found 643.3.Step 5

[0201] Cpd 21 (58.3 mg, 10.0 eq., 560 mol) in anhydrous 1,4-dioxane (2.0 ml_) was added to a mixture of 20 (40.0 mg, 1.00 eq., 56.0 pmol), Brettphos-Pd-G3 (15.2 mg, 0.30 eq., 16.8 pmol), and Brettphos (10.5 mg, 0.35 eq., 19.6 mol) at RT under nitrogen. The mixture was stirred for 5 min and then LiHMDS (168 L, 1.0 M in THF, 3.00 eq., 168 mol) was added. The mixture was heated to 110 °C and stirred for 21 h. The mixture was cooled to RT and quenched with H2O (10.0 ml_), brine (10.0 ml_), and DCM (20.0 ml_). The layers were separated, and the aqueous layer was extracted with DCM (10.0 ml_). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 4 g cartridge) with DCM and MeOH (0-30%) to provide product 22 (27.3 mg, 38.4 mol, 68.6%) as a tan solid. LRMS: m / z calculated C40H50N6O6 [M+H]+711.4, found 711.4.Step 6Step 6

[0202] Cpd 14 (28.3 mg, 1.10 eq., 42.2 pmol) was added to a mixture of 22 (27.3 mg, 1.0 eq., 38.4 pmol) and DIPEA (33.4 pL, 5.00 eq., 192 pmol) in anhydrous MeCN (2.0 ml_) under nitrogen. The mixture was stirred for 1 h and concentrated under reduced pressure to provide the tetra-tBu-protected intermediate, which was used immediately in the next step. LRMS: m / z calculated C68H100N10O13[M+H]+1265.8, found 1265.8. TFA (1.0 mL) was added to a mixture of the protected intermediate, TIS (100 μL, 12.7 eq., 488 μmol), and DCM (1.00 mL) at RT under nitrogen. The mixture was stirred for 21 h and concentrated under reduced pressure. The crude product was purified by HPLC with an isocratic gradient of 41% MeCN and 59% H2O (0.1% TFA) and lyophilized to provide RD09-014 (14.7 mg, 8.3 pmol, 22%) as an orange solid. LRMS: m / z calculated C52H68N10O13[M+H]+1041.5, found 1041.1.Synthesis of RD09-015Step 123 Step 11824a 24b

[0203] A mixture of 18 (200 mg, 1.00 eq., 415 pmol), 23 (86.4 mg, 1.05 eq., 436 pmol), and K2CO3 (115 mg, 2.0 eq., 831 mol) in anhydrous DMSO (2.0 mL) was heated to 120 °C and stirred for 20 h under nitrogen. The mixture was cooled to RT and quenched with water (10.0 mL), brine (10.0 mL), and EtOAc (10.0 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10.0 mL). The combined organic layers were washed with brine (30.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by HPLC with an isocratic gradient of 5% H2O and 95% MeCN (0.1% TFA) and lyophilized to provide 24a (8.30 mg, 12.9 mol, 3.11%) as a white solid, 24b (158.6 mg, 0.23 mmol, 56%) as a white solid, and the third regioisomer 24c (32.6 mg, 50.7 mol, 12.2%) as a white solid.24a: LRMS: m / z calculated C36H39CIN4O5 [M+H]+643.3, found 643.3.24b:1H-NMR (600 MHz, CDCIs) 5 8.02 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.74 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.52 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 7.13 (s, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 6.40 (d, J = 8.4 Hz, 2H), 3.42 (s, 6H), 2.66 (d, J = 5.1 Hz, 2H), 2.17 - 2.11 (m, 2H), 2.08 - 2.03 (m, 2H), 1.86 (s, 1H), 1.82 (s, 1H), 1.76 (d, J = 11.7 Hz, 2H), 1.72 (s, 2H), 1.68 (d, J = 13.8 Hz, 2H), 1.51 (s, 9H).13C-NMR (151 MHz, CDCIs) 5 171.60, 160.72, 158.01, 149.73, 148.96, 148.54, 146.42, 139.74, 131.79, 131.08, 128.57, 127.37, 124.81, 123.39, 118.95, 110.72, 106.51, 103.81, 81.01, 64.17, 55.38, 38.00, 34.15, 33.36, 32.92, 28.17, 27.09, 26.80. LRMS: m / z calculated C36H39CIN4O5 [M+H]+643.3, found 643.3.24c: LRMS: m / z calculated C36H39ClN4O5[M+H]+643.3, found 643.3.Step 2

[0204] Cpd 21 (64.8 mg, 10.0 eq., 622 μmol) in anhydrous 1,4-dioxane (2.0 mL) was added to a mixture of 24b (40.0 mg, 1.00 eq., 62.2 μmol), Brettphos-Pd-G3 (16.9 mg, 0.30 eq., 18.7 μmol), and Brettphos (11.7 mg, 0.35 eq., 21.8 μmol) at RT under nitrogen. The mixture was stirred for 5 min and then LiHMDS (187 μL, 1.0 M in THF, 3.00 eq., 187 μmol) was added. The mixture was heated to 110 °C and stirred for 21 h. The mixture was cooled to RT and quenched with H2O (10.0 mL), brine (10.0 mL), and DCM (20.0 mL). The layers were separated, and the aqueous layer was extracted with DCM (10.0 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 4 g cartridge) with DCM and MeOH (0-50%) to provide product 25 (15.4 mg, 21.7 pmol, 34.8%) as a white solid. LRMS: m / z calculated C40H50N6O6 [M+H]+711.4, found 711.5.Step 3

[0205] Cpd 14 (16.0 mg, 1.10 eq., 23.8 μmol) was added to a mixture of 25 (15.4 mg, 1.00 eq., 21.7 μmol) and DIPEA (18.9 μL, 5.00 eq., 108 μmol) in anhydrous MeCN (1.00 mL) under nitrogen. The mixture was stirred for 1 h and concentrated under reduced pressure to provide the tetra-tBu-protected intermediate, which was used immediately in the next step. LRMS: m / z calculated C68H100N10O13[M+H]+1265.8, found 1265.8. TFA (950 μL) was added to a mixture of the protected intermediate and TIS (50.0 μL, 11.3 eq., 244 μmol) in DCM (1.00 mL) at RTunder nitrogen. The mixture was stirred for 21 h and concentrated under reduced pressure. The crude product was purified by HPLC with an isocratic gradient of 36% MeCN and 64% H2O (0.1% TFA) and lyophilized to provide RD09-015 (8.89 mg, 4.9 mol, 23%) as a white solid. LRMS: m / z calculated C68H100N10O13[M+H]+1041.5, found 1041.6.Synthesis of RD09-025Step 1

[0206] A mixture of 18 (200 mg, 90% wt, 1.00 eq., 374 pmol), K2CO3(103 mg, 2.00 eq., 748 pmol), and 26 (95.2 mg, 1.05 eq., 392 mol) in anhydrous DMSO (2.00 mL) was heated to 120 °C and stirred for 24 h under nitrogen. The mixture was heated to 155 °C and stirred for an additional 6 h. The mixture was cooled to RT and diluted with H2O (10.0 mL), brine (10.0 mL), and EtOAc (20.0 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (20.0 mL). The combined organic layers were washed with brine (40.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (C18, 48 g cartridge) with H2O and MeOH (50-90%, 0.1% TFA) and lyophilized to provide product 27a (10.9 mg, 12 mol, 3.2%) as a white solid and product 27b (93.1 mg, 135 mol, 36.2%) as a yellow solid. 27a: LRMS: m / z calculated C36H39BrN4O5[M+H]+687.2, found 687.2. 27b: LRMS: m / z calculated C36H39BrN4O5[M+H]+687.2, found 687.3.Step 2

[0207] A solution of 21 (60.6 mg, 10.0 eq., 582 μmol) in anhydrous 1,4-dioxane (2.00 mL) was added to a mixture of 27b (40.0 mg, 1.00 eq., 58.2 μmol), Brettphos-Pd-G3 (15.8 mg, 0.300 eq., 17.5 μmol), and Brettphos (10.9 mg, 0.350 eq., 20.4 μmol) at RT under nitrogen. The mixture was stirred for 5 min and then LiHMDS (175 μL, 1.0 M in THF, 3.00 eq., 175 μmol) was added. The mixture heated to 110 °C and was stirred for 21 h. The mixture was cooled to RT and quenched with H2O (10.0 mL), brine (10.0 mL), and DCM (20.0 mL). The layers were separated, and the aqueous layer was extracted with DCM (10.0 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 4 g cartridge) with DCM and MeOH (0-30%) to provide product 28 (14.4 mg, 20.3 mol, 34.8%) as an off-white solid. LRMS: m / z calculated C40H50N6O6[M+H]+711.4, found 711.4.Step 3

[0208] Cpd 14 (14.9 mg, 1.10 eq., 22.3 μmol) was added to a mixture of 28 (14.4 mg, 1.00 eq., 20.3 μmol) and DIPEA (17.6 μL, 5.00 eq., 101 μmol) in anhydrous MeCN (1.00 mL) under nitrogen. The mixture was stirred for 1 h and concentrated under reduced pressure. To the mixture were added TFA (1.0 ml_), TIS (50.0 μL, 12.0 eq., 244 μmol) and DCM (1.00 mL) at RT under nitrogen. The mixture was stirred for 21 h and concentrated under reduced pressure. The crude product was purified by HPLC with an isocratic gradient of 38% MeCN and 62% H2O (0.1% TFA) and lyophilized to provide product RD09-025 (8.94 mg, 5.1 pmol, 25%) as an off-white solid. LRMS: m / z calculated C68H100N10O13[M+H]+1041.5, found 1041.2.Synthesis of RD09-037 and RD09-046Synthesis of RD09-037 and RD09-046Step 1Cl Cl

[0209] Aqueous hydrogen chloride (4.14 mL, 12.2 M, 8 eq., 50.5 mmol) was added dropwise to a stirred solution of 2,4-dichloroquinoline 1 (1.25 g, 1 eq., 6.31 mmol) in 1,4-dioxane (6.3 mL) at RT. The reaction mixture was then heated to 90 °C and stirred for 16 h. After reaction completion, as judged by LCMS, the reaction mixture was poured onto an excess of ice and stirred for 1 h. The precipitate was then collected by vacuum filtration and dried under vacuum to provide the product 4-chloroquinolin-2-ol 2 (1.00 g, 5.57 mmol, 88.2%) as a white powder. LRMS: m / z calculated CgHeCINO [M+H]+180.0, found 180.0.Step 2

[0210] 4-chloroquinolin-2-ol 2 (800 mg, 1 eq., 4.45 mmol) was dissolved in ethanol (11.1 mL) in a 20 mL reaction vessel. Hydrazine hydrate (533 μL, 65% wt, 2.5 eq., 11.1 mmol) was added to the reaction dropwise and the mixture was subsequently heated to 80 °C for 8 h. The reaction vessel was then transferred to a heating block which was at 70 °C and subsequently stirred for 16 h. Upon reaction completion as judged by TLC, the reaction was diluted with ice cold water and the precipitate was collected and washed with minimal ice-cold water, yielding 4-hydrazineylquinolin-2-ol, 3 (734 mg, 4.19 mmol, 94.1%) as a beige powder. LRMS: m / z calculated C9H9N3O [M+H]+176.1, found 176.2.Step 33 5

[0211] Acetic acid (9.3 mL) was added to a mixture of 4-hydrazineylquinolin-2-ol, 3 (987.0 mg, 1.5 eq., 5.63 mmol) and cpd 4 (1 g, 1 eq., 3.76 mmol) at RT under air. The mixture wasstirred at 65 °C for 3 h. The mixture was cooled to RT and diluted with H₂O (50.0 mL), which resulted in the formation of an off-white precipitate. The precipitate was filtered, washed with H₂O (3 x 50.0 mL), and purified by flash chromatography (Silica gel, 25 g cartridge) with DCM and MeOH (0-50%) to provide product 5 (965 mg, 2.38 mmol, 63.4%). LRMS: m / z calculated C22H19N3O5 [M+H]+406.1, found 406.3.Step 4

[0212] (Tributylphosphoranylidene)acetonitrile (407 L, 1.5 eq., 1.55 mmol) was added to a solution of A (405 mg, 1.5 eq., 1.55 mmol) in toluene (10 mL). The resulting mixture was heated to 70 °C for 10 min. The resulting solution was added to a vial containing 5 (420 mg, 1 eq., 1.04 mmol). The resulting mixture was stirred at 70 °C for 18 h after which the crude LCMS showed complete consumption of starting material. The mixture was cooled to RT and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 12 g cartridge) with DCM and MeOH (1-50%) to provide a (1:1) mixture of 6 and 7 (540 mg, 834 μmol, 80.5%) as a colorless oil. LRMS: m / z calculated C35H45N5O7 [M+H]+648.3, found 648.1.Step 5

[0213] Lithium hydroxide hydrate (87.4 mg, 2.5 eq., 2.08 mmol) was added to a 1:1 mixture of 6 and 7 (540 mg, 1 eq., 834 μmol) in THF (2.0 mL) and water (2.0 mL) at RT under air. The mixture was heated to 60 °C and stirred for 2 h, after which LCMS confirmed the complete consumption of starting material. The reaction mixture was diluted with 3 M aq. HCI (12.0 mL), resulting in a white precipitate. The precipitate was filtered, washed with H₂O (3 x 20.0 mL) and dried to provide a 1:1 inseparable mixture of 8 and 9 (510 mg, 805 μmol, 96.5%) as a white solid. LRMS: m / z calculated C34H43N5O7 [M+H]+634.3, found 634.1.Step 6ClCl— S. 'oStep 610

[0214] Thionyl chloride (0.18 ml_, 3 eq., 2.4 mmol) was added to a solution of 10 (0.25 g, 1 eq., 0.81 mmol) in anhydrous MeOH (4.00 ml_) at RT under nitrogen. The mixture was stirred for 5 min at RT to let the bubbling subside. The reaction mixture was then heated to 65 °C and stirred for 16 h after which it was concentrated under a stream of nitrogen. The resulting crude residue was filtered and washed with diethyl ether (3 x 20.0 ml_). The crude product was purified by flash chromatography (Silica gel, 12 g cartridge) with DCM and MeOH (0-30%) to provide product 11 (82 mg, 0.37 mmol, 45%) as an off-white solid. LRMS: m / z calculated C₁₃H₂₁NO₂ [M+H]+224.2, found 224.1.Step 712 13

[0215] HATU (132 mg, 1.1 eq., 347 μmol) was added at RT to a reaction vial containing a 1:1 mixture of 8 and 9 (200 mg, 1 eq., 316 μmol) DIPEA (204 mg, 275 L, 5.00 eq., 1.58 mmol) dissolved in anhydrous DMF (10.0 ml_) under nitrogen. The mixture was stirred for 15 min afterwhich 11 (200 mg, 1 eq., 316 μmol) was added all at once. The mixture was stirred for 72 h at RT after which reaction completion was confirmed by LCMS. The crude reaction mixture was diluted with brine (40.0 mL), which resulted in the formation of a beige precipitate. The precipitate was filtered, washed with H₂O (3 x 20.0 mL), dried, and purified by flash chromatography (Silica gel, 40 g cartridge) with DCM and MeOH (0-40%) to provide a 1:2 mixture of 12 and 13 (66.9 mg, 79.7 μmol, 25.3%) as an off-white solid. LRMS: m / z calculated C47H62N6O8 [M+H]+839.5, found 839.5.

[0216] Lithium hydroxide (10.0 mg, 3 eq., 239 μmol) was added to a solution of 12 and 13 (66.9 mg, 1 eq., 79.7 μmol) in THF (0.50 mL) and water (0.25 mL) at RT. The mixture was then heated to 60 °C and stirred for 18 h after which LCMS showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure. The crude residue was redissolved in DCM (0.5 mL). Triisopropylsilane, TIS (16.3 μL, 1 eq., 79.7 μmol) and TFA (503 μL, 82.5 eq., 6.58 mmol) were added sequentially to the reaction mixture. The reaction was stirred at RT for 1 h after which LCMS showed complete consumption of the starting material. The reaction was concentrated under a stream of nitrogen. The crude residue was then redissolved in DMF (1 mL) and DIPEA (208 μL, 15 eq., 1.20 mmol) and DOTA-OSu (78.9 mg, 1.3 eq., 104 μmol) were added to the reaction mixture sequentially. The reaction mixture was stirred at RT for 72 h, concentrated, dissolved in 1:1 MeCN / H₂O + 0.1% formicacid and purified by HPLC to afford the products RD09-037 (45.5 mg, 27.0 μmol, 33.9%) and RD09-046 (19.1 mg, 11.4 μmol, 14.2%) as colorless oils.RD09-037: LRMS m / z calculated C57H78N10O13 [M+H]+1111.6, found 1111.6.RD09-046: LRMS m / z calculated C57H78N10O13 [M+H]+1111.6, found 1111.7.Synthesis of RD09-038 and RD09-047Step 1OHSOCI2MeOHStep 1

[0217] Thionyl chloride (486 μL, 1.5 eq., 6.66 mmol) was added dropwise to a solution of 14 (1.00 g, 1 eq., 4.44 mmol) in anhydrous MeOH (15.00 ml_) at RT under nitrogen. The mixture was stirred for 5 min to let the bubbling stop. The mixture was subsequently stirred for 16 h at 65 °C after which the reaction mixture was concentrated and washed with diethyl ether. The precipitate was filtered, washed with diethyl ether (3 x 20.0 ml_) and dried. The resulting crude was redissolved in DCM (20 ml_) and washed with 3 M. NaOH (10 ml_) to provide product 15 (334 mg, 1.40 mmol, 31.4%) as an off-white solid. LRMS: m / z calculated C₁₃H₂₁NO₃ [M+H]+240.2, found 240.1.Step 28 9

[0218] HATU (168 mg, 1.4 eq., 442 μmol) was added to a solution of 8 and 9 (200 mg, 1 eq., 316 μmol) and DIPEA (275 μL, 5.00 eq., 1.58 mmol) in anhydrous DMF (10.0 ml_) at RT undernitrogen. The mixture was stirred for 15 min and then 15 (83.1 mg, 1.1 eq., 347 μmol) was added. The mixture stirred for 72 h at RT after which the reaction was judged to be completed by LCMS. The reaction mixture was diluted with brine (40.0 mL), resulting in a brown precipitate. The precipitate was filtered, washed with H₂O (3 x 20.0 mL), dried, and purified by flash chromatography (Silica gel, 40 g cartridge) with hexanes and EtOAc (0-60%) to provide products 16 (62.4 mg, 73.0 μmol, 23.1%) and 17 (57.4 mg, 67.1 μmol, 21.3%) as clear viscous oils.Cpd 16: LRMS m / z calculated C47H62N6O9 [M+H]+855.5, found 855.5.Cpd 17: LRMS m / z calculated C47H62N6O9 [M+H]+855.5, found 855.5.Step 3AStep 3A

[0219] Cpd 16 (62.4 mg, 1 eq., 73.0 μmol) was added to a solution of lithium hydroxide monohydrate (9.19 mg, 3 eq., 219 μmol) in water (0.200 mL) and THF (0.400 mL). The resulting reaction mixture was stirred at RT for 18 h, after which LCMS showed complete consumption of the starting material. The reaction mixture was then concentrated and resuspended in DCM (0.5 mL). TIS (112 μL, 7.5 eq., 547 μmol) and TFA (558 μL, 100 eq., 7.30 mmol) were subsequently added to the reaction mixture. The reaction mixture was then stirred at RT for 4 h after which LCMS showed complete consumption of the starting material. The reaction mixture was concentrated. The resulting crude residue was dissolved in DMF (1 mL). To the solution was added DIPEA (191 μL, 15 eq., 1.09 mmol) and DOTA-OSu (66.7 mg, 1.2 eq., 87.6 μmol). The resulting reaction mixture was stirred at RT for 18 h. After reaction completion, as judged by LCMS, the reaction mixture was concentrated, dissolved in 1:1 MeCN / H₂O + 0.1% TFA and purified by HPLC to give product RD09-38 (10.8 mg, 6.36 μmol, 8.72%) as a colorless oil. LRMS: m / z calculated C57H78N10O14 [M+2H]2+564.3, found 564.5Step 3BStep 3B

[0220] Cpd 17 (57.4 mg, 1 eq., 67.1 pmol) was added to a solution of lithium hydroxide monohydrate (9.19 mg, 3 eq., 219 μmol) in water (0.20 mL) and THF (0.40 mL). The resulting reaction mixture was stirred at RT for 18 h, after which LCMS showed complete consumption of the starting material. The reaction mixture was then concentrated and resuspended in DCM (0.5 mL) and TIS (79.7 mg, 103 μL, 7.5 eq., 503 μmol) and TFA (765 mg, 514 μL, 100 eq., 6.71 mmol) were subsequently added. The reaction mixture was then stirred at RT for 4 h. Upon completion (LCMS), the reaction mixture was concentrated, and the crude oil was dissolved in DMF (1 mL). To the crude solution was added DIPEA (191 μL, 15 eq., 1.09 mmol) and DOTA-OSu (61.3 mg, 1.2 eq., 80.6 μmol). The resulting mixture was stirred at RT for 18 h and concentrated. The crude residue was dissolved in 1:1 MeCN / H₂O + 0.1% TFA and purified by HPLC to give product RD09-047 (44.1 mg, 26.0 μmol, 38.7%) as a colorless oil. LRMS: m / z calculated C57H78N10O14 [M+2H]2+564.3, found 564.5Step 1Step 1

[0221] An aqueous solution of HCI (1.41 ml_, 12.2 M, 8 eq., 17.2 mmol) was added dropwise to a stirred solution of 1 (0.500 g, 1 eq., 2.15 mmol) in 1,4-dioxane (2.15 ml_) at RT. The reaction mixture was then heated to 90 °C. After stirring for 16 h the reaction contents were poured onto an excess of ice and stirred for 1 h. The precipitate was then collected by vacuum filtration and dried under vacuum to provide product 2 (415 mg, 1.8 mmol, 86%) as a beige powder. LRMS: m / z calculated C9H5CI2NO [M+H]+214.0, found 213.9.Step 2

[0222] Cpd 2 (800 mg, 1 eq., 3.74 mmol) was dissolved in ethanol (9.35 ml_) in a 20 ml_ reaction vessel. Hydrazine hydrate (447 L, 65% wt, 2.5 eq., 9.34 mmol) was added to the reaction vessel dropwise and the reaction mixture was heated to 80 °C for 8 h. The reaction vessel was then transferred to a heating block set at 70 °C and subsequently stirred for 16 h. Upon completion, as judged by LCMS, the reaction was diluted with ice-water, and the precipitate was collected and washed with minimal ice-cold water yielding product 3 (0.758 g, 3.62 mmol, 96.7%) as a beige powder. LRMS: m / z calculated C₉H₈ClN₃O [M+H]+210.0, found 210.1.Step 3

[0223] Acetic acid (3 mL) was added to a mixture of 3 (354 mg, 1.5 eq., 1.69 mmol) and 4 (300 mg, 1 eq., 1.13 mmol) at RT under air. The mixture was stirred overnight at 65 °C, cooled to RT and diluted with H2O (50.0 mL), which formed a brown precipitate. The precipitate was filtered, washed with H2O (3 x 50.0 mL), and purified by flash chromatography (Silica gel, 25 g cartridge) with DCM and MeOH (0-50%) to provide product 5 (232 mg, 527 μmol, 46.8%). LRMS: m / z calculated C22H18CIN3O5 [M+H]+440.1, found 440.0.Step 4

[0224] Lithium hydroxide hydrate (111 mg, 5.00 eq., 2.64 mmol) was added to a solution of 5 (232 mg, 1 eq., 527 μmol) in THF (5.0 mL) and water (5.0 mL) at 70 °C under air. The mixture was stirred for 2 h after which LCMS confirmed the consumption of starting material. The reaction mixture was diluted with 3 M aq. HCI (12.0 mL), resulting in a slightly orange precipitate. The precipitate was filtered, washed with H2O (3 x 20.0 mL) and dried to provide product 6 (194 mg, 456 μmol, 86.4%) as a light orange solid. LRMS: m / z calculated C22H18CIN3O5 [M+H]+426.1, found 426.3.Step 5

[0225] HATU (1.32 g, 1.50 eq., 3.47 mmol) was added to a mixture of 6 (0.986 g, 1 eq., 2.32 mmol) and DIPEA (1.50 g, 2.02 mL, 5.00 eq., 11.6 mmol) in anhydrous DMF (10.0 mL) at RT under nitrogen. The mixture was stirred for 15 min and then 7 (640 mg, 1.10 eq., 2.55 mmol) was added. The mixture was stirred for 72 h at RT after which reaction completion was observed by LCMS. The crude reaction mixture was diluted with brine (40.0 mL), resulting in the formation of a light beige precipitate. The precipitate was filtered, washed with H2O (3 x20.0 ml_), dried, and purified by flash chromatography (Silica gel, 40 g cartridge) with hexanes and EtOAc (0-60%) to provide product 8 (1.038 g, 1.575 mmol, 68.0%) as an off-white solid. LRMS: m / z calculated C36H39ClN4O6[M+H]+659.3, found 659.2.

[0226] (Tributylphosphoranylidene)acetonitrile (137 pL, 2.00 eq., 522 pmol) was added to a solution 9 (136 mg, 2.00 eq., 522 pmol) in toluene (2.61 ml_). The resulting mixture was heated to 70 °C for 5 min. The resulting solution was added to a vial containing 8 (172 mg, 1 eq., 261 pmol). The reaction mixture was stirred at 70 °C for 5 h after which LCMS showed complete consumption of the starting material. The mixture was cooled to RT and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 24 g cartridge) with DCM and MeOH (1-50%) to provide a 1:1 mixture of 10 and 11 as a colorless oil. The regioisomers were separated by reverse phase silica gel column chromatography (C18, 24-gram cartridge) using H2O + 0.1% TFA and MeCN 0.1% TFA (5-95%) yielding pure products 10 (87.5 mg, 97.1 pmol, 37.2%) and 11 (96.5 mg, 107 pmol, 41.0%) as colorless oils Cpd 10: LRMS m / z calculated C49H65CIN6O8 [M+H]+901.5, found 901.5.Cpd 11: LRMS m / z calculated C49H65CIN6O8 [M+H]+901.5, found 901.5.Step 7AStep 7A

[0227] TFA (1000 pL, 134 eq., 12.98 mmol) was added dropwise to a solution of 10 (87.5 mg, 1 eq., 97.1 pmol) and TIS (200 pL, 10.1 eq., 976 pmol) in DCM (1.0 mL). The resulting mixture was stirred at RT for 2 h, after which LCMS showed complete consumption of the starting material. The mixture was then concentrated under a stream of nitrogen. The resultingcrude oil was dissolved in DMF (2.00 ml_). To the solution were added DIPEA (169 pL, 10.0 eq., 971 pmol) and DOTA-OSu 12 (81.3 mg, 1.10 eq., 107 pmol). The resulting mixture was stirred at RT for 18 h. The crude reaction mixture was concentrated, dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to give RD09-040 (102.6 mg, 60.29 pmol, 62.1%) as a colorless oil.1H-NMR (500 MHz, MeOD) δ7.83 (d, J = 2.1 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.40 (dd, J = 8.9, 2.1 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 6.97 (s, 1H), 6.74 (s, 1H), 6.53 (d, J = 8.5 Hz, 2H), 4.55 (t, J = 6.0 Hz, 2H), 4.30 - 3.32 (m, 22H), 3.25 - 2.70 (m, 20H), 2.67 (s, 2H), 2.33 - 2.16 (m, 4H), 2.10 (d, J = 13.7 Hz, 2H), 2.00 - 1.92 (m, 2H), 1.90 - 1.69 (m, 8H).LRMS: m / z calculated C56H75ClN10O13[M+H]+1130.5, found 1131.5.Step 7BStep 7B

[0228] TFA (1000 pL, 121 eq., 12.98 mmol) was added dropwise to a solution of 11 (96.5 mg, 1 eq., 107 pmol) and TIS (200 pL, 9.12 eq., 976 pmol) in DCM (1 ml_). The resulting mixture was stirred at RT for 3 h, after which LCMS showed complete consumption of the starting material. The reaction mixture was then concentrated under a stream of nitrogen. The resulting crude oil was dissolved in DMF (0.5 ml_). To the solution was added DIPEA (186 pL, 10.0 eq., 1.07 mmol) and DOTA-OSu 12 (89.7 mg, 1.10 eq., 118 pmol). The resulting mixture was stirred at RT for 72 h. The reaction mixture was concentrated, dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to give RD09-049 (46.2 mg, 27.1 pmol, 25.4%) as a colorless oil.1H-NMR (500 MHz, MeOD) δ7.77 (d, J = 1.8 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.37 (dd, J = 8.7, 1.8 Hz, 1H), 7.31 (t, J = 8.5 Hz, 1H), 6.95 (s, 1H), 6.59 (d, J = 8.5 Hz, 2H), 6.44 (s, 1H), 4.39 (s, 2H), 4.07 - 3.33 (m, 22H), 3.24 -2.79 (m, 20H), 2.66 (s, 2H), 2.26 - 2.14 (m, 4H), 2.08 (d, J = 13.3 Hz, 2H), 1.97 (s, 2H), 1.87 - 1.71 (m, 8H). LRMS: m / z calculated C56H75ClN10O13[M+H]+1130.5, found 1131.3.Step 1NHI

[0229] A mixture of 10 and 11 (205 mg, 1 eq., 227 mol) was dissolved in DCM (1.75 ml_). TFA (1.75 ml_, 100 eq., 22.7 mmol) was added to the mixture at RT. The reaction was stirred for 2 h at RT after which reaction completion was confirmed by LCMS. The reaction was concentrated under reduced pressure to give a crude mixture of products 12 and 13 as a colorless oil (169 mg) which was used in the next step without further purification.Cpd 12: LRMS m / z calculated C40H49ClN6O6[M+H]+745.3, found 745.3.Cpd 13: LRMS m / z calculated C40H49ClN6O6[M+H]+745.3, found 745.3.

[0230] DOTAGA(tBu)3(118 mg, 1.5 eq., 169 pmol) was dissolved in DMF (1.75 ml_) at RT. HATU (51.4 mg, 1.2 eq., 135 pmol), HOSu (38.9 mg, 3 eq., 338 pmol), and DIPEA (314 pL, 16 eq., 1.80 mmol) were added sequentially to the solution. The resulting reaction mixture was stirred at RT for 2 h after which full consumption of the starting material was observed by LCMS. The reaction mixture was then added to a vial containing a stir bar and a mixture of 12 and 13 (84.0 mg, 1 eq., 113 pmol). The resulting mixture was stirred at RT for 16 h. The crude mixture was then concentrated under reduced pressure. The resulting residue was redissolved in TFA (3 ml_) and TIS (0.3 ml_, 10 eq., 1 mmol) and stirred at RT for 8 h. The reaction mixture was concentrated, dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to give the products RD09-060 (51.9 mg, 29.3 mol, 26.0%) and RD09-061 (7.9 mg, 4.5 mol, 4.0%) as colorless oils.RD09-060: LRMS m / z calculated C59H79CIN10O15 [M+H]+1203.5, found 1203.5.RD09-061: LRMS m / z calculated C59H79CIN10O15 [M+H]+1203.5, found 1203.6.Step 2BRD09-062 RD09-063

[0231] Crown(tBu)3 (112 mg, 1.5 eq., 169 pmol) was dissolved in DMF (1.7 ml_) at RT. HATU (51.4 mg, 1.2 eq., 135 pmol), HOSu (25.9 mg, 2 eq., 225 pmol), and DIPEA (314 pl_, 16 eq., 1.80 mmol) were added sequentially to the solution. The resulting mixture was stirred at RT for 2 h after which the reaction added to another vial containing a stir bar and a mixture of 12 and 13 (84.0 mg, 1 eq., 113 pmol). The resulting mixture was stirred at RT for 16 h. The reaction was then concentrated under reduced pressure. The crude residue was redissolved in TFA (3.0 ml_, 39 mmol) and TIS (0.30 ml_, 13 eq., 1.5 mmol) and stirred at RT for 8 h. The reaction mixture was concentrated, dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to give the products RD09-062 (81.8 mg, 45.7 mol, 40.5%) and RD09-063 (44.0 mg, 24.6 mol, 21.8%) as colorless oils.RD09-062:1H-NMR (500 MHz, MeOD) δ7.84 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.43 (dd, J = 8.9, 2.1 Hz, 1H), 7.28 (t, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.73 (s, 1H), 6.54 (d, J = 8.5 Hz, 2H), 4.56 (t, J = 6.0 Hz, 2H), 4.22 (s, 2H), 3.90 - 3.68 (m, 14H), 3.49 (d, J = 2.6 Hz, 9H), 3.42 (d, J = 5.2 Hz, 3H), 3.38 - 3.32 (m, 9H), 3.29 (d, J = 5.2 Hz, 6H), 3.20 (s, 1H), 3.02 (s, 3H), 2.91 (s, 3H), 2.68 (s, 2H), 2.31 - 2.20 (m, 4H), 2.11 (d, J = 13.2 Hz, 3H), 2.02 (t, J = 7.7 Hz, 2H), 1.88 - 1.72 (m, 8H). LRMS m / z calculated C60H83ClN10O15[M+H]+1219.6, found 1219.6.RD09-063:1H-NMR (500 MHz, MeOD) δ7.79 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 8.8, 1.8 Hz, 1H), 7.32 (t, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.43 (s, 1H), 4.40 (d, J = 8.9 Hz, 2H), 4.22 (s, 2H), 3.90 - 3.70 (m, 14H), 3.56 (s, 9H), 3.47 - 3.32 (m, 12H), 3.30 - 3.13 (m, 8H), 3.03 (s, 3H), 2.89 (s, 3H), 2.67 (s, 2H), 2.28 - 2.16 (m, 4H), 2.15 -1.97 (m, 4H), 1.91 - 1.71 (m, 8H). LRMS m / z calculated C60H83ClN10O15[M+H]+1219.6, found 1219.6.Synthesis of RD09-082Step 1

[0232] A mixture of 3 (50.0 mg, 2.08 eq., 85.6 pmol) and sodium carbonate (136 mg, 31.2 eq., 1.28 mmol) in anhydrous acetone (5.00 ml_) was heated to 60 °C and stirred for 30 min under nitrogen. The mixture was cooled to RT and then thiophosgene (150 mg, 100 pL, 85% wt, 27.0 eq., 1.11 mmol) was added. The mixture was heated to 60 °C and stirred for 3 h. The mixture was concentrated under reduced pressure. To the crude residue was added a mixture of 13 (40.0 mg, 1.00 eq., 41.1 pmol), 12 (40.0 mg, 1.00 eq., 41.1 pmol), and DIPEA (37.1 mg, 50.0 pL, 6.98 eq., 287 pmol) in anhydrous THF (5.00 ml_) at RT under nitrogen. The reaction was stirred for 18 h and concentrated under reduced pressure. The crude product was purified by HPLC with an isocratic gradient of 43% MeCN and 57% H2O (0.1% TFA) and lyophilized to provide the product RD09-082 (4.30 mg, 2.0 pmol, 4.8%) as an off-white solid. LRMS: m / z calculated C67H84CIN11O14S [M+H]+1334.6, found 1334.5. Note: RD09-083 (10.0 mg, 5.58 pmol, 13.6%) and 1 (11.6 mg, 11.9 pmol, 29.0%) were isolated as an inseparable mixture.Synthesis of RD09-083 and RD09-087Step 1o

[0233] HOSu (4.11 mg, 3.00 eq., 35.8 pmol) was added to a mixture of 2 (19.4 mg, 3.00 eq., 35.8 pmol), HATU (13.6 mg, 3.00 eq., 35.8 pmol), and DIPEA (41.5 pL, 20.0 eq., 238 pmol) in anhydrous DMF (0.500 ml_) at RT under nitrogen. The mixture was stirred for 30 min, then an inseparable mixture of RD09-083 (10.0 mg, 0.468 eq., 5.58 pmol) and 13 (11.6 mg, 1.00 eq., 11.9 pmol) in anhydrous DMF (0.500 ml_) were added. The mixture was stirred for 18 h and concentrated under reduced pressure. The crude residue was diluted with DCM (1.00 ml_), TIS (50.0 pL, 20.5 eq., 244 pmol), and TFA (200 pL, 218 eq., 2.60 mmol) at RT under nitrogen. The resulting mixture was stirred for 18 h and concentrated under reduced pressure. The crude product was purified by HPLC with an isocratic gradient of 45% MeCN and 55% H2O (0.1% TFA) and lyophilized to provide RD09-083 (5.30 mg, 2.4 pmol, 20%) as a white solid and RD09-087 (7.09 mg, 4.5 pmol, 37%) as a white solid.RD09-083 LRMS: m / z calculated C67H84CIN11O14S [M+H]+1334.6, found 1334.5.RD09-087 LRMS: m / z calculated C55H72CIN9O13 [M+H]+1102.5, found 1102.5Synthesis of RD09-085Step 1

[0234] HOSu (2.52 mg, 1.50 eq., 21.9 pmol) was added to a mixture of HATU (8.31 mg, 1.50 eq., 21.9 pmol), 2 (9.08 mg, 1.50 eq., 21.9 pmol), and DIPEA (20.0 pL, 7.88 eq., 115 pmol) in anhydrous DMF (100 pL) at RT under nitrogen. The mixture was stirred for 30 min and then 13 (15.0 mg, 1.00 eq., 14.6 pmol) in anhydrous DMF (400 pL) was added. The mixture was stirred for 18 h and concentrated under reduced pressure. The crude residue was resuspended in DCM (1 ml_), TIS (50.0 pL, 16.8 eq., 244 pmol), and TFA (950 pL, 846 eq., 12.3 mmol) at RT under nitrogen. The mixture was stirred for 18 h and concentrated under reduced pressure. The crude product was purified by HPLC with an isocratic gradient of 40% MeCN and 60% H2O (0.1% TFA) and lyophilized to provide the product RD09-085 (5.40 mg, 3.63 pmol, 24.9%) as a white solid. LRMS: m / z calculated C52H68CIN9O11 [M+H]+1030.5, found 1030.5.Synthesis of RD09-065 and RD09-088HO

[0235] Cpd 1 (2 g, 1 eq., 12.04 mmol) and potassium carbonate (4.158 g, 2.5 eq., 30.09 mmol) were dissolved in DMF (30 ml_). Benzyl bromide (2.264 g, 1.575 ml_, 1.1 eq., 13.24 mmol) was added to the reaction mixture in a dropwise fashion. The reaction mixture was stirred for 5 h at RT after which LCMS showed complete consumption of the starting material. The reaction mixture was acidified to pH 2 with 1 M aq. HCI and extracted with diethyl ether (2 x 100 ml_). The resulting organic layers were combined and washed with brine (100 ml_). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the crude product 2 (2.82 g) as an off-white solid which was usedin the next step without further purification. LRMS: m / z calculated C16H16O3[M+H]+257.1, found 257.1.Step 2Step 2

[0236] Crude 2 (2.82 g) and dimethyl oxalate (2.842 g, 2 eq., 24.07 mmol) were dissolved in methanolic sodium methoxide (36.11 mL, 0.5 M, 1.5 eq., 18.05 mmol). The resulting reaction mixture was heated to 70 °C for 8 h after which complete consumption of the starting material was observed by LCMS. The reaction mixture was concentrated under reduced pressure to give crude 3 (3.70 g) as a red oil which was used in the next step without purification. LRMS: m / z calculated C19H18O6[M+H]+343.1, found 343.1.Step 3

[0237] Crude 3 (3.70 g) was dissolved in acetic acid (30 mL) and 7-chloro-4-hydrazineylquinoline (4) (2.330 g, 1 eq., 12.04 mmol) was added to the reaction mixture. The reaction mixture was heated to 70 °C for 8 h after which complete conversion of the keto-ester to the pyrazole was observed by LCMS. The reaction mixture was then poured into ice water. The resulting oil was dissolved in DCM (25 mL) and washed with water (25 mL) and brine (25 mL). Organic layer was then separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (Silica gel, EtOAc / hex, 0-50%) to provide product 5 (3.2 g, 6.4 mmol, 53% across 3 steps). LRMS: m / z calculated C28H22CIN3O4 [M+H]+500.1, found 500.1.Step 4

[0238] Lithium hydroxide hydrate (504.4 mg, 5.00 eq., 12.02 mmol) was added to a solution of 5 (1.202 g, 1 eq., 2.404 mmol) in THF (5.0 mL) and water (5.0 mL). The resulting reaction mixture was heated to 70 °C and stirred for 2 h after which LCMS confirmed the consumption of the starting material. The reaction mixture was diluted with 3 M aq. HCI (12.0 mL) resulting in the formation of a light orange precipitate. The precipitate was filtered, washed with H2O (3 x 20.0 mL) and dried to provide the acid intermediate as a light orange solid which was used without further purification. LRMS: m / z calculated C27H20CIN3O4 [M+H]+486.1, found 486.1. The crude residue was dissolved in DMF (15 mL). HATU (1.006 g, 1.1 eq., 2.645 mmol), 6 (664.8 mg, 1.1 eq., 2.645 mmol), and DIPEA (1.554 g, 2.09 mL, 5 eq., 12.02 mmol) were added sequentially to the reaction mixture. The reaction mixture was then stirred at 21 °C for 16 h, after which LCMS confirmed complete consumption of the starting material. The reaction mixture was then concentrated and co-distilled with heptane. The resulting crude mixture was purified by flash chromatography (Silica gel, 40 g cartridge, EtOAc / hex, 0-50%) to provide product 7 (1.126 g, 1.565 mmol, 65.1%) as a beige powder. LRMS: m / z calculated C42H43CIN4O5 [M+H]+719.3, found 719.3.Step 5

[0239] Palladium on carbon (177.0 mg, 10% wt, 0.1 eq., 166.3 mol) was added to a large microwave vial. The reaction vial was then flushed with nitrogen after which a solution of 7 (1.196 g, 1 eq., 1.663 mmol) in MeOH (10 mL) was added at RT. The nitrogen gas was removed, and the vial was purged with a balloon of hydrogen gas. The reaction mixture was stirred under an atmosphere of H2 (balloon) for 16 h after which LCMS confirmed the consumption of the starting material. The reaction mixture was then purged with nitrogen, and the solids were filtered using a pad of celite. The filtrate was collected and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel,EtOAc / hex, 0-50%) to provide product 8 (140 mg, 223 pmol, 13.4%) as a white amorphous solid. LRMS: m / z calculated C35H37CIN4O5 [M+H]+629.3, found 629.3.

[0240] (Tributylphosphoranylidene)acetonitrile (44 pL, 2.00 eq., 0.17 mmol) was added to a solution of 9 (44 mg, 2.00 eq., 0.17 mmol) in toluene (1 mL). The resulting mixture was heated to 60 °C for 10 min. The reaction mixture was added to a vial containing 8 (50 mg, 1 eq., 84 pmol). The resulting mixture was stirred at 60 °C for 4 h, after which LCMS showed complete consumption of the starting material. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, MeOH / DCM, 1-50%) to provide product 10 (44.1 mg, 52.7 pmol, 63%) as a colorless oil. LRMS: m / z calculated C48H64N6O7 [M+H]+837.5, found 837.4.Step 7

[0241] TFA (0.5 mL) was added dropwise to a solution of 10 (44.1 mg, 1 eq., 52.7 pmol) in TIS (108 pL, 10 eq., 527 pmol) and DCM (0.5 mL). The resulting mixture was stirred at RT for 1 h and concentrated under reduced pressure. The crude oil was dissolved in DMF (0.50 mL). DIPEA (91.8 pL, 10.0 eq., 527 pmol) and DOTA-OSu (11) (44.1 mg, 1.10 eq., 58.0 pmol) were added sequentially to the reaction mixture. The mixture was stirred at RT for 18 h, concentrated, and directly purified by HPLC to give RD09-065 (50.2 mg, 30.7 pmol, 58.2%) as a colorless oil. LRMS: m / z calculated C55H73CIN10O12 [M+H]+1101.5, found 1101.5.Step 8

[0242] Cpd 8 (74 mg, 1 eq., 0.12 mmol) and CS2CO3 (0.11 g, 3 eq., 0.35 mmol) were added sequentially to a solution of 4-bromobutan-1-ol (12) (32 L, 80% wt, 1.5 eq., 0.18 mmol) in DMF (1.0 ml_). The resulting mixture was stirred at RT for 4 h, cooled down to room temperature and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, EtOAc / hex, 20-100%) to provide product 13 (34.7 mg, 49.5 pmol, 42%) as a colorless oil. LRMS: m / z calculated C39H45CIN4O6 [M+H]+701.3, found 701.7.Step 9

[0243] Dess-Martin periodinane (23.1 mg, 1.1 eq., 54.4 pmol) was added to a solution of 13 (34.7 mg, 1 eq., 49.5 pmol) in DCM (1.0 ml_). The resulting mixture was stirred at RT for 2 h and tert-butyl methyl(3-(methylamino)propyl)carbamate (50.1 mg, 5 eq., 247 pmol) and sodium triacetoxyborohydride (31.5 mg, 3 eq., 148 pmol) were sequentially added. The resulting mixture was stirred at RT for 16 h and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, MeOH / DCM,1-50%) to provide product 14 (17.2 mg, 19.4 pmol, 39.3%) as a colorless oil. LRMS: m / z calculated C49H65CIN6O7 [M+H]+885.5, found 885.9.Step 10

[0244] TFA (0.5 ml_) and TIS (10 eq.) were added to a solution of 14 (17.2 mg, 1 eq., 19.4 mol) in DCM (1.0 ml_). The resulting mixture was stirred at RT for 2 h and concentrated under reduced pressure. The resulting crude residue was dissolved in DMF (1.0 ml_). DIPEA (51.9 L, 15 eq., 291 pmol) and DOTA-OSu (11) (11.7 mg, 1.2 eq., 23.3 pmol) were added sequentially to the reaction mixture. After stirring at RT for 16 h, the rection mixture was concentrated under reduced pressure and the resulting crude residue was directly purified by HPLC to give RD09-088 (20.7 mg, 12.3 pmol, 63.2%) as a colorless oil. LRMS: m / z calculated C56H75CIN10O12 [M+H]+1115.5, found 1115.6.Synthesis of RD09-096Step 1Cl ClOQ OMe OH1 2

[0245] To stirred solution of 4-chloro-8-methoxyquinoline, 1 (10 g, 51.645 mmol) in DCM (80 mL) was added boron tribromide (1.0 M in heptane, 52 mL, 52 mmol) at 0°C. Then the reaction mixture was stirred for 12 h at RT. Progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was diluted with Et2O (2.5 mL), then it was filtered to afford the product (2) as a yellow solid (7 g, 39.0 mmol, 75.5%).1H-NMR (400 MHz, DMSO-de) 5 ppm 8.86 (d, 1H), 7.97 (d, 1H), 7.69 (m, 2H), 7.32 (m, 1H). LRMS: m / z calculated CgHeCINO [M+H]+180.0, found 180.1.Step 2

[0246] To a stirred solution of 2 (1 g, 5.57 mmol) in ethanol (70 mL) was added hydrazine hydrate (35% wt, 194 mmol) at RT. Then the reaction mixture was stirred for 3 h at 80°C. Progress of the reaction was monitored by LCMS and TLC. The resulting yellow solid was filtered off to afford the product (3) (630 mg, 3.60 mmol, 64.6%).1H-NMR (400 MHz, DMSO-de) 5 ppm 8.35 (br s, 1H), 7.50 (br d, 1H), 7.17 (brt, 1H), 6.91 (br d, 2H), 4.94 (br s, 1H), 4.40 (br s, 2H). LRMS: m / z calculated C9H9N3O [M+H]+176.1, found 175.9.Step 3

[0247] To a stirred solution of 4 (5 g, 17.84 mmol) in acetic acid (50 mL, 870 mmol) was added 4-hydrazineylquinolin-8-ol, 3 (3.75 mg, 0.0214 mmol). The reaction mixture was stirred at 80°C for 12 h. Progress of the reaction was monitored by TLC and LCMS. The mixture was directly concentrated, then the crude residue was purified by Silica gel column chromatography (EtOAc / heptane, 60%) to afford the product (5) as a yellow solid (5 g, 11.92 mmol, 66.8%).1H-NMR (400 MHz, DMSO-de) 5 ppm 10.02 (s, 1H), 8.81 (br d, 1H), 7.44 (brt, 1H), 7.24 (m, 3H), 7.10 (br d, 1H), 7.06 (br d, 2H), 7.00 (s, 1H), 6.52 (br d, 2H), 4.35 (q, 2H), 3.41 (m, 6H), 1.32 (br t, 3H). LRMS: m / z calculated C23H21N3O5 [M+H]+420.2, found 420.0.Step 4

[0248] To a stirred solution of 5 (2 g, 4.769 mmol) in toluene (5 ml_) was added linker 6 (1.4 g, 4.8 mmol), followed by cyanomethylene tributylphosphorane (4.23 g, 4.77 mmol, 1.0 M in toluene). The reaction mixture was stirred at 120°C for 12 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction was worked up with water (50 ml_), and the aqueous layer was extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated. The crude residue was purified by Silica gel column chromatography (MeOH / DCM, 10%) to afford the product, 7 (3 g, 4.312 mmol, 90.4%) as a light red viscous liquid.1H-NMR (400 MHz, DMSO-de) 5 ppm 8.82 (br d, 1H), 7.49 (brt, 1H), 7.33-7.12 (m, 9H), 6.49 (br d, 2H), 5.03 (br s, 2H), 4.34 (q, 2H), 4.16 (br s, 2H), 3.41 (s, 6H), 3.33 (s, 3H), 3.17 (m, 4H), 2.77 (s, 3H), 2.29 -2.15 (m, 5H), 1.98 (br s, 2H), 1.58 (m, 13H). LRMS: m / z calculated C39H45N5O [M+H]+696.3, found 697.0.Step 5

[0249] To a stirred solution of 7 (4 g, 5.75 mmol) in THF (30 ml_) and water (25 ml_) was added lithium hydroxide monohydrate (1.5 eq., 8.62 mmol). The resulting mixture was stirred atRT for 3 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, workup was performed with water (50mL) and EtOAc (2 x 50 mL). The aqueous layer was separated and acidified with 6 N aq. HCI (40 mL) to pH 3-4. The aq. Layer was extracted with 10% MeOH in DCM (2 x 100 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated to afford the crude product (8) as a yellow solid (1.80 g, 47%) which was used in the next step without further purification.1H-NMR (400 MHz, DMSO-de) 5 ppm 10.40 (br s, 1H), 8.90 (m, 1H), 7.61-7.21 (m, 8H), 6.98 (s, 1H), 6.52 (brd, 2H), 5.45 (s, 1H), 5.05 (br s, 2H), 4.31 (br s, 2H), 3.31 (m, 2H), 3.16 (s, 2H), 3.06 (br s, 1H), 2.84 (br s, 5H), 2.29 (m, 2H), 1.97-1.90 (s, 3H), 1.61 (br d, 1H), 1.37 (m, 2H), 0.88 (brt, 1H). LRMS: m / z calculated C37H41N5O7 [M+H]+668.3, found 668.2.Step 6

[0250] To a stirred solution of 9 (655 mg, 2.61 mmol) in DMF (15 mL) was added DIPEA (6.51 mmol) in DMF. To the mixture was added cpd 8 (1.45 g, 2.17 mmol) followed by HATU (1 g, 2.55 mmol) at 0°C over 10 min. The resulting mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (25 mL). The aqueous layer was washed with EtOAc (2 x 50 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by Silica gel column chromatography (MeOH / DCM, 10-20%) to afford the product (10) as a yellow viscous liquid (1.8 g, 2.0 mmol, 92%).1H-NMR (400 MHz, DMSO-de) 5 ppm 9.19 (m, 1H), 7.95 (s, 1H), 7.45-7.55 (m, 2H), 7.20-7.33 (m, 8H), 6.92 (s, 1H), 6.52 (brd, 1H), 5.04 (br s, 2H), 4.30 (br s, 2H), 3.61 (br s, 1H), 3.42 (m, 6H), 2.84-2.88 (m, 14H), 2.68-2.72 (m, 10H), 2.54 (m, 3H), 2.25 (br s, 2H), 1.94-2.05 (m, 5H), 1.67-1.82 (m, 8H), 1.59 (br d, 3H), 1.42 (s, 9H), 1.36 (br s, 6H), 0.88 (brt, 1H). LRMS: m / z calculated C52H64N6O8[M+H]+901.5, found 901.45.Step 7

[0251] To a stirred solution of 10 (700 mg, 0.78 mmol) in ethyl acetate (6 ml_) and methanol (1 ml_), acetic acid (0.1 ml_) was added followed by 10% palladium on carbon (700 mg, 6.5774 mmol). The reaction mixture was stirred in presence of hydrogen (balloon) at RT for 16 h. Progress of the reaction was monitored by TLC and LCMS. The reaction was filtered through a celite pad, then all the solvents were evaporated under reduced pressure to afford the product (11) as a light-yellow solid (500 mg, 0.65 mmol, 83.9%).1H-NMR (400 MHz, DMSO-de) 5 ppm 8.84 (br d, 1H), 7.93 (s, 1H), 7.41 (s, 1H), 7.29 (brd, 1H), 7.22 (m, 2H), 6.89 (s, 1H), 6.51 (br d, 1H), 4.22 (m, 1H), 3.59 (m, 1H), 3.36 (m, 1H), 3.11 (br d, 1H), 2.93 (brt, 1H), 2.87 (s, 2H), 2.70 (m, 2H), 2.53 (m, 2H), 2.33 (m, 2H), 2.00 (m, 4H), 1.89 (s, 2H), 1.80 (br s, 1H), 1.72 (br d, 3H), 1.60 (m, 4H), 1.39 (m, 7H), 1.23 (m, 4H), 0.86 (br t, 2H). LRMS: m / z calculated C44H58N6O6[M+H]+767.4, found 767.4.Step 8

[0252] To a stirred solution of 11 (500 mg, 0.65 mmol) in DMF and DIPEA (258 mg, 1.96 mmol) was added DOTA(tBu)3-OSu (480 mg, 0.7166 mmol). The reaction was stirred at RT for16 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, work-up was performed with water (25 ml_) and 10% MeOH in DCM (2 x 50 ml_). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The crude product was purified by Silica gel column chromatography (MeOH / DCM, 5-10%) to afford the product (13) as a lightyellow solid, which was used in the next step without further purification.Step 9

[0253] To a stirred solution of 13 (220 mg, 0.167 mmol) in DCM (2 ml_) was added 4 M aq. HCI in dioxane (2 ml_, 8 mmol). The mixture was stirred at 40°C for 3 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, solvents were evaporated under reduced pressure, and the crude product was purified by preparative HPLC to afford the product, RD09-096 (102 mg, 0.093 mmol, 55.8%) as a light-yellow viscous solid.1H-NMR (400 MHz, DMSO-de) 5 ppm 12.38 (m, 1H), 9.49 (m, 1H), 8.91 (m, 1H), 7.54 (m, 2H), 7.41 (d, 1H), 7.26 (m, 2H), 7.22 (m, 1H), 6.52 (d, 2H), 4.30 (br s, 2H), 4.06 (br d, 3H), 3.66 (m, 4H), 3.45 (s, 6H), 3.37 (br s, 8H), 3.27 (br s, 12H), 2.88 (m, 6H), 2.54 (m, 2H), 2.32 (m, 2H), 2.28 (m, 2H), 2.08 (m, 2H), 1.98 (br d, 4H), 1.73 (m, 6H), 1.60 (br d, 2H). LRMS: m / z calculated C56H76N10O13[M+H]+1097.6, found 1097.4.Synthesis of RD09-098 and RD09-118

[0254] To a stirred solution of sodium ethoxide (21% in ethanol, 27.14 ml_, 83 mmol) in EtOH (50 ml_) were added diethyl oxalate (2) (8.1 g, 55 mmol) and 1-(2,6-dimethoxyphenyl)ethenone(1) (5.0 g, 28 mmol) dropwise at 0 °C. Then the reaction mixture was allowed to warm to RT and stirred for 16 h. Reaction was monitored by LCMS. The reaction mixture was quenched with water (100 ml_) and ensuring the pH ~6 by using con HCI solution, extracted with 10% MeOH in DCM (2 x 100 ml). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford product 3 (4.28 g, 55%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.34 (m, 1H), 6.70 (d, J = 6.3 Hz, 2H), 6.16 (br s, 1H), 4.20 (m, 2H), 3.73 (brs, 6H), 1.24 (m, 3H). LRMS: m / z calculated C14H17O6[M+H]+281.1, found 281.1.Step 2

[0255] To a stirred solution of 3 (3.0 g, 11 mmol) in acetic acid (30 ml_) was added 4-hydrazinoquinolin-2-ol (4) (2.4 g, 14 mmol) at RT. Then the reaction mixture was heated to 65°C and stirred overnight. The reaction mixture was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude material. The crude material was purified by column chromatography (Silica gel, 5% MeOH in DCM) to afford the product (5) (2.54 g, 57%) as an off white solid.1H-NMR (401 MHz, DMSO-de) 5: 12.03 (s, 1H), 7.60 - 7.53 (m, 1H), 7.39 - 7.25 (m, 3H), 7.24 - 7.18 (m, 1H), 6.97 (s, 1H), 6.63 (d, J = 8.4 Hz, 2H), 6.07 (d, J = 1.6 Hz, 1H), 4.42 - 4.29 (m, 2H), 3.45 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H). LRMS: m / z calculated C23H21N3O5 [M-H]- 418.1, found 418.1.Step 3

[0256] To a stirred solution of 5 (2.0 g, 4.8 mmol) in toluene (20 mL) were added linker 6 (1.7 g, 5.7 mmol) and cyanomethylene tributylphosphorane (2.4 g, 9.5 mmol) at 0 °C. Then, thereaction mixture was heated to 100°C and stirred overnight. The reaction mixture was concentrated under reduced pressure and co-evaporated with DCM (2 x 50 mL) to afford the crude material. The crude material was purified by preparative HPLC using ammonium formate in acetonitrile as the eluent to afford product 7 (Peak-1) (900 mg, 27.12%) as a brown oil and product 8 (Peak-2) (1.58 g, 48%) as a brown oil.Cpd 7 (Peak-1):1H-NMR (400 MHz, DMSO-de) 5: 7.68 (br s, 2H), 7.32 (br s, 7H), 7.04 - 6.92 (m, 1H), 6.69 - 6.51 (m, 2H), 6.31 - 6.14 (m, 1H), 5.04 (br s, 2H), 4.40 - 4.29 (m, 2H), 4.28 -4.16 (m, 2H), 3.44 (br s, 5H), 3.28 - 3.20 (m, 2H), 2.90 - 2.78 (m, 3H), 2.39 - 2.29 (m, 2H), 2.28 - 2.17 (m, 2H), 2.16 - 2.03 (m, 4H), 1.75 - 1.55 (m, 4H), 1.32 (br s, 3H). LRMS: m / z calculated C39H46N5O7 [M+H]+696.3, found 696.3.Cpd 8 (Peak-2):1H-NMR (400 MHz, DMSO-de) 5: 7.78 (br d, J = 8.1 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.54 - 7.48 (m, 1H), 7.47 - 7.41 (m, 1H), 7.33 (br s, 4H), 7.28 - 7.20 (m, 2H), 7.00 (s, 1H), 6.67 - 6.60 (m, 1H), 6.54 (d, J = 8.4 Hz, 2H), 5.03 (s, 2H), 4.46 - 4.29 (m, 4H), 3.40 (s, 6H), 3.20 (br t, J = 7.1 Hz, 2H), 2.80 (br d, J = 9.8 Hz, 3H), 2.40 - 2.28 (m, 2H), 2.23 (br s, 2H), 2.09 (br d, J = 19.1 Hz, 3H), 1.82 (br s, 2H), 1.65 - 1.51 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H). LRMS: m / z calculated C39H46N5O7 [M+H]+696.3, found 696.2.Step 4

[0257] To a stirred solution of 8 (950 mg, 1.365 mmol) in THF (10 mL) and H2O (2 mL) was added LiOH.H2O (67 mg, 2.731 mmol) at 0 °C. Then, the reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was quenched with water (50 mL) and acidified to pH ~2 using concentrated HCI. The aqueous layer was extracted with 10% MeOH in DCM (2 x 50 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford product 9 (833 mg, 91.36%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 10.14 - 9.69 (m, 1H), 7.83 - 7.75 (m, 1H), 7.74 - 7.65 (m, 1H), 7.58 - 7.50 (m, 1H), 7.49 - 7.41 (m, 1H), 7.33 (br s, 5H), 6.94 (s, 1H), 6.63 (br s, 1H), 6.54 (br d, J = 8.2 Hz, 2H), 5.10 - 5.10 (m, 1H), 5.04 (s, 1H), 4.53 - 4.35 (m, 2H), 3.39 (br s, 5H), 3.17 - 2.94 (m, 4H), 2.85 (br s, 3H), 2.79 - 2.64 (m, 4H), 2.11 (br s, 3H), 2.00 - 1.73 (m, 3H). LRMS: m / z calculated C37H42N5O7 [M+H]+668.3, found 668.3.Step 5

[0258] To a stirred solution of 9 (500 mg, 0.749 mmol) in DMF (5 ml_) were added 10 (226 mg, 0.899 mmol), DIPEA (10) (0.66 ml_, 3.744 mmol) and HATU (587 mg, 1.497 mmol) at 0 °C. Then the reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was monitored by LCMS and was quenched with ice water (50 ml_), and the aqueous layer was extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resultant crude material was purified by column chromatography (Silica gel, 3% MeOH in DCM) to afford product 11 (487 mg, 72.2%) as an off-white solid.1H-NMR (401 MHz, DMSO-de) 5: 7.83 - 7.75 (m, 1H), 7.70 (brs, 1H), 7.58 (s, 1H), 7.47 - 7.38 (m, 2H), 7.33 (br s, 4H), 7.29 - 7.21 (m, 2H), 6.91 (s, 1H), 6.71 - 6.64 (m, 1H), 6.55 (br d, J = 8.5 Hz, 2H), 5.04 (s, 2H), 4.51 - 4.36 (m, 2H), 3.41 (s, 6H), 3.25 (br d, J = 2.6 Hz, 2H), 2.88 - 2.77 (m, 4H), 2.69 (s, 4H), 2.55 (br s, 3H), 2.03 (br d, J = 12.9 Hz, 3H), 1.97 (br d, J = 13.3 Hz, 3H), 1.81 (br s, 2H), 1.77 - 1.64 (m, 6H), 1.59 (br d, J = 13.0 Hz, 3H), 1.41 (s, 9H). LRMS: m / z calculated C52H65N6O8 [M+H]+901.5, found 901.2.Step 6

[0259] To a stirred solution of 11 (380 mg, 0.422 mmol) in EtOAc (10 ml_) and MeOH (10 ml_), 10% palladium on Carbon (224 mg, 0.211 mmol) was added at RT. Then the reaction mixture was stirred for 2 h at RT under H2 atmosphere (balloon). LCMS analysis indicated the desired product mass. The reaction mixture was diluted with 50% MeOH in EtOAc (20 mL),filtered through a celite pad and further washed with 50% MeOH in EtOAc (20 ml_). Then, the filtrate was concentrated under reduced pressure to afford product 12 (293 mg, 90.6%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.78 (br d, J = 8.2 Hz, 1H), 7.70 (br s, 1H), 7.58 (br d, J = 7.8 Hz, 1H), 7.44 (br d, J = 18.4 Hz, 2H), 7.26 (brt, J = 7.8 Hz, 1H), 6.91 (br s, 1 H), 6.67 (br s, 1 H), 6.56 (br d, J = 8.2 Hz, 2H), 4.42 (br s, 2H), 3.42 (br s, 6H), 2.87 - 2.78 (m, 2H), 2.69 (br s, 2H), 2.55 (br s, 3H), 2.43 - 2.31 (m, 2H), 2.14 (br s, 4H), 2.10 - 1.93 (m, 4H), 1.91 - 1.78 (m, 4H), 1.78 - 1.54 (m, 10H), 1.42 (br s, 9H). LRMS: m / z calculated C44H59N6O6 [M+H]+767.4, found 767.3.Step 7

[0260] To a stirred solution of 12 (290 mg, 0.378 mmol) in acetonitrile (5 ml_) were added DIPEA (0.33 ml_ 1.890 mmol) and DOTA(tBu)3-OSu (13) (304 mg, 0.454 mmol) at 0 °C. Then the reaction mixture was allowed to warm upto RT and stirred overnight. The reaction mixture was quenched with water (50 ml_) and extracted with DCM (2 x 50 ml_). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford product 14 (567 mg, 99%) as an off-white solid. The resultant crude material was used in the next step without further purification.1H-NMR (400 MHz, DMSO-de) 5: 7.75 (d, J = 8.7 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.44 - 7.32 (m, 2H), 7.24 (t, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.67 - 6.58 (m, 1H), 6.54 (d, J = 8.3 Hz, 2H), 4.46 - 4.28 (m, 2H), 3.40 (br s, 6H), 2.82 (s, 4H), 2.78 (br s, 3H), 2.75 (br s, 2H), 2.67 (s, 4H), 2.65 (br s, 3H), 2.53 (br s, 3H), 2.32 - 2.29 (m, 4H), 2.29 - 2.18 (m, 3H), 2.18 - 2.11 (m, 3H), 2.11 - 2.07 (m, 3H), 2.05 - 1.91 (m, 5H), 1.87 - 1.77 (m, 6H), 1.76 - 1.62 (m, 6H), 1.62 - 1.52 (m, 3H), 1.49 - 1.46 (m, 2H), 1.38 - 1.33 (m, 27H), 1.32 - 1.29 (m, 9H). LRMS: m / z calculated C72H109N10O13 [M+H]+1321.8, found 1322.1.Step 8

[0261] To a stirred solution of 14 (350 mg, 0.265 mmol) in DCM (3.5 ml_) was added 4 M HCI in 1,4-dioxane (3.5 ml_) at 0 °C. Then the reaction mixture was allowed to warm up to RT and stir for 2 h. The reaction mixture was quenched with water (50 ml_) and extracted with DCM (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resultant crude material was purified by preparative HPLC using 0.1% TFA in acetonitrile as an eluent system to afford RD09-098 (80 mg, 24.9%) as a white solid.1H-NMR (400 MHz, DMSO-de) 5: 13.01 - 11.91 (m, 1H), 7.82 - 7.75 (m, 1H), 7.74 - 7.67 (m, 1H), 7.63 - 7.57 (m, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.29 - 7.21 (m, 1H), 6.94 (s, 1H), 6.77 - 6.74 (m, 1H), 6.55 (d, J = 8.5 Hz, 2H), 4.47 (brt, J = 5.1 Hz, 2H), 4.12 - 3.90 (m, 4H), 3.46 (s, 7H), 3.40 -3.00 (m, 23H), 2.94 - 2.82 (m, 3H), 2.82 - 2.71 (m, 3H), 2.61 - 2.56 (m, 2H), 2.46 - 2.36 (m, 2H), 2.21 - 2.06 (m, 4H), 2.03 - 1.94 (m, 2H), 1.91 - 1.74 (m, 4H), 1.73 - 1.65 (m, 4H), 1.64 - 1.56 (m, 2H). LRMS: m / z calculated C56H77N10O13 [M+H]+1097.6, found 1097.2.Step 9

[0262] To a stirred solution of 7 (Peak-1) (1.3 g, 1.9 mmol) in 1,4-dioxane (13 ml_) was added 2 N NaOH in H2O (13 ml_, 3.7 mmol) at 0°C. Then, the reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was quenched with water (20 ml_), acidified with 2 M aq. HCI solution and extracted with DCM (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to affordproduct 15 (1.28 g, 99%) as an off-white solid.1H-NMR (401 MHz, DMSO-de) 5: 9.82 - 9.50 (m, 1H), 7.73 (br s, 2H), 7.48 - 7.20 (m, 8H), 6.94 (s, 1H), 6.62 (d, J = 8.5 Hz, 2H), 6.23 (s, 1H), 5.06 (s, 2H), 4.29 (br s, 2H), 3.57 (s, 6H), 3.45 (s, 2H), 3.29 (br s, 2H), 3.19 - 3.12 (m, 1H), 3.07 - 2.93 (m, 1H), 2.91 - 2.80 (m, 3H), 2.78 - 2.64 (m, 3H), 1.98 (br s, 2H), 1.85 (brs, 2H). LRMS: m / z calculated C37H42N5O7 [M+H]+668.3, found 668.2.Step 10

[0263] To a stirred solution of 15 (1.2 g, 1.8 mmol) in DMF (12 ml_) were added 10 (0.54 g, 2.2 mmol), HATU (1.4 g, 3.6 mmol) and DIPEA (1.6 ml_, 9.0 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was quenched with ice water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica gel, 3% MeOH in DCM) to afford product 16 (658 mg, 41%) as an off-white solid.1H-NMR (401 MHz, DMSO-de) 5: 7.77 - 7.60 (m, 2H), 7.47 - 7.39 (m, 2H), 7.31 (br d, J = 8.4 Hz, 7H), 6.88 (s, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.26 (s, 1H), 5.11 - 4.99 (m, 2H), 4.33 - 4.13 (m, 2H), 3.45 (s, 6H), 3.29 - 3.23 (m, 2H), 2.91 - 2.80 (m, 4H), 2.69 (s, 2H), 2.55 (br s, 3H), 2.08 - 1.93 (m, 6H), 1.74 (br d, J = 13.8 Hz, 6H), 1.70 - 1.55 (m, 7H), 1.41 (s, 9H). LRMS: m / z calculated C52H65N6O8 [M+H]+901.5, found 901.3.Step 11

[0264] To a stirred solution of 16 (600 mg, 0.666 mmol)in EtOAc (6 ml_) and MeOH (6 ml_) was added 10% Palladium in Carbon (354 mg, 0.333 mmol) at RT. The reaction mixture was stirred for 2 h at RT under a H2 atmosphere (balloon). The reaction mixture was filtered through a celite pad and further washed with 50% MeOH in DCM (50 ml_). The filtrate was concentrated under reduced pressure to afford product 17 (510 mg, 99%) as an off-white solid. The crude material was used in next step without further purification.1H-NMR (400 MHz, DMSO-de) 5: 7.69 (br s, 2H), 7.51 - 7.37 (m, 2H), 7.36 - 7.21 (m, 2H), 6.88 (br s, 1H), 6.62 (br d, J = 7.4 Hz, 2H), 6.28 - 6.21 (m, 1H), 4.32 - 4.18 (m, 2H), 3.33 (br s, 6H), 2.71 - 2.60 (m, 4H), 2.36 (br s, 9H), 2.12 (br s, 4H), 2.07 - 1.93 (m, 5H), 1.89 (br s, 4H), 1.59 (br d, J = 9.4 Hz, 5H), 1.41 (brs, 9H). LRMS: m / z calculated C44H59N6O6 [M+H]+767.4, found 767.3.Step 12

[0265] To a stirred solution of 17 (510 mg, 0.665 mmol) in acetonitrile (10 ml_) were added DOTA(tBu)s-OSu (13) (490 mg, 0.732 mmol) and DIPEA (0.58 ml_, 3.325 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction was quenched with water (30 ml_) and extracted with DCM (2 x 30 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by preparative HPLC using 0.1% TFA in H2O / acetonitrile as the eluent to afford product 18 (325 mg, 37.0%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.66 (br s,2H), 7.47 - 7.37 (m, 2H), 7.35 - 7.22 (m, 2H), 6.88 (br s, 1H), 6.67 - 6.57 (m, 2H), 6.31 - 6.18 (m, 1 H), 4.33 - 4.14 (m, 2H), 4.08 - 3.86 (m, 2H), 3.79 - 3.58 (m, 2H), 3.45 (brs, 6H), 3.25 -2.97 (m, 6H), 2.87 (br s, 6H), 2.60 - 2.53 (m, 8H), 2.40 - 2.31 (m, 4H), 2.30 - 2.26 (m, 2H), 2.22 (br s, 2H), 2.11 (br s, 2H), 2.08 - 1.91 (m, 4H), 1.87 - 1.52 (m, 16H), 1.39 (br d, J = 15.7 Hz, 36H). LRMS: m / z calculated C72H109N10O13 [M+H]+1321.8, found 1322.1.Step 13

[0266] To a stirred solution of 18 (225 mg, 0.171 mmol) in DCM (2.5 ml_) was added HCI (4 M in 1,4-dioxane, 2.25 ml_) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and coevaporated with DCM (2 x 5 ml_). The resulting crude material was purified by preparative HPLC using 0.1% TFA in H2O / acetonitrile as the eluent to afford RD09-118 (95 mg, 46.1%) as a white solid.1H-NMR (400 MHz, DMSO-de) 5: 12.75 - 12.11 (m, 1H), 7.70 (brd, J = 3.6 Hz, 2H), 7.55 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.36 - 7.27 (m, 2H), 6.92 (s, 1H), 6.62 (d, J = 8.5 Hz, 2H), 6.34 (s, 1H), 4.28 (brt, J = 6.4 Hz, 2H), 4.11 - 3.86 (m, 4H), 3.49 (s, 6H), 3.40 - 3.07 (m, 19H), 3.04 (br s, 2H), 2.89 (s, 2H), 2.85 - 2.82 (m, 1H), 2.78 - 2.75 (m, 1H), 2.73 (s, 2H), 2.69 -2.65 (m, 2H), 2.57 (br s, 3H), 2.35 - 2.30 (m, 2H), 2.10 (br d, J = 11.6 Hz, 2H), 1.99 (br d, J = 13.1 Hz, 4H), 1.89 - 1.74 (m, 4H), 1.74 - 1.64 (m, 4H), 1.60 (br d, J = 12.8 Hz, 2H). LRMS: m / z calculated C56H77N10O13 [M+H]+1097.6, found 1097.2.Synthesis of RD09-108 and RD09-124

[0267] To a stirred solution of 1 (2.5 g, 12 mmol) in DCM (20 ml_) were added triphenylphosphine (4.9 g, 18 mmol) and CBr4 (5.4 g, 16 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction was quenched with water (50 ml_) and extracted with DCM (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica gel, 20% EtOAc in heptane) to afford product 2 (2.10 g, 64%) as a colorless oil.1H-NMR (400 MHz, DMSO-de) 5: 3.55 (t, J = 6.4 Hz, 2H), 3.18 (t, J = 6.8 Hz, 2H), 2.75 (br s, 3H), 1.81 - 1.67 (m, 2H), 1.63 - 1.50 (m, 2H), 1.39 (S, 9H).Step 2

[0268] To a stirred solution of 3 (3.0 g, 6.6 mmol) in DMF (30 ml_) were added Cs2CO3 (6.5 g, 20 mmol) and 2 (2.1 g, 7.9 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was quenched with water (100 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica gel, 20-50% EtOAc in heptane) to afford products 4 (Peak-1) (1.96 g, 46%) and 5 (Peak-2) (1.78 g, 42%) as off-white solids.Cpd 4 (Peak-1):1H-NMR (400 MHz, DMSO-de) 5: 7.83 (bs, 1H), 7.52 (s, 2H), 7.27 (t, J = 8.40 Hz, 1H), 7.01 (s, 1H), 6.56 (d, J = 8.80 Hz, 2H), 4.41-4.32 (m, 4H), 3.42 (s, 6H), 3.18 (t, J = 7.20 Hz, 2H), 2.73 (s, 3H), 1.66 (q, 1 = 6.40 Hz, 2H), 1.54 (m, 2H), 1.35-1.30 (m, 12H). LRMS: m / z calculated C23H40CIN4O7 [M+H]+639.3, found 639.1.Cpd 5 (Peak-2):1H-NMR (400 MHz, DMSO-de) 5: 7.77 (bs, 1H),7.39 (dd, J = 1.60, 8.80 Hz, 1H), 7.34-7.30 (m, 2H), 6.99 (s, 1H), 6.62 (d, J = 8.80 Hz, 2H), 6.20 (bs, 1H), 4.34 (q, J = 7.20 Hz, 2H), 4.26 (m, 2H), 3.45 (s, 6H), 3.16 (t, J = 6.00 Hz, 2H), 2.72 (s, 3H), 1.50 (m, 4H), 1.34-1.30 (m, 12H). LRMS: m / z calculated C23H40CIN4O7 [M+H]+639.3, found 639.1.Step 3Step 3

[0269] To a stirred solution of 4 (1.0 g, 1.6 mmol) in DCM (10 ml_) was added TFA (0.60 ml_,7.8 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was quenched with saturated aq. NaHCOs (50 ml_) and extracted with DCM (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford product 6 (842 mg, 100%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.84 (s, 1H), 7.52 (s, 2H), 7.28 (t, J = 8.4 Hz, 1H), 7.02 (s, 1H), 6.67 (s, 1H), 6.58 (d, J = 8.6 Hz, 2H), 4.41 (t, J = 6.4 Hz, 2H), 4.38 - 4.31 (m, 2H), 3.44 (s, 6H), 2.88 - 2.78 (m, 2H), 2.48 (s, 3H), 1.84 - 1.70 (m, 2H), 1.68 - 1.57 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H). LRMS: m / z calculated C28H32CIN4O5 [M+H]+539.2, found 539.1.Step 4

[0270] To a stirred solution of 6 (842 mg, 1.562 mmol) in acetonitrile (20 ml_) were added K2CO3 (648 mg, 4.686 mmol) and linker 7 (694 mg, 2.343 mmol) at 0°C. The reaction mixture was heated to 80°C and stirred overnight. The reaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica gel, 6% MeOH in DCM) to afford product 8 (250 mg, 21.2%) as a colorless oil.1H-NMR (400 MHz, DMSO-de) 5: 7.84 (s, 1H), 7.52 (d, J = 0.9 Hz, 2H), 7.28 (t, J = 8.4 Hz, 1H), 7.02 (s, 2H), 6.65 (s, 1H), 6.57 (d, J = 8.6 Hz, 2H), 4.44 - 4.37 (m, 2H), 4.37 - 4.30 (m, 2H), 4.06 - 3.97 (m, 2H), 3.43 (s, 6H), 2.95 (br d, J = 5.9 Hz, 2H), 2.47 - 2.35 (m, 2H), 2.34 -2.15 (m, 3H), 1.79 - 1.66 (m, 2H), 1.62 - 1.49 (m, 2H), 1.38 (br d, J = 5.9 Hz, 8H), 1.32 (t, J = 7.1 Hz, 3H), 0.97 - 0.83 (m, 2H), 0.03 (s, 9H). LRMS: m / z calculated C38H53ClN5O7Si [M+H]+754.3, found 754.2.Step 5

[0271] To a stirred solution of 8 (250 mg, 0.332 mmol) in 1,4-dioxane (2 ml_) was added 2 N aq. NaOH (0.199 ml_, 0.398 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was concentrated under reduced pressure and coevaporated with 1,4-dioxane (2 x 5 ml_) to afford product 9 (248 mg, 100%) as an off-white solid. The crude product was used in the next step without further purification.1H-NMR (400 MHz, DMSO-de) 5: 7.77 (br d, J = 1.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 1 H), 7.48 - 7.35 (m, 1 H), 7.26 - 7.17 (m, 1H), 6.64 (s, 1H), 6.60 - 6.45 (m, 3H), 4.45 - 4.31 (m, 4H), 4.07 - 3.94 (m, 2H), 3.40 (s, 6H), 2.93 (br s, 2H), 2.82 (brt, J = 6.4 Hz, 2H), 2.31 - 2.15 (m, 3H), 2.08 (d, J = 4.6 Hz, 2H), 1.78 - 1.62 (m, 2H), 1.57 - 1.40 (m, 2H), 1.39 - 1.18 (m, 2H), 0.89 (m, 2H). 0.03 (s, 9H). LRMS: m / z calculated C36H48ClN5O7Si [M+H]+726.3, found 726.2.Step 6

[0272] To a stirred solution of sodium 9 (248 mg, 0.332 mmol) in DMF (5 ml_) were added DIPEA (0.289 ml_, 1.657 mmol), 10 (125 mg, 0.497 mmol) and HATU (259 mg, 0.6628 mmol)at 0°C. The reaction mixture was allowed to warm upto RT and stirred overnight. The reaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica gel, 6% MeOH in DCM) to afford product 11 (213 mg, 67.0%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.83 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.48 (s, 2H), 7.27 (t, J = 8.4 Hz, 1H), 7.08 - 6.96 (m, 1H), 6.92 (s, 1H), 6.69 (s, 1H), 6.57 (d, J = 8.6 Hz, 2H), 4.47 - 4.36 (m, 2H), 4.00 (br t, J = 8.2 Hz, 2H), 3.44 (s, 6H), 3.02 - 2.90 (m, 2H), 2.55 (br d, J = 5.9 Hz, 3H), 2.11 - 1.92 (m, 4H), 1.68 (br s, 8H), 1.63 - 1.49 (m, 4H), 1.42 (s, 9H), 0.89 (br s, 2H), 0.00 (s, 9H). LRMS: m / z calculated C5iH72CIN6O8Si [M+H]+959.5, found 959.4.Step 7

[0273] To a stirred solution of 11 (300 mg, 0.313 mmol) in THF (5 ml_) was added TBAF (1.0 M in THF, 1.56 ml_, 1.56 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was quenched with saturated aq. NH4CI (20 ml_) and extracted with EtOAc (2 x 20 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford product 12 (254 mg, 99.6%) as a brown oil. The crude material was used in the next step without further purification. LRMS: m / z calculated C45H60ClN6O6[M+H]+815.4, found 815.5.Step 8

[0274] To a stirred solution of 12 (230 mg, 0.282 mmol) in DMF (5 ml_) were added DIPEA (0.25 ml_, 1.410 mmol), Crown(tBu)3(13) (224 mg, 0.339 mmol) and HATU (221 mg, 0.564 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product 14 (411 mg, 99.9%) as an off-white solid, which was used in the next step without further purification. LRMS: m / z calculated C77H118CIN10O15 [M+H]+1457.8, found 1457.7.Step 9

[0275] To a stirred solution of 14 (380 mg, 0.261 mmol) in DCM (5 ml_) was added TFA (0.39 ml_, 5.21 mmol) at 0°C. The reaction mixture was allowed to warm upto RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and co-evaporated with DCM (2 x 5 ml_) to afford the crude product as a brown solid. The crude material was purified by preparative HPLC 0.1% formic acid in H2O / acetonitrile as the eluent to afford RD09-108 (51 mg, 15.9%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.93 - 7.79 (m, 2H), 7.63 - 7.54 (m, 2H), 7.51 - 7.45 (m, 1H), 7.27 (t, J = 8.4 Hz, 1H), 6.93 (s, 1H), 6.74 (s, 1H), 6.57 (d, J = 8.5 Hz, 2H),4.41 (br s, 2H), 3.52 (br s, 12H), 3.46 (s, 10H), 3.27 - 3.21 (m, 6H), 3.11 (br d, J = 10.3 Hz, 12H), 3.01 - 2.78 (m, 8H), 2.77 - 2.65 (m, 2H), 2.58 (br s, 4H), 2.36 - 2.30 (m, 1H), 2.10 (br d, J = 11.4 Hz, 2H), 1.98 (br s, 2H), 1.85 - 1.65 (m, 6H), 1.60 (br d, J = 11.9 Hz, 4H), 1.43 (br s, 2H). LRMS: m / z calculated C61H86ClN10O15 [M+H]+1233.6, found 1233.9.Step 10

[0276] To a stirred solution of 5 (1.78 g, 2.79 mmol) in DCM (20 ml_) was added HCI (4 M in 1,4-dioxane, 3.48 ml_) at 0°C. The reaction mixture was allowed to warm upto RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and co-evaporated with DCM (2 x 10 ml_) to afford product 15 (1.60 g, 99.8%) as an off-white solid which was used in the next step without further purification.1H-NMR (400 MHz, DMSO-de) 5: 8.67 - 8.38 (m, 2H), 7.80 (s, 1H), 7.39 (brd, J = 1.3 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.00 (s, 1H), 6.64 (d, J = 8.5 Hz, 2H), 6.24 (s, 1 H), 4.41 - 4.22 (m, 4H), 3.57 (s, 3H), 3.47 (s, 6H), 2.90 (br s, 2H), 1.64 (br s, 4H), 1.32 (t, J = 7.1 Hz, 3H). LRMS: m / z calculated C28H31CIN4O5 [M+H]+539.2, 539.1.Step 11

[0277] To a stirred solution of 15 (600 mg, 1.043 mmol) in acetonitrile (6 ml_) was added K2CO3 (721 mg, 5.213 mmol) and linker 7 (371 mg, 1.251 mmol) at 0°C. The reaction mixture was heated to 80°C and stirred overnight. The reaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica gel, 6% MeOH in DCM) to afford product 16 (452 mg, 57.5%; yield combined with another batch) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.80 (br s, 1H), 7.45 - 7.22 (m, 3H), 7.06 - 6.91 (m, 2H), 6.63 (br s, 2H), 6.29 - 6.14 (m, 1H), 4.34 (br s, 2H), 4.23 (br s, 2H), 3.99 (br s, 2H), 3.45 (br s, 6H), 2.94 (br s, 2H), 2.41 - 2.08 (m, 8H), 1.67 -1.26 (m, 10H), 0.88 (br d, J = 6.6 Hz, 2H), 0.03 (s, 9H). LRMS: m / z calculated C38H53ClN5O7Si [M+H]+754.3, found 754.2.Step 12

[0278] To a stirred solution of 16 (400 mg, 0.530 mmol) in 1,4-dioxane (4 ml_) was added 2 N aq. NaOH (0.32 ml_, 0.636 mmol) at 0°C. The reaction mixture was allowed to warm upto RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and coevaporated with 1,4-dioxane (2 x 5 ml_) to afford product 17 (396 mg, 99.8%) as an off-white solid which was used in the next step without further purification.1H-NMR (400 MHz, DMSO-de) 5: 7.76 (s, 1H), 7.61 - 7.45 (m, 1H), 7.37 - 7.17 (m, 3H), 6.59 (d, J = 8.3 Hz, 2H), 6.56 - 6.51 (m, 1H), 6.13 - 6.04 (m, 1H), 4.21 (br s, 2H), 3.99 (brt, J = 7.9 Hz, 2H), 3.47 - 3.40 (m, 6H), 2.93 (br s, 2H), 2.85 - 2.76 (m, 1H), 2.37 - 2.16 (m, 4H), 2.10 (s, 3H), 1.58 (s, 4H), 1.46 (br s, 2H), 1.36 (br s, 3H), 0.02 (s, 9H). LRMS: m / z calculated C36H49ClN5O7Si [M+H]+726.3, found 726.2.Step 13

[0279] To a stirred solution of 17 (395 mg, 0.528 mmol) in DMF (5 ml_) were added DIPEA (0.46 ml_, 2.639 mmol), 10 (199 mg, 0.7918 mmol) and HATU (413 mg, 1.056 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica gel, 6% MeOH in DCM) to afford product 18 ( 259 mg, 51.1%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.80 (s, 1H), 7.49 (s, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.04 - 6.94 (m, 1H), 6.88 (s, 1H), 6.63 (d, J = 8.6 Hz, 2H), 6.24 (s, 1H), 4.32 - 4.17 (m, 2H), 4.00 (br s, 2H), 3.47 (s, 6H),2.95 (br d, J = 5.5 Hz, 3H), 2.55 (m s, 6H), 2.02 (br s, 5H), 1.68 (br s, 7H), 1.58 (br s, 5H), 1.41 (s, 14H), 0.88 (br s, 2H), 0.02 (bs, 9H). LRMS: m / z calculated C51H72ClN6O8Si [M+H]+959.5, found 959.3.Step 14

[0280] To a stirred solution of 18 (235 mg, 0.245 mmol) in THF (5 mL) was added TBAF (1.0 M in THF, 1.23 mL, 1.224 mmol) at 0°C. The reaction mixture was allowed to warm upto RT and stirred overnight. The reaction was quenched with saturated aq. NH4CI (30 mL) and extracted with EtOAc (2 x 30 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford product 19 (157 mg, 78.6%) as an off-white solid. The crude material was used in the next step without further purification. LRMS: m / z calculated C45H60CIN6O6 [M+H]+815.4, found 815.3.

[0281] To a stirred solution of 19 (140 mg, 0.172 mmol) in DMF (2 mL) were added DIPEA (0.15 mL, 0.859 mmol), Crown(tBu)3(13) (136 mg, 0.206 mmol) and HATU (134 mg, 0.344 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. Thereaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford crude product 20 (250 mg, 99.9%) as an off-white solid, which was used in the next step without further purification. LRMS: m / z calculated C77H118CIN10O15 [M+H]+1457.8, found 1457.6.Step 16

[0282] To a stirred solution of 20 (250 mg, 0.171 mmol) in DCM (5 ml_) was added HCI (4 M in 1,4-dioxane, 0.86 ml_) dropwise at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and coevaporated with DCM (2 x 5 ml_). The resulting crude material was purified by preparative HPLC using 0.1% TFA in H2O / acetonitrile as the eluent to afford RD09-124 (14 mg, 6.1%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 8.45 - 8.32 (m, 1H), 7.75 (d, J = 1.3 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.46 (s, 1H), 7.40 - 7.28 (m, 3H), 6.92 (s, 1H), 6.63 (d, J = 8.5 Hz, 3H), 6.30 (s, 1H), 4.26 (brs, 2H), 3.75 (br s, 4H), 3.73 - 3.56 (m, 12H), 3.50 (s, 6H), 3.23 - 3.10 (m, 18H), 3.07 (br s, 2H), 2.72 (s, 4H), 2.58 (br s, 3H), 2.14 - 2.06 (m, 2H), 1.98 (br s, 2H), 1.85 - 1.55 (m, 14H), 1.51 - 1.42 (m, 2H). LRMS: m / z calculated C61H86ClN10O15 [M+H]+1233.6, found 1233.5.

[0283] To a stirred solution of 4-aminobutan-1-ol (21) (5.0 g, 56 mmol) in THF (50 ml_) were added EtsN (23.5 ml_, 160 mmol) and 22 (10.6 g, 40.1 mmol) at RT. The reaction was stirred at RT overnight and was quenched with ice water (100 ml_) and extracted with EtOAc ( 2 x 100 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silicagel, 20% EtOAc in heptane) to afford product 23 (8.6 g, 66.0%) as a colorless oil.1H-NMR (400 MHz, DMSO-de) 6: 6.96 (m, 1H), 4.35 (t, J = 4.80 Hz, 1H), 4.01 (t, J = 8.40 Hz, 2H), 3.37 (t, J = 4.80 Hz, 2H), 2.94 (t, J = 6.00 Hz, 2H), 1.39 (d, J = 2.80 Hz, 4H), 0.90 (t, J = 8.40 Hz, 2H), 0.01 (s, 9H).Step 18Step-18

[0284] To a stirred solution 23 (4.0 g, 17 mmol) in DCM (40 ml_) were added triphenylphosphine (6.9 g, 26 mmol) and CBr4 (7.5 g, 22 mmol) portion-wise at 0 °C. The reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction was quenched with water (100 ml_) and extracted with EtOAc ( 2 x 100 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica gel, 20% EtOAc in heptane) to afford product 7 (4.29 g, 84%) as a colorless oil.1H-NMR (400 MHz, DMSO-de) 5: 7.03 (br s, 1H), 4.02 (brt, J = 8.1 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.28 - 3.18 (m, 1H), 3.06 - 2.91 (m, 2H), 1.85 - 1.69 (m, 2H), 1.59 - 1.41 (m, 2H), 0.90 (brt, J = 8.3 Hz, 2H), 0.02 (s, 9H).Synthesis of RD09-130Step 1

[0285] To a stirred solution of 1 (225 mg, 0.273 mmol) in 1,4-dioxane (4 ml_) was added 2 N aq. NaOH (0.16 ml_, 0.328 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was concentrated under reduced pressure and coevaporated with 1,4-dioxane (2 x 5 ml_) to afford product 2 (223 mg, 99.9%) as an off-white solid. The crude material was used in the next step without further purification.1H-NMR (400 MHz, DMSO-de) 5: 7.72 (s, 1H), 7.52 (br d, J = 8.6 Hz, 1H), 7.39 - 7.19 (m, 2H), 6.63 - 6.53 (m, 3H), 6.08 (s, 1H), 4.22 (brd, J = 7.1 Hz, 4H), 3.44 (s, 6H), 3.40 - 3.35 (m, 1H), 3.15 - 3.09 (m, 1H), 2.73 - 2.63 (m, 3H), 2.43 - 2.38 (m, 3H), 2.36 - 2.15 (m, 12H), 1.62 - 1.52 (m, 3H), 1.51 -1.42 (m, 3H), 1.35 (br s, 6H), 0.03 (d, J = 18.8 Hz, 9H). LRMS: m / z calculated C40H56ClN6O7Si [M+H]+795.4, found 795.5.Step 2

[0286] To a stirred solution of 2 (210 mg, 0.257 mmol) in DMF (5 ml_) were added DIPEA (0.23 mL, 1.285 mmol), 3 (8 mg, 0.308 mmol) and HATU (206 mg, 0.514 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 30 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (Silica gel, 10% MeOH in DCM) to affordproduct 4 (42 mg, 15.9%) as an off-white solid. LRMS: m / z calculated C55H79ClN7O8Si [M+H]+1028.5, found 1028.6.Step 3 /

[0287] To a stirred solution of 4 (40 mg, 0.0389 mmol) in THF (2 mL) were added TBAF (1.0 M in THF, 0.194 mL, 0.194 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was quenched with saturated aq. NH4CI solution (30 mL) and extracted with EtOAc (2 x 30 mL). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford crude product 5 (34 mg, 98.9%) as an off-white solid, which was used in the next step without further purification. LRMS: m / z calculated C49H67CIN7O6 [M+H]+884.5, found 884.4.

[0288] To a stirred solution of 5 (34 mg, 0.0385 mmol) in DMF (2 mL) were added Crown(tBu)s (6) (31 mg, 0.046 mmol,), DIPEA (0.034 mL, 0.192 mmol) and HATU (31 mg, 0.077 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was quenched with water (30 mL) and extracted with EtOAc (2 x 30 mL).Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford crude product 7 (58 mg, 98.8%) as a brown oil, which was used in the next step without further purification. LRMS: m / z calculated C81H125CIN11O15 [M+H]+1526.9, found 1526.8.

[0289] To a stirred solution of 7 (58 mg, 0.038 mmol) in DCM (2 ml_) was added HCI (4 M in 1,4-dioxane, 0.18 ml_, 0.759 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and coevaporated with DCM (2 x 30 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by preparative HPLC using 0.1% formic acid in H2O / acetonitrile as the eluent to afford RD09-130 (3.6 mg, 7.3%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 12.76 - 11.78 (m, 1H), 7.74 (d, J = 1.0 Hz, 1H), 7.58 (s, 1H), 7.49 - 7.43 (m, 1H), 7.40 - 7.28 (m, 2H), 7.21 (s, 1H), 7.08 (s, 1H), 6.96 (s, 1H), 6.91 (s, 1H), 6.63 (d, J = 8.5 Hz, 2H), 6.29 (s, 1H), 4.25 (br s, 4H), 3.68 (br s, 4H), 3.66 - 3.53 (m, 6H), 3.49 (s, 6H), 3.20 - 3.12 (m, 6H), 3.10 (brs, 4H), 3.00 -2.85 (m, 6H), 2.82 - 2.69 (m, 3H), 2.61 - 2.54 (m, 3H), 2.08 (br s, 4H), 1.99 (br d, J = 12.0 Hz, 3H), 1.85 - 1.74 (m, 2H), 1.74 - 1.65 (m, 4H), 1.63 - 1.45 (m, 8H), 1.35 - 1.26 (m, 4H), 1.23 (s, 2H), 0.93 (t, J = 7.4 Hz, 9H). LRMS: m / z calculated C65H93ClN11O15 [M+H]+1302.7, found 1302.5.Step 11. BnBr, K2CO32. Dimethyl oxalate, NaOMeStep 1

[0290] Benzyl bromide (1.57 mL, 1.10 eq., 13.2 mmol) was added to a mixture of 1 (2.00 g, 1.00 eq., 12.0 mmol) and potassium carbonate (4.16 g, 2.50 eq., 30.1 mmol) in anhydrous DMF (30.0 mL) at 70 °C under nitrogen. The mixture was stirred for 18 h and then diluted with H2O (50.0 mL) and EtOAc (50.0). The layers were separated, and the aqueous layer was extracted with EtOAc (50.0 mL). The combined organic layers were washed with brine (3 x 50.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the crude intermediate 1-(2-(benzyloxy)-6-methoxyphenyl)ethan-1-one, which was used immediately in the next step. LRMS: m / z calculated C16H16O3[M+H]+257.1, found 257.1. Sodium methoxide (1.08 g, 40.0 mL, 0.5 M in MeOH, 1.66 eq., 20.0 mmol) was added to a mixture of the intermediate (2.84 g, 2.00 eq., 24.1 mmol) at RT under nitrogen. The mixture was heated to 70 °C, stirred for 18 h, and concentrated under reduced pressure to provide the crude product 2 (4.12 g, 9.6 mmol) as a red oil, which was used in the next step without further purification. LRMS: m / z calculated CigHisOe [M+H]+343.1, found 343.1.Step 2

[0291] A solution of 2 (1.63 g, 1.00 eq., 4.76 mmol) in acetic acid (10.0 mL) was added to 3 (1.10 g, 1.10 eq., 5.24 mmol) at RT under nitrogen. The mixture was heated to 70 °C and stirred for 24 h. The mixture was cooled to RT, diluted with H2O (5.00 mL), 3 M aq. HCI (5.00 mL), MeCN (5.00 mL), and MeOH (5.00 mL), and sonicated for 5 min, which formed a precipitate. The precipitate was filtered, washed with H2O (3 x 20.0 mL) and MeCN (2 x 5.00 mL), and dried to provide the product 4 (1.64 g, 3.18 mmol, 66.8%) as a yellow solid. LRMS: m / z calculated C28H22CIN3O5 [M+H]+516.1, found 516.2.Step 36

[0292] Lithium hydroxide hydrate (667 mg, 5.00 eq., 15.9 mmol) was added to a mixture of 4 (1.64 g, 1.00 eq., 3.18 mmol) in THF (20.0 mL) and H2O (20.0 mL) at RT under air. The mixture was stirred for 4 h and the THF was evaporated under reduced pressure. The aqueous layer was acidified with 6 M aq. HCI (20.0 mL), which formed a precipitate. The precipitate was filtered, washed with H2O (3 x 20.0 mL), and dried to provide the intermediate 5-(2-(benzyloxy)-6-methoxyphenyl)-1-(7-chloro-2-hydroxyquinolin-4-yl)-1H-pyrazole-3-carboxylic acid, which was used immediately in the next step. LRMS: m / z calculated C27H20CIN3O5 [M+H]+502.1, found 502.1. DIPEA (2.77 mL, 5.00 eq., 15.9 mmol) was added to a mixture of the intermediate in anhydrous DMF (30.0 mL) at RT under nitrogen. The mixture was stirred for 15 min and then HATU (1.81 g, 1.50 eq., 4.77 mmol) was added. The mixture was further stirred for 15 min and then 5 (879 mg, 1.10 eq., 3.50 mmol) was added. The mixture was further stirred for 18 h and diluted with brine (60.0 mL), which formed a solid. The aqueous layer was decanted, MeOH (20.0 mL) was added to the solid, and the suspension was sonicated for 5 min. The resulting precipitate was filtered, washed with MeOH (3 x 5.00 mL), and dried to provide product 6 (1.68 g, 2.28 mmol, 71.9%) as a beige solid. LRMS: m / z calculated C42H43CIN4O6 [M+H]+735.3, found 735.3.

[0293] Cpd 7 (189 mg, 2.00 eq., 1.36 mmol) was added to a mixture of 6 (500 mg, 1.00 eq., 680 mol) and K2CO3 (282 mg, 3.00 eq., 2.04 mmol) in anhydrous MeCN (3.00 mL) at RT under nitrogen. The mixture was heated to 85 °C and stirred for 1 h. The mixture was cooled to RT and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 25 g cartridge) with hexanes and EtOAc (0-100%) to provide cpd 8 (155 mg, 195 mol, 28.7%) as a colorless oil and cpd 9 (213 mg, 268 mol, 39.5%) as a colorless oil.Cpd 8: LRMS: m / z calculated C45H49CIN4O7 [M+H]+793.3, found 793.3.Cpd 9: LRMS: m / z calculated C45H49CIN4O7 [M+H]+793.3, found 793.3.Step 5

[0294] DMP (101 mg, 1.10 eq., 238 pmol) was added to a mixture of 9 (172 mg, 1.00 eq., 217 pmol) in anhydrous DCM (2.00 mL) at RT under nitrogen. The mixture was stirred for 30 min and then cpd 10 (219 mg, 5.00 eq., 1.08 mmol) was added. The mixture was further stirred for 30 min, sodium triacetoxyborohydride (138 mg, 3.00 eq., 650 pmol) was added, and then stirring continued for 18 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 12 g cartridge) with DCM and MeOH (0-100%) to provide product 11 (157 mg, 161 pmol, 74.1%) as a colorless oil. LRMS: m / z calculated CssHegClNeOs [M+H]+977.5, found 977.5.

[0295] TFA (900 pL, 571 eq., 11.7 mmol) was added to a mixture of 11 (20.0 mg, 1.00 eq., 20.5 pmol) and TIS (100 pL, 23.9 eq., 488 pmol) in anhydrous DCM (1.00 mL) at RT under nitrogen. The mixture was stirred for 4 h and then concentrated under reduced pressure. The crude residue was diluted with DMF (1.00 mL) and DIPEA (71.3 pL, 20.0 eq., 409 pmol) and stirred for 15 min at RT under nitrogen. DOTA-OSu (15.4 mg, 1.50 eq., 30.7 pmol) was added and the mixture was further stirred for 16 h and concentrated under reduced pressure. The crude product was purified by HPLC with an isocratic gradient of 45% MeCN and 55% H2O(0.1% TFA) and lyophilized to provide the product RD09-145 (16.7 mg, 8.8 mol, 43%) as a white solid. LRMS: m / z calculated C62H79CIN10O13 [M+H]+1207.5, found 1207.3.Synthesis of RD09-146 and RD09-147Step 1Aq. HCIStep 11

[0296] An aqueous HCI solution (3.6 mL, 12.2 M, 8 eq., 43 mmol) was added dropwise to a stirred solution of 7-bromo-2,4-dichloroquinoline, 1 (1.5 g, 1 eq., 5.4 mmol) in 1,4-dioxane (5.4 mL) at RT. The reaction mixture was then heated to 90 °C. After stirring for 16 h, the reaction mixture was poured onto ice and stirred for 1 h. The precipitate was then collected by vacuum filtration, washed with minimal water, and dried under vacuum to provide the product 7-bromo-4-chloroquinolin-2-ol, 2 (1.28 g, 4.7 mmol, 87%) as a beige powder. LRMS: m / z calculated CgHsBrCINO [M+H]+257.9, found 257.9.Step 2Hydrazine Hydrate Step 2

[0297] Cpd 2 (0.950 g, 1 eq., 3.68 mmol) was dissolved in ethanol (9.35 mL) in a 20 ml_ reaction vessel. Hydrazine hydrate (440 L, 65% wt, 2.5 eq., 9.19 mmol) was added to the reaction vessel dropwise and the reaction mixture was subsequently heated to 80 °C for 8 h. The reaction vessel was then transferred to a heating block at 70 °C and subsequently stirred for 16 h. Upon completion, as judged by TLC, the reaction was diluted with ice cold water and the precipitate was collected and washed with minimal cold water, yielding 7-bromo-4-hydrazineylquinolin-2-ol, 3 (0.879 g, 3.46 mmol, 94.1%) as a beige powder. LRMS: m / z calculated C9H8BrN3O [M+H]+254.0, found 253.9.Step 3Step 3

[0298] Acetic acid (10 mL) was added to a mixture of 3 (860 mg, 1.5 eq., 3.38 mmol) and methyl-4-(2,6-dimethoxyphenyl)-4-hydroxy-2-oxobut-3-enoate (601 mg, 1 eq., 2.26 mmol) at RT under air. The reaction mixture was stirred overnight at 65 °C. The mixture was cooled to RT and diluted with HgO (50.0 mL), which resulted in the formation of a brown precipitate. The brown precipitate was filtered, washed with H2O (3 x 50.0 mL), and purified by flash chromatography (Silica gel, 25 g cartridge) with DCM and MeOH (0-50%) to provide the product 4 (576 mg, 1.19 mmol, 52.7%) as a beige amorphous solid.Step 4

[0299] Lithium hydroxide hydrate (250 mg, 5.00 eq., 5.95 mmol) was added to a solution of 4 (576 mg, 1 eq., 1.19 mmol) in THF (2.5 mL) and water (2.5 mL). The resulting reaction mixture was heated to 70 °C and stirred for 2 h, after which reaction completion was observed by LCMS. The reaction mixture was diluted with 3 M aq. HCI (12.0 mL), resulting in the formation of a light orange precipitate. The precipitate was filtered, washed with H2O (3 x 20.0 mL) and dried to provide the product 5 (559 mg) as a light orange solid. The crude material was used in the next step without further purification. LRMS: m / z calculated C2iHieBrN3O5 [M+H]+470.0, found 470.1.

[0300] Cpd 5 (559 mg, 1.19 mmol) was dissolved in DMF (5 mL) at RT. HATU (497 mg, 1.1 eq., 1.31 mmol), 7 (329 mg, 1.1 eq., 1.31 mmol) and DIPEA (1.04 mL, 5 eq., 5.95 mmol) were added sequentially to the reaction mixture. After stirring the reaction mixture for 16 h at RT, completion was observed by LCMS. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 40 g cartridge) with hexanes and EtOAc (0-50%) to provide product 6 (459.6 mg, 653.2 mol, 54.9%) as a beige powder. LRMS: m / z calculated CseHsgBrIXLOe [M+H]+703.2, found 703.3.Step 6

[0301] (Tributylphosphoranylidene)acetonitrile (299 pL, 1.75 eq., 1.14 mmol) was added to a solution of A (297 mg, 1.75 eq., 1.14 mmol) in toluene (5.0 ml_). The resulting reaction mixture was heated to 70 °C for 5 min. The reaction was added to a vial containing cpd 6 (459 mg, 1 eq., 652 pmol). The reaction mixture was stirred at 70 °C for 5 h, after which LCMS showed complete consumption of the starting material. The mixture was cooled to RT and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 24 g cartridge) with DCM and MeOH (1-50%) to provide a (4:1) mixture 7 and 8 (559 mg, 591 pmol, 90.6%) as a colorless oil. LRMS: m / z calculated C49He5BrNeO8 [M+H]+945.4, found 945.4.Step 7Step 7

[0302] TFA (2.05 ml_, 90 eq., 26.60 mmol) was added dropwise to a solution of 7 and 8 (279.6 mg, 1 eq., 295.6 pmol, 4:1 mixture) and TIS (200 pL, 3.30 eq., 976 pmol) in DCM (2.00 ml_). The resulting mixture was stirred at RT for 2 h, after which the crude LCMS showedcomplete consumption of the starting material. The reaction mixture was then concentrated under a stream of nitrogen. The resulting crude oil was dissolved in DMF (5.00 ml_). To the crude reaction mixture was added DIPEA (515 L, 10.0 eq., 2.956 mmol) and DOTA-OSu (247.6 mg, 1.10 eq., 325.1 pmol). The reaction mixture was stirred at RT for 18 h. The resulting reaction was concentrated, dissolved in 1:1 MeCN / FW + 0.1% formic acid and purified by HPLC to give the products RD09-146 (67.3 mg, 38.5 pmol, 13.0%) and RD09-147 (14.2 mg, 8.13 pmol, 2.75%) as clear colorless oils.RD09-146: LRMS m / z calculated CeHysBrNioO [M+H]+1175.5, found 1175.5.RD09-147: LRMS m / z calculated CeHysBrNioO [M+H]+1175.5, found 1175.3.Synthesis of RD09-117, RD09-138 and RD09-151Step 1

[0303] To a stirred solution of 2-bromo-3-methoxy-phenol (1) (2 g, 9.85 mmol) in DMF (20 ml_) was added 3-bromopropionic acid (2) (1 eq., 9.85 mmol). The mixture was stirred at 0°C for 15 min, then sodium hydride (4 eq., 39.403 mmol) was added at 0°C and the resulting mixture was warmed up to RT and stirred overnight. The reaction was quenched with water (50ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford crude product 3 (2 g, 3.700 mmol, 37.56%) which was used in the next step without further purification.Step 2

[0304] A stirred solution of 3 (200 mg, 0.727 mmol) in polyphosphoric acid (1 g) was stirred at 100°C for 12 h. The reaction mixture was quenched with saturated aq. NaHCOs (15 ml_) and extracted with EtOAc (2 x 25 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (Silica gel, 35-40% EtOAc in heptane) to afford product 4 (50 mg, 0.185 mmol, 25.4%) as an off-white viscous oil.Step 3

[0305] To stirred solution of 4 (2 g, 7.78 mmol) in DCM (20 ml_) were added triethylsilane (7.3 g, 62 mmol) and BF3. OEt2 (9.3 g, 62 mmol) at 0°C. After 10 minutes, the reaction mixture was allowed to warm up to RT and stirred for 12 h. The reaction was quenched with saturated aq. NaHCOs (10 ml_) and then extracted with EtOAc (2 x 25 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (Silica gel, 15-20% EtOAc in heptane) to afford product 5 (600 mg, 2.45 mmol, 31.7%) as white solid.1H-NMR (400 MHz, DMSO-de) 5 ppm 7.01 (br d, 1H), 6.58 (br d, 1H), 4.20 (m, 2H), 3.78 (s, 3H), 2.70 (m, 2H), 2.50 (m, 1H), 1.88 (m, 2H). LRMS: m / z calculated C10H12BrO2[M+H]+243.0, found 242.9.Steps 4 and 55 6A6

[0306] To a stirred solution of tributyl(1-ethoxyvinyl)stannane (3.3 g, 9.1 mmol) in toluene (4 ml_) was added 5 (1.1 g, 4.5 mmol). The vessel was purged with argon for 5 min, then Pd(dppf)2Cl2. DCM (380 mg, 0.456 mmol) was added and the mixture was stirred at 110°C for 16 h. The reaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (Silica gel, 15-20% EtOAc in heptane) to afford product 6 (800 mg, 3.88 mmol, 86%) as a colorless viscous oil. LRMS: m / z calculated C12H15O3 [M+H]+207.1, found 207.Step 6

[0307] To a stirred solution of 6 (800 mg, 3.88 mmol) in EtOH, diethyl oxalate (1.1 g, 7.5 mmol) and sodium ethoxide (4 ml_, 20% wt in methanol) were added at RT. The reaction mixture was stirred at 80°C for 12 h. The reaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated to afford crude product 8 (600 mg, 1.96 mmol, 50.5%) which was used in the next step without further purification.1H-NMR (400 MHz, CDCI3) 5 ppm 7.05 (br d, 1H), 6.63 (s, 1H), 6.46 (br d, 1H), 4.35 (q, 2H), 4.17 (m, 2H), 2.74 (m, 2H), 2.00 (m, 2H), 1.64 (m, 2H), 1.32 (m, 3H). LRMS: m / z calculated C16H19O6[M+H]+307.1, found 307.1.Step 7

[0308] To a stirred solution of 8 (400 mg, 1.31 mmol) in acetic acid (5 mL) was added 9 (328 mg, 1.56 mmol). The reaction mixture was stirred at 110°C for 12 h and was directly concentrated under reduced pressure. The crude residue was purified by column chromatography (Silica gel, 60% EtOAc in heptane) to afford product 10 (220.00 mg, 0.46 mmol, 35%) as yellow solid. LRMS: m / z calculated C25H23CIN3O5 [M+H]+480.1, found 480.3.Step 8

[0309] To a stirred solution of 10 (120 mg, 0.25 mmol) in toluene (1 mL) was added cyanomethylene tributylphosphorane (1 M in toluene, 1.2 mmol) followed by A1 (88 mg, 0.30 mmol). The reaction mixture was stirred at 150°C for 2 h in a microwave. The reaction was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (Silica gel, 60% EtOAc in heptane) to afford an inseparable mixture of products 11 and 11A (60 mg, 0.079 mmol, 31.7%) as a viscous brown oil which was used in the next step without further purification. LRMS: m / z calculated C41H47CIN5O7 [M+H]+756.3, found 756.2.Step 9

[0310] To a stirred solution of 11 and 11A (1 g, 1.322 mmol) in THF (8 mL) and water (8 mL) was added lithium hydroxide mono hydrate (64 mg, 2.62 mmol). The reaction mixture stirred atRT for 6 h and was directly concentrated in vacuo. The aqueous residue was diluted with water (25 ml_) and extracted with EtOAc (2 x 25 ml_). The aqueous layer was separated and acidified with 2 M aq. HCI (pH 2-3) and then was extracted with 10% MeOH in DCM. Combined organic layers were dried over Na2SC>4, filtered and concentrated to afford an inseparable mixture of 12 and 12A (300 mg, 0.41 mmol, 31.2%) as an off-white viscous oil, which was used in the next step without further purification. LRMS: m / z calculated C39H43CIN5O7 [M+H]+728.3, found 728.1.Step 10

[0311] To a stirred solution of a mixture of 12 and 12A (250 mg, 0.34 mmol) in DMF (5 ml_) were added DIPEA (453 mg, 3.43 mmol) followed by HATU (403 mg, 1.03 mmol) at 0°C over 10 min. The reaction mixture warmed upto RT and stirred for 16 h. The reaction was diluted with water (10 ml_) and extracted with EtOAc (2 x 20 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified with preparative HPLC to afford pure products 14 (190 mg, 0.20 mmol, 57.6%) and 14A (70 mg, 0.073 mmol, 21.2%) as light brown solids.Cpd 14:1H-NMR (400 MHz, MeOD) 5 ppm 7.76 (s, 1H), 7.57 (m, 2H), 7.31 (m, 6H), 7.01 (d, 1H), 6.92(s, 1H), 6.46 (m, 2H), 5.09 (m, 2H), 4.39 (m, 2H), 3.84 (s, 1H), 3.52 (m, 3H), 3.42 (br s, 1H), 3.08 ( m, 2H), 2.97 (br s, 3H), 2.86 (br s, 3H), 2.61 (m, 4H), 2.16 (br s, 4H), 2.04 (br d, 4H), 1.76 (m, 12H), 1.33-1.55 (s, 14H), 0.97 (t, 3H). LRMS: m / z calculated C54H66ClN6O8[M+H]+961.5, found 961.3.Cpd 14A:1H-NMR (400 MHz, MeOD) 5 ppm 7.77 (br s, 1H), 7.57 (m, 2H), 7.31 (m, 6H), 7.01 (d, 1H), 6.93 (s, 1H), 6.46 (m, 2H), 5.09 (s, 2H), 4.40 (br t, 2H), 3.77 (s, 1H), 3.52 (s, 3H), 3.48 (m, 1H), 3.20 (br s, 1H), 3.12 (m, 2H), 2.97 (br s, 3H), 2.85 (m, 3H), 2.61 (m, 4H), 2.17 (m, 4H), 2.02 (m, 4H), 1.77 (m, 12H), 1.49 (m, 14H), 0.96 (m, 3H). LRMS: m / z calculated C54H66ClN6O8[M+H]+961.5, found 961.3.

[0312] To a stirred solution of 14 (80 mg, 0.083 mmol) in ethyl acetate (1.5 ml_) was added 10% Palladium on Carbon (80 mg) and the reaction was placed / stirred under an atmosphere of H2 (balloon) for 3 h. After completion (LCMS and TLC), the reaction mixture was filtered off through a celite pad, and the filtrate was concentrated in vacuo to afford an inseparable mixture of 15 and 15A (60 mg, 0.038 mmol, 84%) as a dark viscous oil which was used in the next step without further purification.Cpd 15: LRMS: m / z calculated C46H60ClN6O6[M+H]+827.4, found 827.6.Cpd 15A: LRMS: m / z calculated C46H61N6O6[M+H]+793.5, found 793.2.Step 12

[0313] To a stirred solution of 15 and 15A (50 mg, 0.063 mmol) in acetonitrile (1 ml_) was added DIPEA (0.055 ml_, 0.318 mmol) and DOTA(tBu)3-OSu (50.6 mg, 0.076 mmol) at 0°C. The reaction mixture was stirred at RT for 3 h and then diluted with water (10 ml_). The aq. Residue was extracted with 10% MeOH in DCM (2 x 25 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated in vacuo to afford an inseparable mixture of 17 and 18 (60 mg, 0.045 mmol, 70.6%) which was used in the next step without further purification.Step 13

[0314] To a stirred solution of a mixture of 17 and 18 (30 mg, 0.0223 mmol) in DCM (2 ml_) was added HCI (4 M in 1,4-dioxane, 2 ml_, 8 mmol) at 0°C. The reaction was allowed to warm up to RT and stir for 3 h. The volatiles were removed in vacuo and the crude residue was purified by preparative HPLC to afford pure products RD09-138 (13.8 mg, 0.012 mmol, 54.9%) and RD09-151 (15.9 mg, 0.014 mmol, 65.2%) as white solids.RD09-138:1H-NMR (400 MHz, MeOD) 5 ppm 7.84 (m, 1H), 7.65-7.71 (d, 1H), 7.39-7.40 (dd, 1H), 6.97 (m, 1H), 6.93-6.96 (m, 1H), 6.76 (d, 1H), 6.40 (d, 1H), 4.57 (m, 2H), 3.66-3.89 (m, 9H), 3.49-3.67 (m, 5H), 3.41 (br s, 6H), 3.20 (m, 6H), 3.05 (m, 4H), 3.00 (s, 3H), 2.93 (m, 3H), 2.86 (s, 2H), 2.69 (s, 1H), 2.68 (m, 2H), 2.58 (br s, 2H), 2.23-2.24 (m, 8H), 1.30-1.96 (m, 14H). LRMS: m / z calculated C58H78ClN10O13[M+H]+1157.5, found 1157.8.RD09-151:1H-NMR (400 MHz, MeOD) 5 ppm 7.83 (d, 1H), 7.67 (m, 2H), 7.41 (m, 1H), 6.98 (s, 1H), 6.95 (d, 1H), 6.78 (s, 1H), 6.39 (d, 1H), 4.81 (m, 1H), 4.58 (br t, 2H), 3.66-3.91 (m, 10H), 3.48 (s, 3H), 3.41 (br s, 6H), 3.14 (m, 2H), 3.02 (br s, 2H), 3.00 (s, 2H), 2.86 (s, 3H), 2.68 (m, 2H), 2.57 (br s, 2H), 2.26 (m, 4H), 2.12 (br d, 2H), 1.96 (br d, 2H), 1.80 (m, 10H), 1.29 (s, 4H), 0.89 (br d, 2H). LRMS: m / z calculated C58H79N10O13 [M+H]+1123.6, found 1123.1.Step 14

[0315] To a stirred solution of 14A (135 mg, 0.14 mmol) in ethyl acetate (2 ml_) was added 10% Palladium on carbon (110 mg) and the resulting mixture was placed / stirred under H2 atmosphere (balloon) for3 h. After completion (LCMS and TLC), the reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to afford product 19 (50 mg, 0.063 mmol, 44.9%) as a viscous oil which was used in the next step without further purification. LRMS: m / z calculated C46H61N6O6[M+H]+793.5, found 793.5.Step 15

[0316] To a stirred solution of 19 (50 mg, 0.063 mmol) in acetonitrile (1 ml_) was added DIPEA (0.056 ml_, 0.318 mmol) followed by DOTA(tBu)3-OSu (16) (50.6 mg, 0.0755 mmol) 0°C. The reaction mixture was allowed to warm up to RT and stir for 3 h. The reaction was diluted with water (20 ml_) and extracted with 10% MeOH in DCM (2 x 20 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford product 20 (60 mg, 0.045 mmol, 70.6%) as a viscous oil which was used in the next step without further purification. LRMS: m / z calculated C74H111 N10O13 [M+2H]2+674.4, found 674.0.Step 16

[0317] To a stirred solution of 20 (60 mg, 0.044 mmol) in DCM (1 ml_) was added HCI (4 M in 1,4-dioxane, 0.2 ml_) at 0°C. The resulting mixture was stirred at RT for 3 h and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford RD09-117 (5 mg, 0.0045 mmol, 10.1%) as an off-white solid.1H-NMR (400 MHz, MeOD) 5 ppm 7.76-7.74 (m, 2H), 7.66-7.58 (m, 1H), 7.37-7.33 (m, 1H), 6.99-7.01 (d, 1H), 6.94-6.92 (m, 1H), 6.47-6.43 (m, 2H), 4.45 (m, 2H), 3.94-3.81 (m, 10H), 3.50 (m, 2H), 3.42 (br s, 6H), 3.21 (m, 4H), 3.13 (m, 5H), 2.89-2.84 (s, 5H), 2.66 (m, 1H), 2.55 (m, 4H), 2.24 (m, 5H), 2.09 (m, 4H), 1.79-1.73 (m, 10H), 1.32-1.29 (m, 2H). LRMS: m / z calculated C58H79N10O13 [M+H]+1123.6, found 1123.8.Synthesis of RD09-152Step 1

[0318] To a stirred solution of 1 (200 mg, 0.151 mmol) in DCM (2 ml_) was added mCPBA (30 mg, 0.172 mmol) and the resulting mixture was stirred at RT for 12 h. The reaction was diluted with water (15 ml_) and extracted with EtOAc (2 x 20 ml_). Combined organic layers were washed with saturated aq. NaHCOs (15 ml_), dried over Na2SC>4, filtered and concentrated to afford product 2 (180 mg, 0.135 mmol, 88.9%) as a yellow solid.1H-NMR (400 MHz, DMSO-d6) 5 ppm 8.81 (br d, 1H), 7.86 (m, 2H), 7.61 (br d, 1H), 7.48 (brt, 2H), 7.26 (m, 2H), 7.23 (m, 2H), 6.52 (br d, 1H), 4.29 (br s, 1H), 4.16 (s, 1H), 4.05 (m, 1H), 3.80 (br s, 1H), 3.60 (m, 3H), 3.40 (m, 5H), 3.03 (br s, 3H), 2.86 (m, 2H), 2.72 (m, 4H), 2.59 (m, 1H), 1.95-2.16 (m, 7H), 1.60-1.82 (m, 4H), 1.58-160 (d, 2H), 1.36-147 (m, 33H), 1.20-1.29 (m, 8H), 0.88 (brt, 2H). LRMS: m / z calculated C72H109N10O14 [M+H]+1337.8, found 1337.7.Step 2

[0319] To a stirred solution 2 (170 mg, 0.127 mmol) in DCM (5 ml_) was added HCI (4 M in 1,4-dioxane, 2.4 ml_, 9.6 mmol). The resulting mixture stirred at 40°C for 3 h and directly concentrated in vacuo. The crude residue was purified by preparative HPLC to afford RD09-152 (59 mg, 41.7%) as a light-yellow solid.1H-NMR (400 MHz, MeOD) 5 ppm 8.84 (d, 1H), 7.67 (s, 1H), 7.54-7.58 (m, 1H), 7.39-7.45 (dd, 2H), 7.21-7.29 (m, 2H), 6.92 (s, 1H), 6.50 (d, 2H), 4.39 (br s, 3H), 3.98 (br s, 4H), 3.79 (br s, 4H), 3.48 (m, 10H), 3.00 (s, 4H), 2.67 (br s, 3H), 2.56 (br s, 3H), 2.11-2.24 (br d, 8H), 1.73-1.84 (m, 10H). LRMS: m / z calculated C56H77N10O14 [M+H]+1113.6, found 1113.8.Synthesis of RD09-158 and RD09-159Step 1Step 1OH 2

[0320] Nitric acid (6.72 mL, 9 eq., 150 mmol) was added dropwise to a stirred solution of 7-chloroisoquinolin-1-ol, 1 (3.00 g, 1 eq., 16.7 mmol) in acetic acid (20 mL) at RT. The reaction mixture was then heated to 65 °C and stirred for 3 h. After completion, the reaction mixture was poured onto an excess of ice and stirred for 1 h. The precipitate was then collected by vacuum filtration, washed with minimal water, and dried under vacuum to provide product 2 (2.134 g, 9.501 mmol, 56.9%) as a white powder. LRMS: m / z calculated C9H5CIN2O3 [M-H]’ 223.0, found 222.9.Step 2

[0321] 7-Chloro-4-nitroisoquinolin-1-ol, 2 (1.47 g, 1 eq., 6.54 mmol) was suspended in POCl3(9.15 mL, 15 eq., 98.2 mmol) at RT. The resulting mixture was heated to 100 °C for 16 h. After completion (LCMS), the crude reaction mixture was concentrated under reduced pressure. Ice cold water was added to the crude residue which resulted in the formation of an off-white precipitate. The solid was filtered, washed with water and dried under vacuum to give 1,7-dichloro-4-nitroisoquinoline, 3 (1.45 g, 5.97 mmol, 91.2%) as an off white amorphous solid. LRMS: m / z calculated C9H4Cl2N2O2[M+H]+243.0, found 242.8.Step 3

[0322] Acetic acid (2.35 mL, 10 eq., 41.1 mmol) was added to a suspension of 1, 7-dichloro-4-nitroisoquinoline, 3 (1.00 g, 1 eq., 4.11 mmol) and Iron (1.15 g, 5 eq., 20.6 mmol) in ethanol (24 mL). The reaction mixture was stirred at 65 °C for 3 h, after which LCMS showed full consumption of the starting material. The reaction mixture was filtered through a celite pad. The resulting filtrate was concentrated, diluted with DCM (100 mL), washed with water (100 mL) and brine (100 mL). After drying the organic layers over sodium sulfate, the mixture was filteredand concentrated under reduced pressure to provide product 4 (0.870 g, 4.08 mmol, 99.2%) as an off white amorphous solid. LRMS: m / z calculated C9H6Cl2N2[M+H]+213.0, found 212.9.Step 4

[0323] A solution of sodium nitrite (162 mg, 1.0 eq., 2.35 mmol) in water (7.0 mL) was added dropwise to a solution of 1,7-dichloroisoquinolin-4-amine, 4 (0.500 g, 1 eq., 2.35 mmol) in 12 M aq. HCI (7.0 mL) at 0 °C. The reaction was stirred vigorously at 0 °C for 5 min, after which LCMS showed complete consumption of the starting material. A solution of SnCl2(1.33 g, 3.0 eq., 7.04 mmol) in 12 M aq. HCI (7.0 mL) was added dropwise to the reaction mixture maintaining the temperature at 0 °C. After stirring the reaction mixture at 0 °C for 1 h, the precipitate was collected by filtration and washed with minimal cold diethyl ether to provide product 5 (299 mg, 1.31 mmol, 55.9%) as an amorphous solid. LRMS: m / z calculated C9H7CI2N3 [M+H]+228.0, found 228.0.Step 5Step 5

[0324] Acetic acid (3.5 mL) was added to a mixture of methyl-4-(2,6-dimethoxyphenyl)-4-hydroxy-2-oxobut-3-enoate (299 mg, 0.8 eq., 1.12 mmol) and cpd 5 (320 mg, 1 eq., 1.40 mmol) at RT under air. The mixture was stirred overnight at 65 °C. The mixture was cooled to RT and diluted with H2O (50.0 mL), which resulted in the formation of a brown precipitate. The brown precipitate was filtered, washed with H2O (3 x 50.0 mL), and purified by flash chromatography (Silica gel, 25 g cartridge) with EtOAc and Hexanes (0-50%) to provide product 6 (231 mg, 525 mol, 37.4%) as an off white amorphous solid. LRMS: m / z calculated C22H18CIN3O5 [M+H]+440.1, found 440.0.Step 6Step 6

[0325] Lithium hydroxide hydrate (114 mg, 4 eq., 2.73 mmol) was added to a mixture of 6 (300 mg, 1 eq., 682 pmol) in THF (2.50 mL) and water (2.50 mL) at 70 °C under air. The mixture was stirred for 2 h after which LCMS confirmed the consumption of starting material. The reaction mixture was diluted with 3 M aq. HCI (12.0 mL), resulting in an off-white precipitate. The precipitate was filtered, washed with H2O (3 x 20.0 mL) and dried to provide product 7 (260 mg, 611 pmol, 89.5%) as a light orange solid. LRMS: m / z calculated C21H16CIN3O5 [M+H]+426.1, found 426.1.Step 7

[0326] HATU (245 mg, 1.1 eq., 644 pmol) was added to a mixture of 7 (249 mg, 1 eq., 585 mol) and DIPEA (510 pL, 5.00 eq., 2.93 mmol) in anhydrous DMF (10.0 mL) at RT under nitrogen. The mixture was stirred for 15 min and then tert-butyl (5r,7r)-2-aminoadamantane-2-carboxylate (162 mg, 1.10 eq., 644 pmol) was added. The mixture was stirred for 72 h at RT after which LCMS showed complete consumption of starting material. The reaction was diluted with brine (40.0 mL) resulting in the formation of a brown precipitate. The precipitate was filtered, washed with H2O (3 x 20.0 mL), dried, and purified by flash chromatography (Silica gel, 40 g cartridge) with hexanes and EtOAc (0-60%) to provide product 8 (250 mg, 379 pmol, 64.8%) as an off-white solid. LRMS: m / z calculated C36H39ClN4O6[M+H]+659.3, found 659.3.Step 8

[0327] DIAD (40% wt in toluene, 1.75 eq., 313 pmol) was added to a solution of A (81.6 mg, 1.75 eq., 313 pmol) and 8 (118 mg, 1 eq., 179 pmol) in THF (2.0 mL). The resulting mixture was stirred at RT for 16 h after which LCMS showed complete consumption of starting material. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (C18 Silica gel, 24 g cartridge) with H2O + 0.1% TFA and MeCN + 0.1% TFA (5-90%) to provide products 9 (36.6 mg, 40.6 pmol, 22.7%) and 10 (16.4 mg, 18.2 pmol, 10.2%) as colorless oils.Cpd 9: LRMS m / z calculated C49H65CIN6O8 [M+H]+901.5, found 901.5.Cpd 10: LRMS m / z calculated C49H65CIN6O8 [M+H]+901.5, found 901.5.Step 9A

[0328] TIS (62.4 pL, 7.5 eq., 304 pmol) and TFA (311 pL, 100 eq., 4.06 mmol) were added sequentially to a solution of 9 (36.6 mg, 1 eq., 40.6 pmol) in DCM (0.5 mL). The resulting mixture was stirred at RT for 4 h, after which the reaction was judged to be complete by LCMS. The reaction mixture was concentrated in vacuo. To the resulting crude residue was added a preactivated solution of Crown(tBu)3(40.2 mg, 1.5 eq., 60.9 pmol), HATU (20.1 mg, 1.3 eq., 52.8 pmol) and DIPEA (108 pL, 15 eq., 609 pmol) in DMF (1 mL). The resulting mixture was stirred at RT for 16 h, after which the crude LCMS showed complete consumption of the starting material. The mixture was concentrated in vacuo, and the resulting residue was redissolved in TFA (311 pL, 100 eq., 4.06 mmol) and TIS (62.4 pL, 7.5 eq., 304 pmol). Thereaction was stirred at RT for 4 h after which LCMS showed complete consumption of starting material. The mixture was concentrated in vacuo and purified by HPLC to give RD09-158 (40.5 mg, 22.6 pmol, 55.7%) as a colorless oil. LRMS: m / z calculated C65H93CIN10O15 [M+H]+1219.6, found 1219.6.Step 9BStep 9B

[0329] TFA (139 pL, 100 eq., 1.82 mmol) and TIS (28.0 pL, 7.5 eq., 136 pmol) were added to a solution of 10 (16.4 mg, 1 eq., 18.2 pmol) in DCM (0.5 ml_). The resulting mixture was stirred at RT for 4 h, after which the reaction was judged to be complete by LCMS. The reaction mixture was concentrated in vacuo and to the resulting crude residue was added a preactivated solution of Crown(tBu)3(18.0 mg, 1.5 eq., 27.3 pmol), HATU (8.99 mg, 1.3 eq., 23.6 pmol) and DIPEA (48.6 pL, 15 eq., 273 pmol) in DMF (2.5 mL). The resulting mixture was stirred at RT for 4 h, after which the crude LCMS showed complete consumption of the starting material. The reaction was concentrated in vacuo, and the resulting residue was redissolved in TFA (139 pL, 100 eq., 1.82 mmol) and TIS (28.0 pL, 7.5 eq., 136 pmol). The reaction was stirred at RT for 4 h after which LCMS showed complete consumption of starting material. The reaction was concentrated in vacuo and purified by HPLC to give RD09-159 (20 mg, 11 pmol, 61%) as a colorless oil. LRMS: m / z calculated C60H83ClN10O15[M+H]+1219.6, found 1219.6.Synthesis of RD09-137Step 1

[0330] TFA (0.5 mL, 7 mmol) and TIS (13.6 pL, 6 eq., 66.2 pmol) were added to a solution of 10 (11.2 mg, 1 eq., 11.0 pmol) in DCM (0.5 mL). The resulting mixture was stirred at RT for 2 h, after which the reaction was judged to be complete by LCMS. The reaction mixture was concentrated in vacuo. The resulting crude residue was dissolved in DMF (0.5 mL). DIPEA (29.5 pL, 15 eq., 165 pmol) and DOTA-OSu (14.7 mg, 1.75 eq., 19.3 pmol) were added sequentially to the reaction mixture. After stirring the reaction for 16 h complete consumption of starting material was observed by LCMS. The reaction mixture was concentrated in vacuo and purified by HPLC to give RD09-137 (13.3 mg, 7.82 pmol, 70.9%) as a colorless oil. LRMS: m / z calculated C56H75CIN10O13 [M+H]+1131.5, found 1131.3.Synthesis of RD09-148Step 1

[0331] TFA (0.5 mL, 7 mmol) and TIS (10 pL, 6 eq., 50 pmol) were added to a solution of 9 (8.5 mg, 1 eq., 8.4 pmol) in DCM (0.5 mL). The resulting mixture was stirred at RT for 2 h afterwhich the reaction was judged to be complete by LCMS. The reaction was concentrated in vacuo, and the resulting crude residue was dissolved in DMF (0.5 ml_). DIPEA (22 pL, 15 eq., 0.13 mmol) and DOTA-OSu (8.4 mg, 2 eq., 17 pmol) were added sequentially to the reaction mixture. After stirring for 16 h, complete consumption of starting material was observed by LCMS. The reaction was concentrated in vacuo and purified by HPLC to give RD09-148 (11.7 mg, 6.87 pmol, 82%) as a colorless oil. LRMS: m / z calculated C56H75ClN10O13[M+H]+1131.5, found 1131.2.Synthesis of the intermediate for compounds containing Butyl-based linkersStep 1

[0332] 4-bromobutan-1-ol (305 pL, 80% wt, 1.5 eq., 1.71 mmol) was added to a solution of 8 (750 mg, 1 eq., 1.14 mmol) and CS2CO3 (1.11 g, 3 eq., 3.41 mmol) in DMF (10 mL). The resulting mixture was stirred at RT for 16 h, after which LCMS showed complete consumption of the starting material. The mixture was concentrated and was purified by flash chromatography (Silica gel, 24 g cartridge) with Hexanes and EtOAc (20-100%) to provide products 18 (334 mg, 457 pmol, 40.1%) and 19 (138 mg, 189 pmol, 16.6%) as colorless oils Cpd 18: LRMS m / z calculated C40H47CIN4O7 [M+H]+731.3, found 731.8.Cpd 19: LRMS m / z calculated C40H47CIN4O7 [M+H]+731.3, found 731.8.Synthesis of RD09-115 and RD09-167

[0333] Dess-Martin periodinane (17.2 mg, 1.1 eq., 40.6 mol) was added to a solution of 18 (27.0 mg, 1 eq., 36.9 mol) in DCM (1.0 ml_). The resulting mixture was heated to RT for 4 h, after which complete consumption of starting material was observed by LCMS. To the reaction vessel was added tert-butyl methyl(3-(methylamino)propyl)carbamate (37.3 mg, 5 eq., 185 mol) and sodium triacetoxyborohydride (23.5 mg, 3 eq., 111 mol) sequentially. The resultingmixture was stirred at RT for 16 h, after which the crude LCMS showed complete consumption of the starting material. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 12 g cartridge) with DCM and MeOH (1-50%) to provide product 20 (10.5 mg, 11.5 mol, 31.1%) as a colorless oil. LRMS: m / z calculated C50H67ClN6O8[M+H]+915.5, found 915.9.Step 2A

[0334] TFA (0.5 ml_) was added to a solution of 20 (10.5 mg, 1 eq., 11.5 mol) in DCM (0.5 ml_). The resulting mixture was stirred at RT for 2 h after which the reaction was judged to be complete by LCMS. The reaction mixture was concentrated under reduced pressure. The resulting crude mixture was redissolved in DMF (0.5 mL). To the reaction mixture was added DIPEA (30.6 L, 15 eq., 172 mol) and DOTA-OSu (6.90 mg, 1.2 eq., 13.8 pmol). After stirring the reaction mixture at RT for 16 h, the contents were concentrated under reduced pressure and the resulting crude mixture was dissolved in 1:1 MeCN / H₂O + 0.1% formic acid and purified by HPLC to give product RD09-115 (10.5 mg, 6.12 mol, 53.4%) as a colorless oil. LRMS: m / z calculated C57H77ClN10O13[M+H]+1145.5, found 1145.7.Step 2B

[0335] TFA (0.5 ml_) was added to a solution of 20 (38.4 mg, 1 eq., 41.9 pmol) and TIS (64.4 pL, 7.5 eq., 315 pmol) in DCM (0.5 ml_). The resulting mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. To this mixture was added a solution of HATU (20.7 mg, 1.3 eq., 54.5 pmol), DIPEA (112 pL, 15 eq., 629 pmol), HOSu (14.5 mg, 3 eq., 126 pmol), and Crown(tBu)3 (41.6 mg, 1.5 eq., 62.9 pmol) in DMF (0.5 ml_) which had been preactivated for 5 min at RT. The resulting reaction mixture was stirred at RT for 16 h after which the reaction was judged to be complete by LCMS. The mixture was concentrated in vacuo and co-evaporated with heptanes. The resulting crude mixture was dissolved in TFA (1 ml_) and TIS (64.4 pL, 7.5 eq., 315 pmol) and stirred at RT for 16 h. The mixture was concentrated under reduced pressure, and the resulting crude residue was dissolved in 1:1 MeCN / H2O + 0.1% formic acid and purified by HPLC to give product RD09-167 (11.0 mg, 6.10 pmol, 14.5%) as a colorless oil. LRMS: m / z calculated C61H83ClN10O15[M+H]+1233.6, found 1233.5.Step 1

[0336] Cpd 19 (10.2 mg, 1 eq., 13.9 mol) and sodium triacetoxyborohydride (8.87 mg, 3 eq., 41.8 mol) were dissolved in DCM (0.5 ml_). The resulting mixture was stirred at RT for 2 h after which reaction completion was observed by LCMS. tert-butyl methyl(3-(methylamino)propyl)carbamate (14.1 mg, 5 eq., 69.7 mol) and sodium triacetoxyborohydride(8.87 mg, 3 eq., 41.8 pmol) were added to the reaction vessel. The resulting mixture was stirred at RT for 16 h after which the mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 12 g cartridge) with DCM and MeOH (1-50%) to provide product 21 (4.5 mg, 4.9 mol, 35%) as a colorless oil. LRMS: m / z calculated C50H67ClN6O8[M+H]+915.5, found 916.0.Step 2AHO

[0337] TFA (0.49 ml_, 100 eq., 6.4 mmol) was added to a solution of 21 (59 mg, 1 eq., 64 mol) in DCM (0.5 ml_). The resulting reaction mixture was stirred at RT for 2 h after which the reaction was judged to be complete by LCMS. The reaction mixture was concentrated under reduced pressure. The resulting crude mixture was redissolved in DMF (0.8 ml_). To this solution was added DIPEA (0.17 ml_, 15 eq., 0.97 mmol) and DOTA-OSu (39 mg, 1.2 eq., 77 pmol). After stirring the mixture at RT for 16 h, the reaction was judged to be complete by LCMS. The mixture was concentrated under reduced pressure, and the crude residue was dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to give product RD09-131 (23 mg, 13 mol, 21%) as a clear colorless oil. LRMS: m / z calculated C57H77ClN10O13[M+H]+1145.5, found 1145.7.Step 2B

[0338] TFA (0.5 ml_) was added to a solution of 21 (38.0 mg, 1 eq., 41.5 mol) and TIS (7.5 eq., 311 mol) in DCM (0.5 ml_). The resulting mixture was stirred at RT for 2 h after which the reaction was judged to be complete by LCMS. The reaction was concentrated in vacuo and to it was added a solution of HATU (20.5 mg, 1.3 eq., 54.0 pmol), HOSu (14.3 mg, 3 eq., 125 pmol), DIPEA (111 pL, 15 eq., 623 pmol), and Crown(tBu)3(41.1 mg, 1.5 eq., 62.3 pmol) in DMF (0.8 ml_) which had been preactivated for 5 min at RT. The resulting mixture was stirred at RT for 16 h after which the reaction was judged to be complete by LCMS. The reaction was concentrated in vacuo and co-evaporated with heptanes. The resulting crude residue was dissolved in TFA (1 mL) and TIS (7.5 eq., 311 pmol) and stirred at RT for 16 h. The mixture was concentrated under reduced pressure, and the crude product was dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to give RD09-168 (8.2 mg, 4.5 pmol, 11%) as a colorless oil. LRMS: m / z calculated C61H85ClN10O15[M+H]+1233.6, found 1233.6.Synthesis of RD09-107Boc 18 23Step 2RD09-107OHStep 1

[0339] Cpd 18 (136 mg, 1 eq., 186 pmol) and Dess-Martin periodinane (86.8 mg, 1.1 eq., 205 pmol) were dissolved in DCM (2 ml_). The resulting mixture was stirred at RT for 2 h. After reaction completion, as judged by LCMS, 22 (201 mg, 5 eq., 930 pmol) and sodium triacetoxyborohydride (118 mg, 3 eq., 558 pmol) were added to the reaction vessel. The resulting mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure, and the crude product was purified by flash chromatography (Silica gel, 12 g cartridge) with DCM and MeOH (1-50%) to provide 23 (73.8 mg, 79.4 pmol, 42.7%) as a colorless oil. LRMS: m / z calculated C50H67ClN6O8[M+H]+929.5, found 929.3.Step 2

[0340] TIS (22.1 pL, 7.5 eq., 108 pmol) and TFA (0.5 ml_) were added to a solution of 23 (13.4 mg, 1 eq., 14.4 pmol) in DCM (0.5 ml_). The resulting mixture was stirred at RT for 2 h, after which the reaction was judged to be complete by LCMS. The reaction was concentrated under reduced pressure, and the resulting residue was dissolved in DMF (0.8 mL). To the reaction mixture was added DIPEA (38.5 pL, 15 eq., 216 pmol) and DOTA-OSu (8.67 mg, 1.2 eq., 17.3 pmol). After stirring at RT for 16 h, the mixture was concentrated under reduced pressure, the resulting crude residue was dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to give RD09-107 (11.5 mg, 6.65 pmol, 46.1%) as a colorless oil. LRMS: m / z calculated C58H79ClN10O13[M+H]+1159.6, found 1159.4.Synthesis of RD09-123

[0341] Dess-Martin periodinane (59.6 mg, 1.1 eq., 140 mol) and 19 (93.4 mg, 1 eq., 128 mol) were dissolved in DCM (2 ml_). The resulting mixture was stirred at RT for 2 h. After reaction completion, as judged by LCMS, 22 (138 mg, 5 eq., 639 mol) and sodium triacetoxyborohydride (81.2 mg, 3 eq., 383 mol) were added to the reaction vessel. The resulting mixture was stirred at RT for 16 h. The reaction was concentrated under reduced pressure and purified by flash chromatography (Silica gel, 12 g cartridge) with DCM and MeOH (1-50%) to provide product 24 (73.8 mg, 79.4 mol, 62.2%) as a colorless oil. LRMS: m / z calculated C51H69ClN6O8[M+H]+929.5, found 929.3.Step 2

[0342] TIS (54.0 pL, 7.5 eq., 264 pmol) and TFA (0.5 ml_) were added to a solution of 24 (32.7 mg, 1 eq., 35.2 pmol) in DCM (0.5 ml_). The resulting mixture was stirred at RT for 2. The reaction was concentrated under reduced pressure, and the resulting crude residue was dissolved in DMF (0.8 ml_). To the reaction mixture was added DIPEA (93.9 pL, 15 eq., 528 pmol) and DOTA-OSu (21.2 mg, 1.2 eq., 42.2 pmol). After stirring at RT for 16 h, the reaction was judged to be complete by LCMS. The mixture was concentrated under reduced pressure, and the resulting crude residue was dissolved in 1:1 MeCN / FhO + 0.1% TFA and purified by HPLC to give RD09-123 (50.4 mg, 29.1 pmol, 82.8%) as a colorless oil. LRMS: m / z calculated C58H79ClN10O13[M+H]+1159.6, found 1159.4.Synthesis of RD09-113 and RD09-129Step 126

[0343] A mixture of 25 (1.00 g, 1 eq., 4.38 mmol), 4-bromobutan-1-ol (939 L, 80% wt, 1.2 eq., 5.26 mmol), and potassium carbonate (1.51 g, 2.5 eq., 10.9 mmol) in anhydrous MeCN (10.0 ml_) was heated to 85 °C and stirred for 16 h under nitrogen. The mixture was cooled to RT and diluted with 2.5 M aq. NaOH (20.0 ml_). The aqueous layer was extracted with EtOAc (3 x 20.0 ml_), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel,12 g cartridge) with DCM and MeOH (0-30%) to provide the linker product 26 (312 mg, 1.04 mmol, 23.7%) as a colorless oil. LRMS: m / z calculated C16H32N2O3[M+H]+301.2, found 301.3.Step 2

[0344] (Tributylphosphoranylidene)acetonitrile (104 L, 1.75 eq., 398 mol) was added to a solution of 26 (120 mg, 1.75 eq., 398 mol) in toluene (2 ml_). The resulting mixture was heated to 70 °C for 5 minutes. The reaction was added to a vial containing 8 (150 mg, 1 eq., 228 pmol). The resulting mixture was stirred at 95 °C for 12 h, after which LCMS showed complete consumption of the starting material. The mixture was cooled to RT and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 24 g cartridge) with DCM and MeOH (1-50%) to provide a 1:4 mixture of products 27 and 28 (194 mg, 206 mol, 90.5%) as a colorless oilCpd 27: LRMS m / z calculated C52H69ClN6O8[M+H]+941.5, found 941.9.Cpd 28: LRMS m / z calculated C52H69ClN6O8[M+H]+941.5, found 941.9.

[0345] TFA (2 ml_) and TIS (139 L, 3.3 eq., 680 pmol) were added to a solution of a mixture of 27 and 28 (194 mg, 1 eq., 206 pmol) in DCM (2 ml_). The resulting mixture was stirred at RT for 2 h after which the reaction was judged to be complete by LCMS. The reaction was concentrated under reduced pressure. The crude residue was dissolved in DMF (2.5 ml_). To the reaction mixture was added DIPEA (15 eq.) and DOTA-OSu (1.0 eq.). After stirring at RT for 16 h, the reaction was concentrated under reduced pressure. The crude residue was dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to give the products RD09-113 (117 mg, 67.2 pmol, 32.6%) and RD09-129 (23.1 mg, 13.3 pmol, 6.44%) as clear colorless oils.RD09-113: LRMS m / z calculated C59H79ClN10O13[M+H]+1171.6, found 1172.0.RD09-129: LRMS: m / z calculated C59H79ClN10O13[M+H]+1171.6, found 1171.6.Synthesis of RD09-162EtOStep 1Step 1

[0346] To a stirred solution of 1 (550 mg, 0.944 mmol) in DCM (10 ml_) was added TFA (0.36 ml_) at 0°C. Then the reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and co-distilled with DCM (2 x 5 ml_) to afford product 2 (563 mg) as a brown oil which was used in the next step without further purification. LRMS m / z calculated C26H35N4O5 [M+H]+483.3, found 483.2.Step 2

[0347] To a stirred solution of 2 (535 mg, 0.897 mmol) in acetonitrile (10 ml_) was added potassium carbonate (620 mg, 4.484 mmol) and linker 3 (319 mg, 1.076 mmol) at O°C. The reaction mixture was heated to 80°C and stirred overnight. The reaction was diluted with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica gel, 4% MeOH in DCM) to afford product 4 (234 mg, 37.4%) as a colorless oil.1H-NMR (400 MHz, DMSO-de): 8.18 (s, 1H), 7.33 (t, J = 8.8 Hz, 1H), 6.83 (s, 1H), 6.64 (d, J = 8.4 Hz, 2H), 6.49 (s, 1H), 5.75 (s, 1H), 4.34-4.27 (m, 2H), 4.23-4.20 (m, 2H), 4.07-4.03 (m, 2H), 3.61-3.59 (m, 4H), 3.18-3.14 (m, 2H), 2.77-2.75 (m, 2H), 2.33-2.31 (m, 2H), 2.24-2.22 (m, 2H), 2.11-2.09 (m, 3H), 1.78-1.76 (m, 2H), 1.57-1.55 (m, 2H), 1.32-1.29 (m, 3H),1.00-0.99 (m, 4H), 0.93-0.89 (m, 2H), 0.02 (s, 9H). LRMS m / z calculated C36H56N5O7Si [M+H]+698.4, found 698.3.Step 3

[0348] To a stirred solution of 4 (230 mg, 0.329 mmol) in 1,4-dioxane (2 ml_) was added 2 N aq. NaOH (1.2 eq., 0.40 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was concentrated under reduced pressure and co-distilled with 1,4-dioxane (2 x 5 ml_) to afford product 5 (228 mg) as an off-white solid. The crude material was used in the next step without further purification. LRMS m / z calculated C34H52N5O7Si [M+H]+670.4, found 670.3.Step 4

[0349] To a stirred solution of 5 (140 mg, 0.209 mmol) in DMF (1 ml_) were added 6 (63 mg, 0.251 mmol), EDCI. HCI (82 mg, 0.418 mmol), HOBt (58 mg, 0.418 mmol) and DIPEA (5.0 eq., 1.045 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was diluted with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material (combined with a different batch of crude product) was purified by columnchromatography (Silica gel, 8% MeOH in DCM) to afford product 7 (97 mg, 53.1%) as an off-white solid. LRMS m / z calculated C49H75N6O8Si [M+H]+903.5, found 903.5.Step 5

[0350] To a stirred solution of 7 (90 mg, 0.099 mmol) in THF (2 ml_) were added TBAF (1.0 M in THF, 0.199 ml_, 0.199 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was quenched with saturated aq. NH4CI (30 ml_) and extracted with EtOAc (2 x 30 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product 8 (75 mg) as a brown oil. The crude material was used in the next step without further purification. LRMS m / z calculated C43H63N6O6 [M+H]+759.5, found 759.3.Step 6

[0351] To a stirred solution of 8 (65 mg, 0.0857 mmol) in DMF (2 ml_) were added Crown(tBu)3(9) (64 mg, 0.103 mmol), EDCI. HCI (34 mg, 0.172 mmol), HOBt (24 mg, 0.172 mmol) and DIPEA (0.074 ml_, 0.429 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was diluted with ice water (30 ml_) and extracted with EtOAc (2 x 30 ml_). Combined organic layers were dried over Na2SO4M, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford product 10 (23 mg, 19.2%) as a colorless oil.1H-NMR (400 MHz, DMSO-de) 5 = 8.46 (s, 1 H), 8.20 (s, 1 H), 7.37 - 7.29 (m, 2 H), 6.67 (s, 1 H), 6.66 (d, 2 H), 6.41 (s, 1 H), 4.14 -4.23 (m, 2 H), 3.63 (s, 6 H), 3.44 - 3.38 (m, 8 H), 3.32 - 3.29 (m, 16 H), 2.32 (m, 2 H), 2.23 (br s, 2 H), 2.11-1.93 (m, 8 H), 1.82 - 1.61 (m, 12 H), 1.39 (s, 38 H), 1.10 (d, 3H). LRMS m / z calculated C75H121 N10O15 [M+H]+1401.9, found 1401.7.Step 7

[0352] To a stirred solution of 10 (18 mg, 0.0129 mmol) in DCM (2 ml_) was added HCI (4 M in 1,4-dioxane, 0.064 ml_, 0.257 mmol) dropwise at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The mixture was concentrated under reduced pressure and co-distilled with DCM (2 x 5 ml_), and the resulting crude material was purified by preparative HPLC to afford product RD09-162 (5.01 mg, 31.9%) as a white solid.1H-NMR (400 MHz, DMSO-de) 5 = 8.21-8.27 (m, 1H), 7.37 - 7.28 (m, 2H), 6.74 - 6.71 (m, 1H), 6.66 (d, 3H), 6.58 (br s, 2H), 6.44 (s, 1H), 4.22 (br s, 2H), 3.63 (s, 8H), 3.06 (m, 8 H), 2.86 (brd, 6 H), 2.76 (s, 6 H), 2.71 - 2.57 (m, 6 H), 2.57 - 2.52 (m, 6H), 2.41 - 2.23 (m, 6 H), 2.20 - 2.04 (m, 6 H), 1.97 (br d, 4H), 1.90 (s, 1H), 1.78 (m, 4 H), 1.72 - 1.59 (m, 8H), 1.48 -1.55 (br s, 2 H), 1.23 (d, 5 H), 1.19 - 1.01 (m, 6 H), 0.91 - 0.79 (m, 1H). LRMS m / z calculated C59H89N10O15 [M+H]+1177.7, found 1177.9.Synthesis of RD09-171 and RD09-172Step 127 28RD09-171 RD09-172Step 1

[0353] TIS (133 pL, 6 eq., 652 pmol) and TFA (1 ml_) were added to a solution of a mixture of 27 and 28 (51.3 mg, 1 eq., 54.5 pmol) in DCM (1 ml_). The resulting mixture was stirred at RT for 1 h, after which the reaction was concentrated in vacuo. To the resulting residue was added a preactivated solution of Crown(tBu)3 (108 mg, 1.5 eq., 163 pmol), HATU (53.7 mg, 1.3 eq., 141 pmol) and DIPEA (290 pL, 15 eq., 1.63 mmol) in DMF (2 ml_). The resulting mixture was stirred at RT for 16 h and concentrated in vacuo. The crude residue was redissolved in TIS (133 pL, 6 eq., 652 pmol) and TFA (1 ml_). The reaction mixture was stirred at RT for 2 h and concentrated in vacuo. The crude residue was dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to yield the products RD09-171 (31.4 mg, 17.2 pmol, 31.5%) and RD09-172 (20.7 mg, 11.3 pmol, 20.8%) as clear colorless oils.RD09-171: LRMS m / z calculated C63H87ClN10O15[M+H]+1259.6, found 1259.6.RD09-172: LRMS m / z calculated C63H87ClN10O15[M+H]+1259.6, found 1259.6.Synthesis of RD09-105 and RD09-121Step 1

[0354] (Tributylphosphoranylidene)acetonitrile (139 L, 1.75 eq., 531 pmol) was added to a solution of 29 (179 mg, 1.75 eq., 531 pmol) in toluene (2.5 ml_). The resulting mixture was heated to 70 °C for 5 min. The reaction was added to a vial containing 8 (200 mg, 1 eq., 303 pmol). The resulting mixture was stirred at 70 °C for 5 h, cooled down to RT and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, 24 g cartridge) with DCM and MeOH (1-50%) to provide a mixture of products 30 and 31 with tributylphosphine oxide as impurity (419 mg, 428 pmol) as a colorless oil.Cpd 30: LRMS m / z calculated C51H68CIN5O12 [M+H]+978.5, found 978.4.Cpd 31: LRMS m / z calculated C51H68CIN5O12 [M+H]+978.5, found 978.4.Step 2

[0355] TFA (2 ml_) and TIS (205 pL, 3.3 eq., 1.00 mmol) were added to a solution of a mixture of 30 and 31 (297 mg, 1 eq., 303 pmol) in DCM (2 ml_). The resulting mixture was stirred at RT for 2 h after which the reaction was judged to be complete by LCMS. The reaction was concentrated under reduced pressure, and the crude residue was dissolved in DMF (5 ml_). To this solution was added DIPEA (809 pL, 15 eq., 4.55 mmol) and DOTA-OSu (205 mg, 1.1 eq., 333 pmol). After stirring at RT for 16 h, the mixture was concentrated under reduced pressure, the resulting crude residue was dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to give the products RD09-105 (149.1 mg, 83.82 pmol, 27.7%) and RD09-121 (47.3 mg, 26.6 pmol, 8.78%) as colorless oils.RD09-105: LRMS m / z calculated C58H78ClN9O17[M+H]+1208.5, found 1208.6.RD09-121: LRMS m / z calculated C58H78ClN9O17[M+H]+1208.5, found 1208.6.Synthesis of RD09-177RD09-177

[0356] 2-Chlorotrityl chloride (CTC) resin was loaded using Fmoc-Aad(tBu)-OH (132 mg, 1.5 eq., 300 pmol) and DIPEA (139 pL, 4 eq., 800 pmol) in anhydrous DCM (10 ml_ per gram of resin). The resin was shaken vigorously at RT for 1 h and then capped with the addition of methanol (0.8 mL / gram of resin). Shaking was continued for another 15 minutes. The resin was washed (DCM x 3, DMF x 3, DCM x 3) and deprotected with 20% piperidine in DMF (2 ml_ x 2) for 5 minutes each time. Then, the resin was washed with DMF (x 5) for 1 minute each time. DOTA(tBu)s (458 mg, 4 eq., 800 pmol) was added to a solution of DIPEA (139 pL, 4 eq., 800 pmol) and HATU (304 mg, 4 eq., 800 pmol) in DMF (3 ml_). After stirring for 5 minutes, this solution was added to the resin. After shaking the resin for 4 h, the resin was suspended inHFIP / DCM (20%, 8 ml_) for 1 h and the crude material was collected and concentrated under reduced pressure. The crude residue was purified by flash chromatography (Silica gel, 24 g cartridge) with DCM and MeOH (1-50%) to provide 32 (102.3 mg, 132.5 mol, 66.3%). LRMS: m / z calculated C38H69N5O11[M+H]+772.5, found 772.7.Step 2

[0357] TFA (0.5 ml_) and TIS (7.5 eq., 283 mol) were added to a solution of 20 (34.5 mg, 1 eq., 37.7 mol) in DCM (0.5 ml_). The resulting mixture was stirred at RT for 2 h and concentrated under reduced pressure. The crude residue was redissolved in DMF (0.8 ml_). To the reaction mixture was added a solution of 32 (34.9 mg, 1.2 eq., 45.2 pmol), DIPEA (67.1 L, 10 eq., 377 mol) and HATU (17.2 mg, 1.2 eq., 45.2 mol) in DMF (0.8 ml_) which had been preactivated for 5 minutes. After stirring at RT for 16 h, the mixture was concentrated and coevaporated with heptanes under reduced pressure. The crude residue was redissolved in DCM (0.5 ml_). TIS (7.5 eq., 283 mol) and TFA (0.5 ml_) were added sequentially to the reaction mixture. After stirring at RT for 8 h, the reaction was concentrated under reduced pressure, the crude residue was dissolved in 1:1 MeCN / H2O + 0.1% TFA and purified by HPLC to give RD09-177 (25.8 mg, 14.5 mol, 38.5%) as a colorless oil. LRMS: m / z calculated C63H86ClN11O16[M+H]+1288.6, found 1288.4.Synthesis of RD09-102 and RD09-150Step 1A►CbZ'N-^^OH2A Step 1 A I2B

[0358] To a stirred solution of 2A (20 g, 224.4 mmol) in 1,4-dioxane (250 ml_) and H2O (250 ml_) were added benzyl chloroformate (42.93 ml_, 291.7 mmol) and 3.5 M aq. KOH (64.10 ml_) (pH 10) at 0°C. The reaction mixture was allowed to warm upto RT and stirred for 3 h. The reaction mixture was quenched with saturated aq. NaHCOs (500 ml_) and extracted with diethyl ether (2 x 500 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica gel, 25% EtOAc in heptane) to afford product 2B (29.4 g, 58.7%) as a colorless oil.1H-NMR (400 MHz, DMSO-de) 5: 7.53 - 7.21 (m, 5H), 5.06 (s, 2H), 4.46 (br s, 1 H), 3.45 - 3.36 (m, 2H), 2.85 (br d, J = 10.0 Hz, 3H), 2.50 (br s, 2H), 1.73 - 1.52 (m, 2H). LRMS: m / z calculated C12H18NO3 [M+H]+224.1, found 224.0.Step 1 B2BStep lB2

[0359] To a stirred solution of 2B (2.0 g, 9.0 mmol) in DCM (20 ml_) was added Dess-Martin periodinane (7.7 g, 18 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction mixture was quenched with saturated aq. NaHCOs (100 ml_) and extracted with DCM (2 x 100 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica gel, 30% EtOAc in heptane) to afford 2 (1.31 g, 66%) as a colorless oil.1H-NMR (400 MHz, DMSO-de) 5: 9.64 (br s, 1H), 7.45 - 7.22 (m, 5H), 5.03 (s, 2H), 3.50 (br s, 2H), 2.83 (br d, J = 12.2 Hz, 3H), 2.65 (br s, 2H).Step 3AStep 3A

[0360] To a stirred solution of 6A (2.0 g, 9.6 mmol) in THF (20 ml_) were added 3,4-dihydropyran (1.2 g, 14 mmol) and TFA (0.07 ml_, 0.96 mmol) at 0°C. The reaction mixture was heated to 80°C and stirred overnight. The reaction mixture was concentrated under reduced pressure and co-distilled with DCM (2 x 25 ml_). The crude material was purified by columnchromatography (Silica gel, 20% EtOAc in petroleum ether) to afford product 6 (2.01 g, 72%) as a colorless oil.1H-NMR (400 MHz, DMSO-de) 5: 8.11 - 7.32 (m, 1H), 5.49 - 5.20 (m, 1H), 3.89 (br d, J = 11.0 Hz, 1H), 3.70 - 3.46 (m, 1H), 2.41 (s, 1H), 2.23 (s, 2H), 2.14 - 1.74 (m, 3H), 1.70 - 1.42 (m, 3H), 1.24 (s, 12H). LRMS: m / z calculated C15H26BN2O3 [M+H]+293.2, found 293.0.Step 1

[0361] To a stirred solution of 1 (890 mg, 1.646 mmol) in MeOH (10 ml_) were added 2 (728 mg, 3.291 mmol), triethylamine (1.38 ml_, 9.874 mmol) and NaOAc (818 mg, 9.874 mmol) at 0°C. The reaction mixture was stirred for 20 mins at 0°C, followed by addition of NaCNBH4 (218 mg, 3.291 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3 (1.51 g) as a brown solid which was used in the next step without further purification. LRMS: m / z calculated C35H42BrN4O7 [M+H]+709.2, found 711.1.Step 2

[0362] To a stirred solution of 3 (1.0 g, 1.4 mmol) in DMF (10 ml_) were added 4 (430 mg, 1.7 mmol), DIPEA (1.2 ml_, 7.0 mmol) and HATU (1.1 g, 2.8 mmol) at 0°C. The reaction mixturewas allowed to warm up to RT and stirred overnight. The reaction mixture was quenched with water (100 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica gel, 10% MeOH in DCM) to afford product 5 (275 mg, 21%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.43 - 7.23 (m, 6H), 7.17 (br d, J = 6.7 Hz, 1H), 7.12 - 7.05 (m, 1H), 6.90 (br d, J = 3.0 Hz, 1H), 6.70 (s, 1H), 6.60 (br d, J = 8.0 Hz, 2H), 5.49 (br s, 1H), 5.05 (br s, 2H), 4.15 - 3.98 (m, 2H), 3.88 - 3.76 (m, 2H), 3.61 (br s, 4H), 3.48 - 3.37 (m, 2H), 3.27 - 3.18 (m, 2H), 3.05 - 2.97 (m, 1H), 2.96 - 2.72 (m, 5H), 2.39 (br d, J = 3.1 Hz, 3H), 2.27 (br s, 3H), 2.03 (br s, 5H), 1.99 - 1.88 (m, 3H), 1.85 - 1.65 (m, 6H), 1.61 (br d, J = 12.3 Hz, 2H), 1.39 (s, 9H). LRMS: m / z calculated C50H65BrN5O8 [M+H]+942.4, found 944.2.Step 3

[0363] To a stirred solution of 5 (150 mg, 0.159 mmol) in 1,4-dioxane (4 ml_) and H2O (1 ml_) were added K3PO4 (103 mg, 0.477 mmol) and 6 (233 mg, 0.795 mmol) at RT. Then the reaction mixture was degassed with argon for 10 mins, followed by addition of Pd(PPh3)4 (38 mg, 0.032 mmol) at RT. The reaction mixture was heated to 100°C and stirred overnight. The reaction mixture was quenched with water (30 ml_) and extracted with EtOAc (2 x 30 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column purification (Silica gel, 8% MeOH in DCM) to afford product 7 (118 mg, 72.1%) as an off-white solid. LRMS: m / z calculated C59H78N7O9 [M+H]+1028.6, found 1028.5.Step 4

[0364] To a stirred solution of 7 (110 mg, 0.107 mmol) in ethyl acetate (1 ml_) and methanol (1 ml_) was added 10% Palladium on carbon (0.057 g, 0.054 mmol) at RT. Then the reaction mixture was stirred for 2 h at RT under H2 atmosphere (balloon). The reaction mixture was filtered through a celite pad and further washed with 20% MeOH in DCM (50 ml_). The filtrate was concentrated under reduced pressure to afford product 8 (95 mg, 99.3%) as an off-white solid, which was used in the next step without further purification. LRMS: m / z calculated C51H72N7O7 [M+H]+894.5, found 894.5.Step 5

[0365] To a stirred solution of 8 (95 mg, 0.106 mmol) in acetonitrile (2 ml_) were added DIPEA (0.93 ml_, 0.531 mmol) and DOTA(tBu)3-OSu (9) (0.085 g 0.128 mmol) at 0°C. Then the reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction mixture was quenched with water (30 ml_) and extracted with EtOAc (2 x 30 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford product 10(128 mg, 83.1%) as an off-white solid, which was used in the next step without further purification. LRMS: m / z calculated C79H122N11O14 [M+H]+1448.9, found 1448.8.Step 6

[0366] To a stirred solution of 10 (125 mg, 0.086 mmol) in DCM (2 ml_) was added HCI (4 M in 1,4-dioxane, 2 ml_) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and co-distilled with DCM (2 x 20 ml_). The crude material was purified by preparative HPLC using 0.1% TFA in FW / acetonitrile as the eluent to afford RD09-102 (32 mg, 29.6%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 6: 12.39 (bs, 1H), 7.36 (m, 2H), 7.30 (t, J = 8.40 Hz, 1H), 7.05 (d, J = 8.40 Hz, 1H), 6.83 (s, 1H), 6.70 (s, 1H), 6.61 (d, J = 8.40 Hz, 2H), 3.94-3.90 (m, 3H), 3.67 (m, 4H), 3.61 (s, 6H), 3.32 (m, 4H), 3.17 (m, 18H), 2.94 (m, 7H), 2.91 (m, 1H), 2.68-2.66 (m, 1H), 2.63 (m, 2H), 2.56-2.54 (m, 2H), 2.11-2.08 (m, 2H), 1.99-1.96 (m, 4H), 1.93 (m, 2H), 1.87 (m, 2H), 1.81-1.78 (m, 5H), 1.73 (m, 3H), 1.63-1.60 (m, 2H). LRMS: m / z calculated C58H82N11O13 [M+H]+1140.6, found 1140.8.Step 7

[0367] To a stirred solution of 3 (870 mg, 0.923 mmol) in 1,4-dioxane (16 ml_) and H2O (4 ml_) were added K3PO4 (593 mg, 2.768 mmol) and 11 (406 mg, 1.845 mmol) at RT. The reaction mixture was degassed with argon for 10 mins, followed by addition of Pd(PPh3)4 (220 mg, 0.185 mmol) at RT. The reaction mixture was heated to 100°C and stirred overnight. The reaction mixture was quenched with water (50 ml_) and acidified with 2 N aq. HCI (30 ml_), then extracted with EtOAc (2 x 30 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica gel, 8% MeOH in DCM) to afford product 12 (485 mg, 55.0%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 9.46 (br s, 1H), 7.43 - 7.24 (m, 6H), 7.18 (br d, J = 4.8 Hz, 1H), 6.97 (br d, J = 9.2 Hz, 2H), 6.87 - 6.78 (m, 1H), 6.74 (br d, J = 5.9 Hz, 1H), 6.68 (s, 2H), 6.63 (br d, J = 8.1 Hz, 1H), 6.49 (br s, 1H), 5.07 (br s, 2H), 3.89 (br s, 2H), 3.61 (br s, 6H), 3.27 (br d, J = 11.7 Hz, 2H), 2.86 (br s, 6H), 2.57 - 2.53 (m, 4H), 2.21 - 2.10 (m, 1H), 2.03 (br d, J = 12.8 Hz, 4H), 1.99 - 1.92 (m, 2H), 1.81 (br s, 2H), 1.78 - 1.65 (m, 9H), 1.61 (br d, J = 12.1 Hz, 3H), 1.38 (s, 9H). LRMS: m / z calculated C56H70N5O8 [M+H]+956.5, found 956.5.Step 8

[0368] To a stirred solution of 12 (380 mg, 0.397 mmol) in ethyl acetate (4 ml_) and methanol (4 ml_) was added 10% Palladium on carbon (211 mg, 0.199 mmol) at RT. The reaction mixture was stirred for 2 h at RT under H2 (balloon). The reaction mixture was filtered through a celite pad and further washed with 50% MeOH in DCM (30 ml_). The filtrate was concentrated under reduced pressure to afford product 13 (326, 99.8%) as an off-white solid, which was used in the next step without further purification.1H-NMR (400 MHz, DMSO-de) 5: 9.52 - 9.15 (m, 1H), 7.38 - 7.25 (m, 2H), 7.20 (brt, J = 7.9 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.80 (br d, J = 8.7 Hz, 1H), 6.73 (br d, J = 7.5 Hz, 1H), 6.67 (s, 1H), 6.64 (br d, J = 8.3 Hz, 2H), 6.47 (br s, 2H), 3.86 (brt, J = 5.4 Hz, 2H), 3.61 (br s, 5H), 2.81 (br t, J = 7.3 Hz, 2H), 2.55 (br s, 2H), 2.47 (s, 2H), 2.39 (br s, 2H), 2.27 (br s, 2H), 2.23 - 2.10 (m, 2H), 2.04 (br s, 6H), 2.00 - 1.91 (m, 2H), 1.79 (br d, J =16.6 Hz, 2H), 1.74 - 1.55 (m, 14H), 1.38 (s, 9H). LRMS: m / z calculated C48H64N5O7 [M+H]+822.5, found 822.4.Step 9

[0369] To a stirred solution of 13 (325 mg, 0.396 mmol) in acetonitrile (5 ml_) were added DIPEA (0.345 ml_, 1.98 mmol) and DOTA(tBu)3-OSu (9) (238 mg, 0.396 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction mixture was quenched with water (50 ml_) and extracted with DCM (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product 14 (487 mg, 89.46g) as an off-white solid, which was used in the next step without further purification. LRMS: m / z calculated C76H114N9O14 [M+H]+1376.8, found 1376.7.Step 10

[0370] To a stirred solution of 14 (150 mg, 0.109 mmol) in DCM (4 ml_) was added HCI (4 M in 1,4-dioxane, 0.544 ml_, 2.179 mmol) dropwise at 0°C. The reaction mixture was allowed towarm up to RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and co-distilled with DCM (2 x 20 ml_). The crude material was purified by preparative HPLC using 0.1% TFA in FW / acetonitrile as the eluent to afford RD09-150 (55 mg, 40%) as a white solid.1H-NMR (400 MHz, DMSO-de) 5: 12.45 (bs, 1H), 9.73 (bs, 1 H), 7.36-7.30 (m, 2H), 7.22 (t, J = 7.60 Hz, 1H), 7.01 (d, J = 8.80 Hz, 1H), 6.86-6.82 (m, 1H), 6.76 (d, J = 7.60 Hz, 1H), 6.69 (s, 1H), 6.64 (d, J = 8.40 Hz, 2H), 3.96-3.92 (m, 4H), 3.62 (m, 11 H), 3.30-3.17 (m, 15H), 2.89 (m, 6H), 2.59-2.57 (m, 8H), 2.11-2.07 (m, 4H), 1.99-1.96 (m, 4H), 1.89-1.88 (m, 4H), 1.81 (s, 3H), 1.78-1.72 (m, 1H), 1.69 (m, 3H), 1.63-1.60 (m, 2H). LRMS: m / z calculated C60H82N9O14 [M+H]+1152.6, found 1152.8.Synthesis of RD09-183Step 1Step 1

[0371] A mixture of 1 (1.00 g, 1.00 eq., 3.76 mmol) and 2 (1.05 g, 1.20 eq., 4.51 mmol) in TFA (10.0 ml_) was heated to 70°C and stirred for 18 h under nitrogen. The mixture was cooled to RT and diluted with H2O (40.0 ml_), which formed a brown precipitate. The precipitate was filtered, washed with H2O (3 x 10.0 ml_), triturated with MeOH (3 x 5.00 ml_), and dried to provide product 3 (1.44 g, 3.12 mmol, 82.9%) as a brown solid. LRMS: m / zcalculated Ci9Hi6BrN3O6[M+H]+462.0, found 462.1.Step 2

[0372] A mixture of Fe (455 mg, 4.00 eq., 8.15 mmol), NH4CI (436 mg, 4.00 eq., 8.15 mmol), and 3 (942 mg, 1.00 eq., 2.04 mmol) in EtOH (12.0 ml_) and H2O (4.00 ml_) was heated to 90°C and stirred for 2 h under air. The mixture was cooled to RT and filtered through a pad of celite. The celite pad was washed with EtOH (3 x 20.0 ml_) and DCM (3 x 20.0 ml_) and the combined organic filtrates were evaporated under reduced pressure. The aqueous filtrate was diluted with H2O (30.0 ml_) and extracted with 3:1 DCM / MeOH (3 x 30.0 ml_). The combined organic phases were washed with brine (50.0 ml_), dried (Na2SO4), filtered, and concentrated under reduced pressure. To the residue, was added K2CO3 (704 mg, 2.50 eq., 5.09 mmol), DMSO (6.00 ml_), and iodomethane (723 mg, 319 pL, 2.50 eq., 5.09 mmol). The mixture was heated to 100°C and stirred for 24 h. The mixture was cooled down to RT and iodomethane (723 mg, 319 pL, 2.50 eq., 5.09 mmol) was added to the mixture. The mixture was heated to 100°C and further stirred for 24 h. The reaction was cooled to RT and diluted with H2O (30.0 ml_). The aqueous layer was extracted with EtOAc (3 x 25.0 ml_) and the combined organic phases were washed with brine (3 x 50.0 ml_), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, hexanes and EtOAc, 0-100%, followed by DCM and MeOH, 0-50%) to provide an inseparable mixture of 4a and 4 (237 mg, 515 pmol, 25.3%) as a yellow oil.Cpd 4a. LRMS: m / z calculated C20H20BrN3O4[M+H]+446.1, found 446.1.Cpd 4. LRMS: m / z calculated C21H22BrN3O4[M+H]+460.1, found 460.1.

[0373] Lithium hydroxide hydrate (223 mg, 10.0 eq., 5.31 mmol) was added to a mixture of 4a and 4 (244 mg, 1.00 eq, 531 mol) in THF (3.00 mL) and H2O (3.00 mL) at RT under air. The mixture was stirred for 17 h and then the THF was evaporated under reduced pressure. The aqueous layer was acidified with TFA (pH 1) and extracted with EtOAc (2 x 10.0 mL) and 2-Me-THF (10.0 mL). The combined organic layers were washed with brine (30.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to provide an inseparable mixture of 5a and 5 (244 mg) as a yellow oil.5a. LRMS: m / z calculated C20H20BrN3O4[M+H]+432.1, found 432.0.5. LRMS: m / z calculated C21H22BrN3O4[M+H]+446.1, found 446.0.Step 4

[0374] HATU (633 mg, 3.13 eq., 1.66 mmol) was added to a mixture of 5a and 5 (237 mg, 1.00 eq., 532 pmol), and DIPEA (1.00 mL, 10.8 eq., 5.74 mmol) in anhydrous DMF (7.00 mL) at RT under nitrogen. The mixture was stirred for 5 min and then 6 (308 mg, 2.30 eq., 1.23 mmol) was added. The mixture was stirred for 1 h and diluted with H2O (40.0 mL). The aqueous layer was extracted with EtOAc (3 x 25.0 mL), and the combined organic phases were washed with brine (75.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, hexanes and EtOAc, 0-100%) to provide an inseparable mixture of 7a and 7 (273 mg, 402 mol, 75.5%) as a colorless oil.Cpd 7a. LRMS: m / z calculated C20H20BrN3O4[M+H]+665.2, found 665.1.Cpd 7. LRMS: m / z calculated C21H22BrN3O4[M+H]+679.2, found 679.1.

[0375] KOH (92.1 mg, 4.00 eq., 1.64 mmol) in H2O (222 µL, 30.0 eq., 12.3 mmol) was added to a mixture of 7a and 7 (279 mg, 1.00 eq., 410 pmol), t-BuBrettPhos (118 mg, 0.594 eq., 243 pmol), and Pd2(dba)3. CHCl3 (168 mg, 0.396 eq., 162 mol) in anhydrous 1,4-dioxane (8.50 mL) at RT under nitrogen. The mixture was stirred for 1 min, heated to 90°C, and further stirred for 1 h. The mixture was cooled to RT and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, hexanes and EtOAc, 0-75%) to provide an inseparable mixture of products 8a and 8 (175 mg, 284 mol, 69.2%) as a colorless oil.Cpd 8a. LRMS: m / z calculated C34H42N4O6 [M+H]+ 603.3, found 603.3.Cpd 8. LRMS: m / z calculated C35H44N4O6 [M+H]+ 617.3, found 617.3.Step 6

[0376] DBAD (140 mg, 2.93 eq., 608 mol) was added to a mixture of 8a and 8 (128 mg, 1.00 eq., 207 mol) in anhydrous THF (2.00 mL) at RT under nitrogen. The mixture was stirred for 1 h and then 9 (159 mg, 2.94 eq., 611 mol) in anhydrous THF (2.00 mL) was added. The mixture was further stirred for 18 h and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel, DCM / MeOH, 0-10%, 3% aq. NH4OH) to provide an inseparable mixture of 10a and 10 (112 mg, 130 mol, 62.9%) as a colorless oil.Cpd 10a. LRMS: m / z calculated C47H68N6O8 [M+H]+845.5, found 845.2.Cpd 10. LRMS: m / z calculated C48H70N6O8 [M+H]+859.5, found 859.3.Step 7

[0377] TFA (900 pL) was added to a mixture of 10a and 10 (56.9 mg, 1.00 eq., 66.3 pmol) and TIS (100 pL, 7.37 eq., 488 pmol) in DCM (1.00 ml_) at RT under nitrogen. The mixture was stirred for 4 h and concentrated under reduced pressure. The residue was diluted with DMF (2.00 ml_) and DIPEA (231 pL, 20.0 eq., 1.33 mmol). The mixture was stirred for 15 min and then DOTA-Osu (11) (49.8 mg, 1.50 eq., 99.4 pmol) was added. The mixture was stirred for 1 h and concentrated under reduced pressure. The crude product was purified by HPLC (MeCN and H2O with 0.1% TFA) and lyophilized to provide product RD09-183 (31.0 mg, 20 pmol, 30%) as a white solid. LRMS: m / z calculated C55H80N10O13 [M+H]+1089.6, found 1089.4.

[0378] To a stirred solution of 1A (0.356 g, 1.094 mmol) and triethylamine (0.766 ml_, 5.47 mmol) in acetonitrile (5 ml_) was added 3-(2-aminoethyl)phenol (2A) (250 mg, 1.822 mmol) at RT. The mixture was stirred at 80°C for 16 h. The reaction was diluted with water (20 ml_) and extracted with ethyl acetate (2 x 50 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (Silica gel, 80% EtOAc / heptane) to afford product 5 (370 mg, 0.66 mmol, 65%) as a yellow viscous liquid.1H-NMR (400 MHz, DMSO-de) 5 ppm: 7.28-7.38 (m, 4H), 5.05 (s, 1H), 4.46 (br s, 1H), 3.40-3.41 (brs, 2H), 3.16-3.23 (br s, 2H), 2.83-2.86 (d, 2H), 2.11-2.32 (m, 4H), 2.08-2.10 (d, 3H), 1.51-1.63 (m, 4 H). LRMS: m / z calculated C19H35N2O3Si [M+H]+367.2, found 367.3.Step 1

[0379] To a stirred solution of a mixture of 1 and 2 (750 mg, 1.026 mmol) in DCM (10 ml_) was added Dess-Martin periodinane (0.653 g, 1.54 mmol) at 0°C under nitrogen. The reaction mixture was allowed to warm up to RT and stirred for 6 h. The reaction was quenched with water (30 ml_) and extracted with ethyl acetate (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated to afford a crude, inseparable mixture of 3 and 4 (680 mg 0.3732 mmol) as a white oily solid. The crude mixture was used in the next step without further purification. LRMS: m / z calculated C40H46CIN4O7 [M+H]+729.3, found 729.3.Step 2

[0380] To a stirred solution of a mixture of 3 and 4 (680 mg 0.373 mmol) in methanol (7 ml_) was added 5 (0.342 g., 0.93 mmol) followed by acetic acid (0.2 eq., 0.187 mmol). The resulting mixture was stirred at RT for 3 h, then sodium cyanoborohydride (0.0925 g, 1.40 mmol) wasadded at 0°C. The reaction mixture was allowed to warm up to RT and stirred 12 h. The reaction was quenched with saturated aq. NaHCOs (30 ml_) and extracted with 10% MeOH in DCM (2 x 50 ml_). Combined organic layers were washed with brine (30 ml_), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford product 7 (35 mg) as an off-white solid and product 6 (10.50 mg) as an off-white solid.Cpd 7:1H-NMR (400 MHz, DMSO-de) 5 ppm: 9.43 (br s, 1H), 9.27 (br s, 1H), 9.82 (d, 1H), 7.60-7.62 (d, 1H), 7.46-7.47 (m, 2H), 7.23-7.27 (t, 1H), 7.08-7.12 (t, 1H), 6.92 (s, 1H), 6.64-6.70 (m, 4H), 6.54-6.56 (d, 2H), 4.43 (s, 2H), 4.01-4.06 (q, 2H), 3.42 (m, 3H), 3.19-3.22 (m, 8H), 2.84-2.89 (m, 2H), 2.79 (s, 3H), 2.49-2.54 (m, 2H), 1.94-2.05 (m, 4H), 1.67-1.76 (m, 10H), 1.57-1.60 (m, 4H), 1.48 (m, 2H), 1.41 (s, 9H), 1.23 (s, 1H), 0.87-0.91 (t, 2H), 0.02 (s, 9 H). LRMS: m / z calculated C59H80ClN6O9Si [M+H]+1079.5, found 1079.8.Cpd 6:1H-NMR (400 MHz, DMSO-de) 5 ppm: 9.33-9.42 (br d, 2H), 9.78 (s, 1H), 7.47-7.36 (m, 2H), 7.23-7.27 (m, 2H), 7.24 (t, 1H), 6.90 (s, 1H), 6.61-6.69 (m, 5H), 6.34 (s, 1H), 4.23 (s, 2H), 4.01-4.06 (q, 2H), 3.46 (m, 6H), 3.21-3.24 (m, 8H), 2.81-2.88 (m, 5H), 2.54 (m, 3H), 1.94-2.05 (m, 4H), 1.54-1.76 (m, 17H), 1.41 (s, 9H), 1.23 (s, 2H), 0.87-0.91 (t, 2H), 0.02 (s, 9 H). LRMS: m / z calculated C59H80ClN6O9Si [M+H]+1079.5, found 1079.8.Step 3

[0381] TBAF (1.0 M in THF, 47.3 pL, 10.0 eq., 47.3 pmol) was added to 6 (5.25 mg, 1.00 eq., 4.73 pmol) at RT under nitrogen. The mixture was stirred for 18 h and concentrated under reduced pressure. The crude residue was dissolved in MeCN (100 pL) and HgO (800 pL), eluted through a Waters Sep-Pak C18 with 1:1 MeCN:H2O, and concentrated under reduced pressure. The residue was diluted in DMF (1.00 mL) and DIPEA (10.0 pL, 12.1 eq., 57.4 pmol) at RT under nitrogen. To the mixture was added HATU (1.98 mg, 1.10 eq., 5.20 pmol) and the resulting mixture was stirred for 15 min. Then, 8 (3.64 mg, 1.10 eq., 5.20 pmol) was added, the mixture was stirred at RT for 18 h and concentrated under reduced pressure. The crude residue was re-dissolved in DCM (500 pL), TIS (20.0 pL, 20.7 eq., 97.6 pmol), and TFA (500 pL) at RT under nitrogen. The mixture was stirred at 50°C for 18 h and concentrated underreduced pressure. The crude residue was purified by HPLC to provide product RD09-202 (2.18 mg, 1.2 mol, 24%) as a white solid. LRMS: m / z calculated C68H89ClN10O16[M+H]+1337.6, found 1337.4.Synthesis of RD09-205Step 1A

[0382] To a stirred solution of 9A (10.00 g, 112.2 mmol) in THF (50 ml_) were added triethylamine (47.1 ml_, 336.5 mmol) and 9B (35.6 g, 134.6 mmol) at 0 °C. Then the reaction mixture was heated to 70 °C and stirred overnight. The reaction was diluted with water (300 ml_) and extracted with EtOAc (2 x 200 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica gel, 30% EtOAc in heptane) to afford product 9C (18.64 g, 71.2%) as a colorless oil.1H-NMR (400 MHz, DMSO-de) 5: 4.41 (t, J = 6.40 Hz, 1H), 4.06-4.02 (m, 2H), 3.39-3.34 (m, 2H), 3.21 (t, J = 7.60 Hz, 2H), 2.78 (s, 3H), 1.58 (t, J = 6.80 Hz, 2H), 0.93-0.89 (m, 2H), 0.01 (s, 9H).Step 2A^OH y=QTeoc— N - •- Teoc— N9C step 2A 9

[0383] To a stirred solution of 9C (5.0 g, 21 mmol) in DCM (50 ml_) was added Dess-Martin periodinane (14 g, 32 mmol) slowly and portion-wise at 0°C. Then the reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction mixture was quenched with saturated aq. NaHCOs (100 ml_), filtered through a celite pad and further washed with DCM (2 x 100 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica gel, 20% EtOAC in heptane) to afford product 9 (3.64 g, 73%) as a colorless oil.1H-NMR (400 MHz, DMSO-de) 5: 9.65 (s, 1H), 4.07-4.02 (m, 2H), 3.45 (q, J = 17.60 Hz, 2H), 2.79 (s, 3H), 2.63 (m, 2H), 0.94-0.90 (m, 2H), 0.03 (s, 9H).Step 1

[0384] To a stirred solution of 1 (15 g, 80.623 mmol) in DMSO (150 ml_) was added N-lodosuccinimide (19.44 g, 84.655 mmol) slowly and portion-wise at -10°C. Then the reaction mixture was allowed to warm up to RT and stirred for 1 h. The reaction was quenched with water (500 ml_) and extracted with EtOAc (2 x 200 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica gel, 20% EtOAc in heptane) to afford product 2 (25.04 g, 99.6%) as a brown solid.1H-NMR (400 MHz, DMSO-de): 57.38 (d, J = 8.00 Hz, 1H), 6.46 (d, J = 8.00 Hz, 1H), 2.26 (s, 3H). LRMS: m / z calculated CyHsBrIN [M+H]+311.9, found 311.8.Step 2Step 2

[0385] To a stirred solution of 2 (10 g, 32.06 mmol) in acetic acid (200 ml_) and HCI (200 ml_) was added a solution of NaNO2 (3.32 g, 48.085 mmol) in H2O (40 ml_) dropwise at 0°C. Thenthe reaction mixture was stirred overnight at RT. The reaction mixture was cooled to 0°C and to it was added a solution of SnCl₂ (31.33g, 160.28 mmol) in HCI (40 ml_) dropwise at 0°C. Then the reaction mixture was allowed to warm up to RT and stirred for 3 h. The reaction mixture was quenched with ice water (200 ml_), the solids were filtered and dried under vacuum to afford product 3 (7.54 g, 64.7%) as an off-white solid which was used in the next step without further purification.1H-NMR (400 MHz, DMSO-de) 5: 10.22 (3H, S), 8.17 (s, 1H), 7.79 (d, J = 8.40 Hz, 1H), 6.73 (d, J = 8.80 Hz, 1H), 2.38 (s, 3H).Step 3

[0386] To a stirred solution of 4 (5 g, 18 mmol) in acetic acid (50 ml_) was added 3 (7.0 g, 21 mmol) at RT. The reaction mixture was heated to 65°C and stirred overnight. The reaction mixture was diluted with water (500 ml_) and extracted with EtOAc (2 x 300 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Silica gel, 20% EtOAc / heptane) to afford product 5 (5.45 g, 53%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.80 (d, J = 8.00 Hz, 1H), 7.32 (t, J = 8.80 Hz, 1H), 6.87-6.85 (m, 2H), 6.62 (d, J = 8.80 Hz, 2H), 4.31 (q, 1 = 6.80 Hz, 2H), 3.60 (s, 6H), 2.11 (s, 3H), 1.31 (t, J = 6.80 Hz, 3H). LRMS: m / z calculated C₂₁H₂₁BrN₂O₄ [M+H]+571.0, found 571.0.Step 4

[0387] To a stirred solution of 5 (4 g, 7.00 mmol) in neat 6 (27.90 g, 140.1 mmol) were added CS2CO3 (6.85 g, 21.01 mmol), Copper (I) Iodide (0.134 g, 0.700 mmol) and 1,10-Phenanthroline (0.254 g, 1.401 mmol) at RT under an argon atmosphere. The reaction mixture was heated to 120°C and stirred for 48 h. The reaction mixture was filtered through a celite pad and washed with water (200 ml_). The filtrate was acidified to pH 4 using 2 M aq. HCI (50 ml_)and extracted with EtOAc (2 x 200 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC using 0.1% formic acid in FW / acetonitrile as the eluent to afford product 7 (2.74 g, 64.7%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 12.82 (bs, 1H), 7.31-7.27 (m, 1H), 7.06 (d, J = 8.40 Hz, 1H), 6.89 (d, J = 8.00 Hz, 1H), 6.75 (s, 1H), 6.61 (d, J = 8.00 Hz, 2H), 4.00 (m, 2H), 3.62 (s, 6H), 2.77 (s, 3H), 2.07 (m, 5H), 1.91 (t, J = 5.60 Hz, 2H), 1.25 (s, 9H). LRMS: m / z calculated C₂₈H₃₅BrN₃O₇ [M+H]+604.2, found 604.0.Step 5

[0388] To a stirred solution of 7 (2.74 g, 4.53 mmol) in DCM (10 ml_) was added HCI (4 M in 1,4-dioxane, 11.3 ml_, 45.30 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and coevaporated with DCM (2 x 10 ml_) to afford product 8 (2.45 g, 99.9%) as a brown solid which was used in the next step without further purification. LRMS: m / z calculated C₂₃H₂₇BrN₃O₅ [M+H]+504.1, found 504.1.Step 6

[0389] To a stirred solution of 8 (2.45 g, 4.53 mmol) in MeOH (25 ml_) were added 9 (2.10 g, 9.06 mmol), triethylamine (2.76 g, 27.2 mmol), NaOAc (2.25 g, 27.2 mmol) and NaCNBHs (0.599 g, 9.06 mmol) at 0°C. The reaction mixture was allowed to warm upto RT and stirred overnight. The reaction was quenched with ice water (100 ml_), acidified with 2 N aq. HCI (30ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford product 10 (1.51 g, 46.3%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.25 (t, J = 8.2 Hz, 1H), 7.07 - 6.98 (m, 1H), 6.92 - 6.79 (m, 1H), 6.78 - 6.64 (m, 1H), 6.57 (d, J = 8.2 Hz, 2H), 4.10 - 3.94 (m, 4H), 3.58 (s, 6H), 3.12 (t, J = 7.0 Hz, 3H), 2.72 (s, 3H), 2.46 - 2.35 (m, 4H), 2.28 - 2.19 (m, 2H), 2.11 (s, 3H), 1.98 (s, 3H), 1.87 - 1.74 (m, 2H), 1.62 - 1.49 (m, 2H), 0.97 - 0.82 (m, 2H), 0.02 (s, 9H). LRMS: m / z calculated C₃₃H₄₈BrN₄O₇Si [M+H]+719.2, found 719.2.Step 7

[0390] To a stirred solution of 10 (1.45 g, 2.01 mmol) in DMF (15 ml_) were added 11 (0.608 g, 2.42 mmol), DIPEA (1.33 g, 10.10 mmol) and HATU (1.58 g, 4.03 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was diluted with ice water (100 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by C18 reverse phase column chromatography to afford product 12 (1.13 g, 58.8%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5: 7.28 (t, J = 8.40 Hz, 2H), 7.06 (d, J = 8.80 Hz, 1H), 6.89 (d, J = 8.80 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J = 8.40 Hz, 2H), 4.05 (t, J = 6.00 Hz, 4H), 3.61 (s, 6H), 3.14 (t, J = 7.20 Hz, 3H), 2.73 (s, 3H), 2.68-2.67 (m, 2H), 2.45 (t, J = 6.80 Hz, 2H), 2.25 (t, J = 6.80 Hz, 2H), 2.12 (s, 3H), 2.03 (s, 4H), 1.97-1.91 (m, 2H), 1.84-1.81 (m, 3H), 1.77-1.72 (m, 1H), 1.68-1.63 (m, 4H), 1.59-1.55 (m, 4H), 1.39 (s, 9H), 0.91 (m, 2H), 0.02 (s, 9H). LRMS: m / z calculated C₄₈H₇₁BrN₅O₈Si [M+H]+952.4, found 952.4.Step 8

[0391] Cpd 12 (100 mg, 1 eq., 105 pmol), potassium carbonate (43.5 mg, 3 eq., 315 pmol), Pd(dppf)Cl2 (15.4 mg, 0.2 eq., 21.0 mol) and pyrimidin-5-ylboronic acid (2) (39.0 mg, 3 eq., 315 mol) were dissolved in a mixture of 1,4-dioxane (1 ml_) and water (0.1 ml_). The reaction mixture was purged extensively with nitrogen, heated to 95 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (Silica gel, MeOH / DCM, 0-50%) to provide product 14 (9.2 mg, 9.7 mol, 9.2%) as a viscous light-brown oil. LRMS: m / z calculated C₅₂H₇₃N₇O₈Si [M+H]+952.5, found 952.6.Step 9OH

[0392] TIS (20 pL, 10 eq., 97 pmol) and TFA (0.5 ml_) were added to a solution of 14 (9.2 mg, 1 eq., 9.7 pmol) in DCM (0.5 ml_). The resulting mixture was stirred at RT for 1 h and concentrated in vacuo. The resulting crude residue was added to a preactivated solution of DOTAGA(tBu)4(15 mg, 2.2 eq., 21 pmol) using HATU (7.3 mg, 2 eq., 19 pmol) and DIPEA (12 mg, 17 pL, 10 eq., 97 pmol) in DCM (0.5 ml_). The resulting mixture was stirred at RT for 16 h and concentrated in vacuo. The crude residue was redissolved in TIS (20 pL, 10 eq., 97 pmol) and TFA (0.5 ml_), and the resulting mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure, and the resulting crude residue was directly purified by HPLC to give RD09-205 (3.05 mg, 1.7 pmol, 18%) as a colorless oil. LRMS: m / z calculated C61H83N11O15 [M+2H]2+605.8, found 606.1.Synthesis of RD09-215

[0393] To a stirred solution of 1A (5 g, 48.47 mmol) in THF (40 ml_) under argon were added triethylamine (3 eq., 145.41 mmol) and 2A (1.1 eq., 53.31 mmol) at 0°C. The reaction mixture was stirred at RT for 12 h and was quenched with water (30 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were washed with saturated aq. NaHCOs (2.4 ml_), dried over Na2SC>4, filtered and concentrated to afford product 3A (10 g, 34.34 mmol, 70.9%). LRMS: m / z calculated C₁₁H₂₆NO₃Si [M+H]+248.2, found 248.2.Step 2A0 0 (Me)3Si\^\oAN / \ / x / OH - - (Me)3Si^^ X I U IN1Step 2A I3A 4A

[0394] To a stirred solution of 3A (2.5 g, 10 mmol) in DCM (25 ml_) was added triethylamine (4.2 ml_, 30 mmol) followed by methanesulfonyl chloride (1.2 ml_, 15 mmol) at 0°C. The reaction mixture was stirred for 6 h and was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were washed with 5% aqueous NaHCOs (50 ml_), dried over Na2SC>4, filtered and concentrated to afford product 4A (3.2 g, 9.8 mmol, 97%) as a brown viscous oil.1H-NMR (400 MHz, CDCIs) 5 ppm: 4.22 (brt, 1H), 4.12 (m, 2H), 3.26 (br s, 2H), 3.11 (m, 1H), 2.97 (s, 2H), 2.83 (s, 3H), 1.67-1.73 (m, 4H), 0.96 (m, 2H), -0.04 (m, 9H).Step 3A(Me)3Si NIStep 3A 4A

[0395] To a stirred solution of 5A (4.1 g, 24 mmol) in acetonitrile (40 ml_) was added triethylamine (7.7 ml_, 55 mmol) followed by 4A (3.6 g, 11 mmol). The resulting mixture was refluxed at 80°C for 12 h. After completion, the solvents were evaporated and the crude residue was purified by column chromatography (Silica gel, 60-70% EtOAc in heptane) to afford product 4 (1.5 g, 4.2 mmol, 38%) as yellow oil.1H-NMR (400 MHz, CDCIs) 5 ppm 4.12 (m, 2H), 3.26 (m, 5H), 2.83 (s, 3H), 2.57 (t, 2H), 1.62 (m, 2H), 0.96 (m, 2H), 0.04 (m, 9H). LRMS: m / z calculated C₁₇H₃₇N₂O₄Si [M+H]+361.3, found 361.4.Step 1

[0396] To a stirred solution of 1 (10 g, 21.08 mmol) in DMF (20 ml_, 99.9 mass%) under argon were added CS2CO3 (3 eq., 63.25 mmol), KI (1 eq., 21.08 mmol) and 5A (5 eq., 105.4 mmol) at 0°C. The reaction mixture was stirred at 70°C for 12 h and was quenched with water (50 ml_) and extracted with EtOAc (2 x 50 ml_). Combined organic layers were washed with saturated aq. NaHCOs (2.4 ml_) and brine (20 ml_), dried over Na2SC>4 (0.5 g), filtered and concentrated. The crude material was purified by column chromatography (Silica gel, 2-5% MeOH in DCM) to afford products 6A (5.25 g, 6.90 mmol, 32.7%) and 2 (6.97 g, 6.88 mmol, 32.6%). LRMS: m / z calculated C29H33CIN3O7 [M+H]+570.2, found 570.4.Step 2

[0397] To a stirred solution of 2 (1 g, 1.754 mmol) in DCM (10 ml_) was added TFA (0.8 ml_, 10 mmol) dropwise at 0°C. The mixture was stirred at RT for 3 h. All the solvents were evaporated to afford crude product 3 (0.90 g, 1.7 mmol, 98%) as a brown oil which was used in the next step without further purification.1H-NMR (400 MHz, DMSO-de) 5 ppm: 9.67 (s, 1H), 7.89 (s, 1H), 7.36 (m, 3H), 7.00 (m, 1H), 6.64 (br d, 2H), 6.21 (m, 1H), 4.34 (q, 2H), 4.20 (brt, 2H), 2.58 (m, 2H), 1.81 (dt, 2H), 1.32 (t, 3H), 1.23 (s, 1H). LRMS: m / z calculated C27H27CIN3O6 [M+H]+524.2, found 524.3.Step 3

[0398] To a stirred solution of 4 (0.789 g, 2.19 mmol) in methanol (9 ml_) was added 3 (0.9 g, 2 mmol) dropwise at 0°C. Then, acetic acid (0.05 ml_, 0.9 mmol) was added at RT and the reaction mixture was stirred at RT for 3 h. Sodium cyanoborohydride (0.6 g, 10 mmol) was added at 0°C and the reaction mixture was allowed to warm up to RT and stirred for 10 h. The reaction mixture was quenched with water (30 ml_) and extracted with EtOAc (2 x 30 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated. The crude material was purified by column chromatography (Silica gel, 2-5% MeOH in DCM) to afford product 5 (390 mg, 0.4491 mmol, 30%).1H-NMR (400 MHz, DMSO-de) 5 ppm: 7.81 (s, 1H), 7.33 (m, 1H), 6.98 (s, 1H), 6.63 (br d, 1H), 6.02 (s, 1H), 4.36-4.23 (m, 2H), 4.06 (m, 2H), 3.46 (s, 3H), 3.17 (m, 5H), 2.79 (m, 3H), 1.58-1.44 (d, 2H), 1.38-130 (m, 12H), 0.93 (m, 2H), 0.01 (m, 9H). LRMS: m / z calculated C44H63CIN5O9Si [M+H]+868.4, found 868.5.Step 4

[0399] To a stirred solution of 5 (350.0 mg, 0.403 mmol) in THF (3.5 ml_) and water (3.5 ml_) was added lithium hydroxide monohydrate (20 mg, 0.835 mmol) at RT. The reaction mixture was stirred at RT for 12 h, then the solvents were evaporated in vacuo to afford the lithium salt of product 6 (330.0 mg, 0.393 mmol, 97.4%) as white solid.1H-NMR (400 MHz, DMSO-de) 5ppm: 7.75 (s, 1 H), 7.56 (s, 1 H), 7.31-7.14 (m, 3H), 6.58 (d, 2H), 6.53 (s, 1 H), 6.00 (s, 1 H), 4.24 (m, 2H), 4.02 (m, 2H), 3.41 (m, 6H), 3.32 (m, 8H), 3.12 (m, 7H), 2.72 (m, 4H), 2.86 (m, 5H), 2.42 (t, 2H), 1.38 (m, 6H), 0.91 (m, 4H), 0.01 (m, 9H). LRMS: m / z calculated C₄₂H₅₉ClN₅O₉Si [M+H]+840.4, found 840.7.Step 5

[0400] To a stirred solution of 6 (330 mg, 0.393 mmol) in DMF (4 mL) was added DIPEA (177 mg, 1.37 mmol) dropwise at 0°C. Then, 7 (128 mg, 0.509 mmol) was added at RT and the reaction mixture was stirred at RT for 10 h. The reaction mixture was diluted with water (30 ml_) and extracted with EtOAc (2 x 30 ml_). Combined organic layers were dried over Na2SC>4, filtered and concentrated. The crude material was purified by column chromatography (Silica gel, 60-70% EtOAc in heptane) to afford product 8 (130 mg, 0.118 mmol, 30.0%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5 ppm: 7.86 (s, 1H), 7.51 (s, 1H), 7.42 (d, 1H), 7.32 (m, 2H), 6.87 (s, 1H), 6.63 (d, 2H), 6.23 (s, 1H), 4.23 (t, 2H), 4.03 (t, 2H), 3.46 (s, 6H), 3.17 (m, 3H), 2.73 (m, 3H), 2.47 (m, 4H), 2.03 (m, 4H), 1.72-1.59 (m, 11 H), 1.38 (m, 27H), 0.88 (m, 3H), 0.01 (s, 9H). LRMS: m / z calculated C₅₇H₈₂ClN₆O₁₀Si [M+H]+1073.6, found 1073.8.

[0401] TBAF (118 mg, 452 pL, 1 molar, 10.0 eq., 452 pmol) was added to 8 (50.0 mg, 1.00 eq., 45.2 pmol) at RT under nitrogen. The mixture was stirred for 18 h and concentrated under reduced pressure. The residue was diluted with 2.5 M NaOH (10.0 ml_), which formed a white precipitate. The precipitate was filtered, washed with H2O (2 x 10.0 ml_), and dissolved in EtOAc (15.0 ml_). The organic layer was washed with brine (2 x 15.0 ml_), dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the product 9 (28.0 mg, 30.1 pmol, 66.6%) as an off-white semi-solid. LRMS: m / z calculated C51H69ClN6O8[M+H]+929.5, found 929.6.

[0402] DOTA-NHS (23.5 mg, 1.50 eq., 46.8 pmol) was added to a mixture of 9 (29.0 mg, 1.00 eq., 31.2 pmol) and DIPEA (20.2 mg, 27.2 pL, 5.00 eq., 156 pmol) in anhydrous DMF (1.00 ml_) at RT under nitrogen. The mixture was stirred for 48 h and then concentrated under reduced pressure. The crude residue was diluted with DCM (1.00 ml_), TIS (77.3 mg, 100 pL, 15.6 eq., 488 pmol), TFA (1.33 g, 900 pL, 374 eq., 11.7 mmol), and stirred for 18 h at RT under nitrogen. The mixture was concentrated under reduced pressure and the crude residue was triturated with Et2O (2 x 5.00 ml_) and purified by HPLC with H2O and MeCN (35-55%, 0.1%TFA) and lyophilized to provide the product RD09-215 (3.75 mg, 6.6%, 98%) as a white solid. LRMS: m / z calculated C59H79CIN10O15 [M+H]+1203.5, found 1203.6Step 9

[0403] To a stirred solution of ethyl 6A (1.50 g, 2.63 mmol) in DCM (20 mL) added TFA (5 eq., 13.2 mmol) dropwise at 0°C. The reaction mixture was stirred at RT for 16 h and volatiles were evaporated in vacuo. The crude residue was diluted with saturated aq. NaHCOs (50 mL) and extracted with 10% MeOH in DCM (2 x 75 mL). Combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to afford crude product 11 (1.35 g, 1.75 mmol, 66.4%) as a brown oil which was used in the next step without further purification. LRMS: m / z calculated C27H27CIN3O6 [M+H]+524.2, found 524.2.Step 10

[0404] To a stirred solution of 11 (1 g, 1.294 mmol) and 4 (0.574 g, 1.552 mmol) in methanol (5 mL) under nitrogen were added acetic acid (0.5 eq., 0.65 mmol) and sodium cyanoborohydride (0.514 g, 7.76 mmol) at 0°C. The reaction mixture was allowed to warm up to RT and stirred for 12 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (2 x 30 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography (Silica gel, 80-90% EtOAc in heptane) to afford product 12 (640 mg, 0.587 mmol, 45.4%) as a viscous oil. LRMS: m / z calculated C₄₄H₆₃ClN₅O₉Si [M+H]+868.4, found 868.8.Step 11

[0405] A solution of 12 (590 mg, 0.541 mmol) and lithium hydroxide mono hydrate (0.0400 g, 1.624 mmol) in water (3 ml_) and THF (3 ml_) was prepared at 0°C. The resulting mixture was allowed to warm up to RT and stirred for 12 h. The volatiles (THF) were removed in vacuo and the aqueous residue was diluted with water (20 ml_) and extracted with diethyl ether (50 ml_). The aqueous layer was acidified with saturated aq. KHSO4 (1.4 ml_) to pH 2-3 and extracted with ethyl acetate (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated to afford crude product 13 (480 mg, 0.538 mmol) which was used in the next step without further purification. LRMS: m / z calculated C₄₂H₅₉ClN₅O₈Si [M+H]+840.4, found 840.4.Step 12

[0406] To a stirred solution of 13 (430.00 mg, 0.4820 mmol) in DMF (5 ml_) under nitrogen were added HATU (0.283 g, 0.723 mmol), 7 (0.145 g, 0.578 mmol), and DIPEA (0.337 ml_, 1.928 mmol) at 0°C. The reaction mixture warmed up to RT and stirred for 12 h. The reaction was diluted with water (30 ml_) and extracted with ethyl acetate (2 x 50 ml_). Combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to afford product 14 (230.0 mg, 0.204 mmol, 42.3%) as an off-white solid.1H-NMR (400 MHz, DMSO-de) 5 ppm: 9.54 (s, 1H), 7.82 (s, 1H), 7.60-7.63 (s, 1H), 7.45 (m, 2H), 7.27 (t, 1H), 6.92 (s, 1H), 6.69 (s, 1H), 6.56-6.58 (m, 1H), 4.74 (q, 2H), 4.12-4.24 (m, 4H), 3.47 (s, 6H), 3.02-3.22 (m, 6H), 2.82 (s, 3H), 2.52 (s, 2H), 1.97-2.04 (m, 4H), 1.70-1.82 (m,10H), (t, 3H), 1.43-1.67 (m, 21 H); 0.82 (t, 3 H). LRMS: m / z calculated C₅₇H₈₁ClN₆O₁₀Si [M+H]+1073.6, found 1073.9.

[0407] Tables 8 and 9 summarize MS characterization of exemplary radiolabeled compounds.Table 8. MS characterization data for Lu3+cold metal complexesProtonatedCompound Calculated (m / z) Found (m / z) speciesLU-RD09-014 [M+H]+1213.4 1213.4LU-RD09-015 [M+H]+1213.4 1213.5LU-RD09-025 [M+H]+1213.4 1213.4LU-RD09-035 [M+H]+1260.5 1260.5LU-RD09-037 [M+H]+1283.5 1283.8LU-RD09-038 [M+H]+1299.5 1299.8LU-RD09-040 [M+H]+1303.4 1303.7LU-RD09-046 [M+H]+1283.5 1283.8LU-RD09-047 [M+H]+1299.5 1299.7LU-RD09-049 [M+H]+1303.4 1303.5LU-RD09-060 [M+H]+1375.5 1375.7LU-RD09-061 [M+H]+1375.5 1375.6LU-RD09-098 [M+H]+1269.5 1269.6LU-RD09-118 [M+H]+1269.5 1269.6LU-RD09-146 [M+H]+1347.4 1347.7LU-RD09-147 [M+H]+1347.4 1347.7Table 9. MS characterization data for La3+cold metal complexesProtonatedCompound Calculated (m / z) Found (m / z) speciesLa-RD09-014 [M+H]+1177.4 1177.6La-RD09-015 [M+H]+1177.4 1177.6La-RD09-035 [M+H]+1224.5 1224.8La-RD09-037 [M+2H]2+642.3 642.3La-RD09-038 [M+2H]2+632.3 632.3La-RD09-040 [M+2H]2+634.2 634.3ProtonatedCompound Calculated (m / z) Found (m / z) speciesLa-RD09-046 [M+2H]2+624.2 624.4La-RD09-049 [M+2H]2+634.2 634.3La-RD09-060 [M+2H]2+670.2 670.3La-RD09-062 [M+2H]2+678.2 678.5La-RD09-063 [M+2H]2+678.2 678.3La-RD09-096 [M+2H]2+617.2 617.7La-RD09-098 [M+H]+1233.4 1233.7 La-RD09-102 [M+H]+1276.5 1277.0 La-RD09-105 [M+H]+1208.5 1208.2La-RD09-113 [M+H]+1208.5 1208.2La-RD09-115 [M+2H]2+641.2 641.3La-RD09-118 [M+H]+1233.4 1233.6La-RD09-121 [M+2H]2+672.7 672.8La-RD09-123 [M+2H]2+648.2 648.3La-RD09-129 [M+2H]2+654.2 654.2La-RD09-130 [M+H]+1438.5 1438.4La-RD09-131 [M+2H]2+641.2 641.3La-RD09-137 [M+2H]2+634.2 634.3La-RD09-145 [M+2H]2+672.2 672.2La-RD09-148 [M+2H]2+634.2 634.4La-RD09-150 [M+2H]2+644.7 645.1La-RD09-151 [M+H]+1293.4 1293.8 La-RD09-158 [M+2H]2+678.3 678.4La-RD09-159 [M+2H]2+678.3 678.4La-RD09-167 [M+2H]2+685.3 685.5La-RD09-168 [M+2H]2+685.3 685.5La-RD09-171 [M+2H]2+698.3 698.5La-RD09-172 [M+2H]2+698.3 698.5La-RD09-177 [M+2H]2+712.8 712.8La-RD09-183 [M+H]+1225.5 1225.5 La-RD09-200 [M+H]+1401.5 1401.8 La-RD09-202 [M+2H]2+737.3 737.3La-RD09-205 [M+2H]2+673.7 674.0ProtonatedCompound Calculated (m / z) Found (m / z) speciesLa-RD09-215 [M+H]+1339.4 1339.7Example 2: In vitro binding assaysGeneral proceduresHCT 116 cell-based radioligand competition binding assay

[0408] HCT 116 cells (obtained from ATCC) were plated for 24-48 h in 24-well poly-D-lysine plates for 80-90% confluence on assay date. Cells were washed twice with PBS, and cell growth medium was replaced with assay medium (McCoy’s medium with 2 mg / mL BSA and 10 mM HEPES at pH = 7.4). Test ligand (at various concentrations) and [125l-Tyr3]Neurotensin (to a final concentration of 0.04 nM) were added and incubated for 1 h at 37°C with mild agitation. Cells were washed with ice-cold PBS twice after incubation and trypsinized to collect cell fractions for counting on the gamma counter. All experiments were performed in triplicates. Curve fitting and statistical analyses were performed by GraphPad Prism 10 using One Site-Fit IC50 Competitive Binding with R2> 0.95.HT-29 cell-based radioligand competition binding assay

[0409] HT-29 cells (obtained from ATCC) were plated for 24-48 h in 24-well TC plates for 80-90% confluence on assay date. Cells were washed twice with PBS, and cell growth medium was replaced with assay medium (McCoy’s medium with 2 mg / mL BSA and 10 mM HEPES at pH = 7.4). Test ligand (at various concentrations) and [125l-Tyr3]Neurotensin (to a final concentration of 0.04 nM) were added and incubated for 1 h at 37°C with mild agitation. Cells were washed with ice-cold PBS twice after incubation and trypsinized to collect cell fractions for counting on the gamma counter. All experiments were performed in triplicates. Curve fitting and statistical analyses were performed by GraphPad Prism 10 using One Site-Fit IC50 Competitive Binding with R2> 0.95.NTSR1 membrane-based radioligand competition binding assay

[0410] Type C 96-well plates were pre-soaked with 0.33% polyethylenimine (PEI) for 30 min and then washed with pre-assay medium (50 mM HEPES and 0.5% BSA buffered at pH = 7.4). Test ligand (at indicated concentrations), [125l-Tyr3]Neurotensin (to a final concentration of 0.05 nM) and 5 pg ChemiSCREEN™ NTR1 Neurotensin receptor membrane were added in assay buffer (50 mM HEPES, 5 mM MgCl₂, 1 mM CaCl₂, and 0.2% BSA). Plates were incubated at 27°C for 1 h with agitation. After incubation, they were washed with ice cold wash buffer (50 mM HEPES, 500 mM NaCI, and 0.1% BSA) three times. After drying, the filter membranes were removed for counting on the gamma counter. All experiments were performed intriplicates. Curve fitting and statistical analyses were performed by GraphPad Prism 10 using One Site-Fit Ki Competitive Binding with R2> 0.95. Table 10 summarizes the in vitro binding affinities (Ki) of exemplary radiolabeled compounds.Table 10. In vitro binding affinities, Ki (nM)Ki Ki Ki Compound Compound Compound(n=1-4) (n=1-4) (n=1-4) DOTA-NT20.3* 1.70 La-RD09-098 0.729 RD09-026 1029.95 LU-3BP-227* 3.12 La-RD09-105 0.269 FL-091* 0.422 LU-RD09-005 65.84 La-RD09-107 0.279 RD09-037 0.158 LU-RD09-006 34.23 La-RD09-113 0.281 RD09-038 0.769 LU-RD09-014 2.29 La-RD09-115 0.73 RD09-040 0.093 LU-RD09-015 1.06 La-RD09-118 0.357 RD09-046 0.174 LU-RD09-025 3.14 La-RD09-121 0.169 RD09-047 0.404 Lu-FL-091* 0.104 La-RD09-123 0.623 RD09-049 0.004 LU-RD09-037 0.361 La-RD09-129 0.457 RD09-060 4.54 LU-RD09-038 0.818 La-RD09-131 1.063 RD09-061 4.575 LU-RD09-040 0.069 La-RD09-137 0.85 RD09-062 3.565 LU-RD09-046 0.472 La-RD09-138 0.721 RD09-063 2.49 LU-RD09-047 0.349 La-RD09-145 0.633 RD09-065 43.895 LU-RD09-049 0.027 La-RD09-148 2.89 RD09-096 0.336 LU-RD09-060 2.987 La-RD09-150 0.395 RD09-098 0.319 LU-RD09-061 3.663 La-RD09-158 0.16 RD09-102 0.718 LU-RD09-065 17.707 La-RD09-159 0.43 RD09-108 2.87 LU-RD09-098 0.271 La-RD09-167 0.648 RD09-117 15.405 LU-RD09-118 0.527 La-RD09-168 0.39 RD09-118 0.121 LU-RD09-146 1.886 La-RD09-171 1.39 RD09-124 2.16 LU-RD09-147 2.480 La-RD09-172 1.03 RD09-138 6.114 LU-RD09-150 1.22 La-RD09-177 2.74 RD09-146 2.07 La-3BP-227* 2.314 La-RD09-183 2.02 RD09-147 3.295 La-RD09-014 2.128 La-RD09-205 5.5 RD09-150 0.91 La-RD09-015 2.053 DOTA-NT20.3* 1.12 RD09-151 0.473 La-FL-091* 0.114 3BP-227* 0.76 RD09-152 1.79Ki Ki Ki Compound Compound Compound(n=1-4) (n=1-4) (n=1-4) La-RD09-040 0.466 RD09-003 42.953 RD09-167 0.683 La-RD09-049 0.57 RD09-005 28.64 RD09-168 0.45 La-RD09-062 1.863 RD09-006 5.41 RD09-171 1.06 La-RD09-063 1.863 RD09-014 1.363 RD09-172 0.33 La-RD09-088 6.143 RD09-015 0.63 RD09-183 3.11 La-RD09-096 3.001 RD09-025 1.43 RD09-215 0.28* Reference compoundsExample 3: Ex vivo biodistribution in NTSR1 expressing tumor-bearing mice General protocol

[0411] All animal experiments were conducted in compliance with the guidelines of the Canadian Council on Animal Care and approved by the University of British Columbia Animal Care Committee. Female athymic nude mice were subcutaneously inoculated below the right shoulder with 5 * 106HT-29 cells (NTSR-1 positive) under 2% isoflurane anesthesia. When tumors reached an appropriate size, animals were intravenously injected with the radiopharmaceutical of interest: 10 kBq of the a-emitter225Ac or 2 MBq and 1.5 MBq of tracers labeled with177Lu and1111 n, respectively. At designated time points post-injection, animals were euthanized, and blood, tumor, and major organs were collected, rinsed with PBS, blotted dry, weighed, and measured for radioactivity using an automated y-counter. Uptake in tissues were reported as the percentage of injected dose per gram of tissue (%ID / g), and all values were decay corrected. The biodistribution data of exemplary radiolabeled compounds are shown in Tables 11-46 and the biodistribution data of reference compounds (i.e., FL-091 and 3BP-227) are shown in Tables 47 and 48.In vivo biodistribution data177Lu-Labeled compoundsTable 11. In vivo biodistribution of177Lu-RD09-037177Lu-RD09- %ID / g037 1 h 4h 24 h 48 h 72 h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood 9.36 1.22 6 2.67 0.82 6 0.06 0.01 6 0.02 0.01 6 0 0 6 Tail 4.45 2.27 6 1.23 0.51 6 0.15 0.04 6 0.12 0.03 6 0.07 0.03 6 Tumor 8.76 1.21 6 10.64 2.13 6 4.73 0.41 6 2.56 0.44 6 1.34 0.34 6 Kidneys 3.01 0.56 6 1.61 0.62 6 0.64 0.15 6 0.41 0.08 6 0.27 0.05 6177Lu-RD09- %ID / g037 1 h 4h 24 h 48 h 72 h Liver 3.29 0.81 6 2.04 0.54 6 0.69 0.1 6 0.64 0.18 6 0.43 0.09 6 Lungs 4.88 1.85 6 2.39 0.88 6 0.53 0.05 6 0.29 0.07 6 0.13 0.04 6 Large Intestine 1.5 0.2 6 1.45 0.16 5 0.54 0.12 6 0.25 0.11 6 0.12 0.04 6Table 12. In vivo biodistribution of177Lu-RD09-040177Lu-RD09- %ID / g040 1 h 4h 24 h 48 h 96 h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood 13.54 1.47 4 5.85 0.97 4 0.21 0.03 4 0.07 0.02 3 0.04 0 3 Tail 3.02 0.66 3 1.55 0.34 4 0.47 0.16 4 0.38 0.16 3 0.53 0.6 3 Tumor 6.69 1.04 4 21.78 2.32 4 18.21 2.6 4 15.03 3.88 3 12.03 0.62 3 Kidneys 5.17 0.19 4 4.24 0.78 4 2.12 0.5 4 1.25 0.48 3 0.78 0.2 3 Liver 7.23 0.92 4 13 0.97 4 4.77 1.06 4 1.83 0.62 3 0.85 0.13 3 Lungs 8.54 1.84 4 3.64 0.79 4 0.98 0.19 4 0.6 0.12 3 0.52 0.17 3 Large Intestine 1.59 0.27 4 2.91 0.78 4 2.41 0.71 4 0.96 0.33 3 0.37 0.04 3Table 13. In vivo biodistribution of177Lu-RD09-049177Lu-RD09- %ID / g049 1 h 4h 24 h 48 h 96 h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood 8.15 0.82 4 2.01 0.46 4 0.02 0 3 0.01 0 4 - - 4 Tail 2.37 0.36 4 0.63 0.2 4 0.23 0.06 4 0.05 0.01 4 0.04 0.03 4 Tumor 15.64 2.3 4 19.63 5.18 4 13.53 1.28 4 9.98 3.51 4 5.3 0.71 4 Kidneys 5.26 0.62 4 3.33 0.88 4 1.25 0.26 4 0.86 0.54 4 0.23 0.12 4 Liver 2.19 0.33 4 1.17 0.14 4 0.39 0.05 4 0.39 0.08 4 0.24 0.03 4 Lungs 4.46 0.64 4 1.35 0.36 4 0.14 0 3 0.13 0.05 4 0.06 0.03 4 Large Intestine 1.91 0.41 4 1.71 0.38 4 0.93 0.53 4 0.16 0.09 4 0.13 0.05 4Table 14. In vivo biodistribution of177Lu-RD09-060177Lu-RD09- %ID / g060 1 h 4h 24 h 48 h 96 h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood 13.720.68 5 5.56 0.48 5 0.28 0.06 5 0.08 0.02 5 0.03 0.01 5177Lu-RD09- %ID / g060 1 h 4h 24 h 48 h 96 h Tail 5.94 3.97 5 1.64 0.09 4 0.31 0.05 5 0.33 0.21 5 0.17 0.04 5 Tumor 10.74 1.45 5 20.5 2.63 5 21.36 2.16 5 19.41 2.51 5 14.43 1.3 5 Kidneys 9.02 5.27 5 3.2 0.36 5 1.21 0.33 5 1.00 0.23 5 0.64 0.14 5 Liver 6.64 0.77 5 5.45 0.66 5 0.88 0.08 5 0.42 0.1 5 0.31 0.04 5 Lungs 6.86 0.56 5 3.24 0.5 5 0.73 0.14 5 0.46 0.1 5 0.31 0.03 4 Large Intestine 2.04 0.22 5 4.34 0.87 5 2.13 0.71 5 0.38 0.11 5 0.28 0.12 5Table 15. In vivo biodistribution of177Lu-RD09-061177Lu-RD09- %ID / g061 1 h 4h 24 h 48 h 96 h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood 10.96 1.75 6 3.25 0.72 6 0.09 0.03 6 0.03 0.01 6 0.01 0 5 Tail 2.95 0.57 6 1.09 0.35 6 0.09 0.03 5 0.06 0.02 6 0.06 0.04 5 Tumor 14.34 2.02 6 18.16 1.99 6 10.1 0.79 6 7.44 0.61 6 3.89 0.49 6 Kidneys 2.93 0.23 6 1.34 0.36 6 0.33 0.1 6 0.16 0.12 6 0 0 6 Liver 3.28 0.07 5 1.55 0.25 6 0.31 0.09 6 0.18 0.05 6 0.1 0.02 6 Lungs 5.55 0.7 6 2.3 0.57 6 0.19 0.05 6 0.09 0.03 6 0.04 0 5 Large Intestine 1.67 0.26 6 3.69 1.66 6 1.06 0.62 6 0.15 0.08 5 0.1 0.08 6225Ac-Labeled compoundsTable 16. In vivo biodistribution of225Ac-RD09-040225Ac-RD09- %ID / g040 1 h 4h 24 h 48 h 120h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood 16.3 3.77 6 12.87 1.13 6 1.42 0.3 6 0.16 0.03 6 0 0 6 Tail 11.96 11.26 6 4.64 3.36 6 2.29 2.34 6 2.01 1.87 6 1.48 1.11 6 Tumor 4.26 1.07 6 9.65 0.95 6 12.33 0.97 6 9.73 0.6 6 6.72 0.8 6 Kidneys 4.54 1.28 6 4.33 0.52 6 2.45 0.43 6 1.76 0.15 6 1.38 0.09 6 Liver 8.4 3.19 6 11.11 1.73 6 16.44 2.14 6 15.86 1.75 6 16.79 1.35 6 Lungs 7.66 2.69 6 6.25 0.82 6 2.01 0.54 6 1.06 0.2 6 0.95 0.08 6 Large Intestine 1.11 0.33 6 1.62 0.3 5 2.92 0.86 6 1.15 0.14 6 0.66 0.26 6Table 17. In vivo biodistribution of225Ac-RD09-046225Ac-RD09- %ID / g046 1 h 4h 24 h 48 h 120 h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood - - - 8.65 0.63 5 0.51 0.15 5 0.2 0.06 5 - - - Tail - - - 1.93 0.14 4 0.71 0.57 5 0.43 0.06 5 - - - Tumor - - - 7.9 0.94 5 6.77 0.97 5 11.4 6.19 5 - - - Kidneys - - - 4.36 0.72 5 3.1 0.58 5 2.7 0.41 5 - - - Liver - - - 7.27 0.86 5 3.68 0.88 5 3.59 0.73 5 - - - Lungs - - - 6.43 1.08 5 0.95 0.13 5 1.09 0.3 5 - - - Large Intestine - - - 1.21 0.06 5 2.69 0.9 5 0.83 0.3 5 - - -Table 18. In vivo biodistribution of225Ac-RD09-047225Ac-RD09- %ID / g047 1 h 4h 24 h 48 h 120 h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood - - - 0.11 0.06 5 0 0 5 - - - - - - Tail - - - 0.43 0.39 5 0.08 0.02 4 - - - - - - Tumor - - - 2.08 0.45 5 0.6 0.1 5 - - - - - - Kidneys - - - 1.39 0.35 5 0.65 0.11 5 - - - - - - Liver - - - 0.6 0.14 5 0.21 0.04 5 - - - - - - Lungs - - - 0.33 0.23 5 0 0 5 - - - - - - Large Intestine - - - 0.86 0.49 5 2.19 1.62 5 - - - - - -Table 19. In vivo biodistribution of225Ac-RD09-049225Ac-RD09- %ID / g049 1 h 4h 24 h 48 h 120h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood 17.12 5.46 6 9.63 2.41 6 0.98 0.29 6 0.28 0.03 6 0 0 6 Tail 3.33 0.61 6 2.27 0.26 6 0.42 0.09 6 0.37 0.03 6 0.28 0.05 5 Tumor 10.15 3.54 6 13.44 2.24 6 18.16 1.87 6 16.41 2.19 6 11.89 1.63 6 Kidneys 6.03 1.46 6 4.89 1.03 6 2.8 0.81 6 3.48 0.65 6 2.02 0.21 6 Liver 3.91 1.1 6 3.13 0.55 6 1.45 0.27 6 1.71 0.23 6 2.3 0.49 6 Lungs 11.33 5.22 6 5.16 1 6 0.94 0.01 5 0.79 0.07 6 0.37 0.04 6 Large Intestine 2.1 0.53 6 1.76 0.2 6 0.81 0.24 6 0.45 0.09 6 0.27 0.08 6Table 20. In vivo biodistribution of225Ac-RD09-060225Ac-RD09- %ID / g060 1 h 4h 24 h 48 h 120 h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood - - - 6.1 0.52 4 0.36 0.12 5 - - - - - - Tail - - - 1.6 0.11 4 0.49 0.11 5 - - - - - - Tumor - - - 15.27 1.89 4 14.34 2.26 5 - - - - - - Kidneys - - - 5.23 0.88 4 2.67 0.73 5 - - - - - - Liver - - - 5.67 0.24 4 1.85 0.49 5 - - - - - - Lungs - - - 3.55 0.42 4 0.71 0.14 5 - - - - - - Large Intestine - - - 4.18 1.58 4 2.72 1.21 5 - - - - - -Table 21. In vivo biodistribution of225Ac-RD09-061225Ac-RD09- %ID / g061 1 h 4h 24 h 48 h 120 h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood - - - 2.15 0.49 5 0.07 0.05 5 0 0 5 - - - Tail - - - 0.92 0.14 5 0.33 0.1 5 0.12 0.02 5 - - - Tumor - - - 13.18 1.11 5 10.08 1.59 5 6.26 1.2 5 - - - Kidneys - - - 4.61 0.95 5 2.25 0.57 5 1.37 0.5 5 - - - Liver - - - 1.05 0.18 5 0.4 0.08 5 0.38 0.07 5 - - - Lungs - - - 1.48 0.38 5 0.14 0.2 5 0 0 5 - - - Large Intestine - - - 3.42 0.86 5 1.03 0.71 5 0.95 0.81 5 - - -Table 22. In vivo biodistribution of225Ac-RD09-062225Ac-RD09- %ID / g062 1 h 4h 24 h 48 h 120h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood - - - 1.35 0.5 5 0.04 0.04 5 - - - - - - Tail - - - 0.81 0.2 5 0.38 0.12 5 - - - - - - Tumor - - - 20.66 4.33 5 19.66 2.99 5 - - - - - - Kidneys - - - 2.82 0.54 5 2.1 0.82 5 - - - - - - Liver - - - 6.53 0.99 5 5.98 1.19 5 - - - - - - Lungs - - - 1.41 0.39 5 0.5 0.1 5 - - - - - - Large Intestine - - - 3.4 0.89 5 2.57 0.65 5 - - - - - -Table 23. In vivo biodistribution of225Ac-RD09-063225Ac-RD09- %ID / g063 1 h 4h 24 h 48 h 120h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood 4.53 0.46 5 0.69 0.14 5 0.04 0.04 5 0 0 5 0 0 5 Tail 1.38 0.24 5 0.33 0.05 5 0.14 0.06 5 0.1 0.01 5 0.16 0.04 5 Tumor 14.41 1.76 5 21.47 2.18 5 21.2 2.81 5 19.02 1.58 5 14.55 3.2 5 Kidneys 3.43 0.43 5 2.86 0.44 5 2.09 0.17 5 1.77 0.28 5 1.22 0.25 5 Liver 1.65 0.34 5 1.32 0.19 5 1.12 0.06 5 1.35 0.24 5 1.67 0.32 5 Lungs 3.16 0.39 5 0.77 0.25 5 0.2 0.19 5 0 0 5 0 0 5 Large Intestine 2.47 0.03 4 2.23 0.39 5 1.18 0.15 5 1.16 0.41 5 0.48 0.12 5Table 24. In vivo biodistribution of225Ac-RD09-096225Ac-RD09- %ID / g096 1 h 4h 24 h 48 h 120h Organs AVG SD N AVG SD N AVG SD N AVG SD N AVG SD N Blood - - - 2.72 0.51 5 0 0 4 - - - - - - Tail...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula A or Formula B:A / VA / Vwherein:Ring A is an optionally substituted 5- to 6-membered heteroaryl;Ring B is optionally substituted phenyl, optionally substituted chromanyl, or optionally substituted naphthyl;Ring C is optionally substituted quinolinyl, optionally substituted N-oxide quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinolone, optionally substituted isoquinolinone, optionally substituted tetrahydroquinolinyl, optionally substituted dihydroquinolinone, optionally substituted phenyl, or optionally substituted pyridyl;L is a linker, optionally comprising one or more charge-modifying groups;X is a chelator optionally chelated with a radionuclide;p is 0 or 1; andW is a natural or unnatural amino acid;provided that:when p is 1, then V is O; andwhen p is 0, then V is tethered to Ring A to form an optionally substituted 5- to 6-membered heteroaryl fused to Ring A;or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein the compound comprises the structure of Formula A-l:X(A-l),wherein:A is CH, CH2, or N;B is C, C=O, CH, CH2, or N;D is C, C=O, N, or N+-O-(N-oxide);E is C or CRC;F is CR4;wherein indicates a single bond or a double bond and at least one of A, B, and D is N;each of R1, R2, R3, R4, Ra, Rb, Rc, Rd, and Re, independently, is H, halo, hydroxy, CN, amino, amido, carbamoyl, carboxylic acid, ester, optionally substituted C1-3alkyl, optionally substituted C1-3haloalkyl, optionally substituted C3-6cycloalkyl, optionally substituted C1-3alkoxy, or optionally substituted C1-3aminoalkyl; orR1 and R2 are tethered to form an optionally substituted carbocycle or optionally substituted heterocycle;L is a linker, optionally comprising one or more charge-modifying groups, wherein * indicates an attachment point that attaches the linker to B, D, E, or F;X is a chelator optionally chelated with a radionuclide;U is H, halo, C1-3 alkyl, or C1-3 haloalkyl;V is O; orU and V are tethered to form an optionally substituted 5- to 6-membered heteroaryl; andW is an optionally substituted natural or unnatural amino acid.

3. The compound of claim 1 or 2, wherein the compound comprises the structure of Formula I:wherein:A is CH, CH2, or N;B is C, CH, CH2, or N;D is C or N;E is C or CRC;wherein = indicates a single bond or a double bond and at least one of A, B, and D is N;each of R1, R2, Rs, R4, Ra, Rb, Rc, Rd, and Re, independently, is H, halo, hydroxy, CN, amino, amido, carbamoyl, carboxylic acid, ester, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, C1-3 alkoxy, or C1.3 aminoalkyl; or R1 and R2 are tethered to form an optionally substituted carbocycle or heterocycle;L is a linker, optionally comprising one or more charge-modifying groups at either end of the linker, wherein * indicates an attachment point that attaches the linker to B, D, or E;X is a chelator optionally chelated with a radionuclide;U is H, halo, C1-3 alkyl, or C1-3 haloalkyl;V is O; orU and V are tethered to form an optionally substituted 5- or 6-membered heteroaryl; andW is a natural or unnatural amino acid.

4. The compound of any one of claims 1 to 3, wherein the compound comprises the structure of Formula (l-a):(l-a).

5. The compound of any one of claims 1 to 3, wherein the compound comprises the structure of Formula (l-b), Formula (I-c), or Formula (l-d):(l-b),(I-c), or6. The compound of any one of claims 1 to 3, wherein the compound comprises the structure of Formula (l-e):(l-e).

7. The compound of any one of claims 1 to 3, wherein the compound comprises the structure of Formula (I-f):X(I-f).

8. The compound of any one of claims 2 to 7, wherein each of Ri and Rs is OMe, R2 is H, and R4 is H or halo.

9. The compound of claim 1, wherein the compound comprises the structure of Formula II:(II),wherein:A is CH, CH2, or N;B is C, C=O, CH, CH2, or N;D is C, C=O, N, or N+-O-(N-oxide);E is C or CRC;F is CR4;wherein indicates a single bond or a double bond and at least one of A, B, and D is N;each of R2, Rs, R4, Ra, Rb, Rc, Rd, and Re, independently, is H, halo, hydroxy, CN, amino, amido, carbamoyl, carboxylic acid, ester, optionally substituted C1-3 alkyl, optionally substituted C1-3 haloalkyl, optionally substituted Cs-e cycloalkyl, optionally substituted C1-3 alkoxy, or optionally substituted C1-3 aminoalkyl; orR1 and R2are tethered to form an optionally substituted carbocycle or optionally substituted heterocycle;L is a linker, optionally comprising one or more charge-modifying groups;X is a chelator optionally chelated with a radionuclide;U is H, halo, C1-3 alkyl, or C1-3 haloalkyl;V is O; orU and V are tethered to form an optionally substituted 5- to 6-membered heteroaryl; andW is an optionally substituted natural or unnatural amino acid.

10. The compound of claim 9, wherein the compound comprises the structure of Formula II-a:R411. The compound of claim 10 or 11, wherein R3is OMe and R4is halo.

12. The compound of claim 1, wherein Ring C is substituted with halo.

13. The compound of any one of claims 2 to 10, wherein R4is halo.

14. The compound of claim 1, wherein the compound comprises the structure of Formula III:(HI),wherein:G is N or CRf;H is N, C, or CRg;J is N, C, or CRj;wherein no more than two N atoms are assigned to G, H, and J;each of Ri, R2, Rs, Re, Rf, Rg, Rh, Ri, and Rjindependently, is H, halo, hydroxy, CN, amino, amido, carbamoyl, carboxylic acid, ester, C1-6 alkyl, Cs-e cycloalkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 aminoalkyl; orR1 and R2 are tethered to form an optionally substituted carbocycle or optionally substituted heterocycle;Rs is H, optionally substituted aryl, or optionally substituted heteroaryl;L is a linker, optionally comprising one or more charge-modifying groups at either end of the linker, wherein * indicates an attachment point that attaches the linker to H or J;X is a chelator optionally chelated with a radionuclide;U is H, halo, C1-3 alkyl, or C1-3 haloalkyl;V is O; orU and V are tethered to form an optionally substituted 5- or 6-membered heteroaryl; andW is a natural or unnatural amino acid.

15. The compound of claim 14, wherein the compound comprises the structure of Formula III-a:(lll-a).

16. The compound of claim 14 or 15, wherein the compound comprises the structure of Formula lll-d:Xwherein:Ri and Rs are C1-3 alkoxy;Rs is optionally substituted aryl or optionally substituted heteroaryl; andRe is C1-6 alkyl.

17. The compound of any one of claims 14 to 16, wherein Rs is heteroaryl comprising at least one N, optionally substituted with C1.3 alkyl, or C1-3 alkoxy.

18. The compound of any one of claims 14 to 16, wherein Rs is phenyl optionally substituted with C1-3 alkyl or C1-3 alkoxy.

19. The compound of claim 14, wherein the compound comprises the structure of Formula III-e:

20. The compound of claim 14 or 19, wherein the compound comprises the structure of Formula lll-f:X(III-f)wherein:Ri and Rs are C1-3 alkoxy; andRe is C1-6 alkyl.

21. The compound of any one of claims 1 to 20, wherein W is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic acid, 2-amino-2-(adamantan-1-yl)acetic acid, 2-amino-2-(3-hydroxyadamantan-1-yl)acetic acid, cyclohexylglycine, and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid, wherein the backbone of each amino acid is optionally substituted with hydroxy, halo, alkoxy, or amino.

22. The compound of claim 21, wherein W is 2-amino-2-adamantane carboxylic acid, 2-amino-2-(adamantan-1-yl)acetic acid, or 2-amino-2-(3-hydroxyadamantan-1-yl)acetic acid.

23. The compound of any one of claims 1 to 22, wherein the linker comprises the structure of Formula L:J1-(Q1)g-(T1)h-(Q2)i-(T2)j-( Q3)k-(T3)|-(Q4)m-(T4)n-( Q5)o- J2Formula Lwherein J1is a bond attached to the compound; J2is a bond attached to chelator X; each of Q1, Q2, Q3, Q4, and Q5is, independently, optionally substituted C1-C40 alkylene, optionally substituted C1-C40 heteroalkylene, optionally substituted C1-C40 alkoxylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C2-C20 heterocycloalkylene, optionallysubstituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; each of T1, T2, T3, T4is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, imino, or oximo; R' is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C2-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; each of g, h, i, j, k, I, m, n, and 0 is, independently, 0, 1, or 2; and each of Q1, Q2, Q3, Q4, and Q5is, independently, optionally substituted with one or more charge-modifying groups.

24. The compound of any one of claims 1 to 23, wherein the linker is optionally substituted C1-50 alkyl, wherein one or more carbons are each, independently, replaced with O, S, NRX, O, O? / C=O, or+7 wherein Rxis H, C1-3 alkyl, or CH2COOH.

25. The compound of any one of claims 1 to 24, wherein the linker further comprises one to three charge-modifying groups at either end of the linker.

26. The compound of claim 25, wherein the charge-modifying group is an amino acid unit formed from a natural or unnatural amino acid.

27. The compound of claim 26, wherein the charge-modifying group is 4-amino-1-carboxymethyl-piperidine (ACMP), 2-aminohexanedioic acid (Aad), aspartic acid (Asp), or glutamic acid (Glu).

28. The compound of any one of claims 1 to 27, wherein the chelator is selected from the group consisting of 1,4,7,10-tetraazacyclotetradecane-1,4,7,10-tetraacetic acid (DOTA), 1,4, 7, 10-tetraazacyclododececane,1 -(glutaric acid)-4,7, 10-triacetic acid (DOTAGA), 1,4,7-triazacyclononane-triacetic acid (NOTA), 1,4,7-triazacyclononane-1-glutaric acid-4, 7-diacetic acid (NODAGA), 1,8-N, N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane (TE2A), 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 11, 13-triene-3,6,9-triacetic acid (PCT A), 1 -substituted 1,4,7,-tricarboxymethyl-1,4,7,10-teraazacyclododecane triacetic acid (DO3A), DEDPA (6,6’-[1,2-ethanediylbis(iminomethylene)]bis(2-pyridinecarboxylic acid) and 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), ethylenediaminetetraacetic acid(EDTA), diethylenetriamine pentaacetic acid (DTPA), NODASA, CB-DO2A, 3p-C-DEPA, TCMC, DO3A, DTPA, CHX-A”-DTPA, 1 B4M-DTPA, TETA, NOPO, Me-3,2-HOPO, CB-TE1A1P, CB-TE2P, MM-TE2A, DM-TE2A, sarcophagine, SarAr, SarAr-NCS, diamSar, AmBaSar, BaBaSar, TRAP, AAZTA, DATA, H2-macropa, H2dedpa, H4octapa, H4py4pa, H4Pypa, H2azapa, H5decapa, H4CHXoctapa, H4neunpa-p-Bn-NO2, CP256, PCTA, {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid (NET A), C-NETA, C-NE3TA, HBED, HBED-CC, BCPA, CP256, YM103, desferrioxamine (DFO), H6phospa, a trithiol chelate, mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1,2-ethylenediylbis-L-cysteine diethyl ester, methylenediphosphonate, N, N’-bis(2-hydroxy-5-sulfobenzyl)-ethylenediamine-N, N-diacetic acid (SHBED), hexamethylpropyleneamineoxime, hexakis(methoxy isobutyl isonitrile), 2,2',2",2"'-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7, 13, 16-tetrayl)tetraacetic acid (CROWN), CROWN Amide, PYTA, PY3A, PYTA-GA, PYTA-PE, and macropa-NCS.

29. The compound of any one of claims 1 to 28, wherein the chelator is chelated with a radionuclide selected from the group consisting of18F,44Sc,47Sc,61Cu,64Cu,67Cu,67Ga,68Ga,72AS, 77As, 86Y]89Zr89y, 90y, 90^ 94mTc, 99mTc, 105R h, 109pd, 111 |n114-1,^, 117mS n, 137QS, 141QS,140l_a,141Ce,142Pr,143Pr,145Pr,149Pm,149Tb,152Tb,155Tb,150Eu,153Sm,159Gd,161Tb,161Ho,166Ho,165Er,169Er,165Dy,166Dy,167Tm,170Tm,169Yb,175Yb,177Lu,186Re,188Re,198Au,199Au,203Pb,211At,211Fr,212Pb,212Bi,213Bi,223Ra,224Ra,225Ac,226Th, or227Th.

30. The compound of claim 1, wherein the compound is selected from T able 3, or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition for diagnostic or therapeutic use, comprising a compound of any one of claims 1 to 30 and a pharmaceutical excipient.

32. A method for imaging a tissue or cancer expressing or overexpressing neurotensin receptor 1 (NTSR1) in a patient, comprising administering to the patient in need thereof a compound of any one of claims 1 to 30, or the pharmaceutical composition of claim 31, with a radionuclide suitable for in vivo imaging.

33. A method for treating cancer expressing or overexpressing NTSR1 in a patient, comprising administering to the patient in need thereof a compound of any one of claims 1 to 30, or the pharmaceutical composition of claim 31, with a radionuclide suitable for radiotherapeutic treatment.

34. The method of claim 33, wherein the cancer is selected from the group consisting ofpancreatic ductal adenocarcinoma, small cell lung cancer, non-small cell lung cancer, breast cancer, bladder cancer, colorectal cancer, cervical cancer, gastrointestinal stromal tumors, head and neck cancer, meningioma, Ewing's sarcoma, pleural mesothelioma, prostate cancer, pancreatic cancer, uterine leiomyoma, and cutaneous T-cell lymphoma.

Images