Radiopharmaceuticals targeting somatostatin receptor 2 and uses thereof

Abstract

Provided herein are peptides and conjugates (e.g., radiopharmaceutical conjugates) having avidity for a somatostatin receptor and uses thereof. The conjugate can comprise a 6-mer peptide, such as a monocyclic 6-mer peptide, a metal chelator, and optionally a linker connecting the peptide to the chelator. The radiopharmaceutical conjugate can further comprise a radionuclide bound to the metal chelator. Further provided herein are methods of preparing the conjugates, and methods of treating cancer by administering the described conjugates to a subject in need thereof.

Description

RADIOPHARMACEUTICALS TARGETINGSOMATOSTATIN RECEPTOR 2 AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority of US Provisional Patent Application No. 63 / 614,474, filed December 22, 2023, which is incorporated by reference herein in its entirety for all purposes.REFERENCE TO SEQUENCE LISTING

[0002] The present application is being filed with a Sequence Listing in electronic format. The sequence listing filed, entitled “01277-0073-00PCT-RYZ_SL.xml” was created December 18, 2024, and is 754,191 bytes in size. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety.BACKGROUND

[0003] In the United States, cancer is the leading cause of death forthose under 65 years of age, and it accounted for about 21% of all deaths in 2018. Many tumors express certain biomarkers such as somatostatin receptors (SSTRs). For example, neuroendocrine tumors (NETs) arise from neuroendocrine cells and most commonly develop in the lung, digestive tract and pancreas. NETs are one of the cancers that need systemic therapies because either they are inoperable, or they are diagnosed at an advanced stage with distant spread of tumor cells. Traditional radiotherapies such as external beam radiation therapy have been used for decades as a standard-of-care treatment for diagnosed cancer patients. While some patients respond to external beam radiation therapy, many others do not. Further, metastasis and circulating tumor cells can spread and remain in the bloodstream or bodily fluids after standard-of-care treatment and lead to resistance to therapy. The presence of cancer cells in vanous parts of the body reduces the therapeutic efficacy of traditional radiotherapies. Accordingly, strategies for targeted radiotherapies are being developed for better cancer treatment and diagnosis.SUMMARY

[0004] In one aspect, the present disclosure relates to a peptide having avidity for a somatostatin receptor, wherein the peptide comprises a structure of Formula (I) or a salt thereof, X1-X2-X3-X4-X5-X6Formula (I) wherein. X1 is any amino acid;X2 is any amino acid;X3 is a non-natural, aromatic amino acid;X4 is a non-aromatic amino acid having a side chain comprising an amine;X5 is any amino acid; and X6 is any amino acid.In some embodiments, the peptide is a monocyclic peptide. In some embodiments, the peptide has a structure of Formula (II),

[0005] In one aspect, the present disclosure relates to a conjugate or a pharmaceutically acceptable salt thereof, wherein the conjugate comprises a monocyclic peptide having avidity for a somatostatin receptor, wherein the monocyclic peptide comprises a structure of Formula (II), wherein,X1 is any amino acid;X2 is any amino acid;X3 is a non-natural, aromatic amino acid;X4 is a non-natural amino acid having a side chain comprising an amine;X5 is any amino acid; andX6 is any amino acid.In some embodiments, the conjugate further compri ses a metal chelator covalently connected to the monocyclic peptide. In some embodiments, the metal chelator is connected to the monocyclic peptide through a linker. In some embodiments, the conjugate has a structure of Formula (III),wherein,L is a linker; s is 0 or 1 ; andCL is a metal chelator.In some embodiments, CL-(L)S- is attached to X1, X2, or X6. In some embodiments, s is 0 and the linkeris a bond. In some embodiments, the conjugate further comprises a radionuclide bound to the metal chelator. In some embodiments, the metal chelator comprises DOTA, DOTA -GA, pBn-DOTA, pBn- SCN-DOTA, NH2-D0TA, NH2-DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn- oxo-DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn-NOTA, p-SCN- Bn-NOTA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p- SCN-Bn-HEHA, H2-MACROPA-NCS, Hl-MACROPA, H2-MACROPA-NH2, H4-OCTAPA, tetra-(S,S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTAIn some embodiments, wherein the metal chelator has a structure ofIn some embodiments, the radionuclide is an alpha particle-emitting radionuclide. In some embodiments, the alpha particle-emitting radionuclide is Ac-225, At-211, Bi-213, Bi-209, Tb-149, Ra-223, Th-227, Fr- 223, Gd- 148, Th-229, Pb-212, or Po-213. In some embodiments, the alpha particle-emitting radionuclide is Ac-225, Bi-213, Bi-209, Tb-149, Ra-223, Th-227, Fr-223, Gd-148, Th-229, Pb-212, or Po-213. In some embodiments, the alpha particle-emitting radionuclide is Ac-225. In some embodiments, the radionuclide is a beta particle-emitting radionuclide. In some embodiments, the beta particle -emitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, or In-111, In some embodiments, the beta particle-emitting radionuclide is lutetium- 177. In some embodiments, the radionuclide is a positron-emitting radionuclide. In some embodiments, the positron-emiting radionuclide is Ga-68, Cu-62, Cu-64, Zr-89, Tb-152.

[0006] In some embodiments, X1 is an N-methylated amino acid. In some embodiments, XI is any amino acid comprising apolar side chain. In some embodiments, X1 is an L-amino acid. In some embodiments, X1 is Cys, Lys, Ala, Glu, Asp, Ser, Pro, or a derivative thereof. In some embodiments, XI is Cys, Lys, Ala, Glu, Asp, Ser, or a derivative thereof. In some embodiments, X1 is not Pro or a derivative thereof. In some embodiments, X1 has a structure of:wherein,R11is hydrogen or C1-C alky I optionally substituted with one to three substituents independently selected from Rf; each Rfis independently halogen, -CN, -NO2, -ORa, -SRaor -NRcRd;R11and Lv-R2are taken together with the intervening atoms to form a 5 - to 6- membered heterocycloalkyl, which is optionally substituted with one or more R12a.( )( )( ), ( ) , y , y, y y, y y, , , ==N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, aikynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Re; or, one of Rlaais a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo [6.1.OJnonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;R1’ is hydrogen or Ci-Csalkyl;with one or more Re; or Rcand Raare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X6 represents the point of attachment to X6; and*X2 represents the point of attachment to X2.

[0007] In some embodiments, X2 is an aromatic amino acid. In some embodiments, X2 is Tyr, Phe, Trp, His, Gly, Ala, or a derivative thereof. In some embodiments, X2 has a structure of:wherein:ring A2 is an aryl or heteroaryl;the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R22a; or two R are taken together to form =0, =S, or =N(Ra); m2 is 0, 1, 2, 3, 4, or 5;=N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, my I. heteroaiyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Rs; or, one of R22ais a conjugation group (CG);and heteroaryl is independently optionally substituted with one or more Re; or two RX2agroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocy cloalky 1 ring, each of which is optionally substituted with one or more Re; each Rais independently hydrogen, Ci-C6alkyl, C|-C6haloalkyl, Ci-C6hydroxy alkyl,CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo [6. 1 ,0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;form a heterocycloaikyl optionally substituted with one or more Re;*X1 represents the point of attachment to X1 ; and*X3 represents the point of attachment to X3.

[0008] In some embodiments, X3 is a non-natural amino acid comprising an optionally substituted N- containing 5- to 10- membered heteroaryl. In some embodiments, X3 has a structure of:wherein:R31is hydrogen or C1-C5 alkyl optionally substituted with one to three substituents independently selected from R1; each R: is independently halogen, -CN, -NO2, -ORa, -SRaor -NRcRd;LX3is a bond, -O-, -S-, -NR33-, Ci-C3alkylene, or Ci -C3heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more RX3a; ring A3 is an aryl or heteroaryl; each R32is independently Ci-Cgalkyl, C i-C(Jialoalkyl, C •( hydroxyalkyl, Ci-Cgaminoalkyl, C •• Cgheteroalkyl, Cs-Cgalkenyl, C2-Cgalkynyl, halogen, -CN, -NO2, -ORa, -SRa, -SF5, -NR°Rd, - S(=O)Ra, -S(=O)2Ra, -S(=O)2RcRd, -S(=O)(=NRa)Ra, -N=S(=O)R°Rd, -NRaS(=O)2Ra, amidinyl, - NRaC(=NH)NRcRd, -NRaS(=O)2RcRd, -C(O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, - OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroary l, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R ' : or two R32are taken together to form =0, =S, or =N(Ra); m3 is 0, 1, 2, 3, 4, or 5; each R32ais independently halogen, Ci-Cgalkyl, Ci-Cghaloalkyl, Ci-Cehydroxyalkyl, Ci- Cgaminoalkyl, Ci -Cgheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(==O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, - OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =0, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, an I. heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re;Ra3is hydrogen or Ci-Csalkyl;R34is hydrogen or Ci-Csalkyl;or two Rx,agroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re;form a heterocycloalkyl optionally substituted with one or more Re;*X2 represents the point of attachment to X2; and*X4 represents the point of atachment to X4.In some embodiments, X3 has a structure of:wherein:Y3iis N, CH, or CR32;Y32is N, CH, or CR32; Y33is N, CH, or CR32; Y34is N, CH, or CR32; Y33is N, or C; Y36is N or C;Y3 / is N, CH, or CR32; andY38is 0, S, N orNH; provided that no more than two of Y3‘, Y32, Y33, Y34, Y33, Y3D, and Y37are N.

[0009] In some embodiments, X4 is a non-natural amino acid having a side chain comprising an amine. In some embodiments, the amine comprises a primary amine, secondary amine, tertiary amine, or quaternary amine. In some embodiments, the amine comprises a primary amine, secondary amine, or tertiary amine. In some embodiments, the amine comprises a primary amine. In some embodiments, the amine comprises a secondary amine. In some embodiments, the amine comprises a tertiary amine. In some embodiments, the amine comprises a quaternary amine. In some embodiments, X4 is a non-natural amino acid having a side chain comprising an amine, and wherein the side chain comprises azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, X4 is anon-natural amino acid having a side chain comprising an amine, and the non-natural amino acid is a Lys derivative. In some embodiments, X4 has a structure of:wherein,R41is hydrogen or Ci -Csalkyl optionally substituted with one to three substituents independently selected from Rf;each Rfis independently halogen, -CN, -NO2, -ORa, -SRaor -NRcRd;attached to form a heterocycloalkyl optionally substituted with one or more Re;*X3 represents the point of atachment to X3; and*X5 represents the point of atachment to X5.

[0010] In some embodiments, X5 is an aliphatic amino acid or a polar amino acid. In some embodiments, X5 is Thr, Vai, Ala, Ser, Pro, or a derivative thereof. In some embodiments, X5 has a structure of:wherein,alky ny 1, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;with one or more Re; or Rcand RJare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;* X 4 represents the point of attachment to X4; and*X6 represents the point of attachment to X6.

[0011] In some embodiments, X6 is an aromatic amino acid, a hydrophilic amino acid, or Gly, or a derivative thereof. In some embodiments, X6 is Phe, Ala, Gly, Ser, His, Tyr, Asn, Pro, or a derivative thereof. In some embodiments, X6 has a structure of:wherein:CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo [6. 1.OJnonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;alkynyl, cycloalkyi, heterocydoalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Raare taken together with the atom to which they are attached to form a heterocydoalkyl optionally substituted with one or more Re;*X5 represents the point of attachment to X5; and*X1 represents the point of attachment to XI.In some embodiments, X6 has a structure of:wherein:heterocycloalkyl is optionally substituted with one or more R6; or, one of R64ais a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1.OJnonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or R° and Raare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X5 represents the point of attachment to X5; and*X1 represents the point of attachment to XI.

[0012] In some embodiments, X1 is NMe-Hcy, NMe-Lys, or NMe-hLys, NMe-Glu, orNMe-Amp; X2 is Tyr; X3 is D-Trp, (S-βMe)D-Trp, (S-βMe)-Trp, (R-βMe)D-Trp, or (R-βMe)-Trp; X4 is (S)-2-amino-3- (piperazin-l-yl)propanoic acid (PipzaA), (S)-2-amino-4-(azetidin-3-yl)butanoic acid (3-Azetidine-hAla), Lys(Me), (S)-2-amino-2-(piperidin-4-yl)acetic acid (Chg4N) or (S)-2-amino-3-(piperidin-4-yl)propanoic acid (Cha4N); X5 is Thr, Vai, Ala, or Alt; and X6 is Phe.

[0013] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a conjugate, or a pharmaceutically acceptable salt thereof, as described herein, and a pharmaceutically acceptable excipient or carrier.

[0014] In one aspect, the present disclosure relates to a method of treating a disease or disorder characterized by overexpression of SSTR, in a subject in need of treatment, the method comprisingadministering to the subject the conjugate or pharmaceutically acceptable salt thereof as described herein. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is a somatostatin receptor-positive (SSTR+) tumor. In some embodiments, provided herein is a method of killing an SSTR+ cell, comprising contacting the cell with a conjugate described herein.

[0015] In one aspect, the present disclosure relates to a kit, tester, or composition for determining the expression level of SSTR in a sample, wherein the kit, tester, or composition comprises the conjugate or pharmaceutically acceptable salt thereof as described herein.

[0016] In one aspect, the present disclosure relates to the use of the conjugate or pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for diagnosing and / or treating a disease or disorder characterized by an overexpression or a decreased expression of SSTR.

[0017] In one aspect, the present disclosure relates to the use of the conjugate or pharmaceutically acceptable salt thereof as described herein for use in diagnosing and / or treating a disease or disorder characterized by an overexpression or a decreased expression of SSTR.INCORPORATION BY REFERENCE

[0018] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The novel features of the disclosure are set forth with particularity' in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which tire principles of the disclosure are utilized, and the accompanying drawing (also “figure” and “FIG.” herein), of which:

[0020] FIG. 1A illustrates exemplary metal chelators of the present disclosure, whereinrepresents the attachment point of a metal chelator to tire remaining conjugate. FIG. IB illustrates the same metal chelators as FIG. 1 A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle

[0021] FIG. 2A illustrates exemplary metal chelators of the present disclosure, whereinrepresents the attachment point of a metal chelator to the remaining conjugate. FIG. 2B illustrates the same metal chelators as FIG. 2A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle

[0022] FIG. 3A illustrates exemplary' metal chelators of the present disclosure, whereinrepresents the attachment point of a metal chelator to the remaining conjugate. FIG . 3B illustrates the same metal chelators as FIG. 3A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle

[0023] FIG. 4A illustrates exemplary' metal chelators of the present disclosure, wherein representsthe attachment point of a metal chelator to the remaining conjugate. FIG. 4B illustrates the same metal chelators as FIG. 4A, except tliat a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle.

[0024] FIG. 5A illustrates exemplary metal chelators of the present disclosure, whereinrepresents the attachment point of a metal chelator to the remaining conjugate. FIG. 5B illustrates the same metal chelators as FIG. 5 A, except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circleand R represents hydrogen, alkyl (such as methyl) or other suitable group on the nitrogen.

[0025] FIG. 6 illustrates the structures of representative metal chelators.

[0026] FIG. 7 illustrates the structures of representative metal chelators.

[0027] FIG. 8 illustrates the structures of representative metal chelators.

[0028] FIG. 9 illustrates the structures of representative metal chelators.

[0029] FIG. 10 illustrates the structures of representative metal chelators.

[0030] FIG. 11 illustrates the structures of representative metal chelators.

[0031] FIG. 12 illustrates the structures of representative metal chelators.

[0032] FIG. 13 illustrates the structures of representative metal chelators.

[0033] FIG. 14 illustrates the structures of representative metal chelators.

[0034] FIG. 15 illustrates the structures of representative metal chelators.

[0035] FIG. 16 illustrates the structures of representative metal chelators.

[0036] FIG. 17 illustrates the structures of representative metal chelators.

[0037] FIG. 18 illustrates the structures of representative metal chelators.

[0038] FIG. 19 illustrates the structures of representative metal chelators.

[0039] FIG. 20 illustrates the structures of representative metal chelators.

[0040] FIG. 21 illustrates the structures of representative metal chelators.

[0041] FIG. 22 illustrates the structures of representative metal chelators.

[0042] FIG. 23 illustrates the structures of representative metal chelators.

[0043] FIG. 24 illustrates the structures of representative metal chelators.

[0044] FIG. 25 illustrates the structures of representative metal chelators.DETAILED DESCRIPTION

[0045] The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope.

[0046] Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments forclarity, the present disclosure may also be implemented in a single embodiment.

[0047] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0048] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0049] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.I, Definitions

[0050] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0051] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, reference to “a stabilizer” includes a plurality of such stabilizers, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0052] 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 mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5 -fold, or within 2-fold, of a value.

[0053] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features

[0054] “Amine” refers to a moiety formally derived from ammonia (NFfi) by replacing one, two, or three hydrogen atoms. In some embodiments, the amine is a primary amine, a secondary amine, a tertiary amine, or a quaternary amine. In some embodiment, the amine is present in a heterocycloalkyl. In some embodiments, the amine is present in an aminoalkyl. In some embodiments, the amine is present in analkylamino. In some embodiments, the amine is present in an amino group. In some embodiments, “Amine” refers to a moiety having the formula N(R«)2where Ra is hydrogen or an alkyl radical as defined herein, or two Ra, taken together with the nitrogen atom, can form a substituted or unsubstituted C2-C7heterocyloalkyl ring. In some embodiments, the side chain comprising an amine is a side chain comprising a primary amine, a secondary amine, a tertiary amine, or a quaternary amine. In some embodiments, the side chain comprising an amine is a side chain comprising a heterocycloalkyl In some embodiments, the side chain comprising an amine is a side chain comprising an aminoalkyl. In some embodiments, the side chain comprising an amine is a side chain comprising an alkylamino.

[0055] "Amino" refers to the -NH2radical.

[0056] "Cyano" refers to the CN radical.

[0057] "Nitro" refers to the NO2radical.

[0058] "Oxo" refers to the =0 radical.

[0059] "Imino" refers to the =N-H radical.

[0060] "Oximo" refers to the =N-0H radical.

[0061] "Hydrazine" refers to the =N-NH2radical.

[0062] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0063] “Acyl” refers to a substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide, or ester, wherein the carbonyl atom of the carbonyl group is the point of attachment. Unless stated otherwise specifically in the specification, an alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, amide group, or ester group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0064] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical. An alkyl group can have from one to about twenty carbon atoms, from one to about ten carbon atoms, or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2 -methyl- 1 -propyl, 2-methyl-2 -propyl, 2-methyl-l- butyl, 3-methyl-l-butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l-pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl -2 -pentyl, 2,2-dimethyl-l -butyl, 3,3- dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cw alkyl, a C1-C9 alkyl, a Ci-Cs alkyl, a C1-C7 alkyl, a Ci-Ce alkyl, a Ci- C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile,nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, -NO2, or -C=CH. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, or - OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0065] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alkylene is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH(CH3)CH2-. In some embodiments, the alkylene is -CH2-. In some embodiments, the alkylene is -CH2CH2-. In some embodiments, the alkylene is -CH2CH2CH2-.

[0066] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds. In some embodiments, an alkenyl group has from two to about ten carbon atoms, or two to about six carbon atoms. The group may be in either the cis or trans configuration about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl [C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-Cio alkenyl, a C2-C2alkenyl, a C2-Cs alkenyl, a C2-C? alkenyl, a C2-Cs alkenyl, a C2-Cs alkenyl, a C2-C4 alkenyl, a C2-C3alkenyl, or a C2alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, - CN, -CF3, OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0067] The term “alkenylene” or “alkenylene chain” refers to an optionally substituted straight or branched divalent hydrocarbon chain in which at least one carbon-carbon double bond is present linking the rest of the molecule to a radical group. In some embodiments, the alkenylene is -CH=CH-, - CH2CH=CH-, or -CH=CHCH2-. In some embodiments, the alkenylene is -CH=CH-. In some embodiments, the alkenylene is -CH2CH=CH-. In some embodiments, the alkenylene is -CH=CHCH2-.

[0068] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds. In some embodiments, an alkynyl group has from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and thelike. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a Ch-Ch alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2alkynyl Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. The term “alkynylene” refers to an optionally substituted straightchain or optionally substituted branched-chain divalent hydrocarbon having one or more carbon-carbon triple-bonds.

[0069] “Alkylamino” refers to a radical of the formula N(Ra)2where Ra is an alkyl radical as defined herein, or two Ra, taken together with the nitrogen atom, can form a substituted or unsubstituted C2-C7 heterocyloalkyl ring. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an alkylamino is optionally substituted with oxo, halogen, -CN, -CF3, OH, or -OMe. In some embodiments, the alkylamino is optionally substituted with halogen.

[0070] “Alkoxy” refers to a radical of the formula ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0071] “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, aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. An aminoalkyl group may be a primary aminoalkyl group, e.g., a radical of the formula -alkyl-NH2, a secondary aminoalkyl group, e g., a radical of the formula -alkyl-NHR,, a tertiary aminoalkyl group, e g., a radical of formula -alkyl-NiFUfi. or a quaternary aminoalkyl group, e.g., a radical of formula -alkyl- N+(Ra)3, wherein R is an alkyl radical as defined herein, or two Ra, taken together with the nitrogen atom, can form a substituted or unsubstituted C2-C7 heterocyloalkyl ring. Unless stated otherwise specifically in the specification, an aminoalkyl group may be optionally substituted, for example, withoxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aminoalkyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, -OMe, NH2, or -N02. In some embodiments, an aminoalkyl is optionally substituted with oxo, halogen, -CN, -CF3, OH, or -OMe. In some embodiments, the aminoalkyl is optionally substituted with halogen

[0072] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyl groups. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyls include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0073] The term “aryl” refers to a radical comprising at least one aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted. In some embodiments, an aryl group comprises a partially reduced cycloalkyl group defined herein (e.g., 1,2-dihydronaphthalene). In some embodiments, an aryl group comprises a fully reduced cycloalkyl group defined herein (e.g., 1,2,3,4-tetrahydronaphthalene). When aryl comprises a cycloalkyl group, the aryl is bonded to the rest of the molecule through an aromatic ring carbon atom. An aryl radical can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused, spiro or bridged ring systems. Unless stated otherwise specifically m the specification, an aryl may be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-CI- Cgalkyl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3, -S(O)2NHCH2CH3, -S(O)2NHCH(CH3)2, - S(O)2N(CH3)2, or -S(O)2NHC(CH3)3. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. In some embodiments, the aryl is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted, or substituted with halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2

[0074] 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. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, a cycloalkyl is fully saturated. In some embodiments, a cycloalkyl is partially saturated (e.g., comprising more or more carbon-carbon double bond). In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non- aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl is cyclopentyl In some embodiments, the monocyclic cycloalkyl is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl is cyclopentenyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4- dihydronaphthalenyl-l(2H)-one, spiro[2.2]pentyl, norbomyl and bicycle [1.1.1] pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (Cf-G cycloalkyl), from three to six carbon atoms (C3-C, cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). A cycloalkyl can comprise a fused, spiro or bridged ring system. In some embodiments, the cycloalkyl comprises a fused ring system. In some embodiments, the cycloalkyl comprises a spiro ring system. In some embodiments, the cycloalkyl comprises a bridged ring system. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, cis-decalm, trans-decalm, bicyclo [2. l.l]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0075] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0076] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl can include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl. For example, "fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2trifluoroethyl, lfluoromethyl2fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical isoptionally substituted as defined above for an alkyl group.

[0077] “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. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e g., oxygen, nitrogen (e g -NH-, -N(alkyl)- ), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of heteroalkyl are, for example, -CH2-O-CH3, -CEb-N(alkyl)- CH3, -CH2-N(aryl)-CH3-OCH2CH2OH, -OCH2CH2OCH2CH2OH, or - OCH2CH2OCH2CH2OCH2CH2OH. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, - OMe, NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0078] As used herein, a “heteroalkylene” refers to divalent heteroalkyl group. Examples of such heteroalkylene are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, - OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-

[0079] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one 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 atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quatemized. The heterocycloalkyl radical is partially or fully saturated. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl is partially saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, loxothiomorpholinyl, l,ldioxothiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring and 3 or 4 N atoms. In some embodiments, heterocycloalkyls have from 2 to12 carbons, 0-2 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 12 carbons, 1-3 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring) Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0080] “Heteroaryl” refers to a ring system radical comprising carbon atom(s) and one or more ring heteroatoms that 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, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofiiran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-6 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, 0-1 P atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a Ce-Cg heteroaryl. In some embodiments, a heteroaryl group comprises a partially reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 7,8-dihydroquinoline). In some embodiments, a heteroaryl group comprises a fully reduced cycloalkyl or heterocycloalkyl group defined herein (e.g., 5,6,7,8-tetrahydroquinoline). When heteroaryl comprises a cycloalkyl or heterocycloalkyl group, the heteroaryl is bonded to the rest of the molecule through a heteroaromatic ring carbon or hetero atom. 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.Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0081] 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.

[0082] 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. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. 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.

[0083] In certain embodiments, “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.

[0084] The term "therapeutically effective amount" as used herein to refer 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 of the protein to elicit the desired response of the individual. A therapeutically effective amount can also be an amount that exceeds any toxic or deleterious effect of the composition that would have a beneficial effect on the treatment.

[0085] 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 either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (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 ).

[0086] 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 is assumed 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.

[0087] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). For example, “optionally substituted” or “substituted” can mean that the referenced group is optionally substituted with one or more substituents individually and independently selected from halogen, -CN, -NHz, -NH(alkyl), -N(alkyl)2, -OH, oxo, -COzH, - COzalkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, - NH(CH3), -N(CH3)2, -OH, OXO, -C02H, -CO2(Ci-C4alkyl), -C(=0)NH2, -C(=O)NH(Ci-C4alkyl), - C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(Ci-C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0) When indicating the number of substituents, the term “one or more” means from one substituent to the highest possible number of substitutions, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents. In some embodiments, an “optionally substituted” group is unsubstituted. In some embodiments, an “optionally substituted” group is independently substitued with 1-6 substituents. In some embodiments, an “optionally substituted” group is independently substitued with 1-3 substituents. In some embodiments, an “optionally substituted” group is independently substitued with 1- 2 substituents.

[0088] The term “unsubstituted” means that the specified group bears no substituents.

[0089] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds being within the scope of the disclosure.

[0090] 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.

[0091] In the present disclosure, the term “amino acid” is used in its broadest meaning and it embraces not only natural amino acids but also derivatives thereof and unnatural amino acids. For example, the term “ammo acid” encompasses unnatural or non-natural ammo acids, and peptoids.

[0092] As used herein, the term “unnatural amino acid” or “non-natural amino acid” refers to an amino acid other than the 20 canonical amino acids. The 20 canonical amino acids refer to alanine (ala or A), arginine (arg or R), asparagine (asn or N), aspartic acid (asp or D), cysteine (cys or C), glutamine (gin or Q), glutamic acid (glu or E), glycine (gly or G), histidine (his or H), isoleucine (ile or I), leucine (leu or L), lysine (lys or K), methionine (met or M), phenylalanine (phe or F), proline (pro or P), serine (ser or S), threonine (thr or T), tryptophan (trp or W), tyrosine (tyr or Y), and valine (val or V). As used herein, canonical amino acids are L- amino acids.

[0093] In some embodiments, an amino acid described herein can be replaced with a derivative thereof. Examples of an amino acid derivatives include derivatives having an amine, amide, ester, or carboxyl group as the C-terminus and / or N-terminus thereof. An amino acid derivative further encompasses amino acid isomers, including D-amino acids. An amino acid derivative further encompasses alkylated amino acids, for example N-alkylation (e g., N-methylation), beta-carbon alkylation or alpha-carbon alkylation. In some embodiments, a derivative of an amino acid is the amino acid with alpha-carbon alkylation. In some embodiments, a derivative of an amino acid is the amino acid with beta-carbon alkylation. In some embodiments, a derivative of an amino acid is the amino acid with N-alkylation. An amino acid derivative further encompasses the amino acids that have the same functional groups but with differentlengths of the side chain (e.g., LysAc vs. OmAc and cysteine vs. homocysteine). An amino acid derivative further encompasses amino acids with heteroatoms in the side chain (e.g., O-(aminomethyl)- homoserine is a derivative of lysine and serine). An amino acid derivative further encompasses amino acids containing conjugation groups, including azides and alkynes. For example, propargylglycine is a derivative of alanine, and azidolysine is a derivative of lysine. An amino acid derivative further encompasses amino acids with a different aromatic moiety compared to the canonical amino acid (e.g., the indole in tryptophan vs the 7-azaindole in 7-AzaTrp; the phenyl in phenylalanine vs the pyridine in 4Py). An amino acid derivative further encompasses amino acids with optional substituents, i.e., optionally substituted amino acid.

[0094] In some embodiments, an amino acid derivative refers to an optionally substituted amino acid. In some embodiments, an optionally substituted amino acid is optionally substituted with one or more substituents described herein. For example, in some embodiments, an optionally substituted amino acid is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, amino, amide, nitro, ureidoy y y y y , membered heterocycloalkyl, and 6-to 10- membered heteroaryl. In some embodiments, the optionally substituted amino acid is optionally substituted with one or more substituents independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, oxo, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, - C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH2), SF5, RbORa, RbOC(O)Ra, RbOC(O)ORa, RbOC(O)N(Ra)2, RbN(Ra)2, RbC(O)Ra, RbC(O)ORa, RbC(O)N(Ra)2, RbORcC(O)N(Ra)2, RbN(Ra)C(O)ORa, RbN(Ra)C(O)Ra, RbN(Ra)S(O)tRa(where t is 1 or 2), RbS(O)tRa(where t is 1 or 2), RbS(O)tORa(where t is 1 or 2), and RbS(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), RbORa, RbOC(O)Ra, RbOC(O)ORa, RbOC(O)N(Ra)2, RbN(Ra)2, RbC(O)Ra, RbC(O)ORa, RbC(0)N(Ra)2, RbORcC(O)N(Ra)2, RbN(Ra)C(O)ORa, RbN(Ra)C(O)Ra, RbN(Ra)S(O)tRa(where t is 1 or 2), RbS(O)tRa(where t is 1 or 2), RbS(O)tORa(where t is 1 or 2) and RbS(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), Rb0Ra, RbOC(O)Ra, RbOC(O)ORa, Rb0C(0)N(Ra)2, RbN(Ra)2, RbC(0)Ra, RbC(O)ORa, RbC(0)N(Ra)2, RbORcC(O)N(Ra)2, RbN(Ra)C(O)ORa, RbN(Ra)C(O)Ra, RbN(Ra)S(0)tRa(where t is 1 or 2), RbS(O)tRa(where t is 1 or 2), RbS(O)tORa(where t is 1 or 2) and RbS(O)tN(Ra)2(where t is 1 or 2); and whereineach Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. Additional examples of amino acid / peptide derivatives include those obtained by modification such as phosphorylation, alkylation (e.g., methylation), acetylation, adenylylation, ADP-ribosylation, or glycosylation. These derivatives can be prepared by those skilled in the art in a known manner or a method based thereon.

[0095] In some embodiments, an amino acid comprising a cycloalkyl group can be a derivative of another amino acid having a cycloalkyl group. In some embodiments, an amino acid comprising a heterocycloalkyl group can be a derivative of another amino acid having a heterocycloalkyl group.

[0096] In some embodiments, a derivative of an amino acid is selected from amino acids that have similar polarity and / or charge with the amino acid. For example, in some embodiments, a polar, uncharged amino acid can be a derivative of another polar, uncharged amino acid (e.g., Hgn, Q, S, T, Qglucamine).

[0097] In some embodiments, a derivative of an amino acid has the same number of hydrogen donor as the amino acid. In some embodiments, a derivative of an amino acid has the same number of hydrogen acceptor as the amino acid.

[0098] In some embodiments, the amino acid derivative has a molecular weight that does not vary for more than 14, 28, 30, 45, or 60 g / mol compared to the amino acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 14 g / mol compared to the amino acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 50 g / mol compared to the amino acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 28 g / mol compared to the ammo acid.

[0099] An ammo acid derivative further encompasses amino acids wherein a functional group is substituted with another functional group having similar properties, e.g., a cysteine can be substituted with a homocysteine. In some embodiments, an aryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, a heteroaryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, an amino functional group can be substituted with an NH(alkyl) group.

[0100] The term “protein” as used herein refers to a polypeptide (i.e., a string of at least 3 amino acids linked to one another by peptide bonds). Proteins can include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and / or can be otherwise processed or modified. A protein can be a complete polypeptide as produced by and / or active in a cell (with or without a signal sequence). In some embodiments, a protein is or comprises a characteristic portion such as a polypeptide as produced by and / or active in a cell. A protein can include more than one polypeptide chain. For example, polypeptide chains can be linked by one or more disulfide bonds or associated by other means.

[0101] The term “peptide” as used herein refers to a compound that includes two or more amino acids. A peptide described herein can comprise one or more unnatural amino acids. The term “peptide” also encompasses peptide mimetics.

[0102] The term “peptide mimetic” or “mimetic” refers to biologically active compounds that mimic the biological activity of a peptide or a protein but are no longer entirely peptidic in chemical nature, e.g., they can contain non-peptide bonds (that are, bonds other than amide bonds between amino acids). As used herein, the term peptide mimetic is used in a broader sense to include molecules that are no longer completely peptidic in nature, such as pseudo-peptides, semi-peptides and peptoids. Whether completely or partially non-peptide, peptide mimetics described herein can provide a spatial arrangement of reactive chemical moieties that closely resemble the three-dimensional arrangement of active groups in the subject amino acid sequence or subject molecule on which the peptide mimetic is based. As a result of this similar active-site geometry, the peptide mimetic can have effects on biological systems that are similar to the biological activity of the subject entity.

[0103] In some embodiments, the peptide mimetics are substantially similar in both three-dimensional shape and biological activity to the subject amino acid sequence or subject molecule on which the peptide mimetic is based. Examples of methods of structurally modifying a peptide to create a peptide mimetic include the inversion of backbone chiral centers leading to D-amino acid residue structures that may, particularly at the N-terminus, lead to enhanced stability for proteolytical degradation without adversely affecting activity. An example is described in the paper “Tritiated D-alal -Peptide T Binding”, Smith C. S. et al., Drug Development Res., 15, pp. 371-379 (1988). A second method is altering cyclic structure for stability, such as N to C interchain imides and lactames (Ede et al. in Smith and Rivier (Eds.) “Peptides: Chemistry and Biology”, Escom, Leiden (1991), pp. 268-270). An example of this is provided in conformationally restricted thymopentin-like compounds, such as those disclosed in US4457489. A third method is to substitute peptide bonds in the subject entity by pseudopeptide bonds that confer resistance to proteolysis.

[0104] The term “organic atoms” refers to atoms which would be found in organic compounds, such as carbon, hydrogen, nitrogen, oxygen, sulfur, phosphorus, fluorine, chlorine, bromine, or iodine. In some embodiments, an organic atoms refers to carbon, nitrogen, oxygen, sulfur, or phosphorus.

[0105] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 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, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0106] As used herein, Ci-Cx (or Ci-x) includes C1-C2, C1-C3... Ci-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkylgroup is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Also, by way of example, C0-C2alkylene includes a direct bond, -CH2-, and -CH2CH2- linkages.

[0107] The term “cyclized” or “cyclization” as used herein means that two amino acids apart from each other by at least one amino acid bind directly or bind indirectly to each other in one peptide to form a cyclic structure in the molecule. In some cases, the two amino acids bind via a linker or the like.

[0108] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a companion animal such as a dog or a cat. In one aspect, the mammal is a human.

[0109] Percent sequence identity can be calculated using computer programs or direct sequence comparison. Preferred computer program methods to determine identity between two sequences include, but are not limited to, the GCG program package, FASTA, BLASTP, and TBLASTN (see, e g., D. W. Mount, 2001, Bioinformatics: Sequence and Genome Analysis, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.). The BLASTP and TBLASTN programs are publicly available from NCBI and other sources. The Smith Waterman algorithm can also be used to determine percent identity. Exemplary parameters for amino acid sequence comparison include the following: 1) algorithm from Needleman and Wunsch (J. Mol. Biol., 48:443-453 (1970)); 2) BLOSSUM62 comparison matrix from Hentikoff and Hentikoff (Proc. Nat. Acad. Sci. USA., 89: 10915-10919 (1992)) 3) gap penalty-! 2: and 4) gap length penalty=4. A program useful with these parameters can be publicly available as the “gap” program (Genetics Computer Group, Madison, Wis.). The aforementioned parameters are the default parameters for polypeptide comparisons (with no penalty for end gaps). Alternatively, polypeptide sequence identity can be calculated using the following equation: % identity - (the number of identical residues) / (alignment length in amino acid residues)* 100. For this calculation, alignment length includes internal gaps but does not include terminal gaps.

[0110] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub combination. For example, a conjugate of this disclosure can comprise any peptide ligand described herein (e.g., a peptide ligand of Formula (I), (I’), (I”), (II), or Table 1), any metal chelator described herein (e.g., a metal chelator selected from FIGs 1A, IB, 2A, 2B, 3A, 3B, 4A, 4B, 5A, 5B, and 6-25), optionally a linker described herein (e g., a linker of Formula (V-l), (V-la), or (V-lb)), and optionally a radionuclide described herein (e g., a radionuclide of Table 4). For another example, a peptide of Formula (I), (I’), (I”), or (II) can comprise X1 to X6 amino acids as described herein, and any combinations of the embodiments of amino acids are encompassed by this disclosure (even though, in some cases, they are described in the context of separate embodiments). As another example, the disclosure also encompass any conjugates thatcomprises a structure of Table 3 and a radionuclide of Table 4.

[0111] Unless special definitions are given, the terminology used in relation to analytical chemistry, synthetic organic chemistry, and medical chemistry and pharmaceutical chemistry described in the present specification, as well as their procedures and techniques, are well known and commonly used in the field of the present art. Standard techniques may be used for chemical synthesis and chemical analysis. Those defined from among such techniques and procedures can be found in, for example, “K.J. Jensen, P.T. Shelton, S.L. Pedersen, Peptide Synthesis and Applications, 2nd Edition, Springer, 2013” and the like, and these are incorporated into the present specification by reference for all purposes. All patents, applications, published applications, and other publications, and other data referred to throughout the entire disclosure, when permitted, are incorporated into the present specification by reference.IL Peptides and Radiopharmaceutical Conjugates

[0112] Targeted Radiopharmaceuticals (TRP) are a new generation of nuclear medicine for cancer treatment or diagnosis. A TRP can selectively deliver high concentrations of radionuclide-containing molecules to the target cells such as a tumor, and no or very low concentrations to the undesired cells present in normal, healthy tissues. The process can be achieved by engineering the drug molecule with the high-affinity binder (e.g., targeting ligands) and linking it to the radioactive isotope. The biological targets of these binders are highly expressed on tumor cells and have low or no expression in healthy tissues and organs. When the radioisotope decays, it emits highly energic ionizing radiation in form of alpha, beta, and / or gamma particles. The released energy at the target sites can cause damage or death of the target tissues or be visualized by imaging scanner to achieve therapeutic or diagnostic purposes.

[0113] Provided herein are radiopharmaceutical conjugates, or a pharmaceutically acceptable salt thereof, that have avidity for the somatostatin receptor and pharmaceutical compositions comprising the conjugates. Also provided herein are peptides, or a pharmaceutically acceptable salt thereof, that have avidity for the somatostatin receptor and pharmaceutical compositions comprising the peptides. The conjugates, peptides, and compositions can be useful for treating cancer. The conjugates, peptides, and compositions can also be useful in imaging and disease diagnosis.

[0114] In one aspect, described herein is a peptide having avidity for a somatostatin receptor (SSTR), wherein the peptide comprises a structure of Formula (I) or a salt thereof,X1-X2-X3-X4-X5-X6Formula (I) wherein, X1 is any amino acid;X2 is any amino acid;X3 is a non-natural, aromatic amino acid;X4 is a non-aromatic amino acid having a side chain comprising an amine;X5 is any amino acid; and X6 is any amino acid.

[0115] In one aspect, described herein is a peptide having avidity for a somatostatin receptor (SSTR), wherein the peptide comprises a structure of Formula (I’) or a salt thereof,X1-X2-X3-X4-X5-X6Formula (I’) wherein, X1 is any amino acid;X2 is any amino acid;X3 is an aromatic amino acid;X4 is a non-aromatic amino acid having a side chain comprising an amine;X5 is any amino acid; andX6 is any amino acid.In some embodiments, X3 is a Trp

[0116] In one aspect, described herein is a peptide having avidity for a somatostatin receptor (SSTR), wherein the peptide comprises a structure of Formula (I”) or a salt thereof,X1-X2-X3-X4-X5-X6Formula (I”) wherein, X1 is any amino acid;X2 is any amino acid;X3 is non-natural, aromatic amino acid;X4 is a Lys;X5 is any amino acid; andX6 is any amino acid.

[0117] In some embodiments of Formula (I), (I'), or (F ’), the SSTR is a human SSTR. In some embodiments, the SSTR is somatostatin receptor type 1 (SSTR1), somatostatin receptor type 2 (SSTR2), somatostatin receptor type 3 (SSTR3), somatostatin receptor type 4 (SSTR4), and / or somatostatin receptor type 5 (SSTR5). In some embodiments, the SSTR is SSTR2. In some embodiments, the peptide is cyclic or acyclic. In some embodiments, the peptide is cyclic. In some embodiments, the peptide is monocyclic and has a structure of Formula (II), or a pharmaceutically acceptable salt thereof:

[0118] In some embodiments, the peptide of Formula (I), (T), (I”), or Formula (II), or a pharmaceutically acceptable salt thereof, is a conjugate having avidity for a somatostatin receptor. In some embodiments, the conjugate further comprises a metal chelator covalently connected to the peptide. In some embodiments, the metal chelator is configured to bind with a radionuclide. In someembodiments, the metal chelator is covalently connected to the monocyclic peptide through a linker. In some embodiments, the conjugate has a structure of Formula (III), or a pharmaceutically acceptable salt thereof: wherein.L is a linker; s is 0 or 1; andCL is a metal chelator.

[0119] In some embodiments of Formula (III), CL-(L)S- is attached to the monocyclic peptide at any suitable position. In some embodiments, the conjugate has the structure of Formula (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6):wherein.L is a linker; s is 0 or 1 ; andCL is a metal chelator.

[0120] In some embodiments, CL-(L)S- is attached to the monocyclic peptide at XI, X2, or X6. In some embodiments, the conjugate has the structure of Formula (IV1), (IV2), or (IV6):wherein,L is a linker; s is 0 or 1; andCL is a metal chelator.

[0121] In some embodiments, the conjugate has the structure of Formula (IV 1)Formula (IV1). In some embodiments, the conjugate has the structure ofFormula (IV2)Formula (IV2). In some embodiments, the conjugate has the structure of Formula (IV6)Formula (IV6). In some embodiments, s is 0 and the metal chelator is attached directly to the monocyclic peptide (e g., the linker is a bond). In some embodiments, s is 1 and the metal chelator is attached to the monocyclic peptide through the linker L.

[0122] In some embodiments, a conjugate of Formula (III), (IV 1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, comprises a radionuclide bound to the metal chelator.

[0123] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X1 is an N-alkylated amino acid. In some embodiments, X1 is an N-methylated amino acid. In some embodiments, X1 is any amino acid comprising apolar side chain. In some embodiments, X1 is an L-amino acid. In some embodiments, XI is an N-methylated L-amino acid comprising a polar side chain. In some embodiments, XI is Cys, Lys, Ala, Glu, Asp, Ser, Pro, or a derivative thereof. In some embodiments, X1 is Cys, Lys, Ala, Glu, Asp, Ser, or a derivative thereof. In some embodiments, X1 is Cys or a derivative thereof. In some embodiments, X1 is Lys or a derivative thereof. In some embodiments, X1 is Ala or a derivative thereof. In some embodiments, X1 is Glu or a derivative thereof. In some embodiments, X1 is Asp or a derivativethereof. In some embodiments, X1 is Ser or a derivative thereof. In some embodiments, XI is Gly. In some embodiments, X1 is Pro or a derivative thereof. In some embodiments, X1 is not Pro or a derivative thereof. In some embodiments, X1 is Pro, Hyp, Cha4N, Chg4N, NMe-Cha4N, NMe-Chg4N, NMe-Dap, NMe-Dab, NMe-Om, NMe-Lys, NMe-Azidolysine, NMe-hLys, 4-oxa NMe-Lys, NMe-Ala, NMe-Amp, NMe-Nle, NMe-propargyl glycine, NMe-propargyl alanine, NMe-Asp, NMe-Cys, NMe-Hcy, NMe- hHcy, NMe-Glu, NMe-hGlu, NMe-Hse, orNMe-Hse(Se). In some embodiments, X1 is Cha4N, Chg4N, NMe-Cha4N, NMe-Chg4N, NMe-Dap, NMe-Dab, NMe-Om, NMe-Lys, NMe-Azidolysine, NMe-hLys, 4-oxa NMe-Lys, NMe-Ala, NMe-Amp, NMe-Nle, NMe-propargyl glycine, NMe-propargyl alanine, NMe-Asp, NMe-Cys, NMe-Hcy, NMe-hHcy, NMe-Glu, NMe-hGlu, NMe-Hse, or NMe-Hse(Se).In some embodiments, X1 is optionally substituted Pro. In some embodiments, X1 is optionally substituted Hyp. In some embodiments, X1 is optionally substituted Cha4N. In some embodiments, XI is optionally substituted Chg4N. In some embodiments, X1 is optionally substituted NMe-Cha4N. In some embodiments, X1 is optionally substituted NMe-Chg4N. In some embodiments, X1 is optionally substituted NMe-Dap. In some embodiments, X1 is optionally substituted NMe-Dab. In some embodiments, X1 is optionally substituted NMe-Om. In some embodiments, X1 is optionally substituted NMe-Lys. In some embodiments, X1 is optionally substituted NMe-Azidolysine. In some embodiments, X1 is optionally substituted NMe-hLys. In some embodiments, X1 is optionally substituted 4-oxa NMe- Lys, In some embodiments, X1 is optionally substituted NMe-Ala. In some embodiments, XI is optionally substituted NMe-Amp. In some embodiments, X1 is optionally substituted NMe-Nle. In some embodiments, X1 is optionally substituted NMe-propargyl glycine. In some embodiments, XI is optionally substituted NMe-propargyl alanine. In some embodiments, X1 is optionally substituted NMe- Asp. In some embodiments, X1 is optionally substituted NMe-Cys. In some embodiments, XI is optionally substituted NMe-Hcy. In some embodiments, X1 is optionally substituted NMe-hHcy. In some embodiments, X1 is optionally substituted NMe-Glu. In some embodiments, X1 is optionally substituted NMe-hGlu. In some embodiments, X1 is optionally substituted NMe-Hse. In some embodiments, XI is optionally substituted NMe-Hse(Se). In some embodiments, X1 is Cys, Lys, or a derivative thereof. In some embodiments, X1 is Cha4N, Chg4N, NMe-Cha4N, NMe-Chg4N, NMe-Dap, NMe-Dab, NMe-Om, NMe-Lys, NMe-hLys, 4-oxa NMe-Lys, NMe-Azidolysine, NMe-Cys, NMe-Hcy, NMe-hHcy, or NMe- Hse(Se). In some embodiments, X1 is Cys or a derivative thereof. In some embodiments, XI is NMe- Cys, NMe-Hcy, NMe-Hse(Se), or NMe-hHcy. In some embodiments, X1 is Lys or a derivative thereof. In some embodiments, X1 is NMe-Dap, NMe-Dab, NMe-Lys, NMe-hLys, or NMe-Om. In some embodiments, X1 is Ala or a derivative thereof. In some embodiments, X 1 is NMe-Ala, NMe-Nle, or NMe-propargyl glycine. In some embodiments, X1 is a peptoid. In some embodiments, XI is Nlys. In some embodiments, the metal chelator is attached to X1 and the linker is a bond. In some embodiments, the metal chelator is attached to X1 through a linker

[0124] In some embodiments of Formula (I), (I’), or (I’ ’), or a pharmaceutically acceptable salt thereof, X1 has a structure ofwherein,group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1 ,0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;R13is hydrogen or Ci -C3alkyl;and heteroaryl is independently optionally substituted with one or more Re; or two RXiagroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re;with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X6 represents the point of attachment to X6; and *X2 represents the point of attachment to X2.In some embodiments, X1 has a structuresome embodiments, X1 has a

[0125] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X1 has a structure of:wherein,heterocycloalkyl is optionally substituted with one or more Re; or, one of R,zais a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1.0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;or two RXiagroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re;alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X6 represents the point of attachment to X6; and*X2 represents the point of attachment to X2.

[0126] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X1 is a peptoid and has a structure of:wherein,=N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroary 1, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R‘. or, one of R12ais a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1.0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Raare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X6 represents the point of attachment to X6; and*X2 represents th e point of attachment to X2.

[0127] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, R12is Ci-Cealkyl optionally substituted with one orsome embodiments, each R12ais independently -ORa, -SRa, -NRcRd, -SeRa, -C(=O)Ra, -C(=O)ORa, or - C(=O)NRcRd. In some embodiments, R12is Ci-C6alkyl, C3-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl, wherein each of the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of -ORa, -SRa, -NRcRd, - SeRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRaS(=O)2Ra, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, - OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, and - C(=O)NRcRd. In some embodiments, R12is C -Csalkyl substituted with one substituent selected from the group consisting of -ORa, -SRa, -NRcRd, -SeRa, -C(=O)Ra, -C(=O)ORa, and -C(=O)NRcRd. In some embodiments, R12is Ci-Cealkyl. In some embodiments, LX1is a bond; and R12is Ci-Cealkyl substituted with one substituent selected from the group consisting of -ORa, -SRa, -NRcRd, -SeRa, -C(=O)Ra, - C(=O)ORa, and -C(=O)NRcRd. In some embodiments, LX1is a bond; and R12is Ci-Cealkyl.

[0128] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, LX1is a bond. In some embodiments, LX1is a bond; and R12is C3-Cgcycloalky or 3- to 6- membered heterocycloalkyl, wherein each of the cycloalkyl and heterocycloalkyl is optionally substituted with one or more R12a. In some embodiments, LX1is Ci-optionally substituted with one or more R12a. In some embodiments, X1 is a peptoid wherein LX1is a bond and R12is C i-Cgalkyl optionally substituted with one or more R12a.

[0129] In some embodiments of Formula (I), (F), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, one of R12ais a CG. In some embodiments, R12ais a CG. In some embodiments, the CG is an azide or a terminal alkyne.

[0130] In some embodiments of Formula (I), (F), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, R11is hydrogen or Ci-C3alkyl optionally substituted with one to three substituents independently selected from Rf. In some embodiments, R11is hydrogen. In some embodiments, R11is Ci-C3alkyl. In some embodiments, R11is methyl. In some embodiments, R11and LX1-R12are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more R12a. In some embodiments, R11and LX1-R12are taken together with the intervening atoms to form a 5 - membered heterocycloalkyl, which is optionally substituted with one or more R12a. In some embodiments, R11and LX1-R12are taken together with the intervening atoms to form a 6- membered heterocycloalkyl, which is optionally substituted with one or more R12a. In some embodiments, R11and LX1-R12are taken together with the intervening atoms to form a 5- membered heterocycloalkyl, which is optionally substituted with one or two substitutions selected from Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, -OH, and -OMe.

[0131] In some embodiments of Formula (I), (F), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or(IV 6), or a pharmaceutically acceptable salt thereof, X2 is a D-amino acid. In some embodiments, X2 is an L-amino acid. In some embodiments, X2 is an aromatic amino acid. In some embodiments, X2 is Tyr, Phe, Trp, His, Gly, Ala, or a derivative thereof. In some embodiments, X2 is Tyr or a derivative thereof. In some embodiments, X2 is Phe or a derivative thereof. In some embodiments, X2 is Trp or a derivative thereof. In some embodiments, X2 is His or a derivative thereof. In some embodiments, X2 is Gly or a derivative thereof. In some embodiments, X2 is Ala or a derivative thereof. . In some embodiments, X2 is Tyr, D-Tyr, 4Pal, 3Pal, 5F-Tyr, 3,5-diF-Tyr, Phe, 3MeO-Phe, 4MeO-Phe, Tyr(Phe), (R-βMe)Phe, (S- βMe)Phe, 3,3-diPhe, D-Phg, L-DOPA, Aph(Hor), His, 2-(Aminocarbonyl)-Phe (F2C0N), 3- (Aminocarbonyl)-Phe (F3C0N), Ala, or Gly. In some embodiments, X2 is Tyr, D-Tyr, 4Pal, 3Pal, 5F- Tyr, 3,5-diF-Tyr, Phe, (R-βMe)Phe, (S-βMe)Phe, 3,3-diPhe, D-Phg, L-DOPA, Aph(Hor), His, 2- (Aminocarbonyl)-Phe, 3-(Aminocarbonyl)-Phe, Ala, or Gly. In some embodiments, X2 is optionally substituted Tyr. In some embodiments, X2 is optionally substituted D-Tyr. In some embodiments, X2 is optionally substituted 4Pal. In some embodiments, X2 is optionally substituted 3Pal. In some embodiments, X2 is optionally substituted 5F-Tyr. In some embodiments, X2 is optionally substituted 3,5-diF-Tyr. In some embodiments, X2 is optionally substituted Phe. In some embodiments, X2 is optionally substituted (R-βMe)Phe. In some embodiments, X2 is optionally substituted (S-βMe)Phe. In some embodiments, X2 is optionally substituted 3,3-diPhe. In some embodiments, X2 is optionally substituted D-Phg. In some embodiments, X2 is optionally substituted L-DOPA. In some embodiments, X2 is optionally substituted Aph(Hor) In some embodiments, X2 is optionally substituted His. In some embodiments, X2 is optionally substituted 2-(Aminocarbonyl)-Phe. In some embodiments, X2 is optionally substituted 3-(Aminocarbonyl)-Phe. In some embodiments, X2 is optionally substituted Ala. In some embodiments, X2 is optionally substituted Gly. In some embodiments, X2 is Tyr.

[0132] In some embodiments ofor a pharmaceutically acceptable salt thereof, X2 has a structure of:wherein:ring A2 is an ary 1 or heteroaryl;the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R22a; or two i< are taken together to form:::O.::=S, or:::N(Ra); or one of R22is a conjugation group (CG). m2 is 0, 1, 2, 3, 4, or 5;=N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Re; or, one of R22ais a conjugation group (CG);R2is hydrogen or Ci -Csalkyl;alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1 ,0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine:with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X1 represents the point of attachment to XI; and*X3 represents the point of attachment to X3.

[0133] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, ring A2 is a Cg-Cwaryl or a 5- to 10- membered heteroaryl. In some embodiments, ring A2 is a phenyl or a 5- to 6- membered heteroaryl. In some embodiments ring A2 is phenyl pyridinyl pyrimidinyl or imidazolyl In some embodiments ring A2 ismembered heteroaryl. In some embodiments, ring A2 is a 5- to 6- membered heteroaryl. In some embodiments, ring A2 is pyridinyl, pyrimidinyl, or imidazolyl. In some embodiments, ring A2 is pyridinyl or pyrimidinyl. In some embodiments, ring A2 is imidazolyl.

[0134] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, each R22is independently Ci -Chalky 1. Ci-terminal alkyne.

[0135] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, R21is hydrogen or Ci-C3alkyl optionally substituted with one to three substituents independently selected from Rf. In some embodiments, R21is hydrogen. In some embodiments, R21is In some embodiments, R21is methyl.

[0136] In some embodiments of Formula (I), (F), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, LX2is Ci-C3alkylene, optionally substituted with one or more RX2a. In some embodiments, LX2is Ci-C3alkylene, optionally substituted with one to three substituents selected from Ci-C3alkyl (e.g., methyl). In some embodiments, LX2is -CH2-, -CH(CH3)-, or - CH(phenyl)-. In some embodiments, LX2is -CH2- or -CH(CH3)-. In some embodiments, LX2is -CH2-. In some embodiments, LX2is -CH(CH3)-. In some embodiments, LX2is -CH(phenyl)-.

[0137] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, m2 is 0, 1, or 2. In some embodiments, m2 is 1 or 2. In some embodiments, m2 is 0 or 1. In some embodiments, m2 is 0. In some embodiments, m2 is 1. In some embodiments, m2 is 2.

[0138] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X3 is a non-natural amino acid comprising an optionally substituted N-containing 5- to 10- membered heteroaryl. In some embodiments, X3 is a nonnatural amino acid comprising an optionally substituted pyndinyl, an optionally substituted indolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted benzimidazolyl, an optionally substituted pyrimidazolyl, an optionally substituted pyrazolo[l,5- a]pyridinyl, an optionally substituted quinolinyl, or an optionally substituted isoquinolinyl. In some embodiments, X3 is a Trp derivative. In some embodiments, X3 is D-Trp, NMe-D-Trp, (S-βMe)D-Trp, (S-βMe)Trp, (PGeminal methyl)D-Trp, (pGeminal methyl)Trp, (S-βPropyl)D-Trp, (S-βPropyl)Trp, (S- pisopropyl)D-Trp, (S-βisopropyl)Trp, (S-βCyclopropyl)D-Trp, (S-βCyclopropyl)Trp, (S-βisobutyl)D- Trp, (S-βisobutyl)Trp, (S-βSecbutyl)D-Trp, (S-βSecbutyl)Trp, (S-βNeopentyl)D-Trp, (S- PNeopentyl)Trp, (S-βPhenyl)D-Trp, (S-βPhenyl)Trp, (S-βBenzyl)D-Trp, (S-βBenzyl)Trp, (R-βMe)D- Trp, (R-βMe)Trp, (R-βPropyl)D-Trp, (R-βPropyl)Trp, (R-βisopropyl)D-Trp, (R-βisopropyl)Trp, (R- pCyclopropyl)D-Trp, (R-βCyclopropyl)Trp, (R-βisobutyl)D-Trp, (R-βisobutyl)Trp, (R-βSecbutyl)D-Trp, (R-βSecbutyl)Trp, (R-βNeopentyl)D-Trp, (R-βNeopentyl)Trp, (R-βPhenyl)D-Trp, (R-βPhenyl)Trp, (R- PBenzyl)D-Trp, (R-βBenzyl)Trp, Aza-Trp, Aza-D-Trp, D-6F-Trp, (5-C1) D-Trp, (5-Me) D-Trp, (5-MeO) D-Trp, (6-Me) D-Trp, (7-Me) D-Trp, Bzt, D-Tpi, or D-Aph(Cbm), each of which is further optionally substituted. In some embodiments, the Aza-Trp is 2-aza-Trp, 4-aza-Trp, 5-aza-Trp, 6-aza-Trp, or 7-aza- Trp. In some embodiments, X3 is D-Trp, NMe-D-Trp, (S-βMe)D-Trp, (S-βMe)Trp, (R-βMe)D-Trp, (R- βMe)Trp, Aza-Trp, Aza-D-Trp, D-6F-Trp, or D-Aph(Cbm), each of which is further optionally substituted. In some embodiments, X3 is optionally substituted D-Trp. In some embodiments, X3 is optionally substituted NMe-D-Trp. In some embodiments, X3 is optionally substituted (S-βMe)D-Trp. In some embodiments, X3 is optionally substituted (S-βMe)Trp. In some embodiments, X3 is optionallysubstituted (PGeminal methyl)D-Trp. In some embodiments, X3 is optionally substituted (PGeminal methyl)Trp. In some embodiments, X3 is optionally substituted (S-βPropyl)D-Trp. In some embodiments, X3 is optionally substituted (S-βPropyl)Trp. In some embodiments, X3 is optionally substituted (S-βisopropyl)D-Trp. In some embodiments, X3 is optionally substituted (S-βisopropyl)Trp. In some embodiments, X3 is optionally substituted (S-βCyclopropyl)D-Trp. In some embodiments, X3 is optionally substituted (S-βCyclopropyl)Trp. In some embodiments, X3 is optionally substituted (S- pisobutyl)D-Trp. In some embodiments, X3 is optionally substituted (S-βisobutyl)Trp. In some embodiments, X3 is optionally substituted (S-βSecbutyl)D-Trp. In some embodiments, X3 is optionally substituted (S-βSecbutyl)Trp. In some embodiments, X3 is optionally substituted (S-PNeopentyl)D-Trp. In some embodiments, X3 is optionally substituted (S-PNeopentyl)Trp. In some embodiments, X3 is optionally substituted (S-βPhenyl)D-Trp. In some embodiments, X3 is optionally substituted (S- pPhenyl)Trp. In some embodiments, X3 is optionally substituted (S-PBenzyl)D-Trp. In some embodiments, X3 is optionally substituted (S-PBenzyl)Trp. In some embodiments, X3 is optionally substituted (R-βMe)D-Trp. In some embodiments, X3 is optionally substituted (R-βMe)Trp. (R- pPropyl)D-Trp. In some embodiments, X3 is optionally substituted (R-βPropyl)Trp. In some embodiments, X3 is optionally substituted (R-βisopropyl)D-Trp. In some embodiments, X3 is optionally substituted (R-βisopropyl)Trp. In some embodiments, X3 is optionally substituted (R-βCyclopropyl)D- Trp. In some embodiments, X3 is optionally substituted (R-βCyclopropyl)Trp. In some embodiments, X3 is optionally substituted (R-βisobutyl)D-Trp. In some embodiments, X3 is optionally substituted (R- pisobutyl)Trp. In some embodiments, X3 is optionally substituted (R-βSecbutyl)D-Trp. In some embodiments, X3 is optionally substituted (R-βSecbutyl)Trp. In some embodiments, X3 is optionally substituted (R-βNeopentyl)D-Trp. In some embodiments, X3 is optionally substituted (R- PNeopentyl)Trp. In some embodiments, X3 is optionally substituted (R-βPhenyl)D-Trp. In some embodiments, X3 is optionally substituted (R-βPhenyl)Trp. In some embodiments, X3 is optionally substituted (R-βBenzyl)D-Trp. In some embodiments, X3 is optionally substituted (R-βBenzyl)Trp. In some embodiments, X3 is optionally substituted Aza-Trp. In some embodiments, X3 is optionally substituted Aza-D-Trp. In some embodiments, X3 is optionally substituted Bzt. In some embodiments, X3 is optionally substituted D-6F-Trp. In some embodiments, X3 is optionally substituted or D- Aph(Cbm). In some embodiments, X3 is (S-βMe)D-Trp, (R-βMe)D-Trp, or D-Trp. In some embodiments, X3 is (S-βMe)D-Trp. In some embodiments, X3 is (R-βMe)D-Trp. In some embodiments, X3 is D-Trp. In some embodiments, for example in some embodiments of Formula (I’), X3 is Trp.

[0139] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X3 has a structure of:wherein:R’1is hydrogen or C1-C5 alkyl optionally substituted with one to three substituents independently selected from Rf; each Rfis independently halogen, -CN, -NO2, -ORa, -SRaor -NRcRd;heteroalkylene is optionally substituted with one or more RX3a; ring A3 is an aryl or heteroaryl;heterocycloalkyl is optionally substituted with one or more Rs; or, one of R is a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocy clooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1 .0]nonyne(BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;R33is hydrogen or Ci-C3alkyl;R34is hydrogen or Ci -Cjalkyl; each RX3ais independently halogen, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-CgalkyleneCcycloalkyl), C i-C< salky lene(heterocycloalky 1), Ci-Cealkylenetaryl), or C • -C ealky lene(heteroary I), wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl. and heteroaryl is independently optionally substituted with one or more Re; or two ROigroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re;with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X2 represents the point of attachment to X2; and*X4 represents the point of attachment to X4.

[0140] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), ormembered heteroaryl. In some embodiments, ring A3 is a phenyl, naphthyl, pyridinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, pyrimidazolyl, pyrazolo[l,5-a]pyridinyl, benzofuran, benzothiophene, quinolinyl, or isoquinolinyl. In some embodiments, ring A3 is phenyl or naphthyl. Insome embodiments, ring A3 is indolyl or azaindolyl. In some embodiments, ring A3 is a phenyl. In some embodiments, ring A3 is a naphthyl. In some embodiments, ring A3 is a pyridinyl. In some embodiments, ring A3 is a benzofiiran. In some embodiments, ring A3 is a benzothiophene. In some embodiments, ring A3 is an indolyl. In some embodiments, ring A3 is an azaindolyl. In some embodiments, ring A3 is an indazolyl. In some embodiments, ring A3 is a benzimidazolyl. In some embodiments, ring A3 is a pyrimidazolyl In some embodiments, ring A3 is a pyrazolo[l,5-a]pyridinyl. In some embodiments, ring A3 is a quinolinyl. In some embodiments, ring A3 is a isoquinolinyl.

[0141] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, m3 is 0 or 1. In some embodiments, m3 is 0. In some embodiments, m3 is 1.

[0142] In some embodiments of Formula (I), (F), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X3 has a structure of:wherein:Y3iis N, CH, or CR .Y32is N, CH, or CR32;Y33is N, CH, or CR32;Y34is N, CH, or CR32;Y" is N, or C;Y'° is N or C;Y37is N, CH, or CR32; andY38is 0, S, N orNH.

[0143] In some embodiments, no more than two of Y31, Y32, Y33, Y34, Y35, Y36, and Y37are N. In some embodiments, Y31is N. In some embodiments, Y31is CH. In some embodiments, Y32is N. In some embodiments, Y32is CH. In some embodiments, Y33is N. In some embodiments, Y33is CH. In some embodiments, Y34is N. In some embodiments, Y34is CH. In some embodiments, Y35is N. In some embodiments, Y35is C. In some embodiments, Y36is N. In some embodiments, Y36is C. In some embodiments, Y37is N. In some embodiments, Y37is CH. In some embodiments, Y38is N. In some embodiments, Y38is NH. In some embodiments, Y38is S. In some embodiments, Y38is 0.

[0144] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, each R32is independently Ci-C6alkyl, Ci-SF5, or -NRcRd, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R32a. In some embodiments, each R32is independently Ci-Cealkyl, Ci-Cehaloalkyl, halogen, CN, -ORa, -SRa, or -NRcRd, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R32a. In some embodiments, R32is hydrogen or halogen. In some embodiments, R32is hydrogen or fluoro. In some embodiments, R32is halogen. In some embodiments, R32is fluoro. In some embodiments, one of R32is a CG. In some embodiments, the CG is an azide or a terminal alkyne. In some embodiments the CG is an azide. In some embodiments, the CG is a terminal alkyne.

[0145] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, R31is hydrogen or C i-Csalkyl optionally substituted with one to three substituents independently selected from Rf. In some embodiments, R31is hydrogen. In some embodiments, R31is Ci-C3alkyl. In some embodiments, R31is methyl.

[0146] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, LX3is Ci -C halky lene, optionally substituted with one to three RX3aindependently selected from Ci-C3alkyl (e.g., methyl), phenyl, Ci-C3alkylene(phenyl), C3- C cvcloalkvl. or Ci-C3alkylene(C3-C6cycloalkyl). In some embodiments, LX3is -CH2-, -CH(CH3)-, - C(CH3)2-, -CH(iPr)-, CH(benzyl)-, -CH(cyclopropyl)-, -CH(CH2-CH(CH3)2)-, -CH(CH2-C(CH3)3)-, or - CH(CH2-CH2-CH3)-. In some embodiments, LX3is -CH2- or -CH(CH3)-.

[0147] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X3 is:whereinm3 is 0, 1, or 2;*X2 represents the point of attachment to X2; and*X4 represents the point of attachment to X4.In some embodiments,somesome embodiments, each R32is independently methyl, ethyl, isopropyl, Ci-C2haloalkyl, halogen, -CN, -OH, -OMe, -SH, -SMe, -NH2, -NHMe, or -N(Me)2. In some embodiments, m3 is 0. In some embodiments, m3 is 1 or 2. In some embodiments, m3 is 1. In some embodiments, m3 is 2. In some embodiments, R32is halogen and m3 is 1.

[0148] In some embodiments, modifications to X4 have been shown to improve conjugate biodistribution as determined by measuring conjugate concentrations in tissues by mass spectrometry. A conjugate having improved biodistribution exhibits distribution in desired tissues and decreased distribution in undesired tissues. In some embodiments, a conjugate described herein has improved biodistribution as determined by measuring tissue pharmacokinetics when X4 is a non-natural amino acid having a side chain comprising an amine. In some embodiments, the amine comprises a primary amine, a secondary amine, a tertiary amine, or a quaternary amine. In some embodiments, the amine comprises a primary amine, a secondary amine, or a tertiary amine. In some embodiments, the amine comprises a primary amine. In some embodiments, the amine comprises a secondary amine or a tertiary amine. In some embodiments, the amine comprises a secondary amine. In some embodiments, the amine comprises a tertiary amine. In some embodiments, a conjugate described herein has improved biodistribution as determined by tissue pharmacokinetics when X4 is an amino acid comprising azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0149] In some embodiments of Formula (I), (I’), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6),or a pharmaceutically acceptable salt thereof, X4 is a non-natural amino acid having a side chain comprising an amine. In some embodiments, the amine comprises a primary amine, a secondary amine, a tertiary amine, or a quaternary amine. In some embodiments, the amine comprises a primary amine, a secondary amine, or a tertiary amine. In some embodiments, the amine comprises a primary amine. In some embodiments, the amine comprises a secondary amine or a tertiary amine. In some embodiments, the amine comprises a secondary amine. In some embodiments, the amine comprises a tertiary amine. In some embodiments, X4 is a non-natural amino acid having a side chain comprising an amine, and wherein the side chain comprises azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, X4 is Cba3N, Chg4N, Cha4N, Cha4NH2, Ser(3-azetidine), PipzaA, 3-Azetidine- hAla, or Pic4, each of which is further optionally substituted. In some embodiments, X4 is a Lys derivative. In some embodiments, X4 is NMe-Lys, Lys(Me), Lys(diMe), Lys(iPr), Chg4N, Cha4N, 4- oxa-Lys, or 3-Azetidine-hAla. In some embodiments, X4 is Cba3N, Chg4N, Cha4N, Cha4NH2, Ser(3- azetidine), PipzaA, 3-Azetidine-hAla, Pic4, NMe-Lys, Lys(Me), Lys(diMe), Lys(iPr), or 4-oxa-Lys. In some embodiments, X4 is (D / L) Hly. In some embodiments, X4 is optionally substituted Chg4N. In some embodiments, X4 is optionally substituted Cha4N. In some embodiments, X4 is optionally substituted Ser(3-azetidine). In some embodiments, X4 is optionally substituted PipzaA. In some embodiments, X4 is optionally substituted 3-Azetidine-hAla. In some embodiments, X4 is optionally substituted NMe-Lys. In some embodiments, X4 is optionally substituted Lys(Me). In some embodiments, X4 is optionally substituted Lys(iPr). In some embodiments, X4 is optionally substituted 4-oxa-Lys. In some embodiments, X4 is Chg4N. In some embodiments, X4 is Cha4N. In some embodiments, X4 is Ser(3-azetidine). In some embodiments, X4 is PipzaA. In some embodiments, X4 is 3-Azetidine-hAla. In some embodiments, X4 is Pic4. In some embodiments, X4 NMe-Lys. In some embodiments, X4 is Lys(Me). In some embodiments, X4 is Lys(iPr). In some embodiments, X4 is 4-oxa- Lys. In some embodiments, X4 is D-Lys. In some embodiments, X4 is azaLys. In some embodiments, X4 is Lys(triMe). In some embodiments, X4 is Nva(NH-NH2).

[0150] In some embodiments of Formula (I), (I’), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X4 has a structure of:wherein,R41is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf; each Rfis independently halogen, -CN, -NCL, -ORa, -SRaor -NRcRd;membered heterocycloalkyl, wherein the alkylene, heteroalkylene, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more RX4a;or a heterocycloalkyl comprising one or more sang nitrogen atoms, wherein the heterocycloalkyl is optionally substituted with one or more R4aa;alkenyl, and alkynyl is optionally substituted with one or more Re; or, one of R42ais a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo [6. l.OJnonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;R43is hydrogen or Ci-C3alkyl;R and R4~ are each independently hydrogen,Ci-C3alkylene-heteroaryl; or R44and R4aare taken together to form a 3- to 6- membered heterocycloalkyl, wherein each of the alkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R42a;form a heterocycloalkyl optionally substituted with one or more Re;*X3 represents the point of attachment to X3; and*X5 represents the point of atachment to X5.

[0151] In some embodiments of Formula (I), (I’), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, R42is a 4- to 6- membered N-containing heterocycloalkyl, which is optionally substituted with one or more R42a. In some embodiments, R42is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is optionally substituted with one to fourR42a. In some embodiments, R42is azetidinyl, pipendinyl, or piperazinyl, each of which is optionally substituted with one to four R42a. In some embodiments, R42is azetidinyl optionally substituted with one to four R42a. In some embodiments, R42is pyrrolidinyl optionally substituted with one to four R42a. In some embodiments, R42is piperidinyl optionally substituted with one to four R42a. In some embodiments, R42is piperazinyl optionally substituted with one to four R42a. In some embodiments, R42is morpholinyl optionally substituted with one to four R42a. In some embodiments, R42iseach of which is optionally substituted with 1 or 2 substituents selectedfrom R42a. In some embodiments, R42isoptionally substituted with 1 or 2 substituents selected from R42a. In some embodiments, R42is optionally substituted with 1 or 2substituents selected from R42a. In some embodiments, R42isoptionally substituted with 1 or2 substituents selected from R42a. In some embodiments, R42is optionally substituted with 1or 2 substituents selected from R42a. In some embodiments, each R42ais independently halogen, Ci-ethyl, isopropyl, phenyl, and alkyl are each optionally substituted with 1 or 2 substituents selected from R42a. In some embodiments, R44and R45are each independently hydrogen, methyl, ethyl, isopropyl, phenyl, -Ci-C3alkylene-phenyl, or -NH2In some embodiments, R44and R45are each independently hydrogen, methyl, ethyl, or isopropyl. In some embodiments, R44and R45are each independently hydrogen or methyl. In some embodiments, R44and R45are each independently hydrogen or ethyl. In some embodiments, R44and R45are each independently hydrogen or isopropyl. In some embodiments, R44and R45are each independently hydrogen or phenyl. In some embodiments, R44and R45are each independently hydrogen or -Ci-C3alkylene-phenyl. In some embodiments, R44and R45are each independently hydrogen or -NH2. In some embodiments, one of R42ais a CG. In some embodiments, R42ais a CG. In some embodiments, the CG is an azide or a terminal alkyne.

[0153] In some embodiments of Formula (I), (I’), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, LX4is a bond. In some embodiments, LX4is a Ci- C4alkylene (e.g., -CH2-), wherein the alkylene is optionally substituted with 1 or 2 substituents independently selected from RX4a. In some embodiments, LX4is a Ci-C4heteroalkylene (e.g., - CH2OCH2CH2-) wherein the heteroalkylene is optionally substituted with 1 or 2 substituents independently selected from RX4a. In some embodiments, RX4ais-F, -Me, or -OH.

[0154] In some embodiments of Formula (I), (I’), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, R41is hydrogen or Ci-C3alkyl optionally substituted with one to three substituents independently selected from Rf. In some embodiments, R41is hydrogen. In some embodiments, R41is Ci-C3alkyl. In some embodiments, R41is methyl.

[0155] In some embodiments of Formula (I), (I’), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof,*X3 represents the point of attachment to X3; and*X5 represents the point of attachment to X5.anbodiments, X4 is.

[0156] In some embodiments of Formula (I), , or (IV6), or a pharmaceutically acceptable salt thereof,wherein*X3 represents the point of attachment to X3; and*X5 represents the point of attachment to X5.In some embodiments,some embodiments,

[0157] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X5 a D-amino acid. In some embodiments, X5 is an L-amino acid. In some embodiments, X5 is an aliphatic amino acid or a polar amino acid. In some embodiments, X5 is Thr, Vai, Ala, Ser, Pro, or a derivative thereof. In some embodiments, X5 is Thr or a derivative thereof. In some embodiments, X5 is Vai or a derivative thereof. In some embodiments, X5 is Ala or a derivative thereof. In some embodiments, X5 is Ser or a derivative thereof. In some embodiments, X5 is Pro or a derivative thereof. In some embodiments, X5 is optionally substituted Thr. In some embodiments, X5 is optionally substituted Vai. In some embodiments, X5 is optionally substituted Ala. In some embodiments, X5 is optionally substituted Pro. In some embodiments, X5 isoptionally substituted Alt. In some embodiments, X5 is optionally substituted Cbg. In some embodiments, X5 is optionally substituted Cpg. In some embodiments, X5 is optionally substituted Cba. In some embodiments, X5 is optionally substituted Tme In some embodiments, X5 is Thr, Vai, Ala, Pro, Alt, Cbg, Cpg, Cba, or Tme. In some embodiments, X5 is Thr. In some embodiments, X5 is Vai. In some embodiments, X5 is Ala. In some embodiments, X5 is Pro. In some embodiments, X5 is Alt, Cbg. In some embodiments, X5 is Cpg. In some embodiments, X5 is Cba. In some embodiments, X5 is Tme.

[0158] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X5 has a structure of:wherein,CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo [6. 1.OJnonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X4 represents the point of attachment to X4; and*X6 represents the point of attachment to X6.

[0159] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or

[0160] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, one of R52ais a CG. In some embodiments, R52ais a CG. In some embodiments, the CG is an azide or a terminal alkyne.

[0161] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, R51is hydrogen or Ci-C3alkyl optionally substitutedwith one to three substituents independently selected from Rf. In some embodiments, R51is hydrogen. In some embodiments. In some embodiments, R51is methyl. In some embodiments, R51and R52are taken together and the intervening atoms to form a 5 - to 6- membered heterocycloalkyl, which is optionally substituted with one or more R52a. In some embodiments, R51and R52are taken together and the intervening atoms to form a 5- membered heterocycloalkyl, which is optionally substituted with one or more R12a. In some embodiments, R51and R52are taken together and the intervening atoms to form a 6- membered heterocycloalkyl, which is optionally substituted with one or more R52a. In some embodiments, R51and R52are taken together and the intervening atoms to form a 5- membered heterocycloalkyl which is optionally substituted with one or two substitutions selected fromtaken together and the intervening atoms to form a 5- membered heterocycloalkyl.

[0162] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X6 is a D-amino acid. In some embodiments, X6 is an L-amino acid. In some embodiments, X6 is an aromatic amino acid, a hydrophilic amino acid, or Gly, or a derivative thereof. In some embodiments, X6 is an aromatic amino acid or a derivative thereof. In some embodiments, X6 is Phe, His, Tyr, or a derivative thereof. In some embodiments, X6 is Phe or a derivative thereof. In some embodiments, X6 is His or a derivative thereof. In some embodiments, X6 is Tyr or a derivative thereof. In some embodiments, X6 is a hydrophilic ammo acid or a denvative thereof. In some embodiments, X6 is Ser, Asn, or a derivative thereof. In some embodiments, X6 is Ser or a derivative thereof. In some embodiments, X6 is Asn or a derivative thereof. In some embodiments, X6 is Gly or a derivative thereof. In some embodiments, X6 is Ala or a derivative thereof. In some embodiments, X6 is Vai or a derivative thereof. In some embodiments, X6 is Pro or a derivative thereof. In some embodiments, X6 is Phe, Ala, Gly, Ser, His, Tyr, Asn, Pro, or a derivative thereof. In some embodiments, X6 is Phe, NMe-Phe, (S-[3Me)Phe, (R-[3Me)Phe, His, Mpd, Ala, D-Ala, Gly, Pro, Ser, Ser(Ph), 3Pal, 4Pal, Cha, 3-(Aminocarbonyl)-Phe, F4COO, Phg, G(cPr), Asn, Tyr, meta-Tyr, or 3N-Tyr, each of which is optionally further substituted. In some embodiments, X6 is optionally substituted Phe. In some embodiments, X6 is optionally substituted NMe-Phe. In some embodiments, X6 is optionally substituted (S-[3Me)Phe. In some embodiments, X6 is optionally substituted (R-[3Me)Phe. In some embodiments, X6 is optionally substituted His. In some embodiments, X6 is optionally substituted Mpd. In some embodiments, X6 is optionally substituted Ala. In some embodiments, X6 is optionally substituted Vai. In some embodiments, X6 is optionally substituted D-Ala. In some embodiments, X6 is optionally substituted Gly. In some embodiments, X6 is optionally substituted Pro. In some embodiments, X6 is optionally substituted Ser. In some embodiments, X6 is optionally substituted Ser(Ph). In some embodiments, X6 is optionally substituted 3Pal. In some embodiments, X6 is optionally substituted 4Pal. In some embodiments, X6 is optionally substituted Cha. In some embodiments, X6 is optionally substituted 3-(Aminocarbonyl)-Phe. In some embodiments, X6 is optionally substitutedF4C00. In some embodiments, X6 is optionally substituted Phg. In some embodiments, X6 is optionally substituted G(cPr). In some embodiments, X6 is optionally substituted Asn. In some embodiments, X6 is optionally substituted Tyr. In some embodiments, X6 is optionally substituted meta-Tyr. In some embodiments, X6 is optionally substituted 3N-Tyr. In some embodiments, X6 is Phe. In some embodiments, X6 is NMe-Phe. In some embodiments, X6 is (S-βMe)Phe. In some embodiments, X6 is (R-βMe)Phe. In some embodiments, X6 is His In some embodiments, X6 is Mpd. In some embodiments, X6 is Ala. In some embodiments, X6 is D-Ala. In some embodiments, X6 is Vai. In some embodiments, X6 Gly. In some embodiments, X6 is Pro. In some embodiments, X6 is Ser. In some embodiments, X6 is Ser(Ph). In some embodiments, X6 is 3Pal. In some embodiments, X6 is 4Pal. In some embodiments, X6 is Cha. In some embodiments, X6 is 3-(Aminocarbonyl)-Phe. In some embodiments, X6 is Phg. In some embodiments, X6 is G(cPr). In some embodiments, X6 is Asn. In some embodiments, X6 is Tyr. In some embodiments, X6 is meta-Tyr. In some embodiments, X6 is 3N-Tyr.

[0163] In some embodiments of Formula (I), (I’), or (I’ ’), or a pharmaceutically acceptable salt thereof, X6 has a structure of:wherein: - of dm6 is 0, 1, 2, 3, 4, or 5;=N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re; or, one of R62ais a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1.OJnonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;R63is hydrogen or C -( alkyl;and heteroaryl is independently optionally substituted with one or more Re; or two RX6agroups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re;alky ny 1, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X5 represents the point of attachment to X5; and*X1 represents the point of attachment to XI.

[0164] In some embodiments of Formula (I), (F), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X6 has a structure of:wherein:=N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroary 1, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R‘. or, one of R62ais a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocycloociyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1.0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;membered heteroaryl. In some embodiments, ring A6 is a phenyl or a 5- to 6- membered heteroaryl. In some embodiments, ring A6 is a phenyl. In some embodiments, ring A6 is a 5 - to 6- membered heteroaryl. In some embodiments, ring A6 is phenyl, pyridinyl, pyrimidinyl, or imidazolyl. In some embodiments, ring A6 is pyridinyl, pyrimidinyl, or imidazolyl. In some embodiments, ring A6 is pyridinyl. In some embodiments, ring A6 is, pyrimidinyl. In some embodiments, ring A6 is imidazolyl.embodiments, ring A6 is 5- to 7- membered heterocycloalky. In some embodiments, ring A6 is piperidinyl, piperazinyl, morpholino, or tetrahydropyranyl.

[0166] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, each R62is independently Ci -Calkyl. Ci-heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R62a. In some embodiments, each R62is independently Ci-C3alkyl, -ORa, -SRa, -NRcRd, halogen -C(=O)Ra, -C(=O)ORa, or -C(=O)NRcRd. In some embodiments, one of R62ais a CG. In some embodiments, the CG is an azide or a terminal alkyne. In some embodiments, the CG is an azide. In some embodiments, the CG is a terminal alkyne.

[0167] In some embodiments of Formula (I), (F), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, R61is hydrogen or Ci-C3alkyl optionally substituted with one to three substituents independently selected from Rf. In some embodiments, R61is hydrogen. In some embodiments, R61is Ci-C3alkyl. In some embodiments, R61is methyl.

[0168] In some embodiments of Formula (I), (F), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, LX6is bond, Ci-C3alkylene, or Ci-C3heteroalkylene, wherein the alkylene and heteroalkylene are independently optionally substituted with one to three substituents selected from RX6a. In some embodiments, LX6is bond, Cj-Cbalkylcnc. or Ci-C .lietcroalkylcne. wherein the alkylene and heteroalkylene are independently optionally substituted with one to three Ci-C3alkyl (e.g., methyl). In some embodiments, LX6is bond. In some embodiments, LX6is Ci -Chalky lenc. In some embodiments, LX6is -CH2-, -CH(CH3)-, or -C(CH3)2-. In some embodiments, LX6is Ci-C3heteroalkylene. In some embodiments, LX6is -CH2NH-, -CH2N(Me)-, or -CH2O-.

[0169] In some embodiments of Formula (I), (F), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, m6 is 0. In some embodiments, m6 is 1, 2, 3, 4, or 5. In some embodiments, m6 is 1 or 2. In some embodiments, m6 is 0 or 1. In some embodiments, m6 is 1.

[0170] In some embodiments of Formula (I), (F), or (I”), or a pharmaceutically acceptable salt thereof, X6 has a structure of:wherein:=N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroary 1. cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re; or, one of R64ais a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo [6. l.OJnonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;*X5 represents the point of attachment to X5; and*X1 represents the point of attachment to X1.

[0171] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, X6 has a structure of:wherein:=N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re; or, one of Ro4ais a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1.0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine; each Rais independently hydrogen, Ci-Cgalkyl, Ci-Cghaloalkyl, Ci-Cghydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cgheteroalkyl, C2-Cgalkenyl, C ?-C galky nyl, cycloalkyl, heterocycloalkyl, aryl, heteroary 1, Ci-Cgalkylene(cycloalkyl), C |-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;*X5 represents the point of attachment to X5; and*X 1 represents the point of attachment to XI.

[0172] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, R64is hydrogen, Ci-Cgalkyl, Ci-Cghydroxyalkyl, Ci- Cgaminoalkyl, Ci-Cgheteroalkyl, or C-Cgcycloyalkyl. wherein each of the alkyl, heteroalkyl, andcycloalkyl is optionally substituted with one or more R64a. In some embodiments, R64is hydrogen, Ci-, y g y p y substituted with one to three substituents independently selected from -OH, -OMe, -C(=O)NH2and - C(=O)OH. In some embodiments, R64is hydrogen. In some embodiments, R64is C , -C' .alky l In some embodiments, R64is C1-C3 alkyl optionally substituted with one to three substituents independently selected from -OH, -OMe, -C(=O)NH2and -C(=O)OH. In some embodiments, R64is Ci-Calkyl optionally substituted with -OH or -OMe. In some embodiments, R64is methyl. In some embodiments, R64is Ci-Ceaminoalkyl. In some embodiments, R64and R65are taken together with the carbon to which they are attached to form a G-Cscycloyalkyl, which is optionally substituted with one or more R64a. In some embodiments, R64and R65are taken together with the carbon to which they are attached to form a cyclopropyl. In some embodiments, R64and R65are taken together with the carbon to which they are attached to form a cyclobutyl. In some embodiments, R64and R65are taken together with the carbon to which they are attached to form a cyclopentyl. In some embodiments, R64and R65are taken together with the carbon to which they are attached to form a cyclohexyl. In some embodiments, R63and R64are taken together with the intervening atoms to form a 5 - to 6- membered heterocycloalkyl, which is optionally substituted with one or more R64a. In some embodiments, R63and R64are taken together with the intervening atoms to form a 5- membered heterocycloalkyl, which is optionally substituted with -F, Ci- C3alkyl, Ci-C3haloalkyl, -OH, or phenyl. In some embodiments, one of R64ais a CG. In some embodiments, the CG is an azide or a terminal alkyne. In some embodiments, the CG is an azide. In some embodiments, the CG is a terminal alkyne.

[0173] In some embodiments of Formula (I), (I’), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), or a pharmaceutically acceptable salt thereof, R63is hydrogen or Ci-C3alkyl optionally substituted with one to three substituents independently selected from Rf. In some embodiments, R63is hydrogen. In some embodiments, R63is Ci-C3alkyl. In some embodiments, R63is methyl.

[0174] In some embodiments of Formula (I), (F), (I”), (II), (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV 6), or a pharmaceutically acceptable salt thereof, X1 is NMe-Hcy, NMe-Lys, or NMe-hLys; X2 is Tyr; X3 is D-Trp, or (S-βMc)D-Trp. (S-[3Me)-Trp, (R-[3Me)D-Trp, or (R-[3Me)-Trp; X4 is PipzaA, 3- Azetidine-hAla, Lys(Me), Chg4N or Cha4N; X5 is Thr or Alt; and X6 is Phe.

[0175] The structures of exemplary cyclic peptides of the present disclosure can be found in Table 1. In some embodiments, the monocyclic peptide is a peptide of Table 1.Table 113

[0176] The structures of exemplary cyclic peptides and conjugates of the present disclosure can be found in Table 2.Table 2.AWherein in Table 2, “Ac” is Acetyl; “2.2.2.Octadma” is 4-(aminomethyl)bicyclo[2.2.2]octane-l-carboxylic acid; “3Azeaa” is 2-(azetidin-3-yl)aceticacid; “3AzeCA” is azetidine-3-carboxylic acid; “4Pipaa” is 2-(piperidin-4-yl)acetic acid; “4PipCA” is piperidine-4-catboxylic acid; “Acea” is 2-(2-(2-(2- aminoethoxy)etlioxy)ethoxy)acetic acid; “Alix” is 6-aminohexanoic acid; “Aoc” is 8-aminooctanoic acid; “Apa” is 5-aminopentanoic acid; “CDAE” is carbonyldiaminoethyl; “Dah” is hexane-l,6-diamine; “Daop” is 2,2'-oxybis(ethan-l -amine); “Dap” is pentane- 1,5 -diamine; “en” is ethane- 1,2-diamine; and “TXA” is 4-(aminomethyl)cyclohexane-l-caiboxylic acid.

[0177] Exemplary conjugates of the disclosure are further illustrated in Table 3 below.Table 3.

[0178] In one aspect, provided herein is a compound of Table 2, or a pharmaceutically acceptable salt thereof. In one aspect, provided herein is a compound of Table 3, or a pharmaceutically acceptable salt thereof.

[0179] In one aspect, provided herein is a conjugate of the following structural formula:pharmaceutically acceptable salt thereof, whereinXmis a radionuclide.

[0180] In another aspect, provided herein is a conjugate of the following st ructural formula:pharmaceutically acceptable salt thereof, whereinXmis a radionuclide.

[0181] In another aspect, provided herein is a conjugate of the following structural formula:pharmaceutically acceptable salt thereof, wherein Xmis a radionuclide.

[0182] In another aspect, provided herein is a conjugate of the following structural formula:pharmaceutically acceptable salt thereof, wherein Xmis a radionuclide.

[0183] In another aspect, provided herein is a conjugate of the following structural formula:wherein Xmis a radionuclide.

[0184] In another aspect, provided herein is a conjugate of the following structural formula:pharmaceutically acceptable salt thereof, wherein Xmis a radionuclide.

[0185] In another aspect, provided herein is a conjugate of tire following structural formula:pharmaceutically acceptable salt thereof, wherein Xmis a radionuclide.Linker

[0186] A conjugate described herein can comprise one or more linkers. In some embodiments, the linker covalently attaches the peptide with the metal chelator. In some embodiments, the peptide attaches directly to the metal chelator without a linker.

[0187] In some embodiments, the present disclosure describes linkers that function as a spacer. A linker can comprise a number of intervening atoms (on a linear chain, excluding pendant groups or substituents) between the metal chelator and the binding peptide thereby creating a distance between the metal chelator and the binding peptide. In some embodiments, a linker comprises 10-100 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 2-60 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 2 to 20, 2 to 50, 5 to 15, 5 to 25, 10 to 40, 30 to 60, or 10 to 20 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 3 to 30 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 5 to 25 intervening atoms between the metal chelator and the binding peptide In some embodiments, a linker comprises 6 to 18 intervening atoms between the metal chelator and the binding peptide. In some embodiments, a linker comprises 10 to 20 intervening atoms between the metal chelator and the binding peptide. The intervening atoms can comprise 1 or more carbons, and optionally one or more heteroatoms such as O and N. In some embodiments, the intervening atoms comprise 2 to 20, 2 to 50, 5 to 15, 5 to 25, 10 to 40, 30 to 60, or 10 to 20 carbons. In some embodiments, the intervening atoms comprise 0, 1, 2, 3, 4, 5, or 6 nitrogen atoms. In some embodiments, the intervening atoms comprise 0, 1, 2, 3, 4, 5, 6, 7 or 8oxygen atoms. In some embodiments, the intervening atoms comprise 1 to 6 nitrogen and 0 to 4 oxygen atoms.

[0188] A linker can comprise one or more amino acid residues. In some embodiments, the linker comprises 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. In some embodiments, the linker comprises 1 to 5 amino acid residues. For example, the linker can comprise one or more lysine (K) residues such as K, KK, or KKK sequences. In some embodiments, the linker comprises an ornithine, a lysine, a homolysine, an aspartate, a beta-aspartate, a glutamate, a 2-aminosuberic acid, a glycine, a beta-alanine, or a combination thereof. In some embodiments, the linker comprises a lysine, an aspartate, a betaaspartate, a glutamate, or a derivative thereof. In some embodiments, the linker comprises an ornithine, a lysine, or a homolysine. In some embodiments, the linker comprises an aspartic acid, a beta-aspartate, a glutamic acid, or a 2-aminosuberic acid. In some embodiments, the linker comprises a glycine or a betaalanine.

[0189] A herein-described linker can attach to X1 as shown in Formula (IV1), X2 as shown in Formula (IV2), X3 as shown in formula (IV3), X4 as shown in Formula (IV4), X5 as shown in Formula (IV5), or X6 as shown in Formula (IV6). The linker can be bonded to the peptide, the metal chelator, or both, for example, through a chemically reactive group. Exemplary chemically reactive groups include, but are not limited to, a free amino, imino, hydroxyl, thiol or carboxyl group (e.g., to the N- or C-terminus, to the epsilon amino group of one or more lysine residues, the free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or to the sulfhydryl group of one or more cysteinyl residues). The site to which the linker is bound to the peptide can be a natural or unnatural amino acid of the peptide and / or it can be introduced into the peptide, e.g., by DNA recombinant technology (e.g., by introducing a cysteine or protease cleavage site in the ammo acid sequence) or by protein biochemistry (e.g., reduction, pH adjustment or proteolysis). Exemplary methods for attaching the linker includes carbodiimide reaction, reactions using bifunctional agents such as dialdehydes or imidoesters, Schiff base reaction, Suzuki-Miyaura cross-coupling reactions, Isothiocyanates as coupling agents, and click chemistry.

[0190] The linker can have a prescribed length thereby linking the metal chelator (and optionally radionuclide) and the peptide while allowing an appropriate distance therebetween. In some embodiments, the linker has 1 to 100 atoms, 1 to 60 atoms, 1 to 30 atoms, 1 to 15 atoms, 1 to 10 atoms, 1 to 5, or 2 to 20 atoms in length. In some embodiments, the linker has 1 to 10 atoms in length.

[0191] The linker can comprise flexible and / or rigid regions. Exemplary flexible linker regions include those comprising Gly and Ser residues (“GS” linker), glycine residues, alkylene chain, PEG chain, etc. Exemplary rigid linker regions include those comprising alpha helix-forming sequences (e.g., EAAAK (SEQ ID NO: 327)), proline-rich sequences, and regions rich in double and / or triple bonds.

[0192] In some embodiments, a linker may be further added to the (cyclic) peptide. Examples of the linker include the foregoing amino acid linker (peptide linker), a chemical linker, a fatty acid linker, a nucleic acid linker, a sugar chain linker, or the like, or it may be a complex, for example, a chemical linker, a peptide linker, or the like. Examples of the chemical linker include a PEG (polyethylene glycol)linker. For example, the PEG linker may comprise between 1 to 24 ethylene glycol units. Furthermore, the linker may be a fatty acid linker containing a divalent chemical moiety derived from a fatty acid. In some embodiments, the linker comprises at least one amino acid, and, for example, a glycine-rich peptide such as a peptide having a sequence [Gly-Gly-Gly-Gly-Ser]n(in the formula, n is 1, 2, 3, 4, 5, or 6) (SEQ ID NO: 328)

[0193] The linker can be cleavable, e g., under physiological conditions, e g., under intracellular conditions, such that cleavage of the linker releases the chelator and radionuclide in the intracellular environment. The linker can be, e.g., a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. In some embodiments, the peptidyl linker is at least two amino acids long or at least three amino acids long. Cleaving agents can include cathepsins B and D and plasmin. In other embodiments, the linker is not cleavable. In some embodiments, the linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values. For example, the pH-sensitive linker can be hydrolyzable under acidic conditions. For example, a linker can be an acid-labile linker that is hydrolyzable in the lysosome (e g., a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like). Such linkers can be relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome. In some embodiments, the hydrolyzable linker is a thioether linker.

[0194] In some embodiments, the linker comprises one or more of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted

[0196] In some embodiments, the linker comprises a conjugation moiety such as a click chemistry residue. In some embodiments, the conjugation moiety is a reaction product of a conjugation group. Insome embodiments, the linker is attached to the peptide, to the metal chelator, or both via click chemistry, thereby forming a click chemistry residue. For example, the peptide can comprise an azide group (at N- or C-terminus or at a non-terminal amino acid) that reacts with an alkyne group to form the linker of a conjugate. For another example, the peptide can comprise an alkyne group (at N- or C- terminus or at a non-terminal amino acid) that reacts with an azide to form the linker of a conjugate. The metal chelator and the linker can be attached similarly. In some embodiments, the linker comprises an azide moiety, an alkyne moiety, or both. In some embodiments, the linker comprises a triazole. In some embodiments, the linker comprises 1,4-di-substituted 1,2,3-triazole. In some embodiments, the clicksome embodiments, the click chemistry residue is a DIBO-azide residue, BARAC-azide residue, DBCO- azide residue, DIFO-azide residue, COMBO-azide residue, BCN-azide residue, or DIMAC-azide residue. In some embodiments, the linker comprises a residue of nitrone dipole cycloaddition. In some embodiments, the linker comprises a residue of tetrazine ligation. In some embodiments, the linker comprises a residue of quadricyclane ligation. Exemplary groups of click chemistry residue are shown in Hein at al., “Click Chemistry, A Powerful Tool for Pharmaceutical Sciences,” Pharmaceutical Research volume 25, pages2216-2230 (2008); Thirumurugan et al, “Click Chemistry for Drug Development and Diverse Chemical-Biology Applications,” Chem. Rev. 2013, 113, 7, 4905-4979; US20160107999A1; US10266502B2; and US20190204330A1, each of which is incorporated by reference in its entirety.

[0197] In some embodiments, the linker has a structure ofwherein each L is independently -O-, -NRL-, -N(RL)2+-, -OP(=O)(ORL)O-, -S-, -S(=O)-, - S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, - NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRT-S(=O)2-, -S(=O)2NRL-, - C(=O)NRTS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, substituted or unsubstituted C1-C30 heteroalkylene, -(Ci-heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 1 to 20 (e g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, I I, 12, 13, 14, 15, 16, 17, 18, 19, or 20)

[0198] In some embodiments, the linker has a structure of, wherein each L is

[0199] In some embodiments, the linker of Formula (V-l) has a structure of Formula (V-la),whereinL2is absent, substituted or unsubstituted C1-C30 alkylene, or substituted or unsubstituted C1-C30 heteroalkylene.

[0200] In some embodiments, the linker comprises a structure of Formula (Vlb), wherein each of L1and 1.is independently -O-, -NR1'-, -N(RT')2-, -OP(==O)(ORI')O-, -S-, -S(:=O)-, -substituted or unsubstituted 4- to 6- membered heterocycloalkyl, substituted or unsubstituted Ci- C30 alkylene, or substituted or unsubstituted C1-C30 heteroalkylene.

[0201] In some embodiments, L1is -NH- or substituted or unsubstituted 4- to 6- membered heterocycloalkyl .

[0202] In some embodiments, L2is absent. In some embodiments, L2is substituted or unsubstituted Ci- C3o alkylene, or substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L2is substituted or unsubstituted C1-C30 alkylene. In some embodiments, L2is substituted or unsubstituted Ci- C30 heteroalkylene. In some embodiments, L2is substituted or unsubstituted Ci-Cis alkylene, orp y y heteroaryl, -C(=O)ORL, -OC(=O)RL, -OC(=O)ORL, -C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL.

[0203] In some embodiments, L3is -NH-. In some embodiments, L3is substituted or unsubstituted C4-C6 cycloalkyl or substituted or unsubstituted 4- to 6- membered heterocycloalkyl. In some embodiments, L3is absent.

[0204] In some embodiments, L4is absent. In some embodiments, L4is substituted or unsubstituted C4- C6cycloalkyl, substituted or unsubstituted 4- to 6- membered heterocycloalkyl, substituted or unsubstituted C1-C30 alkylene, or substituted or unsubstituted C1-C30 heteroalkylene.

[0205] In some embodiments, L5is -NH-, -C(=O)-, or -C(=O)Ci -Csalkylene -. In some embodiments, L5is -NH-. In some embodiments, L5is -C(=O)-. In some embodiments, L5is -C(=O)Ci-C6alkylene-.

[0206] In some embodiments for Formula (V-lb), L1is -NH- or substituted or unsubstituted 4- to 6-In some embodiments, the cycloalkyl and heterocycloalkyi are unsubstituted and the alkylene and heteroalkylene are optionally substituted with 1 to 3 groups selected from the group consisting of oxo, - C(=O)ORL, and -Ci-C6alkylene-C(=O)ORL.

[0207] In some embodiments for Formula (V-lb), L2is unsubstituted C1-C12 alkylene, and L3and L4are absent. In some embodiments for Formula (V-lb), L2is unsubstituted C1-C12 heteroalkylene, and L3and L4are absent.

[0208] In some embodiments, the linker comprises substituted or unsubstituted C1-C30 alkylene, C1-C12

[0209] In some embodiments, the linker L (or L!, L2, L3, L4, or L') is substituted with one or more Re,

[0210] In some embodiments, each of L1is independently -O-, -NRL-, -N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, or substituted or unsubstituted C1-C30 heteroalkylene, In some embodiments, L1is -O-, -NRL-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, - C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-. In some embodiments, L1is -O-, -NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L1is -C(=O)NH- or -NHC(=O)-. In some embodiments, L1is substituted or unsubstituted C3-C15 cycloalkyl, or substituted or unsubstituted C1-C12 heterocycloalkyl. In some embodiments, L1is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L1is substituted or unsubstituted C1-C30 alkylene. In some embodiments, L1is substituted or unsubstituted C2- C30 alkenylene. In some embodiments, L1is substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L1is substituted or unsubstituted C -C2^ heteroalkylene. In some embodiments, L1is substituted or unsubstituted C5-Ci2heteroalkylene.

[0211] In some embodiments, each ofL2is independently -O-, -NRL-, -N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted Ci-Ci2heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted G-Cso alkenylene, substituted or unsubstituted C2-C30 alkynylene, or substituted or unsubstituted C1-C30 heteroalkylene, In some embodiments, L2is -O-, -NRL-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, - C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-. In some embodiments, L2is -O-, -NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L2is -C(=O)NH- or -NHC(=O)-. In some embodiments, L2is substituted or unsubstitutedC3-C15 cycloalkyl, or substituted or unsubstituted C1-C12 heterocycloalkyl. In some embodiments, L2is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L2is substituted or unsubstituted C1-C30 alkylene. In some embodiments, L2is substituted or unsubstituted C2- C30 alkenylene. In some embodiments, L2is substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L2is substituted or unsubstituted C5-C25 heteroalkylene. In some embodiments, L2is substituted or unsubstituted C5-C12 heteroalkylene.

[0212] In some embodiments, each ofL3is independently -O-, -NRL-, -N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NR' C(-O)-. - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, or substituted or unsubstituted C1-C30 heteroalkylene, In some embodiments, L3is -O-, -NRL-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, - C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-. In some embodiments, L3is -O-, -NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L3is -C(=O)NH- or -NHC(=O)-. In some embodiments, L3is substituted or unsubstituted C3-C15 cycloalkyl, or substituted or unsubstituted C1-C12 heterocycloalkyl. In some embodiments, L3is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L3is substituted or unsubstituted C1-C30 alkylene. In some embodiments, L3is substituted or unsubstituted C2- C30 alkenylene. In some embodiments, L3is substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L3is substituted or unsubstituted C5-C25 heteroalkylene. In some embodiments, L3is substituted or unsubstituted Cs-Ci2heteroalkylene. In some embodiments, L3is absent.

[0213] In some embodiments, each of L4is independently -O-, -NRL-, -N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, or substituted or unsubstituted C1-C30 heteroalkylene, In some embodiments, L4is -O-, -NRL-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, - C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-. In some embodiments, L4is -O-, -NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L4is -C(=O)NH- or -NHC(=O)-. In some embodiments, L4is substituted or unsubstituted C3-C15 cycloalkyl, or substituted or unsubstituted C1-C12 heterocycloalkyl. In some embodiments, L4is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L4issubstituted or unsubstituted C1-C30 alkylene. In some embodiments, L4is substituted or unsubstituted C2- C30 alkenylene. In some embodiments, L4is substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L4is substituted or unsubstituted C5-C25 heteroalkylene. In some embodiments, L4is substituted or unsubstituted C5-C12 heteroalkylene. In some embodiments, L4is absent.

[0214] In some embodiments, each ofL5is independently -O-, -NRL-, -N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, - OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, - S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C30 alkylene, substituted or unsubstituted C2-C30 alkenylene, substituted or unsubstituted C2-C30 alkynylene, or substituted or unsubstituted C1-C30 heteroalkylene, In some embodiments, L5is -O-, -NRL-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, - C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, - NRLC(=O)NRL-, -NRLC(=S)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or - S(=O)2NRLC(=O)-. In some embodiments, L5is -O-, -NH-, -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L5is -C(=O)NH- or -NHC(=O)-. In some embodiments, L5is substituted or unsubstituted C3-C15 cycloalkyl, or substituted or unsubstituted C1-C12 heterocycloalkyl. In some embodiments, L5is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, L5is substituted or unsubstituted C1-C30 alkylene. In some embodiments, L5is substituted or unsubstituted C2- C30 alkenylene. In some embodiments, L5is substituted or unsubstituted C1-C30 heteroalkylene. In some embodiments, L5is substituted or unsubstituted C5-C25 heteroalkylene. In some embodiments, L5is substituted or unsubstituted C5-C12 heteroalkylene. In some embodiments, L5is absent.

[0215] In some embodiments, the linker comprises one or more selected from AEEA, AEEP, AEEEP, and AEEEEP groups. In some embodiments, the linker comprises(AEEA).In some embodiments, the linker comprises(AEEP). In some embodiments, the linker comprises (AEEEA). In some embodiments, the linker comprises(AEEEP). In some embodiments, the linker comprises

[0217] In some embodiments, a linker of the present disclosure is or comprises O. In some embodiments, a linker of the present disclosure is or comprisessome embodiments, a linker of thepresent disclosure is or comprisesembodiments, a linker of the present disclosure is or comprises

[0219] In some embodiments, the linker is:(i) a bond;

[0220] In some embodiments, a linker of the present disclosure comprises 1 to 20 groups independently selected from -CRbRb-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRa-,-O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)NRa-, -NRaC(=O)-, -S(=O)2NRa-, -NRaS(=O)2-, -NRaC(=O)NRa-, - NRaC(=O)O-, -OC(=O)NRa-, arylene, heteroarylene, wherein each Rais independently hydrogen, halogen, Ci-Cgalkyl, Ci-Cshaloalkyl, Ci-Cghydroxyalkyl, Ci-Ceaminoalkyl, G-Csheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Cj-Cscycloalkyl. C2- Cgheterocycloalkyl, aryl, or heteroaryl, and wherein each Rbis independently hydrogen, halogen, -CN, -NO2, -ORa, -SRa, Ci Coalkyl, CiCehaloalkyi,C1C6hydroxyalkyl, CiCgaminoalkyl, CiCgheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2- C yheterocy cloalky 1, aryl, or heteroaryl. In some embodiments, a linker of the present disclosure comprises 1 to 5, 1 to 3, or 1 to 10 groups as described above.

[0221] In some embodiments, the linker is a bond.Metal Chelator

[0222] In one aspect, described herein are conjugates that comprise a metal chelator that is configured to bind with a radionuclide, for example, a conjugate of Formula (III), (IV1), (IV2), (IV3), (IV4), (IV5), and (IV6). The metal chelator can refer to a moiety of the conjugate that is configured to bind with a radionuclide. In some embodiments, a conjugate described herein comprises two or more independent metal chelators, e.g., 2, 3, 4, 5, or more metal chelators. In some embodiments, a conjugate described herein comprises two metal chelators, which can be the same or different. In some embodiments, a conjugate described herein comprises two or more metal chelators. In some embodiments, the conjugate comprises two radionuclides bound to the metal chelators. The metal chelator can be attached to the linker or the peptide through any suitable group / atom of the chelator.

[0223] In some embodiments, the metal chelator is capable of binding a radioactive atom. The binding can be direct, e.g., the metal chelator can make hydrogen bonds or electrostatic interactions with the radioactive atom. The binding can also be indirect, e.g., the metal chelator binds to a molecule that comprises a radioactive atom. In some embodiments, the metal chelator comprises, or is, a macrocycle. In some embodiments, the metal chelator comprises, or is, 2,2',2",2'''-(l,4,7,10-Tetraazacyclododecane- 1,4,7, 10-tetrayl)tetraacetic acid (DOTA) or l,4,7-triazacyclononane-l,4,7-tnacetic acid (NOTA). In some embodiments, the metal chelator comprises a macrocycle, e g., a macrocycle comprising an O and / or a N, DOTA, NOTA, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTPA, TETA, DO3A, PCTA, or desferrioxamine.

[0224] In some embodiments, the metal chelator comprises a plurality of amines. In some embodiments, the metal chelator includes 4 or more N, 4 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator does not comprise S. In some embodiments, the metal chelator comprises a ring. In some embodiments, the ring comprises an O and / or an N. In some embodiments, the metal chelator is a ring that includes 3 or more N, 3 or more carboxylic acid groups, or a combination thereof. In some embodiments, the metal chelator is polydentate.

[0225] In some embodiments, a metal chelator described herein is selected from: DOTA, DOTA-GA, pBn-DOTA, pBn-SCN-DOTA, NH2-DOTA, NH2-DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo- DO3A, p-SCN-Bn -OXO-DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2- Bn-NOTA, p-SCN-Bn-NOTA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p- SCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACROPA-NCS, Hl-MACROPA, H2-MACROP A-NH2, H4- OCTAPA, tetra-(S, S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, or maleimide-nBu-DOTA. In some embodiments, a metal chelator described herein is selected from: DOTA, DOTA-GA, pBn-DOTA, pBn-SCN-DOTA, NH2-DOTA, NH2-DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn-oxo-DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn- NODA-GA, p-NH2-Bn-NOTA, p-SCN-Bn-NOTA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p- NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACROPA-NCS, Hl-MACROPA, H2-MACR0PA-NH2, H4-0CTAPA, tetra-(S, S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S,S)-iBu-DOTA, PYTA, or maleimide-nBu-DOTA.

[0226] In some embodiments, a metal chelator described herein has a structuremetal chelator described herein has a structuresome embodiments, a metal chelator described herein has a structure(PYTA).

[0227] In some embodiments, a metal chelator described herein comprises a cyclic chelating agent. Exemplary cyclic chelating agents include, but are not limited to, AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, D03A, H3HP-DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A, DOTA, DOTA- 3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-lpy, p-SCN-Bn-DOTA, CHX-A"- EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, NOTA, NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTPA, CHX-A "-DTPA, p-NH2-Bn-CHX-A''-DTPA, p-SCN- DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA, p-SCN-BnlB-DTPA, p-SCN-Bn-lB4M-DTPA, p-SCN- Bn-CHX-A "-DTPA, PEPA, p-SCN-Bn-PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix[4]arene- tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L1, H3L4, H2azapa, I Edccapa. bispa2, EUpypa, EUoctapa, EUCEIXoctapa, p-SCN-Bn-EUoctapa, p-SCN-Bn-EUoctapa, TTEIA, p-NO2-Bn-neunpa, ELoctox, H2inacropa, I Ebispa2. I Lphospa. I Ephospa. p-SCN-Bn-Hgphospa, TETA, p-NO2-Bn-TETA, TRAP, TPA, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycuplAlB, pycup2A, THP, DEDPA, H2DEDPA, p-SCN-Bn-H2DEDPA, p-SCN-Bn-TCMC, motexafm, NTA, NOC, 3p-C-NETA, p- NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C- NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX- Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SB AD, BAPEN, TACHPYR, NEC-SP, L^, LI, L2, L3, and EuK-106. In some embodiments, the metal chelator is DOTA, TRITA, TETA, DOTA-MA, DO3A-HP, DOTMA, DOTA-pNB, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP, DOTBzP, DOTA-monoamide, p-NCS-DOTA, p-NCS-PADOTA, BAT, DO3TMP-Monoamide, p-NCS- TRITA, NOTA, or CHX-A"-DTPA. In some embodiments, a metal chelator described herein comprises an acyclic chelating agent. Exemplary acyclic chelating agents include, but are not limited to, DTA,

[0228] In some embodiments, the metal chelator is DO3A. In some embodiments, the metal chelator is PEPA. In some embodiments, the metal chelator is EDTA. In some embodiments, the metal chelator isCHX-A"-DTPA. In some embodiments, the metal chelator is HEHA. In some embodiments, the metal chelator is DOTMP. In some embodiments, the metal chelator is t-Bu-calix[4]arene-tetracarboxylic acid. In some embodiments, the metal chelator is macropa. In some embodiments, the metal chelator is macropa-NCS. In some embodiments, the metal chelator is H4pypa. In some embodiments, the metal chelator is EEoctapa. In some embodiments, the metal chelator is EECHXoctapa. In some embodiments, the metal chelator is DOTP. In some embodiments, the metal chelator is crown. In some embodiments, the metal chelator is NOTA. In some embodiments, the metal chelator is NODAGA.

[0229] In some embodiments, the metal chelator is DOTA. In some embodiments, the metal chelator is a chiral derivative of DOTA. Exemplary chiral DOTA chelators are described in Dai et al., Nature Communications (2018) 9:857. In some embodiments, the metal chelator is 2,2',2",2'"-((2S,5S,8S,llS)- 2,5,8, 11 -tetramethyl- 1, 4,7, 10-tetraazacyclododecane-l, 4,7, 10-tetrayl)tetraacetic acid. In some embodiments, the metal chelator has a structure ofIn some embodiments, the metal chelator is 2, 2', 2", 2"'-((2S,5S,8S, 11 S)-2, 5, 8, 11 -tetraethyl- 1,4, 7, 10-tetraazacyclododecane-l, 4,7,10- tetrayl)tetraacetic acid. In some embodiments, the metal chelator has a structure of

[0230] In some embodiments, the metal chelator has a structure ofwherein each Reis independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain. In some embodiments, the metal chelator has a structure of wherein each Reis independentlyselected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, or an amino acid side chain.

[0231] In some embodiments, the conjugate comprises DOTA. In some embodiments, the conjugate comprises a DOTA derivative such as p-SCN-Bn-DOTA and MeO-DOTA-NCS. In some embodiments, the conjugate comprises two independent metal chelators, and at least one or both are DOTA. The structures of some exemplary metal chelators are illustrated in FIGs. 6-25 (without showing the attachment points). Exemplary metal chelators are also illustrated in FIGs. 1A, 2A, 3A, 4A, and 5A (attachment point shown as a squiggly line) and FIGs. IB, 2B, 3B, 4B and 5B (except that a part of the linker or the peptide covalently connected to the metal chelator is shown in the dashed circle). In some embodiments, a conjugate comprises a metal chelator of FIG. 1A. In some embodiments, a conjugate comprises a metal chelator of FIG. 2A. In some embodiments, a conjugate comprises a metal chelator of FIG. 3A. In some embodiments, a conjugate comprises a metal chelator of FIG. 4A. In some embodiments, a conjugate comprises a metal chelator of FIG. 5A. Exemplary metal chelators are further described in WO2012 / 174136; US20130183235A1; US20120219495A1; US5334371, EP292689 A2, WO2023202655 Al, Ramogidaand et al., EJNMMI radiopharm. chem. 4, 21 (2019); Thiele et al., Cancer Biotherapy and Radiopharmaceuticals 2018; Li et al., Bioconjugate Chem. 2019, 30, 5, 1539-1553; and Baranyai et al., Eur. J. Inorg. Chem. 36-56 (2020), each of which is incorporated by reference in its entirety.

[0232] A metal chelator such as DOTA can interact with a radionuclide (e.g.,177Lu or225Ac) via one or more functional groups and / or atoms. For example, a metal chelator can interact with a radionuclide vianitrogen and / or oxygen atoms. As another example, a metal chelator can interact with a radionuclide via carbonyl, carboxylic acid, amino, and / or amide groups of the metal chelator. In some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated as In some embodiments, the interaction of a metal chelator and aradionuclide of the conjugates disclosed herein can be illustrated as. In some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated asIn some embodiments, the interaction of a metal chelator and a radionuclide of the conjugates disclosed herein can be illustrated as In some embodiments, the interaction of ametal chelator and a radionuclide of the conjugates disclosed herein can be illustrated asradionuclide of the conjugates disclosed herein can be illustrated as. In some embodiments, the radionuclide exists in a positive oxidation state e.g.,225Ac3+,177Lu3+. In some embodiments, for example in certain aqueous conditions, the radionuclide exists in a salt form, e.g., as225Ac3+,177LU3+. In some embodiments, for example in certain acidic aqueous conditions, the radionuclide exists in a salt form, e.g., as225Ac3+,177Lu3+. In some embodiments, the conjugate is in a salt form. In some embodiments, one or more of the carboxylic acid groups of the conjugate may exist as carboxylate anions. In some embodiments, one or more of the carboxylate anions of the conjugate may coordinate to the radionuclide. A person of ordinary skill would appreciate that the dissociation of an acid can depend on the pH value of the environment and its pK value. Accordingly, in some embodiments, a conjugate described herein can exist in a completely ionized, partially ionized or non-ionized form.Radionuclide

[0233] In one aspect, disclosed herein are radiopharmaceutical conjugates comprising a radionuclide. In some embodiments, the radionuclide is chelated or bound to a metal chelator. In some embodiments, the radionuclide is covalently bound to the conjugate. Generally, the type of radionuclide used in a therapeutic radiopharmaceutical can be tailored to the specific type of cancer, the type of targeting moiety (e.g., binding peptide), etc. Radionuclides that undergo a-decay produce particles composed of two neutrons and two protons, and radionuclides that undergo [3-decay emit energetic electrons from their nuclei. Some radionuclides can also undergo electron capture and emit auger electrons. In some embodiments, the conjugate comprises an alpha particle-emitting radionuclide. Alpha radiation can cause direct, irreparable double-strand DNA breaks compared with gamma and beta radiation, which can cause single-stranded breaks via indirect DNA damage. The range of these particles in tissue and the half-life of the radionuclide can also be considered in designing the radiopharmaceutical conjugate. Table 4 belowillustrates some properties of exemplary radionuclides.Table 4. Exemplary radionuclides

[0234] In some embodiments, the radiopharmaceutical conjugate described herein comprises a radionuclide selected from Table 4.

[0235] In some embodiments, the radiopharmaceutical conjugate described herein comprises one or more independent radionuclides. In some embodiments, the radiopharmaceutical conjugate comprises two radionuclides. In some embodiments, each of the one or more radionuclides is bound to the metal chelator of the radiopharmaceutical conjugate. In some embodiments, two radionuclides of the radiopharmaceutical conjugate are bound to the same metal chelator. In some embodiments, tworadionuclides of the radiopharmaceutical conjugate are bound to two independent metal chelators. In some embodiments, each of the one or more radionuclides is an alpha particle-emitting radionuclide.

[0236] In some embodiments, the radiopharmaceutical conjugate described herein comprises an alpha particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises an alpha-particle emitting radionuclide bound to the metal chelator. In some embodiments, the alpha particle-emitting radionuclide is actinium-225 (225Ac), radium-223 (223Ra), radium-224 (224Ra), bismuth- 209 (209Bi), bismuth-213 (213Bi), gadolinium-148 (148Gd), terbium-149 (149Tb), polonium-213 (213Po), francium-223 (223Fr), thorium-227 (227Th), thorium-229 (229Th), or lead-212 (212Bb). In some embodiments, the alpha particle-emitting radionuclide is selected from225Ac,223Ra,209Bi,213Bi,148Gd,149Tb,213Po,223Fr,227Th,229Th, and212Pb. In some embodiments, the alpha particle-emitting radionuclide is225Ac. In some embodiments, the alpha particle-emitting radionuclide is213Bi. In some embodiments, the alpha particle -emitting radionuclide is212Bi. In some embodiments, the alpha particle-emitting radionuclide is212Pb. In some embodiments, the alpha particle-emitting radionuclide is224Ra. In some embodiments, the alpha particle-emitting radionuclide is223Ra. In some embodiments, the alpha particleemitting radionuclide is227Th. In some embodiments, the alpha particle -emitting radionuclide is149Tb. In some embodiments, the conjugate comprises225Ac. In some embodiments, the conjugate comprises two225Ac radionuclides. In some embodiments, the radionuclide is no-carrier added (i.e., non-carrier-added or n.c.a.)177Lu. In some embodiments, the radionuclide is no-carrier added (i.e., non-carrier-added or n.c.a.)225Ac. In some embodiments, the radionuclide is177Lu free of long-lived radioactive contaminants and byproducts. In some embodiments, the conjugate comprises two177Lu radionuclides. In some embodiments, the radionuclide is a non-carrier-added radionuclide. In some embodiments, the radionuclide is a pseudo-radiometal. In some embodiments, the pseudo-radiometal is aluminum - [18F]fluonde ([18F]A1F) complex.

[0237] In some embodiments, the radiopharmaceutical conjugate described herein comprises a radionuclide selected from62Cu,64Cu,67Cu,90Y,109Pd,u lAg,134Ce,149Pm,153Sm,166Ho, "mTc,67Ga,68Ga,U 1ln,90Y,177LU,186Re,188Re,197Au,198Au,199Au,105Rh,165Ho,161Tb,149Pm,153Pm, ^Sc,47Sc,213Po,212Pb,209Bi,212Bi,213Bi,225Ac,117mSn,67Ga,149Tb,152Tb,167Tm,175Yb,223Ra,223Fr,227Th,229Th,2O1T1,148Gd,150Gd,148Nd,89Sr, and89Zr. In some embodiments, the radionuclide is selected from62Cu,54Cu,67Cu,68Ga,89Zr,90Y, "mTc,105Rh,11’in,134Ce,148Gd,149Tb,152Tb,153Pm,167Tm,175Yb,177Lu,209Bi,212Pb,213Po,213Bi,223Ra,223Fr,227Th,225Ac, and229Th. In some embodiments, the radionuclide is225Ac. In some embodiments, the radionuclide is a decay daughter of225Ac such as221Fr,217At,213Bi,213Po,2O9T1,209Pb, or209Bi. In some embodiments, the radiopharmaceutical conjugate comprises two225Ac radionuclides. In some embodiments, the radionuclide is177Lu. In some embodiments, the radiopharmaceutical conjugate comprises two177Lu radionuclides. In some embodiments, the radionuclide is Ac-225 or Ga-68.

[0238] In some embodiments, the radiopharmaceutical conjugate described herein comprises a beta particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a beta particle-emitting radionuclide bound to the metal chelator. In some embodiments, the beta particleemitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, Tb-161, orIn-111. In some embodiments, the beta particle-emitting radionuclide is copper-67, rhodium-105, ytterbium- 175, thulium-167, promethium- 153, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the beta particle emitting radionuclide is copper-67, yttrium-90, samarium-153, or lutetium-177. In some embodiments, the beta particle emitting radionuclide is lutetium-177.

[0239] In some embodiments, the radiopharmaceutical conjugate described herein comprises a gamma particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a gamma particle-emitting radionuclide bound to the metal chelator. In some embodiments, the gamma particle-emitting radionuclide is indium-111 or tin-117m.

[0240] In some embodiments, the radiopharmaceutical conjugate described herein comprises a positron particle-emitting radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a positron particle-emitting radionuclide bound to the metal chelator. In some embodiments, the positronemitting radionuclide is gallium-68, copper-61, copper-62, copper-64, zirconium-89, or terbium- 152. In some embodiments, the radionuclide is zirconium-89. In some embodiments, the radionuclide is gallium- 68.

[0241] In some embodiments, a conjugate described herein comprises a radionuclide suitable for imaging or diagnostic purposes. In some embodiments, the radionuclide suitable for imaging is selected from62Cu,64Cu,89Zr,134Ce,152Tb,68Ga, " In. and99mTc. In some embodiments, the radionuclide is suitable PET imaging. In some embodiments, the radionuclide suitable for PET imaging is selected from62Cu, '"Cu.89Zr,134Ce,152Tb, and68Ga. In some embodiments, the radionuclide is suitable for SPECT imaging. In some embodiments, the radionuclide suitable for SPECT imaging is selected froml uIn and 99mr" c

[0242] In some embodiments, radiopharmaceutical conjugates described herein do not contain any hot radionuclide, i.e., a cold conjugate. For example, in some cases, a radionuclide can be replaced with a surrogate (e.g.,225Ac replaced with lanthanum) for testing and experimental purposes. In some embodiments, hot lutetium (Lu-177) is replaced with a cold lutetium (Lu-175).

[0243] In some embodiments, a radiopharmaceutical conjugate disclosed herein comprises a pseudoradiometal, for example, an aluminum-18F complex. In some embodiments, the aluminum-18F complex is bound to a metal chelator.Conjugates Comprising Non-Radioactive Drugs

[0244] In one aspect, described herein is a conjugate comprising an SSTR binding peptide as described herein (e.g., a peptide of Formula (I), (I’), (I”), or Formula (II)), a non-radioactive drug, and optionally a linker. In some embodiments, disclosed herein is a conjugate of Formula (III), (IV1), (IV2), (IV3), (IV4), (IV5), or (IV6), except that the metal chelator is replaced with a non-radioactive drug. In some embodiments, the conjugate further comprises both a metal chelator and optionally a radionuclide bound to the metal chelator, and a non-radioactive drug. In some embodiments, the conjugate comprises an SSTR binding peptide herein (e.g., a peptide of Formula (I), (F), (I”), or Formula (II)), a nonradioactive drug, and optionally a tinker connecting the SSTR binding peptide to the non-radioactivedrug. The non-radioactive drug can be a toxin. In some embodiments, the toxin is selected from pseudomonas exotoxin (PE), deBouganin, Bouganin, diphtheria toxin (DT) and ricin. In some embodiments, the non-radioactive drug can be a chemotherapy agent.

[0245] The non-radioactive drug can be a cytotoxic drug. Exemplary cytotoxic drugs include aplidin, azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan (CPT- 11), SN-38, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, 2- pyrrolinodoxorubicin (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, ethinyl estradiol, estramustine, etoposide, etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3',5'-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, L- asparaginase, leucovorin, lomustine, mechlorethamine, medroprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, PSI-341, semustine streptozocin, tamoxifen, taxanes, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, velcade, vinblastine, vinorelbine, vincristine, ricin, abrin, ribonuclease, onconase, rapLRl, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, Pseudomona endotoxin, or combinations of these.

[0246] In some embodiments, the non-radioactive drug is selected from duocarmycin and its analogues, dolastatins, combretastatm, calicheamicin, N-acetyl-n-calicheamycm (CMC), a calicheamycin derivative, maytansme and analogues thereof, DM-I, auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), tubulysin, disorazole, the epothilones, Paclitaxel, docetaxel, Topotecan, echinomycin, estramustine, cemadotine, eleutherobin, methopterin, actinomycin, daunorubicin, the daunorubicin conjugates, mitomycin C, mitomycin A, vincristine, retinoic acid, camptothecin, a camptothecin derivative, SN38, maytansine, a derivative of the maytansinoid type, DM1, DM4, TK1, amanitin, a pyrrolobenzodiazepine, a pyrrolobenzodiazepine dimer, methotrexate, ilomedine, aspirin, an IMIDs, lenalidomide, pomalidomide.

[0247] In some embodiments, the non-radioactive drug is a polypeptide, a small molecule compound, a cell, a polynucleotide, a magnetic nanocluster, a nanoparticle, or a boron cluster.

[0248] In some embodiments, the non-radioactive drug is a polypeptide. In some embodiments, the nonradioactive drug is an antibody, a nanobody, or a functional fragment thereof. In some embodiments, the non-radioactive drug is a peptide ligand.

[0249] In some embodiments, the non-radioactive drug is a small molecule compound. In some embodiments, the small molecule therapeutic is a kinase inhibitor, an apoptosis inducer, a PROTAC, or a molecular glue. In some embodiments, the non-radioactive drug is an antineoplastic agent. In some embodiments, the antineoplastic agent is selected from an auristatin, a maytansinoid, a tubulysin, a cryptophycin, a hemisaterlin, a cemadotin, a rhizoxin, a discodermolide, a pyrrolobenzodiazepine, aduocarmycin, a calicheamicin, a camptothecin, an indolinobenzodiazepine, or an amatoxin. In some embodiments, the non-radioactive drug is a cell therapy such as an immune cell therapy or an engineered cell therapy.

[0250] In some embodiments, the non-radioactive drug is a polynucleotide such as a DNA or RNA oligonucleotide. In some embodiments, the non-radioactive drug is an aptamer.In some embodiments, the non-radioactive drug is a ligand which binds to a second protein. In some embodiments, the second protein is CD137. In some embodiments, the ligand is a vitamin.Amino Acids

[0251] The structures of exemplary unnatural amino acids that are present in Table 1 and Table 2 can be found below. As described in Table 1, 2, or other tables, abbreviations have the following meanings: Upper case and lower case “D” means D-amino acids, e.g., D-Trp or dTrp refers to D-tryptophan; Me refers to a methyl group, e.g., NMe-Hcy represents N-Methyl- homocysteine (i.e., methyl -homocysteine); Ala or A refer to alanine; Asn or N refer to asparagine; Glu or E refer to glutamic acid; Asp or D refer to aspartic acid; Cys or C refer to cysteine; Gin or Q refer to glutamine; Gly or G refer to glycine; His or H refer to histidine; He or I refer to isoleucine; Leu or L refer to leucine; Lys or K refer to lysine; Phe or F refer to phenylalanine; Pro or P refer to proline; Ser or S refer to serine; Thr or T refer to threonine; Trp or W refer to tryptophan; Tyr or Y refer to tyrosine; and Vai or V refer to valine.

[0252] Unless otherwise stated in the present specification, the following abbreviations for non-natural amino acids are used according to the following meanings:(3-Azetidine)-hAla 2-amino-4-(azetidin-3-yl)butanoic acid, such as (S)-2-amino-4-(azetidin-3- yl)butanoic acid;(5-C1) D-Trp (R)-2-amino-3-(5-chloro-lH-indol-3-yl)propanoic acid;(5-Me) D-Trp (R)-2-amino-3 -(5 -methyl- lH-indol-3-yl)propanoic acid; (5-MeO) D-Trp (R)-2-amino-3 -(5 -methoxy- lH-indol-3-yl)propanoic acid; (6-Me) D-Trp (R)-2-amino-3-(6-methyl- lH-indol-3-yl)propanoic acid; (7-Me) D-Trp (R)-2-amino-3-(7-methyl- lH-indol-3-yl)propanoic acid; (D / L)Hly 2,6-diamino-6-hydroxyhexanoic acid; (R-βBenzyl) D-Trp (2R,3R)-2-amino-3-(lH-indol-3-yl)-4-phenylbutanoic acid;(R-βBenzyl) Trp (2S,3R)-2-amino-3-( lH-indol-3-yl)-4-phenylbutanoic acid; (R-βCyclopropyl) D- (2R,3R)-2-amino-3-cyclopropyl-3-(lH-indol-3-yl)propanoic acid; Trp(R-βCyclopropyl) Trp (2S,3R)-2-amino-3-cyclopropyl-3-(lH-indol-3-yl)propanoic acid; (R-βisobutyl) D-Trp (2R,3R)-2-amino-3-(lH-indol-3-yl)-5-methylhexanoic acid; (R-βisobutyl) Trp (2S,3R)-2-amino-3-(lH-indol-3-yl)-5-methylhexanoic acid; (R-βlsopropyl) D-Trp (2R,3R)-2-amino-3-(lH-indol-3-yl)-4-methylpentanoic acid; (R-βlsopropyl) Trp (2S,3R)-2-amino-3-(lH-indol-3-yl)-4-methylpentanoic acid; (R-βMe) D-Trp (2R,3R)-2-amino-3-(lH-indol-3-yl)butanoic acid;(R-βMe) Phe (2S,3R)-2-amino-3-phenylbutanoic acid; (R-βMe) Trp (2S,3R)-2-amino-3-(lH-indol-3-yl)butanoic acid; (R-βNcopcntyl) D-Trp (2R,3R)-2-amino-3-(lH-indol-3-yl)-5,5-dimethylhexanoic acid; (R-βNcopcntyl) Trp (2S,3R)-2-amino-3-(lH-indol-3-yl)-5,5-dimethylhexanoic acid; (R-βPhenyl) D-Trp (2R,3R)-2-amino-3-(lH-indol-3-yl)-3-phenylpropanoic acid; (R-βPhenyl) Trp (2S,3R)-2-amino-3-( lH-indol-3-yl)-3-phenylpropanoic acid; (R-βPropyl) D-Trp (2R,3R)-2-amino-3-(lH-indol-3-yl)hexanoic acid; (R-βPropyl) Trp (2S,3R)-2-amino-3-( lH-indol-3-yl)hexanoic acid; (R-βSecbutyl) D-Trp (2R,3R)-2-amino-3-(lH-indol-3-yl)-4-methylhexanoic acid; (R-βSecbutyl) Trp (2S,3R)-2-amino-3-( lH-indol-3-yl)-4-methylhexanoic acid; (S-PBenzyl) D-Trp (2R,3S)-2-amino-3-(lH-indol-3-yl)-4-phenylbutanoic acid; (S-PBenzyl) Trp (25.35)-2-amino-3-(lH-indol-3-yl)-4-phenylbutanoic acid; (S-βCyclopropyl) D- (2R,3S)-2-amino-3-cyclopropyl-3-(lH-indol-3-yl)propanoic acid; Trp (S-βCyclopropyl) Trp (25.35)-2-amino-3-cyclopropyl-3-(lH-indol-3-yl)propanoic acid; (S-βisobutyl) D-Trp (2R,3S)-2-amino-3-(lH-indol-3-yl)-4-methylpentanoic acid; (S-βisobutyl) Trp (25.35)-2-amino-3-(lH-indol-3-yl)-4-methylpentanoic acid; (S-βisopropyl) D-Trp (2R,3S)-2-amino-3-(lH-indol-3-yl)-4-methylpentanoic acid; (S-βisopropyl) Trp (25.35)-2-amino-3-(lH-indol-3-yl)-4-methylpentanoic acid; (S-βMe) D-Trp (2R,3S)-2-amino-3-(lH-indol-3-yl)butanoic acid; (S-βMe) Phe (25.35)-2-amino-3-phenylbutanoic acid; (S-βMe) Trp (25.35)-2-amino-3-(lH-indol-3-yl)butanoic acid; (S-βNeopentyl) D-Trp (2R,3S)-2-amino-3-(lH-indol-3-yl)-5,5-dimethylhexanoic acid; (S-βNeopentyl) Trp (25.35)-2-amino-3-(lH-indol-3-yl)-5,5-dimethylhexanoic acid; (S-βPhenyl) D-Trp (2R,3S)-2-amino-3-(lH-indol-3-yl)-3-phenylpropanoic acid; (S-βPhenyl) Trp (25.35)-2-amino-3-(lH-indol-3-yl)-3-phenylpropanoic acid; (S-βPropyl) D-Trp (2R,3S)-2-amino-3-(lH-indol-3-yl)hexanoic acid; (S-βPropyl) Trp (25.35)-2-amino-3-(lH-indol-3-yl)hexanoic acid; (S-βSecbutyl) D-Trp (2R,3S)-2-amino-3-(lH-indol-3-yl)-4-methylhexanoic acid; (S-βSecbutyl) Trp (25.35)-2-amino-3-(lH-indol-3-yl)-4-methylhexanoic acid; (PGeminal methyl) D- (R)-2-amino-3-(lH-indol-3-yl)-3-methylbutanoic acid; Trp(PGeminal methyl) Trp (S)-2-amino-3-( lH-indol-3-yl)-3-methylbutanoic acid; 2-aza-Trp 2-amino-3-(lH-indazol-3-yl)propanoic acid, such as (R)-2-amino-3-(lH- indazol-3-yl)propanoic acid;3,3-diPhe 2-amino-3,3-diphenylpropanoic acid, such as (S)-2-amino-3,3- diphenylpropanoic acid;3,5-diF Tyr 2-amino-3-(3,5-difluoro-4-hydroxyphenyl)propanoic acid, such as (S)-2- amino-3-(3,5-difluoro-4-hydroxyphenyl)propanoic acid;3MeO-Phe 2-amino-3-(3-methoxyphenyl)propanoic acid, such as (S)-2-amino-3-(3- methoxyphenyl)propanoic acid;3N-Tyr 2-amino-3-(6-hydroxypyridin-3-yl)propanoic acid, such as (S)-2-amino-3- (6-hydroxypyridin-3-yl)propanoic acid;3Pal 2-amino-3-(pyridin-3-yl)propanoic acid, such as (S)-2-amino-3-(pyridin-3- yl)propanoic acid;4-aminomethyl Phe 2-amino-3-(4-(aminomethyl)phenyl)propanoic acid, such as (S)-2-amino-3- (4-(aminomethyl)phenyl)propanoic acid;4-aza-Trp 2-amino-3-(lH-pyrrolo[3,2-b]pyridin-3-yl)propanoic acid, such as (R)-2- amino-3-(lH-pyrrolo[3,2-b]pyridin-3-yl)propanoic acid;4MeO-Phe 2-amino-3-(4-methoxyphenyl)propanoic acid, such as (S)-2-amino-3-(4- methoxyphenyl)propanoic acid;4-oxa Lys O-(2-aminoethyl)-serine, such as O-(2-aminoethyl)-L-serine;4-oxa NMe-Lys O-(2-aminoethyl)-N-methyl-serine, such as O-(2-aminoethyl)-N-methyl-L- senne;4Pal 2-amino-3-(pyridin-4-yl)propanoic acid, such as (S)-2-amino-3-(pyridin-4- yl)propanoic acid;5-aza-Trp 2-amino-3-(lH-pyrrolo[3,2-c]pyridin-3-yl)propanoic acid, such as (R)-2- amino-3-(lH-pyrrolo[3,2-c]pyridin-3-yl)propanoic acid;5FY / 5F-Tyr 2-amino-3-(3-fluoro-4-hydroxyphenyl)propanoic acid, such as (S)-2-ammo- 3 -(3 -fluoro-4-hydroxyphenyl)propanoic acid;6-aza-Trp 2-amino-3-(lH-pyrrolo[2,3-c]pyridin-3-yl)propanoic acid, such as (R)-2- amino-3 -( 1 H-pyrrolo [2,3 -c]pyridin-3 -yl)propanoic acid;7-aza-Trp 2-amino-3-(lH-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid, such as (R)-2- amino-3-(lH-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid;Alt allothreonine, such as L-allothreonine;Aph(Hor) 2-amino-3-(4-(2,6-dioxohexahydropyrimidine-4- carboxamido)phenyl)propanoic acid, such as (2S)-2-amino-3-(4-(2,6- dioxohexahydropyrimidine-4-carboxamido)phenyl)propanoic acid; azaLys amino(4-aminobutyl)carbamic acid;Aza-Trp azatryptophan;Bzt 2-amino-3-(benzo[b]thiophen-3-yl)propanoic acid, such as (S)-2-amino-3- (benzo [b]thiophen-3 -yl)propanoic acid;Cba 2-amino-3-cyclobutylpropanoic acid, such as (S)-2-amino-3- cyclobutylpropanoic acid;Cba3N 2-amino-3-(azetidin-3-yl)propanoic acid, such as (S)-2-amino-3-(azetidin-3- yl)propanoic acid;Cbg 2-amino-2-cyclobutylacetic acid, such as (S)-2-amino-2-cyclobutylacetic acid;Cha 2-amino-3-cyclohexylpropanoic acid, such as (S)-2-amino-3- cyclohexylpropanoic acid;Cha4N 2-amino-3-(piperidin-4-yl)propanoic acid, such as (S)-2-amino-3-(piperidin- 4-yl)propanoic acid;Cha4NH22-amino-3-(4-aminocyclohexyl)propanoic acid, such as (S)-2-amino-3-(4- aminocyclohexyl)propanoic acid;Chg4N 2-amino-2-(piperidin-4-yl)acetic acid, such as (S)-2-amino-2-(piperidin-4- yl)acetic acid;Cpg 2-amino-2-cyclopentylacetic acid, such as (S)-2-amino-2 -cyclopentylacetic acid;D-6F-Trp (R)-2-amino-3-(6-fluoro-lH-indol-3-yl)propanoic acid; D-Aph(Cbm) (R)-2-amino-3-(4-ureidophenyl)propanoic acid; D-Lys D-lysine; D-Phg (R)-2-amino-2 -phenylacetic acid; D-Tpi (R)-2,3,4,9-tetrahydro- lH-pyrido[3,4-b]indole-3-carboxylic acid; D-Trp D-tryptophan; D-Tyr D-tyrosine;F2CON 2-amino-3-(2-carbamoylphenyl)propanoic acid, such as (S)-2-amino-3-(2- carbamoylphenyl)propanoic acid;F3CON 2-amino-3-(3-carbamoylphenyl)propanoic acid, such as (S)-2-amino-3-(3- carbamoylphenyl)propanoic acid;F4COO 4-(2-amino-2-carboxyethyl)benzoic acid, such as (S)-4-(2-amino-2- carboxyethyl)benzoic acid;G(cPr) 2-amino-2-cyclopropylacetic acid, such as (S)-2-amino-2-cyclopropylacetic acid;L-DOPA 2-amino-3-(3,4-dihydroxyphenyl)propanoic acid, such as (S)-2-amino-3- (3 ,4-dihydroxyphenyl)propanoic acid;Lys(diMe) N6,N6-dimethyl-lysine, such as N6,N6-dimethyl-L-lysine; Lys(iPr) N6-isopropyl-lysine, such as N6-isopropyl-L-lysine; Lys(Me) N6-methyl-lysine, such as N6-methyl-L-lysine; Lys(triMe) N6,N6,N6-trimethyl-lysine, such as N6,N6,N6-trimethyl-L-lysine; Mpd 2-amino-3-(methyl(phenyl)amino)propanoic acid, such as (S)-2-amino-3- (methyl(phenyl)amino)propanoic acid;mTyr 2-amino-3-(3-hydroxyphenyl)propanoic acid, such as (S)-2-amino-3-(3- hydroxyphenyl)propanoic acid;Nlys (4-aminobutyl)glycine;NMe-Ala methyl-alanine, such as methyl-L-alanine;NMe-Amp 2-(methylamino)heptanedioic acid, such as (S)-2-(methylamino)heptanedioic acid;NMe-Asp methyl -L-aspartate, such as methyl -L-aspartate;NMe -Azidolysine N6-diazo-N2-methyl-L-lysine, such as N6-diazo-N2-methyl-lysine;NMe-Cha4N 2-amino-3-(piperidin-4-yl)propanoic acid, such as (S)-2-amino-3-(piperidin- 4-yl)propanoic acid;NMe-Chg4N 2-amino-2-(piperidin-4-yl)acetic acid, such as (S)-2-amino-2-(piperidin-4- yl)acetic acid;NMe-Cys methyl -cysteine, such as methyl-L-cysteine;NMe -Dab 4-amino-2-(methylamino)butanoic acid, such as (S)-4-amino-2- (methylamino)butanoic acid;NMe -Dap 3-amino-2-(methylamino)propanoic acid, such as (S)-3-amino-2- (methylamino)propanoic acid;NMe-D-Hcy methyl-D-homocysteine;NMe-dLys methyl-D-lysine;NMe-D-Trp methyl-D-tryptophan;NMe-Glu methyl-glutamate, such as methyl-L-glutamate;NMe -Hey methyl-homocysteine, such as methyl-L-homocysteine;NMe-hGlu 2-(methylamino)hexanedioic acid, such as (S)-2-(methylamino)hexanedioic acid;NMe-hHcy 5-mercapto-2-(methylamino)pentanoic acid, such as (S)-5-mercapto-2- (methylamino)pentanoic acid;NMe-hLys 7-amino-2-(methylamino)heptanoic acid, such as (S)-7-amino-2- (methylamino)heptanoic acid;NMe-Hse methyl-homoserine, such as methyl-L-homoserine;NMe-Hse(Se) methyl -homoselenocysteine, such as methyl-L-homoselenocysteine;NMe-Lys methyl-lysine, such as methyl-L-lysine;NMe-Nle methyl-norleucine, such as methyl-L-norleucineNMe-Om 5-amino-2-(methylamino)pentanoic acid, such as (S)-5-amino-2- (methylamino)pentanoic acid;NMe-Phe methyl -phenylalanine, such as Methyl -L-phenylalanine;NMe -propargyl alanine 2-methyl-2-(methylamino)pent-4-ynoic acid;NMe -propargyl glycine 2-(methylamino)pent-4-ynoic acid;Nva(NH-NH2) 2-amino-5-hydrazineylpentanoic acid, such as (S)-2-amino-5- hydrazineylpentanoic acid;Phg 2-amino-2-phenylacetic acid, such as (S)-2-amino-2 -phenylacetic acid;Pic4 4-aminopiperidine-4-carboxylic acid;PipzaA 2-amino-3-(piperazin-l-yl)propanoic acid, such as (S)-2-amino-3-(piperazin- l-yl)propanoic acid;Ser(3 -azetidine) O-(azetidin-3-yl)-serine, such as O-(azetidin-3-yl)-L-serine;Ser(Ph) O-phenyl-serine, such as O-phenyl-L-serine;Tme O-methyl-threonine, such as O-methyl-L-threonine; trans-Hyp L-hydroxyproline;Tyr(OBn) 2-amino-3-(4-(benzyloxy)phenyl)propanoic acid, such as (S)-2-amino-3-(4-(benzyloxy)phenyl)propanoic acid; andTyr(Phe) 2-amino-3-(4-phenoxyphenyl)propanoic acid, such as (S)-2-amino-3-(4- phenoxyphenyl)propanoic acid.

[0253] Amino acids used in the disclosed peptides can be substituted with similar amino acids. In some embodiments, an amino acid can be substituted with another amino acid with similar hydrophobicity. In some embodiments, an amino acid can be substituted with another amino acid with similar hydrophilicity. In some embodiments, an amino acid can be substituted with another amino acid with similar size. In some embodiments, an amino acid can be substituted with another amino acid with similar charge. In some embodiment, an amino acid can be substituted with another amino acid with a similar functional group. In some embodiments, an amino acid can be substituted with another amino acid with the same functional group.

[0254] In some embodiments, an amino acid described herein can be replaced with a derivative thereof. Examples of an amino acid substitution or derivative include derivatives having an amine, amide, ester, or carboxyl group as the C-terminus and / or N-terminus thereof. Additional examples of amino acid / peptide derivatives include those obtained by modification such as phosphorylation, alkylation (e.g., methylation), acetylation, adenylylation, ADP-ribosylation, or glycosylation and fused protein obtained by fusion with another peptide or protein. These derivatives can be prepared by those skilled in the art in a known manner or a method based thereon. An amino acid derivative further encompasses the amino acids that have the same functional groups but with different lengths of the side chain (e g., LysAc vs. OmAc and cysteine vs. homocysteine). An amino acid derivative further encompasses amino acids with a different aromatic moiety compared to the canonical amino acid (e.g. , the indole in tryptophan vs the 7- azaindole in 7-AzaTrp; the phenyl in phenylalanine vs the pyridine in 4Py). An amino acid derivative further encompasses amino acids with optional substituents, i.e., optionally substituted amino acid.

[0255] In some embodiments, a derivative of an amino acid is selected from amino acids having one, two or three substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(Ci-C3alkyl), -N(Ci-C3alkyl)2, oxo, -OH, -CO2H, -CO2-C1-C3alkyl, -C(=O)NH2, -C(=O)NH(Ci-C3alkyl), -C(=O)N(Ci-C3alkyl)2, -S(=O)2NH2, -S(=O)2NH(CI- C3alkyl), -S(=O)2N(Ci-C3alkyl)2, Ci-C6alkyl, Ci-C6heteroalkyl, Ci-C6alkoxy, C6-Ci0aryl, C3-C6cycloalkyl, 6- to 10- membered heterocycloalkyl, and 6- to 10- membered heteroaryl. In some embodiments, the derivative is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(Ci- C3alkyl), -N(Ci-C3alkyl)2, oxo, -OH, -CO2H, -CO2-Ci-C3alkyl, -C(=O)NH2, -C(=O)NH(Ci-C3alkyl), - C(=O)N(Ci-C3alkyl)2, and C1-C6 alkyl. In some embodiments, the derivative is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from halogen, -CN, -NH2, -NH(Ci-C3alkyl), -N(Ci-C3alkyl)2, and Ci-Ce alkyl. In some embodiments, the derivative is selected from amino acids having one or two substituents based on the amino acid, and wherein the substituents are independently selected from Ci-Cs alkyl.

[0256] In some embodiments, a derivative of an amino acid is selected from amino acids that have the similar hydrophilicity or hydrophobicity compared to the amino acid. Thus, in some embodiments, a positively charged amino acid can be a derivative of another positively charged amino acid. In some embodiments, a negatively charged amino acid can be a derivative of another negatively charged amino acid. In some embodiments, a zwitterionic amino acid can be a derivative of another zwitterionic amino acid.

[0257] In some embodiments, a hydrophilic amino acid has an electrically charged side chain. In some embodiments, a hydrophilic amino acid has a positive charge. In some embodiments, a hydrophilic amino acid has a negative charge. In some embodiments, a hydrophilic amino acid is zwitterionic (e.g., KCOpipzaa). In some embodiments, a hydrophilic ammo acid comprises a -OH, COOH, -NH- or NH2moiety. In some embodiments, a hydrophilic amino acid comprises -OH, -C(O)OH, -NHC(=NH)NH2, - NHC(O)NH2, -C(O)NH2, or -NHC(O)CH3In some embodiments, a hydrophilic ammo acid comprises a side chain of CiCehydroxyalkyl, CiCeaminoalkyl, -Co-e alkylene-NH-C(=NH)-NH2, -Co-e alkylene-CO- NH2, -Co-e alkylene-COOH, or -NH-CO-Ci o alkyl.

[0258] In some embodiments, a hydrophobic amino acid is not charged. In some embodiments, a hydrophobic amino acid contains at least 2 contiguous carbon atoms. In some embodiments, a hydrophobic amino acid comprises at least 3 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises at least 4 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises at least 5 contiguous carbon atoms, either linear or branched. In some embodiments, a hydrophobic amino acid comprises an ethylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises a propylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises a butylene moiety in the side chain. In some embodiments, a hydrophobic amino acid comprises phenyl moiety. In some embodiments, a hydrophobic amino acid comprises a heteroaryl moiety. In some embodiments, a hydrophobic amino acid is Trp, Tyr, Phe, or derivatives thereof.

[0259] In some embodiments, a derivative of an amino acid is selected from amino acids that have the same functional group as the amino acid, and wherein the derivative has a different length of a side chaincompared to the amino acid. In some embodiments, a derivative of an amino acid is selected from amino acids that have the same charge compared to the amino acid. In some embodiments, a derivative of an amino acid is selected from amino acids that have the same polarity compared to the amino acid. In some embodiments, an amino acid comprising an aromatic group can be a derivative of another amino acid having an aromatic group. In some embodiments, an amino acid comprising a phenyl can be a derivative of another amino acid having a phenyl. In some embodiments, an amino acid comprising a heteroaryl can be a derivative of another amino acid having a heteroaryl.

[0260] In some embodiments, an amino acid comprising a cycloalkyl group can be a derivative of another amino acid having a cycloalkyl group. In some embodiments, an amino acid comprising a heterocycloalkyl group can be a derivative of another amino acid having a heterocycloalkyl group.

[0261] In some embodiments, a derivative of an amino acid is selected from amino acids that have similar polarity and / or charge with the amino acid. For example, in some embodiments, a polar, uncharged amino acid can be a derivative of another polar, uncharged amino acid (e.g., Hgn, Q, S, T, Qglucamine),

[0262] In some embodiments, a derivative of an amino acid has the same number of hydrogen donor as the amino acid. In some embodiments, a derivative of an amino acid has the same number of hydrogen acceptor as the amino acid.

[0263] In some embodiments, the derivative has a molecular weight that does not vary for more than 14, 28, 30, 45 or 60 g / mol compared to the amino acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 14 g / mol compared to the ammo acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 50 g / mol compared to the amino acid. In some embodiments, the derivative has a molecular weight that does not vary for more than 28 g / mol compared to the amino acid.

[0264] An amino acid derivative further encompasses amino acids wherein a functional group is substituted with another functional group having similar properties, e.g., a cysteine can be substituted with a homocysteine. In some embodiments, an aryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, a heteroaryl functional group can be substituted with an aryl or heteroaryl group. In some embodiments, an amino functional group can be substituted with an NH(alkyl) group.

[0265] As used herein, the expression “conservative amino acid substitution” refers to a substitution of functionally equivalent or similar amino acids. A conservative amino acid substitution in a peptide brings about a static change to the amino acid sequence of the peptide. For example, one or two or more amino acids having similar polarity act functionally equivalent to each other and bring about a static change in the amino acid sequence of the peptide In general, a substitution within a certain group may be considered conservative regarding structure and function. However, as is clear to a person having ordinary skill in the art, the role played by a defined amino acid residue may be determined by its implication in the three-dimensional structure of the molecule containing the amino acid. For example, a cysteine residue in an oxidized-type (disulfide) form may have a lower polarity than that of a reduced-type (thiol) form. The long aliphatic part of the arginine side chain may constitute structurally and functionally important features. Furthermore, the side chain (tryptophan, tyrosine, phenylalanine) including an aromatic ring may contribute to ion-aromatic interaction or cation-pi interaction. In such a case, even if the amino acids having these side chains are substituted for amino acids belonging to the acidic or non-polar groups, they may be structurally and functionally conservative. There is a possibility that residues such as proline, glycine, cysteine (disulfide form) have a direct effect on the three- dimensional structure of the main chain and often may not be substituted without structural distortion.

[0266] Conservative amino acid substitution, as shown below, includes specific substitution based on the similarity of side chains (for example, substitutions are described in Lehninger, Biochemistry, Revised 2nd Edition, published in 1975, pp. 73 to 75: L. Lehninger, Biochemistry, 2nd edition, pp. 73 to 75, Worth Publisher, New York (1975)), incorporated herein by reference, and typical substitution.

[0267] Hydrophobic amino acids include amino acids that exhibit hydrophobicity, including alanine (also referred to as “Ala” or simply “A”), glycine (also referred to as “Gly” or simply “G”), valine (also referred to as “Vai” or simply “V”), leucine (also referred to as “Leu” or simply “L”), isoleucine (also referred to as “IIe” or simply “I”), proline (also referred to as “Pro” or simply “P”), phenylalanine (also referred to as “Phe” or simply “F”), tryptophan (also referred to as Trp” or simply “W”), tyrosine (also referred to as “Tyr” or simply “Y”), and methionine (also referred to as “Met” or simply “M”).

[0268] Exemplary hydrophobic amino acids may be further divided into the following groups:• Aliphatic amino acids: Amino acids having a fatty acid or hydrogen in the side chain, including e.g., Ala, Gly, Vai, IIe, and Leu.• Aliphatic / branched-chain amino acids: Amino acids having a branched fatty acid in the side chain, including e.g., Vai, IIe, and Leu.• Aromatic amino acids: Amino acids having an aromatic ring in the side chain, including e.g., Trp, Tyr, and Phe.

[0269] In some embodiments, a hydrophobic amino acid has a Ci-Cs alkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each independently, optionally substituted. In some embodiments, a hydrophobic amino acid has a Ci-Cs alkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each unsubstituted. In some embodiments, a hydrophobic amino acid has a Cunsubstituted alkyl.

[0270] Hydrophilic amino acids include amino acids that exhibit hydrophilicity, including e.g., serine (also referred to as “Ser” or simply “S”), threonine (also referred to as “Thr” or simply “T”), cysteine (also referred to as “Cys” or simply “C”), asparagine (also referred to as “Asn” or simply “N”), glutamine (also referred to as “Gin” or simply “Q”), aspartic acid (also referred to as “Asp” or simply “D”), glutamic acid (also referred to as “Glu” or simply “E”), Elysine (also referred to as “Lys” or simply “K”), arginine (also referred to as “Arg” or simply “R”), and histidine (also referred to as “His” or “H”).

[0271] Exemplary hydrophilic amino acids may be further divided into the following groups:• Acidic amino acids: Amino acids whose side chains exhibit acidity, including Asp and Glu.• Basic amino acids: Amino acids whose side chains exhibit basicity, including Lys, Arg, and His.• Neutral amino acids: Amino acids whose side chains exhibit neutrality, including Ser, Thr, Asn, Gin, and Cys.

[0272] Exemplary hydrophilic amino acids include, for example, D, Q, E, S, N, T, C, H, or a derivative thereof.

[0273] Examples of the amino acids include natural protein L-amino acids, unnatural amino acids, and chemically synthesized compounds having properties known in the art as characteristics of an amino acid. Examples of the unnatural amino acids include, but not limited to, a,a-disubstituted amino acids (such as a-methylalanine), N-alkyl-a-amino acids, N-alkyl-0-amino acids, D-amino acids, 0-amino acids, and a-hydroxy acids, each having a backbone struct urc different from that of natural amino acids; amino acids (such as norleucine and homohistidine) having a side-chain structure different from that of natural amino acids; amino acids (such as “homo” amino acids, homophenylalanine, and homohistidine) having extra methylene in the side chain thereof; and amino acids (such as cysteic acid) obtained by substituting a carboxylic acid functional amino group in the side chain thereof by a sulfonic acid group.

[0274] The peptides described herein can comprise one or more unnatural amino acids. Unnatural amino acids include, but are not limited to, (1) amino acids corresponding to an amino acid residue on a polypeptide subjected to modification after expression (ex. phosphorylated tyrosine, acetylated lysine, or famesylated cysteine), (2) amino acids that cannot be used in expression on a ribosome but occur naturally, and (3) artificial amino acids that do not occur naturally (unnatural amino acids). Non-limiting examples of unnatural amino acids include: p-acetyl-L-phenylalanine, p-iodo-L-phenylalanine, p- methoxyphenylalanine, O-methyl-L-tyrosine, p-propargyloxyphenylalanine, p-propargyl-phenylalanine, L-3-(2-naphthyl)alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl- GlcNAcp-serine, L-Dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L- phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, Boronophenylalanine, O- propargyltyrosine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-bromophenylalanine, selenocysteine, p-amino-L- phenylalanine, isopropyl-L-phenylalanine, and azido-lysine (AzK). In some embodiments, the unnatural amino acid is an unnatural analogue of a tyrosine amino acid; an unnatural analogue of a glutamine amino acid; an unnatural analogue of a phenylalanine amino acid; an unnatural analogue of an alanine amino acid; an unnatural analogue of a serine amino acid; an unnatural analogue of a threonine amino acid; an alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, keto, or amino substituted amino acid; or a combination thereof. In some embodiments, the unnatural amino acid is an amino acid with a photoactivatable cross-linker; a spin-labeled amino acid; a fluorescent amino acid; a metal binding amino acid; a metal-containing amino acid; a photocaged and / or photoisomerizable amino acid; a biotin or biotin-analogue containing amino acid; a keto containing amino acid; an amino acid comprising polyethylene glycol or polyether; a heavy atom substituted amino acid; a chemically cleavable or photocleavable amino acid; an amino acid with an elongated side chain; an amino acid containing a toxic group; a sugar substituted amino acid; a carbon-linked sugar-containing amino acid; a redox-activeamino acid; an a-hydroxy containing acid; an amino thio acid; an a, a-disubstituted amino acid; a P- amino acid; a cyclic amino acid other than proline or histidine, or an aromatic amino acid other than phenylalanine, tyrosine or tryptophan.

[0275] Unnatural amino acids include, for example, N-alkyl amino acids in which a natural amino acid described above is N-alkylated, e.g., those modified with lower alkyl groups (for example, of Cl to C5, Cl to C3, and Cl) in which the nitrogen forming a peptide bond is branched or not branched. Exemplary N-alkyl amino acids include, e.g. , N-ethyl amino acid, N-butyl amino acid, and N-methyl amino acid. Also included are amino acids to which a functional group is further added to the side chain of a natural amino acid or substituted for another functional group (for example, an amino acid having a substitution or an addition in a part such as an arylene group, an alkylene group, or the like of the side chain; an amino acid wherein the arylene group or the alkyl group of the side chain has an increased C-number; an amino acid having a substitution in the aromatic ring of the side chain; a heterocyclic or condensed cyclic amino acid; or the like). Exemplary N-alkyl amino acids further include, e.g. , N-alkyllysine and N- methyllysine.

[0276] In a non-limiting manner, unnatural amino acids include, but are not limited to N-methyl amino acids, (3-Azetidine)-hAla, (5-C1) D-Trp, (5-Me) D-Trp, (5-MeO) D-Trp, (6-Me) D-Trp, (7-Me) D-Trp, (D / L)Hly, (R-βBenzyl) D-Trp, (R-βBenzyl) Trp, (R- Cyclopropyl) D-Trp, (R-βCyclopropyl) Trp, (R- pisobutyl) D-Trp, (R-βisobutyl) Trp, (R-βisopropyl) D-Trp, (R-βisopropyl) Trp, (R- Me) D-Trp, (R- βMe) Phe, (R-βMe) Trp, (R-βNeopentyl) D-Trp, (R-βNeopentyl) Trp, (R-βPhenyl) D-Trp, (R-βPhenyl) Trp, (R-βPropyl) D-Trp, (R-βPropyl) Trp, (R-βSecbutyl) D-Trp, (R-βSecbutyl) Trp, (S-βBenzyl) D-Trp, (S-PBenzyl) Trp, (S-βCyclopropyl) D-Trp, (S-βCyclopropyl) Trp, (S-βisobutyl) D-Trp, (S-βisobutyl) Trp, (S-βisopropyl) D-Trp, (S-βisopropyl) Trp, (S-βMe) D-Trp, (S-βMe) Phe, (S-βMe) Trp, (S- pNeopentyl) D-Trp, (S-βNeopentyl) Trp, (S- Phenyl) D-Trp, (S-βPhenyl) Trp, (S-βPropyl) D-Trp, (S- pPropyl) Trp, (S-βSecbutyl) D-Trp, (S-βSecbutyl) Trp, (pGeminal methyl) D-Trp, (pGeminal methyl) Trp, 2-aza-Trp, 3,3-diPhe, 3,5-diF Tyr, 3MeO-Phe, 3N-Tyr, 3Pal, 4-aminomethyl Phe, 4-aza-Trp, 4MeO- Phe, 4-oxa Lys, 4-oxa NMe-Lys, 4Pal, 5-aza-Trp, 5FY / 5F-Tyr, 6-aza-Trp, 7-aza-Trp, Alt, Aph(Hor), azaLys, Aza-Trp, Bzt, Cba, Cba3N, Cbg, Cha, Cha4N, Cha4NH2, Chg4N, Cpg, D-6F-Trp, D-Aph(Cbm), D-Lys, D-Phg, D-Tpi, D-Trp, D-Tyr, F2CON, F3CON, F4COO, G(cPr), L-DOPA, Lys(diMe), Lys(iPr), Lys(Me), Lys(triMe), Mpd, mTyr, Nlys, NMe-Ala, NMe-Amp, NMe-Asp, NMe-Azidolysine, NMe- Cha4N, NMe-Chg4N, NMe-Cys, NMe-Dab, NMe-Dap, NMe-D-Hcy, NMe-dLys, NMe-D-Trp, NMe- Glu, NMe-Hcy, NMe-hGlu, NMe-hHcy, NMe-hLys, NMe-Hse, NMe-Hse(Se), NMe-Lys, NMe-Nle, NMe-Om, NMe-Phe, NMe-propargyl alanine, NMe-propargyl glycine, Nva(NH-NH2), Phg, Pic4, PipzaA, Ser(3 -azetidine), Ser(Ph), Tme, trans-Hyp, Tyr(OBn), Tyr(Phe), and the like. Note that D-amino acids such as d-alanine may be classified as D-amino acids, but they may also be classified according to the properties of their side chains, and N-methyl amino acids may be classified as N-alkyl amino acids and may also be classified according to the property of the side chain.

[0277] In some embodiments, the unnatural amino acids incorporated into the peptides include one or more of: 1) a ketone functional group (as found in para or meta acetyl-phenylalanine) that can bespecifically reacted with hydrazines, hydroxylamines and their derivatives (Addition of the keto functional group to the genetic code of Escherichia coli. Wang L, Zhang Z, Brock A, Schultz P G. Proc Natl Acad Sci USA. 2003 Jan. 7; 100(l):56-61; Bioorg Med Chem Lett. 2006 Oct. 15; 16(20):5356-9. Genetic introduction of a diketone -containing amino acid into proteins. Zeng H, Xie J, Schultz P G), 2) azides (as found in p-azido-phenylalanine) that can be reacted with alkynes via copper catalyzed “click chemistry” or strain promoted (3+2) cycloadditions to form the corresponding triazoles (Addition of p- azido-L-phenylalanine to the genetic code of Escherichia coli. Chin J W, Santoro S W, Martin A B, King D S, Wang L, Schultz P G. J Am Chem Soc. 2002 Aug. 7; 124(31):9026-7; Adding amino acids with novel reactivity to the genetic code of Saccharomyces cerevisiae. Deiters A, Cropp T A, Mukherji M, Chin J W, Anderson J C, Schultz P G. J Am Chem Soc. 2003 Oct. 1; 125(39): 11782-3), or azides that can be reacted with aryl phosphines, via a Staudinger ligation (Selective Staudinger modification of proteins containing p-azidophenylalanine. Tsao M L, Tian F, Schultz P G. Chembiochem. 2005 December; 6(12):2147-9), to form the corresponding amides, 3) alkynes that can be reacted with azides to form the corresponding triazole (In vivo incorporation of an alkyne into proteins in Escherichia coli. Deiters A, Schultz P G. Bioorg Med Chem Lett. 2005 Mar. 1; 15(5): 1521-4), and 4) boronic acids (boronates) than can be specifically reacted with compounds containing more than one appropriately spaced hydroxyl group or undergo palladium mediated coupling with halogenated compounds (Angew Chem Int Ed Engl. 2008; 47(43):8220-3. A genetically encoded boronate-containing amino acid., Brustad E, Bushey M L, Lee J W, Groff D, Liu W, Schultz P G).Isomers / Stereoisomers

[0278] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.Tautomers

[0279] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0280] In some instances, the compounds disclosed herein exist in tautomeric forms. The structures of said compounds are illustrated in the one tautomeric form for clarity. The alternative tautomeric forms are expressly included in this disclosure.Labeled Compounds

[0281] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such asrespectively. Compounds described herein, and the pharmaceutically acceptablesalts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopesof other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and|4C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are notable for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i. e. , -H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.

[0282] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts.

[0283] In some embodiments, the conjugates described herein exist as their pharmaceutically acceptable salts. In some embodiments, the conjugates disclosed herein include their pharmaceutically acceptable salts.

[0284] In some embodiments, the conjugates described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the conjugates disclosed herein, or by separately reacting a purified conjugate in its free form with a suitable acid or base, and isolating the salt thus formed.

[0285] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-I,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, y-hydroxy buty rate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy ethane sulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfbnate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate.

[0286] Further, the conjugates described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the conjugate with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hy droxy benzoy l)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfomc acid, 4-methylbicyclo- [2.2 2 ]oct-2-ene-l -carboxy lie acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l- carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0287] In some embodiments, the conjugates described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary' amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(Ci-j alkyl)4, and the like.

[0288] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that tire compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates.

[0289] In some embodiments, the conjugates described herein exist as solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are form ed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the conjugates described herein can be conveniently prepared or formed during tire processes described herein. In addition, the conjugates provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Accordingly, one aspect of the present disclosure pertains to hydrates and solvates of conjugates of the present disclosure and / or their pharmaceutical acceptable salts, as described herein, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fisher titration, high resolution X-ray diffraction, and the like.Preparation of the Conjugates

[0290] The disclosure provides methods of preparing and making the conjugates described herein.

[0291] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including ABX advanced biochemical compounds GmbH (Radeberg, Germany), Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avidity Science (U.S.A.), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K ), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), 1TM (Munich, Germany), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd.(Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury; CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Sigma- Aldrich (U.S.A.), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans W’orld Chemicals, Inc. (Rockville, MD), VWR (Radnor, PA, USA), Wako Chemicals USA, Inc (Richmond, VA), and Wuxi-Apptech Inc. (Shanghai, China).Pharmaceutical Compositions

[0292] The radiopharmaceutical conjugate described herein, including e.g., pharmaceutically acceptable salt or solvate thereof, can be adm inistered per se as a pure chemical or as a component of a pharmaceutically acceptable formulation. In some embodiments, a conjugate described herein is combined with a pharmaceutically suitable or acceptable carrier selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Provided herein is a pharmaceutical composition comprising at least one conjugate described herein, or a stereoisomer, pharmaceutically acceptable salt, amide, ester, solvate, orN-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carriers) (or excipient(s)) is acceptable or suitable if the carri er is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.

[0293] In one aspect, the disclosure provides a pharmaceutical composition comprising a herein described conjugate, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.

[0294] The conjugates and pharmaceutical compositions of the current disclosure can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intravenous, intrathecal, epidural, and intranasal, etc.Method of Treatment

[0295] In one aspect, the disclosure provides methods of treating a disease or condition in a subject in need thereof. The methods can comprise administering a radiopharmaceutical conjugate to the subject in need thereof. The methods can provide a therapeutic and / or prophylactic benefit to a subject in need thereof comprising administering a radiopharmaceutical conjugate described herein.

[0296] The methods can comprise administering to a subject a radiopharmaceutical conjugate that comprise a therapeutically effective amount of a conjugate or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is an SSTR-associated cancer. In some embodiments, the cancer is an SSTR2 -associated cancer. In some embodiments, the cancer is a somatostatin receptor-positive (SSTR+) cancer.

[0297] In some embodiments, the cancer is a neuroendocrine cancer, a lymphatic cancer, a pancreatic cancer, a pituitary cancer, a breast cancer, a lung cancer, a stomach cancer, medulloblastoma, or neuroblastoma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a neuroendocrine cancer. In some embodiments, the neuroendocrine cancer is a neuroendocrine lung cancer or a neuroendocrine pancreatic cancer. In some embodiments, the neuroendocrine cancer is a Carcinoid tumor in the lungs, gastrointestinal tract or thymus. Pancreatic neuroendocrine tumor (e.g.. Gastrinoma, Insulinoma, Glucagonoma, VTPoma) Medullary thyroid carcinoma, Merkel cell carcinoma. Pheochromocytoma of the adrenal gland. Adrenal cancer, Small cell carcinoma (such as in the lungs), or Large cell carcinoid tumor (such as in the lungs). In some embodiments, the cancer is a SSTR2+ lung neuroendocrine tumor. In some embodiments, the cancer is somatostatin receptor-positive (SSTR+) gastroenteropancreatic neuroendocrine tumor (GEP-NET). In some embodiments, the cancer is small ceil lung cancer (SCLC). In some embodiments, the cancer is somatostatin receptor expressing (SSTR+) extensive stage small cell lung cancer (ES-SCLC). In some embodiments, the radiopharmaceutical conjugate is administered to the subject in an amount equivalent to about IkBq / kg to about 0.2GBq / kg body weight per dose. In some embodiments, the radiopharmaceutical conjugate is administered to the subject in an amount equivalent to about 5kBq / kg to about 50,000kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical conjugate is administered to the subject in an amount equivalent to about 20 kBq / kg to about 5,000kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical conjugate is administered to the subject in an amount equivalent to about 50 kBq / kg to about 500 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical conjugate is administered to tire subject in an amount equivalent to about 50 kBq / kg to about 200 kBq / kg body weight per dose In some embodiments, the radiopharmaceutical conjugate is administered to the subject in an amount equivalent to about 60 kBq / kg to about 150 kBq / kg body weight per dose. In some embodiments, the radiopharmaceutical conjugate is administered to the subject at a radioactivity of about 1 pCi to 1,000 pCi. In some embodiments, the radiopharmaceutical conjugate is administered to the subject at a radioactivity of about 10 pCi to 500 pCi In some embodiments, the radiopharmaceutical conjugate is administered to the subject at a radioactivity of about 100 pCi to 500 pCi. In some embodiments, theradiopharmaceutical conjugate is administered to the subject at a radioactivity of about 100 pCi to 300 pCi. In some embodiments, the radiopharmaceutical conjugate is administered to achieve a cumulative dose in the subject of about 10,000 kBq to about 100,000 kBq. In some embodiments, the radiopharmaceutical conjugate is administered to achieve a cumulative dose in the subject of about 40,000 kBq to about 70,000 kBq.

[0298] In some embodiments, provided herein are methods for killing a cell comprising contacting the cell with a conjugate disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cell expresses a receptor described herein (e.g., SSTR). In some embodiments, the conjugate or pharmaceutically acceptable salt or solvate thereof binds to a structure on the cell. In some embodiments, the conjugate or pharmaceutically acceptable salt or solvate thereof releases a number of alpha particles by natural radioactive decay. In some embodiments, tire conjugate or pharmaceutically acceptable salt or solvate thereof releases a number of beta particles, gamma rays, and / or Auger electrons by natural radioactive decay. The conjugate described herein can kill a cell by radiation. In some embodiments, the conjugate kills the cell directly by radiation. In some embodiments, the radiation creates, in the cell, oxidized bases, abasic sites, single-stranded breaks, double-stranded breaks, DNA crosslink, chromosomal rearrangement, or a combination thereof. The conjugate can kill the cell by inducing double-stranded DNA breaks. The released alpha particles can be sufficient to kill the cell. The released alpha particles can be sufficient to stop cell growth. The conjugate can also kill the cell indirectly via the production of reactive oxygen species (ROS) such as free hydroxyl radicals. In some embodiments, the conjugate kills the cell indirectly by releasing tumor antigens from one or more different cells, which can have vaccine effect. The conjugate can kill the cell by abscopal effect. The cell can be a cancer cell. In some embodiments, the method comprises killing a cell with an alpha-particle emitting radionuclide.

[0299] After contacting a cell, tire described conjugate can be internalized by the cell. The internalization can be mediated by cell receptors, cell membrane endocytosis, etc. In some embodiments, rapid internalization rate into cancer cells accompanied by a slow extemalization rate can offer therapeutic benefit.

[0300] In one aspect, the disclosed conjugate or a pharmaceutically acceptable salt or solvate thereof is configured to treat cancer by ablating tumor cells. The conjugate or a pharmaceutically acceptable salt or solvate thereof may not modulate the biology of the tumor cell and / or the surrounding stroma. The conjugate or a pharmaceutically acceptable salt or solvate thereof may not modulate immune cells.

[0301] Non-limiting examples of cancers to be treated by tire methods of the present disclosure can include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear’ cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), pancreatic adenocarcinoma, breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, extensive stage small cell lung cancer), esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma, and other neoplastic malignancies. In some embodiments, a subject or population of subjects to be treated with aradiopharmaceutical conjugate of the present disclosure have a solid tumor. In some embodiments, a solid tumor is a melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gall bladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary' gland cancer, prostate cancer, pancreatic cancer, gastroenteropancreatic neuroendocrine tumor, or Merkel cell carcinoma. In some embodiments, a subject or population of subjects to be treated with a radiopharmaceutical conjugate of the present disclosure have a hematological cancer. In some embodiments, the subject has a hematological cancer such as Diffuse large B cell lymphoma (“DLBCL”), Hodgkin’s lymphoma (“HL”), Non-Hodgkin’s lymphoma (“NHL”), Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), or Multiple myeloma (“MM”). In some embodiments, a subject or population of subjects to be treated having the cancer selected from the group consisting of ovarian cancer, lung cancer and melanoma. The cancer can be an SSTR1 -associated cancer. The cancer can be an SSTR2 -associated cancer. The cancer can be an SSTR3-associated cancer. The cancer can be an SSTR4-associated cancer. The cancer can be an SSTR5-associated cancer. The cancer can be a neuroendocrine cancer, a lymphatic cancer, a pancreatic cancer, a pituitaiy cancer, a breast cancer, a stomach cancer, medulloblastoma, or neuroblastoma. The cancer can be a neuroendocrine cancer, ’fire neuroendocrine cancer can be recurrent. The neuroendocrine cancer can be refractory? to a radiotherapy that comprises beta-particle emiting radionuclide. The neuroendocrine cancer can be a neuroendocrine lung cancer or a neuroendocrine pancreatic cancer. The neuroendocrine cancer can be a Carcinoid tumor in the lungs, gastrointestinal tract or thymus. Pancreatic neuroendocrine tumor (e.g., Gastrinoma, Insulinoma, Glucagonoma, VIPoma) Medullary? thyroid carcinoma, Merkel cell carcinoma. Pheochromocytoma of the adrenal gland. Adrenal cancer. Small cell carcinoma (such as in the lungs), or Large cell carcinoid tumor (such as in the lungs). In some embodiments, the neuroendocrine cancer can be a pancreatic neuroendocrine tumor (e.g. gastroenteropancreatic neuroendocrine tumor (GEP-NET)). In some embodiments, the neuroendocrine cancer can be a gastrointestinal neuroendocrine tumor (GI-NET). In some embodiments, the neuroendocrine cancer can be gastroesophageal pancreatic neuroendocrine tumor.

[0302] Gastroenteropancreatic neuroendocrine tumors, or GEP-NETs, are rare tumors with an incidence in the U.S. of 5.45 cases per 100,000. Despite this low incidence, many GEP-NETs follow a more indolent disease course than other epithelial malignancies and thus the prevalence of GEP-NETs in the U.S. is approximately 100,000. GEP-NET tumors can be aggressive and resistant to therapy and based on the Surveillance, Epidemiology, and End Results database, metastatic disease is present at diagnosis in 40-76% of cases. Depending on their morphology and proliferative activity?, GEP-NETs can be classified as well-differentiated tumors or poorly differentiated carcinomas. Well-differentiated GEP- NETs can include low-grade (Grade I, defined as tumors with a mitotic rate of 0 - I per 10 high power field, or HPF, or a Ki67 index from 0-2%) and intermediate-grade tumors (Grade 2, defined as tumors with a mitotic rate from 2-20 per 10 HPF or a Ki67 index from 3-20%), whereas poorly differentiated GEP-NETs can be high-grade (Grade 3, with a mitotic rate greater than 20 per 10 HPF or a K167 index greater than 20%).

[0303] In some embodiments, the site of primary NETs in the digestive tract is the rectum, small intestine, pancreas, stomach, colon, and / or appendix. In some embodiments, the GEP-NET is categorized as hormonally functional (associated with signs and symptoms consistent with excess hormone secretion). In some embodiments, the GEP-NET is categorized as non-functional tumors, wdth clinical features and aggressiveness depending on the primary' tumor site. In some embodiments, the cancer is pancreatic neuroendocrine tumors (pNETs).

[0304] In some embodiments, provided herein are methods and conjugates for treating a disease or condition. Exemplary' disease or condition includes refractory or recurrent malignancies whose growth may be inhibited using the methods of treatment of the present disclosure. In some embodiments, the disease or condition is a cancer. In some embodiments, the cancer is breast cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, small cell lung cancer, extensive stage small cell lung cancer, hepatocellular cancer, colorectal cancer, gastric adenocarcinoma, pancreatic neuroendocrine tumor (e.g. gastroenteropancreatic neuroendocrine tumor), melanoma, or advanced cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is selected from the group consisting of carcinoma, squamous carcinoma, adenocarcinoma, sarcomata, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, fallopian tube cancer, primary peritoneal cancer, colon cancer, colorectal cancer, squamous cell carcinoma of the anogenital region, melanoma, renal cell carcinoma, lung cancer, non-small cell lung cancer, small cell lung cancer, extensive stage small cell lung cancer, squamous cell carcinoma of the lung, stomach cancer, bladder cancer, gall bladder cancer, liver cancer, thyroid cancer, laryngeal cancer, salivary' gland cancer, esophageal cancer, head and neck cancer, glioblastoma, glioma, squam ous ceil carcinoma of the head and neck, prostate cancer, pancreatic cancer, pancreatic neuroendocrine tumors, gastroenteropancreatic neuroendocrine tumors, mesothelioma, sarcoma, hematological cancer, leukemia, lymphoma, neuroma, and combinations thereof. In some embodiments, a cancer to be treated by the methods of the present disclosure include, for example, carcinoma, squamous carcinoma (for example, cervical canal, eyelid, tunica conjunctiva, vagina, lung, oral cavity, skin, urinary' bladder, tongue, larynx, and gullet), and adenocarcinoma (for example, prostate, small intestine, endometrium, cervical canal, large intestine, lung, pancreas, gullet, rectum, uterus, stomach, mammary' gland, and ovary). In some embodiments, the cancer is a hypoxic tumor. In some embodiments, the cancer is GEP-NET. In some embodiments, the cancer is small cell lung cancer. In some embodiments, a cancer to be treated by the methods of the present disclosure further include sarcomata (for example, myogenic sarcoma), leukosis, neuroma, melanoma, and lymphoma. In some embodiments, a cancer to be treated by the methods of the present disclosure is lung cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is small ceil lung cancer (SCLC). In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is extensive stage small cell lung cancer (ES-SCLC). In some embodiments, a cancer to be treated by the methods of the present disclosure is breast cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is triple negative breast cancer (TNBC). In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure ispancreatic cancer. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is a pancreatic neuroendocrine tumor. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is a gastroenteropancreatic neuroendocrine tumor. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is GEP- NET. In some embodiments, a cancer to be treated by the methods of treatment of the present disclosure is gastroesophageal pancreatic neuroendocrine tumor.

[0305] In addition to the methods of treatment described above, the radiopharmaceutical conjugates described herein can be used to image, and / or as part of a treatment for diseases. Conjugates for imaging applications, e.g., single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can comprise a radionuclide suitable for use as imaging isotopes such as the isotopes in Table 4 labeled “Dx”. Accordingly, the conjugate can be administered as a companion diagnostic.

[0306] In one aspect, provided herein are methods for diagnosing a patient harboring a somatostatin receptor (SSTR) expressing cancer or tumor comprising administering to the patient a radiopharmaceutical described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same. In one aspect, provided herein are methods for imaging an SSTR expressing cancer or tumor comprising administering to the patient a radiopharmaceutical described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same. In some embodiments, the method further comprises selecting or confirming that a tumor in the patient expresses SSTR. In some embodiments, the SSTR expressing cancer is an SSTR2 expressing cancer. In some embodiments, the method further comprises measuring the concentration of the radiopharmaceutical accumulated in the patient. In some embodiments, the method further comprises measuring the amount of radiation emitted from the radionuclide. In some embodiments, the method further comprises analyzing the elimination or clearance profile of the radiopharmaceutical in the patient. In some embodiments, the method further comprises measuring an elimination half-life of the radiopharmaceutical in the patient. In some embodiments, the method further comprises analyzing the clearance profile of tire radiopharmaceutical in the patient. In some embodiments, the method of imaging or diagnosing cancer comprises administering a radiopharmaceutical that comprises a radionuclide of Table 4 labeled “Dx”, such as65Ga. For example, radiopharmaceuticals of the present disclosure can be administered for patient selection purposes, such as to confirm the tumor has the appropriate expression of the SSTR target (e.g., SSTR2). As another example, radiopharmaceuticals of the present disclosure can be administered to a patient so that the patient’s care team can make sure the radiopharmaceutical is cleared from the body in a suitable timeframe so that undesired irradiation of other tissues is minimized.

[0307] In some embodiments, a method described herein comprises administering to a patient two radiopharmaceuticals of the present disclosure. In some embodiments, the two radiopharmaceuticals can have the same targeting ligand. In some embodiments, a method described herein comprises administering (i) a radiopharmaceutical of the present disclosure that comprises a radionuclide of Table 4 labeled “Dx”, and followed by (i) a radiopharmaceutical of the present disclosure that comprises aradionuclide of Table 4 labeled “Tx”. In some embodiments, the method comprises administering ao8Ga labeled conjugate described herein followed by the administering of an228Ac labeled conjugate described herein

[0308] The subject can be 4 to 120 years old. The subject can be 5 to 10, 5 to 15, 5 to 18, 5 to 25, 5 to 35, 5 to 45, 5 to 55, 5 to 65, 5 to 75, 10 to 15, 10 to 18, 10 to 25, 10 to 35, 10 to 45, 10 to 55, 10 to 65, 10 to 75, 15 to 18, 15 to 25, 15 to 35, 15 to 45, 15 to 55, 15 to 65, 15 to 75, 18 to 25, 18 to 35, 18 to 45, 18 to 55, 18 to 65, 18 to 75, 25 to 35, 25 to 45, 25 to 55, 25 to 65, 25 to 75, 35 to 45, 35 to 55, 35 to 65, 35 to 75, 45 to 55, 45 to 65, 45 to 75, 55 to 65, 55 to 75, or 65 to 75 years old. The subject can be at least 5, 10, 15, 18, 25, 35, 45, 55, or 65 years old. The subject can be at most 10, 15, 18, 25, 35, 45, 55, 65, or 75 years old.

[0309] In some embodiments, the subject has been diagnosed with a SSTR expressing lesion, neoplasm , cancer, or tumor. In some embodiments, the SSTR expressing lesion, neoplasm, cancer, or tumor is characterized quantifying the amount of SSTR expression and calculating an H-score. In some embodiments, the H-score is derived by a) staining a tissue biopsy for SSTR expression (e.g., SSTR2), b) assigning a cell staining intensity of 0, 1, 2, or 3, c) and multiplying the percentage of ceils by their staining intensity level The H-score has a range of 0 to 300 In some embodiments, the SSTR expressing lesion, neoplasm, cancer, or tumor has an H-score of greater than 10. In some embodiments, the SSTR expressing lesion, neoplasm, cancer, or tumor has an H-score of greater than 100. In some embodiments, the SSTR expressing lesion, neoplasm, cancer, or tumor has an H-score of 11 to 300. In some embodiments, the SSTR expressing lesion, neoplasm, cancer, or tumor has an H-score of greater than 200. In some embodiments, the H-score is between 11 and 100. In some embodiments, the H-score is between 50 and 150. In some embodiments, the H-score is between 100 and 200, In some embodiments, the H-score is between 150 and 250. In some embodiments, the H-score is between 200 and 300.

[0310] Accordingly, provided herein is a method of treating cancer in a subject in need thereof, the method comprising determining an H-score for a lesion, neoplasm, cancer, or tumor tissue sample of the subject and administering to the subject a radiopharmaceutical conjugate described herein. In one aspect, provided herein is a method of treating a subject having an SSTR+ cancer, comprising administering to the subject a radiopharmaceutical conjugate described herein. In some embodiments, a cancer sample of the subject, has been subjected to a determination of an H-score prior to the administration of a conjugate disclosed herein. In some embodiments, a cancer sample of the subject has been subjected to a determination of an H-score, and wherein the H-score is at least 11. In some embodiments, the method comprises determining an H-score for a tumor cancer of the subject. In some embodiments, the H-score is 0 to 300. In some embodiments, tire H-score is greater than 10. In some embodiments, the H-score is greater than 50. In some embodiments, the H-score is greater than 100. In some embodiments, the H- score is greater than 150. In some embodiments, the H-score is greaterthan 100. In some embodiments, the H-score is greaterthan 200. In some embodiments, the H-score is about 120 to 300. n some embodiments, the H-score is about 40 to 300. In some embodiments, the H-score is about 50 to 300. In some embodiments, the H-score is about 100-300. In some embodiments, the H-score is 200-300. An H-score can be calculated according to the method described in WO2023191839A2.

[0311] In one aspect, described herein is a method of treating an SSTR+ cancer in a subject in need thereof, comprising administering to the subject a herein-disclosed radiopharmaceutical conjugate, wherein an H-score of a cancer sample of the subject is at least 11 . In one aspect, described herein is a method of treating a disease in a subject in need thereof, comprising (a) determining a level of S STR expression in a sample of the subject; and (b) administering to the subject a herein-disclosed radiopharmaceutical conjugate. In some embodiments, the level of SSTR expression in a sample is determined by calculating an H-Score, In some embodiments, the H-Score is between 11 and 300. In some embodiments, the H-Score is between 1 1 and 200. In some embodiments, the H-Score is between 11 and 100. In some embodiments, the H-Score is between 101 and 300. In some embodiments, the H- Score is between 101 and 201. In some embodiments, the H-Score is between 201 and 300. In some embodiments, the radiopharmaceutical conjugate comprises the structure of Formula (IV1), (IV2), (IV3), (TV4), (IV5), or (IV6).

[0312] In some embodiments, the radiopharmaceutical conjugates described herein can be administered alone or in combination with one or more additional therapeutic agents. For example, the combination therapy can include a composition comprising a radiopharmaceutical conjugate described herein coformulated with, and / or co-administered with, one or more additional therapeutic agents, e.g., one or more anti-cancer agents, e.g., cytotoxic or cytostatic agents, immune checkpoint inhibitors, hormone treatment, vaccines, and / or immunotherapies. In some embodiments, the radiopharmaceutical conjugate is administered in combination with other therapeutic treatment modalities, including surgery, cryosurgery, and / or chemotherapy. Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies. In some embodiments, the additional anti-cancer agent is a local or regional cancer treatment. In some embodiments, the local or regional cancer treatment comprises microwave ablation. In some embodiments, the local or regional cancer treatment comprises radiofrequency ablation (RFA). In some embodiments, the local or regional cancer treatment comprises ultrasound ablation. In some embodiments, the local or regional cancer treatment comprises magnetic resonance guided focused ultrasound ablation.

[0313] In some embodiments, the local or regional cancer treatment comprises hyperthermia treatment. Different types of techniques can be used to create heat for the hyperthermia treatment. For example, the techniques can include microwaves or probes that make energy from microwaves, radio waves (or radiofrequency), lasers, ultrasound (e.g., high intensity ultrasound), heating fluids such as blood or chemotherapy drags and putting them into the body (or perfusion), placing the entire body in a heated chamber or hot water bath or wrapping with heated blankets, or a combination thereof.

[0314] In some embodiments, the local or regional cancer treatment comprises cryoablation.

[0315] When administered in combination, two (or more) different treatments can be delivered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured oreliminated. In some embodiments, the delivery of one treatment is still occurring when the delivery' of the second begins, so that there is overlap. This is sometimes referred to herein as “simultaneous” or “concurrent delivery'.” In some embodiments, the delivery' of one treatment ends before the deliveiy of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery’ is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery' can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

[0316] Co-admini station of amino acids w ith a radiopharmaceutical described herein may reduce kidney update of the radiopharmaceutical. Reducing kidney uptake and / or increasing clearance of the radiopharmaceutical is a desired property in radiopharmaceutical therapeutics. In some embodiments, a radiopharmaceutical conjugate described herein is concurrently administered with an intravenous infusion of one or more amino acids. In some embodiments, a radiopharmaceutical conjugate described herein is administered after an intravenous infusion of one or more amino acids. In some embodiments, the infusion of the one or more amino acids is administered at least 30 minutes prior to administering a radiopharmaceutical conjugate described herein. In some embodiments, the infusion of the one or more amino acids is administered at least 6 hours, 3 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, or 5 minutes prior to administering a radiopharmaceutical conjugate described herein. In some embodiments, the infusion of the one or more ammo acids is administered 10 to 60 minutes prior to administering a radiopharmaceutical conjugate described herein.

[0317] The radiopharmaceutical conjugates of the current disclosure can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. The term parenteral as used herein includes e.g., subcutaneous, intravenous, intramuscular, intrastemal, intraperitoneal, and infusion techniques. The term parenteral also includes injections, into the eye or ocular, intravitreal, intrabuccal, transdermal, intranasal, into the brain, including intracranial and intradural, into the joints, including ankles, knees, hips, shoulders, elbows, wrists, and the like, and in suppository form. The radiopharmaceutical conjugates can be administered orally. The radiopharmaceutical conjugates can be administered by systemic administration. The radiopharmaceutical conjugates can be administered parenterally. The radiopharmaceutical conjugates can be administered intravenously. The radiopharmaceutical conjugates can be administered locally' at a targeted site.

[0318] The radiopharmaceutical conjugates described herein can be administered via parenteral injection as liquid solution.

[0319] The radiopharmaceutical conjugates can be administered in a manner appropriate to the disease to be treated. An appropriate dose and a suitable duration and frequency of administration can be determined by such factors as the condition of the subject, the type and severity of the subject's disease, the particular form of the active ingredient, and the method of administration. In some embodiments, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the subject. In some embodiments, the radiopharmaceutical conjugate can be administered as part of a first-line therapy. In some embodiments, the radiopharmaceutical conjugate can be administered as part of a first-line therapy with existing standard of care, for example, immune checkpoint blockers and DNA damaging agents.

[0320] In some embodiments, the compositions comprising radiopharmaceutical conjugates described herein can comprise conjugates that exist as solvates. This disclosure provides for methods of treating diseases by administering such solvates. This disclosure further provides for methods of treating diseases by administering such solvates as radiopharmaceutical compositions.

[0321] Although the present disclosure and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the disclosure as defined in the appended claims.

[0322] The present disclosure is further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the disclosure in any way.EXAMPLESA: Synthesis of the Conjugates

[0323] Unless otherwise stated in the present specification, the following abbreviations are used according to the following meanings:Alloc allyloxycarbonyl aq. aqueousBiotin-0 Su biotin iV-hydroxysuccinimide ester (CAS 35013-72-0)Boc tert-butyl oxy carbonylClAcOH chloroacetic acidClAcOSu A-succinimidyl 2-chloroacetate (CAS 27243-15-8)DCM dichloromethane (CAS 75-09-2)DIC A;AP-diisopropylcarbodiimide (CAS 693-13-0)DIPEA, DIEA AJV-diisopropylethylamine (CAS 7087-68-5)DMEM Dulbecco's Modified Eagle MediumDMF A / A-dimethylformamide (CAS 68-12-2)DODT 2,2’-(ethylenedioxy)diethanethiol (CAS 14970-87-7)EDCI-HC1 A7-(3-dimethylammopropyl)-A7' -ethylcarbodiimide hydrochloride(CAS 25952-53-8)EDTA ethylenediaminetetraacetic acidEMEM Eagle's minimal essential medium eq equivalentEt ethylEt3N, TEA triethylamine (CAS 121-44-8)FBS fetal bovine serumFmoc 9-fluorenylmethoxycarbonyl hr hourHAITI l-[bis(dimethylamino)methylene]-l / / -l,2,3-triazolo[4,5-b]pyridinium-3- oxide hexafluorophosphate (CAS 148893-10-1)HOSu A-hydroxysuccinimide (CAS 6066-82-6) iPrOH, IPA isopropanolM molar min minutesNHS A-hydroxysuccinimide (CAS 6066-82-6)NMP A-methylpyrrolidone (CAS 872-50-4)Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0) (CAS 14221-01-3)PG protecting groupPh phenylRP reverse phase rpm rotations per minute rt room temperatureSAPE Streptavidin, R-Phycoerythrin conjugateSPPS solid phase peptide synthesisSu succinimidylSulfoCy5- sulfo Cyanine5 (CAS 2791287-13-1)SulfoCy5-OSu, (CAS 146368-14-1)SulfoCy5-NHS see SulfoCy5-OSu tert tertiary’TFA trifluoroacetic acid (CAS 76-05-1)TIS tri isopropylsilane (CAS 6485-79-6) tr retention timeTrt tritylPyAOP (7-azabenzotriazol- 1 -yloxy)trispyrrolidinophosphonium hexafluorophosphate (CAS 156311-83-0)MeCN acetonitrileAcOH acetic acidEt2O thethyl etherAA amino acidMe methylHFIP 1 ,1, 1,3,3, 3-hexafluoro-2-propanol (CAS 920-66-1)PhSiH3phenylsilane (CAS 694-53-1) tBu tertiary butylDMSO dimethylsulfoxideMpe 3 -Methyl-pent-3 -ylExample Al. Analytical Conditions

[0324] Solid phase peptide synthesis (SPPS) was performed in a standard manual reaction vessel under nitrogen. 2-CTC resin was purchased from Sunresin New Materials Co. (China). Fmoc protected amino acids were purchased from GL Biochem (China). HBTU and HATU were purchased from Highfine Biotech Co. (China). Piperidine was purchased from Damao Chemical Reagent Factory (China). The peptides and their derivatives were purified on a Gilson GX-281 preparative HPLC system using reversephase C18 columns (Gemini, 5 μm, 110 A + luna, 10 μm, 100 A) at 30 °C. HPLC solvents consisted of H2O containing 0.075% trifluoroacetic acid (mobile phase A) and acetonitrile (mobile phase B).

[0325] High performance liquid chromatography (HPLC) analyses were performed on an Agilent 1260 senes equipped with a binary / pump G7112A, micro vacuum degasser, standard autosampler ALS G7129A, thermostatted column compartment TCC G7116A, vanable wavelength detector VWD G7114A, and data were analyzed by OpenLab CDS 2.2 network workstation software from Agilent Technologies. HPLC solvents consisted of H2O containing 0.1% trifluoroacetic acid (mobile phase A) and acetonitrile containing 0.075% trifluoroacetic acid (mobile phase B). Conditions: a Phenomenex Gemini-NX C-18 (5 μm, 110 A, 4.6 * 250 mm) column was used with a flow rate of 1 .0 mL / min.

[0326] LC-MS analyses were carried out on an Agilent 1200 series coupled to an Agilent MSD G6125C, equipped with a binary pump G7112A, micro vacuum degasser, standard autosampler ALS G7129A, thermostatted column compartment TCC G7116A, variable wavelength detector VWD G7114A, and data were analyzed by OpenLab CDS 2.3 standalone workstation software from Agilent Technologies. HPLC solvents consisted of H2O containing 0.1% trifluoroacetic acid (mobile phase A) and acetonitrile containing 0.075% trifluoroacetic acid (mobile phase B). Conditions: a Waters Xbridge C - 18 (3.5 μm , 3 1 x 30mm) column was used with a flow rate of 1.2 mL / min .Example A2. Synthesis of Intermediate (Int) A

[0327] Synthesis of Int A

[0328] 2,2',2"-(10-(2-((6-(2-Chloroacetamido)hexyl)amino)-2-oxoethyl)-l,4,7,10- tetraazacyclododecane-l,4,7-triyl)triacetic acid (Int A). To the swollen 2-CTC resin was added Fmoc- 1,6-diaminohexane hydrochloride (1 mmol) and DIEA (4 mmol) in DCM (5 mL). The mixture was agitated for 15 h under nitrogen. MeOH (1 mL) was then added. The resulting mixture was agitated for 30 min. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL). The Fmoc protecting group was removed via 15 mm agitation with 20% piperidine in DMF followed by filtration and washing.

[0329] To the peptidyl-resin was added DOTA(3tBu) (3 equiv.), DIEA (6 equiv.) and HBTU (3 equiv.) in DMF (5 mL). The mixture was agitated for 1 h under nitrogen. After the reaction solution was removed through filtration, the resin was wmshed three times with DMF (10 mL).

[0330] After the resin was washed three times with MeOH and dried under vacuum, the peptidyl-resin was treated with lOmL TFA cleavage cocktail for 2.5 hour, cold isopropyl ether wsa added. The crude peptide was collected through centrifugation and dried under vacuum.

[0331] The crude peptide was dissolved in H2O (5 mL), then the solution was s adjusted to pH::: 8 with saturated Na^COj aqueous solution and 2,5-dioxopyrrolidin-l-yl 2-chloroacetate (1.5 equiv.) was added. The mixture was stirred at 25 °C for 10 min and keep pH=7-8. After the reaction was completed, the mixture was purified by preparative HPLC to afford Int A (270 mg, 95% purity) as a white solid. Example A3. Synthesis of Intermediate (Int) B

[0332] Synthesis of Int B

[0333] 2,2',2"-(10-(17-Chloro-2,16-dioxo-6,9,12-trioxa-3,15-diazaheptadecyl)-l,4,7,10- tetraazacyclododecane-l,4,7-triyl)triacetic acid (Int B). To the swollen 2-CTC resin were added Fmoc-PEG3-CH2CH2NH2.HC1 (1 mmol) and DIEA (4 mmol) in DCM (5 mL). The mixture was agitated for 15 h under nitrogen MeOH (1 mL) was then added lire resulting mixture was agitated for 30 min. After the reaction solution was removed through filtration, the resin was washed three times with DMF(10 mL). The Fmoc protecting group was removed via 15 min agitation with 20% piperidine in DMF followed by filtration and washing.

[0334] To the peptidyl-resin was added DOTA(3tBu) (3 equiv.), DIEA (6 equiv.) and HBTU (3 equiv.) in DMF (5 mL). The mixture was agitated for 1 h under nitrogen. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL).

[0335] After the resin was washed three times with MeOH and dried under vacuum, the peptidyl-resin was treated with 10 mL TFA cleavage cocktail for 2.5 hour, cold isopropyl ether was added The crude peptide (480mg) was collected through centrifugation and dried under vacuum.

[0336] The crude peptide was dissolved in H2O (5 mL), then the solution was s adjusted to pH= 8 with saturated NaiCOs aqueous solution and 2,5-dioxopyrrolidin-l-yl 2 -chloroacetate (1.5 equiv.) was added. The mixture was stirred at 25 °C for 10 min and keep pH=7-8. After the reaction was completed, the mixture was purified by preparative HPLC to afford Int B (292 mg, 95% purity) as a white solid.Example A4. Synthesis of Intermediate (Int) C

[0337] Synthesis of Int CInt C

[0338] 6-(2-(4,7,10-Tris(2-(tert-butoxy)-2-oxoethyl)-l,4,7,10-tetraazacyclododecan-l- yl)acetamido)hexanoic acid (Int C). To the swollen 2-CTC resin was added 6-(Fmoc-amino)hexanoic acid (0.50 mmol) and DIEA (2 mmol) in DCM (5 mL). The mixture was agitated for 2 h under nitrogen. MeOH (1 mL) was then added. The resulting mixture was agitated for 30 mm. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL). lire Fmoc protecting group was removed via 15 min agitation with 20% piperidine in DMF followed by filtration and washing.

[0339] To the peptidyl-resin was added DOTA(3tBu) (3 equiv.), DIEA (6 equiv.) and HBTU (3 equiv.) in DMF (5 mL). lire mixture was agitated for 1 h under nitrogen. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL).

[0340] After the resin was washed three times with MeOH and dried under vacuum, the resin was treated with 20% HFIP / DCM for 15min 3 times. The mixture was concentrated to dryness and then lyophilized to give Int C (300 mg).Example AS. Synthesis of Intermediate (Int) D

[0341] Synthesis of Int D

[0342] (2S,4R)-l-(((9H-FIuoren-9-yI)methoxy)carb<myI)-4-(((2-(((anyloxy)carbonyl)amino)ethyI)carbamoyI)oxy)pyrroIidine-2-carboxyIic acid (Int D). Fmoc- Hyp(Bom)-OH (1.0g) was treated with 50% TFA / DCM for 30 min, then concentrated to dryness. The material was then dissolved in DMF (10 mL) and Alloc-OSu (1.2 equiv.) and DIPEA (3 equiv.) were added, the mixture was stirred at 25 °C for 1 hour. Then the mixture was purified by preparative HPLC to afford Int D (535mg, 95% purity) as a white solid.Example A6. Synthesis of Intermediate (Int) E

[0343] Synthesis of Int E

[0344] (lr,4r)-4-((2-(4,7,10-Tris(2-(tert-butoxy)-2-oxoethyl)-l,4,7,10-tetraazacyclododecan-l- yl)acetamido)methyl)cydohexane-l-carboxylic acid (Int E). To the swollen 2-CTC resin was added Fmoc-tranexamic acid (2.5 mmol) and DIEA (10 mmol) in DCM (25 mL). The mixture was agitated for 4 h under nitrogen. MeOH (5 mL) was then added. The resulting mixture was agitated for 30 min. After the reaction solution was removed through filtration, the resin was washed three times with DMF. The Fmoc protecting group was removed via 20 min agitation with 20% piperidine in DMF followed by filtration and washing with DMF.

[0345] To the peptidyl-resin was added DOTA(3tBu) (3 equiv.), DIEA (6 equiv.) and FIATU (3 equiv.) in DMF (25 mL). The mixture was agitated for 18 h under nitrogen. After the reaction solution was removed through filtration, the resin was washed three times with DMF.

[0346] After the resin was washed three times with MeOH and dried under vacuum, the resin was treated with 20% HFIP / DCM for 15min 3 times. The mixture was concentrated to dryness and then lyophilized to give Int E (1.7g).

[0347] Example A7. Synthesis of Intermediate (Int) F

[0348] Synthesis of Int FN-(((9H-Fluoren-9-yl)methoxy)carbonyl)-N-(6-(((allyloxy)carbonyl)amino)hexyl)glycine (Int F). To the swollen 2-CTC resin was added BrAc (1 mmol) and DIEA (4 mmol) in DCM (5 mL). The mixture was agitated for 2 h under nitrogen. MeOH (1 mL) was then added. The resulting mixture was agitated for 30 min. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL).To the peptidyl-resin was added tert-butyl (6-aminohexyl)carbamate (2 equiv.) and DIEA (4 equiv.) in DMF (5 mL). The mixture was agitated for 1 h under nitrogen. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL).To the peptidyl-resin was added Fmoc-Cl (2 equiv.) and DIEA (4 equiv.) in DMF (5 mL). The mixture was agitated for 1 h under nitrogen. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL).After the resin was washed three times with MeOH and dried under vacuum, the resin was treated with 50% TFA / DCM for 30 min. The mixture was concentrated to dryness. The crude residue was dissolved in DMF (5 mL) and Alloc-OSu (1.2 equiv.) and DIPEA (3 equiv.) were added, and the mixture was stirred at 25°C for 1 hour. Then the mixture was concentrated and purified by preparative HPLC to afford Int F (292 mg) as a white solid.Example A8. Synthesis of Intermediate (Int) 5 by Method 1:

[0349] Scheme 1 . Synthesis of Int 5 by Method 1 (Scheme 1 discloses SEQ ID NOS 329, 329, 340 and 23, respectively, in order of appearance)Method 1 :

[0350] To the swollen 2-CTC resin was added Fmoc-Lys(Boc)-OH (1 equiv ) and DIEA (4 equiv.) in DCM (10 mL). The mixture was agitated for 2 h under nitrogen. MeOH (1 mL) was then added. The resulting mixture was agitated for 30 min. After the reaction solution was removed through filtration, the resin was washed three times with DMF (15 mL). The Fmoc protecting group was removed via 15 min agitation with 20% piperidine in DMF followed by filtration and washing.

[0351] To the peptidyl-resin 1 were added Fmoc-D-Trp(Boc)-OH (3 equiv ), DIEA (6 equiv.) and HBTU (3 equiv.) in DMF (10 mL), The mixture was agitated for 1 h under nitrogen. After the reaction solution was removed through filtration, the resin was washed three times with DMF (15 mL). The Fmoc protecting group was removed via 20 min agitation with 20% piperidine in DMF followed by filtration and washing.

[0352] Subsequent amino acids were coupled using Fmoc-protected amino acid (3 equiv.), HBTU (3 equiv.) and DIEA (6 equiv.) in dry DMF, shaking for 30 min. Pre-activation of any amino acid was not performed prior to coupling. Between amino acid couplings, the Fmoc protecting group was removed via 30 min agitation with 20% piperidine in DMF followed by filtration and washing. Success of Fmoc removal steps and amino acid couplings were monitored qualitatively using a ninhydrin test.

[0353] The peptidyl-resin 2 was washed three times with MeOH and dried under vacuum, tire resin was treated with 20% HFIP / DCM for 15 min 3 times. The mixture was concentrated to dryness and then lyophilized to give Int 3

[0354] The Int 3 was dissolved in DCM (1 mM) together with EDCI (1.5 equiv.), HOAt (1.5 equiv.) and DIEA (3 equiv.). The mixture was stirred at 20 °C for 13 h. After the reaction was completed, the mixture was concentrated to dryness to give Int 4.

[0355] The peptide was treated with 15 mL of TFA cleavage cocktail for 1 hour, then cold isopropyl ether w as added. The crude peptide was collected through centrifugation and dried under vacuum. The crude product was purified by preparative HPLC to afford Int 5 (93% purity) as a white solid.Example A9. Synthesis of RB-0003149 from Int 5 by Method 1:

[0356] Scheme 2. Synthesis of RB-0003149 from Int 5 by Method 1 (Scheme 2 discloses SEQ ID NOS 23, 160 and 160, respectively, in order of appearance)

[0357] The Int 5 (1 equiv.) was dissolved in 30% ACN / H2O (30 ml) and Int A (1.5 equiv.) was added at 25 °C. The solution was adjusted to pH= 8~9 with saturated CS2CO3 aqueous solution and stirred at 25°C for 3 hour. Then 1 mol / L HO was adjusted to pH=6~7, the mixture was lyophilized to give the crude powder. The crude product was purified by preparative HPLC to afford RB-0003112 as a white solid.

[0358] Following the general protocol for cold labeling of empty-chelator conjugates with Lu, La and Ga metals (See Example A16) — A solution of RB-0003H2 (1 equiv.) in IM Na2CO3 aqueous buffer adjusted to pH = 5~6 was added LuCL (5 equiv.). The resulting mixture was stirred at 40 °C for 1 h. After filtration, the crude product was purified by preparative HPLC to afford RB-0003149 as a white solid.

[0359] Additional peptide analogues were prepared similarly using this modular synthetic approach outlined in Method 1 The amino acids, fragments, linker, and chelator used in this method vary depending on the peptide sequence. In some instances, the X1 amino acid has a side chain with a terminalthiol, hydroxyl functionality. In some instances, the chelator is a chelator described herein. In some embodiments, the chelator is NOTA, DOTA. or NODAGA. Additional peptides prepared according to Method 1 are shown in Table 5.

[0360] Table s.Example A10. Synthesis of Int 9 by Method 2

[0361] Scheme 3. Synthesis of Int 9 by Method 2 (Scheme 3 discloses SEQ ID NOS 329, 329 and 330, respectively, in order of appearance)Method 2:

[0362] To the swollen 2-CTC resin was added Fmoc-Lys(Dde)-OH (1 equiv.) and DIEA (4 equiv.) in DCM (5 mL). The mixture was agitated for 2 h under nitrogen. MeOH (I mb) was then added. The resulting mixture was agitated for 30 min. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL). lire Fmoc protecting group was removed via 15 min agitation with 20% piperidine in DMF followed by filtration and washing.

[0363] To the peptidyl-resin 6 were added Fmoc-D-Trp(Boc)-OH (3 equiv.), DIEA (6 equiv.) andHBTU (3 equiv.) in DMF (5 mL). The mixture was agitated for 1 h under nitrogen. Next, the reaction solution was removed through filtration, and the resin was washed three times with DMF (10 mL). The Fmoc protecting group was removed via 20 min agitation with 20% piperidine in DMF followed by filtration and washing.

[0364] Subsequent amino acids were coupled using Fmoc-proiected amino acid (3 equiv.), HBTU (3 equiv.) and DIEA (6 equiv.) in dry DMF, shaking for 30 min. Pre-activation of any amino acid was not performed prior to coupling. Between amino acid couplings, the Fmoc protecting group w7as removed via 30 min agitation with 20% piperidine in DMF followed by filtration and washing. Success of Fmoc removal steps and amino acid couplings were monitored qualitatively using a ninhydrin test.

[0365] The peptidyl-resin 7 was washed three times with MeOH and dried under vacuum, the resin was treated with 20% HFIP / DCM for 15 min 3 times. The mixture was concentrated to dryness and then lyophilized to give Int 8

[0366] The Int 8 was dissolved in DCM (1 mM) together with EDCI (1.5 equiv.) and HO At (1.5 equiv.) and DIEA (3 equiv.). The mixture was stirred at 20 °C for 15h. After the reaction was completed, the mixture was concentrated to dryness. The mixture was then treated with 10 mL TFA cleavage cocktail for 1 hour, and cold isopropyl ether was added. The crude peptide was collected through centrifugation and dried under vacuum . The crude product was purified by preparative HPLC to afford Int 9 as a white solid.Example All. Synthesis of RB-0005717 from Int 9 by Method 2

[0367] Scheme 4. Synthesis ofRB-0005717 from Int 9 by Method 2 (Scheme 4 discloses SEQ ID NOS 230, 231, 233 and 233, respecti vely, in order of appearance)

[0368] The Int A(1.5 equiv.) and Int 9(1 equiv.) were dissolved in DMF (30mL) and added EDCI (1.5 equiv.) and HO At (1.5 equiv.) and DIEA (3 equiv.). The mixture was stirred at 20 °C for 3h, then concentrated to dryness. The mixture was treated with 10 mL TFA cleavage cocktail for 2 hour, and cold isopropyl ether was added. The crude peptide was collected through centrifugation and dried under vacuum, lire crude product was purified by preparative HPLC to afford Int 10 as a white solid.

[0369] The Int 10 was dissolved in 3% hydrazine hydrate / DMF (5mL), the mixture was stirred at 20 °C for 15 min. After the reaction was completed, the mixture was purified by preparative HPLC to afford RB-0005716 as a white solid.

[0370] Following the general protocol for cold labeling of empty-chelator conjugates with Lu, La and Ga metals (See Example A16) — A solution of RB-0005716 (1 equiv.) in IM Na2CO3aqueous buffer adjusted to pH = 5~6 was added LUC13(5 equiv.). The resulting mixture was stirred at 40 °C for 1 h. After filtration, the crude product was purified by preparative HPLC to afford RB-0005717 as a white solid.

[0371] Additional peptide analogues were prepared similarly using this modular synthetic approach outlined in Method 2 Th amino acids, fragments, linker, and chelator used in this method vary7depending on the peptide sequence. In some instances, the X1 amino acid has a side chain with a terminal amine functionality. In some instances, the chelator is attached directly to X1 or has an extended linker attached to a chelator. In some instances, the chelator is a chelator described herein. In some embodiments, the chelator is NOTA, DOTA, or NOD AGA. Additional peptides prepared according to Method 2 are shown in Table 6.

[0372] Table 6.Example A12. Synthesis of Int 14 by Method 3

[0373] Scheme 5. Synthesis of Int 14 by Method 3 (Scheme 5 discloses SEQ ID NOS 332, 332 and 333, respectively, in order of appearance)Method 3:

[0374] To the swollen 2-CTC resin were added Fmoc-Lys(Dde)-OH (1 equiv .) and DIEA (4 equiv.) in DCM (5 mL). The mixture was agitated for 2 h under nitrogen. MeOH (1 mL) was then added. The resulting mixture was agitated for 30 min. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL). The Fmoc protecting group was removed via 15 mmagitation with 20% piperidine in DMF followed by filtration and washing.

[0375] To the peptidyl-resin 11 were added Fmoc-D-Trp(Boc)-OH (3 equiv.), DIEA (6 equiv.) and HBTU (3 equiv.) in DMF (5 mL). The mixture was agitated for 1 h under nitrogen. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL). The Fmoc protecting group was removed via 20 min agitation with 20% piperidine in DMF followed by filtration and washing.

[0376] Subsequent amino acids were coupled using Fmoc-protected amino acid (3 equiv.), HBTU (3 equiv.) and DIEA (6 equiv.) in dry DMF, shaking for 30 min. Pre-activation of any amino acid was not performed prior to coupling. Between amino acid couplings, the Fmoc protecting group was removed via 30 min agitation with 20% piperidine in DMF followed by filtration and washing. Success of Fmoc removal steps and amino acid couplings were monitored qualitatively using a ninhydrin test.

[0377] The peptidyl-resin 12 was washed three times with MeOH and dried under vacuum, the resin was treated with 20% HFIP / DCM for 15 min 3 times. The mixture was concentrated to dryness and then lyophilized to give Int 13 (610mg)

[0378] The Int 13 was dissolved in DCM (1 mM) and added EDCI (1.5 equiv.) and HOAt (1.5 equiv.) and DIEA (3 equiv.). The mixture was stirred at 20 °C for 15 h. After the reaction was completed, the mixture was concentrated to dryness. Then the mixture was treated with 10 mL TFA cleavage cocktail for 1 hour, cold isopropyl ether was added. The crude peptide was collected through centrifugation and dried under vacuum. The crude product was purified by preparative HPLC to afford Int 14 as a white solid.Example A13, Synthesis of RB-0005895 from Int 14 by Method

[0379] Scheme 6. Synthesis of RB-0005895 from Int 14 by Method 3 (Scheme 6 discloses SEQ ID NOS 333, 333, 256 and 256, respectively, in order of appearance)

[0380] The Int C(1.5 equiv.) and Int 14(1 equiv.) were dissolved in DMF (30 mL) and added EDCI (1.5 equiv.) and HOAt (1.5 equiv.) and DIEA (3 equiv.). The mixture was stirred at 20 °C for 3h. After the reaction was completed, it was concentrated to dryness. The mixture was then treated with 10 mL TFA cleavage cocktail for 2 hour, cold isopropyl ether was added. The crude peptide was collected through centrifugation and dried under vacuum. The crude product was purified by preparative HPLC to afford Int 15 as a white solid.

[0381] The Int 15 was dissolved in 3% hydrazine hydrate / DMF (5mL), the mixture was stirred at 20 °C for 15 min. After the reaction was completed, the mixture was purified by preparative HPLC to afford RB-0005894 as a white solid

[0382] Following the general protocol for cold labeling of empty-chelator conjugates with Lu, La and Ga metals (See Example A16) — A solution of RB-0005894 (1 equiv.) in IMNajCOs aqueous buffer adjusted to pH = 5~6 was added LuCL (5 equiv ) The resulting mixture was stirred at 40 °C for 1 h After filtration, the crude product was purified by preparative HPLC to afford RB-0005895 as a white solid.

[0383] Additional peptide analogues were prepared similarly using this modular synthetic approach outlined in Method 3. The amino acids, peptoid building blocks, fragments, linker, and chelator used in this method vary depending on the peptide sequence. In some instances, the X1 amino acid has a side chain with a terminal acid functionality. In some instances, the chelator is attached directly to XI or has an extended linker attached to a chelator. In some instances, the chelator is a chelator described herein. In some embodiments, the chelator is NOTA, DOTA, or NOD AGA. Additional peptides prepared according to Method 3 are shown in Table 7.Table 7.

[0384] Scheme 7. Synthesis oflnt 19 by Method 4 (Scheme 7 discloses SEQ ID NOS 334, 334 and335, respectively, in order of appearance)

[0385] To the swollen 2-CTC resin were added Fmoc-Tyr(tBu)-OH (1 equiv.) and DIEA (4 equiv.) in DCM (5 mL). The mixture was agitated for 2 h under nitrogen. MeOH (1.00 ml) was then added. The resulting mixture was agitated for 30 min. After the reaction solution was removed through filtration, theresin was washed three times with DMF (10 mL). The Fmoc protecting group was removed via 15 min agitation with 20% piperidine in DMF followed by filtration and washing.

[0386] To the peptidyl-resin 16 were added Int D (2 equiv ), DIEA (4 equiv.) arid HBTU (4 equiv.) in DMF (5 mL). The mixture was agitated for 1 h under nitrogen. After the reaction solution was removed through filtration, the resin was washed three times with DMF (10 mL). The Fmoc protecting group was removed via 20 min agitation with 20% piperidine in DMF followed by filtration and washing.

[0387] Subsequent amino acids were coupled using Fmoc-protected amino acid (3 equiv.), HBTU (3 equiv.) and DIEA (6 equiv.) in dry DMF, shaking for 30 min. Pre-activation of any amino acid was not performed prior to coupling. Between amino acid couplings, the Fmoc protecting group was removed via 30 min agitation with 20% piperidine in DMF followed by filtration and washing. Success of Fmoc removal steps and amino acid couplings were monitored qualitatively using a ninhydrin test.

[0388] After the resin was washed three times with MeOH and dried under vacuum, the resin was treated with 20% HFIP / DCM for 15 min 3 times. The mixture was concentrated to dryness and then lyophilized to give Int 18.

[0389] Int 18 was dissolved in DMF and added EDCI (1.5 equiv.), HOAt (1.5 equiv.) and DIEA (3 equiv.). The mixture was stirred at 20 °C for 15 h. After the reaction was completed, the mixture was concentrated to dryness. The mixture was then dissolved in DCM (20 mL) together with PhSiH3 (10 equiv.) and Pd(PPh3)4 (0.1 equiv ). The mixture was stirred at 25 °C for 0.5 hours. After the reaction was completed, the mixture was concentrated to dryness and purified by preparative HPLC to afford Int 19 as a white solid.Example A15. Synthesis of RB-0006395 from Int 19 by Method 4

[0390] Scheme 8. Synthesis of RB-0006395 from Int 19 by Method 4 (Scheme 8 discloses SEQ ID NOS 335, 306 and 306, respectively, in order of appearance)

[0391] The Int 19 (SEQ ID NO: 335; 1 equiv.) and DOTA-NHS (1.5 equiv.) were dissolved in DMF (20 mL) and added DIEA (5 equiv ). The mixture was stirred at 25 °C for 0.5 hour. After the reaction was completed, the mixture was concentrated to dryness.

[0392] The mixture was treated with 20 mL TFA cleavage cocktail for 1 hour, then concentrated to 2 mL, and cold isopropyl ether was added. The ciude peptide was collected through centrifugation and dried under vacuum. The crude product was purified by preparative HPLC to afford RB-0006394 (SEQ ID NO: 306) as a white solid.

[0393] Following the general protocol for cold labeling of empty-chelator conjugates with Lu, La and Ga metals (See Example A16) — A solution of RB-0006394 (SEQ ID NO: 306; 1 equiv.) in IM Xa CO. aqueous buffer adjusted to pH = 5-6 was added LuCL (5 equiv.). The resulting mixture was stirred at 40 °C for 1 h. After filtration, the crude product was purified by preparative HPLC to afford RB-0006395 (SEQ ID NO: 306) as a white solid.

[0394] Additional peptide analogues were prepared similarly using this modular synthetic approachoutlined in Method 4. The amino acids, fragments, linker, and chelator used in this method vary depending on the peptide sequence. In some instances, the X1 amino acid is a proline derivative. In some instances, the chelator is attached directly to X1 or has an extended linker attached to a chelator. In some instances, the chelator is a chelator described herein. In some embodiments, the chelator is NOTA,DOTA, or NODAGA. Additional peptides prepared according to Method 4 are shown in Table 8.

[0395] Table s.Example A16: Radiolabeling ProtocolsGeneral protocol for cold labeling of empty- chelator conjugates with Lu, La and Ga metals

[0396] To a solution of peptide conjugated to an empty-chelator (1 equiv .) in IM Na2CO3. aqueous buffer (pH = 5-6) was added LuCL LaCL. or GaCh (5 equiv.). The resulting mixture w as stirred at 40-60 °C for 1 h. After filtration, the cnide product was purified by preparative HPLC to afford the corresponding cold metal labeled peptide.General protocol for177Lu Radiolabeling of empty-DOTA conjugate

[0397] A 35 mCi aliquot of1 ,7LuC13 was added to the reaction vessel followed by addition of 10% ethanol in 0.4M NaOAc buffer (1.0 mL; pH=5.0) and the empty-DOTA conjugate (1.0 pg / pL, 32 pL). The resulting mixture was heated and mixed with athermal mixer at 70°C for 0.5h. After 0.5h, the reaction mixture was allowed to cool at room temperature for 3 min. Then the reaction mixture was diluted with 4.8 mL of a pre-mixed formulation buffer To assess the radiochemical purity, 60 pCi of the177LU labeled product was injected on a rad-HPLC At the end of the synthesis (EOS), the radiochemical purity and specific activity was determined. HPLC column: Aeris 3.6 μm PEPTIDE XB-C18 100, LC Column, 150 x 4.6 mm (00F-4507-E0). Flow l.OmL / min. HPLC column Aeris 3.6 μm PEPTIDE XB- C18 100, LC Column, 150 x 4.6 mm (00F-4507-E0). Solvent A was H20 / 0.05% TFA and solvent B was CH3CN / 0.05% TFA. Elution was conducted at flow rate of 1.0 mL / min with gradient from 5 to 95% B over 16 min.General protocol for225Ac Radiolabeling of empty-DOTA conjugate

[0398] A225AC(NO3)3 powder was diluted with 0.5M HC1 to achieve a concentration of 10 pCi / pL. 100pCi aliquot of the 10 pCi / pL225Ac -chloride solution was added to the reaction vessel followed by addition of 10% ethanol in 0.4M NaOAc buffer (200 pL, pH=6.2) and 27.5 pg of the empty-DOTA conjugate (1 .0 pg / pL, 27.5 pL). The resulting mixture was heated and mixed with athermal mixer at 90°C for 0.5 h. After 0.5h, the reaction mixture was allowed to cool at room temperature for 3 min. The reaction mixture was diluted with 1.0 mL of a pre-mixed formulation buffer. The radiochemical puritywas determined at 5 pCi / nmol by radio thin-layer chromatography (radio-TLC). TLC plate: Agilent Technologies Chromatography paper (Cat number A 120B 12); mobile phase: 50mM DTPA, pH=5.56.General protocol for64Cu Radiolabeling of empty-NOTA conjugate

[0399] ( nt I. in 0. IM HC1 was reconstituted with 0.4M NaOAc pH=6.2 to achieve a concentration of 0.2 mCi / pL. A 7.14 mCi aliquot of theo4CuC12 solution was added to the reaction vessel followed by addition of 10% ethanol in 0.4M NaOAc buffer (200 pL; pH=6.2) and the empty-NOTA conjugate (1.0 pg / uL, 6.0 pL). The resulting mixture was heated and mixed with a thermal mixer at 50°C for 0.5h. After 0.5h, the reaction mixture was allowed to cool at room temperature for 3 min. Then the reaction was diluted with 4.8 mL of a pre-mixed formulation buffer. To assess the radiochemical purity, 10 pCi of the product was injected on a rad-HPLC. At the end of the synthesis (EOS), the radiochemical purity and specific activity was determined. HPLC column: Aeris 3.6 μm PEPTIDE XB-C18 100, LC Column, 150 x 4.6 mm (00F-4507-E0). Solvent A was H20 / 0.05% TFA and solvent B was CH 3CN0.05% TFA. Elution was conducted at flow rate of 1.0 mL / min with gradient from 5 to 95% B over 16 min.General protocol for 68Ga Radiolabeling of empty-DOTA conjugate

[0400] A 10 mCi aliquot of68GaCl3in 0.1M HC1 (1.1 mL) was added to the reaction vessel followed by addition of 1.0 M NaOAc, pH 5.5 ,175 pL, and empty DOTA conjugate (0.75 pg / pL; 42pL). The resulting mixture was heated and mixed whth athermal mixer at 95°C for 10 min. After 10 min, the reaction mixture was allowed to cool at room temperature for 3 minutes. Then the reaction mixture was diluted with 4 mL of a pre-mixed formulation buffer. To assess the radiochemical purity, 10 pCi of the product was injected on a rad-HPLC. At the end of the synthesis (EOS), the radiochemical purity and specific activity was determined. HPLC column: Aeris 3.6 μm PEPTIDE XB-C18 100, LC Column, 150 x 4.6 mm (OOF-4507-E0). Solvent A was H20 / 0.05% TFA and solvent B was CH3CN / 0.05% TFA. Elution was conducted at flow7rate of 1.0 mL / min with gradient from 5 to 95% B over 16 min.Example B: Biological examplesExample Bl: SSTR binding affinity measured by radioligand binding competition assay

[0401] Macrocyclic peptides in this invention were tested for binding to SSTR protein by a radioligand binding competition assay. For radioligand binding assay, competition binding is performed in duplicate in the wells of a 96 well plate containing binding buffer (HEPES 25 mM pH 7.4, MgC12 5mM, CaC12 1 mM, BSA 0.5%, Saponine 10 ug / ml)), membrane extracts (0.6 ug protein / well), radiotracer (

[1251] - Tyrl 1 -Somatostatin, Perkin Elmer NEX389) and test compound. Nonspecific binding is determined by co-incubation with 200-fold excess of cold competitor (SST28). The samples are incubated in a final volume of 0. 1 ml for 60 min at room temperature and then filtered over UniFilter-96 GF / C (Revvity 6055690) filter plates. Filters are washed six times with 0.5 ml of ice-cold washing buffer (HEPES 25 mM pH 7.4, MgC12 5mM, CaC12 1 mM) and 50 pl of Microscint 20 (Packard) are added in each well. The plates are incubated 15 min on an orbital shaker and then counted with a TopCountTMfor 1 min / well.For IC50 to Ki detennination, the Cheng Prusoff equation is used: Ki IC50 / (1+ [tracerl / Kd). [Tracer] is0.1 nM as mentioned above.

[0402] Conjugate SSTR2 binding affinity is shown in Table 9.Table 9.Example B2: Peptide Conjugate Biodistribution Measured by Tissue PK

[0403] Macrocyclic peptides and conjugates described herein were tested for tissue distribution by measuring concentrations in tissues by MS using in vivo animal models. Peptide metal chelates were dosed to animals and tissues were collected at specific time points based off tire peptide PK profile. The samples were then analyzed by MS and the results reported as %ID / g (% injected dose / gram). Radiopharmaceutical conjugates of the present disclosure have improved tissue distribution for radi opharmaceutical therapeutics .

[0404] Peptide metal chelate doses were suspended in phosphate-buffered saline (PBS) containing 0.1% Tween 80. An injection volume of 100 pL per mouse was used, and blood and tissue samples w 'ere collected, weighed, and stored frozen at. -80 °C until analysis. Tissue samples were digested with concentrated nitric acid in a microwave digestion apparatus. The sample digest was diluted with internal standard and analyzed using inductively coupled plasma mass spectrometry (ICP-MS). ICP-MS is an elemental analysis technique used to measure elements by using argon plasma to convert the sample into ions that are then measured using the mass spectrometer. Calibration standards were used forquantification of element(s) of interest by constructing a multipoint standard curve covering the range of analyte concentrations anticipated in the samples (typical range is 500 pptto 0.1 ppt). A single quadrupole instrument (iCAP RQ, Thermo Fisher) ICP-MS was coupled with a Teledyne CETAC autosampler and used for the sample analysis.

[0405] The %ID / g of conjugate in kidney tissue at the 2-hour time point (2h) was quantified for various conjugates, and the results are shown in Table 10. Lower kidney tissue % ID / g values indicate lower distribution to the kidney after administration of the conjugate.Table 10.

[0406] The present technology may be used in bio-related industries and the pharmaceutical industry.

[0407] All references cited in this specification, and their references, are incoiporated by reference herein in their entirety where appropriate for teachings of additional or alternative details, features, and / or technical background

[0408] While the disclosure has been particularly shown and described with reference to particular embodiments, it will be appreciated drat variations of the above-disclosed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications Also, that various presently unforeseen or unanticipated alternatives, modifications, variations, or improvements therein may be subsequently made by those skilled in the art which are also intended to be...

Claims

1. A conjugate or a pharmaceutically acceptable salt thereof, wherein the conjugate comprises a monocyclic peptide having avidity for a somatostatin receptor, wherein the monocyclic peptide comprises a structure of Formula (II),Formula (II)wherein,X1 is any amino acid;X2 is any amino acid;X3 is a non-natural, aromatic amino acid;X4 is a non-natural amino acid having a side chain comprising an amine;X5 is any amino acid; andX6 is any amino acid.

2. The conjugate of claim 1, or a pharmaceutically acceptable salt thereof, further comprising a metal chelator covalently connected to the monocyclic peptide.

3. The conjugate of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the metal chelator is connected to the monocyclic peptide through a linker.

4. The conjugate of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the conjugate has a structure of Formula (III), Formula (III)wherein, L is a linker;s is 0 or 1; andCL is a metal chelator.

5. The conjugate of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein the conjugate has a structure of Formula (IV1), (IV2) or (IV6), ,, orFormula (IV1) Formula (IV2) Formula (IV6).

6. The conjugate of any one of claims 2-5, or a pharmaceutically acceptable salt thereof, wherein the conjugate further comprises a radionuclide bound to the metal chelator.

7. The conjugate of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein X1 is an N-methylated amino acid.

8. The conjugate of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X1 is any amino acid comprising a polar side chain.

9. The conjugate of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein X1 is an L-amino acid.

10. The conjugate of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X1 is Cys, Lys, Ala, Glu, Asp, Ser, Pro, or a derivative of any one of the foregoing.

11. The conjugate of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X1 is Pro, Hyp, Cha4N, Chg4N, NMe-Cha4N, NMe-Chg4N, NMe-Dap, NMe-Dab, NMe-Orn, NMe-Lys, NMe-Azidolysine, NMe-hLys, 4-oxa NMe-Lys, NMe-Ala, NMe-Nle, NMe-propargyl glycine, NMe-propargyl alanine, NMe-Asp, NMe-Cys, NMe-Hcy, NMe-hHcy, NMe-Glu, NMe-hGlu, NMe-Amp, NMe-Hse, or NMe-Hse(Se).

12. The conjugate of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X1 is Cys, Lys, or a derivative of either of the foregoing.

13. The conjugate of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein X1 is Cha4N, Chg4N, NMe-Cha4N, NMe-Chg4N, NMe-Dap, NMe-Dab, NMe-Orn, NMe-Lys, NMe-hLys, NMe-Azidolysine, NMe-Cys, NMe-Hcy, NMe-hHcy, or NMe-Hse(Se).

14. The conjugate of any one of claims 1-10 and 12, or a pharmaceutically acceptable salt thereof, wherein X1 is cysteine or a derivative thereof.

15. The conjugate of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein X1 is NMe-Cys, NMe-Hcy, NMe-Hse(Se), or NMe-hHcy.

16. The conjugate of any one of claims 1-10 and 12, or a pharmaceutically acceptable salt thereof, wherein X1 is lysine or a derivative thereof.

17. The conjugate of any one of claims 1-13 and 16, or a pharmaceutically acceptable salt thereof, wherein X1 is NMe-Dap, NMe-Dab, NMe-Lys, NMe-hLys, or NMe-Orn.

18. The conjugate of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X1 is alanine or a derivative thereof.

19. The conjugate of any one of claims 1-11 and 18, or a pharmaceutically acceptable salt thereof, wherein X1 is NMe-Ala, NMe-Nle, or NMe-propargyl glycine.

20. The conjugate of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein X2 is an aromatic amino acid.

21. The conjugate of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein X2 is Tyr, Phe, Trp, His, Gly, Ala, or a derivative of any one of the foregoing.

22. The conjugate of claim 21, or a pharmaceutically acceptable salt thereof, wherein X2 is Tyr, D-Tyr, 4Pal, 3Pal, 5F-Tyr, 3,5-diF-Tyr, Phe, (R-βMe)Phe, (S-βMe)Phe, 3,3-diPhe, D-Phg, L-DOPA, Aph(Hor), His, 2-(Aminocarbonyl)-Phe, 3-(Aminocarbonyl)-Phe, Ala, or Gly.

23. The conjugate of claim 21, or a pharmaceutically acceptable salt thereof, wherein X2 is Tyr.

24. The conjugate of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein X3 is a non-natural amino acid comprising an optionally substituted N-containing 5- to 10- membered heteroaryl.

25. The conjugate of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein X3 is D-Trp, NMe-D-Trp, (S-βMe)D-Trp, (S-βMe)Trp, (R-βMe)D-Trp, (R-βMe)Trp, Aza-Trp, Aza-D-Trp, D-6F-Trp, or D-Aph(Cbm), each of which is further optionally substituted.

26. The conjugate of claim 25, or a pharmaceutically acceptable salt thereof, wherein X3 is (S-βMe)D-Trp.

27. The conjugate of claim 25, or a pharmaceutically acceptable salt thereof, wherein X3 is D-Trp.

28. The conjugate of any one of claims 1-27, wherein the amine of X4 comprises a primary amine, a secondary amine, or a tertiary amine.

29. The conjugate of claim 28, wherein the amine of X4 comprises a secondary amine or a tertiary amine.

30. The conjugate of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein the side chain comprising an amine of X4 comprises azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

31. The conjugate of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein X4 is Cba3N, Chg4N, Cha4N, Cha4NH2, Ser(3-azetidine), PipzaA, 3-Azetidine-hAla, or Pic4.

32. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein X4 is a non-natural Lys derivative.

33. The conjugate of claim 32, wherein X4 is NMe-Lys, Lys(Me), Lys(diMe), Lys(iPr), Chg4N, Cha4N, 4-oxa-Lys, or 3-Azetidine-hAla.

34. The conjugate of any one of claims 1-27, wherein X4 is Cba3N, Chg4N, Cha4N, Cha4NH2, Ser(3-azetidine), PipzaA, 3-Azetidine-hAla, Pic4, NMe-Lys, Lys(Me), Lys(diMe), Lys(iPr), or 4-oxa-Lys.

35. The conjugate of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein X4 has a structure of: ,wherein,R41 is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf; each Rf is independently halogen, CN, -NO2, -ORa, -SRa or -NRcRd;LX4 is a bond, -O-, -S-, -NR43-, C1-C6alkylene, C1-C6heteroalkylene, C3-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl, wherein the alkylene, heteroalkylene, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more RX4a; R42 is -NR44R45 or a heterocycloalkyl comprising one or more ring nitrogen atoms, wherein the heterocycloalkyl is optionally substituted with one or more R42a; each R42a is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re; R43 is hydrogen or C1-C3alkyl;R44 and R45 are each independently hydrogen, C1-C3alkyl, aryl, heteroaryl, -C1-C3alkylene-aryl, or -C1-C3alkylene-heteroaryl, wherein each of the alkyl, aryl, and heteroaryl are optionally substituted with one or more R42a;each RX4a is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, and alkynyl is optionally substituted with one or more Re; or or two RX4a groups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re;each Ra is independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;each Re is independently halogen, -CN, -OH, oxo, -O-C1C6alkyl, -SF5, -S(=O)C1C6alkyl, -S(=O)2C1C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1C6alkyl, -S(=O)2N(C1C6alkyl)2, -NH2, -NHC1C6alkyl, -N(C1C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1C6alkyl, -C(=O)C1C6alkyl, -C(=O)OH, C1C6alkyl-C(=O)OH, -C(=O)OC1C6alkyl, -C(=O)NH2, -C(=O)N(C1C6alkyl)2, -C(=O)NHC1C6alkyl, C1-C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, or C1C6heteroalkyl; and each Rc and Rd are independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X3 represents the point of attachment to X3; and*X5 represents the point of attachment to X5.

36. The conjugate of claim 35, or a pharmaceutically acceptable salt thereof, wherein R42 is a 4- to 8 membered N-containing heterocycloalkyl, which is optionally substituted with one or more R42a.

37. The conjugate of claim 35 or 36, or a pharmaceutically acceptable salt thereof, wherein R42 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is optionally substituted with one to four R42a.

38. The conjugate of claim 35 or 36, or a pharmaceutically acceptable salt thereof, wherein R42 is azetidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one to four R42a.

39. The conjugate of any one of claims 35-38, or a pharmaceutically acceptable salt thereof, wherein R42 is , , , or , each of which is optionally substituted with 1 or 2 R42a.

40. The conjugate of claim 35, or a pharmaceutically acceptable salt thereof, wherein R42 is -NR44R45.

41. The conjugate of claim 35 or 40, wherein R44 and R45 are each independently hydrogen, methyl, ethyl, isopropyl, phenyl, -C1-C3alkylene-phenyl, or -NH2.

42. The conjugate of any one of claims 35-41, or a pharmaceutically acceptable salt thereof, wherein LX4 is a bond.

43. The conjugate of any one of claims 35-41, or a pharmaceutically acceptable salt thereof, wherein LX4 is a C1-C4alkylene (e.g., -CH2-), wherein the alkylene is optionally substituted with 1 or 2 substituents selected from -F, -Me, and -OH.

44. The conjugate of any one of claims 35-41, or a pharmaceutically acceptable salt thereof, wherein LX4 is a C1-C4heteroalkylene (e.g., -CH2OCH2CH2-).

45. The conjugate of any one of claims 35-44, or a pharmaceutically acceptable salt thereof, wherein R41 is hydrogen or methyl.

46. The conjugate of claim 45, or a pharmaceutically acceptable salt thereof, wherein R41 is hydrogen.

47. The conjugate of claim 45, or a pharmaceutically acceptable salt thereof, wherein R41 is methyl.

48. The conjugate of any one of claims 35-37, 45, and 46, or a pharmaceutically acceptable salt thereof, wherein X4 is , , , , , , , , , , , , , , , , , , , , or, wherein *X3 represents the point of attachment to X3; and*X5 represents the point of attachment to X5.

49. The conjugate of any one of claims 35, 40, 41, 45, and 46, or a pharmaceutically acceptable salt thereof, wherein X4 is , , , , , or , wherein *X3 represents the point of attachment to X3; and*X5 represents the point of attachment to X5.

50. The conjugate of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, wherein X5 is an aliphatic amino acid or a polar amino acid.

51. The conjugate of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein X5 is Thr, Val, Ala, Ser, Pro, or a derivative of any one of the foregoing.

52. The conjugate of claim 51, or a pharmaceutically acceptable salt thereof, wherein X5 is Thr, Val, Ala, Pro, Alt, Cbg, Cpg, Cba, or Tme.

53. The conjugate of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein X6 is an aromatic amino acid, a hydrophilic amino acid, or Gly, or a derivative of any one of the foregoing.

54. The conjugate of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein X6 is Phe, Ala, Gly, Ser, His, Tyr, Asn, Pro, or a derivative of any one of the foregoing.

55. The conjugate of claim 54, or a pharmaceutically acceptable salt thereof, wherein X6 is Phe, NMe-Phe, (S-βMe)Phe, (R-βMe)Phe, His, Mpd, Ala, D-Ala, Gly, Pro, Ser, Ser(Ph), 3Pal, 4Pal, Cha, 3-(Aminocarbonyl)-Phe, F4COO, Phg, G(cPr), Asn, Tyr, meta-Tyr, or 3N-Tyr.

56. The conjugate of claim 55, or a pharmaceutically acceptable salt thereof, wherein X6 is Phe.

57. The conjugate of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, whereinX1 is NMe-Hcy, NMe-Lys, or NMe-hLys;X2 is Tyr; X3 is D-Trp, (S-βMe)D-Trp, (S-βMe)-Trp, (R-βMe)D-Trp, or (R-βMe)-Trp;X4 is PipzaA, 3-Azetidine-hAla, Lys(Me), Chg4N or Cha4N; X5 is Thr or Alt; and X6 is Phe.

58. The conjugate of any one of claims 1-6 or 20-56, or a pharmaceutically acceptable salt thereof, wherein X1 has a structure of: ,wherein,R11 is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf;each Rf is independently halogen, CN, -NO2, -ORa, -SRa or -NRcRd;R12 is C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R12a;LX1 is a bond, -O-, -S-, -NR13-, C1-C6alkylene, or C1-C6heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more RX1a; orR11 and LX1-R12 are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more R12a;each R12a is independently halogen, C1-C6alkyl C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, CN, -NO2, -ORa, -SRa, -NRcRd, -SeRa, -S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Re; or, one of R12a is a conjugation group (CG); CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1.0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;R13 is hydrogen or C1-C3alkyl;RX1a is halogen, CN, -NO2, -ORa, -NRcRd, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or two RX1a groups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re;each Ra is independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;each Re is independently halogen, -CN, -OH, oxo, -O-C1C6alkyl, -SF5, -S(=O)C1C6alkyl, -S(=O)2C1C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1C6alkyl, -S(=O)2N(C1C6alkyl)2, -NH2, -NHC1C6alkyl, -N(C1C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1C6alkyl, -C(=O)C1C6alkyl, -C(=O)OH, C1C6alkyl-C(=O)OH, -C(=O)OC1C6alkyl, -C(=O)NH2, -C(=O)N(C1C6alkyl)2, -C(=O)NHC1C6alkyl, C1-C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, or C1C6heteroalkyl; and each Rc and Rd are independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X6 represents the point of attachment to X6; and*X2 represents the point of attachment to X2.

59. The conjugate of claim 58, or a pharmaceutically acceptable salt thereof, wherein R12 is C1-C6alkyl, C3-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl, wherein each of the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of -ORa, -SRa, -NRcRd, -SeRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRaS(=O)2Ra, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, and -C(=O)NRcRd.

60. The conjugate of claim 58 or 59, or a pharmaceutically acceptable salt thereof, wherein R12 is C1-C6alkyl substituted with one substituent selected from the group consisting of -ORa, -SRa, -NRcRd, -SeRa, -C(=O)Ra, -C(=O)ORa, and -C(=O)NRcRd.

61. The conjugate of claim 58, 59, or 60, wherein R12 is C1-C6alkyl.

62. The conjugate of any one of claims 58-61, wherein LX1 is a bond.

63. The conjugate of claim 58, wherein LX1 is C1-C6alkylene; and R12 is C3-C6cycloalkyl or 3- to 6- membered heterocycloalkyl, wherein each of the cycloalkyl and heterocycloalkyl is optionally substituted with one or more R12a.

64. The conjugate of claim 58, wherein R11 and LX1-R12 are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more R12a.

65. The conjugate of any one of claims 58-3, or a pharmaceutically acceptable salt thereof, wherein R11 is hydrogen or methyl.

66. The conjugate of any one of claims 58 and 62-65, or a pharmaceutically acceptable salt thereof, wherein CG is an azide or a terminal alkyne.

67. The conjugate of any one of claims 1-19, 24-56, and 58-66, or a pharmaceutically acceptable salt thereof, wherein X2 has a structure of:,wherein:R21 is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf;each Rf is independently halogen, CN, -NO2, -ORa, -SRa or -NRcRd;LX2 is a bond, -O-, -S-, -NR23-, C1-C6alkylene, or C1-C6heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more RX2a; R23 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl, wherein the alkyl and heteroalkyl is optionally substituted with one or more Re; or R23 is ; ring A2 is an aryl or heteroaryl;each R22 is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2RcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)NRcRd, -NRaS(=O)2RcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R22a; ortwo R22 are taken together to form =O, =S, or =N(Ra);m2 is 0, 1, 2, 3, 4, or 5;each R22a is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more Re; or, one of R22a is a conjugation group (CG);R23 is hydrogen or C1-C3alkyl;RX2a is halogen, CN, -NO2, -ORa, -NRcRd, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or two RX2a groups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re;each Ra is independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;each Re is independently halogen, -CN, -OH, oxo, -O-C1C6alkyl, -SF5, -S(=O)C1C6alkyl, -S(=O)2C1C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1C6alkyl, -S(=O)2N(C1C6alkyl)2, -NH2, -NHC1C6alkyl, -N(C1C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1C6alkyl, -C(=O)C1C6alkyl, -C(=O)OH, C1C6alkyl-C(=O)OH, -C(=O)OC1C6alkyl, -C(=O)NH2, -C(=O)N(C1C6alkyl)2, -C(=O)NHC1C6alkyl, C1-C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, or C1C6heteroalkyl; or, one of Re is a conjugation group (CG); CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1.0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;each Rc and Rd are independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X1 represents the point of attachment to X1; and*X3 represents the point of attachment to X3.

68. The conjugate of claim 67, or a pharmaceutically acceptable salt thereof, wherein ring A2 is a C6-C10aryl or a 5- to 10- membered heteroaryl.

69. The conjugate of claim 67 or 68, or a pharmaceutically acceptable salt thereof, wherein ring A2 is a phenyl or a 5- to 6- membered heteroaryl.

70. The conjugate of any one of claims 67-69, or a pharmaceutically acceptable salt thereof, wherein ring A2 is phenyl, pyridinyl, pyrimidinyl, or imidazolyl.

71. The conjugate of any one of claims 67-70, or a pharmaceutically acceptable salt thereof, wherein each R22 is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, CN, -NO2, -ORa, -SRa, -NRcRd, -NRaC(=NH)NRcRd, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -NRaC(=O)Ra, -NRaC(=O)ORa, -C(=O)NRcRd, C6-C10aryl, 5- to 10- membered heteroaryl, C3-C6cycloalkyl, or 5- to 6- membered heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R22a.

72. The conjugate of any one of claims 67-71, or a pharmaceutically acceptable salt thereof, wherein each R22 is independently C1-C3alkyl, -ORa, -SRa, -NRcRd, halogen -C(=O)Ra, -C(=O)ORa, -C(=O)NRcRd, or phenyl.

73. The conjugate of any one of claims 67-72, or a pharmaceutically acceptable salt thereof, wherein R21 is hydrogen or methyl.

74. The conjugate of any one of claims 67-73, or a pharmaceutically acceptable salt thereof, wherein LX2 is C1-C3alkylene, optionally substituted with one or more RX2a.

75. The conjugate of any one of claims 67-74, or a pharmaceutically acceptable salt thereof, wherein LX2 is C1-C3alkylene, optionally substituted with one to three substituents selected from C1-C3alkyl (e.g., methyl).

76. The conjugate of any one of claims 67-75, or a pharmaceutically acceptable salt thereof, wherein LX2 is -CH2- or -CH(CH3)-.

77. The conjugate of any one of claims 67-76, or a pharmaceutically acceptable salt thereof, wherein m2 is 0, 1, or 2.

78. The conjugate of any one of claims 1-23, 28-56, and 58-77, or a pharmaceutically acceptable salt thereof, wherein X3 has a structure of:,wherein:R31 is hydrogen or C1-C5 alkyl optionally substituted with one to three substituents independently selected from Rf;each Rf is independently halogen, CN, -NO2, -ORa, -SRa or -NRcRd;LX3 is a bond, -O-, -S-, -NR33-, C1-C3alkylene, or C1-C3heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more RX3a;ring A3 is an aryl or heteroaryl;each R32 is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2RcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)NRcRd, -NRaS(=O)2RcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R32a; ortwo R32 are taken together to form =O, =S, or =N(Ra);m3 is 0, 1, 2, 3, 4, or 5;each R32a is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re;R33 is hydrogen or C1-C3alkyl;R34 is hydrogen or C1-C3alkyl;each RX3a is independently halogen, CN, -NO2, -ORa, -NRcRd, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;or two RX3a groups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re;each Ra is independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;each Re is independently halogen, -CN, -OH, oxo, -O-C1-C6alkyl, -SF5, -S(=O)C1-C6alkyl, -S(=O)2C1-C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6alkyl, -S(=O)2N(C1-C6alkyl)2, -NH2, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1-C6alkyl, -C(=O)C1-C6alkyl, -C(=O)OH, C1-C6alkyl-C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; and each Rc and Rd are independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X2 represents the point of attachment to X2; and*X4 represents the point of attachment to X4.

79. The conjugate of claim 78, or a pharmaceutically acceptable salt thereof, wherein ring A3 is a C6-C10aryl or a 5- to 10- membered heteroaryl.

80. The conjugate of claim 78 or 79, or a pharmaceutically acceptable salt thereof, wherein ring A3 is a phenyl, naphthyl, pyridinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, pyrimidazolyl, pyrazolo[1,5-a]pyridinyl, quinolinyl, or isoquinolinyl.

81. The conjugate of any one of claims 78-80, or a pharmaceutically acceptable salt thereof, wherein ring A3 is phenyl or naphthyl.

82. The conjugate of any one of claims 78-80, or a pharmaceutically acceptable salt thereof, wherein ring A3 is indolyl or azaindolyl.

83. The conjugate of any one of claims 78-82, or a pharmaceutically acceptable salt thereof, wherein m3 is 0 or 1.

84. The conjugate of claim 78, or a pharmaceutically acceptable salt thereof, wherein X3 has a structure of: ,wherein:Y31 is N, CH, or CR32;Y32 is N, CH, or CR32;Y33 is N, CH, or CR32; Y34 is N, CH, or CR32;Y35 is N, or C;Y36 is N or C; Y37 is N, CH, or CR32; andY38 is S, N or NH;provided that no more than two of Y31, Y32, Y33, Y34, Y35, Y36, and Y37 are N.

85. The conjugate of claim 84, or a pharmaceutically acceptable salt thereof, wherein Y31 is N.

86. The conjugate of claim 84, or a pharmaceutically acceptable salt thereof, wherein Y31 is CH.

87. The conjugate of any one of claims 84-86, or a pharmaceutically acceptable salt thereof, wherein Y32 is N.

88. The conjugate of any one of claims 84-86, or a pharmaceutically acceptable salt thereof, wherein Y32 is CH.

89. The conjugate of any one of claims 84-88, or a pharmaceutically acceptable salt thereof, wherein Y33 is N.

90. The conjugate of any one of claims 84-88, or a pharmaceutically acceptable salt thereof, wherein Y33 is CH.

91. The conjugate of any one of claims 84-90, or a pharmaceutically acceptable salt thereof, wherein Y34 is N.

92. The conjugate of any one of claims 84-90, or a pharmaceutically acceptable salt thereof, wherein Y34 is CH.

93. The conjugate of any one of claims 84-92, or a pharmaceutically acceptable salt thereof, wherein Y35 is N.

94. The conjugate of any one of claims 84-92, or a pharmaceutically acceptable salt thereof, wherein Y35 is C.

95. The conjugate of any one of claims 84-94, or a pharmaceutically acceptable salt thereof, wherein Y36 is N.

96. The conjugate of any one of claims 84-94, or a pharmaceutically acceptable salt thereof, wherein Y36 is C.

97. The conjugate of any one of claims 84-96, or a pharmaceutically acceptable salt thereof, wherein Y37 is N.

98. The conjugate of any one of claims 84-96, or a pharmaceutically acceptable salt thereof, wherein Y37 is CH.

99. The conjugate of any one of claims 78-98, or a pharmaceutically acceptable salt thereof, wherein each R32 is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, CN, -NO2, -ORa, -SRa, -SF5, or -NRcRd, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R32a.

100. The conjugate of claim 99, or a pharmaceutically acceptable salt thereof, wherein each R32 is independently C1-C6alkyl, C1-C6haloalkyl, halogen, CN, -ORa, -SRa, or -NRcRd, wherein each of the alkyl and heteroalkyl is optionally substituted with one or more R32a.

101. The conjugate of any one of claims 78-100, or a pharmaceutically acceptable salt thereof, wherein R31 is hydrogen or methyl.

102. The conjugate of any one of claims 78-101, or a pharmaceutically acceptable salt thereof, wherein LX3 is C1-C3alkylene, optionally substituted with one to three RX3a independently selected from C1-C3alkyl (e.g., methyl), phenyl, C1-C3alkylene(phenyl), and C3-C6cycloalkyl.

103. The conjugate of any one of claims 78-102, or a pharmaceutically acceptable salt thereof, wherein LX3 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(iPr)-, or -CH(benzyl).

104. The conjugate of claim 78, or a pharmaceutically acceptable salt thereof, wherein X3 is , , , , or, whereineach R32 is independently C1-C6alkyl, C1-C6haloalkyl, halogen, CN, -ORa, -SRa, or -NRcRd;m3 is 0, 1, or 2; *X2 represents the point of attachment to X2; and*X4 represents the point of attachment to X4.

105. The conjugate of any one of claims 1-49, 53-56, and 58-104, or a pharmaceutically acceptable salt thereof, wherein X5 has a structure of:,wherein,R51 is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf;each Rf is independently halogen, CN, -NO2, -ORa, -SRa or -NRcRd;R52 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-C6cycloalkyl, or 4- to 6- membered heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R52a; orR51 and R52 are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more R52a;each R52a is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, CN, -NO2, -ORa, -SRa, -NRcRd, -SeRa, -S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re;each Ra is independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;each Re is independently halogen, -CN, -OH, oxo, -O-C1C6alkyl, -SF5, -S(=O)C1C6alkyl, -S(=O)2C1C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1C6alkyl, -S(=O)2N(C1C6alkyl)2, -NH2, -NHC1C6alkyl, -N(C1C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1C6alkyl, -C(=O)C1C6alkyl, -C(=O)OH, C1C6alkyl-C(=O)OH, -C(=O)OC1C6alkyl, -C(=O)NH2, -C(=O)N(C1C6alkyl)2, -C(=O)NHC1C6alkyl, C1-C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, or C1C6heteroalkyl; and each Rc and Rd are independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X4 represents the point of attachment to X4; and*X6 represents the point of attachment to X6.

106. The conjugate of claim 105, or a pharmaceutically acceptable salt thereof, wherein R52 is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 5- to 6- membered heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R52a.

107. The conjugate of claim 105 or 106, or a pharmaceutically acceptable salt thereof, wherein R52 is C1-C6alkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more R52a.

108. The conjugate of any one of claims 105-107, or a pharmaceutically acceptable salt thereof, wherein R52 is C3-C6cycloalkyl or C1-C3alkyl optionally substituted with one to three substituents independently selected from -OH, -OMe, and C3-C4cycloalkyl.

109. The conjugate of any one of claims 105-108, or a pharmaceutically acceptable salt thereof, wherein R51 is hydrogen or methyl.

110. The conjugate of claim 105, or a pharmaceutically acceptable salt thereof, wherein R51 and R52 are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more R52a.

111. The conjugate of any one of claims 1-52 and 58-110, or a pharmaceutically acceptable salt thereof, wherein X6 has a structure of:,wherein:R61 is hydrogen or C1-C5alkyl optionally substituted with one to three substituents independently selected from Rf;each Rf is independently halogen, CN, -NO2, -ORa, -SRa or -NRcRd;ring A6 is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R62 is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, CN, -NO2, -ORa, -SRa, -SF5, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -S(=O)2RcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)NRcRd, -NRaS(=O)2RcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R62a; ortwo R62 are taken together to form =O, =S, or =N(Ra);LX6 is a bond, -O-, -S-, -NR63-, C1-C3alkylene, or C1-C3heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with one or more RX6a; m6 is 0, 1, 2, 3, 4, or 5;each R62a is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re; or, one of R62a is a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1.0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;R63 is hydrogen or C1-C3 alkyl;RX6a is halogen, CN, -NO2, -ORa, -NRcRd, C1-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or two RX6a groups attached to the same or different atoms are taken together to form a cycloalkyl or heterocycloalkyl ring, each of which is optionally substituted with one or more Re;each Ra is independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;each Re is independently halogen, -CN, -OH, oxo, -O-C1C6alkyl, -SF5, -S(=O)C1C6alkyl, -S(=O)2C1C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1C6alkyl, -S(=O)2N(C1C6alkyl)2, -NH2, -NHC1C6alkyl, -N(C1C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1C6alkyl, -C(=O)C1C6alkyl, -C(=O)OH, C1C6alkyl-C(=O)OH, -C(=O)OC1C6alkyl, -C(=O)NH2, -C(=O)N(C1C6alkyl)2, -C(=O)NHC1C6alkyl, C1-C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, or C1C6heteroalkyl; and each Rc and Rd are independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X5 represents the point of attachment to X5; and*X1 represents the point of attachment to X1.

112. The conjugate of claim 111, or a pharmaceutically acceptable salt thereof, wherein ring A6 is a C6-C10aryl or a 5- to 10- membered heteroaryl.

113. The conjugate of claim 111 or 112, or a pharmaceutically acceptable salt thereof, wherein ring A6 is a phenyl or a 5- to 6- membered heteroaryl.

114. The conjugate of any one of claims 111-113, or a pharmaceutically acceptable salt thereof, wherein ring A6 is phenyl, pyridinyl, pyrimidinyl, or imidazolyl.

115. The conjugate of any one of claims 111-114, or a pharmaceutically acceptable salt thereof, wherein each R62 is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, CN, -NO2, -ORa, -SRa, -NRcRd, -NRaC(=NH)NRcRd, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -NRaC(=O)Ra, -NRaC(=O)ORa, -C(=O)NRcRd, C6-C10aryl, 5-10 membered heteroaryl, C3-C6cycloalkyl, or 5- to 6- membered heterocycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R62a.

116. The conjugate of any one of claims 111-115, or a pharmaceutically acceptable salt thereof, wherein each R62 is independently C1-C3alkyl, -ORa, -SRa, -NRcRd, halogen -C(=O)Ra, -C(=O)ORa, or -C(=O)NRcRd117. The conjugate of any one of claims 111-116, or a pharmaceutically acceptable salt thereof, wherein R61 is hydrogen or methyl.

118. The conjugate of any one of claims 111-117, or a pharmaceutically acceptable salt thereof, wherein LX6 is bond, C1-C3alkylene, or C1-C3heteroalkylene, wherein the alkylene and heteroalkylene are independently optionally substituted with one to three substituents selected from C1-C3alkyl (e.g., methyl).

119. The conjugate of any one of claims 111-118, or a pharmaceutically acceptable salt thereof, wherein LX6 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2NH-, -CH2N(Me)-, or -CH2O-.

120. The conjugate of any one of claims 111-119, or a pharmaceutically acceptable salt thereof, wherein m6 is 0 or 1.

121. The conjugate of any one of claims 1-52 or 58-110, or a pharmaceutically acceptable salt thereof, wherein X6 has a structure of:,wherein:R63 is hydrogen or C1-C5alkyl optional substituted with one to three substituents independently selected from Rf;each Rf is independently halogen, CN, -NO2, -ORa, -SRa or -NRcRd;R64 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloyalkyl, or 3- to 6- membered heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R64a; R65 is hydrogen, halogen, or C1-C6alkyl, wherein the alkyl is optionally substituted with one or more R64a; orR64 and R65 are taken together with the carbon to which they are attached to form a C3-C6cycloalkyl or a 4- to 6- membered heterocycloalkyl, each of which is optionally substituted with one or more R64a; orR63 and R64 are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more R62a;each R64a is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Ra, -S(=O)2Ra, -SF5, -S(=O)2NRcRd, -S(=O)(=NRa)Ra, -N=S(=O)RcRd, -NRaS(=O)2Ra, amidinyl, -NRaC(=NH)(NRa)2, -NRaS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)NRcRd, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S, or =N(Ra), wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more Re; or, one of R64a is a conjugation group (CG);CG is an optionally substituted conjugated diene, an optionally substituted tetrazine, an optionally substituted alkyne, an azide, an optionally substituted dibenzocyclooctyne (DBCO), an optionally substituted trans-cyclooctene (TCO), an optionally substituted bicyclo[6.1.0]nonyne (BCN), an optionally substituted aldehyde, an optionally substituted ketone, or an optionally substituted hydrazine;each Ra is independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re;each Re is independently halogen, -CN, -OH, oxo, -O-C1C6alkyl, -SF5, -S(=O)C1C6alkyl, -S(=O)2C1C6alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1C6alkyl, -S(=O)2N(C1C6alkyl)2, -NH2, -NHC1C6alkyl, -N(C1C6alkyl)2, -NHC(=NH)NH2, -NHC(=O)OC1C6alkyl, -C(=O)C1C6alkyl, -C(=O)OH, C1C6alkyl-C(=O)OH, -C(=O)OC1C6alkyl, -C(=O)NH2, -C(=O)N(C1C6alkyl)2, -C(=O)NHC1C6alkyl, C1-C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, or C1C6heteroalkyl; and each Rc and Rd are independently hydrogen, C1C6alkyl, C1C6haloalkyl, C1C6hydroxyalkyl, C1C6aminoalkyl, C1C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1C6alkylene(cycloalkyl), C1C6alkylene(heterocycloalkyl), C1C6alkylene(aryl), or C1C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Re; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more Re;*X5 represents the point of attachment to X5; and*X1 represents the point of attachment to X1.

122. The conjugate of claim 121, or a pharmaceutically acceptable salt thereof, wherein R64 is hydrogen, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloyalkyl, wherein each of the alkyl, heteroalkyl, and cycloalkyl is optionally substituted with one or more R64a.

123. The conjugate of claim 121 or 122, or a pharmaceutically acceptable salt thereof, wherein R64 is hydrogen or C1-C6alkyl, wherein the alkyl is optionally substituted with one to three R64a.

124. The conjugate of any one of claims 121-123, or a pharmaceutically acceptable salt thereof, wherein R64 is hydrogen or C1-C6alkyl optionally substituted with one to three substituents independently selected from -OH, -OMe, -C(=O)NH2 and -C(=O)OH.

125. The conjugate of claim 121, or a pharmaceutically acceptable salt thereof, wherein R64 and R65 are taken together with the carbon to which they are attached to form a C3-C6cycloyalkyl, which is optionally substituted with one or more R64a.

126. The conjugate of claim 125, wherein R64 and R65 are taken together with the carbon to which they are attached to form a cyclopropyl.

127. The conjugate of any one of claims 121-126, or a pharmaceutically acceptable salt thereof, wherein R63 is hydrogen or methyl.

128. The conjugate of claim 121, or a pharmaceutically acceptable salt thereof, wherein R63 and R64 are taken together with the intervening atoms to form a 5- to 6- membered heterocycloalkyl, which is optionally substituted with one or more R64a.

129. The conjugate of claim 128, or a pharmaceutically acceptable salt thereof, wherein R63 and R64 are taken together with the intervening atoms to form a 5- membered heterocycloalkyl, which is optionally substituted with -F, C1-C3alkyl, C1-C3haloalkyl, -OH, or phenyl.

130. The conjugate of any one of claims 2-129, or a pharmaceutically acceptable salt thereof, wherein the metal chelator comprises DOTA, DOTA-GA, pBn-DOTA, pBn-SCN-DOTA, NH2-DOTA, NH2-DOTA-GA, p-NCS-Bn-DOTA-GA, p-NH2-Bn-oxo-DO3A, p-SCN-Bn-oxo-DO3A, NOTA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn-NOTA, p-SCN-Bn-NOTA, NCS-MP-NODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACROPA-NCS, H1-MACROPA, H2-MACROPA-NH2, H4-OCTAPA, tetra-(S, S, S, S)-Me-DOTA, tetra-(S, S, S, S)-Et-DOTA, tetra-(S, S, S, S)-iBu-DOTA, PYTA, or maleimide-nBu-DOTA.

131. The conjugate of claim 130, or a pharmaceutically acceptable salt thereof, wherein the metal chelator is (DOTA), (DOTA-GA), (PCTA), (p-NH2-Bn-PCTA), (pBn-SCN-PCTA), (SCN-NOTA), (H2-MACROPA-NCS), (tetra-(S,S,S,S)-Et-DOTA), (PYTA), (NOTA), (NODA-GA), or (maleimide-nBu-DOTA).

132. The conjugate of claim 130, or a pharmaceutically acceptable salt thereof, wherein the metal chelator is (DOTA).

133. The conjugate of any one of claims 3-132, or a pharmaceutically acceptable salt thereof, wherein the linker comprises 3 to 30 intervening non-hydrogen, organic atoms between the metal chelator and the peptide.

134. The conjugate of any one of claims 3-133, or a pharmaceutically acceptable salt thereof, wherein the linker comprises 3 to 18 intervening non-hydrogen, organic atoms between the metal chelator and the peptide.

135. The conjugate of claim 133 or 134, or a pharmaceutically acceptable salt thereof, wherein the intervening atoms comprise 1 to 6 nitrogen atoms and 0 to 4 oxygen atoms.

136. The conjugate of any one of claims 3-135, or a pharmaceutically acceptable salt thereof, wherein the linker comprises one or more amino acid residues.

137. The conjugate of claim 136, or a pharmaceutically acceptable salt thereof, wherein the linker comprises one amino acid residue.

138. The conjugate of claim 136, or a pharmaceutically acceptable salt thereof, wherein the linker comprises two amino acid residues.

139. The conjugate of any one of claims 136-138, or a pharmaceutically acceptable salt thereof, wherein the one or more amino acid residues are selected from an ornithine, a lysine, a homolysine, an aspartate, a beta-aspartate, a glutamate, a 2-aminosuberic acid, a glycine, a beta-alanine, or a combination thereof.

140. The conjugate of any one of claims 3-139, or a pharmaceutically acceptable salt thereof, wherein the linker has a structure of Formula (V-1)Formula (V-1)wherein each L is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, =CH-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLC(=S)NRL-, -CRL=N-, -N=CRL, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C3-15 cycloalkyl, substituted or unsubstituted C1-12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-30 alkylene, substituted or unsubstituted C2-30 alkenylene, substituted or unsubstituted C2-30 alkynylene, substituted or unsubstituted C1-30 heteroalkylene, -(C1-30 alkylene)-O-, -O-(C1-30 alkylene)-, -(C1-30 alkylene)-NRL-, -NRL-(C1-30 alkylene)-, -(C1-30 alkylene)-N(RL)2-, or -N(RL)2-(C1-30 alkylene)-, or a click chemistry residue; and each RL is independently hydrogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 heteroalkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-5 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C2-7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; andn is an integer from 1 to 20.

141. The conjugate of claim 140, or a pharmaceutically acceptable salt thereof, wherein the linker comprises a structure of Formula (V-1a), Formula (V-1a) wherein each of L1 and L3 is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)C1-C6alkylene -, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, or -S(=O)2NRLC(=O)-; andL2 is absent, substituted or unsubstituted C1-30 alkylene, or substituted or unsubstituted C1-30 heteroalkylene.

142. The conjugate of claim 141, or a pharmaceutically acceptable salt thereof, wherein L1 is -NH-.

143. The conjugate of claim 141 or 142, or a pharmaceutically acceptable salt thereof, wherein L2 is substituted or unsubstituted C1-30 alkylene, or substituted or unsubstituted C1-30 heteroalkylene.

144. The conjugate of claim 141 or 142, or a pharmaceutically acceptable salt thereof, wherein L2 is substituted or unsubstituted C1-18 alkylene, or substituted or unsubstituted C1-18 heteroalkylene.

145. The conjugate of any one of claims 141 to 144, or a pharmaceutically acceptable salt thereof, wherein L2 is optionally substituted with one or more substituents independently selected from -OH, -SH, oxo, amino, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 aminoalkyl, -C(=O)ORL, -C1-C6alkylene-C(=O)ORL, -OC(=O)RL, -OC(=O)ORL, -C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL; and the C1-6 alkyl is further optionally substituted with one or more substituents independently selected from -OH, -SH, oxo, amino, C6-C10aryl, 6- to 10- membered heteroaryl, -C(=O)ORL, -OC(=O)RL, -OC(=O)ORL, -C(=O)N(RL)2, -NRLC(=O)RL, -OC(=O)N(RL)2, and -NRLC(=O)ORL.

146. The conjugate of any one of claims 141 to 145, or a pharmaceutically acceptable salt thereof, wherein L3 is -NH- or -C(=O)C1-C6alkylene-.

147. The conjugate of claim 140, or a pharmaceutically acceptable salt thereof, wherein the linker comprises a structure of Formula (V-1b), Formula (V-1b) wherein each of L1 and L5 is independently -O-, –NRL-, –N(RL)2-, -OP(=O)(ORL)O-, -S-, -S(=O)-, -S(=O)2-, -CH=CH-, =CH-, -C≡C-, -C(=O)-, -C(=O)C1-C6alkylene -, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NRL-, -NRLC(=O)-, -OC(=O)NRL-, -NRLC(=O)O-, -NRLC(=O)NRL-, -NRLS(=O)2-, -S(=O)2NRL-, -C(=O)NRLS(=O)2-, -S(=O)2NRLC(=O)-, substituted or unsubstituted C4-C6 cycloalkyl, or substituted or unsubstituted 4- to 6- membered heterocycloalkyl; andL2, L3 and L4 are each independently absent, substituted or unsubstituted C4-C10cycloalkyl, substituted or unsubstituted 4- to 6- membered heterocycloalkyl, substituted or unsubstituted C1-C30 alkylene, or substituted or unsubstituted C1-C30 heteroalkylene.

148. The conjugate of claim 147, wherein L1 is -NH- or substituted or unsubstituted 4- to 6- membered heterocycloalkyl.

149. The conjugate of claim 147 or 148, wherein L5 is -NH-, -C(=O)-, or -C(=O)C1-C6alkylene-.

150. The conjugate of any one of claims 3-132, or a pharmaceutically acceptable salt thereof, wherein the linker is a bond.

151. The conjugate of any one of claims 3-132, or a pharmaceutically acceptable salt thereof, wherein the linker comprises a conjugation moiety.

152. The conjugate of claim 151, or a pharmaceutically acceptable salt thereof, wherein the conjugation moiety is a reaction product of azide-alkyne pair, an alkyne-nitrone pair, an alkene and tetrazole pair, or an isonitrile (e.g., isocyanide) and tetrazine pair.

153. The conjugate of claim 151, or a pharmaceutically acceptable salt thereof, wherein the conjugation moiety is 1,4-di-substituted 1,2,3-triazole.

154. The conjugate of any one of claims 3-132, wherein the linker is a bond or , , , , , , , , , ,, , or.

155. The conjugate of claim 154, wherein the linker is:(i) a bond; (ii) , , , , ,,, , ,,,, , or ;(iii) ,, , , , , , , or ;(iv) , ,, , or ; or(v) , , , , or .

156. The conjugate of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the monocyclic peptide is a peptide of Table 1.

157. A conjugate of the following structural formula:, and pharmaceutically acceptable salts and stereoisomers thereof, wherein Xm is a radionuclide.

158. A conjugate of the following structural formula:, and pharmaceutically acceptable salts and stereoisomers thereof, wherein Xm is a radionuclide.

159. A conjugate of the following structural formula:, and pharmaceutically acceptable salts and stereoisomers thereof, wherein Xm is a radionuclide.

160. A conjugate of the following structural formula:, and pharmaceutically acceptable salts and stereoisomers thereof, wherein Xm is a radionuclide.

161. A conjugate of the following structural formula:, and pharmaceutically acceptable salts and stereoisomers thereof, wherein Xm is a radionuclide.

162. A conjugate of the following structural formula:, and pharmaceutically acceptable salts and stereoisomers thereof, wherein Xm is a radionuclide.

163. A conjugate of the following structural formula:, and pharmaceutically acceptable salts and stereoisomers thereof, wherein Xm is a radionuclide.

164. The conjugate of any one of claims 7-163, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is an alpha particle-emitting radionuclide.

165. The conjugate of claim 164, or a pharmaceutically acceptable salt thereof, wherein the alpha particle-emitting radionuclide is Ac-225, At-211, Bi-213, Bi-209, Tb-149, Ra-223, Th-227, Fr-223, Gd-148, Th-229, Pb-212, or Po-213.

166. The conjugate of claim 165, or a pharmaceutically acceptable salt thereof, wherein the alpha particle-emitting radionuclide is Ac-225.

167. The conjugate of any one of claims 7-163, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is a beta particle-emitting radionuclide.

168. The conjugate of claim 168, or a pharmaceutically acceptable salt thereof, wherein the beta particle-emitting radionuclide is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, Tb-161, or In-111.

169. The conjugate of claim 168, or a pharmaceutically acceptable salt thereof, wherein the beta particle-emitting radionuclide is Lu-177.

170. The conjugate of any one of claims 7-163, or a pharmaceutically acceptable salt thereof, wherein the radionuclide is a positron-emitting radionuclide.

171. The conjugate of claim 170, or a pharmaceutically acceptable salt thereof, wherein the positron-emitting radionuclide is Ga-68, Cu-62, Cu-64, Zr-89, Tb-152.

172. The conjugate of any one of claims 7-163, wherein the radionuclide is Ac-225 or Ga-68.

173. A compound of Table 3, or a pharmaceutically acceptable salt thereof.

174. A peptide having avidity for a somatostatin receptor, wherein the peptide comprises a structure of Formula (I) or a salt thereof,X1-X2-X3-X4-X5-X6Formula (I)wherein,X1 is any amino acid;X2 is any amino acid;X3 is a non-natural, aromatic amino acid;X4 is a non-aromatic amino acid having a side chain comprising an amine; X5 is any amino acid; andX6 is any amino acid.

175. The peptide of claim 174 or a salt thereof, wherein the peptide has a structure of Formula (II),Formula (II).

176. A method of treating a somatostatin receptor-positive (SSTR+) tumor in a subject in need thereof, comprising administering to the subject a conjugate of any one of claims 6 to 168 or a pharmaceutically acceptable salt thereof.

177. A method of imaging or diagnosing a somatostatin receptor-positive (SSTR+) tumor in a subject, comprising administering to the subject a conjugate of any one of claims 6 to 168 or a pharmaceutically acceptable salt thereof, wherein the conjugate comprises a radionuclide selected from Ce-134, Cu-61, Cu-62, Cu-64, Ga-68, Ho-166, In-111, Tb-152, Tb-161, Tc-99m, and Zr-89.

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