Radiopharmaceutical compositions targeting phosphatidylinositol proteoglycan-3 and uses thereof

Abstract

The present invention provides radiopharmaceuticals and conjugates targeting GPC3 as well as compositions and uses thereof. In one aspect, provided herein are conjugates comprising a peptide having affinity for GPC3 and a metal chelating agent configured to bind to a radionuclide. The conjugates described herein may further comprise a linker linking the chelating agent and the peptide. The conjugates described herein may further comprise radionuclides. In one aspect, provided herein is a radiopharmaceutical comprising a peptide and a metal chelating agent that binds to a radionuclide. The conjugates described herein may further comprise a linker linking the chelating agent and the peptide. Further provided herein are methods of treating cancer by administering the described radiopharmaceuticals, conjugates, compositions thereof.

Description

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 63 / 506,721, filed June 7, 2023, which is incorporated herein by reference in its entirety.

[0002] Joint research agreement The subject matter disclosed herein was developed by one or more parties to a Joint Research Agreement (JRA) or their representatives, and the claimed invention was made by such party or their representatives, in accordance with 35 USC § 100(h) and 37 CFR § 1.9(e), which was effective on or before the effective filing date of the claimed invention. The one or more parties to the JRA are PeptiDream, Inc. (Kanagawa, Japan) and RayzeBio, Inc. (San Diego, California, USA). The claimed invention is the result of activities carried out within the scope of the Joint Research Agreement.

[0003] sequence list This application contains a sequence list, which has been submitted electronically in .xml format as part of this specification and is incorporated herein by reference in its entirety. The XML file was created on June 5, 2024, named 59541-732601SL.xml, and has a size of 689,382 bytes. Technical Field

[0004] In one aspect, the present invention relates to radiopharmaceutical conjugates comprising a peptide bound to phosphatidylinositol proteoglycan-3 (GPC3), and compositions comprising the radiopharmaceutical conjugate and their uses. In another aspect, the present invention relates to the use of the radiopharmaceutical conjugate in the prevention, inhibition, or treatment of a disease or condition characterized by overexpression or decreased expression of GPC3 in diseased tissues, such as GPC3 overexpression in tumors. Background Technology

[0005] Phosphatidylinositol proteoglycan-3 (GPC3) is a heparan sulfate (HS) glycoprotein belonging to the heparan sulfate proteoglycan family and anchored to the cell membrane surface via a phosphatidylinositol (GPI) anchor. The GPC3 core protein contains 580 amino acids and has a molecular weight of approximately 70 kDa. It is cleaved by furin to produce a 40 kDa N-terminal subunit and a 30 kDa C-terminal subunit linked together by disulfide bonds. The two HS side chains of GPC3 are bound near the C-terminus (Takahiro Nishida, Hiroaki Kataoka. Glypican 3-Targeted Therapy in Hepatocellular Carcinoma, Cancer 2019; 11 (9): 1339).

[0006] GPC3 plays an important role in cell proliferation in embryonic tissues. GPC3 gene deletion may lead to excessive growth syndrome, namely Simpson-Golabi-Behmel syndrome (SGBS). GPC3 is clearly expressed throughout the fetal period, and from birth to adulthood, it is not significantly expressed in normal tissues except for weak expression in the placenta, mammary gland, mesoderm, ovary, lung, and kidney tissues.

[0007] Abnormal GPC3 expression has been found in various adult tumor tissues, such as hepatocellular carcinoma (HCC), squamous cell carcinoma of the lung, gastric cancer, and ovarian cancer. GPC3 is particularly highly expressed in HCC cells, improving autocrine / paracrine typical Wnt signaling and promoting HCC cell growth and invasion (Capurro MI, Xiang YY, Lobe C, Filmus J. Glypican-3 promotes the growth of hepatocellular carcinoma by-stimulating canonical Wnt signaling; Cancer Res 2005, 65(14): 6245-54.). Immunohistochemical staining has shown that approximately 70% of HCC patients' tumor tissues exhibit high GPC3 protein expression (Capurro M, Wanless IR, Sherman M et al., Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma; Gastroenterology 2003, 125(1):89-97). Therefore, GPC3 is considered a candidate target for cancer treatment.

[0008] Codrituzumab (also known as GC33 antibody) is a recombinant humanized monoclonal antibody developed by Chugai Pharmaceutical Co. in Japan. It binds to the proximal membrane region of the GPC3 protein. GC33 antibody targets GPC3-positive HCC cells and induces antibody-dependent cytotoxicity (ADCC). In a phase I clinical trial, codrituzumab demonstrated good immune tolerance and produced antitumor effects in HCC patients (Ikeda M, Ohkawa S, Okusaka T et al., Japanese phase I study of GC33, a-antibody against glypican-3 for advanced hepatocellular carcinoma. Cancer Sci. 2014, 105, 455-462). However, in a phase II clinical trial involving 185 patients with advanced liver cancer, the therapeutic efficacy of codrituzumab was not significant compared to the control group.

[0009] Therefore, novel GPC3-binding peptides and compositions containing GPC3-binding peptides are useful and desirable. Summary of the Invention

[0010] In one aspect, this document discloses a radiopharmaceutical or a medically acceptable salt thereof, the radiopharmaceutical comprising: (a) Peptide of formula (I-1), Formula (I-1), in: R 1 It can be -NH2 or -OH; R 2 C 1-3 alkyl; R 3 For optional one or more R 4 Replacement C 1-3 Alkylene; Each R 4 Independently for C 1-3 Alkyl or C 3-6 cycloalkyl; kxR is 1, 2, 3, 4, 5 or 6; X R It can be -S-, -CH2-, or -O-; X1 can be any amino acid; X2 can be any amino acid; X3 can be any amino acid; X4 can be any amino acid; X5 is an amino acid containing an aromatic ring, cycloalkyl group, or heterocyclic alkyl group, or X5 is a peptide-like substance; X6 is a hydrophobic amino acid, a hydrophilic amino acid, or a polar amino acid, wherein the polar amino acid has a substituted side chain. X7 is a hydrophobic amino acid containing C1-C8 alkyl, cycloalkyl, or heterocycloalkyl groups, wherein each of the alkyl, cycloalkyl, and heterocycloalkyl groups is optionally substituted independently; X8 is A, I, L, V, Y, or F or a variant thereof; X9 is an N-alkylated amino acid containing an aromatic ring; X10 is G or A or its N-alkylated variant, or a D-amino acid; and X11 is an amino acid containing an aromatic ring; and (b) A metal chelating agent that binds to a radionuclide, wherein the metal chelating agent is covalently linked to the peptide.

[0011] In some implementations, the radiopharmaceutical is selected from Table 3A or Table 3B.

[0012] In one aspect, this document discloses a conjugate or a pharmaceutically acceptable salt thereof, the conjugate comprising: (a) Peptide of formula (I-1), Formula (I-1), in: R 1 It can be -NH2 or -OH; R 2 C 1-3 alkyl; R 3 For optional one or more R 4 Replacement C 1-3 Alkylene; Each R 4 Independently for C 1-3 Alkyl or C 3-6 cycloalkyl; kxR is 1, 2, 3, 4, 5 or 6; X R It can be -S-, -CH2-, or -O-; X1 can be any amino acid; X2 can be any amino acid; X3 can be any amino acid; X4 can be any amino acid; X5 is an amino acid containing an aromatic ring, cycloalkyl group, or heterocyclic alkyl group, or X5 is a peptide-like substance; X6 is a hydrophobic amino acid, a hydrophilic amino acid, or a polar amino acid, wherein the polar amino acid has a substituted side chain. X7 is a hydrophobic amino acid containing C1-C8 alkyl, cycloalkyl, or heterocycloalkyl groups, wherein each of the alkyl, cycloalkyl, and heterocycloalkyl groups is optionally substituted independently; X8 is A, I, L, V, Y, or F or a variant thereof; X9 is an N-alkylated amino acid containing an aromatic ring; X10 is G or A or its N-alkylated variant, or a D-amino acid; and X11 is an amino acid containing an aromatic ring; and (b) A metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent is covalently linked to the peptide.

[0013] In some implementations, the conjugate is selected from Table 9.

[0014] In one aspect, the present invention relates to a radiopharmaceutical conjugate comprising: (a) A peptide with affinity for phosphatidylinositol proteoglycan 3 (GPC3) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid sequence including the deletion, substitution and / or addition of one or more (e.g., 1 to 6) amino acids from the amino acid sequence of SEQ ID NO: 1: MeK-MeI-D-MeQ-F4COO-IIY-MeNal27N-G-3Py6Ph-MeC (SEQ ID NO: 1), The peptide consists of 10 to 12 amino acid residues; and (b) (i) a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide; or (ii) a covalently bound radionuclide.

[0015] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide bound to the metal chelating agent. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide. In some embodiments, the peptide is a cyclic peptide. In some embodiments, the peptide is a monocyclic peptide.

[0016] In one aspect, the present invention relates to a radiopharmaceutical conjugate comprising: (a) A peptide or a pharmaceutically acceptable salt thereof having an affinity for phosphatidylinositol proteoglycan 3 (GPC3), wherein the peptide comprises the amino acid sequence of formula (I). X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) in, X1 can be any amino acid; X2 can be any amino acid; X3 can be any amino acid; X4 can be any amino acid; X5 is an amino acid containing an aromatic ring (e.g., W, F, Y or variants thereof), an amino acid containing a cycloalkyl group, or an amino acid containing a heterocyclic alkyl group, or X5 is a peptide (e.g., Cha4cH, Cha4tH, Almor, Atp, Cha4cOMe). X6 is a hydrophobic amino acid, a hydrophilic amino acid, or a polar amino acid, wherein the polar amino acid has a substituted side chain. X7 is a hydrophobic amino acid containing C1-C8 alkyl, cycloalkyl, or heterocycloalkyl groups, wherein each of the alkyl, cycloalkyl, and heterocycloalkyl groups is independently and optionally substituted (e.g., X7 is I, Eva, alI, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe, or Cbg). X8 is A, I, L, V, Y, or F or a variant thereof; X9 is an N-alkylated amino acid containing an aromatic ring; X10 is a G, A, or D-amino acid (e.g., da, ds, de, or dp); X11 is an amino acid containing an aromatic ring (e.g., F, Y, or a variant thereof); and X12 is N-alkylated cysteine ​​(e.g., MeC); and (b) (i) a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide; or (ii) a covalently bound radionuclide.

[0017] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide. In some embodiments, the peptide is a monocyclic peptide. In some embodiments, the peptide has an amino acid sequence according to formula (I) or a pharmaceutically acceptable salt thereof. X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) in, X1 is I, R, Cit, F4G, 4Py, 3Py, KCOpipzaa, V, Eva, Q, E, MeI, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeV, MeHseMe , Aib, MeT, alI, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe, MeDapCOpipzaa, MeK, MeKAc, MeK(de), MeK(H), MeK(df) or MeK(datb); X2 is I, K, Cit, F4G, 4Py, 3Py, KCOpipzetOH, V, KCOpipzaa, Eva, Q, E, S, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeI, MeV, MeL, HseMe, MeY, Me3Py, MeHseMe, MeKAc, alI, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe or MeDapCOpipzaaa; X3 is D, Har, KCOpipzetOH, Cit, KCO meglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, KAc, Hgn, MeY or DapCOpipzaa; X4 is D, Har, KCOpipzetOH, KCO meglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, dd, MeQ, MeQdMe, MeA, MeSMe, MeG, EtG, MeeG, CmG, CmpG, CrmG, CeG, CrpG, MeK, MeKAc, MeHgl, Hgn, MeDapCOpipzaa, MeKCOpipzaa, Medd, Cit, MeCit, MeN, MeS, MeE, MeY, W5N or MeA4paa; X5 is Y, F3G, 3Py6COO, 4Py2NH2, 3Py5COO, F3COO, 3Py6NHAc, F, F4C, F4OMe, F4COO, Nal2, F3aao, F4aa, F4aao, 3Py6NHaa, 5Pdo, F3CON, F4F, F4OEt, F4Me, F4CON, F4CONPEG4Me, F3OMe, F3CON, Yae, YaeCOpipzaa, F4aaopipzaa, 4Pdo, 3Py6CON, Atp, Cha4cH, Cha4tH, Cha4cOMe, A1mor or F4amCOpipzaa; X6 is I, V, Eva, Chg, Tbg, A, L, Ahp, F4COO, Gcpr, Gcpe, alI, Cle, S3REt, TMe, Acpr, Cba, Gthp, NleCOO, NleOH, P, Atb, Nva, Nle, N, DapAc, Abu, Nmm, Ndm, Ncit, Cit, SMe, HseMe, HseEt, HseiPr, dMeS, TdMe, Cbg, NvaOMe, SiPr, Spr, NleOMe, Sbu, Scbm, Scpe, AhpOMe, HseBu, Spent or Hsecpe; X7 is I, Eva, alI, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe or Cbg; X8 is A, I, L, V, Y, F4OMe, F4COO, F4OEt, F4u, F4Me, F4CONdMe, F4CON, F4ms, F4CONPEG4Me, F34dOMe, F3OMe, F3C, F3CON, F3CONdMe , 3Py6CON, Yae, YaeCOpipzaa, 5Inda, F3aao, F3aa, F4aao, F4aa, 3Py6Nhae, 3Py6NHAc, 3Py6OMe, F4aaopipzaa or F4amCOpipzaa; X9 is MeNal2, MeNal27N, MeF34diox, MeF34dOMe, MeF4T, MeY, MeW1Me, MeW7N, MeF3C4Me or MeF3Me4C; X10 is a G, A, or D-amino acid (e.g., da, ds, de, or dp); X11 is Bph, 3Py6Ph, F41Me4Pyz, F43Pyz, F44Pyz, F41Pyz, F41Me3Pyz, F41Et4Pyz, F41MeOe4Pyz, F41MeOp4Pyz, F44thp, F4Ac4pip, PhNva, PhNle, Yph, Ybn, F4tb, F4oPr, or F4CONdMe; and X12 is MeC.

[0018] In one aspect, the present invention relates to a radiopharmaceutical conjugate comprising: (a) A peptide or a pharmaceutically acceptable salt thereof having an affinity for phosphatidylinositol proteoglycan 3 (GPC3), wherein the peptide has the amino acid sequence of formula (I). X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) in, X1 can be any amino acid; X2 can be any amino acid; X3 can be any amino acid; X4 can be any amino acid; X5 is ,in: R n5 It is hydrogen or C 1-3 alkyl; Ring A5 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Each R X5 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)NR c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X5 -heterocyclic alkyl, -L X5 -cycloalkyl, -L X5 -Aryl or -L X5 - Heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally derived from one or more R... X5a Replace; or Two RsX5 Together they form =O, =S, or =N(R) a ); L X5 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X5a replace; kx5 is 0, 1, 2 or 3; mx5 can be 0, 1, 2, 3, 4 or 5; *X4 indicates the connection point with X4; and *X6 indicates the connection point with X6; X6 is ,in: R n6 It is hydrogen or C 1-3 alkyl; R X6 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X6 -heterocyclic alkyl, -L X6 -cycloalkyl, -L X6 -Aryl or -L X6 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X6a Replace; or R n6 and R x6 Together with intermediary atoms, they form one or more optional R atoms. X6a Substituted 5- to 6-membered heterocyclic alkyl groups; L X6 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X6a replace; *X5 indicates the connection point with X5; and *X7 indicates the connection point with X7; X7 is ,in: R n7 It is hydrogen or C 1-3alkyl; R X7 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, heteroalkyl, alkenyl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R groups. X7a replace; *X6 indicates the connection point with X6; and *X8 indicates the connection point with X8; X8 is ,in: R n8 It is hydrogen or C 1-3 alkyl; Ring A8 is aryl or heteroaryl; Each R X8 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a-OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X8 -heterocyclic alkyl, -L X8 -cycloalkyl, -L X8 -Aryl or -L X8 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X8a Replace; or Two Rs X8 Together they form =O, =S, or =N(R) a ); L X8 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X8a replace; kx8 is 0, 1, 2, or 3; mx8 can be 0, 1, 2, 3, 4 or 5; *X7 indicates the connection point with X7; and *X9 indicates the connection point with X9; X9 is ,in: R n9 It is hydrogen or C 1-3 alkyl; Ring A9 is aryl or heteroaryl; Each R X9 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -ORa -SR a -SF5 or -NR c R d The alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally derived from one or more R groups. X9a Replace; or Two Rs X9 Together they form =O, =S, or =N(R) a ); kx9 is 0, 1, 2, or 3; mx9 can be 0, 1, 2, 3, 4 or 5; *X8 indicates the connection point with X8; and *X10 indicates the connection point with X10; X10 is glycine or a D-amino acid (e.g., da, ds, de, or dp); X11 is ,in: R n11 It is hydrogen or C 1-3 alkyl; Ring A11 is aryl or heteroaryl; Each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)ORa -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X11 -heterocyclic alkyl, -L X11 -cycloalkyl, -L X11 -Aryl or -L X11 -heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X11a Replace; or Two Rs X11 Together they form =O, =S, or =N(R) a ); L X11 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X11a replace; kx11 is 0, 1, 2, 3, 4 or 5; mx11 can be 0, 1, 2, 3, 4 or 5; *X10 indicates the connection point with X10; and *X12 indicates the connection point with X12; X12 is N-alkylated cysteine; R X5a R X6a R X7a R X8a R X9a and R X11a Each independently constitutes a halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR cR d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; Each R a Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is independently optionally etched with one or more R... e replace; Each R eIndependently, it can be halogen, -CN, -OH, -O-C1-C6 alkyl, -SF5, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=NH)NH 2. -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, C1-C6 alkyl-C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; or two R e Together they form = O; and Each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is independently optionally etched with one or more R... e Replace; or R c and R d Together with the atoms they are attached to, they form one or more optional R... e Substituted heterocyclic alkyl groups; and (b) (i) a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide; or (ii) a covalently bound radionuclide.

[0019] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide. In some embodiments, the peptide is a monocyclic peptide.

[0020] In some embodiments of the radiopharmaceutical conjugate, the peptide of formula (I) has the structure of formula (I-1): Formula (I-1), in, R 1Choose the group composed of -NH2 and -OH; R 2 C 1-3 alkyl; R 3 For optional one or more R 4 Replacement C 1-3 Alkylene; Each R 4 Independently for C 1-3 Alkyl or C 3-6 cycloalkyl; kxR is 1, 2, 3, 4, 5 or 6; X R Choose from groups consisting of -S-, -CH2-, or -O-; and Where X1 to X11 have the definitions described in equation (I).

[0021] In some embodiments of the radiopharmaceutical conjugate, the peptide of formula (I) has the structure of formula (I-2): (I-2).

[0022] In some embodiments, the radiopharmaceutical conjugate comprises a peptide having an amino acid sequence having at least 90% identity with a sequence selected from SEQ ID NO: 1-72, or having at most 1, 2, 3, 4, or 5 conserved variant substitutions compared to any of the sequences selected from SEQ ID NO: 1-72. In some embodiments, the radiopharmaceutical conjugate comprises a peptide having an amino acid sequence having at least 90% identity with a sequence selected from SEQ ID NO: 1-72. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-72.

[0023] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to a peptide of formula (I) or SEQ ID NO: 1. In some embodiments, the radiopharmaceutical conjugate further comprises a linker connecting the peptide to the metal chelating agent. In some embodiments, the linker is linked to the peptide via a non-terminal amino acid residue. In some embodiments, the linker is linked to the peptide via the N-terminus. In some embodiments, the linker is linked to the peptide via the C-terminus. In some embodiments, the linker is linked to a first amino acid residue (or X1), a second amino acid residue (or X2), a third amino acid residue (or X3), a fourth amino acid residue (or X4), an eighth amino acid residue (or X8), or a twelfth amino acid residue (or X12). In some embodiments, the linker comprises 3 to 30 intercalary non-hydrogen organic atoms between the metal chelating agent and the peptide. In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker is a bond. In some embodiments, the metal chelating agent 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, or maleic anhydride-nBu-DOTA. In some embodiments, the metal chelating agent has the following structure: (DOTA). In some embodiments, the radiopharmaceutical conjugate further comprises a radionuclide bound to a metal chelating agent. In some embodiments, the radionuclide is a radionuclide that emits alpha particles. In some embodiments, the radionuclide that emits alpha particles 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 radionuclide that emits alpha particles is Ac-225. In some embodiments, the radionuclide is a radionuclide that emits beta particles. In some embodiments, the radionuclide that emits beta particles is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153, or In-111. In some embodiments, the radionuclide that emits beta particles is ruthenium-177. In some embodiments, the radionuclide is a positron-emitting radionuclide. In some embodiments, the positron-emitting radionuclide is Ga-68, Cu-62, Cu-64, Zr-89, or Tb-152.

[0024] In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide, wherein the radionuclide is bound to a peptide of formula (I) or SEQ ID NO: 1. In some embodiments, the radiopharmaceutical conjugate further comprises a linker connecting the peptide to the covalently bound radionuclide. In some embodiments, the radionuclide is covalently bound to an amino acid comprising an aromatic ring. In some embodiments, the radionuclide is linked to a 5th amino acid or X5, an 8th amino acid or X8, a 9th amino acid or X9, or an 11th amino acid or X11. In some embodiments, the radionuclide is covalently bound to a residualizing agent linked to the peptide, wherein the residualizing agent has the following structure: or , where R* represents a covalently bonded radionuclide. In some embodiments, the covalently bonded radionuclide is... 18 F, 74 As、 76 Br、 123 I, 124 I, 125 I, 131 I or 211 At.

[0025] In one aspect, the present invention relates to a pharmaceutical composition comprising a radiopharmaceutical conjugate as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In another aspect, the present invention relates to a pharmaceutical composition comprising a radiopharmaceutical as described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0026] In one aspect, the present invention relates to a method for treating a disease or condition characterized by overexpression of phosphatidylinositol proteoglycan 3 (GPC3) in an individual requiring treatment, the method comprising administering to the individual a therapeutically effective amount of a radiopharmaceutical or a medically acceptable salt thereof, or a pharmaceutical composition as described herein. In another aspect, the present invention relates to a method for treating a disease or condition characterized by overexpression of GPC3 in an individual requiring treatment, the method comprising: administering to the individual a first radiopharmaceutical or a medically acceptable salt thereof; and administering to the individual a therapeutically effective amount of a second radiopharmaceutical or a medically acceptable salt thereof, wherein: the first radiopharmaceutical or a medically acceptable salt thereof is described herein, and wherein the radionuclide is a diagnostic radionuclide; and the second radiopharmaceutical or a medically acceptable salt thereof is described herein, and wherein the radionuclide is a therapeutic radionuclide. In one aspect, the present invention relates to a method for diagnosing a disease or condition characterized by overexpression of GPC3 in an individual requiring diagnosis, comprising: administering a radiopharmaceutical or a medically acceptable salt thereof, or a pharmaceutical composition described herein, to the individual; and imaging the individual thereby determining the expression level of GPC3 in the individual, wherein the radionuclide is suitable as an imaging isotope. In another aspect, the present invention relates to a method for treating a disease or condition characterized by overexpression of GPC3 in an individual requiring treatment, comprising administering a radiopharmaceutical conjugate or a medically acceptable salt thereof, as described herein, to the individual. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is selected from hepatocellular carcinoma, squamous cell carcinoma of the lung, adenocarcinoma of the lung, germ cell tumors, hepatoblastoma, Wilms' tumor, malignant rhabdomyosarcoma, rhabdomyosarcoma, liposarcoma, thyroid cancer, pancreatic cancer, small intestinal cancer, small cell neuroendocrine carcinoma (SCNC), hormone-treated castration-resistant prostate cancer, ovarian cancer, gastric cancer, esophageal cancer, and malignant melanoma.

[0027] In one aspect, the present invention relates to a kit, assay, or composition for determining the expression level of GPC3 in a sample, wherein the kit, assay, or composition comprises a radiopharmaceutical or conjugate as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit, assay, or composition is adapted for use in methods for diagnosing a disease or condition characterized by overexpression or underexpression of GPC3. In some embodiments, the sample is from an individual suspected of having a disease or condition characterized by overexpression or underexpression of GPC3.

[0028] In one aspect, the present invention relates to the use of the radiopharmaceutical or conjugate described herein or a medically acceptable salt thereof for the preparation of a medicament for the diagnosis and / or treatment of a disease or condition characterized by overexpression or underexpression of GPC3.

[0029] In one aspect, the present invention relates to the use of the radiopharmaceuticals or conjugates or their pharmaceutically acceptable salts described herein for the diagnosis and / or treatment of diseases or conditions characterized by overexpression or underexpression of GPC3.

[0030] Incorporate by reference For the specific purposes identified herein, all publications, patents and patent applications mentioned in this specification are incorporated herein by reference. Attached Figure Description

[0031] All features of the embodiments described in this invention are not mutually exclusive and can be combined with each other. For example, an element of one embodiment may be used in other embodiments without further mention. A detailed description of specific embodiments is provided below with reference to the accompanying drawings, in which: Figure 1 illustrates the flowchart of HepG2 cells, which have GPC3 on their cell surface, stained with biotin-labeled peptides, and then stained with streptavidin, R-Phycoerythrin Conjugate.

[0032] Figure 2 illustrates the flowchart of Huh-7 cells, which have GPC3 on their cell surface, stained with biotin-labeled peptides, and subsequently stained with streptavidin R-phycoerythrin conjugate.

[0033] Figure 3 illustrates the flowchart of SK-Hep1 cells, which are negative control cell lines stained with biotin-labeled peptides and subsequently stained with streptavidin R-phycoerythrin conjugate.

[0034] Figure 4A illustrates an exemplary metal chelating agent of the present invention, wherein... The connection points between the metal chelating agent and the remaining conjugate are shown in Figure 4B. Figure 4B illustrates the same metal chelating agent as Figure 4A, except that the linkers or portions of the peptide covalently attached to the metal chelating agent are circled with dashed lines. show.

[0035] Figure 5A illustrates an exemplary metal chelating agent of the present invention, wherein... The connection points between the metal chelating agent and the remaining conjugate are shown in Figure 5B. Figure 5B illustrates the same metal chelating agent as Figure 5A, except that the linkers or portions of the peptide covalently attached to the metal chelating agent are circled with dashed lines. show.

[0036] Figure 6A illustrates an exemplary metal chelating agent of the present invention, wherein... The connection points between the metal chelating agent and the remaining conjugate are shown in Figure 6B. Figure 6B illustrates the same metal chelating agent as Figure 6A, except that the linkers or portions of the peptide covalently attached to the metal chelating agent are circled with dashed lines. show.

[0037] Figure 7A illustrates an exemplary metal chelating agent of the present invention, wherein... The connection points between the metal chelating agent and the remaining conjugate are shown in Figure 7B. Figure 7B illustrates the same metal chelating agent as Figure 7A, except that the linkers or portions of the peptide covalently attached to the metal chelating agent are circled with dashed lines. show.

[0038] Figure 8 illustrates the structure of a representative metal chelating agent.

[0039] Figure 9 illustrates the structure of a representative metal chelating agent.

[0040] Figure 10 illustrates the structure of a representative metal chelating agent.

[0041] Figure 11 illustrates the structure of a representative metal chelating agent.

[0042] Figure 12 illustrates the structure of a representative metal chelating agent.

[0043] Figure 13 illustrates the structure of a representative metal chelating agent.

[0044] Figure 14 illustrates the structure of a representative metal chelating agent.

[0045] Figure 15 illustrates the structure of a representative metal chelating agent.

[0046] Figure 16 illustrates the structure of a representative metal chelating agent.

[0047] Figure 17 illustrates the structure of a representative metal chelating agent.

[0048] Figure 18 illustrates the structure of a representative metal chelating agent.

[0049] Figure 19 illustrates the structure of a representative metal chelating agent.

[0050] Figure 20 illustrates the structure of a representative metal chelating agent.

[0051] Figure 21 illustrates the structure of a representative metal chelating agent.

[0052] Figure 22 illustrates the structure of a representative metal chelating agent.

[0053] Figure 23A illustrates the flowchart of SK-Hep1 cells, which do not express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (PLD-45) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0054] Figure 23B illustrates the flowchart of Huh-7 cells, which express GPC3 on their cell surface and are stained with the biotin-labeled GPC3-binding peptide (PLD-45) of the present invention or a negative control, followed by staining with streptavidin R-phycoerythrin conjugate.

[0055] Figure 23C illustrates the flowchart of HepG2 cells, which express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (PLD-45) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0056] Figure 24A illustrates the flowchart of SK-Hep1 cells, which do not express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (PLD-30) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0057] Figure 24B illustrates the flowchart of Huh-7 cells, which express GPC3 on their cell surface and are stained with the biotin-labeled GPC3-binding peptide (PLD-30) of the present invention or a negative control, followed by staining with streptavidin R-phycoerythrin conjugate.

[0058] Figure 24C illustrates the flowchart of HepG2 cells, which express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (PLD-30) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0059] Figure 25A illustrates the flowchart of SK-Hep1 cells, which do not express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (PLD-1) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0060] Figure 25B illustrates the flowchart of Huh-7 cells, which express GPC3 on their cell surface and are stained with the biotin-labeled GPC3-binding peptide (PLD-1) of the present invention or a negative control, followed by staining with streptavidin R-phycoerythrin conjugate.

[0061] Figure 25C illustrates the flowchart of HepG2 cells, which express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (PLD-1) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0062] Figure 26A illustrates the flowchart of SK-Hep1 cells, which do not express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (Mod-3) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0063] Figure 26B illustrates the flowchart of Huh-7 cells, which express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (Mod-3) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0064] Figure 26C illustrates the flowchart of HepG2 cells, which express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (Mod-3) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0065] Figure 27A illustrates the flowchart of SK-Hep1 cells, which do not express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (Mod-5) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0066] Figure 27B illustrates the flowchart of Huh-7 cells, which express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide of the present invention (Mod-5) or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0067] Figure 27C illustrates the flowchart of HepG2 cells, which express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide of the present invention (Mod-5) or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0068] Figure 28A illustrates the flowchart of SK-Hep1 cells, which do not express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (Mod-6) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0069] Figure 28B illustrates the flowchart of Huh-7 cells, which express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide of the present invention (Mod-6) or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0070] Figure 28C illustrates the flowchart of HepG2 cells, which express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (Mod-6) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0071] Figure 29A illustrates the flowchart of SK-Hep1 cells, which do not express GPC3 on their cell surface. The cells are stained with the biotin-labeled GPC3-binding peptide (Mod-7) of the present invention or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0072] Figure 29B illustrates the flowchart of Huh-7 cells, which express GPC3 on their cell surface. The cells are stained with the biotinylated GPC3-binding peptide of the present invention (Mod-7) or a negative control, and then stained with streptavidin R-phycoerythrin conjugate.

[0073] Figure 29C illustrates the flowchart of HepG2 cells, which express GPC3 on their cell surface. The cells are stained with the biotinylated GPC3-binding peptide of the present invention (Mod-7) or a negative control, and then stained with streptavidin R-phycoerythrin conjugate. Detailed Implementation

[0074] It should be understood that the general and detailed descriptions below are illustrative and descriptive only, and do not limit the technical scope of the invention. Those skilled in the art will recognize that various variations and modifications are possible with respect to this invention, all of which are covered within its scope.

[0075] Although various features of the invention may be described in the context of a single embodiment, these features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of individual embodiments for clarity, the invention may also be practiced in the form of a single embodiment.

[0076] The headings used in this specification are for structural purposes only and should not be construed as limiting the objects described.

[0077] In this specification, unless otherwise specified, the use of a single form includes the plural form. In this specification, unless otherwise stated, the use of “or” means “and / or”. Furthermore, unless otherwise specified, terms such as “element” or “component” cover both elements and components comprising one unit and elements and components comprising two or more sub-units.

[0078] The use of endpoints to describe numerical ranges in this document is intended to include all numbers contained within that range (e.g., the description of 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 4.32, and 5).

[0079] All terms are intended to be understood in the same way as those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[0080] The following definitions are supplementary to those in the art and specific to this application, and should not be attributed to any related or unrelated circumstances, such as any jointly owned patents or applications. While any methods and materials similar to or equivalent to any methods and materials described herein may be used for testing in the practice of this invention, preferred materials and methods are described herein. Therefore, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be restrictive.

[0081] I. Definition Unless the context clearly requires otherwise, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include a plurality of indicators. Thus, for example, a reference to “an agent” includes a plurality of such agents, and a reference to “the cell” includes a reference to one or more cells (or a plurality of cells) and their equivalents known to those skilled in the art. When used for physical properties such as molecular weight or chemical properties such as chemical formulas, the scope as used herein is intended to include all combinations and sub-combinations of the scope herein and specific embodiments.

[0082] The terms “about” or “approximately” can mean within an acceptable margin of error for a particular value as determined by someone skilled in the art, depending in part on how that value is measured or determined (i.e., limitations of the measurement system). For example, “about” can mean within one or more standard deviations according to 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 orders of magnitude, within five times, or within two times the value.

[0083] As used herein, the term "conjugate" may be used interchangeably with "radiopharmaceutical conjugate." The conjugates described herein may contain a radionuclide. In some embodiments, the conjugates described herein do not contain a radionuclide.

[0084] As used herein, the term "radiopharmaceutical" refers to a conjugate containing a radionuclide. In some embodiments, the radionuclide is covalently bound to the conjugate. In some embodiments, the radionuclide is bound to the conjugate via a metal chelating agent.

[0085] The term “comprising” (and related terms such as “comprise”, “comprises”, “having”, or “including”) should be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”. The term “comprising” (and related terms such as “comprise”, “comprises”, “having”, or “including”) is not intended to exclude embodiments, such as any of the material compositions, combinations, methods, or processes described herein, from being “consistent with” or “substantially composed of” the described features.

[0086] "Amino" refers to the -NH2 group.

[0087] “Cyano” refers to the -CN group.

[0088] "Nitro" refers to the -NO2 group.

[0089] "Oxo" refers to the =O group.

[0090] "Imine" refers to the =NH group.

[0091] "Oxime group" refers to the =N-OH group.

[0092] "Hydrazine" refers to the =N-NH2 group.

[0093] "Hydroxyl" or "hydroxyl" refers to the -OH group.

[0094] "Hydroxyamino" refers to the -NH-OH group.

[0095] "Acyl" means a substituted or unsubstituted alkyl carbonyl group, a substituted or unsubstituted alkenyl carbonyl group, a substituted or unsubstituted alkynyl carbonyl group, a substituted or unsubstituted cycloalkyl carbonyl group, a substituted or unsubstituted heterocycloalkyl carbonyl group, a substituted or unsubstituted aryl carbonyl group, a substituted or unsubstituted heteroaryl carbonyl group, an amide, or an ester, wherein the carbonyl atom of the carbonyl group is a connecting point. Unless otherwise specifically stated in this specification, the alkyl carbonyl group, alkenyl carbonyl group, alkynyl carbonyl group, cycloalkyl carbonyl group, amide group, or ester group may optionally be substituted with, for example, an oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, or similar groups.

[0096] "alkyl" refers to a monovalent group of a straight-chain or branched saturated hydrocarbon that is optionally substituted. Alkyl groups may have one to about twenty carbon atoms, one to about ten carbon atoms, or 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-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, dibutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and similar groups. Whenever it appears herein, numerical ranges such as "C1-C6 alkyl" mean that an alkyl group consists of 1, 2, 3, 4, 5, or 6 carbon atoms, although this definition also covers the occurrence of the term "alkyl" without a specified numerical range. In some embodiments, the alkyl group is C1-C6. 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless otherwise specifically stated in this specification, the alkyl group may be optionally substituted with, for example, an oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, or similar groups. In some embodiments, the alkyl group may be optionally substituted with an oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, -NO2, or -C≡CH. In some embodiments, the alkyl group may be optionally substituted with an oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl group may be optionally substituted with a halogen.

[0097] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically stated in this specification, alkylene may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the alkylene may be optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene may be optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene may be 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-.

[0098] "Alkenyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monovalent group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl group has two to about ten carbon atoms or two to about six carbon atoms. The group may be configured in cis or trans around the double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and similar groups. Whenever it appears herein, numerical ranges such as "C2-C6 alkenyl" mean that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkenyl" where no numerical range is specified. In some embodiments, the alkenyl group is C2-C6. 10 The alkenyl group can be C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, or C2. Unless otherwise specifically stated in this specification, the alkenyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, or similar groups. In some embodiments, the alkenyl group may be optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group may be optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl group may be optionally substituted with halogen.

[0099] The term "alkenyl" or "alkenyl chain" refers to an optionally substituted straight-chain or branched divalent hydrocarbon chain, wherein at least one carbon-carbon double bond is present, connecting the remainder of the molecule to a group. In some embodiments, the alkenyl group is -CH=CH-, -CH2CH=CH-, or -CH=CHCH2-. In some embodiments, the alkenyl group is -CH=CH-. In some embodiments, the alkenyl group is -CH2CH=CH-. In some embodiments, the alkenyl group is -CH=CHCH2-.

[0100] "Alynyl" refers to a monovalent group of a linear or branched hydrocarbon that has one or more carbon-carbon linkages and is optionally substituted. In some embodiments, the alkynyl group has two to ten carbon atoms, more preferably two to six carbon atoms. Examples include, but are not limited to, acetylenyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and similar groups. Whenever it appears herein, numerical ranges such as "C2-C6 alkynyl" mean that the alkynyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkynyl" where no numerical range is specified. In some embodiments, the alkynyl group is C2-C6. 10 The alkynyl group can be C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, or C2. Unless otherwise specifically stated in this specification, the alkynyl group may be optionally substituted with, for example, an oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, or similar groups. In some embodiments, the alkynyl group may be optionally substituted with an oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group may be optionally substituted with an oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl group may be optionally substituted with a halogen. The term "alkynylene" refers to an optionally substituted straight-chain or optionally substituted branched divalent hydrocarbon having one or more carbon-carbon linkages.

[0101] "alkylamino" refers to -N(R a )2 groups, wherein R a For the defined alkyl group, or two R groups aTogether with a nitrogen atom, it can form a substituted or unsubstituted C2-C7 heterocyclic alkyl ring. Unless otherwise specifically stated in this specification, the alkylamino group may optionally be substituted with, for example, an oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, or similar groups. In some embodiments, the alkylamino group is optionally substituted with an oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2 group. In some embodiments, the alkylamino group is optionally substituted with an oxo, halogen, -CN, -CF3, -OH, or -OMe group. In some embodiments, the alkylamino group is optionally substituted with a halogen.

[0102] "Alkoxy" refers to -OR a The group, wherein R a The alkyl group is defined as such. Unless otherwise specifically stated in this specification, the alkoxy group may optionally be substituted with, for example, an oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, or similar groups. In some embodiments, the alkoxy group may optionally be substituted with an oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2 group. In some embodiments, the alkoxy group may optionally be substituted with an oxo, halogen, -CN, -CF3, -OH, or -OMe group. In some embodiments, the alkoxy group may optionally be substituted with a halogen.

[0103] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Hydroxyalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl group is aminomethyl.

[0104] The term "aryl" refers to a group comprising at least one aromatic ring, wherein each of the atoms forming the ring is a carbon atom. Aryl groups may optionally be substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl group is phenyl. Depending on the structure, the aryl group may be a monovalent or divalent group (i.e., arylene). Unless otherwise specifically stated in this specification, the term "aryl" or the prefix "ar-" (such as "aryl") means including optionally substituted aryl groups. In some embodiments, the aryl group comprises a partially reduced cycloalkyl group (e.g., 1,2-dihydronaphthalene) as defined herein. In some embodiments, the aryl group comprises a fully reduced cycloalkyl group (e.g., 1,2,3,4-tetrahydronaphthalene) as defined herein. When the aryl group comprises a cycloalkyl group, the aryl group is bonded to the rest of the molecule through carbon atoms of the aromatic ring. The aryl group may be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused ring, spirocyclic, or bridged ring systems. Unless otherwise specifically stated in this specification, the aryl group may optionally be substituted with, for example, the following groups: halogen, amino, alkylamino, aminoalkyl, nitrile, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-C1-C6 alkyl, and similar groups. In some embodiments, the aryl group may optionally be substituted with the following groups: 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, the aryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with a halogen. In some embodiments, the aryl group is substituted with an alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl group, wherein each alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl group is independently unsubstituted or substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0105] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group, wherein each of the atoms forming the ring (i.e., the skeleton atoms) is a carbon atom. In some embodiments, the cycloalkyl group is saturated or partially unsaturated. In some embodiments, the cycloalkyl group is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl group is fused to an aromatic ring (in which case the cycloalkyl group is bonded through non-aromatic carbon atoms). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to ten carbon atoms, three to eight carbon atoms, three to six carbon atoms, or three to five carbon atoms. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentenyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrahydronaphthyl, decalinyl, 3,4-dihydronaphthyl-1(2H)-one, spiro[2.2]pentyl, nor[2.2]pentyl, and bicyclic[1.1.1]pentyl. Unless otherwise specifically stated in this specification, cycloalkyl groups may optionally be substituted. Representative cycloalkyl groups include, but are not limited to, those having three to fifteen carbon atoms (e.g., C3-C4). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl groups, three to ten carbon atoms (e.g., C3-C) 10 Fully saturated cycloalkyl or C3-C 10Cycloalkyl groups are cycloalkyl groups comprising three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkyl), three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkyl), three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkyl). In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic compounds include, for example, adamantyl, northoalkyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl compounds include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in this specification, cycloalkyl compounds may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0106] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine.

[0107] "Haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogens. In some embodiments, the alkyl group is substituted with one, two, or three halogens. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six halogens. Haloalkyl groups may include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl groups. For example, "fluoroalkyl" refers to an alkyl group as defined above that is substituted with one or more fluorinated groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and similar groups. In some embodiments, the alkyl portion of the fluoroalkyl group may optionally be substituted as defined above for alkyl groups.

[0108] "Heteroalkyl" refers to an alkyl group whose skeletal atoms are selected from atoms other than carbon, such as alkyl groups of oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom. Examples of such heteroalkyl groups are, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-. Unless otherwise specifically stated in this specification, heteroalkyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the heteroalkyl group may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group may be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group may be optionally substituted with halogen.

[0109] As used herein, “heteroalkylene” refers to a divalent heteroalkylene group. Examples of such heteroalkylene groups include, for example, -CH2-O-CH2-, -CH2-N(alkyl)-CH2-, -CH2-N(aryl)-CH2-, -OCH2CH2O-, -OCH2CH2OCH2CH2O-, or -OCH2CH2OCH2CH2OCH2CH2O-.

[0110] The term "heterocyclic alkyl" refers to a cycloalkyl group comprising at least one heterocyclic atom, such as a heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in this specification, a heterocyclic alkyl group may be a monocyclic or bicyclic system, which may include fused rings (where the heterocyclic alkyl group is bonded through non-aromatic atoms when fused with an aryl or heteroaryl ring) or bridged ring systems. The nitrogen, carbon, or sulfur atom in the heterocyclic group may optionally be oxidized. The nitrogen atom may optionally be quaternarily ammonized. The heterocyclic alkyl group may be partially or fully saturated. Examples of heterocyclic alkyl groups include, but are not limited to, dioxolane, thienyl[1,3]dithiaalkyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolinyl, isothiazolinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidylyl, oxazolinyl, piperidinyl, piperazine, 4-piperidinoneyl, pyrrolylyl, pyrazolyl, quininecycloyl, thiazolinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. Representative heterocyclic alkyl groups include, but are not limited to, those having two to fifteen carbon atoms (e.g., C2-C). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, two to ten carbon atoms (e.g., C2-C) 10 Fully saturated heterocyclic alkyl or C2-C 10Heterocyclic alkyl groups are defined as having two to eight carbon atoms (e.g., C2-C8 fully saturated heterocyclic alkyl or C2-C8 heterocyclic alkenyl), two to seven carbon atoms (e.g., C2-C7 fully saturated heterocyclic alkyl or C2-C7 heterocyclic alkenyl), two to six carbon atoms (e.g., C2-C6 fully saturated heterocyclic alkyl or C2-C6 heterocyclic alkenyl), two to five carbon atoms (e.g., C2-C5 fully saturated heterocyclic alkyl or C2-C5 heterocyclic alkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocyclic alkyl or C2-C4 heterocyclic alkenyl). The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocyclic alkyl groups have 2 to 12 carbon atoms in the ring. In some embodiments, heterocyclic alkyl groups have 2 to 10 carbon atoms in the ring. In some embodiments, heterocyclic alkyl groups have 2 to 10 carbon atoms in the ring and have 1 or 2 nitrogen atoms. In some embodiments, the heterocyclic alkyl group has 2 to 10 carbon atoms and 3 or 4 nitrogen atoms in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 12 carbon atoms, 0 to 2 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 2 phosphorus atoms, and 0 to 1 sulfur atom in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 12 carbon atoms, 1 to 3 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is not the same as the total number of atoms constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring) (including heteroatoms). Unless otherwise specifically stated in this specification, the heterocyclic alkyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, and similar groups. In some embodiments, the heterocyclic alkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic alkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[0111] "Heteroaryl" refers to a cyclic group comprising a carbon atom and one or more cyclic heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group is monocyclic, bicyclic, or polycyclic. Illustrative examples of monocyclic heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, pyridazinyl, triazinyl, oxadiazolyl, thiazolyl, furazolyl, indazine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinazine, quinoline, isoquinoline, chlorophyll, thiazoline, quinazolin, 1,8-phenylene, and pteridine. Illustrative embodiments of monocyclic heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiopheneyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, pyridazinyl, triazinyl, oxadiazolyl, thiazolyl, and furazolidone. Illustrative embodiments of bicyclic heteroaryl groups include indazine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinazine, quinoline, isoquinoline, phosphazene, quinazolin, quinazolin, quinazolin, 1,8-phenylene, and pteridine. In some embodiments, the heteroaryl group is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thiopheneyl, thiazolyl, or furanyl. In some embodiments, the heteroaryl group contains 0 to 6 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 1 to 4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 4 to 6 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 0 to 4 nitrogen atoms, 0 to 1 oxygen atom, 0 to 1 phosphorus atom, and 0 to 1 sulfur atom in the ring. In some embodiments, the heteroaryl group contains 1 to 4 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom in the ring. In some embodiments, the heteroaryl group is a C1-C9 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C6-C9 heteroaryl group. In some embodiments, the heteroaryl group comprises a partially reduced cycloalkyl or heterocyclic alkyl group (e.g., 7,8-dihydroquinoline) as defined herein. In some embodiments, the heteroaryl group comprises a fully reduced cycloalkyl or heterocyclic alkyl group (e.g., 5,6,7,8-tetrahydroquinoline) as defined herein. When a heteroaryl group comprises a cycloalkyl or heterocyclic alkyl group, the heteroaryl group is bonded to the remainder of the molecule through carbon atoms or heteroatoms of the heteroaryl ring. The heteroaryl group can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) ring system, which may include fused ring, spirocyclic, or bridged ring systems. Unless otherwise specifically stated in this specification, the heteroaryl group may optionally be substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, and similar groups.In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0112] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is a generally recognized chemical entity that is embedded in or attached to a molecule.

[0113] As used herein, the terms “treatment,” “prevention,” “improvement,” and “inhibition,” and phrases derived therefrom, do not necessarily imply 100% or complete treatment, prevention, improvement, or inhibition. Rather, varying degrees of treatment, prevention, improvement, and inhibition exist, and those skilled in the art would generally consider such degrees to have potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount and degree of treatment, prevention, improvement, or inhibition of a symptom in mammals. For example, a symptom, including its symptoms or signs, can 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, treatment, prevention, improvement, or inhibition provided by the methods disclosed herein may include treatment, prevention, improvement, or inhibition of one or more symptoms or signs of a symptom, such as cancer or an inflammatory disease.

[0114] In some implementations, "treatment" includes the concept of "remission," which refers to reducing the frequency or severity of the occurrence or recurrence of any symptoms or other disease effects and / or related side effects associated with the condition. In some implementations, the term "treatment" also encompasses the concept of "management," which refers to reducing the severity of a patient's specific disease or condition or delaying its recurrence, such as prolonging the remission period for a patient suffering from the disease.

[0115] In some implementations, the terms “prevent” or “preventing” related to a disease or condition may refer to, in a statistical sample, a compound reducing the occurrence of a disease or condition in a treated sample relative to an untreated control sample, or delaying the onset of one or more symptoms of a disease or condition or reducing its severity relative to an untreated control sample.

[0116] As used herein, the term "therapeutic effective amount" refers to the amount effective at the dose and duration necessary to achieve the desired therapeutic outcome. Therapeutic effective amounts of a composition can vary depending on various factors, such as an individual's condition, age, sex, and weight, as well as the protein's ability to elicit the desired response in an individual. Therapeutic effective amounts can also exceed any toxic or harmful effects of the composition that would have a beneficial therapeutic effect.

[0117] The terms “optionally present” or “optional” mean that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined above. Furthermore, the optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted to any degree between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0118] As used herein, the term "substituent" means a positional variable on the atom of a core molecule that replaces one or more hydrogen atoms at a specified atomic position, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution produces a stable compound. Combinations of substituents and / or variables are permissible only if such combinations produce a stable compound. Those skilled in the art will note that any carbon and heteroatom having an unsaturated valence as described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the described or shown valence. In some cases, one or more substituents having double bonds (e.g., "oxo" or "=O") as connection points may be described, shown, or listed within the substituents herein, wherein the structure may show only single bonds as connection points to the core structure. Those skilled in the art will understand that although only single bonds are shown, double bonds are intended to be used for those substituents.

[0119] For the purposes of this invention, a single "substitution" event in an amino acid or amino sequence is not considered as two separate events: a deletion and an addition. Therefore, to avoid ambiguity, as an example, a sequence variation of "at most two deletions, substitutions, and / or additions" includes one deletion and one substitution, one deletion and one addition (at different positions), one substitution and one addition, only one deletion, only one substitution, only one addition, two deletions, two substitutions, two additions, etc. The deletion, addition, or substitution may be located at one or both ends of the peptide, or in the middle of the peptide.

[0120] The terms “optionally substituted” or “substituted” mean that the mentioned group is optionally substituted with one or more additional groups. For example, “optionally substituted” or “substituted” may mean that the mentioned group is optionally substituted with one or more substituents individually and independently selected from the following: D, halogen, -CN, -NH2, -NH (alkyl), -N (alkyl)2, -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, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some other embodiments, the optional substituents are independently selected from D, halogens, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl, and -S(=O)2C1-C4 alkyl. In some embodiments, the "optionally substituted" group is independently substituted by 1 to 6 substituents selected from the following: halogen, -CN, oxo, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N =S(=O)(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, aryl, heteroaryl, heterocyclic alkyl and cycloalkyl.In some embodiments, the "optionally substituted" group is independently substituted by 1 to 6 substituents selected from the following: halogen, -CN, oxo, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N= S(=O)(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, 5- to 6-membered heterocyclic alkyl and C3-C6 cycloalkyl. In some embodiments, the "optionally substituted" group is independently substituted with 1 to 6 substituents selected from the following: halogen, oxo, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)OH, -C(=O)NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, and C3-C6 cycloalkyl. In some embodiments, the 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, the substituted group is substituted with one or both of the aforementioned groups. In some embodiments, the optional substituents on the aliphatic carbon atom (acyclic or cyclic) include oxo (=O). When indicating the number of substituents, the term "one or more" means from one substituent to the highest possible number of substitutions, i.e., substitution of one hydrogen atom up to substitution of all hydrogen atom by the substituent. In some embodiments, the "optionally substituted" group is unsubstituted. In some embodiments, the "optionally substituted" group is independently substituted by 1 to 6 substituents. In some embodiments, the "optionally substituted" group is independently substituted by 1 to 3 substituents. In some embodiments, the "optionally substituted" group is independently substituted by 1 to 2 substituents.

[0121] The term "unsubstituted" means that the specified group does not carry any substituents.

[0122] Some of the compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of this invention.

[0123] Unless otherwise stated, the structures described herein are intended to include all stereochemical forms of the structures; namely, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of the compounds of this invention, as well as mirror-image and non-mirror-image isomer mixtures, are within the scope of this invention.

[0124] As used herein, the term "peptide" refers to a compound comprising two or more amino acids. The peptides described herein may contain one or more non-natural amino acids. The term "peptide" also encompasses peptide analogs. In this invention, the term "amino acid" is used in its broadest sense and includes not only natural amino acids but also their derivatives and synthetic amino acids. For example, the term "amino acid" encompasses non-natural amino acids.

[0125] As used herein, the term "peptide-like" refers to N-substituted glycine. Peptides may optionally be substituted. Peptides may optionally contain additional substitutions at the α-carbon.

[0126] As used herein, the term "non-natural amino acid" refers to amino acids other than the 20 typical amino acids. The 20 typical amino acids are alanine (Ala or A), arginine (arg or R), asparagine (asn or N), aspartic acid (asp or D), cysteine ​​(cys or C), glutamine (gln 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).

[0127] As used herein, the term "protein" refers to a polypeptide (i.e., a string of at least three amino acids linked together by peptide bonds). Proteins may include portions other than amino acids (e.g., glycoproteins, proteoglycans, etc.) and / or may be otherwise treated or modified. Proteins may be intact polypeptides (with or without a signal sequence) produced by cells and / or active in cells. In some embodiments, a protein is or contains characteristic portions, such as polypeptides produced by cells and / or active in cells. Proteins may include more than one polypeptide chain. For example, polypeptide chains may be linked by one or more disulfide bonds or otherwise associated.

[0128] The term "peptide mimic" or "mimic" refers to a bioactive compound that mimics the biological activity of a peptide or protein but is no longer a complete peptide in chemical properties, for example, it may contain non-peptide bonds (i.e., bonds other than amide bonds between amino acids). As used herein, the term peptide mimic is used more broadly to include molecules that are no longer entirely peptides in nature, such as pseudo-peptides, hemipeptides, and peptide-like molecules. Whether completely or partially non-peptide, the peptide mimics described herein provide a spatial arrangement of reactive chemical parts that is remarkably similar to the three-dimensional arrangement of the active groups in the individual amino acid sequence on which the peptide mimic is based. Due to this similar geometry of the active site, peptide mimics can have effects on biological systems similar to the biological activity of the individual entity.

[0129] In some implementations, the peptide mimic is substantially similar to the individual amino acid sequence or individual molecule on which the peptide mimic is based, both in terms of three-dimensional shape and biological activity. An example is described in the paper “Tritiated D-ala1-Peptide T Binding”, Smith CS et al., Drug Development Res., 15, pp. 371-379 (1988). A second approach involves altering the cyclic structure to obtain stability, such as with N- to C-chain imides and lactams (Ede et al. in Smith and Rivier (eds.), “Peptides: Chemistry and Biology”, Escom, Leiden (1991), pp. 268-270). Examples of this approach are provided in conformationally restricted thymopentin-like compounds, such as those disclosed in US4457489. A third approach involves replacing the peptide bonds in the individual entity with pseudopeptide bonds that impart resistance to proteolytic degradation.

[0130] The term "organic atom" refers to atoms found in organic compounds, such as carbon, hydrogen, nitrogen, oxygen, sulfur, phosphorus, fluorine, chlorine, bromine, or iodine.

[0131] The ranges provided herein should be understood as abbreviations of all values ​​within the range. For example, the range 1 to 50 should be understood as including any number, combination of numbers, or subrange selected from the following groups: 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, and all intermediate decimal values ​​between the aforementioned integers, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. In terms of subranges, "nested" subranges that extend from either endpoint of a range are specifically covered. For example, nested subranges of the exemplary range 1 to 50 may include 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 another direction.

[0132] As used in this article, C1-C x (or C) 1-x This includes C1-C2, C1-C3...C1-C x By way of example only, the designation "C1-C4" indicates the presence of one to four carbon atoms in the indicator portion, i.e., a group containing 1, 2, 3, or 4 carbon atoms. Therefore, by way of example only, "C1-C4 alkyl" indicates the presence of one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl, and tert-butyl. Furthermore, by way of example, C0-C2 alkylene groups include direct bonds, -CH2- bonds, and -CH2CH2- bonds.

[0133] As used herein, the term "cyclized" or "cyclization" refers to the direct or indirect binding of two amino acids in a peptide that are at least one amino acid apart to form a ring structure in the molecule. In some cases, the two amino acids are bound together via a linker or other means.

[0134] The terms "individual" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans; non-human primates such as chimpanzees and other ape and monkey species; livestock such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; and similar animals. In one aspect, a mammal is a companion animal, such as a dog or cat. In another aspect, a mammal is a human.

[0135] The percentage of sequence identity can be calculated using computer programs or direct sequence comparison. Preferred computer program methods for determining the identity between two sequences include, but are not limited to, the GCG package, FASTA, BLASTP, and TBLASTN (see, for example, DW Mount, 2001, Bioinformatics: Sequence and Genome Analysis, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY). The BLASTP and TBLASTN programs are publicly available from NCBI and other sources. The Smith Waterman algorithm can also be used to determine the percentage of identity. Indicative parameters for amino acid sequence comparison include the following: 1) the algorithm from Needleman and Wunsch (J. Mol. Biol., 48:443-453 (1970)); 2) the BLOSSUM62 comparison matrix from Hentikoff and Hentikoff (Proc. Nat. Acad. Sci. USA., 89:10915-10919 (1992)); 3) gap penalty = 12; and 4) gap length penalty = 4. The program used with these parameters is publicly available as the "Gap" program (Genetics Computer Group, Madison, Wis.). The aforementioned parameters are default parameters for peptide comparison (no penalty for terminal gaps). Alternatively, peptide sequence identity can be calculated using the following equation: Identity % - (number of identical residues) / (alignment length of amino acid residues) × 100. For this calculation, the alignment length includes internal gaps but excludes terminal gaps.

[0136] It should be understood that certain features of the invention described in the context of individual embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination. For example, the conjugates of the invention may comprise any peptide ligands described herein (e.g., peptide ligands of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5) or Table 1), any metal chelating agent described herein (e.g., metal chelating agents selected from Figures 4A, 5A, 6A, 7A, 4B, 5B, 6B, 7B and Figures 8 to 22), optionally present linkers described herein (e.g., linkers of formulas (II-1), (II-1a) or (II-1b), and optionally present radionuclides described herein (e.g., radionuclides of Table 7). As another example, a peptide of formula (I) (or any other formula, such as (III-1) and (III-2)) may contain the X1 to X12 amino acids described herein, and the invention covers any combination of embodiments of amino acids (even in some cases, which are described in the context of individual embodiments).

[0137] Unless otherwise defined, the terminology, procedures, and techniques used in analytical chemistry, synthetic organic chemistry, medical chemistry, and pharmaceutical chemistry described in this specification are well-known and commonly used in the present invention. Standard techniques can be used for chemical synthesis and chemical analysis. Those terms defined in such techniques and procedures can be found, for example, in "KJ Jensen, PT Shelton, SL Pedersen, Peptide Synthesis and Applications, 2nd Edition, Springer, 2013," etc., and such terms are incorporated herein by reference for all purposes. Where permitted, all patents, applications, published applications, and other publications and data referenced throughout this disclosure are incorporated herein by reference.

[0138] II. Radiopharmaceutical conjugates This article provides radiopharmaceutical conjugates or pharmaceutically acceptable salts thereof with affinity for phosphatidylinositol proteoglycan 3 (GPC3), and pharmaceutical compositions comprising such conjugates. The conjugates and compositions may be used for the treatment of cancer. They may also be used for imaging and disease diagnosis.

[0139] In one aspect, this document describes a conjugate comprising a peptide with affinity for phosphatidylinositol proteoglycan 3 (GPC3) and a metal chelating agent configured to bind to a radionuclide. In some embodiments, the GPC3 is human GPC3. The peptide may be cyclic or acyclic, and may be monocyclic, bicyclic, or polycyclic. In one aspect, this document describes a conjugate comprising a cyclic peptide and a metal chelating agent configured to bind to a radionuclide. In some embodiments, the peptide (such as a cyclic peptide) is configured to bind to a target. The conjugate described herein may further comprise a linker covalently linking the peptide to the metal chelating agent. In some embodiments, the conjugate comprises a radionuclide bound to the metal chelating agent, such as... 225 Ac.

[0140] In another aspect, this document describes a conjugate comprising a peptide with affinity for phosphatidylinositol proteoglycan 3 (GPC3) and a covalently bound radionuclide. In some embodiments, the GPC3 is human GPC3. The peptide may be cyclic or acyclic, and may be monocyclic, bicyclic, or polycyclic. In one aspect, this document describes a conjugate comprising a cyclic peptide and a metal chelating agent configured to bind to a radionuclide. In some embodiments, the peptide (such as a cyclic peptide) is configured to bind to a target. The conjugates described herein may further comprise a linker for attaching a covalently bound radionuclide to the peptide. In some embodiments, the conjugate comprises a bound covalently bound radionuclide, such as... 131 I.

[0141] In one aspect, this document describes a radiopharmaceutical conjugate comprising: (a) A peptide with affinity for phosphatidylinositol proteoglycan 3 (GPC3) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid sequence including the deletion, substitution and / or addition of one or more (e.g., 1 to 6) amino acids from the amino acid sequence of SEQ ID NO: 1: MeK-MeI-D-MeQ-F4COO-IIY-MeNal27N-G-3Py6Ph-MeC (SEQ ID NO: 1), The peptide consists of 10 to 12 amino acid residues; and (b) (i) a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide; or (ii) a covalently bound radionuclide.

[0142] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide bound to the metal chelating agent.

[0143] In some implementations, the radiopharmaceutical conjugate contains a covalently bound radionuclide.

[0144] In some implementations, the peptide is a cyclic peptide.

[0145] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide. In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent is covalently linked to the peptide. In some embodiments, the radionuclide is bound to the metal chelating agent. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide. In some embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 1 with two or fewer amino acids missing. In some embodiments, one amino acid is missing from SEQ ID NO: 1. In some embodiments, the one amino acid missing from SEQ ID NO: 1 is MeI at position 2. In some embodiments, the one amino acid missing from SEQ ID NO: 1 is D at position 3. In some embodiments, 1, 2, 3, 4, or 5 amino acids are added to the peptide of SEQ ID NO: 1. In some embodiments, 1, 2, or 3 amino acids are added to the peptide of SEQ ID NO: 1. In some embodiments, one or two amino acids are added to the peptide of SEQ ID NO: 1. In some embodiments, one amino acid is added to the peptide of SEQ ID NO: 1. In some embodiments, two amino acids are added to the peptide of SEQ ID NO: 1.

[0146] In one aspect, this document describes a radiopharmaceutical conjugate comprising: (a) A peptide or a pharmaceutically acceptable salt thereof having an affinity for phosphatidylinositol proteoglycan 3 (GPC3), wherein the peptide comprises the amino acid sequence of formula (I). X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) in, X1 can be any amino acid; X2 can be any amino acid; X3 can be any amino acid; X4 can be any amino acid; X5 is an amino acid containing an aromatic ring (e.g., W, F, Y or variants thereof), an amino acid containing a cycloalkyl group, or an amino acid containing a heterocyclic alkyl group, or X5 is a peptide (e.g., Cha4cH, Cha4tH, Almor, Atp, Cha4cOMe). X6 is a hydrophobic amino acid, a hydrophilic amino acid, or a polar amino acid, wherein the polar amino acid has a substituted side chain. X7 is a hydrophobic amino acid containing C1-C8 alkyl, cycloalkyl, or heterocycloalkyl groups, wherein each of the alkyl, cycloalkyl, and heterocycloalkyl groups is independently and optionally substituted (e.g., X7 is I, Eva, alI, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe, or Cbg). X8 is A, I, L, V, Y, or F or a variant thereof; X9 is an N-alkylated amino acid containing an aromatic ring; X10 is a G, A, or D-amino acid (e.g., da, ds, de, or dp); X11 is an amino acid containing an aromatic ring (e.g., F, Y, or a variant thereof); and X12 is N-alkylated cysteine ​​(e.g., MeC); and (b) (i) a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide; or (ii) a covalently bound radionuclide.

[0147] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide bound to the metal chelating agent. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide.

[0148] In one aspect, this document describes a radiopharmaceutical conjugate comprising: (a) A peptide or a pharmaceutically acceptable salt thereof having an affinity for phosphatidylinositol proteoglycan 3 (GPC3), wherein the peptide comprises the amino acid sequence of formula (I). X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) in, X1 is I, R, Cit, F4G, 4Py, 3Py, KCOpipzaa, V, Eva, Q, E, MeI, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeV, MeHseMe , Aib, MeT, alI, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe, MeDapCOpipzaa, MeK, MeKAc, MeK(de), MeK(H), MeK(df) or MeK(datb); X2 is I, K, Cit, F4G, 4Py, 3Py, KCOpipzetOH, V, KCOpipzaa, Eva, Q, E, S, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeI, MeV, MeL, HseMe, MeY, Me3Py, MeHseMe, MeKAc, alI, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe or MeDapCOpipzaaa; X3 is D, Har, KCOpipzetOH, Cit, KCO glucosamine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, KAc, Hgn, MeY or DapCOpipzaa; X4 is D, Har, KCOpipzetOH, KCO glucosamine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, dd, MeQ, MeQdMe, MeA, MeSMe, MeG, EtG, MeeG, CmG, CmpG, CrmG, CeG, CrpG, MeK, MeKAc, MeHgl, Hgn, MeDapCOpipzaa, MeKCOpipzaa, Medd, Cit, MeCit, MeN, MeS, MeE, MeY, W5N or MeA4paa; X5 is Y, F3G, 3Py6COO, 4Py2NH2, 3Py5COO, F3COO, 3Py6NHAc, F, F4C, F4OMe, F4COO, Nal2, F3aao, F4aa, F4aao, 3Py6NHaa, 5Pdo, F3CON, F4F, F4OEt, F4Me, F4CON, F4CONPEG4Me, F3OMe, F3CON, Yae, YaeCOpipzaa, F4aaopipzaa, 4Pdo, 3Py6CON, Atp, Cha4cH, Cha4tH, Cha4cOMe, A1mor or F4amCOpipzaa; X6 is I, V, Eva, Chg, Tbg, A, L, Ahp, F4COO, Gcpr, Gcpe, alI, Cle, S3REt, TMe, Acpr, Cba, Gthp, NleCOO, NleOH, P, Atb, Nva, Nle, N, DapAc, Abu, N mm, Ndm, Ncit, Cit, SMe, HseMe, HseEt, HseiPr, dMeS, TdMe, Cbg, NvaOMe, SiPr, Spr, NleOMe, Sbu, Scbm, Scpe, AhpOMe, HseBu, Spent or Hsecpe; X7 is I, Eva, aliI, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe, or Cbg; X8 is A, I, L, V, Y, F4OMe, F4COO, F4OEt, F4u, F4Me, F4CONdMe, F4CON, F4ms, F4CONPEG4Me, F34dOMe, F3OMe, F3C, F3CON, F3CONdMe , 3Py6CON, Yae, YaeCOpipzaa, 5Inda, F3aao, F3aa, F4aao, F4aa, 3Py6Nhae, 3Py6NHAc, 3Py6OMe, F4aaopipzaa or F4amCOpipzaa; X9 is MeNal2, MeNal27N, MeF34diox, MeF34dOMe, MeF4T, MeY, MeW1Me, MeW7N, MeF3C4Me or MeF3Me4C; X10 is a G, A, or D-amino acid (e.g., da, ds, de, or dp); X11 is Bph, 3Py6Ph, F41Me4Pyz, F43Pyz, F44Pyz, F41Pyz, F41Me3Pyz, F41Et4Pyz, F41MeOe4Pyz, F41MeOp4Pyz, F44thp, F4Ac4pip, PhNva, PhNle, Yph, Ybn, F4tb, F4oPr, or F4CONdMe; and X12 is MeC; and (b) (i) a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide; or (ii) a covalently bound radionuclide.

[0149] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide bound to the metal chelating agent. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide.

[0150] In one aspect, this document describes a radiopharmaceutical conjugate comprising: (a) A peptide or a pharmaceutically acceptable salt thereof having an affinity for phosphatidylinositol proteoglycan 3 (GPC3), wherein the peptide comprises the amino acid sequence of formula (I). X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) in, X1 can be any amino acid; X2 can be any amino acid; X3 can be any amino acid; X4 can be any amino acid; X5 is ,in: R n5 It is hydrogen or C 1-3 alkyl; Ring A5 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Each R X5 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)NR c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NRa S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X5 -heterocyclic alkyl, -L X5 -cycloalkyl, -L X5 -Aryl or -L X5 - Heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally derived from one or more R... X5a Replace; or Two Rs X5 Together they form =O, =S, or =N(R) a ); L X5 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X5a replace; kx5 is 0, 1, 2 or 3; mx5 can be 0, 1, 2, 3, 4 or 5; *X4 indicates the connection point with X4; and *X6 indicates the connection point with X6; X6 is ,in: R n6 It is hydrogen or C 1-3 alkyl; R X6 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X6 -heterocyclic alkyl, -L X6 -cycloalkyl, -L X6 -Aryl or -L X6 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X6a Replace; or R n6 and R x6 Together with intermediary atoms, they form one or more optional R atoms. X6a Substituted 5- to 6-membered heterocyclic alkyl groups; L X6 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X6a replace; *X5 indicates the connection point with X5; and *X7 indicates the connection point with X7; X7 is ,in: R n7 It is hydrogen or C 1-3 alkyl; R X7 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, heteroalkyl, alkenyl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R groups. X7a replace; *X6 indicates the connection point with X6; and *X8 indicates the connection point with X8; X8 is ,in: R n8 It is hydrogen or C 1-3 alkyl; Ring A8 is aryl or heteroaryl; Each R X8 Independently for C 1-6 Alkyl, C 1-6Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X8 -heterocyclic alkyl, -L X8 -cycloalkyl, -L X8 -Aryl or -L X8 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X8a Replace; or Two Rs X8 Together they form =O, =S, or =N(R) a ); L X8 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X8a replace; kx8 is 0, 1, 2, or 3; mx8 can be 0, 1, 2, 3, 4 or 5; *X7 indicates the connection point with X7; and *X9 indicates the connection point with X9; X9 is ,in: R n9 It is hydrogen or C 1-3 alkyl; Ring A9 is aryl or heteroaryl; Each R X9 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5 or -NR c R d The alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally derived from one or more R groups. X9a Replace; or Two Rs X9 Together they form =O, =S, or =N(R) a ); kx9 is 0, 1, 2, or 3; mx9 can be 0, 1, 2, 3, 4 or 5; *X8 indicates the connection point with X8; and *X10 indicates the connection point with X10; X10 is glycine or a D-amino acid (e.g., da, ds, de, or dp); X11 is ,in: R n11 It is hydrogen or C 1-3 alkyl; Ring A11 is aryl or heteroaryl; Each RX11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X11 -heterocyclic alkyl, -L X11 -cycloalkyl, -L X11 -Aryl or -L X11 -heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X11a Replace; or Two Rs X11 Together they form =O, =S, or =N(R) a ); L X11 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X11a replace; kx11 is 0, 1, 2, 3, 4 or 5; mx11 can be 0, 1, 2, 3, 4 or 5; *X10 indicates the connection point with X10; and *X12 indicates the connection point with X12; X12 is N-alkylated cysteine; R X5a R X6a R X7a R X8a R X9a and R X11a Each independently constitutes a halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d-NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; Each R a Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is independently optionally etched with one or more R... e replace; Each R e Independently, it can be halogen, -CN, -OH, -O-C1-C6 alkyl, -SF5, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=NH)NH 2. -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, C1-C6 alkyl-C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; or two R e Together they form = O; and Each R c and R dIndependently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is independently optionally etched with one or more R... e Replace; or R c and R d Together with the atoms they are attached to, they form one or more optional R... e Substituted heterocyclic alkyl groups; and (b) (i) a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide; or (ii) a covalently bound radionuclide.

[0151] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide. In some embodiments, the radiopharmaceutical conjugate comprises a radionuclide bound to the metal chelating agent. In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide.

[0152] In one aspect, this paper describes a radiopharmaceutical conjugate having the following structure: , in Indicates a connector.

[0153] In some embodiments, the radiopharmaceutical conjugate comprises a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide. In some embodiments, the metal chelating agent is covalently linked to the peptide. In some embodiments, the conjugate further comprises a linker connecting the peptide to the metal chelating agent. In some embodiments, the linker covalently links the peptide to the metal chelating agent. In some embodiments, the linker covalently links the metal chelating agent to the N-terminus of the peptide. In some embodiments, the linker covalently links the metal chelating agent to the C-terminus of the peptide. In some embodiments, the linker is linked to the peptide via a non-terminal amino acid residue. In some embodiments, the linker is linked to amino acid X1. In some embodiments, the linker is linked to amino acid X2. In some embodiments, the linker is linked to amino acid X3. In some embodiments, the linker is linked to amino acid X4. In some embodiments, the linker is linked to amino acid X5. In some embodiments, the linker is linked to amino acid X6. In some embodiments, the linker is linked to amino acid X7. In some embodiments, the linker is linked to amino acid X8. In some embodiments, the linker is linked to amino acid X9. In some embodiments, the linker is linked to amino acid X10. In some embodiments, the linker is linked to amino acid X11. In some embodiments, the linker is linked to amino acid X12. In some embodiments, the linker is linked to amino acids X1, X2, X3, X4, X8, or X12. In some embodiments, the linker is linked to a lysine residue of the peptide. In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises a lysine residue, an alanine residue, a glycine residue, a D-phenylalanine residue, a histidine residue, a dAtb residue, or a D-glutamic acid residue. In some embodiments, the linker comprises two amino acids selected from the group consisting of lysine, alanine, glycine, D-phenylalanine, histidine, dAtb, and D-glutamic acid. In some embodiments, the linker is C... 1-6 Heteroalkyl groups. In some embodiments, the linker is a bond.

[0154] In one aspect, this paper describes a radiopharmaceutical conjugate having the following structure: in Indicates a connector; and R* represents a covalently bonded radionuclide.

[0155] In some embodiments, the radiopharmaceutical conjugate comprises a covalently bound radionuclide. In some embodiments, the conjugate further comprises a linker connecting the peptide to the covalently bound radionuclide. In some embodiments, the linker covalently links the peptide to the covalently bound radionuclide. In some embodiments, the linker covalently links the covalently bound radionuclide to the N-terminus of the peptide. In some embodiments, the linker covalently links the covalently bound radionuclide to the C-terminus of the peptide. In some embodiments, the linker is linked to the peptide via a non-terminal amino acid residue. In some embodiments, the linker is linked to amino acid X1. In some embodiments, the linker is linked to amino acid X2. In some embodiments, the linker is linked to amino acid X3. In some embodiments, the linker is linked to amino acid X4. In some embodiments, the linker is linked to amino acid X5. In some embodiments, the linker is linked to amino acid X6. In some embodiments, the linker is linked to amino acid X7. In some embodiments, the linker is linked to amino acid X8. In some embodiments, the linker is linked to amino acid X9. In some embodiments, the linker is linked to amino acid X10. In some embodiments, the linker is linked to amino acid X11. In some embodiments, the linker is linked to amino acid X12. In some embodiments, the covalently bound radionuclide is directly covalently bound to an amino acid containing an aromatic ring. In some embodiments, the covalently bound radionuclide is directly covalently bound to X5, X8, X9, X4, or X11. In some embodiments, the linker is a bond.

[0156] In some embodiments, a conjugate is described herein comprising: (a) a targeting portion comprising a monocyclic peptide or a pharmaceutically acceptable salt thereof having an affinity for phosphatidylinositol proteoglycan 3 (GPC3); and (b) (i) a metal chelator configured to bind to a radionuclide, wherein the metal chelator binds to the peptide, or (ii) a covalently bound radionuclide. In some embodiments, a conjugate is described herein comprising: a monocyclic peptide configured to bind to GPC3; and a metal chelator configured to bind to a radionuclide. In some embodiments, a conjugate is described herein comprising: a monocyclic peptide configured to bind to GPC3; and a covalently bound radionuclide. In some embodiments, the monocyclic peptide is cyclized via a non-disulfide bond. In some embodiments, the monocyclic peptide does not contain a disulfide bond. In some embodiments, the monocyclic peptide comprises 5 to 20 amino acid residues. In some embodiments, the monocyclic peptide comprises 7 to 14 amino acid residues. The conjugates described herein may further comprise a linker covalently linking a cyclic peptide to a metal chelating agent or a covalently radioactive nuclide. In some embodiments, the conjugate comprises a radioactive nuclide, such as one bound to a metal chelating agent. 225 Ac or binding to cyclic peptides 131 I.

[0157] In some embodiments, the conjugates described herein comprise two or more peptides (i.e., a first peptide, a second peptide, etc.). For example, the conjugate may comprise two distinct peptides configured to bind to the same target (e.g., GPC3) at the same or different binding sites. As another example, the conjugate may comprise two distinct peptides configured to bind to different targets (including GPC3). As yet another example, the conjugate may comprise two identical peptides.

[0158] In some embodiments, the conjugates described herein are in salt form. In some embodiments, the conjugates described herein are in free base form.

[0159] In some embodiments, the metal chelating agent binds to the peptide directly or indirectly through a linker. In some embodiments, the metal chelating agent binds to the peptide covalently or nonvalently.

[0160] In some embodiments, the conjugates of the present invention are selected from Tables 2, 3A to 3B, and 9. In some embodiments, the conjugates of the present invention comprise peptides from Table 1, chelating agents selected from Tables 4 to 22, and radionuclides from Table 7.

[0161] Radiopharmaceutical conjugates with GPC3 affinity Phosphatidylinositol proteoglycan-3 (GPC3) is a protein encoded by the GPC3 gene in humans. GPC3 may be upregulated in a variety of cancers and is often associated with disease progression, metastasis, and poor prognosis, such as in solid tumors like hepatocellular carcinoma, lung cancer, gastric cancer, and ovarian cancer.

[0162] GPC3 belongs to the heparin sulfate proteoglycan family and is anchored to the cell membrane surface via phosphatidylinositol (GPI) anchors.

[0163] GPC3 plays an important role in cell proliferation in embryonic tissues. GPC3 gene deletion may lead to excessive growth syndrome, also known as singobiasis (SGBS). GPC3 is expressed throughout the fetal period, and from birth to adulthood, it is not significantly expressed in normal tissues except for weak expression in the placenta, mammary gland, mesoderm, ovary, lung, and kidney tissues.

[0164] In some embodiments, the radiopharmaceutical conjugates of the present invention bind to GPC3. In some embodiments, the radiopharmaceutical conjugates have GPC3 antagonistic activity. In some embodiments, the radiopharmaceutical conjugates bind to human GPC3 (hGPC3) and have hGPC3 antagonistic activity, such as inhibiting the ability of GPC3 to promote or stabilize Wnt / Frizzled protein interactions and / or downstream signaling.

[0165] As used herein, the term “GPC3” refers to any form of GPC3 and its variants that retain at least a portion of GPC3 activity. Unless otherwise specifically described as human GPC3 (hGPC3), GPC3 includes all naturally occurring sequences of GPC3 in mammals such as humans, dogs, cats, horses, and cattle. An example of GPC3 is hGPC3 (gene ID: 2719), which is human GPC3 and is a protein having the following amino acid sequence (SEQ ID NO: 398, isotype 1, P51654-1): .

[0166] As used herein, the expressions "affinity for GPC3" or "binds to GPC3" indicate activity bound to GPC3. The binding site of the peptides of the present invention on GPC3 is not limited; the peptides may bind to any site on the GPC3 protein. Binding to GPC3 can be measured by any method used to measure known intermolecular binding. For example, in a non-limiting manner, this can be determined by competitive binding assays, such as surface plasma resonance (SPR) assays, scattering analysis and / or radioimmunoassay (RIA), enzyme immunoassay (EIA), and sandwich and competitive assays, and by any known suitable method, including different variations of the examples given in the art.

[0167] In one aspect, the binding affinity of the radiopharmaceutical conjugate of the present invention is up to 100 nM, as determined by Kd in surface plasma resonance (SPR) analysis. In some implementations, the Kd of the peptides of the radiopharmaceutical conjugates disclosed herein is 100 nM or less, 50 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.9 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.1 nM or less, 0.09 nM or less, 0.08 nM or less, 0.07 nM or less, 0.06 nM or less, 0.05 nM or less, 0.04 nM or less, 0.03 nM or less, 0.02 nM or less, or 0.01 nM or less.

[0168] In some embodiments, the binding affinity of the radiopharmaceutical conjugates described herein to human GPC3 is at most 1, 5, 10, 50, 100, 200, 500, 1000, 5000, or 10,000 nM, as determined by Kd in surface plasma resonance (SPR) analysis. In some embodiments, the binding affinity of the radiopharmaceutical conjugates described herein to human GPC3 is at most 100 nM, as determined by Kd in surface plasma resonance (SPR) analysis. In some embodiments, the binding affinity of the radiopharmaceutical conjugates described herein to human GPC3 is at most 1 nM, as determined by Kd in surface plasma resonance (SPR) analysis. In some embodiments, the binding affinity of the radiopharmaceutical conjugates described herein to human GPC3 is at most 2 nM, as determined by Kd in surface plasma resonance (SPR) analysis. In some embodiments, the radiopharmaceutical conjugates described herein have a binding affinity for human GPC3 of up to 5 nM, as determined by Kd in surface plasma resonance (SPR) analysis. In some embodiments, the radiopharmaceutical conjugates described herein have a binding affinity for human GPC3 of up to 10 nM, as determined by Kd in surface plasma resonance (SPR) analysis.

[0169] In one aspect, the binding affinity of the peptide or radiopharmaceutical conjugate of the present invention is up to 100 nM, as determined by Kd in surface plasma resonance (SPR) analysis. In some embodiments, the Kd of the peptide or radiopharmaceutical conjugate of the present invention is 100 nM or less, 50 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.9 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.1 nM or less, 0.09 nM or less, 0.08 nM or less, 0.07 nM or less, 0.06 nM or less, 0.05 nM or less, 0.04 nM or less, 0.03 nM or less, 0.02 nM or less, or 0.01 nM or less.

[0170] GPC3 peptide binding ligand In one aspect, the present invention relates to a radiopharmaceutical conjugate comprising a peptide (e.g., a binding peptide) having affinity for phosphatidylinositol proteoglycan-3 (GPC3). GPC3 may be mammalian GPC3. GPC3 may be human GPC3. GPC3 may be wild-type or mutant GPC3. In some embodiments, the conjugate of the present invention comprises two or more peptides, which may be the same or different. The peptide may be linear or cyclic. In some embodiments, the peptide is monocyclic. The peptide may contain any suitable number of amino acid residues. In some embodiments, the peptide contains 5 to 50, 6 to 40, 7 to 30, 8 to 25, 12 to 25, or 9 to 20 amino acid residues. In some embodiments, the peptide contains 5 to 14 amino acid residues. In some embodiments, the peptide contains 7 to 12 amino acid residues. In some embodiments, the peptide contains 8 to 12 amino acid residues. In some embodiments, the peptide contains 8 to 10 amino acid residues. In some embodiments, the peptide contains 7 to 13 amino acid residues. In some embodiments, the peptide comprises 12 to 15 amino acid residues. In some embodiments, the peptide comprises 13 to 14 amino acid residues. In some embodiments, the peptide comprises 6 amino acid residues. In some embodiments, the peptide comprises 7 amino acid residues. In some embodiments, the peptide comprises 8 amino acid residues. In some embodiments, the peptide comprises 9 amino acid residues. In some embodiments, the peptide comprises 10 amino acid residues. In some embodiments, the peptide comprises 11 amino acid residues. In some embodiments, the peptide comprises 12 amino acid residues. In some embodiments, the peptide comprises 13 amino acid residues. In some embodiments, the peptide comprises 14 amino acid residues. In some embodiments, the peptide comprises 15 amino acid residues. In some embodiments, the peptide comprises 16 amino acid residues. In some embodiments, the peptide consists of 6 amino acid residues. In some embodiments, the peptide consists of 7 amino acid residues. In some embodiments, the peptide consists of 8 amino acid residues. In some embodiments, the peptide consists of 9 amino acid residues. In some embodiments, the peptide consists of 10 amino acid residues. In some embodiments, the peptide consists of 11 amino acid residues. In some embodiments, the peptide consists of 12 amino acid residues. In some embodiments, the peptide consists of 13 amino acid residues. In some embodiments, the peptide consists of 14 amino acid residues. In some embodiments, the peptide consists of 15 amino acid residues. In some embodiments, the peptide consists of 16 amino acid residues. In some embodiments, the conjugate comprises a monocyclic peptide having 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. The peptide described herein may be a binding peptide that binds to GPC3. In some embodiments, the binding peptide consists of 6 to 20 amino acid residues. In some embodiments, the binding peptide consists of 7 to 12 amino acid residues.In some embodiments, the binding peptide consists of 10 to 12 amino acid residues. In some embodiments, the binding peptide consists of 8 to 12 amino acid residues. In some embodiments, the binding peptide is monocyclic. In some embodiments, the peptide of the present invention is an isolated peptide. In some embodiments, the peptide of the present invention is a purified peptide.

[0171] In one aspect, this document describes a radiopharmaceutical conjugate comprising: (a) A peptide with affinity for phosphatidylinositol proteoglycan 3 (GPC3) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an amino acid sequence including the deletion, substitution and / or addition of one or more (e.g., 1 to 6) amino acids from the amino acid sequence of SEQ ID NO: 1: MeK-MeI-D-MeQ-F4COO-IIY-MeNal27N-G-3Py6Ph-MeC (SEQ ID NO: 1), The peptide consists of 10 to 12 amino acid residues; and (b) (i) a metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide; or (ii) a covalently bound radionuclide.

[0172] In some embodiments, the metal chelating agent is configured to bind to a radionuclide, wherein the metal chelating agent binds to the peptide. In some embodiments, the radionuclide binds to the metal chelating agent. In some embodiments, the radionuclide is a covalently bound radionuclide.

[0173] In some embodiments, the peptide comprises an amino acid sequence including up to six deletions, substitutions, and / or additions of one or more amino acids from SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence including up to five deletions, substitutions, and / or additions of one or more amino acids from SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence including up to four deletions, substitutions, and / or additions of one or more amino acids from SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence including up to three deletions, substitutions, and / or additions of one or more amino acids from SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence including up to two deletions, substitutions, and / or additions of one or more amino acids from SEQ ID NO: 1. In some embodiments, the peptide comprises an amino acid sequence including up to one deletion, substitution, and / or addition of one or more amino acids from SEQ ID NO: 1. In some embodiments, the amino acid substitutions are conserved amino acid substitutions. The deletion, addition, or substitution may occur at the end or middle of the peptide. In some embodiments, MeI at position 2 is deleted from SEQ ID NO: 1. In some embodiments, D at position 3 is deleted from SEQ ID NO: 1. In some embodiments, the peptide of SEQ ID NO: 1 is a cyclic peptide. In some embodiments, the peptide is a monocyclic peptide. In some embodiments, 1, 2, 3, 4, or 5 amino acids are added to the peptide of SEQ ID NO: 1. In some embodiments, 1, 2, or 3 amino acids are added to the peptide of SEQ ID NO: 1. In some embodiments, 1 or 2 amino acids are added to the peptide of SEQ ID NO: 1. In some embodiments, 5 amino acids are added to the peptide of SEQ ID NO: 1. In some embodiments, 4 amino acids are added to the peptide of SEQ ID NO: 1. In some embodiments, 3 amino acids are added to the peptide of SEQ ID NO: 1. In some embodiments, 2 amino acids are added to the peptide of SEQ ID NO: 1. In some embodiments, 1 amino acid is added to the peptide of SEQ ID NO: 1. Amino acid addition may be made at the N-terminus, C-terminus, or middle of the peptide of SEQ ID NO: 1.

[0174] In one aspect, this document describes a peptide or a pharmaceutically acceptable salt thereof with affinity for phosphatidylinositol proteoglycan 3 (GPC3), wherein the peptide comprises the amino acid sequence of formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) in, X1 can be any amino acid; X2 may be absent or be any amino acid; X3 may be absent or be any amino acid; X4 can be any amino acid; X5 is an amino acid containing an aromatic ring (e.g., W, F, Y or variants thereof), an amino acid containing a cycloalkyl group, or an amino acid containing a heterocyclic alkyl group, or X5 is a peptide (e.g., Cha4cH, Cha4tH, Almor, Atp, Cha4cOMe). X6 is a hydrophobic amino acid, a hydrophilic amino acid, or a polar amino acid, wherein the polar amino acid has a substituted side chain. X7 is a hydrophobic amino acid containing C1-C8 alkyl, cycloalkyl, or heterocycloalkyl groups, wherein each of the alkyl, cycloalkyl, and heterocycloalkyl groups is independently and optionally substituted (e.g., X7 is I, Eva, alI, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe, or Cbg). X8 is A, I, L, V, Y, or F or a variant thereof; X9 is an N-alkylated amino acid containing an aromatic ring; X10 is a G, A, or D-amino acid (e.g., da, ds, de, or dp); X11 is an amino acid containing an aromatic ring (e.g., F, Y, or a variant thereof); and X12 is N-alkylated cysteine ​​(e.g., MeC).

[0175] In some embodiments, the peptide of formula (I) is a cyclic peptide. In some embodiments, the peptide is a monocyclic peptide.

[0176] In some embodiments, the peptide of formula (I) is a cyclic peptide. In some embodiments, the cyclic peptide of formula (I) has the structure of formula (I-1): Formula (I-1), in, R 1 Choose the group composed of -NH2 and -OH; R 2 C 1-3 alkyl; R 3 For optional one or more R 4 Replacement C 1-3 Alkylene; Each R 4 Independently for C 1-3 Alkyl or C 3-6 cycloalkyl; kxR is 1, 2, 3, 4, 5 or 6; X R Choose from groups consisting of -S-, -CH2-, or -O-; and Where X1 to X11 have the definitions described in equation (I).

[0177] In some embodiments, the peptide of formula (I-1) has the structure of formula (I-2): Formula (I-2) Where X1 to X11 have the definitions described in equation (I).

[0178] In some embodiments, the peptide of formula (I) is a cyclic peptide and X2 is absent. In some embodiments, the cyclic peptide of formula (I) has the structure of formula (I-3): Formula (I-3), in, R 1 Choose the group composed of -NH2 and -OH; R 2 C 1-3 alkyl; R 3 For optional one or more R 4 Replacement C 1-3 Alkylene; Each R 4 Independently for C 1-3 Alkyl or C 3-6 cycloalkyl; kxR is 1, 2, 3, 4, 5 or 6; X R Choose from groups consisting of -S-, -CH2-, or -O-; and Where X1 to X11 have the definitions described in equation (I).

[0179] In some embodiments, the peptide of formula (I-3) has the structure of formula (I-4): Formula (I-4) Where X1 to X11 have the definitions described in equation (I).

[0180] In some embodiments, the peptide of formula (I) has the structure of formula (I-5) or a pharmaceutically acceptable salt thereof: Formula (I-5) Wherein X1 to X12 have the definitions described in formula (I), and Lcyc is a closed-ring group covalently linked to X1 and X12. In some embodiments, Lcyc is a group selected from Table 4B. In some embodiments, Lcyc is formed by reacting a first functional group in Table 4C with a second functional group.

[0181] In one aspect, this document describes a radiopharmaceutical conjugate comprising: A peptide or a pharmaceutically acceptable salt thereof having an affinity for phosphatidylinositol proteoglycan 3 (GPC3), wherein the peptide comprises the amino acid sequence of formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 Formula (I) in, X1 can be any amino acid; X2 can be any amino acid; X3 can be any amino acid; X4 can be any amino acid; X5 is ,in: R n5 It is hydrogen or C 1-3 alkyl; Ring A5 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Each R X5 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)NR c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X5 -heterocyclic alkyl, -L X5 -cycloalkyl, -L X5 -Aryl or -L X5 - Heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally derived from one or more R... X5a Replace; or Two Rs X5 Together they form =O, =S, or =N(R) a ); L X5 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X5a replace; kx5 is 0, 1, 2 or 3; mx5 can be 0, 1, 2, 3, 4 or 5; *X4 indicates the connection point with X4; and *X6 indicates the connection point with X6; X6 is ,in: R n6 It is hydrogen or C 1-3 alkyl; R X6 C 1-6 Alkyl, C 1-6 Halogenated, C1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X6 -heterocyclic alkyl, -L X6 -cycloalkyl, -L X6 -Aryl or -L X6 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X6a Replace; or R n6 and R x6 Together with intermediary atoms, they form one or more optional R atoms. X6a Substituted 5- to 6-membered heterocyclic alkyl groups; L X6 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X6a replace; *X5 indicates the connection point with X5; and *X7 indicates the connection point with X7; X7 is ,in: R n7 It is hydrogen or C 1-3 alkyl; R X7 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, heteroalkyl, alkenyl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R groups. X7a replace; *X6 indicates the connection point with X6; and *X8 indicates the connection point with X8; X8 is ,in: R n8 It is hydrogen or C 1-3 alkyl; Ring A8 is aryl or heteroaryl; Each R X8 Independently for C 1-6 Alkyl, C1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X8 -heterocyclic alkyl, -L X8 -cycloalkyl, -L X8 -Aryl or -L X8 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X8a Replace; or Two Rs X8 Together they form =O, =S, or =N(R) a ); L X8 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X8a replace; kx8 is 0, 1, 2, or 3; mx8 can be 0, 1, 2, 3, 4 or 5; *X7 indicates the connection point with X7; and *X9 indicates the connection point with X9; X9 is ,in: R n9 It is hydrogen or C 1-3 alkyl; Ring A9 is aryl or heteroaryl; Each R X9 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5 or -NR c R d The alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally derived from one or more R groups. X9a Replace; or Two Rs X9 Together they form =O, =S, or =N(R) a ); kx9 is 0, 1, 2, or 3; mx9 can be 0, 1, 2, 3, 4 or 5; *X8 indicates the connection point with X8; and *X10 indicates the connection point with X10; X10 is glycine or a D-amino acid (e.g., da, ds, de, or dp); X11 is ,in: R n11 It is hydrogen or C 1-3 alkyl; Ring A11 is aryl or heteroaryl; Each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X11 -heterocyclic alkyl, -L X11 -cycloalkyl, -L X11 -Aryl or -L X11 -heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X11a Replace; or Two Rs X11 Together they form =O, =S, or =N(R) a ); L X11 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X11a replace; kx11 is 0, 1, 2, 3, 4 or 5; mx11 can be 0, 1, 2, 3, 4 or 5; *X10 indicates the connection point with X10; and *X12 indicates the connection point with X12; X12 is N-alkylated cysteine; R X5a R X6a R X7a R X8a R X9a and R X11a Each independently constitutes a halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d-NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; Each R a Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is independently optionally etched with one or more R... e replace; Each R e Independently, it can be halogen, -CN, -OH, -O-C1-C6 alkyl, -SF5, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=NH)NH 2. -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, C1-C6 alkyl-C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; or two R e Together they form = O; and Each R c and R dIndependently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is independently optionally etched with one or more R... e Replace; or R c and R d Together with the atoms they are attached to, they form one or more optional R... e Substituted heterocyclic alkyl groups.

[0182] In some embodiments of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X1 is an N-methylated amino acid. In some embodiments, X1 is an N-methylated amino acid (e.g., MeK, MeQ, or variants thereof) containing a polar side chain.

[0183] In some formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1) or (IV-2) In embodiments, X1 is I, R, Cit, F4G, 4Py, 3Py, KCOpipzaa, V, Eva, Q, E, Mel, Ahp, F4COO, KCOpip 4COO, MeQdMe, MeA, MeSMe, MeG, MeV, MeHseMe, Aib, MeT, alI, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe, MeDapCOpipzaa, MeK, MeKAc, MeK(de), MeK(H), MeK(df) or MeK(datb). In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X1 is a substituted I, R, Cit, F4G, 4Py, 3Py, KCOpipzaa, V, Eva, Q, E, MeI, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeV, MeHseMe, Aib, MeT, a1I, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe, MeDapCOpipzaa, MeK, MeKAc, MeK(de), MeK(H), MeK(df), or MeK(datb). In some embodiments, X1 is a substituted I. In some embodiments, X1 is a substituted R. In some embodiments, X1 is optionally substituted Cit. In some embodiments, X1 is optionally substituted F4G. In some embodiments, X1 is optionally substituted 4Py. In some embodiments, X1 is optionally substituted 3Py. In some embodiments, X1 is optionally substituted KCOpipzaa. In some embodiments, X1 is optionally substituted V. In some embodiments, X1 is optionally substituted Eva. In some embodiments, X1 is optionally substituted Q. In some embodiments, X1 is optionally substituted E. In some embodiments, X1 is optionally substituted MeI. In some embodiments, X1 is optionally substituted Ahp. In some embodiments, X1 is optionally substituted F4COO. In some embodiments, X1 is optionally substituted KCOpip4COO. In some embodiments, X1 is optionally substituted MeQdMe. In some embodiments, X1 is optionally substituted MeA. In some embodiments, X1 is optionally substituted MeSMe. In some implementations, X1 is an optional substituted MeG.In some embodiments, X1 is optionally substituted MeV. In some embodiments, X1 is optionally substituted MeHseMe. In some embodiments, X1 is optionally substituted Aib. In some embodiments, X1 is optionally substituted MeT. In some embodiments, X1 is optionally substituted a1I. In some embodiments, X1 is optionally substituted TMe. In some embodiments, X1 is optionally substituted MeKCOpipzaa. In some embodiments, X1 is optionally substituted MeQ. In some embodiments, X1 is optionally substituted Hpr. In some embodiments, X1 is optionally substituted MeTMe. In some embodiments, X1 is optionally substituted MeDapCOpipzaa. In some embodiments, X1 is optionally substituted MeK. In some embodiments, X1 is optionally substituted MeKAc. In some embodiments, X1 is optionally substituted MeK(de). In some embodiments, X1 is optionally substituted MeK(H). In some embodiments, X1 is optionally substituted MeK(df). In some embodiments, X1 is optionally substituted MeK(datb). In some embodiments, X1 is MeQ or a derivative thereof. In some embodiments, X1 is MeK or a derivative thereof.

[0184] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X1 is any amino acid. In some embodiments, X1 is a D-amino acid. In some embodiments, X1 is an L-amino acid. In some embodiments, X1 is an N-alkylated amino acid. In some embodiments, X1 is an N-methylated amino acid. In some embodiments, X1 does not contain a cyclic group. In some embodiments, X1 contains a cyclic group. In some embodiments, X1 contains a 5- to 6-membered heterocyclic alkyl group. In some embodiments, X1 contains a 5- to 6-membered heteroaryl group. In some embodiments, X1 contains a phenyl group. In some embodiments, X1 is a peptide-like substance.

[0185] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X1 has the following structure: or in: R n1 It is hydrogen or C 1-3 alkyl; R X1 For hydrogen, C1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X1 -heterocyclic alkyl, -L X1 -cycloalkyl, -L X1 -Aryl or -L X1 - Heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X1a replace; R X1' It is hydrogen or C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X1a Replace; or R n1 and R X1' Together with intermediary atoms, they form one or more optional R atoms. X1a Substituted 5- to 6-membered heterocyclic alkyl groups; L X1 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X1a replace; Each R X1a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR aS(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X12 indicates the connection point with X12, or *X12 indicates the connection point with C(O)(CH2). kxR The connection points (e.g., in equations (I-1) and (I-2); *X2 represents the connection point with X2; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0186] In some implementations, X1 has the following structure: In some implementations, X1 has the following structure: .

[0187] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X1 has the following structure: , in: R n1 It can be hydrogen or methyl; R X1For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X1 -5 to 6-membered heterocyclic alkyl groups, -L X1 -C 4-6 cycloalkyl, -L X1 -C 6-10 Aryl or -L X1 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X1a replace; R X1' It is hydrogen or methyl; or R n1 and R X1' Together with intermediary atoms, they form one or more optional R atoms. X1a Substituted 5- to 6-membered heterocyclic alkyl groups; L X1 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X1a replace; Each R X1a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a-OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X12 indicates the connection point with X12, or *X12 indicates the connection point with C(O)(CH2). kxR The connection points (e.g., in equations (I-1) and (I-2); *X2 represents the connection point with X2; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0188] In some implementation schemes, R n1 It is hydrogen. In some implementations, R n1 C 1-3 Alkyl group. In some embodiments, R n1 It is a methyl group.

[0189] In some implementation schemes, R X1 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X1 -heterocyclic alkyl, -L X1 -cycloalkyl, -L X1 -Aryl or -LX1 - Heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X1a replace.

[0190] In some implementation schemes, R X1 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X1 -5 to 6-membered heterocyclic alkyl groups, -L X1 -C 4-6 cycloalkyl, -L X1 -C 6-10 Aryl or -L X1 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X1a Replacement. In some implementations, R X1 For hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -L X1 -piperidinyl, -L X1 -piperazinyl, -L X1 -phenyl or -L X1 -pyridyl, wherein the alkyl, heteroalkyl, phenyl, pyridyl, piperidyl, and piperazine group are each optionally denoted by one or more R- groups. X1a replace.

[0191] In some implementation schemes, R X1 It is hydrogen. In some implementations, R X1 For optional replaced C 1-6 Alkyl group. In some embodiments, R X1 For optional one or more R X1a Replacement C 1-6 Alkyl group. In some embodiments, R X1 For optional replaced C 1-6 Heteroalkyl. In some embodiments, R X1 For optional one or more R X1a Replacement C 1-6 Heteroalkyl. In some embodiments, R X1 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 1-6Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 Each of the heteroalkyl groups is optionally hydroxylated by one or more R X1a Replacement. In some implementations, R X1 C 1-6 Aminoalkyl. In some embodiments, R X1 -(CH) 1-6 NH2. In some implementations, R X1 It is -(CH)4NH2. In some implementations, R X1 C 2-6 alkenyl or C 2-6 alkynyl group, wherein the C 2-6 alkenyl or C 2-6 Each of the alkynyl groups is optionally etherified by one or more R groups. X1a Replacement. In some implementations, R X1 It is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is optionally derived from one or more R groups. X1a Replacement. In some implementations, R X1 It is an aryl or heteroaryl group, wherein each of the aryl or heteroaryl groups is optionally derived from one or more R groups. X1a Replacement. In some implementations, R X1 It is a cycloalkyl or heterocycloalkyl group, wherein each of the cycloalkyl or heterocycloalkyl groups is optionally derived from one or more R groups. X1a Replacement. In some implementations, R X1 -L X1 -heterocyclic alkyl, -L X1 -cycloalkyl, -L X1 -Aryl or -L X1 -Heteroaryl, wherein the -L X1 -heterocyclic alkyl, -L X1 -cycloalkyl, -L X1 -Aryl or -L X1 - Each of the heteroaryl groups is selected from one or more R... X1a Replacement. In some implementations, R X1 For optional one or more R X1a Replacement -L X1 - Heterocyclic alkyl. In some embodiments, R X1 For optional one or more R X1a Replacement -L X1 -Cycloalkyl. In some embodiments, R X1 For optional one or more R X1a Replacement -L X1 -Aryl. In some implementations, R X1 For optional one or more RX1a Replacement -L X1 - Mixed aromatic compounds.

[0192] In some implementation schemes, R X1' It is hydrogen. In some implementations, R X1' C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X1a Replacement. In some implementations, R X1' C 1-6 Alkyl group. In some embodiments, R X1' It is a methyl group.

[0193] In some implementation schemes, R n1 and R X1' Together with intermediary atoms, they form one or more optional R atoms. X1a Substituted 5- to 6-membered heterocyclic alkyl groups.

[0194] In some implementations, L X1 C 1-6 Alkylene, wherein the alkylene is optionally derived from one or more R... X1a Replacement. In some implementations, L X1 C 1-6 Alkylene. In some embodiments, L X1 C 1-6 Heteroalkylene, wherein the heteroalkylene is optionally derived from one or more R... X1a Replacement. In some implementations, L X1 C 1-6 Heteroalkyl groups. In some embodiments, L X1 For -O-. In some implementations, L X1 For -S-. In some implementations, L X1 For -NR a - In some implementations, L X1 It is -NH-.

[0195] In some implementation schemes, each R X1a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NRa S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0196] In some implementation schemes, each R X1a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NRc R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0197] In some implementation schemes, each R X1a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, OH, -CN, -NO2, NH2, -C(=O)R a -C(=O)OR a -NR a C(=O)NR c R d Or oxygenation.

[0198] In some implementation schemes, R n1 For methyl, R X1' It is hydrogen, and R X1 C 1-6 Aminoalkyl. In some embodiments, R n1 It is methyl, R X1' It is hydrogen, and R X1 C 3-6 Aminoalkyl. In some embodiments, R n1 For methyl, R X1' It is hydrogen, and R X1 C 3-6 Alkyl group, wherein the alkyl group is substituted with an amino group.

[0199] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X2 is absent or is an L-amino acid. In some embodiments, X2 is absent. In some embodiments, X2 is an L-amino acid. In some embodiments, X2 is an N-methylated amino acid.

[0200] In some embodiments of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1) or (IV-2), X2 is I, K, Cit, F4G, 4Py, 3Py, KCOpipzetOH, V, KCOpipzaa, Eva, Q, E, S, A hp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeI, MeV, MeL, HseMe, MeY, Me3Py, MeHseMe, MeKAc, alI, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe or MeDapCOpipzaaa. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X2 is I, K, Cit, F4G, 4Py, 3Py, KCOpipzetOH, V, KCOpipzaa, Eva, Q, E, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeI, MeV, MeHseMe, MeKAc, alI, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe, or MeDapCOpipzaaa. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X2 is a substituted I, K, Cit, F4G, 4Py, 3Py, KCOpipzetOH, V, KCOpipzaa, Eva, Q, E, S, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeI, MeV, MeL, HseMe, MeY, Me3Py, MeHseMe, MeKAc, a1I, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe, or MeDapCOpipzaaa. In some embodiments, X2 is a substituted I. In some embodiments, X2 is a substituted K. In some embodiments, X2 is a substituted Cit. In some embodiments, X2 is optionally substituted F4G. In some embodiments, X2 is optionally substituted 4Py. In some embodiments, X2 is optionally substituted 3Py. In some embodiments, X2 is optionally substituted KCOpipzetOH. In some embodiments, X2 is optionally substituted V. In some embodiments, X2 is optionally substituted KCOpipzaa.In some embodiments, X2 is optionally substituted Eva. In some embodiments, X2 is optionally substituted Q. In some embodiments, X2 is optionally substituted E. In some embodiments, X2 is optionally substituted S. In some embodiments, X2 is optionally substituted MeL. In some embodiments, X2 is optionally substituted HseMe. In some embodiments, X2 is optionally substituted MeY. In some embodiments, X2 is optionally substituted Me3Py. In some embodiments, X2 is optionally substituted Ahp. In some embodiments, X2 is optionally substituted F4COO. In some embodiments, X2 is optionally substituted KCOpip4COO. In some embodiments, X2 is optionally substituted MeQdMe. In some embodiments, X2 is optionally substituted MeA. In some embodiments, X2 is optionally substituted MeSMe. In some embodiments, X2 is optionally substituted MeG. In some embodiments, X2 is optionally substituted MeI. In some embodiments, X2 is optionally substituted MeV. In some embodiments, X2 is optionally substituted MeHseMe. In some embodiments, X2 is optionally substituted MeKAc. In some embodiments, X2 is optionally substituted a1I. In some embodiments, X2 is optionally substituted TMe. In some embodiments, X2 is optionally substituted MeKCOpipzaa. In some embodiments, X2 is optionally substituted MeQ. In some embodiments, X2 is optionally substituted Hpr. In some embodiments, X2 is optionally substituted MeTMe. In some embodiments, X2 is optionally substituted. In some embodiments, X2 is optionally substituted MeDapCOpipzaaa.

[0201] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X2 is any amino acid. In some embodiments, X2 is a D-amino acid. In some embodiments, X2 is an L-amino acid. In some embodiments, X2 is an N-alkylated amino acid. In some embodiments, X2 is an N-methylated amino acid. In some embodiments, X2 does not contain a cyclic group. In some embodiments, X2 contains a cyclic group. In some embodiments, X2 contains a 5- to 6-membered heterocyclic alkyl group. In some embodiments, X2 contains a 5- to 6-membered heteroaryl group. In some embodiments, X2 contains a phenyl group. In some embodiments, X2 is a peptide-like substance.

[0202] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X2 has the following structure: , in, R n2 It is hydrogen or C 1-3 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X2a replace; R X2 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X2 -heterocyclic alkyl, -L X2 -cycloalkyl, -L X2 -Aryl or -L X2 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X2a replace; R X2' It is hydrogen or C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X2a Replace; or R n2 and R X2' Together with intermediary atoms, they form one or more optional R atoms. X2a Substituted 5- to 6-membered heterocyclic alkyl groups; L X2 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X2a replace; Each R X2a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a-S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X1 represents the connection point with X1; *X3 represents the connection point with X3; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0203] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X2 has the following structure: , in: R n2 It can be hydrogen or methyl; R X2 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X2 -5 to 6-membered heterocyclic alkyl groups, -L X2 -C 4-6 cycloalkyl, -L X2 -C 6-10 Aryl or -L X2 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X2a replace; R X2' It is hydrogen or methyl; or R n2 and R X2' Together with intermediary atoms, they form one or more optional R atoms. X2a Substituted 5- to 6-membered heterocyclic alkyl groups; L X2 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X2a replace; Each R X2a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a)2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X1 represents the connection point with X1; *X3 represents the connection point with X3; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0204] In some implementation schemes, R n2 It is hydrogen. In some implementations, R n2 C 1-3 Alkyl group. In some embodiments, R n2 It is a methyl group.

[0205] In some implementation schemes, R X2 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X2 -heterocyclic alkyl, -L X2 -cycloalkyl, -LX2 -Aryl or -L X2 - Heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X2a replace.

[0206] In some implementation schemes, R X2 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X2 -5 to 6-membered heterocyclic alkyl groups, -L X2 -C 4-6 cycloalkyl, -L X2 -C 6-10 Aryl or -L X2 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X2a Replacement. In some implementations, R X2 For hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -L X2 -piperidinyl, L X2 -piperazinyl, -L X2 -phenyl or -L X2 -pyridyl, wherein the alkyl, heteroalkyl, phenyl, pyridyl, piperidyl, and piperazine group are each optionally denoted by one or more R- groups. X2a replace.

[0207] In some implementation schemes, R X2 It is hydrogen. In some implementations, R X2 For optional replaced C 1-6 Alkyl group. In some embodiments, R X2 For optional one or more R X2a Replacement C 1-6 Alkyl group. In some embodiments, R X2 For optional replaced C 1-6 Heteroalkyl. In some embodiments, R X2 For optional one or more R X2a Replacement C 1-6 Heteroalkyl. In some embodiments, R X2 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 Heteroalkyl, wherein the C 1-6Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 Each of the heteroalkyl groups is optionally hydroxylated by one or more R X2a Replacement. In some implementations, R X2 C 2-6 alkenyl or C 2-6 alkynyl group, wherein the C 2-6 alkenyl or C 2-6 Each of the alkynyl groups is optionally etherified by one or more R groups. X2a Replacement. In some implementations, R X2 It is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is optionally derived from one or more R groups. X2a Replacement. In some implementations, R X2 It is an aryl or heteroaryl group, wherein each of the aryl or heteroaryl groups is optionally derived from one or more R groups. X2a Replacement. In some implementations, R X2 It is a cycloalkyl or heterocycloalkyl group, wherein each of the cycloalkyl or heterocycloalkyl groups is optionally derived from one or more R groups. X2a Replacement. In some implementations, R X2 -L X2 -heterocyclic alkyl, -L X2 -cycloalkyl, -L X2 -Aryl or -L X2 -Heteroaryl, wherein the -L X2 -heterocyclic alkyl, -L X2 -cycloalkyl, -L X2 -Aryl or -L X2 - Each of the heteroaryl groups is selected from one or more R... X2a Replacement. In some implementations, R X2 For optional one or more R X2a Replacement -L X2 - Heterocyclic alkyl. In some embodiments, R X2 For optional one or more R X2a Replacement -L X2 -Cycloalkyl. In some embodiments, R X2 For optional one or more R X2a Replacement -L X2 -Aryl. In some implementations, R X2 For optional one or more R X2a Replacement -L X2 - Mixed aromatic compounds.

[0208] In some implementation schemes, R X2' It is hydrogen. In some implementations, R X2'C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X2a Replacement. In some implementations, R X2' C 1-6 Alkyl group. In some embodiments, R X2' It is a methyl group.

[0209] In some implementation schemes, R n2 and R X2' Together with intermediary atoms, they form one or more optional R atoms. X2a Substituted 5- to 6-membered heterocyclic alkyl groups.

[0210] In some implementations, L X2 C 1-6 Alkylene, wherein the alkylene is optionally derived from one or more R... X2a Replacement. In some implementations, L X2 C 1-6 Alkylene. In some embodiments, L X2 C 1-6 Heteroalkylene, wherein the heteroalkylene is optionally derived from one or more R... X2a Replacement. In some implementations, L X2 C 1-6 Heteroalkyl groups. In some embodiments, L X2 For -O-. In some implementations, L X2 For -S-. In some implementations, L X2 For -NR a - In some implementations, L X2 It is -NH-.

[0211] In some implementation schemes, each R X2a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a-OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0212] In some implementation schemes, each R X2a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0213] In some implementation schemes, each R X2aIndependently for C 1-6 Alkyl, C 1-6 Alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, OH, -CN, -NO2, NH2, -C(=O)R a -C(=O)OR a -NR a C(=O)NR c R d Or oxygenation.

[0214] In some implementation schemes, R n2 For methyl, R X2' It is hydrogen, and R X2 C 1-6 Alkyl group. In some embodiments, R n2 For methyl, R X2' It is hydrogen, and R X2 For branch chain C 1-6 Alkyl group. In some embodiments, R n2 For methyl, R X2' It is hydrogen, and R X2 For branch chain C 3-6 Alkyl group. In some embodiments, R X2 It is -CH(CH3)CH2CH3.

[0215] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X3 is a polar and / or L-amino acid. In some embodiments, X3 is an amino acid containing a hydrophilic side chain (e.g., D, K, Q, or variants thereof) or an N-methylated variant thereof. In some embodiments, X3 is absent.

[0216] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X3 is D, Har, KCOpipzetOH, Cit, KCO meglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, KAc, Hgn, MeY, or DapCOpipzaa. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X3 is optionally substituted D, Har, KCOpipzetOH, Cit, KCO meglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, KAc, Hgn, MeY, or DapCOpipzaa. In some embodiments, X3 is optionally substituted D. In some embodiments, X3 is optionally substituted Har. In some embodiments, X3 is optionally substituted KCOpipzetOH. In some embodiments, X3 is optionally substituted Cit. In some embodiments, X3 is optionally substituted KCO meglumine. In some embodiments, X3 is optionally substituted KCOpipzaa. In some embodiments, X3 is optionally substituted A4paa. In some embodiments, X3 is optionally substituted Q. In some embodiments, X3 is optionally substituted A. In some embodiments, X3 is optionally substituted E. In some embodiments, X3 is optionally substituted MeD. In some embodiments, X3 is optionally substituted S. In some embodiments, X3 is optionally substituted N. In some embodiments, X3 is optionally substituted Hgl. In some embodiments, X3 is optionally substituted F4COO. In some embodiments, X3 is optionally substituted KCOpip4COO. In some embodiments, X3 is optionally substituted KAc. In some embodiments, X3 is optionally substituted Hgn. In some embodiments, X3 is optionally substituted MeY. In some embodiments, X3 is optionally substituted DapCOpipzaa.

[0217] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X3 is any amino acid. In some embodiments, X3 is a D-amino acid. In some embodiments, X3 is an L-amino acid. In some embodiments, X3 is an N-alkylated amino acid. In some embodiments, X3 is an N-methylated amino acid. In some embodiments, X3 does not contain a cyclic group. In some embodiments, X3 contains a cyclic group. In some embodiments, X3 contains a 5- to 6-membered heterocyclic alkyl group. In some embodiments, X3 contains a 5- to 6-membered heteroaryl group. In some embodiments, X3 contains a phenyl group. In some embodiments, X3 is a peptide-like substance. In some embodiments, X3 is a polar amino acid.

[0218] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X3 has the following structure: , in: R n3 It is hydrogen or C 1-3 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X3a replace; R X3 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X3 -heterocyclic alkyl, -L X3 -cycloalkyl, -L X3 -Aryl or -L X3 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X3a replace; R X3' It is hydrogen or C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X3a Replace; or R n3 and R X3' Together with intermediary atoms, they form one or more optional R atoms. X3a Substituted 5- to 6-membered heterocyclic alkyl groups; LX3 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X3a replace; Each R X3a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X2 represents the connection point with X2; *X4 indicates the connection point with X4; Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0219] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X3 has the following structure: , in: R n3 It can be hydrogen or methyl; R X3 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X3 -5 to 6-membered heterocyclic alkyl groups, -L X3 -C 3-6 cycloalkyl, -L X3 -C 6-10 Aryl or -L X3 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X3a replace; L X3 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X3a replace; Each R X3a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a-SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X2 represents the connection point with X2; *X4 indicates the connection point with X4; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0220] In some implementation schemes, R n3 It is hydrogen. In some implementations, R n3 C 1-3 Alkyl group. In some embodiments, R n3 It is a methyl group.

[0221] In some implementation schemes, R X3 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X3 -heterocyclic alkyl, -L X3 -cycloalkyl, -L X3 -Aryl or -L X3 - Heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X3a Replacement. In some implementations, R X3 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X3 -5 to 6-membered heterocyclic alkyl groups, -L X3 -C 3-6 cycloalkyl, -L X3 -C 6-10 Aryl or -L X3 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X3a replace.

[0222] In some implementation schemes, R X3 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X3 -5 to 6-membered heterocyclic alkyl groups, -L X3 -C 4-6 cycloalkyl, -L X3 -C 6-10 Aryl or -L X3 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X3a Replacement. In some implementations, R X3 For hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -L X3 -piperidinyl, L X3-piperazinyl, -L X3 -phenyl or -L X3 -pyridyl, wherein the alkyl, heteroalkyl, phenyl, pyridyl, piperidyl, and piperazine group are each optionally denoted by one or more R- groups. X3a replace.

[0223] In some implementation schemes, R X3 It is hydrogen. In some implementations, R X3 For optional replaced C 1-6 Alkyl group. In some embodiments, R X3 For optional one or more R X3a Replacement C 1-6 Alkyl group. In some embodiments, R X3 For optional replaced C 1-6 Heteroalkyl. In some embodiments, R X3 For optional one or more R X3a Replacement C 1-6 Heteroalkyl. In some embodiments, R X3 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 Each of the heteroalkyl groups is optionally hydroxylated by one or more R X3a Replacement. In some implementations, R X3 C 2-6 alkenyl or C 2-6 alkynyl group, wherein the C 2-6 alkenyl or C 2-6 Each of the alkynyl groups is optionally etherified by one or more R groups. X3a Replacement. In some implementations, R X3 It is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is optionally derived from one or more R groups. X3a Replacement. In some implementations, R X3 It is an aryl or heteroaryl group, wherein each of the aryl or heteroaryl groups is optionally derived from one or more R groups. X3a Replacement. In some implementations, R X3 It is a cycloalkyl or heterocycloalkyl group, wherein each of the cycloalkyl or heterocycloalkyl groups is optionally derived from one or more R groups. X3a Replacement. In some implementations, R X3 -L X3 -heterocyclic alkyl, -LX3 -cycloalkyl, -L X3 -Aryl or -L X3 -Heteroaryl, wherein the -L X3 -heterocyclic alkyl, -L X3 -cycloalkyl, -L X3 -Aryl or -L X3 - Each of the heteroaryl groups is selected from one or more R... X3a Replacement. In some implementations, R X3 For optional one or more R X3a Replacement -L X3 - Heterocyclic alkyl. In some embodiments, R X3 For optional one or more R X3a Replacement -L X3 -Cycloalkyl. In some embodiments, R X3 For optional one or more R X3a Replacement -L X3 -Aryl. In some implementations, R X3 For optional one or more R X3a Replacement -L X3 - Mixed aromatic compounds.

[0224] In some implementation schemes, R X3' It is hydrogen. In some implementations, R X3' C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X3a Replacement. In some implementations, R X3' C 1-6 Alkyl group. In some embodiments, R X3' It is a methyl group.

[0225] In some implementation schemes, R n3 and R X3' Together with intermediary atoms, they form one or more optional R atoms. X3a Substituted 5- to 6-membered heterocyclic alkyl groups.

[0226] In some implementations, L X3 C 1-6 Alkylene, wherein the alkylene is optionally derived from one or more R... X3a Replacement. In some implementations, L X3 C 1-6 Alkylene. In some embodiments, L X3 C 1-6 Heteroalkylene, wherein the heteroalkylene is optionally derived from one or more R... X3a Replacement. In some implementations, L X3 C 1-6 Heteroalkyl groups. In some embodiments, LX3 For -O-. In some implementations, L X3 For -S-. In some implementations, L X3 For -NR a - In some implementations, L X3 It is -NH-.

[0227] In some implementation schemes, each R X3a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0228] In some implementation schemes, each R X3a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a-S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0229] In some implementation schemes, each R X3a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, OH, -CN, -NO2, NH2, -C(=O)R a -C(=O)OR a -NR a C(=O)NR c R d Or oxygenation.

[0230] In some implementation schemes, R n3 For hydrogen, R X3' It is hydrogen, and R X3 For optional one or more R X3a Replacement C 1-6 Alkyl group. In some embodiments, R n3 For hydrogen, R X3' It is hydrogen, and R X3 For optional one or more R X3a Replacement C 1-3 Alkyl group. In some embodiments, R n3 For hydrogen, R X3' It is hydrogen, and R X3 C substituted with -COOH 1-3alkyl.

[0231] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X4 is a polar and / or L-amino acid. In some embodiments, X4 is an N-methylated amino acid, a polar amino acid (e.g., D, K, Q, S, or variants thereof), or a peptide-like substance (e.g., EtG, MeeG, CmG, CmpG, CrmG, CeG, or CrpG).

[0232] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X4 is D, Har, KCOpipzetOH, KCO meglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, dd, MeQ, MeQdMe, MeA, MeSMe, MeG, EtG, MeeG, CmG, CmpG, CrmG, CeG, CrpG, MeK, MeKAc, MeHgl, Hgn, MeDapCOpipzaa, MeKCOpipzaa, Medd, Cit, MeCit, MeN, MeS, MeE, MeY, W5N, or MeA4paa. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X4 is optionally substituted D, Har, KCOpipzetOH, KCO meglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, dd, MeQ, MeQdMe, MeA, MeSMe, MeG, EtG, MeeG, CmG, CmpG, CrmG, CeG, CrpG, MeK, MeKAc, MeHgl, Hgn, MeDapCOpipzaa, MeKCOpipzaa, Medd, Cit, MeCit, MeN, MeS, MeE, MeY, W5N, or MeA4paa. In some embodiments, X4 is optionally substituted D. In some embodiments, X4 is optionally substituted Har. In some embodiments, X4 is optionally substituted KCOpipzetOH. In some embodiments, X4 is optionally substituted KCO meglumine. In some embodiments, X4 is optionally substituted KCOpipzaa. In some embodiments, X4 is optionally substituted A4paa. In some embodiments, X4 is optionally substituted Q. In some embodiments, X4 is optionally substituted A. In some embodiments, X4 is optionally substituted E. In some embodiments, X4 is optionally substituted MeD. In some embodiments, X4 is optionally substituted S. In some embodiments, X4 is optionally substituted N. In some embodiments, X4 is optionally substituted Hgl. In some embodiments, X4 is optionally substituted F4COO. In some embodiments, X4 is optionally substituted KCOpip4COO. In some embodiments, X4 is optionally substituted dd. In some embodiments, X4 is optionally substituted MeQ.In some embodiments, X4 is optionally substituted MeQdMe. In some embodiments, X4 is optionally substituted MeA. In some embodiments, X4 is optionally substituted MeSMe. In some embodiments, X4 is optionally substituted MeG. In some embodiments, X4 is optionally substituted EtG. In some embodiments, X4 is optionally substituted MeeG. In some embodiments, X4 is optionally substituted CmG. In some embodiments, X4 is optionally substituted CmpG. In some embodiments, X4 is optionally substituted CrmG. In some embodiments, X4 is optionally substituted CeG. In some embodiments, X4 is optionally substituted CrpG. In some embodiments, X4 is optionally substituted MeK. In some embodiments, X4 is optionally substituted MeKAc. In some embodiments, X4 is optionally substituted MeHgl. In some embodiments, X4 is optionally substituted Hgn. In some embodiments, X4 is optionally substituted MeDapCOpipzaa. In some embodiments, X4 is optionally substituted MeKCOpipzaa. In some embodiments, X4 is optionally substituted Medd. In some embodiments, X4 is optionally substituted Cit. In some embodiments, X4 is optionally substituted MeCit. In some embodiments, X4 is optionally substituted MeN. In some embodiments, X4 is optionally substituted MeS. In some embodiments, X4 is optionally substituted MeE. In some embodiments, X4 is optionally substituted MeY. In some embodiments, X4 is optionally substituted W5N. In some embodiments, X4 is optionally substituted MeA4paa.

[0233] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X4 is any amino acid. In some embodiments, X4 is a D-amino acid. In some embodiments, X4 is an L-amino acid. In some embodiments, X4 is an N-alkylated amino acid. In some embodiments, X4 is an N-methylated amino acid. In some embodiments, X4 does not contain a cyclic group. In some embodiments, X4 contains a cyclic group. In some embodiments, X4 contains a 5- to 6-membered heterocyclic alkyl group. In some embodiments, X4 contains a 5- to 6-membered heteroaryl group. In some embodiments, X4 contains a phenyl group. In some embodiments, X4 is a peptide-like substance. In some embodiments, X4 is a polar amino acid.

[0234] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X4 has the following structure: , in: R n4 It is hydrogen or C 1-3 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X4a replace; R X4 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X4 -heterocyclic alkyl, -L X4 -cycloalkyl, -L X4 -Aryl or -L X4 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X4a replace; R X4' It is hydrogen or C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X4a Replace; or R n4 and R X4' Together with intermediary atoms, they form one or more optional R atoms. X4a Substituted 5- to 6-membered heterocyclic alkyl groups; L X4 C 1-6 Alkylene or C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X4a replace; Each R X4a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a-S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X3 represents the connection point with X3; *X5 indicates the connection point with X5; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0235] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X4 has the following structure: , in: R n4 It is hydrogen or C 1-3 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X4a replace; R X4 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X4 -5 to 6-membered heterocyclic alkyl groups, -L X4 -C 3-6 cycloalkyl, -L X4 -C 6-10 Aryl or -L X4 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X4a replace; L X4 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X4a replace; Each R X4a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a-C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X3 represents the connection point with X3; *X5 indicates the connection point with X5; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0236] In some implementation schemes, R n4 It is hydrogen. In some implementations, R n4 C 1-3 Alkyl group. In some embodiments, R n4 It is a methyl group.

[0237] In some implementation schemes, R X4 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X4 -heterocyclic alkyl, -L X4 -cycloalkyl, -L X4 -Aryl or -L X4- Heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X4a Replacement. In some implementations, R X4 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X4 -5 to 6-membered heterocyclic alkyl groups, -L X4 -C 3-6 cycloalkyl, -L X4 -C 6-10 Aryl or -L X4 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X4a replace.

[0238] In some implementation schemes, R X4 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X4 -5 to 6-membered heterocyclic alkyl groups, -L X4 -C 4-6 cycloalkyl, -L X4 -C 6-10 Aryl or -L X4 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X4a Replacement. In some implementations, R X4 For hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -L X4 -piperidinyl, L X4 -piperazinyl, -L X4 -phenyl or -L X4 -pyridyl, wherein the alkyl, heteroalkyl, phenyl, pyridyl, piperidyl, and piperazine group are each optionally denoted by one or more R- groups. X4a replace.

[0239] In some implementation schemes, R X4 It is hydrogen. In some implementations, R X4 For optional replaced C 1-6 Alkyl group. In some embodiments, R X4 For optional one or more R X4a Replacement C1-6 Alkyl group. In some embodiments, R X4 For optional replaced C 1-6 Heteroalkyl. In some embodiments, R X4 For optional one or more R X4a Replacement C 1-6 Heteroalkyl. In some embodiments, R X4 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 Each of the heteroalkyl groups is optionally hydroxylated by one or more R X4a Replacement. In some implementations, R X4 C 2-6 alkenyl or C 2-6 alkynyl group, wherein the C 2-6 alkenyl or C 2-6 Each of the alkynyl groups is optionally etherified by one or more R groups. X4a Replacement. In some implementations, R X4 It is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is optionally derived from one or more R groups. X4a Replacement. In some implementations, R X4 It is an aryl or heteroaryl group, wherein each of the aryl or heteroaryl groups is optionally derived from one or more R groups. X4a Replacement. In some implementations, R X4 It is a cycloalkyl or heterocycloalkyl group, wherein each of the cycloalkyl or heterocycloalkyl groups is optionally derived from one or more R groups. X4a Replacement. In some implementations, R X4 -L X4 -heterocyclic alkyl, -L X4 -cycloalkyl, -L X4 -Aryl or -L X4 -Heteroaryl, wherein the -L X4 -heterocyclic alkyl, -L X4 -cycloalkyl, -L X4 -Aryl or -L X4 - Each of the heteroaryl groups is selected from one or more R... X4a Replacement. In some implementations, R X4 For optional one or more R X4a Replacement -L X4 - Heterocyclic alkyl. In some embodiments, RX4 For optional one or more R X4a Replacement -L X4 -Cycloalkyl. In some embodiments, R X4 For optional one or more R X4a Replacement -L X4 -Aryl. In some implementations, R X4 For optional one or more R X4a Replacement -L X4 - Mixed aromatic compounds.

[0240] In some implementation schemes, R X4' It is hydrogen. In some implementations, R X4' C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X4a Replacement. In some implementations, R X4' C 1-6 Alkyl group. In some embodiments, R X4' It is a methyl group.

[0241] In some implementation schemes, R n4 and R X4' Together with intermediary atoms, they form one or more optional R atoms. X4a Substituted 5- to 6-membered heterocyclic alkyl groups.

[0242] In some implementations, L X4 C 1-6 Alkylene, wherein the alkylene is optionally derived from one or more R... X4a Replacement. In some implementations, L X4 C 1-6 Alkylene. In some embodiments, L X4 C 1-6 Heteroalkylene, wherein the heteroalkylene is optionally derived from one or more R... X4a Replacement. In some implementations, L X4 C 1-6 Heteroalkyl groups. In some embodiments, L X4 For -O-. In some implementations, L X4 For -S-. In some implementations, L X4 For -NR a - In some implementations, L X4 It is -NH-.

[0243] In some implementation schemes, each R X4a Independent of halogen, C 1-6Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0244] In some implementation schemes, each R X4a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)Ra -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0245] In some implementation schemes, each R X4a Independently for C 1-6 Alkyl, C 1-6 Alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, OH, -CN, -NO2, NH2, -C(=O)R a -C(=O)OR a -NR a C(=O)NR c R d Or oxidative oxidation. In some implementations, each R X4a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -OR a -CN, -NO2, NH2, -C(=O)R a -C(=O)OR a -NR a C(=O)NR c R d Or oxygenation.

[0246] In some implementation schemes, R n4 For methyl, R X4' It is hydrogen, and R X4 For optional one or more R X4a Replacement C 1-6 Alkyl group. In some embodiments, R n4 For methyl, R X4' It is hydrogen, and R X4 For optional one or more R X4a Replacement C 1-3 Alkyl group. In some embodiments, R n4 For methyl, R X4' It is hydrogen, and R X4C is optionally substituted with one or more -C(=O)NH2. 1-6 Alkyl group. In some embodiments, R n4 For methyl, R X4' It is hydrogen, and R X4 C is optionally substituted with -C(=O)NH2 1-3 alkyl.

[0247] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X5 has an aromatic side chain, such as F, Y, or variants thereof. In some embodiments, X5 is F or a variant thereof comprising a phenyl, pyridyl, or naphthyl group, wherein the phenyl, pyridyl, or naphthyl group is optionally substituted with one or more substituents, each independently selected from: halogen, -C 1-3 Alkyl, -OH, -NH2, -CN, -C(=O)OH, -C(=O)NH2, -NHC(=O)CH3, -C 1-3 Alkylene -C(=O)OH, -C 1-3 Alkylene -C(=O)NH2, -OC 1-3 Alkylene -C(=O)OH, -OC 1-3 Alkylene -C(=O)NH2, -C 1-3 alkylene-C(=O)-5 to 6-membered heterocyclic alkylene-C 1-3 Alkylene -C(=O)OH, -OC 1-3 alkylene-C(=O)-5 to 6-membered heterocyclic alkylene-C 1-3 Alkylene -C(=O)OH, -C 1-3 Alkylene-NHC(=O)-5 to 6-membered heterocyclic alkylene-C 1-3 Alkylene -C(=O)OH, -OC 1-3 Alkylene-NHC(=O)-5 to 6-membered heterocyclic alkylene-C 1-3 Alkylene -C(=O)OH and -NH-C 1-3 Alkylene-C(=O)OH. In some embodiments, X5 is Y or a variant thereof containing a hydroxyphenyl group, wherein the hydrogen atom in the hydroxyphenyl group of Y or the variant is optionally oriented via one or more atoms selected from -C 1-3 Alkyl and -C 1-3 Substituents of alkylene-C(=O)OH.

[0248] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X5 is Y, F3G, 3Py6COO, 4Py2NH2, 3Py5COO, F3COO, 3Py6NHAc, F, F4C, F4OMe, F4COO, Nal2, F3aao, F4aa, F4aao, 3Py6NHaa, 5Pdo, F3CON, F4F, F4OEt, F4Me, F4CON, F4CONPEG4Me, F3OMe, F3CON, YaeCOpipzaa, F4aaopipzaa, 4Pdo, 3Py6CON, Atp, Cha4cH, Cha4tH, Cha4cOMe, Almor, or F4amCOpipzaa. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X5 is a optionally substituted Y, F3G, 3Py6COO, 4Py2NH2, 3Py5COO, F3COO, 3Py6NHAc, F, F4C, F4OMe, F4COO, Na12, F3aao, F4 aa, F4aao, 3Py6NHaa, 5Pdo, F3CON, F4F, F4OEt, F4Me, F4CON, F4CONPEG4Me, F3OMe, F3CON, Yae, YaeCOpipzaa, F4aaopipzaa, 4Pdo, 3Py6CON, Atp, Cha4cH, Cha4tH, Cha4cOMe, Almor, or F4amCOpipzaa. In some embodiments, X5 is optionally substituted Y. In some embodiments, X5 is optionally substituted F3G. In some embodiments, X5 is optionally substituted 3Py6COO. In some embodiments, X5 is optionally substituted 4Py2NH2. In some embodiments, X5 is optionally substituted 3Py5COO. In some embodiments, X5 is optionally substituted F3COO. In some embodiments, X5 is optionally substituted 3Py6NHAc. In some embodiments, X5 is optionally substituted F. In some embodiments, X5 is optionally substituted F4C. In some embodiments, X5 is optionally substituted F4OMe. In some embodiments, X5 is optionally substituted F4COO. In some embodiments, X5 is optionally substituted Na12. In some embodiments, X5 is optionally substituted F3aao. In some embodiments, X5 is optionally substituted F4aa. In some embodiments, X5 is optionally substituted F4aao.In some embodiments, X5 is optionally substituted 3Py6NHaa. In some embodiments, X5 is optionally substituted 5Pdo. In some embodiments, X5 is optionally substituted F3CON. In some embodiments, X5 is optionally substituted F4F. In some embodiments, X5 is optionally substituted F4OEt. In some embodiments, X5 is optionally substituted F4Me. In some embodiments, X5 is optionally substituted F4CON. In some embodiments, X5 is optionally substituted F4CONPEG4Me. In some embodiments, X5 is optionally substituted F3OMe. In some embodiments, X5 is optionally substituted F3CON. In some embodiments, X5 is optionally substituted Yae. In some embodiments, X5 is optionally substituted YaeCOpipzaa. In some embodiments, X5 is optionally substituted F4aaopipzaa. In some embodiments, X5 is optionally substituted 4Pdo. In some embodiments, X5 is optionally substituted 3Py6CON. In some embodiments, X5 is optionally substituted Atp. In some embodiments, X5 is optionally substituted Cha4cH. In some embodiments, X5 is optionally substituted Cha4tH. In some embodiments, X5 is optionally substituted Cha4cOMe. In some embodiments, X5 is optionally substituted Almor. In some embodiments, X5 is optionally substituted F4amCOpipzaa.

[0249] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X5 is any amino acid. In some embodiments, X5 is a D-amino acid. In some embodiments, X5 is an L-amino acid. In some embodiments, X5 is an N-alkylated amino acid. In some embodiments, X5 is an N-methylated amino acid. In some embodiments, X5 does not contain a cyclic group. In some embodiments, X5 contains a cyclic group. In some embodiments, X5 contains a 5- to 6-membered heterocyclic alkyl group. In some embodiments, X5 contains a 5- to 6-membered heteroaryl group. In some embodiments, X5 contains a phenyl group. In some embodiments, X5 is a peptide-like substance.

[0250] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X5 has the following structure: , in: Rn5 It is hydrogen or C 1-3 alkyl; Ring A5 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Each R X5 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)NR c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X5-heterocyclic alkyl, -L X5 -cycloalkyl, -L X5 -Aryl or -L X5 - Heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally derived from one or more R... X5a Replace; or Two Rs X5 Together they form =O, =S, or =N(R) a ); L X5 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X5a replace; kx5 is 0, 1, 2 or 3; mx5 can be 0, 1, 2, 3, 4 or 5; *X4 indicates the connection point with X4; *X6 indicates the connection point with X6; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0251] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), wherein: R n5 It can be hydrogen or methyl; Ring A5 is C 6-10 Aryl, 5- to 10-membered heteroaryl, C 6-10 Cycloalkyl or 5- to 10-membered heterocyclic alkyl; Each R X5 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NRc R d -S(=O)(=NR) a )R a -N=S(=O)NR c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X5 -5 to 6-membered heterocyclic alkyl groups, -L X5 -C 3-6 cycloalkyl, -L X5 -C 6-10 Aryl or -L X5 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally derived from one or more R groups. X5a Replace; or Two Rs X5 Together they form = O; and L X5 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X5a replace.

[0252] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), wherein: Ring A5 can be phenyl, naphthyl, pyridyl, cyclohexyl, piperidyl, piperazinyl, morpholinyl, or tetrahydropyranyl; Each R X5 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -L X5 -piperidinyl or L X5 -piperazinyl, wherein the alkyl, heteroalkyl, piperidinyl, and pipeazinyl groups are each optionally etched with one or more R groups. X5a Replace; or Two Rs X5 Together they form = O; kx5 is 1 or 2; and mx5 can be 0, 1, or 2.

[0253] In some implementation schemes, R n5 It is hydrogen. In some implementations, R n5 C 1-3 Alkyl group. In some embodiments, R n5 It is a methyl group.

[0254] In some implementations, ring A5 is C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl or 3- to 10-membered heterocyclic alkyl. In some embodiments, ring A5 is C. 6-10 Aryl, 5- to 10-membered heteroaryl, C 6-10 Cycloalkyl or 5- to 10-membered heterocyclic alkyl groups. In some embodiments, ring A5 is phenyl, naphthyl, pyridyl, cyclohexyl, piperidinyl, piperazine, morpholinyl, or tetrahydropyranyl. In some embodiments, ring A5 is C 6-10 Aryl. In some embodiments, ring A5 is phenyl. In some embodiments, ring A5 is naphthyl. In some embodiments, ring A5 is a 5- to 10-membered heteroaryl. In some embodiments, ring A5 is a 6- to 10-membered heteroaryl. In some embodiments, ring A5 is a 5- to 6-membered heteroaryl. In some embodiments, ring A5 is pyridine. In some embodiments, ring A5 is pyridine. In some embodiments, ring A5 is C 3-10 Cycloalkyl. In some embodiments, ring A5 is C. 5-10 Cycloalkyl. In some embodiments, ring A5 is C. 5-6 Cycloalkyl. In some embodiments, ring A5 is C. 3-6 Cycloalkyl. In some embodiments, ring A5 is cyclohexane. In some embodiments, ring A5 is a 3- to 10-membered heterocyclic alkyl group. In some embodiments, ring A5 is a 5- to 6-membered heterocyclic alkyl group. In some embodiments, ring A5 is tetrahydropiperanone. In some embodiments, ring A5 is α-oxoline.

[0255] In some implementation schemes, each R X5 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2Ra -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)NR c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X5 -5 to 6-membered heterocyclic alkyl groups, -L X5 -C 3-6 cycloalkyl, -L X5 -C 6-10 Aryl or -L X5 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally derived from one or more R groups. X5a Replacement. In some implementations, each R X5 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6Alkyne, halogen, -CN, -NO2, -OR a -SR a -NR c R d -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -NR a C(=O)R a -NR a C(=O)OR a -C(=O)NR c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X5 -5 to 6-membered heterocyclic alkyl groups, -L X5 -C 3-6 cycloalkyl, -L X5 -C 6-10 Aryl or -L X5 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally derived from one or more R groups. X5a Replacement. In some implementations, each R X5 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)Ra -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -L X5 -piperidinyl or L X5 -piperazinyl, wherein the alkyl, heteroalkyl, piperidinyl, and pipeazinyl groups are each optionally etched with one or more R groups. X5a replace.

[0256] In some implementation schemes, each R X5a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R dOr =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0257] In some implementations, two R X5 Together they form = O.

[0258] In some implementations, kx5 is 0. In some implementations, kx5 is 1. In some implementations, kx5 is 2. In some implementations, kx5 is 3.

[0259] In some implementations, mx5 is 0. In some implementations, mx5 is 1. In some implementations, mx5 is 2. In some implementations, mx5 is 3. In some implementations, mx5 is 4. In some implementations, mx5 is 5.

[0260] In some embodiments, Rn5 is hydrogen, kx5 is 1 or 2, mx5 is 0, 1 or 2, ring A5 is phenyl, and each R X5 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated or -C(=O)OR a In some embodiments, Rn5 is hydrogen, kx5 is 1, mx5 is 1, ring A5 is phenyl, and R X5 It is -C(=O)OH.

[0261] In some embodiments of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X6 is an aliphatic amino acid (e.g., V, L, I, A, G or variants thereof), a hydrophilic amino acid (e.g., D, E or variants thereof), threonine (T), serine (S), O-methylthreonine (TMe), or methionine (M).

[0262] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X6 is I, V, Eva, Chg, Tbg, A, L, Ahp, F4COO, Gcpr, Gcpe, alI, Cle, S3REt, TMe, Acpr, Cba, Gthp, NleCOO, NleOH, P, Atb, Nva, Nle, N, DapAc, Abu, Nmm, Ndm, Ncit, Cit, SMe, HseMe, HseEt, HseiPr, dMeS, TdMe, Cbg, NvaOMe, SiPr, Spr, NleOMe, Sbu, Scbm, Scpe, AhpOMe, HseBu, Spent, or Hsecpe. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X6 is each of the optionally substituted I, V, Eva, Chg, Tbg, A, L, Ahp, F4COO, Gcpr, Gcpe, alI, Cle, S3REt, TMe, Acpr, Cba, Gthp, NleCOO, NleOH, P, Atb, Nva, Nle, N, DapAc, Abu, Nmm, Ndm, Ncit, Cit, SMe, HseMe, HseEt, HseiPr, dMeS, TdMe, Cbg, NvaOMe, SiPr, Spr, NleOMe, Sbu, Scbm, Scpe, AhpOMe, HseBu, Spent, or Hsecpe. In some embodiments, X6 is optionally substituted I. In some embodiments, X6 is optionally substituted V. In some embodiments, X6 is optionally substituted Eva. In some embodiments, X6 is optionally substituted Chg. In some embodiments, X6 is optionally substituted Tbg. In some embodiments, X6 is optionally substituted A. In some embodiments, X6 is optionally substituted L. In some embodiments, X6 is optionally substituted Ahp. In some embodiments, X6 is optionally substituted F4COO. In some embodiments, X6 is optionally substituted Gcpr. In some embodiments, X6 is optionally substituted Gcpe. In some embodiments, X6 is optionally substituted a1I. In some embodiments, X6 is optionally substituted Cle. In some embodiments, X6 is optionally substituted S3REt. In some embodiments, X6 is optionally substituted TMe. In some embodiments, X6 is optionally substituted Accr. In some embodiments, X6 is optionally substituted Cba.In some embodiments, X6 is optionally substituted Gthp. In some embodiments, X6 is optionally substituted NleCOO. In some embodiments, X6 is optionally substituted NleOH. In some embodiments, X6 is optionally substituted P. In some embodiments, X6 is optionally substituted Atb. In some embodiments, X6 is optionally substituted Nva. In some embodiments, X6 is optionally substituted Nle. In some embodiments, X6 is optionally substituted N. In some embodiments, X6 is optionally substituted DapAc. In some embodiments, X6 is optionally substituted Abu. In some embodiments, X6 is optionally substituted Nmm. In some embodiments, X6 is optionally substituted Ndm. In some embodiments, X6 is optionally substituted Ncit. In some embodiments, X6 is optionally substituted Cit. In some embodiments, X6 is optionally substituted SMe. In some embodiments, X6 is optionally substituted HseMe. In some embodiments, X6 is optionally substituted HseEt. In some embodiments, X6 is optionally substituted HseiPr. In some embodiments, X6 is optionally substituted dMeS. In some embodiments, X6 is optionally substituted TdMe. In some embodiments, X6 is optionally substituted Cbg. In some embodiments, X6 is optionally substituted NvaOMe. In some embodiments, X6 is optionally substituted SiPr. In some embodiments, X6 is optionally substituted Spr. In some embodiments, X6 is optionally substituted NleOMe. In some embodiments, X6 is optionally substituted Sbu. In some embodiments, X6 is optionally substituted Scbm. In some embodiments, X6 is optionally substituted Scpe. In some embodiments, X6 is optionally substituted AhpOMe. In some embodiments, X6 is optionally substituted HseBu. In some embodiments, X6 is optionally substituted Spent. In some embodiments, X6 is optionally substituted Hsecpe.

[0263] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X6 is any amino acid. In some embodiments, X6 is a D-amino acid. In some embodiments, X6 is an L-amino acid. In some embodiments, X6 is an N-alkylated amino acid. In some embodiments, X6 is an N-methylated amino acid. In some embodiments, X6 does not contain a cyclic group. In some embodiments, X6 contains a cyclic group. In some embodiments, X6 contains a 5- to 6-membered heterocyclic alkyl group. In some embodiments, X6 contains a 5- to 6-membered heteroaryl group. In some embodiments, X6 contains a phenyl group. In some embodiments, X6 is a peptide-like substance.

[0264] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X6 has the following structure: , in: R n6 It is hydrogen or C 1-3 alkyl; R X6 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X6 -heterocyclic alkyl, -L X6 -cycloalkyl, -L X6 -Aryl or -L X6 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X6a Replace; or R n6 and R x6 Together with intermediary atoms, they form one or more optional R atoms. X6a Substituted 5- to 6-membered heterocyclic alkyl groups; L X6 C 1-6 Alkylene, C 1-6 Heteroalkyl, O, S or NR a The alkylene and heteroalkylene groups are optionally derived from one or more R... X6a replace; *X5 indicates the connection point with X5; *X7 indicates the connection point with X7; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0265] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), wherein R n6 It can be hydrogen or methyl; R X6 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X6 -5 to 6-membered heterocyclic alkyl groups, -L X6 -C 3-6 cycloalkyl, -L X6 -C 6-10 Aryl or -L X6 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally denoted by one or more R groups. X6a Replace; and L X6 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X6a replace.

[0266] In some implementation schemes, R n6 It is hydrogen. In some implementations, R n6 C 1-3 Alkyl group. In some embodiments, R n6 It is a methyl group.

[0267] In some implementation schemes, R X6 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C1-6 Heteroalkyl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X6 -5 to 6-membered heterocyclic alkyl groups, -L X6 -C 3-6 cycloalkyl, -L X6 -phenyl or -L X6 -6-membered heteroaryl, wherein the alkyl, heteroalkyl, phenyl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X6a replace.

[0268] In some implementation schemes, R X6 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X6 -5 to 6-membered heterocyclic alkyl groups, -L X6 -C 3-6 cycloalkyl, -L X6 -C 6-10 Aryl or -L X6 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X6a replace.

[0269] In some implementation schemes, R X6 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -L X6 -5 to 6-membered heterocyclic alkyl groups, -L X6 -C 4-6 cycloalkyl, -L X6 -C 6-10 Aryl or -L X6 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X6a Replacement. In some implementations, R X6 C 1-6 Alkyl, C 1-6 Heteroalkyl, 6-L X6 -phenyl or -L X6 -pyridyl, wherein the alkyl, heteroalkyl, phenyl and pyridyl groups are each optionally derived from one or more R groups. X6a replace.

[0270] In some implementation schemes, R X6For optional replaced C 1-6 Alkyl group. In some embodiments, R X6 For optional one or more R X6a Replacement C 1-6 Alkyl group. In some embodiments, R X6 For optional replaced C 1-6 Heteroalkyl. In some embodiments, R X6 For optional one or more R X6a Replacement C 1-6 Heteroalkyl. In some embodiments, R X6 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 Each of the heteroalkyl groups is optionally hydroxylated by one or more R X6a Replacement. In some implementations, R X6 C 2-6 alkenyl or C 2-6 alkynyl group, wherein the C 2-6 alkenyl or C 2-6 Each of the alkynyl groups is optionally etherified by one or more R groups. X6a Replacement. In some implementations, R X6 It is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, wherein each of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is optionally derived from one or more R groups. X6a Replacement. In some implementations, R X6 It is an aryl or heteroaryl group, wherein each of the aryl or heteroaryl groups is optionally derived from one or more R groups. X6a Replacement. In some implementations, R X6 It is a cycloalkyl or heterocycloalkyl group, wherein each of the cycloalkyl or heterocycloalkyl groups is optionally derived from one or more R groups. X6a Replacement. In some implementations, R X6 For optional one or more R X6a Replacement C 3-6 Cycloalkyl. In some embodiments, R X6 -L X6 -heterocyclic alkyl, -L X6 -cycloalkyl, -L X6 -Aryl or -L X6 -Heteroaryl, wherein the -L X6 -heterocyclic alkyl, -L X6 -cycloalkyl, -LX6 -Aryl or -L X6 - Each of the heteroaryl groups is selected from one or more R... X6a Replacement. In some implementations, R X6 For optional one or more R X6a Replacement -L X6 - Heterocyclic alkyl. In some embodiments, R X6 For optional one or more R X6a Replacement -L X6 -Cycloalkyl. In some embodiments, R X6 For optional one or more R X6a Replacement -L X6 -Aryl. In some implementations, R X6 For optional one or more R X6a Replacement -L X6 - Mixed aromatic compounds.

[0271] In some implementation schemes, R n6 and R x6 Combined with intermediary atoms to form one or more optional R X6a Substituted 5- to 6-membered heterocyclic alkyl groups.

[0272] In some implementation schemes, each R X6a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR aC(=O)NR c R d -C(=O)NR c R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0273] In some implementation schemes, R n6 It is hydrogen, and R X6 For optional one or more R X6a Replacement C 1-6 Alkyl groups. In some embodiments, each R... X6a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl or -OR a In some implementation schemes, each R X6a Independently halogen or -OC 1-6 Alkyl group. In some embodiments, R X6a It is -O-CH3. In some implementations, R X6 It is -CH(CH3)OCH3.

[0274] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X7 comprises a branched alkyl side chain, C 3-5 An amino acid with a cycloalkyl side chain or a 3- to 5-membered heterocyclic alkyl side chain, or an N-methylated variant thereof. In some embodiments, the branched alkyl side chain contains 3 to 5 carbon atoms. In some embodiments, the alkyl, cycloalkyl, or heterocyclic alkyl side chain is optionally substituted with an -O-C1-C6 alkyl group.

[0275] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X7 is I, Eva, alI, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe, or Cbg. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X7 is each optionally substituted I, Eva, alI, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe, or Cbg. In some embodiments, X7 is optionally substituted I. In some embodiments, X7 is optionally substituted Eva. In some embodiments, X7 is optionally substituted alI. In some embodiments, X7 is optionally substituted TMe. In some embodiments, X7 is optionally substituted SMe. In some embodiments, X7 is optionally substituted Gcpr. In some embodiments, X7 is optionally substituted Gcpe. In some embodiments, X7 is optionally substituted Gthp. In some embodiments, X7 is optionally substituted dMeS. In some embodiments, X7 is optionally substituted TdMe. In some embodiments, X7 is optionally substituted Cbg.

[0276] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X7 is any amino acid. In some embodiments, X7 is a D-amino acid. In some embodiments, X7 is an L-amino acid. In some embodiments, X7 is an N-alkylated amino acid. In some embodiments, X7 is an N-methylated amino acid. In some embodiments, X7 does not contain a cyclic group. In some embodiments, X7 contains a cyclic group. In some embodiments, X7 contains a 5- to 6-membered heterocyclic alkyl group. In some embodiments, X7 contains a 5- to 6-membered heteroaryl group. In some embodiments, X7 contains a phenyl group. In some embodiments, X7 is a peptide-like substance.

[0277] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X7 has the following structure: , in: R n7 It is hydrogen or C 1-3 alkyl; R X7 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, heteroalkyl, alkenyl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R groups. X7a replace; *X6 indicates the connection point with X6; and *X8 indicates the connection point with X8; Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0278] In some implementations, R n7 It is hydrogen or methyl; and R X7 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 5- to 6-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X7a replace.

[0279] In some implementation schemes, R n7 It is hydrogen. In some implementations, R n7 C 1-3 Alkyl group. In some embodiments, R n7 It is a methyl group.

[0280] In some implementation schemes, R X7 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 5- to 6-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X7aReplacement. In some implementations, R X7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 5- to 6-membered heterocyclic alkyl, wherein the alkyl, heteroalkyl, cycloalkyl and heterocyclic alkyl are each optionally derived from one or more R... X7a Replacement. In some implementations, R X7 For optional one or more R X7a Replacement C 1-6 Alkyl group. In some embodiments, R X7 C 1-6 Alkyl group. In some embodiments, R X7 For branch chain C 1-6 Alkyl group. In some embodiments, R X7 For optional one or more R X7a Replacement C 1-6 Heteroalkyl. In some embodiments, R X7 C 1-6 Heteroalkyl. In some embodiments, R X7 For optional one or more R X7a Replacement C 3-6 Cycloalkyl. In some embodiments, R X7 C 3-6 Cycloalkyl. In some embodiments, R X7 For optional one or more R X7a Substituted 5- to 6-membered heterocyclic alkyl groups. In some embodiments, R X7 It is a 5- to 6-membered heterocyclic alkyl group.

[0281] In some implementation schemes, each R X7a Independent of halogen, -CN, -OR a -SR a -NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R dOr = O.

[0282] In some implementation schemes, R n7 It is hydrogen, and R X7 For optional one or more R X7a Replacement C 1-6 Alkyl group. In some embodiments, R n7 It is hydrogen, and R X7 C 1-6 Alkyl group. In some embodiments, R n7 It is hydrogen, and R X7 C 3-6 Alkyl group. In some embodiments, R n7 It is hydrogen, and R X7 For branch chain C 1-6 alkyl.

[0283] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X8 is Y or a variant thereof comprising a hydroxyphenyl ring, wherein the hydroxyphenyl ring of Y or the variant is optionally substituted with one or more substituents selected from: halogen, -C 1-3 Alkyl, -OH, -C(=O)OH, -O-CH3, -C 1-3 Alkylene -C(=O)OH, -C 1-3 alkylene-C(=O)-5 to 6-membered heterocyclic alkylene-C 1-3 Alkylene -C(=O)OH and -C 1-3 Alkylene-NHC(=O)-5 to 6-membered heterocyclic alkylene-C 1-3 Alkylene -C(=O)OH. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X8 is F or a variant thereof comprising a phenyl, pyridyl, or indazole group, wherein the phenyl group of F or the phenyl, pyridyl, or indazole group of the variant is optionally substituted with one or more substituents, each independently selected from: halogen, -C 1-3 Alkyl, -OH, -C(=O)OH, -C(=O)NH2, -NHC(=O)NH2, -C 1-3 Alkylenes -C(NH2)-COOH, -NH-CO-CH3, -NH-C 1-3 Alkylenes -NH2, -C(=O)-N(CH2)2, -S(=O)2-CH3, -C 1-3 alkylene-NH-C(=O)-5 to 6-membered heterocyclic alkylene-C 1-3 Alkylene-C(=O)OH and -OC 1-3alkylene-NH-C(=O)-5 to 6-membered heterocyclic alkylene-C 1-3 Alkylene-C(=O)OH.

[0284] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X8 is Y, F4OMe, F4COO, F4OEt, F4u, F4Me, F4CONdMe, F4CON, F4ms, F4CONPEG4Me, F34dOMe, F3OMe, F3C, F3CON, F3CONdMe, 3Py6CON, Yae, YaeCOpipzaa, 5Inda, F3aao, F3aa, F4aao, F4aa, 3Py6Nhae, 3Py6NHAc, 3Py6OMe, F4aaopipzaa, or F4amCOpipzaa. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X8 is a substituted Y, F4OMe, F4COO, F4OEt, F4u, F4Me, F4CONdMe, F4CON, F4ms, F4CONPEG4Me, F34dOMe, F3OMe, F3C, F3CON, F3CONdMe, 3Py6CON, Yae, YaeCOpipzaa, 5Inda, F3aao, F3aa, F4aao, F4aa, 3Py6Nhae, 3Py6NHAc, 3Py6OMe, F4aaopipzaa, or F4amCOpipzaa. In some embodiments, X8 is a substituted Y. In some embodiments, X8 is a substituted F4OMe. In some embodiments, X8 is optionally substituted F4COO. In some embodiments, X8 is optionally substituted F4OEt. In some embodiments, X8 is optionally substituted F4u. In some embodiments, X8 is optionally substituted F4Me. In some embodiments, X8 is optionally substituted F4CONdMe. In some embodiments, X8 is optionally substituted F4CON. In some embodiments, X8 is optionally substituted F4ms. In some embodiments, X8 is optionally substituted F4CONPEG4Me. In some embodiments, X8 is optionally substituted F34dOMe. In some embodiments, X8 is optionally substituted F3OMe. In some embodiments, X8 is optionally substituted F3C. In some embodiments, X8 is optionally substituted F3CON. In some embodiments, X8 is optionally substituted F3CONdMe. In some embodiments, X8 is optionally substituted 3Py6CON. In some embodiments, X8 is optionally substituted Yae. In some implementations, X8 is optionally replaced YaeCOpipzaa.In some embodiments, X8 is optionally substituted 5Inda. In some embodiments, X8 is optionally substituted F3aao. In some embodiments, X8 is optionally substituted F3aa. In some embodiments, X8 is optionally substituted F4aao. In some embodiments, X8 is optionally substituted F4aa. In some embodiments, X8 is optionally substituted 3Py6Nhae. In some embodiments, X8 is optionally substituted 3Py6NHAc. In some embodiments, X8 is optionally substituted 3Py6OMe. In some embodiments, X8 is optionally substituted F4aaopipzaa. In some embodiments, X8 is optionally substituted F4amCOpipzaa.

[0285] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X8 is A, I, L, or V. In some embodiments, X8 is A. In some embodiments, X8 is A or a derivative thereof. In some embodiments, X8 is I or a derivative thereof. In some embodiments, X8 is L or a derivative thereof. In some embodiments, X8 is V or a derivative thereof.

[0286] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X8 is any amino acid. In some embodiments, X8 is a D-amino acid. In some embodiments, X8 is an L-amino acid. In some embodiments, X8 is an aliphatic amino acid. In some embodiments, X8 is an N-alkylated amino acid. In some embodiments, X8 is an N-methylated amino acid. In some embodiments, X8 does not contain a cyclic group. In some embodiments, X8 contains a cyclic group. In some embodiments, X8 contains a 5- to 6-membered heterocyclic alkyl group. In some embodiments, X8 contains a 5- to 6-membered heteroaryl group. In some embodiments, X8 contains a phenyl group. In some embodiments, X8 is a peptide-like substance.

[0287] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X8 has the following structure: , in, R n8 It is hydrogen or C 1-3 alkyl; Ring A8 is aryl or heteroaryl; Each R X8 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X8 -heterocyclic alkyl, -L X8 -cycloalkyl, -L X8 -Aryl or -L X8- Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X8a Replace; or Two Rs X8 Together they form =O, =S, or =N(R) a ); L X8 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X8a replace; kx8 is 0, 1, 2, or 3; mx8 can be 0, 1, 2, 3, 4 or 5; *X7 indicates the connection point with X7; *X9 indicates the connection point with X9; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0288] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), wherein Ring A8 is C 6-10 Aryl or 5 to 10-membered heteroaryl groups; Each R X8 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NRa S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X8 -5 to 6-membered heterocyclic alkyl groups, -L X8 -C 3-6 cycloalkyl, -L X8 -C 6-10 Aryl or -L X8 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally denoted by one or more R groups. X8a Replace; or Two Rs X8 Together they form = O; and L X8 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X8a replace.

[0289] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), wherein Ring A8 can be phenyl, pyridyl, indolyl, azaindolyl, indazole, or benzimidazole. Each R X8 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -L X5 -piperidinyl or L X5 -piperazinyl, wherein the alkyl, heteroalkyl, piperidinyl, and pipeazinyl groups are each optionally etched with one or more R groups. X8a Replace; or Two Rs X5 Together they form = O; kx8 is 1 or 2; and mx8 can be 0, 1, or 2.

[0290] In some implementation schemes, R n8 It is hydrogen. In some implementations, R n8 C 1-3Alkyl group. In some embodiments, R n8 It is a methyl group.

[0291] In some implementations, ring A8 is C 6-10 Aryl. In some embodiments, ring A8 is phenyl. In some embodiments, ring A8 is naphthyl.

[0292] In some embodiments, ring A8 is a 5- to 10-membered heteroaryl group. In some embodiments, ring A8 is a 5- to 6-membered heteroaryl group. In some embodiments, ring A8 is a monocyclic heteroaryl group. In some embodiments, ring A8 is a bicyclic heteroaryl group. In some embodiments, ring A8 is a bicyclic fused heteroaryl group. In some embodiments, ring A8 is a bicyclic 5-6 or 6-5 fused heteroaryl group. In some embodiments, ring A8 is phenyl, pyridyl, indole, azaindole, indazole, or benzimidazolyl.

[0293] In some implementation schemes, each R X8 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NRa C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X8 -5 to 6-membered heterocyclic alkyl groups, -L X8 -C 3-6 cycloalkyl, -L X8 -C 6-10 Aryl or -L X8 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally denoted by one or more R groups. X8a replace.

[0294] In some implementation schemes, each R X8 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NRc R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d or -L X8 -5 to 6-membered heterocyclic alkyl groups (e.g., -L) X8 -piperidinyl or L X8 -piperazinyl), wherein the alkyl, heteroalkyl, or heterocyclic alkyl (e.g., piperidinyl and piperazinyl) is optionally etched with one or more R-terminal groups. X8a replace.

[0295] In some implementation schemes, R X8 Together they form oxygen.

[0296] In some implementations, L X8 For optional one or more R X8a Replacement C 1-6 Alkylene. In some embodiments, L X8 For optional one or more R X8a Replacement C 1-6 Heteroalkyl groups. In some embodiments, L X8 For -O-. In some implementations, L X8 For -S-. In some implementations, L X8 For -NR a -

[0297] In some implementations, kx8 is 0. In some implementations, kx8 is 1. In some implementations, kx8 is 2. In some implementations, kx8 is 3.

[0298] In some implementations, mx8 is 0. In some implementations, mx8 is 1. In some implementations, mx8 is 2. In some implementations, mx8 is 3. In some implementations, mx8 is 4. In some implementations, mx8 is 5.

[0299] In some implementation schemes, R n8 For hydrogen, kx8 is 0, 1, or 2, mx8 is 0, 1, or 2, ring A8 is phenyl, and each R X8 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C1-6 Heteroalkyl or -OR a The alkyl or heteroalkyl group is optionally oxidized by one or more R... X8a Replacement. In some implementations, R n8 It is hydrogen, kx8 is 1, mx8 is 1, ring A8 is phenyl, and each R X8 Independent of halogen, C 1-6 Alkyl or -OR a The alkyl or heteroalkyl group is optionally oxidized by one or more R... X8a Replacement. In some implementations, R n8 It is hydrogen, kx8 is 1, mx8 is 1, ring A8 is phenyl, and each R X8 Independent of halogen, C 1-6 Alkyl or -OCH2C(=O)OH. In some embodiments, R n8 It is hydrogen, kx8 is 1, mx8 is 1, ring A8 is phenyl, and R X8 It is -OCH2C(=O)OH.

[0300] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X9 is an N-methyl aromatic amino acid, optionally a bicyclic aromatic amino acid. In some embodiments, X9 is an N-methyl amino acid comprising a phenyl or monocyclic heteroaryl group, each optionally substituted. In some embodiments, X9 is an N-methyl amino acid comprising a naphthyl or bicyclic heteroaryl group, each optionally substituted. In some embodiments, the bicyclic heteroaryl group is a 5-6, 6-6, or 6-5 fused heteroaryl group. In some embodiments, the heteroaryl group comprises 1 to 3 cyclic nitrogen atoms. In some embodiments, the heteroaryl group comprises 1 to 2 cyclic nitrogen atoms. In some embodiments, the heteroaryl group comprises 1 cyclic nitrogen atom. In some embodiments, the N-methyl aromatic amino acid is an N-methyl monocyclic aromatic amino acid containing a phenyl or pyridinium group, wherein the phenyl or pyridinium group is optionally derived from one or more halogens, -C 1-3 Alkyl and trifluoromethyl substituents are used for substitution. In some embodiments, the N-methyl aromatic amino acid is an N-methyl bicyclic aromatic amino acid comprising a naphthyl, quinolinyl, or indazole group, wherein the naphthyl, quinolinyl, or indazole group is optionally substituted with one or more groups, each independently selected from H or C. 1-3 Alkyl substituents.

[0301] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X9 is MeNal2, MeNal27N, MeF34diox, MeF34dOMe, MeF4T, MeY, MeW1Me, MeW7N, MeF3C4Me, or MeF3Me4C. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X9 is each optionally substituted MeNal2, MeNal27N, MeF34diox, MeF34dOMe, MeF4T, MeY, MeW1Me, MeW7N, MeF3C4Me, or MeF3Me4C. In some embodiments, X9 is optionally substituted MeNal2. In some embodiments, X9 is optionally substituted MeNal27N. In some embodiments, X9 is optionally substituted MeF34diox. In some embodiments, X9 is optionally substituted MeF34dOMe. In some embodiments, X9 is optionally substituted MeF4T. In some embodiments, X9 is optionally substituted MeY. In some embodiments, X9 is optionally substituted MeW1Me. In some embodiments, X9 is optionally substituted MeW7N. In some embodiments, X9 is optionally substituted MeF3C4Me. In some embodiments, X9 is optionally substituted MeF3Me4C.

[0302] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X9 is a D-amino acid. In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X9 is an L-amino acid. In some embodiments, X9 is an N-alkylated amino acid. In some embodiments, X9 is an N-methylated amino acid. In some embodiments, X9 comprises a cyclic group. In some embodiments, X9 comprises a 5- to 6-membered heterocyclic alkyl group. In some embodiments, X9 comprises a 5- to 6-membered heteroaryl group. In some embodiments, X9 comprises a bicyclic heteroaryl group. In some embodiments, X9 comprises a phenyl group. In some embodiments, X9 is a peptide-like group.

[0303] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X9 has the following structure: , in: R n9 It is hydrogen or C 1-3 alkyl; Ring A9 is aryl or heteroaryl; Each R X9 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5 or -NR c R d The alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally derived from one or more R groups. X9a Replace; or Two Rs X9 Together they form =O, =S, or =N(R) a ); kx9 is 0, 1, 2, or 3; mx9 can be 0, 1, 2, 3, 4 or 5; *X8 indicates the connection point with X8; *X10 indicates the connection point with X10; and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0304] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), wherein R n9 It can be hydrogen or methyl; Ring A9 is C 6-10 aryl or 5 to 10 heteroaryl groups; and Each R X9 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, -CN, -NO2, -OR a -SR a -SF5 or -NR c R d The alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally derived from one or more R groups. X9a Replace; or Two Rs X9 Together they form = O.

[0305] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), wherein Ring A9 can be phenyl, naphthyl, pyridyl, indolyl, azaindolyl, indazole, benzimidazolyl, or isoquinolinyl; Each R X9 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated groups, -CN, -OR a -SR a or -NR c R d The alkyl and heteroalkyl groups are each optionally derived from one or more R... X9a replace; kx9 is 1 or 2; and mx9 can be 0, 1, or 2.

[0306] In some implementation schemes, R n9 It is hydrogen. In some implementations, R n9 C 1-3 Alkyl group. In some embodiments, R n9 It is a methyl group.

[0307] In some implementations, ring A9 is C 6-10 Aryl group. In some embodiments, ring A9 is a 5- to 10-membered heteroaryl group. In some embodiments, ring A9 is a monocyclic heteroaryl group. In some embodiments, ring A9 is a bicyclic heteroaryl group. In some embodiments, ring A9 is a bicyclic 6-6 fused heteroaryl group. In some embodiments, ring A9 is a bicyclic 6-5 or 5-6 fused heteroaryl group. In some embodiments, ring A9 is phenyl, naphthyl, pyridyl, indole, azaindole, indazole, benzimidazolyl, or isoquinolinyl.

[0308] In some implementation schemes, each RX9a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e Replacement. In some implementations, each R X9 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated groups, -CN, -OR a -SR a or -NR c R d The alkyl and heteroalkyl groups are each optionally derived from one or more R... X9a replace.

[0309] In some implementations, kx9 is 0. In some implementations, kx9 is 1. In some implementations, kx9 is 2. In some implementations, kx9 is 3.

[0310] In some implementations, mx9 is 0. In some implementations, mx9 is 1. In some implementations, mx9 is 2. In some implementations, mx9 is 3. In some implementations, mx9 is 4. In some implementations, mx9 is 5.

[0311] In some implementation schemes, R n9 The methyl group is methyl, kx9 is 1, and ring A9 is a bicyclic 6-6 fused heteroaryl group. In some embodiments, ring A9 is isoquinolinyl.

[0312] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X10 is G. In some embodiments, X10 is a D-amino acid (e.g., da, ds, de, or dp). In some embodiments, X10 is a D-amino acid selected from da, ds, de, and dp. In some embodiments, X10 is da.

[0313] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X11 is F or a variant thereof, or contains -C. 1-6 An amino acid of alkylene-phenyl. In some embodiments, F or its variants are F or variants thereof containing a phenyl or heteroaryl group (e.g., monocyclic or bicyclic), each of which is optionally substituted. In some embodiments, F or its variants are F or variants thereof containing a phenyl or pyridyl group, each of which is optionally substituted with one or more substituents independently selected from: phenyl, -O-phenyl, -OC. 1-3 alkylene-phenyl, pyridinyl, imidazole, pyrazolyl, NC 1-3 alkylenepyrazolyl, NC 1-3 Alkylene (-OC) 1-3 Alkyl)pyrazolyl, pyranyl, tetrahydropyranyl, piperidinyl, NC 1-3 Alkylene-C(=O)-piperidinyl.

[0314] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X11 is Bph, 3Py6Ph, F41Me4Pyz, F43Pyz, F44Pyz, F41Pyz, F41Me3Pyz, F41Et4Pyz, F41MeOe4Pyz, F41MeOp4Pyz, F44thp, F4Ac4pip, PhNva, PhNle, Yph, Ybn, F4tb, F4oPr, or F4CONdMe. In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X11 is a optionally substituted Bph, 3Py6Ph, F41Me4Pyz, F43Pyz, F44Pyz, F41Pyz, F41Me3Pyz, F41Et4Pyz, F41MeOe4Pyz, F41MeOp4Pyz, F44thp, F4Ac4pip, PhNva, PhNle, Yph, Ybn, F4tb, F4oPr, or F4CONdMe. In some embodiments, X11 is an optionally substituted Bph. In some embodiments, X11 is an optionally substituted 3Py6Ph. In some embodiments, X11 is an optionally substituted F41Me4Pyz. In some embodiments, X11 is optionally substituted F43Pyz. In some embodiments, X11 is optionally substituted F44Pyz. In some embodiments, X11 is optionally substituted F41Pyz. In some embodiments, X11 is optionally substituted F41Me3Pyz. In some embodiments, X11 is optionally substituted F41Et4Pyz. In some embodiments, X11 is optionally substituted F41MeOe4Pyz. In some embodiments, X11 is optionally substituted F41MeOp4Pyz. In some embodiments, X11 is optionally substituted F44thp. In some embodiments, X11 is optionally substituted F4Ac4pip. In some embodiments, X11 is optionally substituted PhNva. In some embodiments, X11 is optionally substituted PhNle. In some embodiments, X11 is optionally substituted Yph. In some embodiments, X11 is optionally substituted Ybn. In some embodiments, X11 is optionally substituted F4tb. In some embodiments, X11 is optionally substituted F4oPr. In some embodiments, X11 is optionally substituted F4CONdMe.

[0315] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X11 is any amino acid. In some embodiments, X11 is a D-amino acid. In some embodiments, X11 is an L-amino acid. In some embodiments, X11 is an N-alkylated amino acid. In some embodiments, X11 is an N-methylated amino acid. In some embodiments, X11 contains a cyclic group. In some embodiments, X11 contains a 5- to 6-membered heterocyclic alkyl group. In some embodiments, X11 contains a 5- to 6-membered heteroaryl group. In some embodiments, X11 contains a bicyclic heteroaryl group. In some embodiments, X11 contains a phenyl group. In some embodiments, X11 is a peptide-like substance.

[0316] In some embodiments of the peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X11 has the following structure: , in: R n11 It is hydrogen or C 1-3 alkyl; Ring A11 is aryl or heteroaryl; Each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c Rd -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X11 -heterocyclic alkyl, -L X11 -cycloalkyl, -L X11 -Aryl or -L X11 -heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X11a Replace; or Two Rs X11 Together they form =O, =S, or =N(R) a ); L X11 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X11a replace; kx11 is 0, 1, 2, 3, 4 or 5; mx11 can be 0, 1, 2, 3, 4 or 5; *X10 indicates the connection point with X10; *X12 represents the connection point with X12, or *X12 represents the connection point with N(R). 2 The connection points (e.g., in equations (I-1) and (I-2)); and Other groups (such as R) a R c R d and R e It has the meaning defined in equation (I).

[0317] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), wherein Ring A11 is C 6-10 Aryl or 5 to 10-membered heteroaryl groups; Each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d C 6-10Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X11 -5 to 6-membered heterocyclic alkyl groups, -L X11 -C 3-6 cycloalkyl, -L X11 -C 6-10 Aryl or -L X11 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X11a Replace; or Two Rs X11 Together they form = O; and L X11 C 1-6 Alkylene, C 1-6 Heteroalkylene or -O-, wherein the alkylene and heteroalkylene are optionally derived from one or more R- groups. X11a replace.

[0318] In some embodiments of peptides of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), wherein Ring A11 is phenyl or pyridyl; Each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -NR a S(=O)2R a -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NRc R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X11 -5 to 6-membered heterocyclic alkyl groups, -L X11 -C 3-6 cycloalkyl, -L X11 -C 6-10 Aryl or -L X11 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X11a Replace; or Two Rs X11 Together they form = O; kx11 is 1, 2, 3, or 4; and mx11 can be 0, 1, or 2.

[0319] In some implementation schemes, R n11 It is hydrogen. In some implementations, R n11 C 1-3 Alkyl group. In some embodiments, R n11 It is a methyl group.

[0320] In some implementations, A11 is C 6-10 Aryl group. In some embodiments, A11 is phenyl. In some embodiments, A11 is a 5- to 10-membered heteroaryl group. In some embodiments, A11 is a 5- to 6-membered heteroaryl group. In some embodiments, A11 is a monocyclic heteroaryl group. In some embodiments, A11 is a bicyclic heteroaryl group.

[0321] In some implementation schemes, each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)Ra -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X11 -5 to 6-membered heterocyclic alkyl groups, -L X11 -C 3-6 cycloalkyl, -L X11 -C 6-10 Aryl or -L X11 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X11a replace.

[0322] In some implementation schemes, each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -NR a S(=O)2R a -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X11 -5 to 6-membered heterocyclic alkyl groups, -L X11 -C 3-6 cycloalkyl, -L X11 -C 6-10 Aryl or -L X11 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X11a replace.

[0323] In some implementation schemes, each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SRa -NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -NR a C(=O)R a -C(=O)NR c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X11 -5 to 6-membered heterocyclic alkyl groups, -L X11 -C 3-6 cycloalkyl, -L X11 -C 6-10 Aryl or -L X11 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X11a replace.

[0324] In some implementation schemes, each R X11 Independently, it is phenyl, pyridyl, pyrroleyl, pyrazolyl, imidazoleyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, -L X11 -5 to 6-membered heterocyclic alkyl groups, -L X11 -phenyl or -L X11 -pyridyl, wherein the phenyl, pyridyl, pyrroloyl, pyrazolyl, imidazolyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and heterocyclic alkyl groups are each optionally derived from one or more R... X11a replace.

[0325] In some implementations, two R X11 Together they form oxygen.

[0326] In some implementations, L X11 For optional one or more R X11a Replacement C 1-6 Alkylene. In some embodiments, L X11 For optional one or more R X11a Replacement C 1-6 Heteroalkyl groups. In some embodiments, L X11 For -O-. In some implementations, L X11 For -S-. In some implementations, L X11 For -NR a -

[0327] In some implementation schemes, each R X11aIndependent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d Or =O, wherein the alkyl and heteroalkyl groups are each optionally derived from one or more R groups. e replace.

[0328] In some implementations, kx11 is 0. In some implementations, kx11 is 1. In some implementations, kx11 is 2. In some implementations, kx11 is 3. In some implementations, kx11 is 4. In some implementations, kx11 is 5.

[0329] In some implementations, mx11 is 0. In some implementations, mx11 is 1. In some implementations, mx11 is 2. In some implementations, mx11 is 3. In some implementations, mx11 is 4. In some implementations, mx11 is 5.

[0330] In some implementation schemes, R n11 It is hydrogen, kx11 is 0, 1 or 2, mx11 is 1, ring A11 is a monocyclic heteroaryl group, and R X11 It is phenyl. In some embodiments, R n11It is hydrogen, kx11 is 1, mx11 is 1, ring A11 is pyridyl, and R X11 It is a phenyl group.

[0331] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X12 is N-methylcysteine ​​or a derivative thereof. In some embodiments, X12 is N-methylcysteine. In some embodiments, X12 is optionally substituted N-methylcysteine.

[0332] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X1 is I, R, Cit, F4G, 4Py, 3Py, KCOpipzaa, V, Eva, Q, E, MeI, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeV, MeHseMe , Aib, MeT, alI, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe, MeDapCOpipzaa; MeK, MeKAc, MeK(de), MeK(H), MeK(df) or MeK(datb); X2 is I, K, Cit, F4G, 4Py, 3Py, KCOpipzetOH, V, KCOpipzaa, Eva, Q, E, S, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeI, MeV, MeL, HseMe, MeY, Me3Py, MeHseMe, MeKAc, alI, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe or MeDapCOpipzaaa; X3 is D, Har, KCOpipzetOH, Cit, KCO meglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, KAc, Hgn, MeY or DapCOpipzaa; X4 is D, Har, KCOpipzetOH, KCO meglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, dd, MeQ, MeQdMe, MeA, MeSMe, MeG, EtG, MeeG, CmG, CmpG, CrmG, CeG, CrpG, MeK, MeKAc, MeHgl, Hgn, MeDapCOpipzaa, MeKCOpipzaa, Medd, Cit, MeCit, MeN, MeS, MeE, MeY, W5N or MeA4paa; X5 is Y, F3G, 3Py6COO, 4Py2NH2, 3Py5COO, F3COO, 3Py6NHAc, F, F4C, F4OMe, F4COO, Nal2, F3aao, F4aa, F4aao, 3Py6NHaa, 5Pdo, F3CON, F4F, F4OEt, F4Me, F4CON, F4CONPEG4Me, F3OMe, F3CON, Yae, YaeCOpipzaa, F4aaopipzaa, 4Pdo, 3Py6CON, Atp, Cha4cH, Cha4tH, Cha4cOMe, A1mor or F4amCOpipzaa; X6 is I, V, Eva, Chg, Tbg, A, L, Ahp, F4COO, Gcpr, Gcpe, alI, Cle, S3REt, TMe, Acpr, Cba, Gthp, NleCOO, NleOH, P, Atb, Nva, Nle, N, DapAc, Abu, Nmm, Ndm, Ncit, Cit, SMe, HseMe, HseEt, HseiPr, dMeS, TdMe, Cbg, NvaOMe, SiPr, Spr, NleOMe, Sbu, Scbm, Scpe, AhpOMe, HseBu, Spent or Hsecpe; X7 is I, Eva, alI, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe or Cbg; X8 is A, I, L, V, Y, F4OMe, F4COO, F4OEt, F4u, F4Me, F4CONdMe, F4CON, F4ms, F4CONPEG4Me, F34dOMe, F3OMe, F3C, F3CON, F3CONdMe , 3Py6CON, Yae, YaeCOpipzaa, 5Inda, F3aao, F3aa, F4aao, F4aa, 3Py6Nhae, 3Py6NHAc, 3Py6OMe, F4aaopipzaa or F4amCOpipzaa; X9 is MeNal2, MeNal27N, MeF34diox, MeF34dOMe, MeF4T, MeY, MeW1Me, MeW7N, MeF3C4Me or MeF3Me4C; X10 is a G or D-amino acid (e.g., da, ds, de, or dp); X11 is Bph, 3Py6Ph, F41Me4Pyz, F43Pyz, F44Pyz, F41Pyz, F41Me3Pyz, F41Et4Pyz, F41MeOe4Pyz, F41MeOp4Pyz, F44thp, F4Ac4pip, PhNva, PhNle, Yph, Ybn, F4tb, F4oPr, or F4CONdMe; and X12 is MeC.

[0333] In some embodiments of formula (I), (I-5), (III-2), or (IV-2), X1 is MeA, MeK, MeK(datb), MeK(de), MeK(df), MeK(H), MeKAc, MeKCOpipzaa, MeDapCOpipzaa or MeQ; X2 is MeA, HseMe, MeHseMe, MeI, MeL, MeQ, MeY, S, TMe, MeKCOpipzaa or Me3Py; X3 can be D, Hgn, KAc, MeY, or Q; X4 is MeA4paa, MeD, MeK, Q, MeQ, MeY, W5N, MeDapCOpipzaa or MeKCOpipzaa; X5 is 3Py6NHaa, F4aao, F4COO, Y or Yae; X6 is a1I, Cle, I, S3REt or TMe; X7 is I; X8 is F4aa, F4aao, F4aaopipzaa, F4amCOpipzaa, F4COO, F4u, Y, Yae or YaeCOpipzaa; X9 is MeNal2, MeNal27N, or MeY; X10 is G; X11 is either 3Py6Ph or F41Me4Pyz; and X12 is MeC.

[0334] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (III-1), (III-2), (IV-1), or (IV-2), X1 is MeA, MeK, MeK(datb), MeK(de), MeK(df), MeK(H), MeKAc, MeKCOpipzaa, MeDapCOpipzaa or MeQ; X2 is MeA, HseMe, MeHseMe, MeI, MeL, MeQ, MeY, S, TMe, MeKCOpipzaa or Me3Py; X3 can be D, Hgn, KAc, MeY, or Q; X4 is MeA4paa, MeD, MeK, Q, MeQ, MeY, W5N, MeDapCOpipzaa or MeKCOpipzaa; X5 is 3Py6NHaa, F4aao, F4COO, Y or Yae; X6 is a1I, Cle, I, S3REt or TMe; X7 is I; X8 is F4aa, F4aao, F4aaopipzaa, F4amCOpipzaa, F4COO, F4u, Y, Yae or YaeCOpipzaa; X9 is MeNal2, MeNal27N, or MeY; X10 is G; and X11 is either 3Py6Ph or F41Me4Pyz.

[0335] In some embodiments, the radiopharmaceutical conjugates of the present invention comprising the cyclic peptide of formula (I) have the structure of formula (III-1). Equation (III-1), in, -Connector- indicates a connector; R 1Choose the group composed of -NH2 and -OH; R 2 C 1-3 alkyl; R 3 For optional one or more R 4 Replacement C 1-3 Alkylene; Each R 4 Independently for C 1-3 Alkyl or C 3-6 cycloalkyl; kxR is 1, 2, 3, 4, 5 or 6; X R Choose from groups consisting of -S-, -CH2-, or -O-; and Where X1 to X11 have the definitions described in equation (I).

[0336] In some embodiments, the linker is connected to the first amino acid residue (or X1), the second amino acid residue (or X2), the third amino acid residue (or X3), the fourth amino acid residue (or X4), the eighth amino acid residue (or X8), or R. 1 The 12th amino acid residue at [location missing]. In some embodiments, the linker is linked to the 1st amino acid residue (or X1). In some embodiments, the linker is linked to the 2nd amino acid residue (or X2). In some embodiments, the linker is linked to the 3rd amino acid residue (or X3). In some embodiments, the linker is linked to the 4th amino acid residue (or X4). In some embodiments, the linker is linked to the 8th amino acid residue (or X8). In some embodiments, the linker is linked to R [location missing]. 1 The 12th amino acid residue at that position. In some embodiments, the linker is a bond. In some embodiments, the metal chelating agent is... (DOTA). In some embodiments, the radiopharmaceutical conjugate further comprises a radionuclide bound to a metal chelating agent.

[0337] In some embodiments, the radiopharmaceutical conjugates of the present invention comprising the cyclic peptide of formula (I) have the structure of formula (III-2). Equation (III-2) in X1 to X12 have the definitions described in formula (I), and Lcyc is a closed-ring group that covalently links X1 and X12; and -Connector- indicates a connector.

[0338] In some embodiments, the linker is attached to the first amino acid residue (or X1), the second amino acid residue (or X2), the third amino acid residue (or X3), the fourth amino acid residue (or X4), the eighth amino acid residue (or X8), or the twelfth amino acid residue (or X12). In some embodiments, the linker is attached to the first amino acid residue (or X1). In some embodiments, the linker is attached to the second amino acid residue (or X2). In some embodiments, the linker is attached to the third amino acid residue (or X3). In some embodiments, the linker is attached to the third amino acid residue (or X3). In some embodiments, the linker is attached to the fourth amino acid residue (or X4). In some embodiments, the linker is attached to the eighth amino acid residue (or X8). In some embodiments, the linker is attached to the twelfth amino acid residue (or X12). In some embodiments, the linker is a bond. In some embodiments, the metal chelating agent is... (DOTA). In some embodiments, the radiopharmaceutical conjugate further comprises a radionuclide bound to a metal chelating agent.

[0339] In some embodiments, the radiopharmaceutical conjugates of the present invention comprising the cyclic peptide of formula (I) have the structure of formula (IV-1). Formula (IV-1), in, -Connector- indicates a connector; R* represents a covalently bonded radionuclide; R 1 Choose the group composed of -NH2 and -OH; R 2 C 1-3 alkyl; R 3 For optional one or more R 4 Replacement C 1-3 Alkylene; Each R 4 Independently for C 1-3 Alkyl or C 3-6 cycloalkyl; kxR is 1, 2, 3, 4, 5 or 6; X R Choose from groups consisting of -S-, -CH2-, or -O-; and Where X1 to X11 have the definitions described in equation (I).

[0340] In some embodiments, the linker is attached to the 5th amino acid residue (or X5), the 8th amino acid residue (or X8), the 9th amino acid residue (or X9), or the 11th amino acid residue (or X11). In some embodiments, the linker is attached to the 5th amino acid residue (or X5). In some embodiments, the linker is attached to the 8th amino acid residue (or X8). In some embodiments, the linker is attached to the 9th amino acid residue (or X9). In some embodiments, the linker is attached to the 11th amino acid residue (or X11). In some embodiments, the linker is a bond.

[0341] In some embodiments, the radiopharmaceutical conjugates of the present invention comprising the cyclic peptide of formula (I) have the structure of formula (IV-2). Formula (IV-2) in X1 to X12 have the definitions described in formula (I), and Lcyc is a closed-ring group that covalently links X1 and X12; and -Connector- indicates a connector.

[0342] In some embodiments, the linker is attached to the 5th amino acid residue (or X5), the 8th amino acid residue (or X8), the 9th amino acid residue (or X9), or the 11th amino acid residue (or X11). In some embodiments, the linker is attached to the 5th amino acid residue (or X5). In some embodiments, the linker is attached to the 8th amino acid residue (or X8). In some embodiments, the linker is attached to the 9th amino acid residue (or X9). In some embodiments, the linker is attached to the 11th amino acid residue (or X11). In some embodiments, the linker is a bond.

[0343] In some embodiments, Lcyc is a group selected from Table 4B. In some embodiments, Lcyc is formed by reacting a first functional group in Table 4C with a second functional group. In some embodiments, Lcyc is -C(=O)-CH2-. In some embodiments, Lcyc is -C(=O)-CH2- formed by reacting a chloroacetylated (or bromoacetylated) amino acid with cysteine. In some embodiments, Lcyc is -C(=O)-CH2-S- formed by reacting a chloroacetylated (or bromoacetylated) amino acid with an amino acid containing an SH group.

[0344] In some embodiments, the radiopharmaceutical conjugates or their pharmaceutically acceptable salts disclosed herein have a cyclic structure in which an amino acid (e.g., a chloroacetylated amino acid) and a cysteine ​​residue or a variant thereof are present in the first residue X1, and wherein the amino acid (e.g., a chloroacetylated amino acid) in X1 is bound to a cysteine ​​residue or a variant thereof. In some embodiments, the radiopharmaceutical conjugates or their pharmaceutically acceptable salts disclosed herein have a cyclic structure in which an amino acid (e.g., a chloroacetylated amino acid) and a cysteine ​​residue or a variant thereof are present in the first residue X1, and wherein the amino acid (e.g., a chloroacetylated amino acid) in X1 is covalently bonded to a cysteine ​​residue or a variant thereof. In some embodiments, the radiopharmaceutical conjugates or their pharmaceutically acceptable salts disclosed herein have a cyclic structure in which a bromoacetylated amino acid and a cysteine ​​residue or a variant thereof are present in the first residue X1, and wherein the bromoacetylated amino acid in X1 is covalently bonded to a cysteine ​​residue or a variant thereof.

[0345] In some embodiments, the radiopharmaceutical conjugate consists of an amino acid sequence selected from SEQ ID NO: 1-72, and the peptide has a cyclic structure with a cysteine ​​residue or a variant thereof at the 12th residue (X12). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-72, and the peptide has a cyclic structure with a cysteine ​​residue or a variant thereof at the 12th residue (X12), wherein the chloroacetylated amino acid forms a covalent bond with the cysteine ​​residue or a variant thereof at the 12th residue. In some embodiments, the chloroacetyl group may be replaced by a bromoacetyl group.

[0346] In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 66-71, lacking any of the X3 amino acid residues, and has a cyclic structure with a cysteine ​​residue or a variant thereof at the "12th residue" (X12). In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-72, and has a cyclic structure with a cysteine ​​residue or a variant thereof at the 12th residue (X12), wherein the amino acid at X1 (e.g., a chloroacetylated amino acid) forms a covalent bond with the cysteine ​​residue or a variant thereof at the 12th residue. In some embodiments, the chloroacetyl group may be replaced by a bromoacetyl group.

[0347] In some embodiments, the radiopharmaceutical conjugates or their pharmaceutical salts disclosed herein have a cyclic structure having a first amino acid covalently linked to the last amino acid.

[0348] In some embodiments, the radiopharmaceutical conjugate or its pharmaceutically acceptable salt has a cyclic structure having a chloroacetylated amino acid in X1 and a cysteine ​​or cysteine ​​variant residue therefrom, wherein the chloroacetylated amino acid in X1 is bound to a cysteine ​​or a substituted cysteine. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-72. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-72 and has a cyclic structure. In some embodiments, the peptide consists of an amino acid sequence selected from SEQ ID NO: 1-72 and has a cyclic structure having a chloroacetylated amino acid and a cysteine ​​or cysteine ​​variant residue at a C-terminus, wherein the chloroacetylated amino acid is bound to a cysteine ​​or cysteine ​​variant therefrom at the C-terminus. In some embodiments, the peptide has a cyclic structure comprising a chloroacetylated amino acid, and (i) a total of 12 or more amino acids, a cysteine ​​residue or a cysteine ​​variant thereof at the 12th residue, wherein the chloroacetylated amino acid is bound to the cysteine ​​residue or a cysteine ​​variant thereof at the 12th residue; or (ii) a total of 11 or fewer amino acids, particularly lacking the X3 residue, the cysteine ​​residue or a cysteine ​​variant thereof at the 12th residue, wherein the chloroacetylated amino acid is bound to the cysteine ​​residue or a substituted cysteine ​​residue at the 12th residue. In some embodiments, the chloroacetyl group may be replaced by a bromoacetyl group.

[0349] In some embodiments, the radiopharmaceutical conjugate or its pharmaceutically acceptable salt comprises a peptide having an amino acid sequence having at least 95% identity with the sequences selected from SEQ ID NO: X1-X12 of SEQ ID NO: 1-72. In some embodiments, the peptide or its salt comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, or 98% identity with the sequences selected from SEQ ID NO: X1-X12 of SEQ ID NO: 1-72. In some embodiments, the peptide or its salt consists of an amino acid sequence selected from SEQ ID NO: X1-X12 of SEQ ID NO: 1-72. In some embodiments, the peptide or its salt comprises an amino acid sequence that differs from the sequences selected from SEQ ID NO: X1-X12 of SEQ ID NO: 1-72 by up to 1, 2, 3, 4, or 5 amino acid residues. In some embodiments, the amino acid sequence comprising the peptide or its salt has up to 1, 2, 3, 4, or 5 additions, deletions, and / or substitutions (including conservative substitutions) of the sequences selected from SEQ ID NO: X1-X12 of SEQ ID NO: 1-72. In some embodiments, the amino acid sequence comprising the peptide or its salt has up to 1 addition, deletion, or substitution (including conservative substitutions) of the sequences selected from SEQ ID NO: X1-X12 of SEQ ID NO: 1-72.

[0350] In some embodiments, the peptide or its salt comprises an amino acid sequence lacking the X3 amino acid residue of any of SEQ ID NO: 1-72 and having at least 70%, 80%, or 90% identity with the remaining residues of any of SEQ ID NO: 1-72. In some embodiments, the peptide or its salt comprises an amino acid sequence having at least 70%, 80%, or 90% identity with a sequence selected from SEQ ID NO: 66-71.

[0351] The exemplary peptides of the present invention include the peptides described in Table 1. In some embodiments, the peptides of Table 1 have a -C(=O)-halogen group attached to the N-terminus. In some embodiments, the peptides of Table 1 have a -C(=O)-CH2-halogen group attached to the N-terminus. In some embodiments, the peptides of Table 1 have a -C(=O)-halogen group attached at residue position 1. In some embodiments, the peptides of Table 1 have a -C(=O)-CH2-halogen group attached at residue position 1. In some embodiments, the peptides of Table 1 have a -C(=O)-Cl group attached to the N-terminus. In some embodiments, the peptides of Table 1 have a -C(=O)-CH2-Cl group attached to the N-terminus. In some embodiments, the peptides of Table 1 have a -C(=O)-Cl group attached at residue position 1. In some embodiments, the peptides of Table 1 have a -C(=O)-CH2-Cl group attached at residue position 1. In some embodiments, the peptides of Table 1 have a -C(=O)-Br group attached at residue position 1. In some embodiments, the peptides in Table 1 have a -C(=O)-CH2-Br group attached at residue position 1.

[0352] In some embodiments, the radiopharmaceutical conjugate of the present invention has a -C(=O)-halogen group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugate of the present invention has a -C(=O)-CH2-halogen group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugate of the present invention has a -C(=O)-halogen group attached at residue position 1. In some embodiments, the radiopharmaceutical conjugate of the present invention has a -C(=O)-Cl group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugate of the present invention has a -C(=O)-CH2-Cl group attached to the N-terminus. In some embodiments, the radiopharmaceutical conjugate of the present invention has a -C(=O)-Cl group attached at residue position 1. In some embodiments, the radiopharmaceutical conjugate of the present invention has a -C(=O)-CH2-Cl group attached at residue position 1. In some embodiments, the radiopharmaceutical conjugate of the present invention has a -C(=O)-Br group attached at residue position 1. In some embodiments, the radiopharmaceutical conjugate of the present invention has a -C(=O)-CH2-Br group attached at residue position 1. In some embodiments, the peptide in the radiopharmaceutical conjugate of the present invention is a monocyclic peptide.

[0353] In some embodiments, the peptide of the radiopharmaceutical conjugate described herein is a monocyclic peptide, wherein a -C(=O)-Cl residue at position 1 forms a bond with a cysteine ​​residue at position 12. In some embodiments, the peptide of the radiopharmaceutical conjugate described herein is a monocyclic peptide, wherein a -C(=O)-CH2-Cl residue at position 1 forms a bond with a cysteine ​​residue at position 12. In some embodiments, the peptide in the radiopharmaceutical conjugate described herein is a monocyclic peptide having a ring-forming 12 amino acid residue.

[0354] In some embodiments, the conjugates described herein are selected from the conjugates described in Table 2, Table 3A or Table 3B.

[0355] In some embodiments, this document describes a conjugate having the following structure or a pharmaceutically acceptable salt thereof: (C-30) (SEQ ID NO: 376). In some embodiments, this document describes a conjugate having the following structure or a pharmaceutically acceptable salt thereof: (C-30NOTA) (SEQ ID NO: 406). In some embodiments, this document describes a conjugate having the following structure or a pharmaceutically acceptable salt thereof: (Cu-C-30NOTA) (SEQ ID NO: 406). In some embodiments, Cu-C-30NOTA is... 64 Cu-C-30NOTA. In some embodiments, this document describes a conjugate having the following structure or a pharmaceutically acceptable salt thereof (SEQ ID NO:376): In some embodiments, this document describes a radiopharmaceutical having the following structure or a pharmaceutically acceptable salt thereof (SEQ ID NO:376): , where X M It is a radionuclide. In some embodiments, this document describes a radiopharmaceutical or a pharmaceutically acceptable salt thereof having the following structure (SEQ ID NO: 376): , where X M It is a radionuclide. In some embodiments, this document describes a radiopharmaceutical or a pharmaceutically acceptable salt thereof having the following structure (SEQ ID NO: 376): , where X M It is a radioactive nuclide. In some implementations, X M The radionuclides are selected from those in Table 7. In some embodiments, X M It is Ac-225. In some implementations, X M It is Lu-177. In some implementations, XM It is Ga-68.

[0356] In some embodiments, this document provides conjugates having the same peptide sequence and linker as those described in Tables 2, 3A, or 3B, except that the closed-loop bond between the amino acid residue at position 1 and the cysteine ​​(e.g., at position 12) is covalently linked by a different group. For example, the amino acid residue at position 1 may contain a group selected from maleic diamiimide, halides, disulfides, electron-deficient alkynes, thioesters, and alkenes, which forms a covalent bond with the cysteine.

[0357] In some embodiments, the peptides of the conjugates in Table 1 are monocyclic peptides, wherein the -C(=O)-Cl residue at position 1 forms a bond with the cysteine ​​residue at position 12. In some embodiments, the peptides of the conjugates in Table 1 are monocyclic peptides, wherein the -C(=O)-CH2-Cl residue at position 1 forms a bond with the cysteine ​​residue at position 12. In some embodiments, the peptides in the conjugates in Table 1 are monocyclic peptides having a ring-forming 12 amino acid residue.

[0358] In one aspect, this article describes a peptide with affinity for GPC3, wherein the peptide competes with peptides comprising the amino acid sequence of the following SEQ ID NO: 1, including deletions, substitutions, and / or additions of one or more amino acids: 1, for binding to human GPC3: MeK-MeI-D-MeQ-F4COO-IIY-MeNal27N-G-3Py6Ph-MeC (SEQ ID NO: 1) Or its medically acceptable salt.

[0359] In one aspect, this document describes a peptide with affinity for GPC3, wherein the peptide competes with peptides having the structure of formula (I) (e.g., formulas (I-1), (I-2), (I-3), (I-4) and (I-5)) for binding to human GPC3, or a pharmaceutically acceptable salt thereof.

[0360] In some embodiments, the binding affinity of the radiopharmaceutical conjugate to human GPC3 is at most 100 nM, as determined by Kd in surface plasma resonance (SPR) analysis. In some embodiments, the binding affinity of the radiopharmaceutical conjugate to human GPC3 is at most 1 nM, as determined by Kd in surface plasma resonance (SPR) analysis.

[0361] The structures of the illustrative non-natural amino acids present in Table 1 can be found in Table 5G.

[0362] As described in Table 1 or other tables, the abbreviations have the following meanings: The lowercase letter d refers to D-amino acids, for example, dF refers to d-phenylalanine; Me refers to methyl, for example, MeG represents N-methylglycine; Ala or A refers to alanine; Arg or R refers to arginine; Asn or N refers to asparagine; Asp or D refers to aspartic acid; Cys or C refers to cysteine; Gln or Q refers to glutamine; Gly or G refers to glycine; His or H refers to histidine; Ile or I refers to isoleucine; Leu or L-leucine; Lys or K refers to lysine; Met or M-methylthionine; Phe or F refers to phenylalanine; Pro or P refers to proline; Ser or S refers to serine; Thr or T refers to threonine; Trp or W refers to tryptophan; Tyr or Y refers to tyrosine; Val or V refers to valine; Unless otherwise stated in this specification, the following non-natural amino acid abbreviations shall be used as follows: F4G 2-amino-3-(4-guanidinylphenyl)propionic acid, such as (S)-2-amino-3-(4-guanidinylphenyl)propionic acid (CAS59574-11-7); 4Py 2-amino-3-(pyridin-4-yl)propionic acid, such as (S)-2-amino-3-(pyridin-4-yl)propionic acid (CAS37535-49-2); 3Py 2-amino-3-(pyridin-3-yl)propionic acid, such as (S)-2-amino-3-(pyridin-3-yl)propionic acid (CAS64090-98-8); Cit 2-amino-5-urevaline, such as (S)-2-amino-5-urevaline (CAS 372-75-8); KCOpipzaa 2-amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid, such as (2S)-2-amino-6-{[4-(carboxymethyl)piperazine-1-carbonyl]amino}hexanoic acid ; Eva 2-amino-3-ethylpentanoic acid, such as (S)-2-amino-3-ethylpentanoic acid (CAS 14328-49-5); Ahp 2-aminoheptanoic acid, such as (S)-2-aminoheptanoic acid (CAS No. 44902-02-5); F4COO 4-(2-amino-2-carboxyethyl)benzoic acid, such as (S)-4-(2-amino-2-carboxyethyl)benzoic acid (CAS126109-42-0); KCOpip4COO 1-((5-amino-5-carboxypentyl)carbamoyl)piperidine-4-carboxylic acid, such as (S)-1-((5-amino-5-carboxypentyl)carbamoyl)piperidine-4-carboxylic acid ; Aib 2-amino-2-methylpropionic acid (CAS 62-57-7); Hpr piperidine-2-carboxylic acid, such as (S)-piperidine-2-carboxylic acid (CAS 3105-95-1); Sbu 2-amino-3-butoxypropionic acid, such as (2S)-2-amino-3-butoxypropionic acid (CAS 138320-46-4); MeDapCOpipzaa 3-(4-(carboxymethyl)piperazin-1-formamide)-2-(methylamino)propionic acid, such as (S)-3-(4-(carboxymethyl)piperazin-1-formamide)-2-(methylamino)propionic acid ; Scbm 2-amino-3-(cyclobutylmethoxy)propionic acid, such as (2S)-2-amino-3-(cyclobutylmethoxy)propionic acid ; Sbu 2-amino-3-butoxypropionic acid, such as (2S)-2-amino-3-butoxypropionic acid (CAS 138320-46-4); Scpe 2-amino-3-(cyclopentoxy)propionic acid, such as (2S)-2-amino-3-(cyclopentoxy)propionic acid (CAS1509921-28-1); HseBu 2-amino-4-butoxybutyric acid, such as (2S)-2-amino-4-butoxybutyric acid (CAS 17673-71-1); A4paa 2-amino-3-(1-(carboxymethyl)piperidin-4-yl)propionic acid, such as (S)-2-amino-3-(1-(carboxymethyl)piperidin-4-yl)propionic acid ; Spent 2-amino-3-(pentoxy)propionic acid, such as (2S)-2-amino-3-(pentoxy)propionic acid (CAS1502644-74-7); Hgl 2-Aminohexanoic acid, such as (S)-2-aminohexanoic acid (CAS 1118-90-7) Hsecpe 2-amino-4-(cyclopentoxy)butyric acid, such as (2S)-2-amino-4-(cyclopentoxy)butyric acid (CAS1501949-22-9); Hgn 2,6-diamino-6-oxohexanoic acid, such as (S)-2,6-diamino-6-oxohexanoic acid (CAS 7433-32-1); DapCOpipzaa 2-amino-3-(4-(carboxymethyl)piperazin-1-formylamino)propionic acid, such as (S)-2-amino-3-(4-(carboxymethyl)piperazin-1-formylamino)propionic acid ; MeD 2-(methylamino)succinic acid, such as (2S)-2-(methylamino)succinic acid (CAS 4226-18-0); CmG 2-[(2-carbamoylethyl)amino]acetic acid (CAS 34299-32-6); Medd 2-(methylamino)succinic acid, such as (2R)-2-(methylamino)succinic acid (CAS 6384-92-5); HseEt 2-amino-4-ethoxybutyric acid, such as (2S)-2-amino-4-ethoxybutyric acid (CAS 17268-93-8); HseiPr 2-amino-4-(prop-2-yloxy)butyric acid, such as (2S)-2-amino-4-(prop-2-yloxy)butyric acid (CAS 685842-10-8); CrmG 2,2'-N-dimethyldiacetic acid (CAS 142-73-4); CeG 3-((carboxymethyl)amino)propionic acid (CAS 505-72-6); CrpG 4-((carboxymethyl)amino)butyric acid (CAS 4386-04-3); MeHgl 2-(methylamino)adipic acid, such as (S)-2-(methylamino)adipic acid (CAS 261943-13-9); MeCit 2-(methylamino)-5-urevaline, such as (S)-2-(methylamino)-5-urevaline (CAS2226129-88-8); F3G 2-amino-3-(3-guanidinylphenyl)propionic acid, such as (S)-2-amino-3-(3-guanidinylphenyl)propionic acid (CAS1019057-42-1); 3Py6COO 5-(2-amino-2-carboxyethyl)pyridinecarboxylic acid, such as (S)-5-(2-amino-2-carboxyethyl)pyridinecarboxylic acid (CAS 1269945-31-4); 4Py2NH2 2-Amino-3-(2-aminopyridin-4-yl)propionic acid, such as (S)-2-amino-3-(2-aminopyridin-4-yl)propionic acid (CAS 1269969-46-1); 3Py5COO 5-(2-amino-2-carboxyethyl)nicotinic acid, such as (S)-5-(2-amino-2-carboxyethyl)nicotinic acid (CAS 1270138-35-6); F3COO 3-(2-amino-2-carboxyethyl)benzoic acid, such as (S)-3-(2-amino-2-carboxyethyl)benzoic acid (CAS13861-02-4) 3Py6NHAc 3-(6-acetamidopyridin-3-yl)-2-aminopropionic acid, such as (S)-3-(6-acetamidopyridin-3-yl)-2-aminopropionic acid (CAS 1270189-35-9); F4C 2-amino-3-(4-chlorophenyl)propionic acid, such as (S)-2-amino-3-(4-chlorophenyl)propionic acid (CAS14173-39-8) F4OMe 2-amino-3-(4-methoxyphenyl)propionic acid, such as (S)-2-amino-3-(4-methoxyphenyl)propionic acid (CAS 6230-11-1); Nal2 2-amino-3-(naphthyl-2-yl)propionic acid, such as (S)-2-amino-3-(naphthyl-2-yl)propionic acid (CAS 58438-03-2); F3aao 2-Amino-3-(3-(carboxymethoxy)phenyl)propionic acid, such as (S)-2-amino-3-(3-(carboxymethoxy)phenyl)propionic acid ; F4aa 2-Amino-3-(4-(carboxymethyl)phenyl)propionic acid, such as (S)-2-amino-3-(4-(carboxymethyl)phenyl)propionic acid (CAS 140233-60-9); F4aao 2-amino-3-(4-(carboxymethoxy)phenyl)propionic acid, such as (S)-2-amino-3-(4-(carboxymethoxy)phenyl)propionic acid (CAS 24558-63-2); 3Py6NHaa 2-amino-3-(6-((carboxymethyl)amino)pyridin-3-yl)propionic acid, such as (S)-2-amino-3-(6-((carboxymethyl)amino)pyridin-3-yl)propionic acid ; 5Pdo 2-amino-3-(6-oxo-1,6-dihydropyridin-3-yl)propionic acid, such as (S)-2-amino-3-(6-oxo-1,6-dihydropyridin-3-yl)propionic acid (CAS 140681-92-1); F3CON 2-amino-3-(3-carbamoylphenyl)propionic acid, such as (S)-2-amino-3-(3-carbamoylphenyl)propionic acid (CAS 1217651-22-3); F4F 2-Amino-3-(4-fluorophenyl)propionic acid, such as (S)-2-amino-3-(4-fluorophenyl)propionic acid (CAS 1132-68-9); F4OEt 2-Amino-3-(4-ethoxyphenyl)propionic acid, such as (S)-2-amino-3-(4-ethoxyphenyl)propionic acid (CAS 32795-52-1); F4Me 2-Amino-3-(p-Tolyl)propionic acid, such as (S)-2-amino-3-(p-Tolyl)propionic acid (CAS1991-87-3); F4CON 2-amino-3-(4-carbamoylphenyl)propionic acid, such as (S)-2-amino-3-(4-carbamoylphenyl)propionic acid (CAS 223593-04-2); F4CONPEG4Me 3-(4-((2,5,8,11-tetraoxatridecane-13-yl)carbamoyl)phenyl)-2-aminopropionic acid, such as (S)-3-(4-((2,5,8,11-tetraoxatridecane-13-yl)carbamoyl)phenyl)-2-aminopropionic acid ; F3OMe 2-amino-3-(3-methoxyphenyl)propionic acid, such as (S)-2-amino-3-(3-methoxyphenyl)propionic acid (CAS 33879-32-2); YaeCOpipzaa 2-amino-3-(4-(2-(4-(carboxymethyl)piperazin-1-formylamino)ethoxy)phenyl)propionic acid, such as (S)-2-amino-3-(4-(2-(4-(carboxymethyl)piperazin-1-formylamino)ethoxy)phenyl)propionic acid ; F4aaopipzaa 2-amino-3-(4-(2-(4-(carboxymethyl)piperazin-1-yl)-2-oxoethoxy)phenyl)propionic acid, such as (S)-2-amino-3-(4-(2-(4-(carboxymethyl)piperazin-1-yl)-2-oxoethoxy)phenyl)propionic acid ; 4Pdo 2-amino-3-(2-oxo-1,2-dihydropyridin-4-yl)propionic acid, such as (S)-2-amino-3-(2-oxo-1,2-dihydropyridin-4-yl)propionic acid (CAS 1270061-10-3); 3Py6CON 2-amino-3-(6-carbamoylpyridin-3-yl)propionic acid, such as (S)-2-amino-3-(6-carbamoylpyridin-3-yl)propionic acid ; Atp 2-amino-3-(tetrahydro-2H-piperan-4-yl)propionic acid, such as (S)-2-amino-3-(tetrahydro-2H-piperan-4-yl)propionic acid (CAS 1344910-91-3); Cha4cH 2-Amino-3-((1s,4R)-4-hydroxycyclohexyl)propionic acid, such as (S)-2-amino-3-((1s,4R)-4-hydroxycyclohexyl)propionic acid ; Cha4tH 2-amino-3-((1r,4S)-4-hydroxycyclohexyl)propionic acid, such as (S)-2-amino-3-((1r,4S)-4-hydroxycyclohexyl)propionic acid (CAS 221243-22-7); Cha4cOMe 2-Amino-3-((1s,4R)-4-methoxycyclohexyl)propionic acid, such as (S)-2-amino-3-((1s,4R)-4-methoxycyclohexyl)propionic acid ; A1mor 2-amino-3-N-morpholinopropionic acid, such as (S)-2-amino-3-N-morpholinopropionic acid (CAS1931924-34-3); F4amCOpipzaa 2-Amino-3-(4-((4-(carboxymethyl)piperazin-1-formylamino)methyl)phenyl)propionic acid, such as (S)-2-amino-3-(4-((4-(carboxymethyl)piperazin-1-formylamino)methyl)phenyl)propionic acid ; Chg 2-amino-2-cyclohexylacetic acid, such as (S)-2-amino-2-cyclohexylacetic acid (CAS 14328-51-9); Cle 1-aminocyclopentane-1-carboxylic acid (CAS 52-52-8); Tbg 2-amino-3,3-dimethylbutyric acid, such as (S)-2-amino-3,3-dimethylbutyric acid (CAS 20859-02-3); Gcpr 2-amino-2-cyclopropylacetic acid, such as (S)-2-amino-2-cyclopropylacetic acid (CAS 49606-99-7); Gcpe 2-amino-2-cyclopentylacetic acid, such as (S)-2-amino-2-cyclopentylacetic acid (CAS 2521-84-8); Acpr 2-amino-3-cyclopropylpropionic acid, such as (S)-2-amino-3-cyclopropylpropionic acid (CAS 102735-53-5); Cba 2-amino-3-cyclobutylpropionic acid, such as (S)-2-amino-3-cyclobutylpropionic acid (CAS 1201593-65-8); Gthp 2-amino-2-(tetrahydro-2H-piperan-4-yl)acetic acid, such as (S)-2-amino-2-(tetrahydro-2H-piperan-4-yl)acetic acid (CAS 811842-25-8); NleCOO 2-Aminopimelic acid, such as (S)-2-aminopimelic acid (CAS 26630-55-7); NleOH 2-amino-6-hydroxyhexanoic acid, such as (S)-2-amino-6-hydroxyhexanoic acid (CAS 6033-32-5); Atb 2-amino-4,4-dimethylvaleric acid, such as (S)-2-amino-4,4-dimethylvaleric acid (CAS 57224-50-7); Nva 2-aminovaleric acid, such as (S)-2-aminovaleric acid (CAS 6600-40-4); Nle 2-aminohexanoic acid, such as (S)-2-aminohexanoic acid (CAS 327-57-1); DapAc 3-acetamido-2-aminopropionic acid, such as (S)-3-acetamido-2-aminopropionic acid (CAS 20584-70-7); Abu 2-aminobutyric acid, such as (S)-2-aminobutyric acid (CAS 1492-24-6); Ncit 2-amino-4-ureobutyric acid, such as (S)-2-amino-4-ureobutyric acid (CAS 1190-47-2); dMeS 2-amino-3-hydroxy-3-methylbutyric acid, such as (S)-2-amino-3-hydroxy-3-methylbutyric acid (CAS2280-27-5); TdMe 2-amino-3-methoxy-3-methylbutyric acid, such as (S)-2-amino-3-methoxy-3-methylbutyric acid (CAS 2280-29-7); Cbg 2-amino-2-cyclobutylacetic acid, such as (S)-2-amino-2-cyclobutylacetic acid (CAS 49607-08-1); NvaOMe 2-amino-5-methoxyvalerate, such as (S)-2-amino-5-methoxyvalerate (CAS 1315051-48-9); NleOMe 2-amino-6-methoxyhexanoic acid, such as (S)-2-amino-6-methoxyhexanoic acid (CAS 1690134-89-4); AhpOMe 2-amino-7-methoxyheptanoic acid, such as (S)-2-amino-7-methoxyheptanoic acid; F4u 2-amino-3-(4-ureophenyl)propionic acid, such as (S)-2-amino-3-(4-ureophenyl)propionic acid (CAS32401-733-4); F4CONdMe 2-Amino-3-(4-(dimethylcarbamoyl)phenyl)propionic acid, such as (S)-2-amino-3-(4-(dimethylcarbamoyl)phenyl)propionic acid (CAS 2349530-31-8); F4ms 2-Amino-3-(4-(methanesulfonyl)phenyl)propionic acid, such as (S)-2-amino-3-(4-(methanesulfonyl)phenyl)propionic acid (CAS 1195655-47-0); F34dOMe 2-amino-3-(3,4-dimethoxyphenyl)propionic acid, such as (S)-2-amino-3-(3,4-dimethoxyphenyl)propionic acid (CAS 32161-30-1); F3C 2-amino-3-(3-chlorophenyl)propionic acid, such as (S)-2-amino-3-(3-chlorophenyl)propionic acid (CAS80126-51-8); F3CONdMe 2-Amino-3-(3-(dimethylcarbamoyl)phenyl)propionic acid, such as (S)-2-amino-3-(3-(dimethylcarbamoyl)phenyl)propionic acid ; 5Inda 2-amino-3-(1H-indazol-5-yl)propionic acid, such as (S)-2-amino-3-(1H-indazol-5-yl)propionic acid (CAS 1335577-14-4); F3aa 2-amino-3-(3-(carboxymethyl)phenyl)propionic acid, such as (S)-2-amino-3-(3-(carboxymethyl)phenyl)propionic acid (CAS 1270107-31-7); 3Py6Nhae 2-amino-3-(6-((2-aminoethyl)amino)pyridin-3-yl)propionic acid, such as (S)-2-amino-3-(6-((2-aminoethyl)amino)pyridin-3-yl)propionic acid ; 3Py6OMe 2-amino-3-(6-methoxypyridin-3-yl)propionic acid, such as (S)-2-amino-3-(6-methoxypyridin-3-yl)propionic acid (CAS 1270178-24-9); MeNal2 2-(methylamino)-3-(naphth-2-yl)propionic acid, such as (S)-2-(methylamino)-3-(naphth-2-yl)propionic acid ; MeNal27N 3-(isoquinolin-7-yl)-2-(methylamino)propionic acid, such as (S)-3-(isoquinolin-7-yl)-2-(methylamino)propionic acid ; MeF34diox 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylamino)propionic acid, such as (S)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylamino)propionic acid ; MeF34dOMe 3-(3,4-dimethoxyphenyl)-2-(methylamino)propionic acid, such as (S)-3-(3,4-dimethoxyphenyl)-2-(methylamino)propionic acid (CAS 52939-34-1); MeF4T 2-(methylamino)-3-(4-(trifluoromethyl)phenyl)propionic acid, such as (S)-2-(methylamino)-3-(4-(trifluoromethyl)phenyl)propionic acid ; MeW7N 2-(methylamino)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propionic acid, such as (S)-2-(methylamino)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propionic acid (CAS 356067-71-5); MeF3C4Me 3-(3-chloro-4-methylphenyl)-2-(methylamino)propionic acid, such as (...

Claims

1. A radiopharmaceutical or a medically acceptable salt thereof, the radiopharmaceutical comprising: (a) Peptide of formula (I-1), Formula (I-1), in: R 1 It can be -NH2 or -OH; R 2 C 1-3 alkyl; R 3 For optional one or more R 4 Replacement C 1-3 Alkylene; Each R 4 Independently for C 1-3 Alkyl or C 3-6 cycloalkyl; kxR is 1, 2, 3, 4, 5 or 6; X R It can be -S-, -CH2-, or -O-; X1 can be any amino acid; X2 can be any amino acid; X3 can be any amino acid; X4 can be any amino acid; X5 is an amino acid containing an aromatic ring, cycloalkyl group, or heterocyclic alkyl group, or X5 is a peptide-like substance; X6 is a hydrophobic amino acid, a hydrophilic amino acid, or a polar amino acid, wherein the polar amino acid has a substituted side chain. X7 is a hydrophobic amino acid containing C1-C8 alkyl, cycloalkyl, or heterocycloalkyl groups, wherein each of the alkyl, cycloalkyl, and heterocycloalkyl groups is optionally substituted independently; X8 is A, I, L, V, Y, or F or a variant thereof; X9 is an N-alkylated amino acid containing an aromatic ring; X10 is G or A or its N-alkylated variant, or a D-amino acid; and X11 is an amino acid containing an aromatic ring; and (b) A metal chelating agent that binds to a radionuclide, wherein the metal chelating agent is covalently linked to the peptide.

2. The radiopharmaceutical of claim 1 or a medically acceptable salt thereof, wherein the radiopharmaceutical conjugate is selected from Table 3A or Table 3B.

3. A radiopharmaceutical having the following structure: or its medically acceptable salt, wherein X M It is a radioactive nuclide.

4. A conjugate or a pharmaceutically acceptable salt thereof, the conjugate comprising: (a) Peptide of formula (I-1), Formula (I-1), in: R 1 It can be -NH2 or -OH; R 2 C 1-3 alkyl; R 3 For optional one or more R 4 Replacement C 1-3 Alkylene; Each R 4 Independently for C 1-3 Alkyl or C 3-6 cycloalkyl; kxR is 1, 2, 3, 4, 5 or 6; X R It can be -S-, -CH2-, or -O-; X1 can be any amino acid; X2 can be any amino acid; X3 can be any amino acid; X4 can be any amino acid; X5 is an amino acid containing an aromatic ring, cycloalkyl group, or heterocyclic alkyl group, or X5 is a peptide-like substance; X6 is a hydrophobic amino acid, a hydrophilic amino acid, or a polar amino acid, wherein the polar amino acid has a substituted side chain. X7 is a hydrophobic amino acid containing C1-C8 alkyl, cycloalkyl, or heterocycloalkyl groups, wherein each of the alkyl, cycloalkyl, and heterocycloalkyl groups is optionally substituted independently; X8 is A, I, L, V, Y, or F or a variant thereof; X9 is an N-alkylated amino acid containing an aromatic ring; X10 is G or A or its N-alkylated variant, or a D-amino acid; and X11 is an amino acid containing an aromatic ring; and (b) A metal chelating agent configured to bind to a radionuclide, wherein the metal chelating agent is covalently linked to the peptide.

5. The radiopharmaceutical of claim 1 or a pharmaceutically acceptable salt thereof, or the conjugate of claim 4 or a pharmaceutically acceptable salt thereof, wherein the metal chelating agent 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, NOA, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2-Bn-NO TA, 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, or maleic anhydride-nBu-DOTA.

6. The radiopharmaceutical of claim 1 or a medically acceptable salt thereof, or the conjugate of claim 4 or a medically acceptable salt thereof, wherein the metal chelating agent has the following structure: (DOTA) (DOTA-GA) , (PCTA) (p-NH2-Bn-PCTA) (pBn-SCN-PCTA) (SCN-NOTA) (H2-MACROPA-NCS) (4-(S,S,S,S)-Et-DOTA) or (cis-butenedimide-nBu-DOTA).

7. The radiopharmaceutical of claim 6 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein the metal chelating agent has the following structure: (DOTA)。 8. A radiopharmaceutical or a medically acceptable salt thereof as claimed in any one of claims 1 to 3 or 5 to 7, or a conjugate or a medically acceptable salt thereof as claimed in any one of claims 4 to 7, wherein the radionuclide is a radionuclide that emits alpha particles.

9. The radiopharmaceutical of claim 8 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein the radionuclide emitting alpha particles is Ac-225, Bi-213, Bi-209, Tb-149, Ra-223, Th-227, Fr-223, Gd-148, Th-229, Pb-212 or Po-213.

10. The radiopharmaceutical of claim 9 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein the radionuclide emitting alpha particles is Ac-225.

11. A radiopharmaceutical or a medically acceptable salt thereof as claimed in any one of claims 1 to 3 or 5 to 7, or a conjugate or a medically acceptable salt thereof as claimed in any one of claims 4 to 7, wherein the radionuclide is a radionuclide that emits beta particles.

12. The radiopharmaceutical of claim 11 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein the radionuclide emitting β particles is Cu-67, Lu-177, Y-90, Rh-105, Yb-175, Tm-167, Pm-153, Sm-153 or In-111.

13. The radiopharmaceutical of claim 12 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein the radionuclide emitting β particles is Lu-177.

14. A radiopharmaceutical or a medically acceptable salt thereof as claimed in any one of claims 1 to 3 or 5 to 7, or a conjugate or a medically acceptable salt thereof as claimed in any one of claims 4 to 7, wherein the radionuclide is a positron-emitting radionuclide.

15. The radiopharmaceutical of claim 14 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein the positron-emitting radionuclide is Ga-68, Cu-62, Cu-64, Zr-89, or Tb-152.

16. The radiopharmaceutical of claim 15 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein the positron-emitting radionuclide is Ga-68.

17. A radiopharmaceutical or a medically acceptable salt thereof as claimed in any one of claims 1 to 3 or 5 to 7, or a conjugate or a medically acceptable salt thereof as claimed in any one of claims 4 to 7, wherein the radionuclide is Ac-225, Lu-177 or Ga-68.

18. The radiopharmaceutical or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 17, or the conjugate or a pharmaceutically acceptable salt thereof as claimed in any one of claims 4 to 17, further comprising a linker covalently linking the peptide to the metal chelating agent.

19. A radiopharmaceutical or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 18, or a conjugate or a pharmaceutically acceptable salt thereof as claimed in any one of claims 4 to 18, wherein the linker is attached to a lysine residue of the peptide.

20. A radiopharmaceutical or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 19, or a conjugate or a pharmaceutically acceptable salt thereof as claimed in any one of claims 4 to 19, wherein the connector is connected to X1, X2, X3, X4, X8, or X12.

21. A radiopharmaceutical or a medically acceptable salt thereof as claimed in any one of claims 1 to 20, or a conjugate or a medically acceptable salt thereof as claimed in any one of claims 4 to 20, wherein the connector is connected to X1.

22. A radiopharmaceutical or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 21, or a conjugate or a pharmaceutically acceptable salt thereof as claimed in any one of claims 4 to 21, wherein the linker is a bond.

23. A radiopharmaceutical or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 21, or a conjugate or a pharmaceutically acceptable salt thereof as claimed in any one of claims 4 to 21, wherein the linker comprises 3 to 30 intercalary non-hydrogen organic atoms between the metal chelating agent and the peptide.

24. A radiopharmaceutical or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 23, or a conjugate or a pharmaceutically acceptable salt thereof as claimed in any one of claims 4 to 23, wherein the peptide has the structure of formula (I-2): (I-2)。 25. A radiopharmaceutical as claimed in any one of claims 1 to 24, or a medically acceptable salt thereof, or a conjugate as claimed in any one of claims 4 to 24, or a medically acceptable salt thereof, wherein: X1 is I, R, Cit, F4G, 4Py, 3Py, KCOpipzaa, V, Eva, Q, E, MeI, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, MeV, MeHseMe, A ib, MeT, alI, TMe, MeKCOpipzaa, MeQ, Hpr, MeTMe, MeDapCOpipzaa, MeE, MeK, MeKAc, MeK(de), MeK(H), MeK(df) or MeK(datb); X2 is I, K, Cit, F4G, 4Py, 3Py, KCOpipzetOH, V, KCOpipzaa, Eva, Q, E, S, Ahp, F4COO, KCOpip4COO, MeQdMe, MeA, MeSMe, MeG, M eI, MeV, MeL, HseMe, MeY, Me3Py, MeHseMe, MeKAc, aI, TMe, MeTMe, MeK, MeKCOpipzaa, MeQ, Hpr, MeTMe or MeDapCOpipzaaa; X3 is D, Har, KCOpipzetOH, Cit, KCO meglumine, KCOpipzaa, A4paa, Q, A, da, MeA, Abu, Dap, diMeDap, G, MeG, V, E, MeD, S, T, N, Hgl, F4COO, KCOpip4COO, K, KAc, Hgn, MeY or DapCOpipzaa; X4 is D, Har, KCOpipzetOH, KCO meglumine, KCOpipzaa, A4paa, Q, A, E, MeD, S, N, Hgl, F4COO, KCOpip4COO, dd, MeQ, MeQdMe, MeA, MeSMe, MeG, EtG, Mee G, CmG, CmpG, CrmG, CeG, CrpG, MeK, MeKAc, MeHgl, Hgn, MeDapCOpipzaa, MeKCOpipzaa, Medd, Cit, MeCit, MeN, MeS, MeE, MeY, W5N or MeA4paa; X5 is Y, F3G, 3Py6COO, 4Py2NH2, 3Py5COO, F3COO, 3Py6NHAc, F, F4C, F4OMe, F4COO, MeF4COO, Nal2, F3aao, F4aa, F4aao, 3Py6NHaa, 5Pdo, F3CON, F4F, F4OEt, F4Me, F4CON, F4CONPEG4Me, F3OMe, F3CON, Yae, YaeCOpipzaa, F4aaopipzaa, 4Pdo, 3Py6CON, Atp, Cha4cH, Cha4tH, Cha4cOMe, A1mor or F4amCOpipzaa; X6 is I, V, Eva, Chg, Tbg, A, L, Ahp, F4COO, Gcpr, Gcpe, alI, Cle, S3REt, TMe, alTMe, Acpr, Cba, Gthp, NleCOO, NleOH, P, Atb, Nva, Nle, N, DapAc, Abu, Nmm, Ndm, Ncit, Cit, SMe, HseMe, HseEt, HseiPr, dMeS, TdMe, Cbg, NvaOMe, SiPr, Spr, NleOMe, Sbu, Scbm, Scpe, AhpOMe, HseBu, Spent or Hsecpe; X7 is I, A, L, V, Eva, alI, TMe, SMe, Gcpr, Gcpe, Gthp, dMeS, TdMe or Cbg; X8 is A, I, L, V, Y, Cha, Aph, F4OMe, F4COO, F4OEt, F4u, F4Me, F4F, F4CONdMe, F4CON, F4ms, F4CONPEG4Me, F34dOMe, F3OMe, F3C, F3CON, F3CONdMe, 3Py6CON, Yae, YaeCOpipzaa, 5Inda, F3OH, F3aao, F3aa, F4aao, F4aa, 3Py6Nhae, 3Py6NHAc, 3Py6OMe, F4aaopipzaa or F4amCOpipzaa; X9 is MeNal2, MeNal27N, MeF34diox, MeF34dOMe, MeF4T, MeY, MeW1Me, MeiW, Me(7Me)6inda, Me(7Me)6indol, Me6inda, MeW7N, MeF3C4Me or MeF3Me4C; X10 is G, MeG, A or D - amino acid; and X11 is Bph, 3Py6Ph, F41Me4Pyz, F43Pyz, F44Pyz, F41Pyz, F41Me3Pyz, F41Et4Pyz, F41MeOe4Pyz, F41M eOp4Pyz, F44thp, F4Ac4pip, PhNva, PhNle, Yph, Ybn, F4tb, F4oPr, F4CONdMe, 3Py(6-(2-Py)), 3Py( 6-(3-Py)), 3Py(6-(4-Py)), 3Py6(Pip1), 3Py6Imidaz1, 3Py6Me, 3Py6Oxaz5, 3Py6Pipza, 3Py6Pyra zol1, 3Py6Pyrazol3, 3Py6Pyrrol1, Phe(4-(2-Py)), Phe(4-(3-Py)), Phe(4-(4-Py)) or Phe35N4Ph.

26. A radiopharmaceutical as claimed in any one of claims 1 to 24, or a medically acceptable salt thereof, or a conjugate as claimed in any one of claims 4 to 24, or a medically acceptable salt thereof, wherein: X1 can be any amino acid; X2 can be any amino acid; X3 can be any amino acid; X4 can be any amino acid; X5 is ,in: R n5 It is hydrogen or C 1-3 alkyl; Ring A5 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; Each R X5 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)NR c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X5 -heterocyclic alkyl, -L X5 -cycloalkyl, -L X5 -Aryl or -L X5 - Heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally derived from one or more R... X5a Replace; or Two Rs X5 Together they form =O, =S, or =N(R) a ); L X5 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X5a replace; kx5 is 0, 1, 2 or 3; mx5 can be 0, 1, 2, 3, 4 or 5; *X4 indicates the connection point with X4; and *X6 indicates the connection point with X6; X6 is ,in: R n6 It is hydrogen or C 1-3 alkyl; R X6 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X6 -heterocyclic alkyl, -L X6 -cycloalkyl, -L X6 -Aryl or -L X6 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X6a Replace; or R n6 and R x6 Together with intermediary atoms, they form one or more optional R atoms. X6a Substituted 5- to 6-membered heterocyclic alkyl groups; L X6 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X6a replace; *X5 indicates the connection point with X5; and *X7 indicates the connection point with X7; X7 is ,in: R n7 It is hydrogen or C 1-3 alkyl; R X7 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, heteroalkyl, alkenyl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R groups. X7a replace; R X7' It is hydrogen or C 1-3 alkyl; *X6 indicates the connection point with X6; and *X8 indicates the connection point with X8; X8 is ,in: R n8 It is hydrogen or C 1-3 alkyl; Ring A8 is aryl or heteroaryl; Each R X8 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X8 -heterocyclic alkyl, -L X8 -cycloalkyl, -L X8 -Aryl or -L X8 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X8a Replace; or Two Rs X8 Together they form =O, =S, or =N(R) a ); L X8 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X8a replace; kx8 can be 0, 1, 2, or 3; mx8 can be 0, 1, 2, 3, 4 or 5; *X7 indicates the connection point with X7; and *X9 indicates the connection point with X9; X9 is ,in: R n9 It is hydrogen or C 1-3 alkyl; Ring A9 is aryl or heteroaryl; Each R X9 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5 or -NR c R d The alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally derived from one or more R groups. X9a Replace; or Two Rs X9 Together they form =O, =S, or =N(R) a ); kx9 is 0, 1, 2, or 3; mx9 can be 0, 1, 2, 3, 4 or 5; *X8 indicates the connection point with X8; and *X10 indicates the connection point with X10; X10 is glycine, methylglycine, or a D-amino acid; X11 is ,in: R n11 It is hydrogen or C 1-3 alkyl; Ring A11 is aryl or heteroaryl; Each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X11 -heterocyclic alkyl, -L X11 -cycloalkyl, -L X11 -Aryl or -L X11 -heteroaryl, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X11a Replace; or Two Rs X11 Together they form =O, =S, or =N(R) a ); L X11 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X11a replace; kx11 is 0, 1, 2, 3, 4 or 5; mx11 can be 0, 1, 2, 3, 4 or 5; *X10 indicates the connection point with X10; and *X12 indicates that N(R) 2 () connection points; R X5a R X6a R X7a R X8a R X9a and R X11a Each independently constitutes a halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; Each R a Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is independently optionally etched with one or more R... e replace; Each R e Independently, it can be halogen, -CN, -OH, -O-C1-C6 alkyl, -SF5, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2-halogen, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=NH)NH 2. -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, C1-C6 alkyl-C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; or two R e Together they form = O; and Each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocycloalkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups is independently optionally etched with one or more R... e Replace; or R c and R d Together with the atoms they are attached to, they form one or more optional R... e Substituted heterocyclic alkyl groups.

27. The radiopharmaceutical of claim 26 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein X1 is an N-alkylated amino acid.

28. The radiopharmaceutical of claim 26 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein: X1 is ,in: R n1 It is hydrogen or C 1-3 alkyl; R X1 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X1 -heterocyclic alkyl, -L X1 -cycloalkyl, -L X1 -Aryl or -L X1 - Heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X1a replace; R X1' It is hydrogen or C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X1a Replace; or R n1 and R X1' Together with intermediary atoms, they form one or more optional R atoms. X1a Substituted 5- to 6-membered heterocyclic alkyl groups; L X1 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X1a replace; Each R X1a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X12 indicates a combination with C(O)(CH2). kxR Connection points; and *X2 represents the connection point with X2.

29. The radiopharmaceutical of claim 28 or a medically acceptable salt or conjugate thereof, wherein: X1 is ,in: R n1 It can be hydrogen or methyl; R X1 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 heteroalkyl, -L X1 -5 to 6-membered heterocyclic alkyl groups, -L X1 -C 4-6 cycloalkyl, -L X1 -C 6-10 Aryl or -L X1 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X1a replace; R X1' It is hydrogen or methyl; or R n1 and R X1' Together with intermediary atoms, they form one or more optional R atoms. X1a Substituted 5- to 6-membered heterocyclic alkyl groups; L X1 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X1a replace; Each R X1a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X12 indicates a combination with C(O)(CH2). kxR Connection points; and *X2 represents the connection point with X2.

30. The radiopharmaceutical of claim 28 or 29, or a medically acceptable salt or conjugate thereof, wherein: R X1 For hydrogen, C 1-6 Alkyl, C 1-6 heteroalkyl, -L X1 -piperidinyl, -L X1 -piperazinyl, -L X1 -phenyl or -L X1 -pyridyl, wherein the alkyl, heteroalkyl, phenyl, pyridyl, piperidyl, and piperazine group are each optionally denoted by one or more R- groups. X1a replace.

31. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 28 to 30, wherein: Each R X1a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d =O, wherein the alkyl group and the heteroalkyl group are each optionally derived from one or more R groups. e replace.

32. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate or its pharmaceutically acceptable salt as claimed in any one of claims 26 to 31, wherein X2 is an N-alkylated amino acid.

33. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 31, wherein: X2 is , in: R n2 It is hydrogen or C 1-3 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X2a replace; R X2 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X2 -heterocyclic alkyl, -L X2 -cycloalkyl, -L X2 -Aryl or -L X2 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X2a replace; R X2' It is hydrogen or C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X2a Replace; or R n2 and R X2' Together with intermediary atoms, they form one or more optional R atoms. X2a Substituted 5- to 6-membered heterocyclic alkyl groups; L X2 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X2a replace; Each R X2a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S, =N(R) a ), aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X1 represents the connection point with X1; and *X3 represents the connection point with X3.

34. The radiopharmaceutical of claim 33 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein: X2 is , in: R n2 It can be hydrogen or methyl; R X2 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 heteroalkyl, -L X2 -5 to 6-membered heterocyclic alkyl groups, -L X2 -C 4-6 cycloalkyl, -L X2 -C 6-10 Aryl or -L X2 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X2a replace; R X2' It is hydrogen or methyl; or R n2 and R X2' Together with intermediary atoms, they form one or more optional R atoms. X2a Substituted 5- to 6-membered heterocyclic alkyl groups; L X2 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X2a replace; Each R X2a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X1 represents the connection point with X1; and *X3 represents the connection point with X3.

35. The radiopharmaceutical of claim 33 or 34, or a medically acceptable salt or conjugate thereof, wherein: R X2 For hydrogen, C 1-6 Alkyl, C 1-6 heteroalkyl, -L X2 -piperidinyl, L X2 -piperazinyl, -L X2 -phenyl or -L X2 -pyridyl, wherein the alkyl, heteroalkyl, phenyl, pyridyl, piperidyl, and piperazine group are each optionally denoted by one or more R- groups. X2a replace.

36. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 33 to 35, wherein: Each R X2a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d =O, wherein the alkyl group and the heteroalkyl group are each optionally derived from one or more R groups. e replace.

37. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 36, wherein: X3 is , in: R n3 It is hydrogen or C 1-3 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X3a replace; R X3 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X3 -heterocyclic alkyl, -L X3 -cycloalkyl, -L X3 -Aryl or -L X3 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X3a replace; R X3' It is hydrogen or C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X3a Replace; or R n3 and R X3' Together with intermediary atoms, they form one or more optional R atoms. X3a Substituted 5- to 6-membered heterocyclic alkyl groups; L X3 C 1-6 Alkylene, C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X3a replace; Each R X3a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X2 represents the connection point with X2; and *X4 represents the connection point with X4.

38. The radiopharmaceutical of claim 37 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein: X3 is , in: R n3 It can be hydrogen or methyl; R X3 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 heteroalkyl, -L X3 -5 to 6-membered heterocyclic alkyl groups, -L X3 -C 3-6 cycloalkyl, -L X3 -C 6-10 Aryl or -L X3 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X3a replace; L X3 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X3a replace; Each R X3a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X2 represents the connection point with X2; and *X4 represents the connection point with X4.

39. The radiopharmaceutical of claim 37 or 38, or a medically acceptable salt or conjugate thereof, wherein: R X3 C 1-6 Alkyl, C 1-6 heteroalkyl, -L X3 -piperidinyl, L X3 -piperazinyl, -L X3 -phenyl or -L X3 -pyridyl, wherein the alkyl, heteroalkyl, phenyl, pyridyl, piperidyl, and piperazine group are each optionally denoted by one or more R- groups. X2a replace.

40. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 37 to 39, wherein: Each R X3a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d =O, wherein the alkyl group and the heteroalkyl group are each optionally derived from one or more R groups. e replace.

41. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 40, wherein: X4 is , in: R n4 It is hydrogen or C 1-3 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X4a replace; R X4 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -L X4 -heterocyclic alkyl, -L X4 -cycloalkyl, -L X4 -Aryl or -L X4 - Heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X4a replace; R X4' It is hydrogen or C 1-6 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X4a Replace; or R n4 and R X4' Together with intermediary atoms, they form one or more optional R atoms. X4a Substituted 5- to 6-membered heterocyclic alkyl groups; L X4 C 1-6 Alkylene or C 1-6 Heteroalkyl, -O-, -S- or -NR a - wherein the alkylene and heteroalkylene are optionally derived from one or more R X4a replace; Each R X4a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X3 represents the connection point with X3; and *X5 represents the connection point with X5.

42. The radiopharmaceutical of claim 41 or a medically acceptable salt or conjugate thereof or a medically acceptable salt thereof, wherein: X4 is , in: R n4 It is hydrogen or C 1-3 Alkyl group, wherein the alkyl group is optionally derived from one or more R... X4a replace; R X4 For hydrogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 heteroalkyl, -L X4 -5 to 6-membered heterocyclic alkyl groups, -L X4 -C 3-6 cycloalkyl, -L X4 -C 6-10 Aryl or -L X4 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X4a replace; L X4 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X4a replace; Each R X4a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -SF5, -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)(NR a )2、-NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d aryl, heteroaryl, cycloalkyl, heterocycloalkyl, =O, =S or =N(R) a ), wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally etched with one or more R groups. e replace; *X3 represents the connection point with X3; and *X5 represents the connection point with X5.

43. The radiopharmaceutical of claim 41 or 42, or a medically acceptable salt or conjugate thereof, wherein: R X4 C 1-6 Alkyl, C 1-6 heteroalkyl, -L X4 -piperidinyl, L X4 -piperazinyl, -L X4 -phenyl or -L X4 -pyridyl, wherein the alkyl, heteroalkyl, phenyl, pyridyl, piperidyl, and piperazine group are each optionally denoted by one or more R- groups. X4a replace.

44. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 41 to 43, wherein: Each R X4a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d =O, wherein the alkyl group and the heteroalkyl group are each optionally derived from one or more R groups. e replace.

45. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate or its pharmaceutically acceptable salt as claimed in any one of claims 26 to 44, wherein X4 is an N-alkylated amino acid.

46. ​​The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate or its pharmaceutically acceptable salt as claimed in any one of claims 26 to 44, wherein X4 is a peptide.

47. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 46, wherein: R n5 It can be hydrogen or methyl; Ring A5 is C 6-10 Aryl, 5- to 10-membered heteroaryl, C 6-10 Cycloalkyl or 5- to 10-membered heterocyclic alkyl; Each R X5 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR) a )R a -N=S(=O)NR c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X5 -5 to 6-membered heterocyclic alkyl groups, -L X5 -C 3-6 cycloalkyl, -L X5 -C 6-10 Aryl or -L X5 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally derived from one or more R groups. X5a Replace; or Two Rs X5 Together they form = O; and L X5 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X5a replace.

48. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 47, wherein: Ring A5 can be phenyl, naphthyl, pyridyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, or tetrahydropyranyl; Each R X5 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -L X5 -piperidinyl or L X5 -piperazinyl, wherein the alkyl, heteroalkyl, piperidinyl, and pipeazinyl groups are each optionally etched with one or more R groups. X5a Replace; or Two Rs X5 Together they form = O; kx5 is 1 or 2; and mx5 can be 0, 1, or 2.

49. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 48, wherein: Each R X5a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d =O, wherein the alkyl group and the heteroalkyl group are each optionally derived from one or more R groups. e replace.

50. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 49, wherein: R n6 It can be hydrogen or methyl; R X6 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X6 -5 to 6-membered heterocyclic alkyl groups, -L X6 -C 3-6 cycloalkyl, -L X6 -C 6-10 Aryl or -L X6 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally denoted by one or more R groups. X6a Replace; and L X6 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X6a replace.

51. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 50, wherein: R X6 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X6 -5 to 6-membered heterocyclic alkyl groups, -L X6 -C 3-6 cycloalkyl, -L X6 -phenyl or -L X6 -6-membered heteroaryl, wherein the alkyl, heteroalkyl, phenyl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X6a replace.

52. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 51, wherein: Each R X6a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d =O, wherein the alkyl group and the heteroalkyl group are each optionally derived from one or more R groups. e replace.

53. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 52, wherein: R n7 It is hydrogen or methyl; and R X7 C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 5- to 6-membered heterocycloalkyl, wherein the alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, and heterocycloalkyl are each optionally derived from one or more R... X7a replace.

54. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 53, wherein: R X7 C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 5- to 6-membered heterocyclic alkyl, wherein the alkyl, heteroalkyl, cycloalkyl and heterocyclic alkyl are each optionally derived from one or more R... X7a replace.

55. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 54, wherein: Each R X7a Independent of halogen, -CN, -OR a -SR a -NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d Or = O.

56. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 55, wherein: Ring A8 is C 6-10 Aryl or 5 to 10-membered heteroaryl groups; Each R X8 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X8 -5 to 6-membered heterocyclic alkyl groups, -L X8 -C 3-6 cycloalkyl, -L X8 -C 6-10 Aryl or -L X8 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally denoted by one or more R groups. X8a Replace; or Two Rs X8 Together they form = O; and L X8 C 1-6 Alkylene or C 1-6 Heteroalkylene, wherein the alkylene and the heteroalkylene are optionally derived from one or more R... X8a replace.

57. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 56, wherein: Ring A8 can be phenyl, pyridyl, indolyl, azaindolyl, indazole, or benzimidazole. Each R X8 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)NR c R d -NR a S(=O)2NR c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -L X8 -piperidinyl or L X8 -piperazinyl, wherein the alkyl, heteroalkyl, piperidinyl, and pipeazinyl groups are each optionally etched with one or more R groups. X8a Replace; or Two Rs X5 Together they form = O; kx8 is 1 or 2; and mx8 can be 0, 1, or 2.

58. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 57, wherein: Each R X8a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d =O, wherein the alkyl group and the heteroalkyl group are each optionally derived from one or more R groups. e replace.

59. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 58, wherein: R n9 It can be hydrogen or methyl; Ring A9 is C 6-10 aryl or 5 to 10 heteroaryl groups; and Each R X9 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 Alkyne, -CN, -NO2, -OR a -SR a -SF5 or -NR c R d The alkyl, heteroalkyl, alkenyl, and alkynyl groups are each optionally derived from one or more R groups. X9a Replace; or Two Rs X9 Together they form = O.

60. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 59, wherein: Ring A9 can be phenyl, naphthyl, pyridyl, indolyl, azaindolyl, indazole, benzimidazolyl, or isoquinolinyl; Each R X9 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated groups, -CN, -OR a -SR a or -NR c R d The alkyl and heteroalkyl groups are each optionally derived from one or more R... X9a replace; kx9 is 1 or 2; and mx9 can be 0, 1, or 2.

61. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 60, wherein: Each R X9a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d =O, wherein the alkyl group and the heteroalkyl group are each optionally derived from one or more R groups. e replace.

62. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 61, wherein: Ring A11 is C 6-10 Aryl or 5 to 10-membered heteroaryl groups; Each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -SF5, -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -S(=O)(=NR) a )R a -N=S(=O)R c R d -NR a S(=O)2R a amidine group, -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d -P(=O)(OR) c (OR) d -P(=O)R c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X11 -5 to 6-membered heterocyclic alkyl groups, -L X11 -C 3-6 cycloalkyl, -L X11 -C 6-10 Aryl or -L X11 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X11a Replace; or Two Rs X11 Together they form = O; and L X11 C 1-6 Alkylene, C 1-6 Heteroalkylene or -O-, wherein the alkylene and heteroalkylene are optionally derived from one or more R- groups. X11a replace.

63. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 62, wherein: Ring A11 is phenyl or pyridyl; Each R X11 Independently for C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Heteroalkyl, halogen, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2R c R d -NR a S(=O)2R a -NR a C(=NH)NR c R d -NR a S(=O)2R c R d -C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, -L X11 -5 to 6-membered heterocyclic alkyl groups, -L X11 -C 3-6 cycloalkyl, -L X11 -C 6-10 Aryl or -L X11 -5 to 10-membered heteroaryl groups, wherein the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are each optionally derived from one or more R groups. X11a Replace; or Two Rs X11 Together they form = O; kx11 is 1, 2, 3, or 4; and mx11 can be 0, 1, or 2.

64. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 63, wherein: Each R X11 Independently, it is phenyl, pyridyl, pyrroleyl, pyrazolyl, imidazoleyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, -L X11 -5 to 6-membered heterocyclic alkyl groups, -L X11 -phenyl or -L X11 -pyridyl, wherein the phenyl, pyridyl, pyrroloyl, pyrazolyl, imidazolyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and heterocyclic alkyl groups are each optionally derived from one or more R groups. X11a replace.

65. The radiopharmaceutical or its pharmaceutically acceptable salt or conjugate as claimed in any one of claims 26 to 64, wherein: Each R X11a Independent of halogen, C 1-6 Alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -CN, -NO2, -OR a -SR a -NR c R d -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR a S(=O)2R a -NR a C(=NH)(NR a )2、-C(=O)R a -C(=O)OR a -OC(=O)R a -OC(=O)OR a -OC(=O)NR c R d -NR a C(=O)R a -NR a C(=O)OR a -NR a C(=O)NR c R d -C(=O)NR c R d =O, wherein the alkyl group and the heteroalkyl group are each optionally derived from one or more R groups. e replace.

66. The conjugate of claim 5 or a pharmaceutically acceptable salt thereof, wherein the conjugate is selected from Table 9.

67. A conjugate having the following structure: ， Or its medically acceptable salt.

68. A pharmaceutical composition comprising a radiopharmaceutical or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 or 5 to 65, and a pharmaceutically acceptable excipient or carrier.

69. A method for treating a disease or condition characterized by overexpression of phosphatidylinositol proteoglycan 3 (GPC3) in an individual requiring treatment, the method comprising administering to the individual a therapeutically effective amount of a radiopharmaceutical or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3 or 5 to 65, or a pharmaceutical composition as claimed in claim 68.

70. A method for treating a disease or condition characterized by overexpression of GPC3 in an individual requiring treatment, the method comprising: Administering the first radiopharmaceutical or its medically acceptable salt to the individual; and Administer to the individual a therapeutically effective amount of a second radiopharmaceutical or its medically acceptable salt. in: The first radiopharmaceutical or its medically acceptable salt is a radiopharmaceutical or its medically acceptable salt as claimed in any one of claims 1 to 3 or 5 to 65, wherein the radionuclide is a diagnostic radionuclide; and The second radiopharmaceutical or its medically acceptable salt is a radiopharmaceutical or its medically acceptable salt as claimed in any one of claims 1 to 3 or 5 to 65, wherein the radionuclide is a therapeutic radionuclide.

71. A method for diagnosing a disease or condition characterized by overexpression of GPC3 in an individual in need, comprising: administering to the individual a radiopharmaceutical as claimed in any one of claims 1 to 3 or 5 to 65, or a medically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 68; and imaging the individual to determine the expression level of GPC3 in the individual, wherein the radionuclide is suitable as an imaging isotope.

72. The method of any one of claims 69 to 71, wherein the disease or condition is cancer.

73. The method of claim 72, wherein the cancer is hepatocellular carcinoma, squamous cell carcinoma of the lung, adenocarcinoma of the lung, germ cell tumor, hepatoblastoma, Wilms' tumor, malignant rhabdomyosarcoma, rhabdomyosarcoma, liposarcoma, thyroid cancer, pancreatic cancer, small intestinal cancer, small cell neuroendocrine carcinoma (SCNC), hormone-treated castration-resistant prostate cancer, ovarian cancer, gastric cancer, esophageal cancer, or malignant melanoma.

74. A kit, assay, or composition for determining the expression level of GPC3 in a sample, wherein the kit, assay, or composition comprises a radiopharmaceutical, conjugate, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 67, or a pharmaceutical composition as claimed in claim 68.

75. The kit, test kit, or composition of claim 74, adapted for use in a method for diagnosing a disease or condition characterized by overexpression or underexpression of GPC3.

76. The kit, test kit, or composition of claim 74 or 75, wherein the sample is derived from an individual suspected of having a disease or condition characterized by overexpression or reduced expression of GPC3.

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