Cell permeable cyclic peptides and uses thereof

Abstract

Described herein are cyclic peptides that inhibit MDM2 or MDM2 and MDM4, pharmaceutical compositions containing these cyclic peptides, and methods of using these cyclic peptides to inhibit MDM2 or MDM2 and MDM4.

Description

[0001] Cross-referencing

[0002] This application claims the benefits of U.S. Provisional Application US62 / 938,864, filed November 21, 2019, and U.S. Provisional Application US63 / 047,178, filed July 1, 2020, each of which is incorporated herein by reference. Invention Overview

[0004] In some embodiments, this document discloses compounds, pharmaceutical compositions comprising said compounds, and the use of said compounds in the treatment of diseases. Furthermore, this disclosure relates to cyclic peptides that can be used as MDM2 inhibitors or MDM2 / MDM4 dual inhibitors, compositions thereof, and their use in the treatment of diseases such as cancer. Additionally, this disclosure relates to cyclic peptides that can be used as MDM2 inhibitors or MDM2 / MDM4 dual inhibitors, compositions thereof, and their use in inducing senescent cell death, particularly for the treatment of diseases or conditions associated with the proliferation of senescent cells.

[0005] In one aspect, this disclosure provides a cyclic peptide comprising:

[0006] 9-11 amino acid residues, which are independently selected from amino acid residues that are uncharged at physiological pH;

[0007] First β hairpin area and second β hairpin area;

[0008] And it has one of the following characteristics:

[0009] At least four amino acid residues comprising a ring independently selected from an optionally substituted monocyclic carbocyclic ring and an optionally substituted monocyclic heterocyclic ring, wherein at least one of the monocyclic carbocyclic ring and the monocyclic heterocyclic ring is substituted;

[0010] At least four amino acid residues having side chains selected from -olefin- (monocyclic carbocyclic) and -olefin- (monocyclic heterocyclic), wherein the monocyclic carbocyclic and monocyclic heterocyclic rings are optionally substituted independently; and

[0011] At least three amino acid residues comprising a ring independently selected from an optionally substituted phenyl group and an optionally substituted monocyclic heteroaryl group.

[0012] In some embodiments, the first β-hairpin region comprises two consecutive amino acid residues. In some embodiments, the first β-hairpin region comprises two consecutive residues independently selected from: L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe, and D-NMe-Val, wherein the phenyl group of L-NMe-Phe is optionally selected by one or more independently from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C. 1-4The alkyl group, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 are substituents. In some embodiments, the first β-hairpin region comprises two consecutive residues independently selected from: L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe, and D-NMe-Val, wherein the phenyl group of L-NMe-Phe is optionally replaced by one or more residues independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The alkyl group is substituted with substituents such as -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, the first β-hairpin region comprises two consecutive residues independently selected from: L-Pro, D-Pro, L-Aze, D-Pip, and D-NMe-Val. In some embodiments, for the two consecutive residues, one is D and the other is L. In some embodiments, the two consecutive amino acid residues are D-Pro and L-Pro. In some embodiments, the two consecutive amino acid residues are D-NMe-Val and L-Pro. In some embodiments, the two consecutive amino acid residues are D-Pro and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally substituted with one or more substituents independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C. 1-4 Alkyl groups, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 are substituents. In some embodiments, the two consecutive amino acid residues are D-Pro and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally replaced by one or more substituents independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 Substitution with alkyl groups, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2.

[0013] In some embodiments, the second β-hairpin region comprises a second pair of consecutive amino acid residues. In some embodiments, the second β-hairpin region comprises a second pair of consecutive residues independently selected from: D-Pro, peptoids (e.g., sarcosine, N-isopropylglycine, N-benzylglycine, N-2-(methoxyethyl)glycine, etc.), DN-alkylated amino acids, and LN-alkylated amino acids. In some embodiments, the second β-hairpin region comprises a second pair of consecutive residues independently selected from: D-Pro, peptoids, and LN-alkylated amino acids. In some embodiments, for the second pair of consecutive residues, one is a peptoid and the other is an LN-alkylated amino acid. In some embodiments, for the second pair of consecutive residues, one is L-NMe-Ala and the other is N-(2-methoxyethyl)glycine. In some embodiments, for the second pair of consecutive residues, one is a DN-alkylated amino acid and the other is an LN-alkylated amino acid. In some embodiments, for the second pair of consecutive residues, one is D-NMe-Ala and the other is L-NMe-Ala. In some embodiments, for the second two consecutive residues, one is a DN-alkylated amino acid and the other is a peptide. In some embodiments, for the second two consecutive residues, one is D-NMe-Ala and the other is N-(2-methoxyethyl)glycine.

[0014] In some embodiments, at least two consecutive amino acids separate the first β-hairpin region from the second β-hairpin region. In some embodiments, at least three consecutive amino acids separate the first β-hairpin region from the second β-hairpin region.

[0015] In some embodiments, the molecular weight of the cyclic peptide is 800-1300 Da. In some embodiments, the molecular weight of the cyclic peptide is 800-1200 Da. In some embodiments, the molecular weight of the cyclic peptide is 900-1200 Da.

[0016] In some embodiments, the cyclic peptide is characterized by comprising at least four amino acid residues of a ring independently selected from optionally substituted monocyclic carbocyclic rings and optionally substituted monocyclic heterocyclic rings, wherein at least one of the monocyclic carbocyclic rings and monocyclic heterocyclic rings is substituted. In some embodiments, the optionally substituted monocyclic carbocyclic ring is phenyl, and the optionally substituted monocyclic heterocyclic ring is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is substituted by one or more substances independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The substituted monocyclic ring is substituted with alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 substituents. In some embodiments, the optionally substituted monocyclic carbide ring is phenyl, and the optionally substituted monocyclic heterocycle is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is independently selected from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The alkyl group, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2 are substituents. In some embodiments, the optionally substituted monocyclic carbide ring is phenyl, and the optionally substituted monocyclic heterocycle is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is substituted by one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, any of which may be substituted.

[0017] In some embodiments, the cyclic peptide is characterized by having at least four amino acid residues having a side chain selected from -olefin- (monocyclic carbocyclic) and -olefin- (monocyclic heterocyclic), wherein the monocyclic carbocyclic and monocyclic heterocyclic are optionally substituted independently. In some embodiments, each of the at least four amino acids having a side chain selected from -olefin- (optionally substituted monocyclic carbocyclic) and -olefin- (optionally substituted monocyclic heterocyclic) is not adjacent to each other. In some embodiments, two of the at least four amino acids having a side chain selected from -olefin- (optionally substituted monocyclic carbocyclic) and -olefin- (optionally substituted monocyclic heterocyclic) are adjacent to each other. In some embodiments, each monocyclic carbocyclic ring is phenyl, and each monocyclic heterocyclic ring is a heteroaryl ring, wherein each phenyl and heteroaryl ring is optionally substituted independently by one or more substances independently selected from halogen, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The alkyl group, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 are substituents. In some embodiments, each monocyclic carbide ring is a phenyl ring, and each monocyclic heterocyclic ring is a heteroaryl ring, wherein each phenyl and heteroaryl ring is independently and optionally optionally substituted by one or more groups independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The alkyl group, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2 are substituents. In some embodiments, each monocyclic carbide ring is a phenyl group, and each monocyclic heterocyclic ring is a heteroaryl ring, wherein each phenyl and heteroaryl ring is independently and optionally substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, wherein any one of them is optionally substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2.

[0018] In some embodiments, the cyclic peptide is characterized by comprising at least three amino acid residues of a ring independently selected from optionally substituted phenyl groups and optionally substituted monocyclic heteroaryl groups. In some embodiments, each phenyl and heteroaryl ring is independently and optionally selected from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 Alkyl groups, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 are substituents. In some embodiments, each phenyl and heteroaryl ring is optionally independently and optionally replaced by one or more substituents independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 Alkyl groups, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2 are substituents. In some embodiments, each phenyl and heteroaryl ring is independently and optionally substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, any of which is optionally substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2.

[0019] In some embodiments, at least three backbone nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In some embodiments, four or five backbone nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In some embodiments, four backbone nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In some embodiments, five backbone nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In some embodiments, one or more of the tertiary backbone nitrogen atoms are part of a heterocyclic alkyl ring. In some embodiments, one or more of the tertiary nitrogen atoms have optional C1-C6 alkyl substituents independently selected at each tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl groups are independently selected from: halogen, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 Alkyl, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, one or more of the tertiary nitrogen atoms have optional C1-C6 alkyl substituents, each independently selected at the tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl groups are independently selected from: halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 Alkyl, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, one or more tertiary nitrogens have optional C1-C6 alkyl substituents independently selected at each tertiary nitrogen, and wherein the substituents on the C1-C6 alkyl groups are independently selected from: halogen, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each tertiary nitrogen is independently composed of... It means that R A It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C1-C6 alkyl groups substituted with alkyl, -OBz, -OCH3, -OCF3, and -OCHF2, wherein This represents the connection point with adjacent amino acid residues. In some embodiments, each tertiary nitrogen is independently formed by... It means that R A It is a C1-C6 alkyl group optionally substituted with one or more substituents independently selected from halogen, -OBz, -OCH3, -OCF3 and -OCHF2, and wherein This indicates the connection point with an adjacent amino acid residue.

[0020] In some implementations, the cyclic peptide has 10 amino acid residues.

[0021] In some implementations, the cyclic peptide is represented by Formula I:

[0022]

[0023] in:

[0024] R 1 R 6 and R 8 Independently selected from hydrogen, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 substituents;

[0025] R 2 Selected from hydrogen and C 1-6 alkyl;

[0026] R 3 Selected from hydrogen, C 1-4 Alkyl, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substituents of alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; and wherein C 1-4 The alkyl group may be selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl groups, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2;

[0027] R 4 Is it hydrogen or C? 1-4 Alkyl, or R 4 and R 14 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0028] R 5 Selected from hydrogen, C 1-4 Alkyl, -(C 1-4 (olefin group)-(C 3-8carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substituents of alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; and wherein C 1-4 The alkyl group may be selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl groups, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 5 and R 15 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0029] R 7 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-6 Alkyl; or R 7 and R 17 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0030] R 9 Is it hydrogen or C? 1-6 Alkyl, or R 9 and R 19 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0031] R 10 Is it hydrogen or C? 1-4 Alkyl, or R 10 and R 20 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0032] R 11 R 12 R 13 R 16 and R 18 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4alkyl;

[0033] R 14 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 14 and R 4 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0034] R 15 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 15 and R 5 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0035] R 17 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 17 and R 7 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0036] R 19 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 19 and R 9 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups; and

[0037] R20 is selected from hydrogen; and optionally is independently selected from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4Alkyl; or R 20 and R 10 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups.

[0038] In some implementations, the cyclic peptide is represented by Formula I:

[0039]

[0040] in:

[0041] R 1 R 6 and R 8 Independently selected from hydrogen, -(C 1-4 (olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2 substituents;

[0042] R 2 Selected from hydrogen and C 1-6 alkyl;

[0043] R 3 Selected from hydrogen, C 1-4 Alkyl, -(C 1-4 (olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substituents of alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; and wherein C 1-4 The alkyl group may be selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl groups, -OH, -OBz, -OCH3, -OCF3, and -OCHF2;

[0044] R 4 Is it hydrogen or C? 1-4 Alkyl, or R 4 and R 14Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0045] R 5 Selected from hydrogen, C 1-4 Alkyl, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substituents of alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; and wherein C 1-4 The alkyl group may be selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl groups, -OH, -OBz, -OCH3, -OCF3, and -OCHF2; or R 5 and R 15 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0046] R 7 Is it hydrogen or C? 1-6 Alkyl, or R 7 and R 17 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0047] R 9 Is it hydrogen or C? 1-6 Alkyl, or R 9 and R 19 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0048] R 10 Is it hydrogen or C? 1-4 Alkyl, or R 10 and R 20 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0049] R 11 R 12 R 13 R 16 and R 18 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 alkyl;

[0050] R 14 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 14 R4, together with the intermediate atom, forms a 4-7 membered heterocyclic alkyl group;

[0051] R 15 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 15 and R 5 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0052] R 17 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 17 and R 7 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0053] R 19 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 19 and R 9 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups; and

[0054] R 20 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 20 and R10 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups.

[0055] In some implementations, the cyclic peptide is represented by Formula II:

[0056]

[0057] in:

[0058] R 21 R 23 R 26 and R 28 Independently selected from hydrogen, -(C 1-4 (olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may be optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2;

[0059] R 24 Is it hydrogen or C? 1-4 Alkyl, or R 24 and R 34 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0060] R 25 Is it hydrogen or C? 1-4 Alkyl, or R 25 and R 35 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0061] R 30 Is it hydrogen or C? 1-4 Alkyl, or R 30 and R 40 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0062] R 22 R 27 and R 29 Independently selected from hydrogen and C 1-6 alkyl;

[0063] R 31 R 32 R 33 R 36 and R 38 The C group is independently selected from hydrogen; and optionally substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl;

[0064] R 37 and R 39 The C group is independently selected from hydrogen; and optionally substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl;

[0065] R 34 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Alkyl; or R 34 and R 24 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0066] R 35 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Alkyl; or R 35 and R 25 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups; and

[0067] R 40 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Alkyl; or R 40 and R 30 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups.

[0068] In some implementations, the cyclic peptide is represented by Formula II:

[0069]

[0070] in:

[0071] R 21 R 23 R 26 and R 28 Independently selected from hydrogen, -(C 1-4 olefinic group)-(C3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may be optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2;

[0072] R 24 Is it hydrogen or C? 1-4 Alkyl, or R 24 and R 34 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0073] R 25 Is it hydrogen or C? 1-4 Alkyl, or R 25 and R 35 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0074] R 30 Is it hydrogen or C? 1-4 Alkyl, or R 30 and R 40 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0075] R 22 R 27 and R 29 Independently selected from hydrogen and C 1-6 alkyl;

[0076] R 31 R 32 R 33 R 36 and R 38 C is independently selected from hydrogen; and optionally substituted by one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 alkyl;

[0077] R 37 and R 39 C is independently selected from hydrogen; and optionally substituted by one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 alkyl;

[0078] R 34 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 Alkyl; or R 34 and R 24 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0079] R 35 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 Alkyl; or R 35 and R25 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups; and

[0080] R 40 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 Alkyl; or R 40 and R 30 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups.

[0081] In some implementation schemes, R 31 R 32 R 33 R 36 and R 38 Each is hydrogen.

[0082] In some implementation schemes, R 34 R 35 R 37 R 39 and R 40 At least four of them are not hydrogen. In some implementations, R 34 R 35 R 37 R 39 and R 40 Four of them are not hydrogen. In some implementations, R 34 R 35 R 37 R 39 and R 40 It's not hydrogen.

[0083] In some implementation schemes, R 24 and R 34 R 25 and R 35 and R 30 and R 40 At least one of them, together with the intermediate atom, forms a 5-7 membered heterocyclic alkyl group. In some embodiments, R 24 and R 34 Together with the intermediate atom, it forms a 5-6 membered heterocyclic alkyl group. In some embodiments, R 25 and R 35 Together with the intermediate atom, it forms a 5-6 membered heterocyclic alkyl group.

[0084] In some implementation schemes, R 37 R 39 and R 40 Each of these is selected from methyl and methoxyethyl. In some embodiments, R 35 R 37 R39 and R 40 Each of them is selected from methyl and methoxyethyl.

[0085] In some implementation schemes, R 40 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 2-4 Alkyl, or R 30 and R 40 Together with the intermediate atom, it forms a 5-7 membered heterocyclic alkyl group. In some embodiments, R 40 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 40 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 2-4 alkyl.

[0086] In some implementation schemes, R 39 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 alkyl.

[0087] In some implementation schemes, R 22 R 27 and R 29 Selected independently from C 1-6 Alkyl group. In some embodiments, R 22 R 27 and R 29 It is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0088] In some implementation schemes, R 21 R 23 R 26 and R 28 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles may be optionally substituted. In some embodiments, R 21 R 23 R 26 and R 28 Independently selected from -CH2-(C 3-8(Carbon ring) and -CH2- (3-10 membered heterocycle). In some embodiments, R 21 R 23 R 26 and R 28 Independently selected from benzyl and pyridylmethyl, wherein the phenyl and pyridyl groups are optionally substituted. In some embodiments, R 21 R 23 R 26 and R 28 Selected independently from:

[0089]

[0090] In some implementations, the cyclic peptide is represented by formula IIa:

[0091]

[0092] In some implementations, the cyclic peptide is represented by formula IIb:

[0093]

[0094] Where R 21' R 23' R 26' and R 28' Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0095] In some implementations, the cyclic peptide is represented by Formula III:

[0096]

[0097] in:

[0098] R 41 R 45 R 46 and R 48 Independently selected from hydrogen, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 substituents;

[0099] R 42 Selected from hydrogen and C 1-6 alkyl;

[0100] R 43 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 alkyl;

[0101] R 44 Is it hydrogen or C? 1-4 Alkyl, or R 44 and R 54 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0102] R 47 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-6 Alkyl; or R 47 and R 57 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0103] R 49 Is it hydrogen or C? 1-6 Alkyl, or R 49 and R 59 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0104] R 50 Is it hydrogen or C? 1-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0105] R 51 R 53 R 56 and R 58 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 alkyl;

[0106] R 52 and R 55Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 alkyl;

[0107] R 54 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 54 and R 44 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0108] R 57 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 57 and R 47 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0109] R 59 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 59 and R 49 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0110] R 60 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 60 and R 50 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups.

[0111] In some implementations, the cyclic peptide is represented by Formula III:

[0112]

[0113] in:

[0114] R 41 R 45 R 46 and R 48 Independently selected from hydrogen, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2 substituents;

[0115] R 42 Selected from hydrogen and C 1-6 alkyl;

[0116] R 43 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 alkyl;

[0117] R 44 Is it hydrogen or C? 1-4 Alkyl, or R 44 and R 54 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0118] R 47 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-6 Alkyl; or R 47 and R 57 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0119] R 49 Is it hydrogen or C? 1-6 Alkyl, or R 49 and R59 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0120] R 50 Is it hydrogen or C? 1-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0121] R 51 R 53 R 56 and R 58 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 alkyl;

[0122] R 52 and R 55 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 alkyl;

[0123] R54 is selected from hydrogen; and optionally is independently selected from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 54 and R 44 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0124] R 57 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 57 and R 47 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0125] R 59Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 59 and R 49 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0126] R 60 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 60 and R 50 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups.

[0127] In some implementation schemes, R 51 R 53 R 56 and R 58 Each is hydrogen.

[0128] In some implementation schemes, R 52 R 54 R 55 R 57 R 59 and R 60 At least four of them are not hydrogen. In some implementations, R 52 R 54 R 55 R 57 R 59 and R 60 Four of them are not hydrogen. In some implementations, R 52 R 54 R 55 R 57 R 59 and R 60 It's not hydrogen.

[0129] In some implementation schemes, R 44 and R 54 and R 50 and R 60 At least one of them, together with the intermediate atom, forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 44 and R 54 Together with the intermediate atom, they form 4-6 membered heterocyclic alkyl groups.

[0130] In some implementation schemes, R 55 R 59 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl. In some embodiments, R 52 R 55 R 59 and R 60 Each of them is selected from methyl, ethyl and methoxyethyl.

[0131] In some implementation schemes, R 60 It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 2-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 60 It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 60 It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 alkyl.

[0132] In some implementation schemes, R 59 It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 alkyl.

[0133] In some implementation schemes, R 42 R 47 and R 49 Selected independently from C 1-6 Alkyl group. In some embodiments, R 42 R47 and R 49 It is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0134] In some implementation schemes, R 41 R 45 R 46 and R 48 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles may be optionally substituted. In some embodiments, R 41 R 45 R 46 and R 48 Independently selected from -CH2-(C 3-8 (Carbon ring) and -CH2- (3-10 membered heterocycle). In some embodiments, R 41 R 45 R 46 and R 48 The methyl group is independently selected from benzyl, pyridylmethyl, and thiazolylmethyl, wherein the phenyl, pyridyl, and thiazolyl groups are optionally substituted. In some embodiments, R 41 R 45 R 46 and R 48 Selected independently from:

[0135]

[0136] In some implementations, the cyclic peptide is represented by formula IIIa:

[0137]

[0138] In some implementations, the cyclic peptide is represented by formula IIIb:

[0139]

[0140] Where R 41' R 45' R 46' and R 48' Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0141] In some embodiments, the cyclic peptide is selected from those in Tables 3 and 4, or a pharmaceutically acceptable salt of any of them.

[0142] On the other hand, this disclosure provides a pharmaceutical composition comprising the cyclic peptide described herein and a pharmaceutically acceptable excipient.

[0143] In another aspect, this disclosure provides a method for inhibiting MDM2, comprising administering the cyclic peptide described herein to a subject in need.

[0144] In another aspect, this disclosure provides a method for inhibiting MDM2 and MDM4, comprising administering the cyclic peptide described herein to a subject in need.

[0145] On the other hand, this disclosure provides a method for treating a disease or condition in a subject in need, comprising administering to the subject a therapeutically effective amount of the cyclic peptide described herein.

[0146] In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is selected from: acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia. In some embodiments, the disease or condition is related to the proliferation of senescent cells. In some embodiments, the disease or condition is selected from: type 2 diabetes, Huntington's disease, non-alcoholic fatty liver disease, and hyperlipidemia. In some embodiments, the disease or condition is selected from: cardiovascular disease, inflammatory disease, autoimmune disease, metabolic disease, lung disease, eye disease, ear disease, kidney disease, and skin disease. Attached Figure Description

[0147] The novel features of the invention are particularly set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description of illustrative embodiments, which utilize the principles of the invention, and the accompanying drawings:

[0148] Figure 1 The changes in mean tumor volume over time after intravenous administration of compound 35 were shown in the MOLM-13 mouse xenograft model.

[0149] Figure 2 The tumor volume was shown on day 13 after intravenous administration of compound 35 in the MOLM-13 mouse xenograft model.

[0150] Figure 3 The changes in tumor volume over time after intravenous administration of compound 35 were shown in the MOLM-13 mouse xenograft model.

[0151] Figure 4 The change in body weight over time after intravenous administration of compound 35 was shown in the MOLM-13 mouse xenograft model.

[0152] Figure 5The changes in mean plasma concentration over time after intravenous administration of compound 35 were shown in the MOLM-13 mouse xenograft model. Invention Details

[0154] Mouse two-microsome 2 homolog (MDM2) and mouse two-microsome 4 homolog (MDM4) have shown promise as therapeutic targets for various cancers. MDM2 and MDM4 act as negative regulators of the p53 tumor suppressor gene by activating E3 ubiquitin ligase and inhibiting p53 transcriptional activation. Furthermore, since disrupting the protein-protein interactions between p53 and MDM2 or MDM4 can lead to senescent cell death, the development of MDM2 and MDM4 inhibitors offers opportunities to treat diseases or dysregulations associated with the proliferation of senescent cells. Age-related diseases are diverse, including cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, lung diseases, ophthalmic diseases, ear diseases, kidney diseases, and skin diseases. Specific examples include type 2 diabetes, Huntington's disease, non-alcoholic fatty liver disease, and hyperlipidemia.

[0155] Cyclic peptides have emerged as potentially useful inhibitors of MDM2 and / or MDM4. Small molecule inhibitors of MDM2 / p53 protein-protein interactions and / or MDM4 / p53 protein-protein interactions are attractive as potential therapeutic agents for cancer. β-hairpin regions are frequently found in nature as a means of displaying residues essential for protein-protein recognition. These β-hairpin regions of natural proteins can be mimicked by carefully designed cyclic peptides, making it possible for cyclic peptides to serve as inhibitors of hard-to-reach targets such as MDM2 and MDM4.

[0156] While they hold promise as therapeutic agents, the use of cyclic peptides may be limited by their poor pharmacokinetic properties, particularly poor cell permeability, low solubility, and high clearance. MDM2 inhibitors and MDM2 / MDM4 dual inhibitors with improved pharmacokinetic properties (such as improved cell permeability) are needed for disease treatment.

[0157] This disclosure describes cyclic peptides that overcome pharmacokinetic challenges such as poor solubility and poor cell permeability. Specifically, this disclosure provides cyclic peptides optimized to enhance cell permeability and solubility.

[0158] In some embodiments, cyclic peptides that can be used as MDM2 inhibitors are disclosed herein. In some embodiments, the cyclic peptides disclosed herein can be used as dual inhibitors of MDM2 / MDM4. In some embodiments, the cyclic peptide comprises 9-11 amino acids, independently selected from amino acid residues that are uncharged at physiological pH; and a first β-hairpin region and a second β-hairpin region. In some embodiments, the cyclic peptide is further characterized by one of the following: at least four amino acid residues comprising a ring independently selected from optionally substituted monocyclic carbocyclic rings and optionally substituted monocyclic heterocyclic rings, wherein at least one of the monocyclic carbocyclic rings and monocyclic heterocyclic rings is substituted; at least four amino acid residues having side chains selected from -olefin- (monocyclic carbocyclic rings) and -olefin- (monocyclic heterocyclic rings), wherein the monocyclic carbocyclic rings and monocyclic heterocyclic rings are independently optionally substituted; and at least three amino acid residues comprising a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl groups.

[0159] In some embodiments, the cyclic peptides disclosed herein exhibit high cell permeability and effective inhibition of MDM2 in both biochemical and cellular assays. In some embodiments, the cyclic peptides disclosed herein exhibit high cell permeability and effective inhibition of both MDM2 and MDM4 in both biochemical and cellular assays. In some embodiments, the cyclic peptides disclosed herein have the potential to treat cancer.

[0160] definition

[0161] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0162] As used herein, the singular forms “a / an” and “the” include plural indications unless the context clearly specifies otherwise.

[0163] As used herein, the abbreviations for amino acids are conventional and may include: alanine (A, Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine ​​(C, Cys); glutamic acid (E, Glu); glutamine (Q, Gln); glycine (G, Gly); histidine (H, His); isoleucine (I, Ile); leucine (L, Leu); lysine (K, Lysine); methionine (M, Met); phenylalanine (F, Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr); valine (V, Val). Other amino acids include citrulline (Cit); homocysteine ​​(Hey); hydroxyproline (Hyp); ornithine (Orn); and thyroxine (Thx). Examples of amino acids that are uncharged at physiological pH include, but are not limited to: alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0164] In embodiments of this disclosure, a cyclic peptide comprising a certain number of amino acid residues is a cyclic peptide in which the backbone of the cyclic peptide comprises the stated number of amino acid residues. In other words, each amino acid residue is an inner ring. For example, for the purposes of this disclosure, the following will be considered as cyclic peptides comprising ten amino acid residues: As another example, the following will also be considered as a cyclic peptide containing ten amino acid residues, rather than a cyclic peptide containing eleven amino acid residues:

[0165] "Continuous" amino acid residues are those inner-ring amino acids that are covalently linked in tandem without the insertion of an inner-ring atom. Below are two examples of continuous proline residues, one D and the other L: Conversely, here is an example of two discontinuous proline residues:

[0166] When a first β-hairpin region and a second β-hairpin region are separated by multiple consecutive amino acid residues, such as at least three consecutive amino acids, this number refers to the number of residues starting from the C-terminus of the first β-hairpin region and terminating at the N-terminus of the second β-hairpin region, and / or the number of residues starting from the C-terminus of the second β-hairpin region and terminating at the N-terminus of the first β-hairpin region. For example, one embodiment is described below, wherein the two β-hairpin regions are separated by three consecutive amino acid residues, which start from the C-terminus of the first β-hairpin region and terminate at the N-terminus of the second β-hairpin region, and three consecutive amino acid residues start from the C-terminus of the second β-hairpin region and terminate at the N-terminus of the first β-hairpin region: For another example, the following describes an embodiment in which two β hairpin regions are separated by three consecutive amino acid residues, which begin at the C-terminus of the first β hairpin region and terminate at the N-terminus of the second β hairpin region, and two consecutive amino acid residues begin at the C-terminus of the second β hairpin region and terminate at the N-terminus of the first β hairpin region:

[0167] "Adjacent" residues are covalently linked to each other via their N- or C-termini. Non-adjacent amino acid residues have at least one amino acid or other atom on either side of their N- or C-termini separating them from each other. For example, consider the following structure: Valine residues are adjacent to serine residues, but valine residues are not adjacent to cysteine ​​residues, while serine residues are adjacent to both valine and cysteine ​​residues.

[0168] When used with a chemical moiety such as alkyl, alkenyl, or ynyl, the term "C" is used. x-y "This refers to groups containing x to y carbons in the chain. For example, the term "C" 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched alkyl groups containing 1-6 carbons. The term –C x-y An olefinic group refers to an olefinic chain with x to y substituted or unsubstituted carbons. For example, -C 1-6 The olefinic group can be selected from: methylene, vinyl, propenyl, butenyl, pentadienyl, and hexenyl, any of which may be substituted.

[0169] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups. Alkyl groups can contain 1-12 carbon atoms (e.g., C12-C12). 1-12 Alkyl groups, such as those with 1-8 carbon atoms (C 1-8 Alkyl group or 1-6 carbon atoms (C 1-6 Alkyl groups. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. The alkyl group is attached to the remainder of the molecule by a single bond. The alkyl group may optionally be substituted with one or more substituents (such as those described herein).

[0170] "Halogenated alkyl" refers to an alkyl group substituted with one or more halogens. Exemplary halogenated alkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0171] As used herein, the term "carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocyclic rings include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, 6-12 membered bridged rings, and spirocyclic rings. Each ring of a bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring (e.g., phenyl) can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Where valence permits, bicyclic carbocyclic rings include any combination of saturated, unsaturated, and aromatic bicyclic rings. Bicyclic carbocyclic rings include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.

[0172] As used herein, the term "heterocycle" refers to a saturated or unsaturated ring or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. Where valence permits, bicyclic heterocycles include any combination of saturated, unsaturated rings and aromatic bicyclic rings. In one exemplary embodiment, an aromatic ring (e.g., pyridyl) may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.

[0173] As used herein, the term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms. Exemplary monocyclic heteroaryl rings are 5- or 6-membered rings whose ring structure includes at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, oxadiazole, thiazole, thiadiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0174] The term "substituted" refers to a portion having a substituent that replaces one or more hydrogen atoms on a carbon atom or a substituted heteroatom, such as NH or NH2 in a compound. It should be understood that "substituted" or "replaced with..." includes the implicit precondition that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that said substitution produces a stable compound, i.e., a compound that does not spontaneously transform through means such as rearrangement, cyclization, elimination, etc. In some embodiments, the substituted refers to a portion having a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon atom with an oxo, imino, or thio group. As used herein, the term "substituted" is intended to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and linear, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents can be one or more and can be the same or different.

[0175] In some embodiments, the substituents may include any substituents described herein, such as: halogen, hydroxyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b-S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and any one of alkyl, alkenyl, alkynyl, aryl, aralkyl, arylenyl, aryynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl may optionally be replaced by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazyl (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(Ra )2 (where t is 1 or 2); where each R a Independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a Where the valence allows, it can be optionally replaced by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and where each R b Independently selected from direct-bonded or straight-chain or branched olefinic, alkenyl, or alkynyl chains, and each R c It is a straight-chain or branched olefinic, alkenyl, or alkynyl chain.

[0176] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and harmless to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppositories; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, and corn oil. (10) Soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Pyrogen-free water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer; and (22) Other non-toxic and compatible substances used in pharmaceutical preparations.

[0177] As used herein, “treatment / treating” refers to a method for obtaining a beneficial or desired outcome regarding a disease, condition, or medical condition, including but not limited to therapeutic and / or preventative benefits. Therapeutic benefits may include, for example, eradication or improvement of an underlying disease being treated. Furthermore, therapeutic benefits may include, for example, eradication or improvement of one or more physiological symptoms associated with an underlying disease, resulting in observed improvement in a subject, although the subject may still have the underlying disease. In some embodiments, for preventative benefits, the composition is administered to a subject at risk of developing a specific disease, or to a subject who reports one or more physiological symptoms of a disease, even if a diagnosis of the disease may not have been made. Treatment by administering the compounds described herein does not require the involvement of a medical professional.

[0178] As used herein, the term "therapeutic effect" includes therapeutic benefits and / or preventive benefits as described above. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0179] compound

[0180] In some aspects, this disclosure provides cyclic peptides. In one aspect, this disclosure provides a cyclic peptide comprising:

[0181] 9-11 amino acid residues, which are independently selected from amino acid residues that are uncharged at physiological pH;

[0182] First β hairpin area and second β hairpin area;

[0183] And it has one of the following characteristics:

[0184] At least four amino acid residues comprising a ring independently selected from an optionally substituted monocyclic carbocyclic ring and an optionally substituted monocyclic heterocyclic ring, wherein at least one of the monocyclic carbocyclic ring and the monocyclic heterocyclic ring is substituted;

[0185] At least four amino acid residues having side chains selected from -olefin- (monocyclic carbocyclic) and -olefin- (monocyclic heterocyclic), wherein the monocyclic carbocyclic and monocyclic heterocyclic rings are optionally substituted independently; and

[0186] At least three amino acid residues comprising a ring independently selected from an optionally substituted phenyl group and an optionally substituted monocyclic heteroaryl group.

[0187] In some embodiments, the first β-hairpin region comprises two consecutive amino acid residues. In some embodiments, the first β-hairpin region comprises two consecutive residues independently selected from: L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe, and D-NMe-Val, wherein the phenyl group of L-NMe-Phe is optionally selected by one or more independently from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C. 1-4 The alkyl group, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 are substituents. In some embodiments, the first β-hairpin region comprises two consecutive residues independently selected from: L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe, and D-NMe-Val, wherein the phenyl group of L-NMe-Phe is optionally replaced by one or more residues independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The alkyl group, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2 are substituents. In some embodiments, the first β-hairpin region comprises two consecutive residues independently selected from: L-Pro, D-Pro, L-Aze, D-Pip, and D-NMe-Val. In some embodiments, for the two consecutive residues, one is D and the other is L. In some embodiments, the two consecutive amino acid residues are D-Pro and L-Aze. In some embodiments, the two consecutive amino acid residues are D-Pro and L-Pro. In some embodiments, the two consecutive amino acid residues are D-Pro and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally replaced by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 Alkyl groups, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 are substituents. In some embodiments, the two consecutive amino acid residues are D-Pro and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally replaced by one or more substituents independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The amino acid residues are substituted with alkyl groups, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, the two consecutive amino acid residues are D-Pip and L-Pro. In some embodiments, the two consecutive amino acid residues are D-Pip and L-Aze. In some embodiments, the two consecutive amino acid residues are D-Pip and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally replaced by one or more groups independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The alkyl group, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 are substituents. In some embodiments, the two consecutive amino acid residues are D-Pip and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally replaced by one or more substituents independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The amino acid residues are substituted with alkyl groups, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, the two consecutive amino acid residues are D-NMe-Val and L-Pro. In some embodiments, the two consecutive amino acid residues are D-NMe-Val and L-Aze. In some embodiments, the two consecutive amino acid residues are D-NMe-Val and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally replaced by one or more groups independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The alkyl group, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 are substituents. In some embodiments, the two consecutive amino acid residues are D-NMe-Val and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally replaced by one or more substituents independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 Substitution with alkyl groups, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2.

[0188] In some embodiments, the second β-hairpin region comprises a second pair of consecutive amino acid residues. In some embodiments, the second β-hairpin region comprises a second pair of consecutive residues, independently selected from: D-Pro, peptides, DN-alkylated amino acids, and LN-alkylated amino acids. In some embodiments, the second β-hairpin region comprises a second pair of consecutive residues, independently selected from: D-Pro, peptides, and LN-alkylated amino acids. In some embodiments, for the second pair of consecutive residues, one is a peptide and the other is an LN-alkylated amino acid. In some embodiments, for the second pair of consecutive residues, one is L-NMe-Ala and the other is N-(2-methoxyethyl)glycine. In some embodiments, for the second pair of consecutive residues, one is D-Pro and the other is a peptide. In some embodiments, for the second pair of consecutive residues, one is D-Pro and the other is an LN-alkylated amino acid. In some embodiments, for the second pair of consecutive residues, one is D-Pro and the other is L-NMe-Ala. In some embodiments, for the second two consecutive residues, one is D-Pro and the other is N-(2-methoxyethyl)glycine. In some embodiments, for the second two consecutive residues, one is a DN-alkylated amino acid and the other is an LN-alkylated amino acid. In some embodiments, for the second two consecutive residues, one is D-NMe-Ala and the other is L-NMe-Ala. In some embodiments, for the second two consecutive residues, one is a DN-alkylated amino acid and the other is a peptide. In some embodiments, for the second two consecutive residues, one is D-NMe-Ala and the other is N-(2-methoxyethyl)glycine.

[0189] In some embodiments, at least two consecutive amino acids separate the first β-hairpin region from the second β-hairpin region. In some embodiments, at least three consecutive amino acids separate the first β-hairpin region from the second β-hairpin region. In some embodiments, two consecutive amino acids separate the first β-hairpin region from the second β-hairpin region. In some embodiments, three consecutive amino acids separate the first β-hairpin region from the second β-hairpin region. In some embodiments, the number of consecutive amino acids refers to the number of residues that start at the C-terminus of the first β-hairpin region and terminate at the N-terminus of the second β-hairpin region. In some embodiments, the number of consecutive amino acids refers to the number of residues that start at the C-terminus of the second β-hairpin region and terminate at the N-terminus of the first β-hairpin region. In some embodiments, the number of consecutive amino acids refers to the number of residues that begin at the C-terminus of the first β hairpin region and terminate at the N-terminus of the second β hairpin region, and the number of consecutive amino acids refers to the number of residues that begin at the C-terminus of the second β hairpin region and terminate at the N-terminus of the first β hairpin region, for example, three consecutive amino acids that begin at the C-terminus of the first β hairpin region and terminate at the N-terminus of the second β hairpin region, and three consecutive amino acids that begin at the C-terminus of the second β hairpin region and terminate at the N-terminus of the first β hairpin region.

[0190] In some embodiments, the molecular weight of the cyclic peptide is 800-1300 Da. In some embodiments, the molecular weight of the cyclic peptide is 800-1200 Da. In some embodiments, the molecular weight of the cyclic peptide is 900-1200 Da. In some embodiments, the molecular weight of the cyclic peptide is 800-900 Da. In some embodiments, the molecular weight of the cyclic peptide is 900-1000 Da. In some embodiments, the molecular weight of the cyclic peptide is 1000-1100 Da. In some embodiments, the molecular weight of the cyclic peptide is 1100-1200 Da. In some embodiments, the molecular weight of the cyclic peptide is 1200-1500 Da. In some embodiments, the molecular weight of the cyclic peptide is 1200-1400 Da. In some embodiments, the molecular weight of the cyclic peptide is 1100-1300 Da.

[0191] In some embodiments, the cyclic peptide has at least four amino acid residues comprising a ring independently selected from optionally substituted monocyclic carbon rings and optionally substituted monocyclic heterocycles, wherein at least one of the monocyclic carbon ring and the monocyclic heterocycle is substituted. In some embodiments, the at least four amino acid residues comprising the ring independently selected from optionally substituted monocyclic carbon rings and optionally substituted monocyclic heterocycles are not adjacent to each other. In some embodiments, the cyclic peptide is characterized by comprising four amino acid residues comprising a ring independently selected from optionally substituted monocyclic carbon rings and optionally substituted monocyclic heterocycles, wherein at least one of the monocyclic carbon ring and the monocyclic heterocycle is substituted. In some embodiments, the cyclic peptide is characterized by comprising three amino acid residues comprising a ring independently selected from optionally substituted monocyclic carbon rings and one amino acid residue comprising a ring independently selected from optionally substituted monocyclic heterocycles. In some embodiments, the optionally substituted monocyclic carbide ring is phenyl, and the optionally substituted monocyclic heterocycle is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is independently selected from halogen, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The substituted monocyclic ring is substituted with alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 substituents. In some embodiments, the optionally substituted monocyclic carbide ring is phenyl, and the optionally substituted monocyclic heterocycle is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is independently selected from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The substituted monocyclic carbide ring is substituted with one or more substituents selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, the optionally substituted monocyclic carbide ring is phenyl, and the optionally substituted monocyclic heterocyclic ring is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, the optionally substituted monocyclic carbide ring is phenyl, and the optionally substituted monocyclic heterocyclic ring is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from: thiophene, thiazole, oxazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, any of which may be substituted. In some embodiments, the optionally substituted monocyclic carbide ring is phenyl, and the optionally substituted monocyclic heterocycle is pyridine, wherein each ring is independently optionally substituted. In some embodiments, at least four amino acid residues comprising the ring independently selected from the optionally substituted monocyclic carbide ring and the optionally substituted monocyclic heterocycle are independently selected from phenylalanine, 3-(3-pyridyl)alanine, and 4-halophenylalanine.

[0192] In some embodiments, the cyclic peptide has at least four amino acid residues having side chains selected from -olefin- (monocyclic carbocyclic) and -olefin- (monocyclic heterocyclic), wherein the monocyclic carbocyclic and monocyclic heterocyclic are optionally substituted independently. In some embodiments, each of the at least four amino acids having side chains selected from -olefin- (optionally substituted monocyclic carbocyclic) and -olefin- (optionally substituted monocyclic heterocyclic) is not adjacent to each other. In some embodiments, two of the at least four amino acids having side chains selected from -olefin- (optionally substituted monocyclic carbocyclic) and -olefin- (optionally substituted monocyclic heterocyclic) are adjacent to each other. In some embodiments, each monocyclic carbocyclic ring is phenyl, and each monocyclic heterocyclic ring is a heteroaryl ring, wherein each phenyl and heteroaryl ring is optionally substituted independently by one or more substances independently selected from halogen, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The alkyl group, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 are substituents. In some embodiments, each monocyclic carbide ring is a phenyl ring, and each monocyclic heterocyclic ring is a heteroaryl ring, wherein each phenyl and heteroaryl ring is independently and optionally optionally substituted by one or more groups independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The cyclic peptide is substituted with alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2 substituents. In some embodiments, the cyclic peptide is characterized by having four amino acid residues with side chains selected from -olefin- (monocyclic carbocyclic) and -olefin- (monocyclic heterocyclic), wherein the monocyclic carbocyclic and monocyclic heterocyclic rings are optionally substituted independently. In some embodiments, the cyclic peptide is characterized by having three amino acids with side chains independently selected from -olefin- (monocyclic carbocyclic) and one amino acid with side chains selected from -olefin- (monocyclic heterocyclic), wherein the monocyclic carbocyclic and monocyclic heterocyclic rings are optionally substituted independently. In some embodiments, each monocyclic carbocyclic ring is phenyl, and each monocyclic heterocyclic ring is a heteroaryl ring, wherein each phenyl and heteroaryl ring is optionally substituted independently with one or more substituents independently selected from halogen, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, each monocyclic carbide ring is a phenyl group, and each monocyclic heterocyclic ring is a heteroaryl ring, wherein each phenyl and heteroaryl ring is independently and optionally substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, wherein any one of them is optionally substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from: thiophene, thiazole, oxazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, wherein any one of them is optionally substituted by one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each monocyclic carbocyclic ring is phenyl, and each monocyclic heterocyclic ring is pyridine, wherein each ring is optionally independently substituted. In some embodiments, at least four amino acid residues having a side chain selected from -olefin-(monocyclic carbocyclic) and -olefin-(monocyclic heterocyclic) are independently selected from phenylalanine, 3-(3-pyridyl)alanine, and 4-halophenylalanine.

[0193] In some embodiments, the cyclic peptide has at least three amino acid residues comprising a ring independently selected from optionally substituted phenyl groups and optionally substituted monocyclic heteroaryl groups. In some embodiments, the at least three amino acid residues comprising a ring independently selected from optionally substituted phenyl groups and optionally substituted monocyclic heteroaryl groups are not adjacent to each other. In some embodiments, the cyclic peptide is characterized by comprising three amino acid residues comprising a ring independently selected from optionally substituted phenyl groups and optionally substituted monocyclic heteroaryl groups. In some embodiments, the cyclic peptide is characterized by comprising four amino acid residues comprising a ring independently selected from optionally substituted phenyl groups and optionally substituted monocyclic heteroaryl groups. In some embodiments, the cyclic peptide is characterized by comprising three amino acid residues comprising a ring independently selected from optionally substituted phenyl groups and optionally substituted pyridine groups. In some embodiments, each phenyl and heteroaryl ring is independently and optionally selected from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 Alkyl groups, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 are substituents. In some embodiments, each phenyl and heteroaryl ring is optionally independently and optionally replaced by one or more substituents independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The alkyl group, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2 are substituents. In some embodiments, each phenyl and heteroaryl ring is optionally independently substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, each phenyl and heteroaryl ring is optionally independently substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from: thiophene, thiazole, oxazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, wherein any one of them is optionally substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from: thiophene, thiazole, oxazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, wherein any one of them is optionally substituted with one or more substituents independently selected from halogens, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each heteroaryl ring is an independently substituted pyridine. In some embodiments, at least three amino acid residues comprising a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl groups are independently selected from phenylalanine, 3-(3-pyridyl)alanine and 4-halophenylalanine.

[0194] In some embodiments, at least three main-chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In some embodiments, four or five main-chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In some embodiments, four main-chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In some embodiments, five main-chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms.

[0195] In some embodiments, one or more of the nitrogen atoms in the tertiary nitrogen backbone are part of a heterocyclic alkyl ring. When two or more tertiary nitrogen backbone nitrogen atoms are part of a heterocyclic alkyl ring, these rings are distinct from each other. For example, when two heterocyclic alkyl rings have tertiary nitrogen backbone nitrogen atom moieties, one nitrogen atom is part of a first proline moiety, and the second nitrogen atom is part of a second proline moiety.

[0196] In some embodiments, one tertiary nitrogen backbone nitrogen atom is part of a heterocyclic alkyl ring. In some embodiments, one tertiary nitrogen backbone nitrogen atom is part of a first heterocyclic alkyl ring, and the second tertiary nitrogen backbone nitrogen atom is part of a second heterocyclic alkyl ring. In some embodiments, one tertiary nitrogen backbone nitrogen atom is part of a first heterocyclic alkyl ring, the second tertiary nitrogen backbone nitrogen atom is part of a second heterocyclic alkyl ring, and the third tertiary nitrogen backbone nitrogen atom is part of a third heterocyclic alkyl ring. In some embodiments, one tertiary nitrogen backbone nitrogen atom is part of a first heterocyclic alkyl ring, the second tertiary nitrogen backbone nitrogen atom is part of a second heterocyclic alkyl ring, the third tertiary nitrogen backbone nitrogen atom is part of a third heterocyclic alkyl ring, and the fourth tertiary nitrogen backbone nitrogen atom is part of a fourth heterocyclic alkyl ring. In some embodiments, a tertiary nitrogen atom in the main chain is part of a first heterocyclic alkyl ring, a second tertiary nitrogen atom in the main chain is part of a second heterocyclic alkyl ring, a third tertiary nitrogen atom in the main chain is part of a third heterocyclic alkyl ring, a fourth tertiary nitrogen atom in the main chain is part of a fourth heterocyclic alkyl ring, and a fifth tertiary nitrogen atom in the main chain is part of a fifth heterocyclic alkyl ring.

[0197] In some embodiments, one or more tertiary nitrogen atoms have optional C1-C6 alkyl substituents, each independently selected at the tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl groups are independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 Alkyl groups, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, one or more tertiary nitrogen atoms have optional C1-C6 alkyl substituents, each independently selected from the group containing halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, and C. 1-4Alkyl, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, one or more tertiary nitrogens have optional C1-C6 alkyl substituents independently selected at each tertiary nitrogen, and wherein the substituents on the C1-C6 alkyl groups are independently selected from halogens, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, one of the tertiary nitrogens has optional C1-C6 alkyl substituents independently selected at each tertiary nitrogen, and wherein the substituents on the C1-C6 alkyl groups are independently selected from halogens, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, one of the tertiary nitrogen atoms has an optionally substituted C1-C6 alkyl substituent, independently selected at each tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl groups are independently selected from halogens, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, two of the tertiary nitrogen atoms have optionally substituted C1-C6 alkyl substituents, independently selected at each tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl groups are independently selected from halogens, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, two of the tertiary nitrogen atoms have optionally substituted C1-C6 alkyl substituents, independently selected at each tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl groups are independently selected from halogens, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, the three tertiary nitrogen atoms have optional C1-C6 alkyl substituents, each independently selected at a tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl groups are independently selected from halogens, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, the three tertiary nitrogen atoms have optional C1-C6 alkyl substituents, each independently selected at a tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl groups are independently selected from halogens, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, the four tertiary nitrogen atoms have optional C1-C6 alkyl substituents, each independently selected at a tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl groups are independently selected from halogens, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, the four tertiary nitrogen atoms have optional C1-C6 alkyl substituents that are independently selected at each tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl atoms are independently selected from halogens, -OBz, -OCH3, -OCF3, and -OCHF2.In some embodiments, the five tertiary nitrogen atoms have optional C1-C6 alkyl substituents, each independently selected at a tertiary nitrogen atom, and wherein the substituents on the C1-C6 alkyl groups are independently selected from halogens, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2.

[0198] In some implementation schemes, each tertiary nitrogen is independently produced by

[0199] It means that R A It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C1-C6 alkyl groups substituted with alkyl, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2, wherein This represents the connection point with adjacent amino acid residues. In some embodiments, each tertiary nitrogen is independently formed by... It means that R A It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C1-C6 alkyl groups substituted with alkyl, -OBz, -OCH3, -OCF3, and -OCHF2, wherein This represents the connection point with adjacent amino acid residues. In some embodiments, each tertiary nitrogen is independently formed by... It means that R A It is a C1-C6 alkyl group optionally substituted with one or more substituents independently selected from halogen, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2, and wherein This indicates the connection point with adjacent amino acid residues. In some embodiments, each tertiary nitrogen is independently formed by... It means that R A It is a C1-C6 alkyl group optionally substituted with one or more substituents independently selected from halogen, -OBz, -OCH3, -OCF3 and -OCHF2, and wherein This indicates the connection point with adjacent amino acid residues. In some embodiments, one or more tertiary nitrogen atoms are... In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are In some implementations, one or more tertiary nitrogen atoms are

[0200] In some embodiments, the cyclic peptide has 8 amino acid residues. In some embodiments, the cyclic peptide has 9 amino acid residues. In some embodiments, the cyclic peptide has 10 amino acid residues. In some embodiments, the cyclic peptide has 11 amino acid residues. In some embodiments, the cyclic peptide has 12 amino acid residues.

[0201] In some implementations, the cyclic peptide is represented by Formula I:

[0202]

[0203] in:

[0204] R 1 R 6 and R 8 Independently selected from hydrogen, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 substituents;

[0205] R 2 Selected from hydrogen and C 1-6 alkyl;

[0206] R 3 Selected from hydrogen, C 1-4 Alkyl, -(C 1-4 (olefin group)-(C3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substituents of alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; and wherein C 1-4 The alkyl group may be selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 substituents;

[0207] R 4 Is it hydrogen or C? 1-4 Alkyl, or R 4 and R 14 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0208] R 5 Selected from hydrogen, C 1-4 Alkyl, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substituents of alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; and wherein C 1-4 The alkyl group may be selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl groups, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 5 and R 15 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0209] R 7 Selected from hydrogen; and C 1-6 The alkyl group may be selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4Substitution with alkyl groups, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 7 and R 17 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0210] R 9 Is it hydrogen or C? 1-6 Alkyl, or R 9 and R 19 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0211] R 10 Is it hydrogen or C? 1-4 Alkyl, or R 10 and R 20 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0212] R 11 R 12 R 13 R 16 and R 18 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 alkyl;

[0213] R 14 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 14 and R 4 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0214] R 15 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 15 and R 5 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0215] R 17Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 17 and R 7 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0216] R 19 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 19 and R 9 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups; and

[0217] R 20 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 20 and R 10 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups.

[0218] In some implementations, the cyclic peptide is represented by Formula I:

[0219]

[0220] in:

[0221] R 1 R 6 and R 8 Independently selected from hydrogen, -(C 1-4 (olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2 substituents;

[0222] R 2 Selected from hydrogen and C 1-6 alkyl;

[0223] R 3 Selected from hydrogen, C 1-4 Alkyl, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substituents of alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; and wherein C 1-4 The alkyl group may be selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl groups, -OH, -OBz, -OCH3, -OCF3, and -OCHF2;

[0224] R 4 Is it hydrogen or C? 1-4 Alkyl, or R 4 and R 14 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0225] R 5 Selected from hydrogen, C 1-4 Alkyl, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substituents of alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; and wherein C 1-4 The alkyl group may be selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl groups, -OH, -OBz, -OCH3, -OCF3, and -OCHF2; or R 5 and R 15 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0226] R 7 Is it hydrogen or C? 1-6 Alkyl, or R 7 and R 17 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0227] R 9 Is it hydrogen or C? 1-6 Alkyl, or R 9 and R 19 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0228] R 10 Is it hydrogen or C? 1-4 Alkyl, or R 10 and R 20 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0229] R 11 R 12 R 13 R 16 and R 18 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 alkyl;

[0230] R 14 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 14 and R 4 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0231] R 15 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 15 and R 5 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0232] R 17Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 17 and R 7 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0233] R 19 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 19 and R 9 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups; and

[0234] R 20 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 20 and R 10 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups.

[0235] In some implementations, the cyclic peptide is represented by Formula II:

[0236]

[0237] in:

[0238] R 21 R 23 R 26 and R 28 Independently selected from hydrogen, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may be optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2;

[0239] R 24 Is it hydrogen or C?1-4 Alkyl, or R 24 and R 34 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0240] R 25 Is it hydrogen or C? 1-4 Alkyl, or R 25 and R 35 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0241] R 30 Is it hydrogen or C? 1-4 Alkyl, or R 30 and R 40 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0242] R 22 R 27 and R 29 Independently selected from hydrogen and C 1-6 alkyl;

[0243] R 31 R 32 R 33 R 36 and R 38 The C group is independently selected from hydrogen; and optionally substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl;

[0244] R 37 and R 39 The C group is independently selected from hydrogen; and optionally substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl;

[0245] R 34 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Alkyl; or R 34 and R 24 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0246] R 35 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Alkyl; or R 35 and R 25Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups; and

[0247] R 40 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Alkyl; or R 40 and R 30 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups.

[0248] In some implementations, the cyclic peptide is represented by Formula II:

[0249]

[0250] in:

[0251] R 21 R 23 R 26 and R 28 Independently selected from hydrogen, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may be optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2;

[0252] R 24 Is it hydrogen or C? 1-4 Alkyl, or R 24 and R 34 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0253] R 25 Is it hydrogen or C? 1-4 Alkyl, or R 25 and R 35 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0254] R 30 Is it hydrogen or C? 1-4 Alkyl, or R 30 and R 40 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0255] R 22 R 27 and R 29 Independently selected from hydrogen and C 1-6 alkyl;

[0256] R31 R 32 R 33 R 36 and R 38 C is independently selected from hydrogen; and optionally substituted by one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 alkyl;

[0257] R 37 and R 39 C is independently selected from hydrogen; and optionally substituted by one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 alkyl;

[0258] R 34 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 Alkyl; or R 34 and R 24 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups;

[0259] R 35 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 Alkyl; or R 35 and R 25 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups; and

[0260] R 40 Selected from hydrogen; and C substituted with one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 Alkyl; or R 40 and R 30 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups.

[0261] In some implementation schemes, R 31 It is hydrogen. In some implementations, R 32 It is hydrogen. In some implementations, R 33 It is hydrogen. In some implementations, R 36 It is hydrogen. In some implementations, R 38 It is hydrogen. In some implementations, R 31 and R 32 Each is hydrogen. In some implementations, R 31 and R 33Each is hydrogen. In some implementations, R 31 and R 36 Each is hydrogen. In some implementations, R 31 and R 38 Each is hydrogen. In some implementations, R 32 and R 33 Each is hydrogen. In some implementations, R 32 and R 36 Each is hydrogen. In some implementations, R 32 and R 38 Each is hydrogen. In some implementations, R 33 and R 36 Each is hydrogen. In some implementations, R 33 and R 38 Each is hydrogen. In some implementations, R 36 and R 38 Each is hydrogen. In some implementations, R 31 R 21 and R 33 Each is hydrogen. In some implementations, R 31 R 32 and R 36 Each is hydrogen. In some implementations, R 31 R 32 and R 38 Each is hydrogen. In some implementations, R 31 R 33 and R 36 Each is hydrogen. In some implementations, R 31 R 33 and R 38 Each is hydrogen. In some implementations, R 31 R 36 and R 38 Each is hydrogen. In some implementations, R 32 R 33 and R 36 Each is hydrogen. In some implementations, R 32 R 33 and R 38 Each is hydrogen. In some implementations, R 32 R 36 and R 38 Each is hydrogen. In some implementations, R 33 R 36 and R 38 Each is hydrogen. In some implementations, R 31 R 32 R 33 and R 36Each is hydrogen. In some implementations, R 31 R 32 R 33 and R 38 Each is hydrogen. In some implementations, R 31 R 33 R 36 and R 38 Each is hydrogen. In some implementations, R 31 R 32 R 36 and R 38 Each is hydrogen. In some implementations, R 32 R 33 R 36 and R 38 Each is hydrogen. In some implementations, R 31 R 32 R 33 R 36 and R 38 Each is hydrogen.

[0262] In some implementation schemes, R 34 R 35 R 37 R 39 and R 40 At least four of them are not hydrogen. In some implementations, R 34 R 35 R 37 R 39 and R 40 Four of them are not hydrogen. In some implementations, R 34 R 35 R 37 and R 39 It is not hydrogen. In some implementations, R 34 R 35 R 37 and R 40 It is not hydrogen. In some implementations, R 35 R 37 R 39 and R 40 It is not hydrogen. In some implementations, R 34 R 35 R 39 and R 40 It is not hydrogen. In some implementations, R 34 R 37 R 39 and R 40 It is not hydrogen. In some implementations, R 34 R 35 R37 R 39 and R 40 It's not hydrogen.

[0263] In some implementation schemes, R 24 and R 34 R 25 and R 35 and R 30 and R 40 At least one of them, together with the intermediate atom, forms a 5-7 membered heterocyclic alkyl group. In some embodiments, R 24 and R 34 R 25 and R 35 and R 30 and R 40 At least two of them, together with the intermediate atom, form a 5-7 membered heterocyclic alkyl group. In some embodiments, R 24 and R 34 Together with the intermediate atom, it forms a 5-6 membered heterocyclic alkyl group. In some embodiments, R 25 and R 35 Together with the intermediate atom, it forms a 5-6 membered heterocyclic alkyl group. In some embodiments, R 30 and R 40 Together with the intermediate atom, it forms a 5-6 membered heterocyclic alkyl group. In some embodiments, R 24 and R 34 and R 25 and R 35 Together with the intermediate atom, it forms a 5-6 membered heterocyclic alkyl group. In some embodiments, R 24 and R 34 and R 30 and R 40 Together with the intermediate atom, it forms a 5-6 membered heterocyclic alkyl group. In some embodiments, R 25 and R 35 and R 30 and R 40 Together with the intermediate atom, it forms a 5-6 membered heterocyclic alkyl group. In some embodiments, R 24 and R 34 R 25 and R 35 and R 30 and R 40 Together with the intermediate atom, it forms a 5-6 membered heterocyclic alkyl group.

[0264] In some implementation schemes, R 37 R 39 and R 40 Each of these is selected from methyl and methoxyethyl. In some embodiments, R 35 R 37 and R39 Each of these is selected from methyl and methoxyethyl. In some embodiments, R 35 R 37 and R 40 Each of these is selected from methyl and methoxyethyl. In some embodiments, R 35 R 39 and R 40 Each of these is selected from methyl and methoxyethyl. In some embodiments, R 35 R 37 R 39 and R 40 Each of them is selected from methyl and methoxyethyl.

[0265] In some implementation schemes, R 40 C is a C that is optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 2-4 Alkyl, or R 30 and R 40 Together with the intermediate atom, it forms a 5-7 membered heterocyclic alkyl group. In some embodiments, R 40 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 2-4 Alkyl, or R 30 and R 40 It forms a 5-7 membered heterocyclic alkyl group with the intermediate atom. In some embodiments, R 40 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl, or R 30 and R 40 When used with an intermediate atom, it forms a 5-7 membered heterocyclic alkyl group. In some embodiments, R 40 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 2-4 Alkyl, or R 30 and R 40 Together with the intermediate atom, it forms a 5-7 membered heterocyclic alkyl group. In some embodiments, R 40 C is a C that is optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 40It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 40 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 40 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 2-4 Alkyl group. In some embodiments, R 40 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, -SF5, and -OCH3. 2-4 Alkyl group. In some embodiments, R 40 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, and -OCH3. 2-4 Alkyl group. In some embodiments, R 30 and R 40 Together with the intermediate atom, they form 5-7 membered heterocyclic alkyl groups.

[0266] In some implementation schemes, R 39 C is a C that is optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 1-4 Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 1-4 Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, -SF5, and -OCH3. 1-4Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, and -OCH3. 1-4 Alkyl group. In some embodiments, R 39 C is a C that is optionally substituted by one or more substituents independently selected from -CHF2, -OBz, -SF5, and -OCHF2. 1-4 Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from -CHF2, -OBz ​​and -OCHF2. 1-4 alkyl.

[0267] In some implementation schemes, R 22 R 27 and R 29 Selected independently from C 1-6 Alkyl group. In some embodiments, R 22 R 27 and R 29 Selected from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. In some embodiments, R 22 R 27 and R 29 Selected from: methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 27 It is methyl. In some embodiments, R 29 It is methyl. In some embodiments, R 27 and R 29 Each is a methyl group.

[0268] In some implementation schemes, R 21 R 23 R 26 and R 28 Independently selected from -C 3-8 Carbon rings, -3-10 membered heterocycles, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles may be optionally substituted. In some embodiments, R 21 R 23 R 26 and R 28 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8The carbon ring and 3-10 membered heterocycles may be optionally substituted. In some embodiments, R 21 R 23 R 26 and R 28 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. In some embodiments, R 21 R 23 R 26 and R 28 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. In some embodiments, R 21 R 23 R 26 and R 28 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, R 21 R 23 R 26 and R 28 Independently selected from -CH2-(C 3-8 (Carbon ring) and -CH2- (3-10 membered heterocycle). In some embodiments, R 21 R 23 R 26 and R 28 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -SF5, and -OCH3. In some embodiments, R 21 R 23 R 26 and R 28 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, and -OCH3. In some embodiments, R 21 R 23 R 26 and R 28 The phenyl group is independently selected from benzyl and pyridylmethyl, wherein the phenyl and pyridyl groups are optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -SF5, and -OCH3. In some embodiments, R 21 R 23 R 26 and R 28 The methyl group is independently selected from benzyl and pyridylmethyl, wherein the phenyl and pyridyl groups are optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, and -OCH3. In some embodiments, R 21 R 23 R 26 and R 28 Selected independently from:

[0269] In some implementation schemes, R 21 yes And R 23 R 26 and R 28 Selected independently In some implementation schemes, R 21 yes R 23 yes And R 26 and R 28 Selected independently In some implementation schemes, R 21 yes R 23 yes R 26 yes And R 28 yes

[0270] In some implementations, the cyclic peptide is represented by formula IIa:

[0271]

[0272] In some implementations, the cyclic peptide is represented by formula IIb:

[0273]

[0274] Where R 21' R 23' R 26' and R 28' Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0275] In some implementation schemes, R 21' R 23' R 26' and R 28' Selected independently from:

[0276] In some implementation schemes, R 21' yes And R 23' R 26' and R 28' Selected independently In some implementation schemes, R 21' yes R 23' yes And R 26' and R 28' Selected independently In some implementation schemes, R 21' yes R 23' yes R 26' yes And R 28' yes

[0277] In some implementations, the cyclic peptide is represented by formula IIc:

[0278]

[0279] Where R 21' R 23' R 26' and R 28' Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0280] In some implementations, the cyclic peptide is represented by formula IId:

[0281]

[0282] Where R 21' R 23' R 26' and R 28' Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0283] In some implementations, the cyclic peptide is represented by formula IIe:

[0284]

[0285] Where R 21' R 23' R 26' and R 28' Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0286] In some implementations, the cyclic peptide is represented by the formula IIf:

[0287]

[0288] Where R 21' R 23' R 26' and R 28' Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0289] In some implementations, the cyclic peptide is represented by formula IIg:

[0290]

[0291] Where R 21' R 23' R 26' and R 28' Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0292] In some implementations, the cyclic peptide is represented by Formula III:

[0293]

[0294] in:

[0295] R 41 R 45 R 46 and R 48 Independently selected from hydrogen, -(C 1-4 (olefin group)-(C3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 substituents;

[0296] R 42 Selected from hydrogen and C 1-6 alkyl;

[0297] R 43 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 alkyl;

[0298] R 44 Is it hydrogen or C? 1-4 Alkyl, or R 44 and R 54 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0299] R 47 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-6 Alkyl; or R 47 and R 57 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0300] R 49 Is it hydrogen or C? 1-6 Alkyl, or R 49 and R 59 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0301] R 50 Is it hydrogen or C? 1-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0302] R 51 R53 R 56 and R 58 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 alkyl;

[0303] R 52 and R 55 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 alkyl;

[0304] R 54 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 54 and R 44 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0305] R 57 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 57 and R 47 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0306] R 59 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 59 and R 49 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0307] R 60 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 1-4 Alkyl; or R 60 and R 50 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups.

[0308] In some implementations, the cyclic peptide is represented by Formula III:

[0309]

[0310] in:

[0311] R 41 R 45 R 46 and R 48 Independently selected from hydrogen, -(C 1-4 (olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently from one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substitution with alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2 substituents;

[0312] R 42 Selected from hydrogen and C 1-6 alkyl;

[0313] R 43 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 alkyl;

[0314] R 44 Is it hydrogen or C? 1-4 Alkyl, or R 44 and R 54 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0315] R 47Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-6 Alkyl; or R 47 and R 57 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0316] R 49 Is it hydrogen or C? 1-6 Alkyl, or R 49 and R 59 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0317] R 50 Is it hydrogen or C? 1-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0318] R 51 R 53 R 56 and R 58 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 alkyl;

[0319] R 52 and R 55 Independently selected from hydrogen; and optionally selected by one or more independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 alkyl;

[0320] R 54 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 54 and R 44 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0321] R 57 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 57 and R 47 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0322] R 59 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 59 and R 49 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups;

[0323] R 60 Selected from hydrogen; and optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Alkyl; or R 60 and R 50 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups.

[0324] In some implementation schemes, R 51 It is hydrogen. In some implementations, R 53 It is hydrogen. In some implementations, R 56 It is hydrogen. In some implementations, R 58 It is hydrogen. In some implementations, R 51 and R 53 Each is hydrogen. In some implementations, R 51 and R 56 Each is hydrogen. In some implementations, R 51 and R 58 Each is hydrogen. In some implementations, R 53 and R 56 Each is hydrogen. In some implementations, R 53 and R 58 Each is hydrogen. In some implementations, R 56 and R 58Each is hydrogen. In some implementations, R 51 R 53 and R 56 Each is hydrogen. In some implementations, R 51 R 53 and R 58 Each is hydrogen. In some implementations, R 51 R 56 and R 58 Each is hydrogen. In some implementations, R 53 R 56 and R 58 Each is hydrogen. In some implementations, R 51 R 53 R 56 and R 58 Each is hydrogen.

[0325] In some implementation schemes, R 52 R 54 R 55 R 57 R 59 and R 60 At least four of them are not hydrogen. In some implementations, R 52 R 54 R 55 R 57 R 59 and R 60 Four of them are not hydrogen. In some implementations, R 52 R 54 R 55 and R 57 It is not hydrogen. In some implementations, R 52 R 54 R 55 and R 59 It is not hydrogen. In some implementations, R 52 R 54 R 55 and R 60 It is not hydrogen. In some implementations, R 52 R 54 R 57 and R 59 It is not hydrogen. In some implementations, R 52 R 54 R 57 and R 60 It is not hydrogen. In some implementations, R 52 R 54 R 59 and R 60 It is not hydrogen. In some implementations, R52 R 55 R 57 and R 59 It is not hydrogen. In some implementations, R 52 R 55 R 57 and R 60 It is not hydrogen. In some implementations, R 52 R 55 R 59 and R 60 It is not hydrogen. In some implementations, R 52 R 57 R 59 and R 60 It is not hydrogen. In some implementations, R 54 R 55 R 57 and R 59 It is not hydrogen. In some implementations, R 54 R 55 R 57 and R 60 It is not hydrogen. In some implementations, R 54 R 55 R 59 and R 60 It is not hydrogen. In some implementations, R 54 R 57 R 59 and R 60 It is not hydrogen. In some implementations, R 55 R 57 R 59 and R 60 It is not hydrogen. In some implementations, R 52 R 54 R 55 R 57 R 59 and R 60 At least five of them are not hydrogen. In some implementations, R 52 R 54 R 55 R 57 R 59 and R 60 Five of them are not hydrogen. In some implementations, R 52 R 54 R 55 R 57 and R 59 It is not hydrogen. In some implementations, R 52 R 54 R 55 R57 and R 60 It is not hydrogen. In some implementations, R 52 R 55 R 57 R 59 and R 60 It is not hydrogen. In some implementations, R 54 R 55 R 57 R 59 and R 60 It is not hydrogen. In some implementations, R 52 R 54 R 55 R 57 R 59 and R 60 It's not hydrogen.

[0326] In some implementation schemes, R 44 and R 54 R 47 and R 57 R 49 and R 59 and R 50 and R 60 At least one of them, together with the intermediate atom, forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 44 and R 54 R 47 and R 57 R 49 and R 59 and R 50 and R 60 At least two of them, together with the intermediate atom, form a 4-7 membered heterocyclic alkyl group. In some embodiments, R 44 and R 54 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 47 and R 57 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 49 and R 59 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 44 and R 54 and R 47 and R 57 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 44 and R 54 and R49 and R 59 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 44 and R 54 and R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 47 and R 57 and R 49 and R 59 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 47 and R 57 and R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 49 and R 59 and R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 44 and R 54 R 47 and R 57 and R 49 and R 59 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 44 and R 54 R 47 and R 57 and R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 44 and R 54 R 49 and R 59 and R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 47 and R 57 R 49 and R 59 and R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 44 and R 54 R 47 and R 57 R 49 and R 59 and R 50 and R 60Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups.

[0327] In some implementation schemes, R 52 R 55 and R 59 Each of these is selected from methyl, ethyl, and methoxyethyl. In some embodiments, R 52 R 55 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl. In some embodiments, R 52 R 59 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl. In some embodiments, R 55 R 59 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl. In some embodiments, R 52 R 55 R 59 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl. In some embodiments, R 52 R 55 R 57 R 59 and R 60 Each of them is selected from methyl, ethyl, and methoxyethyl.

[0328] In some implementation schemes, R 60 It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CF3, -CHF2, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 2-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 60 It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CF3, -CHF2, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 60It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 2-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 60 It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 60 C is a C that is optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 2-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 60 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 2-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups. In some embodiments, R 60 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 60 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 2-4 Alkyl, or R 50 and R 60 Together with the intermediate atom, it forms a 4-7 membered heterocyclic alkyl group. In some embodiments, R 60It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 2-4 Alkyl group. In some embodiments, R 60 It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 Alkyl group. In some embodiments, R 60 C is a C that is optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 60 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 60 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 60 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 2-4 Alkyl group. In some embodiments, R 60 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, -SF5, and -OCH3. 2-4 Alkyl group. In some embodiments, R 60 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, and -OCH3. 2-4 Alkyl group. In some embodiments, R 50 and R 60 Together with the intermediate atom, they form 4-7 membered heterocyclic alkyl groups.

[0329] In some implementation schemes, R 59 It is optionally selected by one or more independently chosen from halogens, -CF3, -CHF2, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 2-4 Alkyl group. In some embodiments, R 59 It is optionally selected by one or more independently chosen from halogens, -CF3, -CHF2, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 Alkyl group. In some embodiments, R 59 It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2 2-4 Alkyl group. In some embodiments, R 59 It is optionally selected by one or more independently chosen from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C-substituents of alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 Alkyl group. In some embodiments, R 59 C is a C that is optionally substituted by one or more substituents independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, -CH3, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 59 C is a C that is optionally substituted with one or more substituents independently selected from halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, -CH3, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 39 C is a C that is optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 39It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 2-4 Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, -SF5, and -OCH3. 2-4 Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from halogen, -OH, -CH3, -CF3, and -OCH3. 2-4 Alkyl group. In some embodiments, R 39 It is a C that is optionally substituted by one or more substituents independently selected from -CHF2, -OBz ​​and -OCHF2. 2-4 alkyl.

[0330] In some implementation schemes, R 42 R 47 and R 49 Selected independently from C 1-6 Alkyl group. In some embodiments, R 42 R 47 and R 49 Selected from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. In some embodiments, R 42 R 47 and R 49 Selected from: methyl, ethyl, isopropyl, and tert-butyl. In some embodiments, R 42 It is methyl. In some embodiments, R 47 It is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R 49 It is methyl. In some embodiments, R 42 It is methyl, R 47 It is methyl, ethyl, isopropyl, or tert-butyl, and R 49 It is hydrogen. In some implementations, R 42 It is methyl, R 47 It is methyl, and R 49 It is hydrogen. In some implementations, R 42 It is methyl, R 47 It is ethyl, and R 49 It is hydrogen. In some implementations, R 42 It is methyl, R 47It is isopropyl, and R 49 It is hydrogen. In some implementations, R 42 It is methyl, R 47 It is tert-butyl, R 49 It is hydrogen. In some implementations, R 42 It is methyl, R 47 It is methyl, ethyl, isopropyl, or tert-butyl, and R 49 It is methyl. In some embodiments, R 42 It is methyl, R 47 It is methyl, and R 49 It is methyl. In some embodiments, R 42 It is methyl, R 47 It is ethyl, and R 49 It is methyl. In some embodiments, R 42 It is methyl, R 47 It is isopropyl, and R 49 It is methyl. In some embodiments, R 42 It is methyl, R 47 It is tert-butyl, and R 49 It is a methyl group.

[0331] In some implementation schemes, R 41 R 45 R 46 and R 48 Selected independently from: –C 3-8 Carbon rings, 3-10 membered heterocycles, -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles may be optionally substituted. In some embodiments, R 41 R 45 R 46 and R 48 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles may be optionally substituted. In some embodiments, R 41 R 45 R 46 and R 48 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substituents include alkyl groups, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, R... 41 R 45 R 46 and R 48 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbon ring and 3-10 membered heterocycles are optionally selected independently by one or more halogens, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Substituents include alkyl groups, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, R... 41 R 45 R 46 and R 48 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. In some embodiments, R 41 R 45 R 46 and R 48 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. In some embodiments, R 41 R 45 R 46 and R 48 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, R 41 R 45 R 46 and R 48 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, R 41 R 45 R 46 and R 48 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, -SF5, and -OCH3. In some embodiments, R 41 R 45 R 46 and R 48 Independently selected from -(C 1-4 olefin group)-(C 3-8 carbon ring) and -(C 1-4 (olefinic)-(3-10 membered heterocycle), where C 3-8 The carbocyclic ring and the 3-10 membered heterocycle may optionally be substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, and -OCH3. In some embodiments, R 41 R 45 R 46 and R 48 Independently selected from –CH2-(C 3-8 (Carbon ring) and –CH2- (3-10 membered heterocycle). In some embodiments, R 41 R 45 R 46 and R 48The group is independently selected from: benzyl, pyridylmethyl, and thiazolylmethyl, wherein the phenyl, pyridyl, and thiazolyl groups are optionally substituted by one or more substituents independently selected from halogens, -OH, -CH3, -CF3, and -OCH3. In some embodiments, R 41’ R 45’ R 46’ and R 48’ Selected independently from:

[0332] In some implementation schemes, R 41’ yes And R 45’ R 46’ and R 48’ Selected independently In some implementation schemes, R 41’ yes R 45’ yes R 46’ and R 48’ Selected independently In some implementation schemes, R 41’ yes R 45’ yes R 46’ yes R 48’ yes In some implementation schemes, R 41’ yes R 45’ yes And R 46’ and R 48’ Selected independently In some implementation schemes, R 41’ yes R 45’ yes R 46’ yes And R 48’ yes

[0333] In some implementations, the cyclic peptide is represented by formula IIIa:

[0334]

[0335] In some implementations, the cyclic peptide is represented by formula IIIb:

[0336]

[0337] Where R 41’ R 45’R 46’ and R 48’ Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0338] In some implementation schemes, R 41’ R 45’ R 46’ and R 48’ Selected independently from: In some implementation schemes, R 41’ yes And R 45’ R 46’ and R 48’ Selected independently In some implementation schemes, R 41’ yes R 45’ yes And R 46’ and R 48’ Selected independently In some implementation schemes, R 41’ yes R 45’ yes R 46’ yes And R 48’ yes In some implementation schemes, R 41’ yes R 45’ yes And R 46’ and R 48’ Selected independently In some implementation schemes, R 41’ yes R 45’ yes R 46’ yes And R 48’ yes

[0339] In some implementations, cyclic peptides are represented by IIIc:

[0340]

[0341] Where R 41’ R 45’ R 46’ and R 48’ Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0342] In some implementations, the cyclic peptide is represented by formula IIId:

[0343]

[0344]

[0345] Where R 41’ R 45’ R 46’ and R 48’ Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0346] In some implementations, the cyclic peptide is represented by formula IIIe:

[0347]

[0348] Where R 41’ R 45’ R 46’ and R 48’ Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0349] In some implementations, the cyclic peptide is represented by formula IIIf:

[0350]

[0351] Where R 41’ R 45’ R 46’ and R 48’ Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0352] In some implementations, cyclic peptides are represented by IIIg:

[0353]

[0354] Where R 41’ R 45’ R 46’ and R 48’ Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0355] In some implementations, the cyclic peptide is represented by formula IIIh:

[0356]

[0357] Where R 41’ R 45’ R 46’ and R 48’Independently selected from optionally substituted phenyl groups and optionally substituted 5- or 6-membered heteroaryl groups.

[0358] In some implementations, the cyclic peptide is selected from those in Tables 3 and 4, or a pharmaceutically acceptable salt of any of them.

[0359] In some embodiments, the cyclic peptides disclosed herein have a content greater than 1.0 x 10⁻⁶. -7 cm S -1 The cell permeability value. In some embodiments, the cyclic peptides disclosed herein have a value greater than 1.0 x 10⁻⁶. -6 cm S -1 The cell permeability value. In some embodiments, the cyclic peptides disclosed herein have a value greater than 1.0 x 10⁻⁶. -5 cm S -1 The cell permeability value. In some embodiments, the cyclic peptides disclosed herein have a value greater than 1.0 x 10⁻⁶. -4 cm S -1 The cell permeability value. In some embodiments, the cyclic peptides disclosed herein have a value greater than 1.0 x 10⁻⁶. -3 cm S -1 The cell permeability value. In some embodiments, the cyclic peptides disclosed herein have a value greater than 0.01 cm⁻¹ S. -1 Cell permeability values. In some embodiments, the cyclic peptides disclosed herein have a value greater than 0.1 cm⁻¹ S. -1 Cell permeability values. In some embodiments, the cyclic peptides disclosed herein have a value greater than 1.0 cm⁻¹ S. -1 The cell permeability values. In some embodiments, the cell permeability values ​​of the cyclic peptides disclosed herein are determined by Caco-2 analysis. In some embodiments, the cell permeability values ​​of the cyclic peptides disclosed herein are determined by MDR1-MDCK analysis.

[0360] In some embodiments, the cyclic peptides disclosed herein have a density greater than 5.0 x 10⁻⁶. -8 The solubility value of M. In some embodiments, the cyclic peptides disclosed herein have a solubility value greater than 5.0 x 10⁻⁶. -7 The solubility value of M. In some embodiments, the cyclic peptides disclosed herein have a solubility value greater than 5.0 x 10⁻⁶. -6 The solubility value of M. In some embodiments, the cyclic peptides disclosed herein have a solubility value greater than 5.0 x 10⁻⁶. -5 The solubility value of M. In some embodiments, the cyclic peptides disclosed herein have a solubility value greater than 5.0 x 10⁻⁶. -4 The solubility value of M. In some embodiments, the cyclic peptides disclosed herein have a solubility value greater than 5.0 x 10⁻⁶. -3The solubility value of M. In some embodiments, the cyclic peptides disclosed herein have a solubility value greater than 0.05 M. In some embodiments, the cyclic peptides disclosed herein have a solubility value greater than 0.5 M. In some embodiments, the cyclic peptides disclosed herein have a solubility value greater than 5.0 M. In some embodiments, the solubility value of the cyclic peptides disclosed herein is determined by kinetic solubility analysis. In some embodiments, the solubility value of the cyclic peptides disclosed herein is determined by equilibrium solubility analysis. In some embodiments, the solubility value of the cyclic peptides disclosed herein is determined by nephelometric assay. In some embodiments, the solubility value of the cyclic peptides disclosed herein is determined by turbidity analysis. In some embodiments, the solubility value of the cyclic peptides disclosed herein is determined by direct UV analysis.

[0361] In some embodiments, the compounds disclosed herein are used in different enriched isotopic forms, for example, enriched... 2 H, 3 H, 11 C 13 C and / or 14 The content of C. The deuterated form can be prepared by the steps described in U.S. Patents US5,846,514 and US6,334,997. As described in U.S. Patents US5,846,514 and US6,334,997, deuteration can improve metabolic stability and / or efficiency, thereby increasing the duration of drug action.

[0362] Unless otherwise stated, the compounds described herein are intended to include compounds with variations in only one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium, or using... 13 C or 14 Compounds having the current structure other than carbon-enriched carbon-substituted carbons are within the scope of this disclosure.

[0363] The compounds disclosed herein may optionally contain non-natural proportions of atomic isotopes at one or more atoms constituting such compounds. For example, these compounds may be labeled with isotopes such as deuterium (…). 2 H), tritium ( 3 H), Iodine-125 125 I) or carbon-14 ( 14 C). Use 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br and 125 Isotopic substitutions of I are all considered. All isotopic variants of the cyclic peptides disclosed herein (whether radioactive or not) are included within the scope of this disclosure.

[0364] In some embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art, and the following synthetic methods are included only by way of non-limiting examples.

[0365] Deuterium-substituted compounds are synthesized using various methods, for example, as described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0366] Deuteration starting materials are readily available and used in the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and components are commercially available from chemical suppliers such as Aldrich Chemical Company.

[0367] The cyclic peptides disclosed herein also include those compounds, their pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity in crystalline and amorphous forms, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of compounds, as well as mixtures thereof.

[0368] In some cases, the compounds described herein may exist in diastereomers, enantiomers, or other stereoisomers. The compounds presented herein include all diastereomers, enantiomers, and epimers, and suitable mixtures thereof. Stereoisomers can be separated by chromatography, or by forming diastereomers and then separating them by recrystallization, chromatography, or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, incorporated herein by reference). Stereoisomers can also be obtained by stereoselective synthesis.

[0369] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). Similarly, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. Furthermore, the compounds described herein can exist in both non-solventized and solvated forms with pharmaceutically acceptable solvents (such as water, ethanol, etc.). Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0370] Synthetic chemical transformations and methodologies that can be used to synthesize the compounds described herein are known in the art, including, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T.W. Greene and P. G.M. Uts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0371] The separation and purification of the chemical entities and intermediates described herein can be achieved, if desired, by any suitable separation or purification procedure (e.g., filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, or a combination of these procedures). Specific instructions for suitable separation and purification procedures can be obtained by referring to the examples below. However, other equivalent separation or purification procedures may also be used.

[0372] This disclosure is also intended to cover in vivo metabolites of the disclosed compounds. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of compounds applied primarily by enzymatic processes. Therefore, this disclosure includes compounds that are produced by a method comprising administering a compound of this disclosure to a mammal for a period sufficient to produce its metabolites. Such products are typically generated by administering a radiolabeled compound of this disclosure to an animal such as a rat, mouse, guinea pig, monkey, or human at a detectable dose, allowing sufficient time for metabolism and separation of its metabolites from urine, blood, or other biological samples.

[0373] pharmaceutical preparations

[0374] The cyclic peptides of this disclosure are formulated in any suitable pharmaceutical preparation. Pharmaceutical preparations of this disclosure typically comprise an active ingredient (e.g., the cyclic peptides disclosed herein) and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. In some embodiments, the pharmaceutically acceptable carriers or excipients are selected from: water, ethanol, glycerol, chitosan, alginate, chondroitin, vitamin E, mineral oil, and dimethyl sulfoxide (DMSO).

[0375] Pharmaceutical formulations are provided in any suitable form, determined based on the route of administration. In some embodiments, the pharmaceutical compositions disclosed herein may be formulated into dosage forms for administration to a subject. In some embodiments, the pharmaceutical compositions are formulated for oral, intravenous, intra-arterial, aerosol, parenteral, oral, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and / or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral administration. For example, the pharmaceutical compositions may be formulated as pills, tablets, capsules, inhalers, liquid suspensions, liquid emulsions, gels, or powders. In some embodiments, the pharmaceutical compositions may be formulated as unit doses in liquid, gel, semi-liquid, semi-solid, or solid forms.

[0376] The dosage of each cyclic peptide will depend on the mammal being treated, the severity of the disease or condition, the rate of administration, the properties of the cyclic peptide, and the prescribing physician's judgment. In some implementations, the effective dose is delivered in a pulsed administration manner (i.e., the compound is administered for several consecutive days, followed by several consecutive rest days).

[0377] In some embodiments, this disclosure provides a pharmaceutical composition for oral administration comprising at least one cyclic peptide disclosed herein and a pharmaceutical excipient suitable for oral administration. The composition is in solid, liquid, gel, semi-liquid, or semi-solid form. In some embodiments, the composition further comprises a second agent.

[0378] In some embodiments, this disclosure provides a solid pharmaceutical composition for oral administration comprising: (i) the cyclic peptide disclosed herein; and (ii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises: (iii) a third agent or even a fourth agent. In some embodiments, each compound or agent is present in a therapeutically effective amount. In other embodiments, one or more compounds or agents are present in a subtherapeutic amount, and the compounds or agents synergistically act to provide a therapeutically effective pharmaceutical composition.

[0379] Pharmaceutical compositions of this disclosure suitable for oral administration can be presented in discrete dosage forms, such as hard or soft capsules, flat capsules, lozenges, rhomboid lozenges or tablets, or liquid or aerosol sprays, each containing a predetermined amount of active ingredient, as powder or granules, solutions or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions, or dispersible powders or granules, or syrups or elixirs. Such dosage forms can be prepared by any pharmaceutical method, which generally includes the step of binding the active ingredient to a carrier. Typically, the composition is prepared by uniformly and tightly mixing the active ingredient with a liquid carrier or a finely chopped solid carrier, or both, and then, if desired, shaping the product into the desired presentation form. For example, tablets can be prepared by compression or molding, optionally with one or more excipient components. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, optionally mixed with excipients (e.g., but not limited to binders, lubricants, inert diluents, and / or surfactants or dispersants). Molded tablets can be prepared by molding a mixture of powdered cyclic peptides wetted with an inert liquid diluent in a suitable machine.

[0380] In some embodiments, this disclosure provides a pharmaceutical composition for injection comprising the cyclic peptide disclosed herein and a pharmaceutical excipient suitable for injection. The components and amounts of the reagents in the composition are as described herein.

[0381] In some embodiments, the cyclic peptides disclosed herein are included in the form of injectable administration, including aqueous or oily suspensions or emulsions, with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, glucose or sterile aqueous solutions, and similar pharmaceutical mediators.

[0382] Aqueous solutions in saline solutions are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Appropriate flowability can be maintained, for example, by using coatings (such as lecithin) to maintain the desired particle size in the case of dispersions, and by using surfactants. Microbial activity can be prevented by various antimicrobial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0383] Sterile injectable solutions are prepared by incorporating the cyclic peptides disclosed herein in the desired amounts, along with various other components listed above (as needed), into a suitable solvent, followed by filtration and sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile medium containing a base dispersion medium and those other desired components listed above. In the case of sterile powders used to prepare sterile injectable solutions, certain ideal preparation methods are vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any other desired components from their previously sterile filtered solutions.

[0384] Pharmaceutical compositions can also be prepared from the cyclic peptides described herein and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalation, sublingual, oral, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of DrugAction, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (ThePharmaceutical Press, London, 1999).

[0385] This disclosure also provides a kit. The kit may include the cyclic peptide disclosed herein and one or more additional reagents, in suitable packaging, and written materials may include instructions for use, discussions of clinical studies, a list of side effects, etc. Such a kit may also include information such as scientific references, packaging inserts, clinical trial results and / or summaries thereof, indicating or identifying the activity and / or benefits of the composition, and / or describing dosage, administration method, side effects, drug interactions, or other information useful to healthcare providers. Such information may be based on the results of various studies, such as studies using laboratory animals involving in vivo models, and studies based on human clinical trials. The kit may further include another reagent. In some embodiments, the cyclic peptide and reagent disclosed herein are provided as separate compositions in separate containers within the kit. In some embodiments, the cyclic peptide and reagent disclosed herein are provided as a single composition within a container of the kit. Suitable packaging and additional items for use (e.g., measuring cups for liquid formulations, foil packaging to minimize air exposure, etc.) are known in the art and may be included in the kit. The kits described herein may be offered, sold, and / or promoted to healthcare providers, including physicians, nurses, pharmacists, prescribing personnel, etc. In some implementations, the test kits can also be sold directly to consumers.

[0386] How to use

[0387] On the one hand, this disclosure provides a method for inhibiting MDM2, comprising administering the cyclic peptide described herein to a subject in need. On the other hand, this disclosure provides a method for inhibiting MDM2 and MDM4, comprising administering the cyclic peptide described herein to a subject in need.

[0388] On the other hand, this disclosure provides a method for treating a disease or condition in a subject in need, comprising administering a therapeutically effective amount of the cyclic peptide described herein to the subject. In some embodiments, the method for treating a disease or condition comprises administering an MDM2 inhibitor to the subject. In some embodiments, the method for treating a disease or condition comprises administering a dual MDM2 / MDM4 inhibitor to the subject. In some embodiments, the cyclic peptide disclosed herein is an MDM2 inhibitor. In some embodiments, the cyclic peptide disclosed herein is a dual MDM2 / MDM4 inhibitor.

[0389] In some implementations, the disease or condition is cancer. In some implementations, the cancer is selected from: acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia. In some implementations, the disease or condition is related to the proliferation of senescent cells. In some implementations, the disease or condition related to the proliferation of senescent cells is selected from: type 2 diabetes, Huntington's disease, non-alcoholic fatty liver disease, and hyperlipidemia. In some implementations, the disease or condition related to the proliferation of senescent cells is selected from: cardiovascular disease, inflammatory disease, autoimmune disease, metabolic disease, lung disease, eye disease, ear disease, kidney disease, and skin disease.

[0390] In further embodiments, this document discloses a method for treating cancer symptoms, wherein the cyclic peptide disclosed herein (e.g., an MDM2 inhibitor, or an MDM2 / MDM4 dual inhibitor) is effective in one or more of the following methods: inhibiting cancer cell proliferation, inhibiting cancer cell metastasis, reducing the severity or incidence of symptoms associated with the presence of cancer cells, and promoting an immune response against tumor cells. In some embodiments, the method includes administering a therapeutically effective amount of the cyclic peptide disclosed herein to cancer cells. In some embodiments, the cancer is selected from: acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia. In some embodiments, the cyclic peptide disclosed herein is an MDM2 inhibitor. In some embodiments, the cyclic peptide disclosed herein is an MDM2 / MDM4 dual inhibitor. In some embodiments, the administration occurs in vitro. In some embodiments, the administration is performed in vivo.

[0391] As used herein, the therapeutically effective amount of the cyclic peptides disclosed herein refers to an amount sufficient to affect the intended application, including but not limited to disease treatment as defined herein. The use of subtherapeutic amounts of the disclosed cyclic peptides to treat a desired disease condition is also contemplated in the methods of the subject matter of this invention.

[0392] The dosage of the cyclic peptides disclosed herein will vary depending on the intended application (in vitro or in vivo), or the subject and the condition of the disease being treated (e.g., the subject's weight and age, the severity of the disease, the method of administration, etc.), which can be readily determined by those skilled in the art.

[0393] In some implementations, efficacy is measured based on the effect of treating proliferative conditions (such as cancer). Generally, the efficacy of the methods and compositions disclosed herein in treating proliferative conditions (such as cancer, whether benign or malignant) can be measured by the extent to which the methods and compositions promote inhibition of tumor cell proliferation, inhibition of tumor angiogenesis, eradication of tumor cells, reduction of tumor growth rate, and / or reduction in the size of at least one tumor. Several parameters to be considered in determining efficacy are discussed herein. Clinicians can establish appropriate combinations of parameters for specific situations. Progress in treating cancer (e.g., reducing tumor size or eradicating cancer cells) using the methods disclosed herein can be determined using any suitable method, such as those currently used in clinical practice to track tumor size and cancer progression. The primary efficacy parameter for evaluating cancer treatment using the methods and compositions disclosed herein is preferably a reduction in tumor size. Tumor size can be calculated by estimating tumor volume using any suitable technique (such as size measurement) or using available computer software (such as FreeFlight software developed by Wake Forest University, which is capable of accurately estimating tumor volume). Tumor size can be determined by tumor visualization using, for example, CT, ultrasound, SPECT, spiral CT, MRI, radiography, etc. In the implementation plan for surgical resection of the tumor after the treatment period, the presence and size of the tumor tissue can be determined by overall analysis of the tissue to be resected and / or by pathological analysis of the resected tissue.

[0394] In some preferred embodiments, as a result of the methods and compositions disclosed herein, tumor growth is stable (i.e., the size of one or more tumors increases by no more than 1%, 5%, 10%, 15%, or 20%, and / or there is no spread). In some embodiments, the tumor is stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks or more. In some embodiments, the tumor is stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more. In some embodiments, the tumor is stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years or more. Preferably, the methods disclosed herein reduce the size of the tumor by at least about 5% (e.g., at least about 10%, 15%, 20%, or 25%). More preferably, the tumor size is reduced by at least about 30% (e.g., at least about 35%, 40%, 45%, 50%, 55%, 60%, or 65%). Even more preferably, the tumor size is reduced by at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, or 95%). Most preferably, the tumor is completely eliminated or reduced below the detectable level. In some embodiments, the subject remains tumor-free (e.g., in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or more after treatment. In some embodiments, the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more after treatment. In some embodiments, the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more after treatment.

[0395] In some embodiments, the efficacy of the methods disclosed herein in reducing tumor size can be determined by measuring the percentage of necrotic (i.e., dead) tissue in the tumor surgically removed after the completion of treatment. In some further embodiments, treatment is clinically effective if the percentage of necrosis in the removed tissue is greater than about 20% (e.g., at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), more preferably about 90% or greater (e.g., about 90%, 95%, or 100%). Most preferably, the percentage of necrosis in the removed tissue is 100%, i.e., no or undetectable tumor tissue.

[0396] The efficacy of the methods disclosed herein can be determined by a number of secondary parameters. Examples of secondary parameters include, but are not limited to: detection of new tumors, detection of tumor antigens or biomarkers (e.g., CEA, PSA, or CA-125), biopsy, surgical degradation (i.e., the transition of a tumor from an unresectable to a resectable surgical stage), PET scans, survival, progression-free survival, time to disease progression, and quality-of-life assessments such as clinical benefit response assessments, all of which can point to overall progression (or regression) of human cancer. Biopsy is particularly useful in detecting the eradication of cancer cells within tissues. Radioimmunoassay (RAID) is used to locate and stage tumors using serum levels of markers (antigens) produced by and / or associated with tumors (“tumor markers” or “tumor-associated antigens”), and can be used as a diagnostic differential before treatment, a diagnostic indicator of recurrence after treatment, and an indicator of treatment efficacy. Examples of tumor markers or tumor-associated antigens that can be evaluated as efficacy endpoints include, but are not limited to: carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), CA-125, CA19-9, ganglioside molecules (e.g., GM2, GD2, and GD3), MART-1, heat shock proteins (e.g., gp96), sialylated Tn (STn), tyrosinase, MUC-1, HER-2 / neu, c-erb-B2, KSA, PSMA, p53, RAS, EGF-R, VEGF, MAGE, and gp100. Other tumor-associated antigens are known in the art. The combination of RAID technology with endoscopic detection systems can also effectively distinguish small tumors from surrounding tissues (see, for example, U.S. Patent 4,932,412).

[0397] In another preferred embodiment, treatment of a human patient with cancer according to the methods disclosed herein is demonstrated by one or more of the following results: (a) complete tumor disappearance (i.e., complete response); (b) a reduction in tumor size of about 25% to about 50% for at least 4 weeks after the end of the treatment period compared to the pre-treatment tumor size; (c) a reduction in tumor size of at least about 50% for at least 4 weeks after the end of the treatment period compared to the pre-treatment tumor size; and (d) a reduction in a specific tumor-associated antigen level of at least 2% (e.g., a reduction of about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%) for about 4–12 weeks after the end of the treatment period compared to the pre-treatment tumor-associated antigen level. While a reduction of at least 2% in tumor-associated antigen levels is preferred, any reduction in tumor-associated antigen levels is evidence of treatment of the patient's cancer by the methods disclosed herein. For example, for unresectable locally advanced pancreatic cancer, efficacy can be demonstrated by a reduction of at least 10% in CA19-9 tumor-associated antigen levels for 4–12 weeks after the end of the treatment period compared to pre-treatment CA19-9 levels. Similarly, for locally advanced rectal cancer, efficacy can be demonstrated by a reduction of at least 10% in CEA tumor-associated antigen levels 4–12 weeks after the end of treatment, compared to pre-treatment CEA levels.

[0398] Regarding quality of life assessments, such as clinical benefit response assessments, the efficacy of treatment according to this disclosure can be demonstrated in terms of pain intensity, analgesic dosage, and / or long-term quality of life assessment scores (Karnofsky Performance Scale score). Alternatively or additionally, cancer treatment in human patients is demonstrated by: (a) a reduction of at least 50% (e.g., at least 60%, 70%, 80%, 90%, or 100%) in pain intensity reported by the patient during any consecutive four-week period within 12 weeks after treatment, compared to the pain intensity reported by the patient before treatment; (b) a reduction of at least 50% (e.g., at least 60%, 70%, 80%, 90%, or 100%) in analgesic dosage reported by the patient during any consecutive four-week period within 12 weeks after treatment, compared to the analgesic dosage reported by the patient before treatment; and / or (c) an increase of at least 20 points (e.g., at least 30, 50, 70, or 90 points) in long-term quality of life assessment score reported by the patient during any consecutive four-week period within 12 weeks after treatment, compared to the long-term quality of life assessment score reported by the patient before treatment.

[0399] Treatment of proliferative disorders (e.g., cancer, whether benign or malignant) in human patients is ideally demonstrated by one or more of the results described above (in any combination), although optional or additional results from the referenced tests and / or other tests may also demonstrate efficacy.

[0400] In some implementations, tumor size is reduced due to the methods disclosed herein, preferably without significant adverse reactions in subjects. Adverse reactions are classified or “graded” using the Cancer Treatment Evaluation Procedure (CTEP) of the National Cancer Institute (NCI), with grade 0 representing the least severe adverse side effect and grade 4 representing the most severe adverse reaction. Ideally, the methods disclosed herein are associated with the least severe adverse reaction, such as a grade 0, 1, or 2 adverse reaction as classified by CTEP / NCI. However, as discussed herein, while tumor size reduction is preferred, it is not essential, because the actual size of the tumor may not shrink despite the eradication of tumor cells. Eradication of cancer cells is sufficient to achieve therapeutic efficacy. Similarly, any reduction in tumor size is sufficient to achieve therapeutic effect.

[0401] The detection, monitoring, and rating of various human cancers are further described in Cancer Facts and Figures 2001, American Cancer Society, New York, NY, and international patent application WO01 / 24684. Therefore, clinicians can use standard tests to determine the efficacy of various implementations of the methods disclosed herein in treating cancer. However, in addition to tumor size and spread, clinicians may also consider patient quality of life and survival when assessing efficacy.

[0402] In some embodiments, administration of the cyclic peptides disclosed herein provides improved efficacy. Improved efficacy can be measured using any method known in the art, including but not limited to those described herein. In some embodiments, improved efficacy is an improvement of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 1000%, or more, using appropriate measurement criteria (e.g., tumor size reduction, duration of tumor size stability, duration of metastatic events-free, duration of disease-free survival). Improved efficacy can also be expressed as a multiple of improvement, such as at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 1000, 10000 or more, using appropriate measurement criteria (e.g., tumor size reduction, duration of tumor size stability, duration of metastasis-free events, duration of disease-free survival).

[0403] Measuring the inhibition of the biological effects of MDM2 and / or MDM4 may include assays on biological samples, such as samples from subjects. Depending on the assay, any of a variety of samples may be selected. Examples of samples include, but are not limited to: blood samples (e.g., plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0404] Subjects receiving treatment with the cyclic peptides disclosed herein can be monitored to determine the effectiveness of the treatment, and the treatment regimen can be adjusted based on the subject's physiological response to the treatment. For example, if the inhibition of the biological effect of MDM2 and / or MDM4 inhibition is above or below a threshold, the dosage or frequency of administration can be reduced or increased, respectively. If the treatment is determined to be effective, the method may further include continuing treatment. If the treatment is determined to be effective, the method may include maintaining, gradually reducing, decreasing, or discontinuing the administration of the compound during treatment. If the compound is determined to be ineffective, the method may include increasing the administration of the compound during treatment. Alternatively, if the treatment is determined to be ineffective, the method may include discontinuing treatment. In some embodiments, treatment with the cyclic peptides disclosed herein is discontinued if the inhibition of the biological effect is above or below a threshold, such as in the absence of response or in the event of adverse reactions. The biological effect can be a change in any of a variety of physiological indicators.

[0405] Typically, MDM2 inhibitors are compounds that inhibit one or more biological effects of MDM2. Examples of biological effects of MDM2 include, but are not limited to, the inhibition of p53 ubiquitination and p53 transcriptional activation. Such biological effects can be inhibited by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

[0406] Typically, MDM2 / MDM4 dual inhibitors are compounds that inhibit one or more biological effects of MDM2 and MDM4. Examples of biological effects of MDM2 and MDM4 include, but are not limited to, the inhibition of p53 ubiquitination and p53 transcriptional activation. Such biological effects can be inhibited by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.

[0407] In some other embodiments, the methods of the present invention can be used to treat disease conditions related to MDM2. Any disease condition directly or indirectly caused by abnormal activity or expression levels of MDM2 can be considered a potential disease condition. In some other embodiments, the methods of the present invention can be used to treat disease conditions related to MDM2 and MDM4. Any disease condition directly or indirectly caused by abnormal activity or expression levels of MDM2 and MDM4 can be considered a potential disease condition. In some embodiments, the disease condition is a proliferative condition, such as those described herein, including but not limited to cancer. In some embodiments, the disease condition is cancer. In some embodiments, the cancer is selected from: acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia.

[0408] In some embodiments, the compounds of this disclosure are applied to treat conditions other than cancer. In some embodiments, the compounds of this disclosure induce the death of senescent cells. In some embodiments, inducing the death of senescent cells is used to treat conditions associated with the proliferation of senescent cells. In some embodiments, the compounds of this disclosure are applied to treat diseases or conditions associated with the proliferation of senescent cells. Exemplary diseases or conditions associated with the proliferation of senescent cells include: cardiovascular diseases, inflammatory or autoimmune diseases, metabolic diseases, lung diseases, eye diseases, ear diseases, and skin diseases.

[0409] Non-limiting examples of cardiovascular diseases associated with the proliferation of senescent cells include, but are not limited to: atherosclerosis, angina pectoris, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disease, carotid artery disease, endocarditis, coronary thrombosis, myocardial infarction, hypertension, aortic aneurysm, diastolic dysfunction, hypercholesterolemia, hyperlipidemia, mitral valve prolapse, peripheral vascular disease, cardiac stress, myocardial fibrosis, cerebral aneurysm, and stroke.

[0410] Non-limiting examples of inflammatory or autoimmune diseases associated with the proliferation of senescent cells, including but not limited to: osteoarthritis, osteoporosis, inflammatory bowel disease, and herniated discs.

[0411] Non-limiting examples of metabolic diseases associated with the proliferation of senescent cells include, but are not limited to, diabetes and metabolic syndrome.

[0412] Non-limiting examples of lung diseases associated with the proliferation of senescent cells include, but are not limited to: idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, cystic fibrosis, emphysema, bronchiectasis, and loss of lung function.

[0413] Non-limiting examples of eye diseases include, but are not limited to: cataracts, macular degeneration, glaucoma, and keratoconus.

[0414] Non-limiting examples of ear diseases associated with the proliferation of senescent cells, including but not limited to conductive hearing loss.

[0415] Non-limiting examples of skin diseases associated with the proliferation of senescent cells include, but are not limited to: eczema, psoriasis, hyperpigmentation, impaired wound healing, hair loss, rashes, atopic dermatitis, urticaria, diseases and conditions associated with photosensitivity or photoaging, wrinkles, pruritus, hypoesthesia, eczema, eosinophilic dermatitis, reactive neutrophilic dermatitis, pemphigus, bullous pemphigoid, immune bullous dermatitis, dermatofibrosis, cutaneous lymphoma, and cutaneous lupus.

[0416] Some embodiments consider human subjects, such as those diagnosed with or at risk of developing or acquiring a proliferative disease. Other embodiments consider non-human subjects, such as non-human primates like macaques, chimpanzees, gorillas, long-tailed macaques, orangutans, baboons, or other non-human primates, including non-human subjects known in the art as preclinical models. Other embodiments consider non-human mammalian subjects, such as mice, rats, rabbits, pigs, sheep, horses, cattle, goats, gerbils, hamsters, guinea pigs, or other mammals. Other embodiments are also considered where the subject or biological source can be a non-mammalian vertebrate, for example, another higher vertebrate, or a species of bird, amphibian, or reptile, or another subject or biological source. In some embodiments of this disclosure, transgenic animals are used. A transgenic animal is a non-human animal in which one or more cells of the animal include non-endogenous (i.e., heterologous) nucleic acids and are present as extrachromosomal elements in a portion of its cells or stably integrated into its germline DNA (i.e., in the genome sequence of most or all of its cells).

[0417] combination therapy

[0418] In some embodiments, methods for further combination therapy are disclosed herein, wherein, in addition to the cyclic peptide described herein, one or more second agents known to regulate other pathways, or other components of the same pathway, or even overlapping groups of target proteins are used. In one aspect, such therapies include, but are not limited to, combining compositions comprising the cyclic peptide described herein with one or more chemotherapeutic agents, therapeutic antibodies, immunotherapeutic agents, and radiotherapy to provide synergistic or cumulative efficacy when needed.

[0419] In some embodiments, methods and pharmaceutical compositions for inhibiting abnormal cell growth in mammals are disclosed herein, comprising an amount of the cyclic peptide described herein and combined with a certain amount of an anticancer agent (e.g., a chemotherapeutic agent). Many chemotherapeutic agents are currently known in the art and can be used in combination with the cyclic peptide disclosed herein.

[0420] In some embodiments, this document discloses a method of using the cyclic peptide or pharmaceutical composition described herein, combined with other tumor treatment methods (including surgery, ionizing radiation, photodynamic therapy, or implants), such as combinations with corticosteroids, hormones, or as radiosensitizers.

[0421] experimental

[0422] Unless otherwise specified, all reagents were purchased from commercial suppliers without further purification. Solvent drying was performed using standard methods when necessary. The following abbreviations were used in the experimental section: COMU = ((1-cyano-2-ethoxy-oxoethylaminooxy)dimethylamino-morpholine-carbomony hexafluorophosphate; DBU = 1,8-diazabicyclo[5.4.0]undecyl-7-ene; DCM = dichloromethane; DMF = N,N-dimethylformamide; DIPEA = diisopropylethylamine; DMSO = dimethyl sulfoxide; Fmoc = 9-fluorenylmethoxycarbonyl; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxyhexafluorophosphate; H PLC = High Performance Liquid Chromatography; MeOH = Methanol; N2 = Nitrogen; SPPS = Solid Phase Peptide Synthesis; FA = Formic Acid; Xaa = Any Amino Acid; UV = Ultraviolet Light; DIC = N,N'-Diisopropylcarbodiimide; HFIP = Hexafluoroisopropanol; MS = Mass Spectrometry; FITC = Fluorescein Isothiocyanate; DTT = Dithiothreitol; MDM2 = Mouse Two-Microsome 2 Homolog; HDM2 = Human Two-Microsome 2 Homolog; FAM = Fluorescein Imidamide; MDM4 = Mouse Two-Microsome 4 Homolog; HDM4 = Human Two-Microsome 4 Homolog; FBS = Fetal Bovine Serum.

[0423] Cyclic peptide synthesis

[0424] Step 1: Loading 2-chlorotriphenylmethyl resin

[0425] Fmoc-Xaa (10 mmol) was dried in a vacuum desiccator with anhydrous calcium sulfate. Dry overnight. Dissolve the dried amino acids in 50 mL of dried DCM containing DIPEA (40 mmol) and dry with a molecular sieve. Sonicate the reaction mixture until Fmoc-Xaa is completely dissolved. Add 5 g of 2-chlorotriphenylmethyl resin under a nitrogen stream and shake the reaction mixture for 4 hours. Treat the resin with a 1:2:17 solution of MeOH / DIPEA / DMF (15 mL) and shake (3 x 15 min). Wash the resin with DMF (3 x 15 mL) and then with DCM (3 x 15 mL). The degree of resin loading is calculated by quantifying the UV release of Fmoc after deprotection.

[0426] Step 2: Amino acid coupling

[0427] Fmoc-Xaa (4 equivalents), DIPEA (6 equivalents), and HATU (3.8 equivalents) were added to a DMF (2 mL) solution of the resin, and the reaction mixture was shaken at room temperature for 1 hour. The resin was washed with DMF (3 x 3 mL) and then with DCM (3 x 3 mL).

[0428] Step 3: Protect the resin with Fmoc.

[0429] Treat the resin with a 20% DMF (3 mL) solution of 4-methyl-piperidine and shake for 20 minutes at room temperature. Alternatively, treat the resin with a DMF (3 mL) solution of 2% piperidine and 2% DBU and shake for 10 minutes at room temperature, twice. Wash the resin with DMF (3 x 3 mL) and then with DCM (3 x 3 mL).

[0430] Step 4: Peptide-like coupling

[0431] Activate the resin with a 2:1 DMF solution of 1M bromoacetic acid / 0.5M DIC by shaking for 20 minutes at room temperature. Allow the resulting precipitate to settle and collect the supernatant, then shake it with the deprotected resin for 20 minutes at room temperature. Wash the resin with DMF (3 x 3 mL) followed by DCM (3 x 3 mL). Treat the resin with a 1M amine solution in DMF and shake for 1 hour at room temperature.

[0432] Step 5: Peptide cleavage

[0433] To cleave complete linear peptides, treat the resin with 5 times the resin volume of 30% HFIP in DCM solution and shake for 1 hour. Wash the resin with 5 times the resin volume of DCM. Treat the resin with 5 times the resin volume of 30% HFIP in DCM solution and shake for 30 minutes.

[0434] Step 6: Circulate using COMU

[0435] The dried linear peptide was dissolved in 2 mL of MeCN containing DIPEA (9 equivalents), and the resulting solution was added dropwise to a 1:10 MeCN / DCM solution containing COMU (4 equivalents) to a final concentration of 1 mg crude peptide per mL. The reaction mixture was shaken at room temperature for 16 hours until complete cyclization was achieved as monitored by LCMS. The reaction mixture was then concentrated under vacuum.

[0436] Step 7: Peptide Purification

[0437] COMU cyclization byproducts, via Xbridge BEH C18 OBD Removal was achieved through mass-directed purification on a Waters HPLC system with a 5 μm, 10 x 250 mm column, using elution with 0.1% FA-modified H2O / MeCN. Peptide purity was analyzed by HPLC-MS on a Waters HPLC system and a Waters 3100 mass spectrometer equipped with a CORTECS T3 2.7 μm 4.6 x 50 column using a 0.1% FA-modified H2O / MeCN gradient.

[0438] Fluorescence polarization measurement 1

[0439] Human MDM2 (HDM2) 1-116 (20 μL) and FITC-labeled p53 (18-26) at 50 nM and 10 nM, respectively, in 10 mM Tris, 50 mM NaCl, 0.01% Tween 20, and 1 mM DTT at pH 7.4, were dispensed into opaque black 384-well plates. Compounds dissolved in DMSO were transferred (~200 nL) via a syringe to 384-well plates containing the MDM2 / p53 solution. After incubation for 10 minutes, fluorescence polarization was read using a Molecular Devices SpectraMax reader equipped with a Fluorescein FP cartridge. In addition to individual probes (positive control) and probe / MDM2 (negative control), each plate included a titration of linear p53 (18-26) as an additional control. IC50 was fitted using Prism or Collaborative Drug Discovery. 50 value.

[0440] Fluorescence polarization measurement 2

[0441] Human MDM2 (HDM2) 1-116 (20 μL) and FAM-labeled RFMDYWEGL-NH2 (50 nM and 10 nM, respectively) were dispensed into opaque black 384-well plates at pH 7.4 in 10 mM Tris, 50 mM NaCl, 0.01% Tween 20, and 1 mM DTT. Compounds dissolved in DMSO were transferred (~100-200 nL) to 384-well plates containing MDM2 / p53 solution using a syringe. After incubation for 60 minutes, fluorescence polarization was read using a Molecular Devices SpectraMax reader equipped with a Fluorescein FP cartridge. In addition to individual probes (positive control) and probe / MDM2 (negative control), each plate included a titration of linear p53 (18-26) as an additional control. IC50 was fitted using Prism or Collaborative Drug Discovery.50 value.

[0442] Fluorescence polarization measurement 2

[0443] Human MDM4 (HDM4) 1-114 (20 μL) and FAM-labeled RFMDYWEGL-NH2 (100 nM and 10 nM, respectively) were dispensed into opaque black 384-well plates at pH 7.4 in 10 mM Tris, 50 mM NaCl, 0.01% Tween 20, and 1 mM DTT. Compounds dissolved in DMSO were transferred (~100-200 nL) to 384-well plates containing MDM4 / p53 solution using a stencil. After incubation for 60 minutes, fluorescence polarization was read on a Mecoeur microplate reader equipped with a Fluorescein FP cartridge. In addition to individual probes (positive control) and probe / MDM4 (negative control), each plate included a titration of linear p53 (18-26) as an additional control. IC50 was fitted using Prism or Collaborative Drug Discovery. 50 value.

[0444] Cell fluorescence detection

[0445] MOLM-13 cells were suspended and grown in T75 culture flasks in RPMI medium containing 10% fetal bovine serum (FBS) at 37°C and 5% CO2. 40 μL of MOLM-13 cells were seeded at a density of 1,500 cells per well in columns 1-22 of a black, clear-bottomed 384-well plate containing 10% FBS in RPMI. Columns 23 and 24 were filled with 40 μL of medium as positive controls. 100 nmol of compound dissolved in DMSO was transferred to columns 3-22 of the 384-well plate. Columns 1 and 2 were used as negative control wells. The plate was incubated at 37°C and 5% CO2 for 72 hours. After incubation, cells were given 10 μL of 2 mM resazurin in RPMI and 10% FBS, and incubated for 3 hours. The fluorescence intensity was read on the Meigu i3x microplate reader (excitation wavelength = 535nm, emission wavelength = 585nm).

[0446] Parallel Artificial Membrane Permeability Measurement (PAMPA)

[0447] For the permeability assay, 96-well donor plates and 96-well Teflon acceptor plates with a 0.45 μm hydrophobic Immobilon-P membrane support (Millipore) were used. Donor wells were prepared by adding triplicate of 150 μL of each cyclic peptide solution (10 μM in 5% DMSO / PBS, pH 7.4). A 1% (w / v) lecithin solution in dodecane was prepared and sonicated for 5 min prior to use. 5 μL of the dodecane-lecithin solution was applied to the membrane support in the donor plate wells. Acceptor plates were prepared by adding 300 μL of 5% DMSO / PBS (pH 7.4) to each well. The donor plates were then placed on top of the acceptor plates, allowing the artificial membrane to contact the buffer solution below. The donor wells were capped, the system was covered with a glass evaporating dish, and incubated at room temperature for 10 hours. A damp paper towel was placed inside the chamber to prevent evaporation.

[0448] Once the assay is complete, 100 μL samples from the donor and acceptor wells are aliquoted into a 96-well plate and sealed. The samples are analyzed on an LC / MS detector in SIM mode, where acceptor and donor concentrations are expressed as integrals under the m / z curves corresponding to (exact mass + one proton) in ESI+ mode or (exact mass - one proton) in ESI- mode.

[0449] LC / MS peak integrals are used to calculate the retention (E) R Adjusted balance value:

[0450] E R =(P A V A +P D V D ) / (V A +V D )

[0451] Where P A It is the peak integral of the receptor, V A The volume of the receptor (cm) 3 ), P D It is the peak from the donor analyte to the standard peak, V D It is the volume of the donor.

[0452] Calculate the transmittance percentage (%T) for each sample:

[0453] %T = (P A / E R )x100

[0454] Furthermore, the %T value is converted into a time-independent Pe value:

[0455] Pe = [(V A x VD ) / (V0 x A xt)]x ln(1-(%T / 100))

[0456] Where V0 is the total volume (cm³) 3 A is the accessible filtration area of ​​the membrane (0.24 cm²). 2 ), and t is the incubation time (s). Calculate the average %T and Pe values ​​for each compound from at least three data points, excluding extremely remote permeability values. Calculate the standard deviation of the means. Because in E R The recovery percentage is taken into account, so no compound loss is assumed in the calculation.

[0457] MOLM-13 mouse xenograft model

[0458] 110 female nu / nu mice were subcutaneously injected with MOLM-13 cells (5 x 10 cells per animal) into the left lower abdomen. 6 100 cells in 200 μL of 1:1 PBS / Matrigel). Mice were divided into 8 treatment groups according to Table 1 and administered the mediators (5% ethanol, 12.5% ​​Solutol HS, 12.5% ​​PEG300, and 70% 50 mM PBS), idasanutlin, or compound 35.

[0459] Table 1

[0460] 1 vehicle Intravenous injection (IV) 0 10 3 2 vehicle Intraperitoneal administration (IP) 0 10 7 3 vehicle Oral administration (PO) 0 10 7 4 Idanulin Oral administration (PO) 30 10 7 5 Compound 35 Intravenous injection (IV) 20 10 3 6 Compound 35 Intravenous injection (IV) 50 10 3 7 Compound 35 Intraperitoneal administration (IP) 20 10 7 8 Compound 35 Intraperitoneal administration (IP) 50 10 7

[0461] Mice were monitored for 2 weeks. The change in mean tumor volume of intravenous compound 35 relative to the mediator over time is shown in the figure. Figure 1 As shown. On day 13 of treatment, the intravenous compound 35 relative to the tumor volume of the medium was as follows. Figure 2 As shown. The change in tumor volume over time in each mouse treated with intravenous compound 35 is shown in the figure. Figure 3 As shown. The change in body weight of each mouse treated with intravenous compound 35 over time is shown in the figure. Figure 4 As shown.

[0462] Pharmacokinetic parameters of compound 35

[0463] Mice were treated intravenously with compound 35 (1 mg / kg), and plasma was collected at different time points to determine pharmacokinetic parameters. The mean plasma concentration over time is shown in the figure. Figure 5 As shown, all the obtained pharmacokinetic parameters are summarized in Table 2:

[0464] Table 2

[0465]

[0466] In some implementations, the cyclic peptides described herein are the cyclic peptides described in Table 3:

[0467] Table 3

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475] *:A<1.0μM; 1.0μM≤B<2.5μM; 2.5μM≤C<5.0μM; 5.0μM≤D

[0476] **: The SMILES string generated from the chemical structure in ChemDraw version 19.1.

[0477] In some implementations, the cyclic peptides described herein are the cyclic peptides described in Table 4:

[0478] Table 4

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485] * :A<25.0nM; 25.0nM≤B<50.0nM; 50.0nM≤C<100.0nM; 100.0nM≤D

[0486] ** :A<50.0nM; 50.0nM≤B<100.0nM; 100.0nM≤C<150.0nM; 150.0nM≤D

[0487] ***: The SMILES string generated from the chemical structure in ChemDraw version 19.1.

Claims

1. A cyclic peptide having the structure shown in the table below: 。 2. A pharmaceutical composition comprising the cyclic peptide of claim 1 and a pharmaceutically acceptable excipient.

3. Use of the cyclic peptide of claim 1 in the preparation of a medicament for treating acute myeloid leukemia in a subject in need.

Images