Cell-permeable cyclic peptides and their uses

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 for the inhibition of MDM2 or MDM2 and MDM4.

Description

[Technical Field]

[0001] cross reference This application claims the benefits pursuant to U.S. Provisional Application 62 / 938,864 filed November 21, 2019, and U.S. Provisional Application 63 / 047,178 filed July 1, 2020, each of which is incorporated herein by reference. [Overview of the project]

[0002] overview Disclosed herein, in some embodiments, is a compound, a pharmaceutical composition containing the compound, and the use of the compound in the treatment of a disease. Furthermore, the present invention relates to a cyclic peptide useful as an MDM2 or dual MDM2 / MDM4 inhibitor, a composition, and its use in the treatment of diseases such as cancer. Furthermore, the present invention relates to a cyclic peptide useful as an MDM2 or dual MDM2 / MDM4 inhibitor, a composition, and its use for inducing the lethality of senescent cells, in particular for treating diseases or disorders related to the proliferation of senescent cells.

[0003] In one embodiment, the present invention is Nine to eleven amino acid residues independently selected from uncharged amino acid residues at physiological pH; First and second beta hairpin regions A cyclic peptide containing, Next 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 -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle), wherein the monocyclic carbocycle and monocyclic heterocycle are independently and optionally substituted; and At least three amino acid residues containing a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl compounds. Characterized by one of the following: Provides a cyclic peptide.

[0004] In one embodiment, the first beta-hairpin region comprises two consecutive amino acid residues. In one embodiment, the first beta-hairpin region comprises two consecutive residues independently selected from L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe and D-NMe-Val, where the phenyl group of L-NMe-Phe is -Hallo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The molecule is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the first beta-hairpin region comprises two consecutive residues independently selected from L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe, and D-NMe-Val, where the phenyl group of L-NMe-Phe is replaced by halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, and C 1-4 The molecule is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, the first beta-hairpin region comprises two consecutive residues independently selected from L-Pro, D-Pro, L-Aze, D-Pip, and D-NMe-Val. In one embodiment, for the two consecutive residues, one is D and the other is L. In one embodiment, the two consecutive amino acid residues are D-Pro and L-Pro. In one embodiment, the two consecutive amino acid residues are D-NMe-Val and L-Pro. In one embodiment, the two consecutive amino acid residues are D-Pro and L-NMe-Phe, where the phenyl group of L-NMe-Phe is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The molecule is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the two consecutive amino acid residues are D-Pro and L-NMe-Phe, where the phenyl group of L-NMe-Phe is replaced with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 It may be substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2.

[0005] In one embodiment, the second beta-hairpin region comprises a second pair of amino acid residues. In one embodiment, the second beta-hairpin region comprises a second pair of 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 one embodiment, the second beta-hairpin region comprises a second pair of residues independently selected from D-Pro, peptoids, and LN-alkylated amino acids. In one embodiment, of the second pair of residues, one is a peptoid and the other is an LN-alkylated amino acid. In one embodiment, of the second pair of residues, one is L-NMe-Ala and the other is N-(2-methoxyethyl)glycine. In one embodiment, of the second pair of residues, one is a DN-alkylated amino acid and the other is an LN-alkylated amino acid. In one embodiment, of the second pair of consecutive residues, one is D-NMe-Ala and the other is L-NMe-Ala. In another embodiment, of the second pair of consecutive residues, one is a DN-alkylated amino acid and the other is a peptoid. In yet another embodiment, of the second pair of consecutive residues, one is D-NMe-Ala and the other is N-(2-methoxyethyl)glycine.

[0006] In one embodiment, at least two consecutive amino acids separate the first beta-hairpin region from the second beta-hairpin region. In another embodiment, at least three consecutive amino acids separate the first beta-hairpin region from the second beta-hairpin region.

[0007] In one embodiment, the molecular weight of the cyclic peptide is 800 to 1300 Da. In another embodiment, the molecular weight of the cyclic peptide is 800 to 1200 Da. In yet another embodiment, the molecular weight of the cyclic peptide is 900 to 1200 Da.

[0008] In one embodiment, the cyclic peptide comprises a ring independently selected from optionally substituted monocyclic carbocyclic rings and optionally substituted monocyclic heterocyclic rings, characterized by at least four amino acid residues in which at least one of the monocyclic carbocyclic rings and monocyclic heterocyclic rings is substituted. In one embodiment, the optionally substituted monocyclic carbocyclic ring is phenyl, and the optionally substituted monocyclic heterocyclic ring is a heteroaryl ring, where at least one phenyl or heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The substituents are independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the optionally substituted monocyclic carbocycle is phenyl, and the optionally substituted monocyclic heterocycle is a heteroaryl ring, where at least one phenyl or heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The rings are substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, the optionally substituted monocyclic carbocycle is phenyl, and the optionally substituted monocyclic heterocycle is a heteroaryl ring, where at least one phenyl or heteroaryl ring is substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, which may all be substituted.

[0009] In one embodiment, the cyclic peptide is characterized by at least four amino acid residues having side chains selected from -alkylene-(monocyclic carbocarriage) and -alkylene-(monocyclic heterocycle), where the monocyclic carbocarriage and monocyclic heterocycle are optionally substituted independently. In one embodiment, each of the at least four amino acid residues selected from -alkylene-(optionally substituted monocyclic carbocarriage) and -alkylene-(optionally substituted monocyclic heterocycle) is not adjacent to each other. In one embodiment, two of the at least four amino acids having side chains selected from -alkylene-(optionally substituted monocyclic carbocarriage) and -alkylene-(optionally substituted monocyclic heterocycle) are adjacent to each other. In one embodiment, each monocyclic carbocarriage is phenyl, and each monocyclic heterocycle is a heteroaryl ring, where each phenyl and heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4It is independently optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. In certain embodiments, each monocyclic carbocyclic ring is phenyl and each monocyclic heterocyclic ring is a heteroaryl ring, where each phenyl and heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 It is independently optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2. In certain embodiments, each monocyclic carbocyclic ring is phenyl and each monocyclic heterocyclic ring is a heteroaryl ring, where each phenyl and heteroaryl ring is independently optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2. In certain embodiments, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole and imidazole, each of which is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2.

[0010] In certain embodiments, the cyclic peptide is characterized by at least three amino acid residues comprising rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl. In certain embodiments, each phenyl and heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 It is independently optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. In certain embodiments, each phenyl and heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C1-4 The rings are optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, each phenyl and heteroaryl ring is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, each of which is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2.

[0011] In one embodiment, at least three main-chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In one embodiment, four or five main-chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In one embodiment, four main-chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In one embodiment, five main-chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In one embodiment, one or more of the tertiary main-chain nitrogen atoms are part of a heterocycloalkyl ring. In one embodiment, one or more of the tertiary nitrogen atoms have a C1-C6 alkyl substituent that is substituted by independently selected C1-C6 alkyl substituents, where the C1-C6 alkyl substituents are halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The substituents are independently selected from alkyl, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the substituents of the tertiary nitrogen are C1-C6 alkyl substituents which are independently selected from each tertiary nitrogen, where the substituents of the C1-C6 alkyl are halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The substituents are independently selected from alkyl, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, one or more tertiary nitrogen atoms have a C1-C6 alkyl substituent that is independently selected from each tertiary nitrogen atom, where the substituents are independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, each tertiary nitrogen atom is independently [ka] It is expressed as follows, where R A -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A C1-C6 alkyl group optionally substituted with one or more substituents independently selected from alkyl, -OBz, -OCH3, -OCF3, and -OCHF2, where, [ka] represents a binding site to an adjacent amino acid residue. In one embodiment, each tertiary nitrogen is independently [ka] It is expressed as follows, where R A is a C1-C6 alkyl group optionally substituted with one or more substituents independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2, where, [ka] The symbol indicates a binding site to an adjacent amino acid residue.

[0012] In one embodiment, the cyclic peptide has 10 amino acid residues.

[0013] In one embodiment, the cyclic peptide is of formula I: [ka] [During the ceremony, R 1, R 6 and R 8 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 2 is hydrogen and C 1-6 Selected from alkyl groups; R 3 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Selected from alkylenes (3-10 membered heterocycles), where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2; and C 1-4 Alkyls are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 4 is hydrogen or C 1-4 Alkyl or R 4 and R 14 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 5 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C3-8 (Carbon ring) and -(C 1-4 Selected from alkylenes (3-10 membered heterocycles), where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2; and C 1-4 Alkyls are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2; or R 5 and R 15 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 7 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-6 Selected from alkyl or R 7 and R 17 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 9 is hydrogen or C 1-6 Alkyl or R 9 and R 19 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 10 is hydrogen or C 1-4 Alkyl or R 10 and R 20 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 11 , R 12 , R 13 , R 16and R 18 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected independently of alkyl; R 14 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 14 and R 4 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 15 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 15 and R 5 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 17 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 17 and R 7 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 19 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 selected from alkyl or R 19 and R 9 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; and R 20 is hydrogen; and halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 selected from alkyl or R 20 and R 10 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. ]] represented by

[0014] In certain embodiments, the cyclic peptide is of formula I:

Chemical formula

[0015] In one embodiment, the cyclic peptide is given by formula II: [ka] [During the ceremony, R 21 , R 23 , R 26 and R 28 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 24 is hydrogen or C 1-4 Alkyl or R 24 and R 34 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R25 is hydrogen or C 1-4 Alkyl or R 25 and R 35 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 30 is hydrogen or C 1-4 Alkyl or R 30 and R 40 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 22 , R 27 and R 29 is hydrogen and C 1-6 Selected independently of alkyl; R 31 , R 32 , R 33 , R 36 and R 38 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected independently of alkyl; R37 and R 39 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected independently of alkyl; R 34 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected from alkyl or R 34 and R 24 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 35 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected from alkyl or R 35 and R 25 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; and R 40 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected from alkyl or R 40 and R 30 It combines with the intermediate atom to form a 5-7 member heterocycloalkyl group. It is represented by [this].

[0016] In one embodiment, the cyclic peptide is given by formula II: [ka] [During the ceremony, R 21 , R 23 , R 26 and R 28 is hydrogen, -(C 1-4 Alkylene)-(C 3-8(Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; R 24 is hydrogen or C 1-4 Alkyl or R 24 and R 34 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R25 is hydrogen or C 1-4 Alkyl or R 25 and R 35 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 30 is hydrogen or C 1-4 Alkyl or R 30 and R 40 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 22 , R 27 and R 29 is hydrogen and C 1-6 Selected independently of alkyl; R 31 , R 32 , R 33 , R 36 and R 38 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Selected independently of alkyl; R 37 and R 39 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Selected independently of alkyl; R 34C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Selected from alkyl or R 34 and R 24 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 35 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Selected from alkyl or R 35 and R 25 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; and R 40 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Selected from alkyl or R 40 and R 30 It combines with the intermediate atom to form a 5-7 member heterocycloalkyl group. It is represented by [this].

[0017] One reason, R 31 , R 32 , R 33 , R 36 and R 38 Each of them is hydrogen.

[0018] One reason, R 34 , R 35 , R 37 , R 39 and R 40 At least four of them are not hydrogen. In one embodiment, R 34 , R 35 , R 37 , R 39 and R 40 These four are not hydrogen. In one embodiment, R 34 , R 35 , R 37 , R39 and R 40 It is not hydrogen.

[0019] One reason, R 24 and R 34 , R 25 and R 35 and R 30 and R 40 At least one of them combines with an intermediate atom to form a 5-7 member heterocycloalkyl group. In one embodiment, R 24 and R 34 It integrates with the atoms in between to form a 5-6 member heterocycloalkyl group. In one embodiment, R 25 and R 35 It combines with the intermediate atom to form a 5-6 member heterocycloalkyl group.

[0020] One reason, R 37 , R 39 and R 40 Each of these is selected from methyl and methoxyethyl. In one embodiment, R 35 , R 37 , R 39 and R 40 Each of these is selected from methyl and methoxyethyl.

[0021] One reason, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 Alkyl or R 30 and R 40 It integrates with the atoms in between to form a 5-7 member heterocycloalkyl group. In one embodiment, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 It is alkyl. In one example, R 40C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 It is alkyl.

[0022] One reason, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 It is alkyl.

[0023] One reason, R 22 , R 27 and R 29 is C 1-6 Selected independently of alkyl. In one embodiment, R 22 , R 27 and R 29 The methyl, ethyl, propyl, i-propyl, butyl, i-butyl, and t-butyl compounds are selected from methyl, ethyl, propyl, i-propyl, butyl, and t-butyl.

[0024] One reason, R 21 , R 23 , R 26 and R 28 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted. In one embodiment, R 21 , R 23 , R 26 and R 28 is -CH2-(C 3-8 A carbon ring and a -CH2- (3-10 membered heteroring) are independently selected. In one embodiment, R 21 , R 23 , R 26 and R 28 R is independently selected from phenylmethyl and pyridinylmethyl, where phenyl and pyridinyl are optionally substituted. In one embodiment, R 21, R 23 , R 26 and R 28 teeth [ka] It is selected independently of others.

[0025] In one embodiment, the cyclic peptide is given by formula IIa: [ka] It is represented by [this].

[0026] In one embodiment, the cyclic peptide is given by formula IIb: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0027] In one embodiment, the cyclic peptide is given by formula III: [ka] [During the ceremony, R 41 , R 45 , R 46 and R 48 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 42 is hydrogen and C 1-6 Selected from alkyl groups; R 43 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl groups; R 44 is hydrogen or C 1-4 Alkyl or R 44 and R 54 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 47 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-6 Selected from alkyl or R 47 and R 57 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 49 is hydrogen or C 1-6 Alkyl or R 49 and R 59 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 50 is hydrogen or C 1-4 Alkyl or R 50 and R 60 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 51 , R 53 , R 56 and R58 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected independently of alkyl; R 52 and R 55 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected independently of alkyl; R 54 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 54 and R 44 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 57 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 57 and R 47 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 59 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2.1-4 Selected from alkyl or R 59 and R 49 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 60 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 60 and R 50 It combines with the intermediate atom to form a 4-7 member heterocycloalkyl group. It is represented by [this].

[0028] In one embodiment, the cyclic peptide is given by formula III: [ka] [During the ceremony, R 41 , R 45 , R 46 and R 48 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; R 42 is hydrogen and C 1-6 Selected from alkyl groups; R 43 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl groups; R 44 is hydrogen or C 1-4 Alkyl or R 44 and R 54 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 47 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-6 Selected from alkyl or R 47 and R 57 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 49 is hydrogen or C 1-6 Alkyl or R 49 and R 59 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 50 is hydrogen or C 1-4 Alkyl or R 50 and R 60 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 51 , R 53 , R 56 and R 58 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected independently of alkyl; R 52 and R 55Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected independently of alkyl; R 54 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 54 and R 44 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 57 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 57 and R 47 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 59 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 59 and R 49 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 60 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 60 and R 50 It combines with the intermediate atom to form a 4-7 member heterocycloalkyl group. It is represented by [this].

[0029] One reason, R 51 , R 53 , R 56 and R 58 Each of them is hydrogen.

[0030] One reason, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 At least four of them are not hydrogen. In one embodiment, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 These four are not hydrogen. In one embodiment, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 It is not hydrogen.

[0031] One reason, R 44 and R 54 and R 50 and R 60 At least one of them combines with an intermediate atom to form a 4-7 member heterocycloalkyl group. In one embodiment, R 44 and R 54 These atoms combine with the atoms in between to form a 4-6 member heterocycloalkyl group.

[0032] One reason, R 55 , R 59 and R60 Each of these is selected from methyl, ethyl, and methoxyethyl. In one embodiment, R 52 , R 55 , R 59 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl.

[0033] One reason, R 60 is Halogen, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl or R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 60 is Halogen, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 Alkyl or R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 60 is Halogen, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 It is alkyl.

[0034] One reason, R 59 is Halogen, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 It is alkyl.

[0035] One reason, R 42 , R 47 and R 49 is C 1-6 Selected independently of alkyl. In one embodiment, R 42 , R 47 and R 49 The methyl, ethyl, propyl, i-propyl, butyl, i-butyl, and t-butyl compounds are selected from methyl, ethyl, propyl, i-propyl, butyl, and t-butyl.

[0036] One reason, R 41 , R 45 , R 46 and R 48 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted. In one embodiment, R 41 , R 45 , R 46 and R 48 is -CH2-(C 3-8 A carbon ring and a -CH2- (3-10 membered heteroring) are independently selected. In one embodiment, R 41 , R 45 , R 46 and R 48 R is independently selected from phenylmethyl, pyridinylmethyl, and thiazolylmethyl, where phenyl, pyridinyl, and thiazolyl are optionally substituted. In one embodiment, R 41 , R 45 , R 46 and R 48 teeth [ka] It is selected independently of others.

[0037] In one embodiment, the cyclic peptide is given by formula IIIa: [ka] It is represented by [this].

[0038] In one embodiment, the cyclic peptide is given by formula IIIb: [ka] [In the formula, R 41’ , R 45’ , R 46’ and R 48’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0039] In one embodiment, the cyclic peptide is selected from those listed in Tables 3 and 4 or any pharmaceutically acceptable salt thereof.

[0040] In another embodiment, the present invention provides a pharmaceutical composition comprising the cyclic peptide described herein and a pharmaceutically acceptable additive.

[0041] In another embodiment, the present invention provides a method for inhibiting MDM2, comprising administering the cyclic peptide described herein to a subject in need thereof.

[0042] In another embodiment, the present invention provides a method for inhibiting MDM2 and MDM4, comprising administering the cyclic peptide described herein to a subject requiring such inhibition.

[0043] In another embodiment, the present invention provides a method for treating a disease or disorder in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the cyclic peptide described herein.

[0044] In one embodiment, the disease or disorder is cancer. In one embodiment, the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. In one embodiment, the disease or disorder is associated with the proliferation of senescent cells. In one embodiment, the disease or disorder is selected from type 2 diabetes, Huntington's disease, non-alcoholic fatty liver disease, and hyperlipidemia. In one embodiment, the disease or disorder is selected from cardiovascular disease, inflammatory disease, autoimmune disease, metabolic disease, lung disease, eye disease, ear disease, kidney disease, and skin disease. [Brief explanation of the drawing]

[0045] The novel features of the present invention are described in detail in the appended claims. The features and advantages of the present invention will be better understood by referring to the following detailed description illustrating explanatory embodiments utilizing the principles of the present invention and the following appended drawings.

[0046] [Figure 1] This shows the change in mean tumor volume over time after intravenous administration of compound 35 in the MOLM-13 mouse xenograft model.

[0047] [Figure 2] This shows the tumor volume 13 days after intravenous administration of compound 35 in the MOLM-13 mouse xenograft model.

[0048] [Figure 3] This shows the changes in tumor volume over time after intravenous administration of compound 35 in the MOLM-13 mouse xenograft model.

[0049] [Figure 4] This shows the time course of body weight changes after intravenous administration of compound 35 in the MOLM-13 mouse xenograft model.

[0050] [Figure 5] This shows the change in mean plasma concentration over time after intravenous administration of compound 35 in the MOLM-13 mouse xenograft model. [Modes for carrying out the invention]

[0051] Detailed description Mouse double-minute 2 homolog (MDM2) and mouse double-minute 4 homolog (MDM4) have been shown to be promising therapeutic targets for the treatment of various cancers. MDM2 and MDM4 are negative regulators of the p53 tumor suppressor gene, both through inhibition of E3 ubiquitin ligase activity and p53 transcriptional activation. Furthermore, since disruption of the protein-protein interaction between p53 and MDM2 or MDM4 can lead to senescent cell lethality, the development of MDM2 and MDM4 inhibitors offers an opportunity to treat diseases or disorders associated with the proliferation of senescent cells. A wide variety of diseases, including cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, lung diseases, eye diseases, ear diseases, kidney diseases, and skin diseases, are associated with cellular senescence. Specific examples include type 2 diabetes, Huntington's disease, non-alcoholic fatty liver disease, and hyperlipidemia.

[0052] Cyclic peptides are emerging as potentially useful as MDM2 and / or MDM4 inhibitors. Small molecule inhibitors of MDM2 / p53 protein-protein interactions and / or MDM4 / p53 protein-protein interactions are attractive as potential cancer treatments. Beta-hairpin regions are often found in nature as a means of indicating residues essential for protein-protein recognition. These beta-hairpin regions in native proteins can be mimicked by carefully designed cyclic peptides, making cyclic peptides potentially useful as inhibitors of hard-to-reach targets such as MDM2 and MDM4.

[0053] Despite their potential as therapeutic agents, the usefulness of cyclic peptides can be limited by their poor pharmacokinetic properties, particularly poor cell permeability, low solubility, and high clearance. There is a need for MDM2 inhibitors and MDM2 / MDM4 dual inhibitors with improved pharmacokinetic properties, such as enhanced cell permeability, to treat diseases.

[0054] This specification describes cyclic peptides that overcome pharmacokinetic challenges such as poor solubility and poor cell permeability. In particular, the present invention provides cyclic peptides optimized to enhance cell permeability and solubility.

[0055] In one embodiment, a cyclic peptide useful as an MDM2 inhibitor is disclosed herein. In one embodiment, the cyclic peptide disclosed herein is useful as an MDM2 / MDM4 dual inhibitor. In one embodiment, the cyclic peptide comprises 9 to 11 amino acids independently selected from amino acid residues not charged at physiological pH, as well as first and second beta-hairpin regions. In one embodiment, the cyclic peptide is further characterized by comprising a ring independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles, with at least 4 amino acid residues having side chains selected from -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle), with the monocyclic carbocycle and monocyclic heterocycle being independently optionally substituted; and at least 3 amino acid residues comprising a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl.

[0056] In one embodiment, the cyclic peptide disclosed herein exhibits high cell permeability and potent inhibition of MDM2 in both biochemical and cellular assays. In another embodiment, the cyclic peptide disclosed herein exhibits high cell permeability and potent inhibition of MDM2 and MDM4 in both biochemical and cellular assays. In yet another embodiment, the cyclic peptide disclosed herein retains therapeutic potential for cancer treatment.

[0057] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention pertains.

[0058] The singular expressions used here include multiple objects unless the context clearly requires a different interpretation.

[0059] The abbreviations used here 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, Lys); 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 not charged 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.

[0060] In embodiments of the present invention, a cyclic peptide containing a certain number of amino acid residues is a cyclic peptide in which the main chain of the cyclic peptide contains the number of amino acid residues listed. In other words, each amino acid residue is within the ring. For example, for the purposes of the present invention, the following is a cyclic peptide containing 10 amino acid residues. [ka] As another example, the following is also considered a cyclic peptide containing 10 amino acid residues, but not a cyclic peptide containing 11 amino acid residues. [ka]

[0061] "Continuous" amino acid residues are intraring amino acids that are covalently linked together without any intraring atoms in between. The following equation is an example of two consecutive proline residues, one being D and the other L. [ka] In contrast, the following equation is an example of two non-contiguous proline residues. [ka]

[0062] When a certain number of consecutive amino acid residues, for example, at least three consecutive amino acids, separate a first beta-hairpin region from a second beta-hairpin region, the residue number refers to the number of residues starting from the C-terminus of the first beta-hairpin region and ending at the N-terminus of the second beta-hairpin region, and / or the number of residues starting from the C-terminus of the second beta-hairpin region and ending at the N-terminus of the first beta-hairpin region. For example, the following describes an embodiment in which two beta-hairpin regions are separated by three consecutive amino acid residues starting from the C-terminus of the first beta-hairpin region and ending at the N-terminus of the second beta-hairpin region, and three consecutive amino acid residues starting from the C-terminus of the second beta-hairpin region and ending at the N-terminus of the first beta-hairpin region. [ka] As another example, the following describes an embodiment in which two beta-hairpin regions are separated by three consecutive amino acid residues starting from the C-terminus of the first beta-hairpin region and ending at the N-terminus of the second beta-hairpin region, and by two consecutive amino acid residues starting from the C-terminus of the second beta-hairpin region and ending at the N-terminus of the first beta-hairpin region. [ka]

[0063] "Adjacent" residues are covalently linked to each other via the N-terminus or C-terminus. Non-adjacent amino acid residues have at least one amino acid or other atom on both the N-terminus and C-terminus sides that separate the amino acid residue from the other. For example, the following structure: [ka] Regarding this, the valine residue is adjacent to the serine residue, but valine is not adjacent to the cysteine ​​residue, while the serine residue is adjacent to both the valine and cysteine ​​residues.

[0064] The term “C x-y When used with chemical moieties such as alkyl, alkenyl, or alkynyl, it is intended to include a group with x~y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl groups and branched-chain alkyl groups containing 1 to 6 carbon atoms. (Terminology - C) x-y Alkylene- refers to an alkylene chain having x~y carbon atoms, whether substituted or unsubstituted. For example, -C 1-6 The alkylene- can be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which may be substituted.

[0065] "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups. Alkyl groups consist of 1 to 12 carbon atoms (for example, C 1-12 Alkyl), for example, 1 to 8 carbon atoms (C 1-8 Alkyl) or 1-6 carbon atoms (C 1-6 Alkyl groups include alkyl groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. Alkyl groups are attached to the rest of the molecule by single bonds. Alkyl groups may be substituted with one or more substituents, such as those listed herein.

[0066] "Haloalkyl" refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0067] The term "carbocyclic ring" as used herein refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocyclic rings include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 6- to 12-membered bridging rings, and spirocyclic rings. Each ring in a bicyclic carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. In exemplary embodiments, an aromatic ring, e.g., phenyl, may be condensed with a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Bicyclic carbocyclic rings include any combination of saturated, unsaturated, and aromatic bicyclic rings as far as valence allows. Bicyclic carbocyclic rings include any combination of ring sizes, e.g., 4-5 condensed ring systems, 5-5 condensed ring systems, 5-6 condensed ring systems, 6-6 condensed ring systems, 5-7 condensed ring systems, 6-7 condensed ring systems, 5-8 condensed ring systems, and 6-8 condensed ring systems. Examples of carbocyclic compounds include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.

[0068] The term "heterocycle" as used herein refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Heteroatoms include N, O, Si, P, B, and S atoms. Examples of heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridging rings. Bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as far as valence allows. In exemplary embodiments, an aromatic ring, e.g., pyridyl, can condense with a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, e.g., 4-5 condensed ring systems, 5-5 condensed ring systems, 5-6 condensed ring systems, 6-6 condensed ring systems, 5-7 condensed ring systems, 6-7 condensed ring systems, 5-8 condensed ring systems, and 6-8 condensed ring systems.

[0069] The term "heteroaryl" as used herein refers to an aromatic ring containing one or more heteroatoms. Examples of monocyclic heteroaryl rings are 5-6 membered rings whose ring structure contains 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.

[0070] The term “substitution” refers to a portion of a compound having substituents that replace one or more carbon atoms or substituteable heteroatoms, such as hydrogen atoms of NH or NH2. “Substitution” or “substituted with” is understood to imply that such substitutions are subject to the allowable valencies of the substituted atom and substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously change through rearrangement, cyclization, removal, etc. In some embodiments, substitution refers to substitutions that replace two hydrogen atoms of the same carbon atom, such as substituting two hydrogen atoms of one carbon atom with an oxo, imino, or thioxo group. The term “substitution” as used herein is intended to include all allowable substituents of an organic compound. In a broader embodiment, allowable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. There may be one or more allowable substituents, and they may be the same or different for a given organic compound.

[0071] In one embodiment, the substituent is any substituent listed herein, e.g.: halogen, hydroxyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazino (=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, -Rb -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 Ure a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); as well as alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxymo (=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 Ure a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) may optionally be substituted with alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralquinyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; where each R a R is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, where each R a If possible, based on valence, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxymo (=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 Ure a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) is often substituted in case of case; where each R b R is independently selected from directly linked, linear, or branched alkylene, alkenylene, or alkynylene chains, and each R c These are linear or branched alkylene, alkenylene, or alkynylene chains.

[0072] The terms “pharmaceutically acceptable additive” or “pharmaceutically acceptable carrier” as used herein refer to a pharmaceutically acceptable substance, composition, or medium such as a liquid or solid extender, diluent, additive, solvent, or encapsulant. Each carrier must be compatible with the other components of the formulation and “acceptable” in that it is not harmful to the patient. Some examples of substances that may serve as pharmaceutically acceptable carriers are (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) additives, e.g., cocoa butter and suppository wax; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, and corn oil. and soybean oil; (10) glycols, e.g., propylene glycol; (11) polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, e.g., ethyl oleate and ethyl laurate; (13) agar; (14) buffers, e.g., magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) water from which pyrogenic substances have been removed; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate-buffered solution; and (21) other non-toxic, suitable substances used in pharmaceutical formulations.

[0073] As used herein, “treatment” or “to treat” refers to an approach to obtain beneficial or desired outcomes with respect to a disease, disorder, or medical condition, including but not limited to therapeutic and / or preventive benefits. Therapeutic benefits may include, for example, the eradication or improvement of the underlying disorder being treated. Therapeutic benefits may also include the eradication or improvement of one or more physiological symptoms associated with the underlying disorder, such as improvement being observed in the subject, even if the subject may still be suffering from the underlying disorder. In some embodiments, preventive benefits include administering the composition to a subject at risk of developing a particular disease or a subject in which one or more physiological symptoms of the disease have been reported, even if the disease has not been diagnosed. Treatment involving the administration of the compounds described herein does not require the involvement of a medical professional.

[0074] The term "therapeutic effect" as used herein includes the therapeutic and / or preventive benefits 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.

[0075] compound In one embodiment, the present invention provides a cyclic peptide. In one embodiment, the present invention provides Nine to eleven amino acid residues independently selected from uncharged amino acid residues at physiological pH; First and second beta hairpin regions A cyclic peptide containing, Next 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 -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle), wherein the monocyclic carbocycle and monocyclic heterocycle are independently and optionally substituted; and At least three amino acid residues containing a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl compounds. Characterized by one of the following: Provides a cyclic peptide.

[0076] In one embodiment, the first beta-hairpin region comprises two consecutive amino acid residues. In one embodiment, the first beta-hairpin region comprises two consecutive residues independently selected from L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe and D-NMe-Val, where the phenyl group of L-NMe-Phe is -Hallo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The molecule is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the first beta-hairpin region comprises two consecutive residues independently selected from L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe, and D-NMe-Val, where the phenyl group of L-NMe-Phe is replaced by halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, and C 1-4 The molecule is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, the first beta-hairpin region comprises two consecutive residues independently selected from L-Pro, D-Pro, L-Aze, D-Pip, and D-NMe-Val. In one embodiment, for the two consecutive residues, one is D and the other is L. In one embodiment, the two consecutive amino acid residues are D-Pro and L-Aze. In one embodiment, the two consecutive amino acid residues are D-Pro and L-Pro. In one embodiment, the two consecutive amino acid residues are D-Pro and L-NMe-Phe, where the phenyl group of L-NMe-Phe is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The molecule is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the two consecutive amino acid residues are D-Pro and L-NMe-Phe, where the phenyl group of L-NMe-Phe is replaced with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The molecule is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, the two consecutive amino acid residues are D-Pip and L-Pro. In one embodiment, the two consecutive amino acid residues are D-Pip and L-Aze. In one embodiment, the two consecutive amino acid residues are D-Pip and L-NMe-Phe, where the phenyl group of L-NMe-Phe is replaced with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The molecule is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the two consecutive amino acid residues are D-Pip and L-NMe-Phe, where the phenyl group of L-NMe-Phe is replaced by halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, and C 1-4 The molecule is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, the two consecutive amino acid residues are D-NMe-Val and L-Pro. In another embodiment, the two consecutive amino acid residues are D-NMe-Val and L-Aze. In yet another embodiment, the two consecutive amino acid residues are D-NMe-Val and L-NMe-Phe, where the phenyl group of L-NMe-Phe is replaced with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The molecule is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the two consecutive amino acid residues are D-NMe-Val and L-NMe-Phe, where the phenyl group of L-NMe-Phe is replaced with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 It may be substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2.

[0077] In one embodiment, the second beta-hairpin region includes a second pair of amino acid residues. In one embodiment, the second beta-hairpin region includes a second pair of residues independently selected from D-Pro, peptoid, DN-alkylated amino acids, and LN-alkylated amino acids. In one embodiment, the second beta-hairpin region includes a second pair of residues independently selected from D-Pro, peptoid, and LN-alkylated amino acids. In one embodiment, of the second pair of residues, one is a peptoid and the other is an LN-alkylated amino acid. In one embodiment, of the second pair of residues, one is L-NMe-Ala and the other is N-(2-methoxyethyl)glycine. In one embodiment, of the second pair of residues, one is D-Pro and the other is a peptoid. In one embodiment, of the second pair of residues, one is D-Pro and the other is an LN-alkylated amino acid. In one embodiment, of the second pair of residues, one is D-Pro and the other is L-NMe-Ala. In one embodiment, of the second pair of consecutive residues, one is D-Pro and the other is N-(2-methoxyethyl)glycine. In one embodiment, of the second pair of consecutive residues, one is a DN-alkylated amino acid and the other is an LN-alkylated amino acid. In one embodiment, of the second pair of consecutive residues, one is D-NMe-Ala and the other is L-NMe-Ala. In one embodiment, of the second pair of consecutive residues, one is a DN-alkylated amino acid and the other is a peptoid. In one embodiment, of the second pair of consecutive residues, one is D-NMe-Ala and the other is N-(2-methoxyethyl)glycine.

[0078] In one embodiment, at least two consecutive amino acids separate the first beta-hairpin region from the second beta-hairpin region. In one embodiment, at least three consecutive amino acids separate the first beta-hairpin region from the second beta-hairpin region. In one embodiment, two consecutive amino acids separate the first beta-hairpin region from the second beta-hairpin region. In one embodiment, three consecutive amino acids separate the first beta-hairpin region from the second beta-hairpin region. In one embodiment, the number of consecutive amino acids between the first and second beta-hairpin regions refers to the number of residues starting from the C-terminus of the first beta-hairpin region and ending at the N-terminus of the second beta-hairpin region. In one embodiment, the number of consecutive amino acids refers to the number of residues starting from the C-terminus of the second beta-hairpin region and ending at the N-terminus of the first beta-hairpin region. In one embodiment, the number of consecutive amino acids refers to the number of residues starting from the C-terminus of the first beta-hairpin region and ending at the N-terminus of the second beta-hairpin region, while the number of consecutive amino acids refers to the number of residues starting from the C-terminus of the second beta-hairpin region and ending at the N-terminus of the first beta-hairpin region, for example, a 3-consecutive-amino

[0079] In one embodiment, the molecular weight of the cyclic peptide is 800 to 1300 Da. In another embodiment, the molecular weight of the cyclic peptide is 800 to 1200 Da. In another embodiment, the molecular weight of the cyclic peptide is 900 to 1200 Da. In another embodiment, the molecular weight of the cyclic peptide is 800 to 900 Da. In another embodiment, the molecular weight of the cyclic peptide is 900 to 1000 Da. In another embodiment, the molecular weight of the cyclic peptide is 1000 to 1100 Da. In another embodiment, the molecular weight of the cyclic peptide is 1100 to 1200 Da. In another embodiment, the molecular weight of the cyclic peptide is 1200 to 1500 Da. In another embodiment, the molecular weight of the cyclic peptide is 1200 to 1400 Da. In another embodiment, the molecular weight of the cyclic peptide is 1100 to 1300 Da.

[0080] In one embodiment, the cyclic peptide comprises a ring independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles, and has at least four amino acid residues in which at least one of the monocyclic carbocycles and monocyclic heterocycles is substituted. In one embodiment, the at least four amino acid residues comprising a ring independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles are not adjacent to each other. In one embodiment, the cyclic peptide is characterized by four amino acid residues comprising a ring independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles, in which at least one of the monocyclic carbocycles and monocyclic heterocycles is substituted. In one embodiment, the cyclic peptide is characterized by three amino acid residues comprising a ring independently selected from optionally substituted monocyclic carbocycles and one amino acid residue comprising a ring independently selected from optionally substituted monocyclic heterocycles. In one embodiment, the optionally substituted monocyclic carbocycle is phenyl, and the optionally substituted monocyclic heterocycle is a heteroaryl ring, where at least one phenyl or heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The substituents are independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the optionally substituted monocyclic carbocycle is phenyl, and the optionally substituted monocyclic heterocycle is a heteroaryl ring, where at least one phenyl or heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The rings are substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, the optionally substituted monocyclic carbocycle is phenyl, and the optionally substituted monocyclic heterocycle is a heteroaryl ring, where at least one phenyl or heteroaryl ring is substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the optionally substituted monocyclic carbocycle is phenyl, and the optionally substituted monocyclic heterocycle is a heteroaryl ring, where at least one phenyl or heteroaryl ring is substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, each heteroaryl ring may be independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, all of which may be substituted. In one embodiment, the optionally substituted monocyclic carbocycle is phenyl, and the optionally substituted monocyclic heterocycle is pyridine, where each ring is independently optionally substituted. In one embodiment, at least four amino acid residues comprising a ring independently selected from the optionally substituted monocyclic carbocycle and the optionally substituted monocyclic heterocycle are independently selected from phenylalanine, 3-(3-pyridyl)alanine, and 4-halophenylalanine.

[0081] In one embodiment, the cyclic peptide has at least four amino acid residues having side chains selected from -alkylene-(monocyclic carbocarriage) and -alkylene-(monocyclic heterocycle), where the monocyclic carbocarriage and monocyclic heterocycle are optionally substituted independently. In one embodiment, each of the at least four amino acid residues selected from -alkylene-(optionally substituted monocyclic carbocarriage) and -alkylene-(optionally substituted monocyclic heterocycle) is not adjacent to each other. In one embodiment, two of the at least four amino acids having side chains selected from -alkylene-(optionally substituted monocyclic carbocarriage) and -alkylene-(optionally substituted monocyclic heterocycle) are adjacent to each other. In one embodiment, each monocyclic carbocarriage is phenyl, and each monocyclic heterocycle is a heteroaryl ring, where each phenyl and heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The rings are optionally independently substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, each monocyclic carbocycle is phenyl, and each monocyclic heterocycle is a heteroaryl ring, where each phenyl and heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The peptide is independently and optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, the cyclic peptide is characterized by four amino acid residues having side chains selected from -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle), where the monocyclic carbocycle and monocyclic heterocycle are independently and optionally substituted. In another embodiment, the cyclic peptide is characterized by three amino acids having side chains independently selected from -alkylene-(monocyclic carbocycle) and one amino acid having a side chain selected from -alkylene-(monocyclic heterocycle), where the monocyclic carbocycle and monocyclic heterocycle are independently and optionally substituted. In one embodiment, each monocyclic carbocycle is phenyl, and each monocyclic heterocycle is a heteroaryl ring, where each phenyl and heteroaryl ring is independently and optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, each of which is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2.In one embodiment, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, each optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, each monocyclic carbocycle is phenyl, and each monocyclic heterocycle is pyridine, where each ring is independently optionally substituted. In one embodiment, at least four amino acid residues having side chains selected from -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle) are independently selected from phenylalanine, 3-(3-pyridyl)alanine, and 4-halophenylalanine.

[0082] In one embodiment, the cyclic peptide has at least three amino acid residues comprising a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl. In one embodiment, the at least three amino acid residues comprising a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl are not adjacent to each other. In one embodiment, the cyclic peptide is characterized by three amino acid residues comprising a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl. In one embodiment, the cyclic peptide is characterized by four amino acid residues comprising a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl. In one embodiment, the cyclic peptide is characterized by three amino acid residues comprising a ring independently selected from optionally substituted phenyl and one amino acid residue comprising a ring selected from optionally substituted monocyclic heteroaryl. In one embodiment, the cyclic peptide is characterized by three amino acid residues comprising a ring independently selected from optionally substituted phenyl and one amino acid residue comprising a ring selected from optionally substituted pyridine. In one embodiment, each phenyl and heteroaryl ring is -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The rings are optionally and independently substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, each phenyl and heteroaryl ring is a halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The rings are independently and optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, each phenyl and heteroaryl ring is independently and optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, each phenyl and heteroaryl ring is independently and optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, and each is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, each heteroaryl ring is independently optionally substituted pyridine. In one embodiment, at least three amino acid residues comprising a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl are independently selected from phenylalanine, 3-(3-pyridyl)alanine, and 4-halophenylalanine.

[0083] In one embodiment, at least three main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In one embodiment, four or five main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In one embodiment, four main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. In one embodiment, five main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms.

[0084] In one embodiment, one or more tertiary main chain nitrogen atoms are part of a heterocycloalkyl ring. When two or more tertiary main chain nitrogen atoms are part of a heterocycloalkyl ring, these rings are distinct from each other. For example, when there are tertiary main chain nitrogen atom portions of two heterocycloalkyl rings, one nitrogen is part of a first proline portion and the second nitrogen is part of a second proline portion.

[0085] In one embodiment, one tertiary main chain nitrogen atom is part of a heterocycloalkyl ring. In one embodiment, one tertiary main chain nitrogen atom is part of a first heterocycloalkyl ring, and a second tertiary main chain nitrogen atom is part of a second heterocycloalkyl ring. In one embodiment, one tertiary main chain nitrogen atom is part of a first heterocycloalkyl ring, a second tertiary main chain nitrogen atom is part of a second heterocycloalkyl ring, and a third tertiary main chain nitrogen atom is part of a third heterocycloalkyl ring. In one embodiment, one tertiary main chain nitrogen atom is part of a first heterocycloalkyl ring, a second tertiary main chain nitrogen atom is part of a second heterocycloalkyl ring, a third tertiary main chain nitrogen atom is part of a third heterocycloalkyl ring, and a fourth tertiary main chain nitrogen atom is part of a fourth heterocycloalkyl ring. In one embodiment, one tertiary main chain nitrogen atom is part of a first heterocycloalkyl ring, a second tertiary main chain nitrogen atom is part of a second heterocycloalkyl ring, a third tertiary main chain nitrogen atom is part of a third heterocycloalkyl ring, a fourth tertiary main chain nitrogen atom is part of a fourth heterocycloalkyl ring, and a fifth tertiary main chain nitrogen atom is part of a fifth heterocycloalkyl ring.

[0086] In one embodiment, the tertiary nitrogen has a C1-C6 alkyl substituent where one or more substituents are independently selected from each tertiary nitrogen, where the substituents of the C1-C6 alkyl are halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The substituents are independently selected from alkyl, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, the substituents of the tertiary nitrogen are C1-C6 alkyl substituents which are independently selected from each tertiary nitrogen, where the substituents of the C1-C6 alkyl are halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The substituents are independently selected from alkyl, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, one or more tertiary nitrogen atoms have a C1-C6 alkyl substituent that is independently selected for each tertiary nitrogen, where the substituents are independently selected from halo, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, one or more tertiary nitrogen atoms have a C1-C6 alkyl substituent that is independently selected for each tertiary nitrogen, where the substituents are independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, one tertiary nitrogen atom has a C1-C6 alkyl substituent that is independently selected for each tertiary nitrogen, where the substituents are independently selected from halo, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, one tertiary nitrogen has a C1-C6 alkyl substituent that is independently selected for each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2. In another embodiment, two tertiary nitrogens have a C1-C6 alkyl substituent that is independently selected for each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In yet another embodiment, two tertiary nitrogens have a C1-C6 alkyl substituent that is independently selected for each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, the tertiary nitrogen has C1-C6 alkyl substituents which are substituted by a substituent that is independently selected for each tertiary nitrogen, where the substituents of the C1-C6 alkyl substituent are independently selected from halo, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2.In one embodiment, three tertiary nitrogen atoms have C1-C6 alkyl substituents that are independently selected for each tertiary nitrogen, where the C1-C6 alkyl substituents are independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2. In another embodiment, four tertiary nitrogen atoms have C1-C6 alkyl substituents that are independently selected for each tertiary nitrogen, where the C1-C6 alkyl substituents are independently selected from halo, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In yet another embodiment, four tertiary nitrogen atoms have C1-C6 alkyl substituents that are independently selected for each tertiary nitrogen, where the C1-C6 alkyl substituents are independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, five tertiary nitrogen atoms have C1-C6 alkyl substituents that are independently selected for each tertiary nitrogen atom, where the C1-C6 alkyl substituents are independently selected from halo, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2.

[0087] In one embodiment, each tertiary nitrogen is independently [ka] It is expressed as follows, where R A -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A C1-C6 alkyl group optionally substituted with one or more substituents independently selected from alkyl, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2, where, [ka] represents a binding site to an adjacent amino acid residue. In one embodiment, each tertiary nitrogen is independently [ka] It is expressed as follows, where R A -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A C1-C6 alkyl group optionally substituted with one or more substituents independently selected from alkyl, -OBz, -OCH3, -OCF3, and -OCHF2, where, [ka] represents a binding site to an adjacent amino acid residue. In one embodiment, each tertiary nitrogen is independently [ka] It is expressed as follows, where R A is a C1-C6 alkyl group optionally substituted with one or more substituents independently selected from halo, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2, where, [ka] represents a binding site to an adjacent amino acid residue. In one embodiment, each tertiary nitrogen is independently [ka] It is expressed as follows, where R A is a C1-C6 alkyl group optionally substituted with one or more substituents independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2, where, [ka] represents a binding site to an adjacent amino acid residue. In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] In one embodiment, one or more tertiary nitrogen atoms are [ka] That is the case.

[0088] In one embodiment, the cyclic peptide has 8 amino acid residues. In another embodiment, the cyclic peptide has 9 amino acid residues. In another embodiment, the cyclic peptide has 10 amino acid residues. In another embodiment, the cyclic peptide has 11 amino acid residues. In yet another embodiment, the cyclic peptide has 12 amino acid residues.

[0089] In one embodiment, the cyclic peptide is of formula I: [ka] [During the ceremony, R 1 , R 6 and R 8 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 2 is hydrogen and C 1-6 Selected from alkyl groups; R 3 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8(Carbon ring) and -(C 1-4 Selected from alkylenes (3-10 membered heterocycles), where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2; and C 1-4 Alkyls are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 4 is hydrogen or C 1-4 Alkyl or R 4 and R 14 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 5 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Selected from alkylenes (3-10 membered heterocycles), where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2; and C 1-4 Alkyls are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2; or R 5 and R 15 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 7 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-6 Selected from alkyl or R 7 and R 17 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 9 is hydrogen or C 1-6 Alkyl or R 9 and R 19 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 10 is hydrogen or C 1-4 Alkyl or R 10 and R 20 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 11 , R 12 , R 13 , R 16 and R 18 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected independently of alkyl; R 14 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 14 and R 4 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R15 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 15 and R 5 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 17 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 17 and R 7 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 19 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 19 and R 9 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; and R 20 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 20 and R 10 It combines with the intermediate atom to form a 4-7 member heterocycloalkyl group. It is represented by [this].

[0090] In one embodiment, the cyclic peptide is of formula I: [ka] [During the ceremony, R 1 , R 6 and R 8 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; R 2 is hydrogen and C 1-6 Selected from alkyl groups; R 3 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Selected from alkylenes (3-10 membered heterocycles), where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2; and C 1-4 Alkyls are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2; R 4 is hydrogen or C 1-4 Alkyl or R 4and R 14 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 5 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Selected from alkylenes (3-10 membered heterocycles), where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2; and C 1-4 Alkyls are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; or R 5 and R 15 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 7 is hydrogen or C 1-6 Alkyl or R 7 and R 17 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 9 is hydrogen or C 1-6 Alkyl or R 9 and R 19 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 10 is hydrogen or C 1-4 Alkyl or R 10 and R 20 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 11 , R 12 , R 13 , R 16 and R18 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected independently of alkyl; R 14 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 14 and R 4 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 15 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 15 and R 5 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 17 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 17 and R 7 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 19 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 19 and R 9 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; and R 20 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 20 and R 10 It combines with the intermediate atom to form a 4-7 member heterocycloalkyl group. It is represented by [this].

[0091] In one embodiment, the cyclic peptide is given by formula II: [ka] [During the ceremony, R 21 , R 23 , R 26 and R 28 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 24 is hydrogen or C 1-4 Alkyl or R 24 and R 34 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R25 is hydrogen or C1-4 Alkyl or R 25 and R 35 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 30 is hydrogen or C 1-4 Alkyl or R 30 and R 40 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 22 , R 27 and R 29 is hydrogen and C 1-6 Selected independently of alkyl; R 31 , R 32 , R 33 , R 36 and R 38 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected independently of alkyl; R 37 and R 39 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected independently of alkyl; R 34 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected from alkyl or R 34 and R 24 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 35 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected from alkyl or R 35 and R 25combines with atoms in between to form a 5-7 membered heterocycloalkyl; and R 40 is hydrogen; and is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2, a C 1-4 alkyl selected from or R 40 and R 30 combines with atoms in between to form a 5-7 membered heterocycloalkyl. ]] is represented by.

[0092] In certain embodiments, the cyclic peptide is of formula II:

Chemical formula

[0093] In certain embodiments, R 31 is hydrogen. In certain embodiments, R 32 is hydrogen. In certain embodiments, R 33 is hydrogen. In certain embodiments, R 36 is hydrogen. In certain embodiments, R 38 is hydrogen. In certain embodiments, R 31 and R 32 are each hydrogen. In certain embodiments, R 31 and R 33 are each hydrogen. In certain embodiments, R 31 and R 36 are each hydrogen. In certain embodiments, R 31 and R 38 are each hydrogen. In certain embodiments, R 32 and R 33 are each hydrogen. In certain embodiments, R 32 and R 36 are each hydrogen. In certain embodiments, R 32 and R 38 are each hydrogen. In certain embodiments, R 33 and R 36 are each hydrogen. In certain embodiments, R 33 and R 38 are each hydrogen. In certain embodiments, R 36 and R 38 are each hydrogen. In certain embodiments, R 31 , R 21 and R 33 are each hydrogen. In certain embodiments, R 31 , R 32 and R 36 are each hydrogen. In certain embodiments, R 31 , R 32 and R 38 are each hydrogen. In certain embodiments, R 31 , R33 and R 36 Each of these is hydrogen. In one embodiment, R 31 , R 33 and R 38 Each of these is hydrogen. In one embodiment, R 31 , R 36 and R 38 Each of these is hydrogen. In one embodiment, R 32 , R 33 and R 36 Each of these is hydrogen. In one embodiment, R 32 , R 33 and R 38 Each of these is hydrogen. In one embodiment, R 32 , R 36 and R 38 Each of these is hydrogen. In one embodiment, R 33 , R 36 and R 38 Each of these is hydrogen. In one embodiment, R 31 , R 32 , R 33 and R 36 Each of these is hydrogen. In one embodiment, R 31 , R 32 , R 33 and R 38 Each of these is hydrogen. In one embodiment, R 31 , R 33 , R 36 and R 38 Each of these is hydrogen. In one embodiment, R 31 , R 32 , R 36 and R 38 Each of these is hydrogen. In one embodiment, R 32 , R 33 , R 36 and R 38 Each of these is hydrogen. In one embodiment, R 31 , R 32 , R 33 , R 36 and R 38 Each of them is hydrogen.

[0094] One reason, R 34 , R35 , R 37 , R 39 and R 40 At least four of them are not hydrogen. In one embodiment, R 34 , R 35 , R 37 , R 39 and R 40 These four are not hydrogen. In one embodiment, R 34 , R 35 , R 37 and R 319 It is not hydrogen. For one reason, R 34 , R 35 , R 37 and R 40 It is not hydrogen. For one reason, R 35 , R 37 , R 39 and R 40 It is not hydrogen. For one reason, R 34 , R 35 , R 39 and R 40 It is not hydrogen. For one reason, R 34 , R 37 , R 39 and R 40 It is not hydrogen. For one reason, R 34 , R 35 , R 37 , R 39 and R 40 It is not hydrogen.

[0095] One reason, R 24 and R 34 , R 25 and R 35 and R 30 and R 40 At least one of them combines with an intermediate atom to form a 5-7 member heterocycloalkyl group. In one embodiment, R 24 and R 34 , R 25 and R 35 and R 30 and R 40At least two of them combine with the intermediate atom to form a 5-7 member heterocycloalkyl group. In one embodiment, R 24 and R 34 It integrates with the atoms in between to form a 5-6 member heterocycloalkyl group. In one embodiment, R 25 and R 35 It integrates with the atoms in between to form a 5-6 member heterocycloalkyl group. In one embodiment, R 30 and R 40 It integrates with the atoms in between to form a 5-6 member heterocycloalkyl group. In one embodiment, R 24 and R 34 and R 25 and R 35 It integrates with the atoms in between to form a 5-6 member heterocycloalkyl group. In one embodiment, R 24 and R 34 and R 30 and R 40 It integrates with the atoms in between to form a 5-6 member heterocycloalkyl group. In one embodiment, R 25 and R 35 and R 30 and R 40 It integrates with the atoms in between to form a 5-6 member heterocycloalkyl group. In one embodiment, R 24 and R 34 , R 25 and R 35 and R 30 and R 40 It combines with the intermediate atom to form a 5-6 member heterocycloalkyl group.

[0096] One reason, R 37 , R 39 and R 40 Each of these is selected from methyl and methoxyethyl. In one embodiment, R 35 , R 37 and R 39 Each of these is selected from methyl and methoxyethyl. In one embodiment, R 35 , R 37 and R 40Each of these is selected from methyl and methoxyethyl. In one embodiment, R 35 , R 39 and R 40 Each of these is selected from methyl and methoxyethyl. In one embodiment, R 35 , R 37 , R 39 and R 40 Each of these is selected from methyl and methoxyethyl.

[0097] One reason, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 2-4 Alkyl or R 30 and R 40 It integrates with the atoms in between to form a 5-7 member heterocycloalkyl group. In one embodiment, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 2-4 Alkyl or R 30 and R 40 It integrates with the atoms in between to form a 5-7 member heterocycloalkyl group. In one embodiment, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl or R 30 and R 40 It integrates with the atoms in between to form a 5-7 member heterocycloalkyl group. In one embodiment, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 Alkyl or R 30 and R 40 It integrates with the atoms in between to form a 5-7 member heterocycloalkyl group. In one embodiment, R40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 2-4 It is alkyl. In one example, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 2-4 It is alkyl. In one example, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 It is alkyl. In one example, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 It is alkyl. In one example, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5, and -OCH3. 2-4 It is alkyl. In one example, R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, and -OCH3. 2-4 It is alkyl. In one example, R 30 and R 40 These atoms combine with the atoms in between to form a 5-7 member heterocycloalkyl group.

[0098] One reason, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 1-4 It is alkyl. In one example, R 39C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 1-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5, and -OCH3. 1-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, and -OCH3. 1-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from -CHF2, -OBz, -SF5, and -OCHF2. 1-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from -CHF2, -OBz, and -OCHF2. 1-4 It is alkyl.

[0099] One reason, R 22 , R 27 and R 29 is C 1-6 Selected independently of alkyl. In one embodiment, R 22 , R 27 and R 29 R is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl. In one embodiment, R 22 , R27 and R 29 R is selected from methyl, ethyl, i-propyl, and t-butyl. In one embodiment, R 27 is methyl. In one example, R 29 is methyl. In one example, R 27 and R 29 Each is a methyl group.

[0100] One reason, R 21 , R 23 , R 26 and R 28 is -C 3-8 Carbon ring, -3 to 10 membered heteroring, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted. In one embodiment, R 21 , R 23 , R 26 and R 28 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted. In one embodiment, R 21 , R 23 , R 26 and R 28 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbocyclic rings and 3- to 10-membered heterocycles are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. In one embodiment, R 21 , R 23 , R 26 and R28 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbocyclic rings and 3- to 10-membered heterocycles are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. In one embodiment, R 21 , R 23 , R 26 and R 28 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbocyclic rings and 3- to 10-membered heterocycles are optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, R 21 , R 23 , R 26 and R 28 is -CH2-(C 3-8 A carbon ring and a -CH2- (3-10 membered heteroring) are independently selected. In one embodiment, R 21 , R 23 , R 26 and R 28 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5, and -OCH3. In one embodiment, R 21 , R 23 , R 26 and R 28 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, and -OCH3. In one embodiment, R 21 , R 23 , R 26 and R 28 R is independently selected from phenylmethyl and pyridinylmethyl, where phenyl and pyridinyl are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5 and -OCH3. In one embodiment, R 21 , R 23 , R 26 and R 28 R is independently selected from phenylmethyl and pyridinylmethyl, where phenyl and pyridinyl are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3 and -OCH3. In one embodiment, R 21 , R 23 , R 26 and R 28 teeth [ka] It is selected independently of R. In one embodiment, 21 teeth [ka] And R 23 , R 26 and R 28 teeth [ka] It is selected independently of R. 21 teeth [ka] And R 23 teeth [ka] And R 26 and R 28 teeth [ka] It is selected independently of R. 21 teeth [ka] And R 23 teeth [ka] And R 26 teeth [ka] And R 28 teeth [ka] That is the case.

[0101] In one embodiment, the cyclic peptide is given by formula IIa: [ka] It is represented by [this].

[0102] In one embodiment, the cyclic peptide is given by formula IIb: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0103] One reason, R 21’ , R23’ , R 26’ and R 28’ teeth [ka] It is selected independently of R. 21’ teeth [ka] And R 23’ , R 26’ and R 28’ teeth [ka] It is selected independently of R. 21’ teeth [ka] And R 23’ teeth [ka] And R 26’ and R 28’ teeth [ka] It is selected independently of R. 21’ teeth [ka] And R 23’ teeth [ka] And R 26’ teeth [ka] And R 28’ teeth [ka] That is the case.

[0104] In one embodiment, the cyclic peptide is given by formula IIc: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0105] In one embodiment, the cyclic peptide is given by formula IId: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0106] In one embodiment, the cyclic peptide is given by formula IIe: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0107] In one embodiment, the cyclic peptide is given by formula IIf: [ka] [In the formula, R 21’ , R 23’ , R26’ and R 28’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0108] In one embodiment, the cyclic peptide is given by formula IIg: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0109] In one embodiment, the cyclic peptide is given by formula III: [ka] [During the ceremony, R 41 , R 45 , R 46 and R 48 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 42 is hydrogen and C 1-6 Selected from alkyl groups; R 43 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl groups; R 44 is hydrogen or C 1-4 Alkyl or R 44 and R 54 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 47 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-6 Selected from alkyl or R 47 and R 57 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 49 is hydrogen or C 1-6 Alkyl or R 49 and R 59 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 50 is hydrogen or C 1-4 Alkyl or R 50 and R 60 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 51 , R 53 , R 56 and R 58 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected independently of alkyl; R 52 and R 55Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected independently of alkyl; R 54 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 54 and R 44 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 57 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 57 and R 47 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 59 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 59 and R 49 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 60 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 60 and R 50 It combines with the intermediate atom to form a 4-7 member heterocycloalkyl group. It is represented by [this].

[0110] In one embodiment, the cyclic peptide is given by formula III: [ka] [During the ceremony, R 41 , R 45 , R 46 and R 48 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; R 42 is hydrogen and C 1-6 Selected from alkyl groups; R 43 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl groups; R 44 is hydrogen or C 1-4 Alkyl or R 44 and R 54It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 47 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-6 Selected from alkyl or R 47 and R 57 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 49 is hydrogen or C 1-6 Alkyl or R 49 and R 59 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 50 is hydrogen or C 1-4 Alkyl or R 50 and R 60 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 51 , R 53 , R 56 and R 58 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected independently of alkyl; R 52 and R 55 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected independently of alkyl; R 54Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 54 and R 44 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 57 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 57 and R 47 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 59 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 59 and R 49 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 60 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 60 and R 50 It combines with the intermediate atom to form a 4-7 member heterocycloalkyl group. It is represented by [this].

[0111] One reason, R 51 R is hydrogen. In one way, 53 R is hydrogen. In one way, 56 R is hydrogen. In one way, 58 R is hydrogen. In one way, 51 and R 53 Each of these is hydrogen. In one embodiment, R 51 and R 56 Each of these is hydrogen. In one embodiment, R 51 and R 58 Each of these is hydrogen. In one embodiment, R 53 and R 56 Each of these is hydrogen. In one embodiment, R 53 and R 58 Each of these is hydrogen. In one embodiment, R 56 and R 58 Each of these is hydrogen. In one embodiment, R 51 , R 53 and R 56 Each of these is hydrogen. In one embodiment, R 51 , R 53 and R 58 Each of these is hydrogen. In one embodiment, R 51 , R 56 and R 58 Each of these is hydrogen. In one embodiment, R 53 , R 56 and R 58 Each of these is hydrogen. In one embodiment, R 51 , R 53 , R 56 and R 58 Each of them is hydrogen.

[0112] One reason, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 At least four of them are not hydrogen. In one embodiment, R 52 , R 54 , R 55 , R57 , R 59 and R 60 These four are not hydrogen. In one embodiment, R 52 , R 54 , R 55 and R 57 It is not hydrogen. For one reason, R 52 , R 54 , R 55 and R 59 It is not hydrogen. For one reason, R 52 , R 54 , R 55 and R 60 It is not hydrogen. For one reason, R 52 , R 54 , R 57 and R 59 It is not hydrogen. For one reason, R 52 , R 54 , R 57 and R 60 It is not hydrogen. For one reason, R 52 , R 54 , R 59 and R 60 It is not hydrogen. For one reason, R 52 , R 55 , R 57 and R 59 It is not hydrogen. For one reason, R 52 , R 55 , R 57 and R 60 It is not hydrogen. For one reason, R 52 , R 55 , R 59 and R 60 It is not hydrogen. For one reason, R 52 , R 57 , R 59 and R 60 It is not hydrogen. For one reason, R 54 , R 55 , R 57 and R 59 It is not hydrogen. For one reason, R 54 , R 55 , R 57 and R60 It is not hydrogen. For one reason, R 54 , R 55 , R 59 and R 60 It is not hydrogen. For one reason, R 54 , R 57 , R 59 and R 60 It is not hydrogen. For one reason, R 55 , R 57 , R 59 and R 60 It is not hydrogen. For one reason, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 At least 5 of them are not hydrogen. In one embodiment, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 Five of these are not hydrogen. In one embodiment, R 52 , R 54 , R 55 , R 57 and R 59 It is not hydrogen. For one reason, R 52 , R 54 , R 55 , R 57 and R 60 It is not hydrogen. For one reason, R 52 , R 55 , R 57 , R 59 and R 60 It is not hydrogen. For one reason, R 54 , R 55 , R 57 , R 59 and R 60 It is not hydrogen. For one reason, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 It is not hydrogen.

[0113] One reason, 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 combines with an intermediate atom to form a 4-7 member heterocycloalkyl group. In one embodiment, 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 combine with the intermediate atom to form a 4-7 member heterocycloalkyl group. In one embodiment, R 44 and R 54 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 47 and R 57 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 49 and R 59 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 44 and R 54 and R 47 and R 57 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 44 and R 54 and R 49 and R 59 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 44 and R 54 and R 50 and R 60It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 47 and R 57 and R 49 and R 59 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 47 and R 57 and R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 49 and R 59 and R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 44 and R 54 , R 47 and R 57 and R 49 and R 59 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 44 and R 54 , R 47 and R 57 and R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 44 and R 54 , R 49 and R 59 and R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 47 and R 57 , R 49 and R 59 and R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 44 and R 54 , R 47 and R57 , R 49 and R 59 and R 50 and R 60 These atoms combine with the atoms in between to form 4- to 7-membered heterocycloalkyl groups.

[0114] One reason, R 52 , R 55 and R 59 Each of these is selected from methyl, ethyl, and methoxyethyl. In one embodiment, R 52 , R 55 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl. In one embodiment, R 52 , R 59 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl. In one embodiment, R 55 , R 59 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl. In one embodiment, R 52 , R 55 , R 59 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl. In one embodiment, R 52 , R 55 , R 57 , R 59 and R 60 Each of these is selected from methyl, ethyl, and methoxyethyl.

[0115] One reason, R 60 -SCH3, -SOCH3, -SO2CH3, -CF3, -CHF2, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl or R 50 and R 60It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 60 -SCH3, -SOCH3, -SO2CH3, -CF3, -CHF2, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 Alkyl or R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 60 is Halogen, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl or R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 60 is Halogen, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 Alkyl or R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 60 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 2-4 Alkyl or R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 60C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 2-4 Alkyl or R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 60 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl or R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 60 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 Alkyl or R 50 and R 60 It integrates with the atoms in between to form a 4-7 member heterocycloalkyl group. In one embodiment, R 60 is Halogen, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 It is alkyl. In one example, R 60 is Halogen, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 It is alkyl. In one example, R 60 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 2-4 It is alkyl. In one example, R 60C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 2-4 It is alkyl. In one example, R 60 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 It is alkyl. In one example, R 60 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 It is alkyl. In one example, R 60 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5, and -OCH3. 2-4 It is alkyl. In one example, R 60 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, and -OCH3. 2-4 It is alkyl. In one example, R 50 and R 60 These atoms combine with the atoms in between to form 4- to 7-membered heterocycloalkyl groups.

[0116] One reason, R 59 -CF3, -CHF2, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 It is alkyl. In one example, R 59 -CF3, -CHF2, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4It is alkyl. In one example, R 59 is Halogen, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 It is alkyl. In one example, R 59 is Halogen, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 It is alkyl. In one example, R 59 C is optionally substituted with one or more substituents independently selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, -CH3, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 2-4 It is alkyl. In one example, R 59 C is optionally substituted with one or more substituents independently selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, -CH3, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. 2-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. 2-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5, and -OCH3. 2-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, and -OCH3. 2-4 It is alkyl. In one example, R 39 C is optionally substituted with one or more substituents independently selected from -CHF2, -OBz, and -OCHF2. 2-4 It is alkyl.

[0117] One reason, R 42 , R 47 and R 49 is C 1-6 Selected independently of alkyl. In one embodiment, R 42 , R 47 and R 49 R is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl. In one embodiment, R 42 , R 47 and R 49 R is selected from methyl, ethyl, i-propyl, and t-butyl. In one embodiment, R 42 is methyl. In one example, R 47 is methyl, ethyl, i-propyl, or t-butyl. In one embodiment, R 49 is methyl. In one example, R 42 is methyl, and R 47 R is methyl, ethyl, i-propyl, or t-butyl, 49 R is hydrogen. In one way, 42 is methyl, and R47 is methyl, and R 49 R is hydrogen. In one way, 42 is methyl, and R 47 is ethyl, and R 49 R is hydrogen. In one way, 42 is methyl, and R 47 It is i-propyl, and R 49 R is hydrogen. In one way, 42 is methyl, and R 47 is t-butyl, and R 49 R is hydrogen. In one way, 42 is methyl, and R 47 R is methyl, ethyl, i-propyl, or t-butyl, 49 is methyl. In one example, R 42 is methyl, and R 47 is methyl, and R 49 is methyl. In one example, R 42 is methyl, and R 47 is ethyl, and R 49 is methyl. In one example, R 42 is methyl, and R 47 It is i-propyl, and R 49 is methyl. In one example, R 42 is methyl, and R 47 is t-butyl, and R 49 It is methyl.

[0118] One reason, R 41 , R 45 , R 46 and R 48 is -C 3-8 Carbon ring, -3 to 10 membered heteroring, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted. In one embodiment, R 41 , R 45, R 46 and R 48 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted. In one embodiment, R 41 , R 45 , R 46 and R 48 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, R 41 , R 45 , R 46 and R 48 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 Carbon rings and 3-10 membered heterorings are halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, R 41 , R 45 , R 46 and R 48 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C3-8 The carbocyclic rings and 3- to 10-membered heterocycles are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2. In one embodiment, R 41 , R 45 , R 46 and R 48 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbocyclic rings and 3- to 10-membered heterocycles are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2. In one embodiment, R 41 , R 45 , R 46 and R 48 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In one embodiment, R 41 , R 45 , R 46 and R 48 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbocyclic rings and 3- to 10-membered heterocycles are optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. In one embodiment, R 41 , R 45 , R 46 and R 48 ha-(C 1-4Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5, and -OCH3. In one embodiment, R 41 , R 45 , R 46 and R 48 ha-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon rings and 3- to 10-membered heterorings are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, and -OCH3. In one embodiment, R 41 , R 45 , R 46 and R 48 is -CH2-(C 3-8 A carbon ring and a -CH2- (3-10 membered heteroring) are independently selected. In one embodiment, R 41 , R 45 , R 46 and R 48 R is independently selected from phenylmethyl, pyridinylmethyl, and thiazolylmethyl, where phenyl, pyridinyl, and thiazolyl are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, and -OCH3. In one embodiment, R 41’ , R 45’ , R 46’ and R 48’ teeth [ka] It is selected independently of R. 41’ teeth [ka] And R45’ , R 46’ and R 48’ teeth [ka] It is selected independently of R. 41’ teeth [ka] And R 45’ teeth [ka] And R 46’ and R 48’ teeth [ka] It is selected independently of R. 41’ teeth [ka] And R 45’ teeth [ka] And R 46’ teeth [ka] And R 48’ teeth [ka] In one example, R 41’ teeth [ka] And R 45’ teeth [ka] And R 46’ and R 48’ teeth [ka] It is selected independently of R. 41’ teeth [ka] And R 45’ teeth [ka] And R 46’ teeth [ka] And R 48’ teeth [ka] That is the case.

[0119] In one embodiment, the cyclic peptide is given by formula IIIa: [ka] It is represented by [this].

[0120] In one embodiment, the cyclic peptide is given by formula IIIb: [ka] [In the formula, R 41’ , R 45’ , R 46’ and R 48’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0121] One reason, R 41’ , R 45’ , R 46’ and R 48’ teeth [ka] It is selected independently of R. 41’ teeth [ka] And R 45’ , R 46’ and R 48’ teeth [ka] It is selected independently of R. 41’ teeth [ka] And R 45’ teeth [ka] And R 46’ and R 48’ teeth [ka] It is selected independently of R. 41’ teeth [ka] And R 45’ teeth [ka] And R 46’ teeth [ka] And R 48’ teeth [ka] In one example, R 41’ teeth [ka] And R 45’ teeth [ka] And R 46’ and R 48’ teeth [ka] It is selected independently of R. 41’ teeth [ka] And R 45’ teeth [ka] And R 46’ teeth [ka] And R 48’ teeth [ka] That is the case.

[0122] In one embodiment, the cyclic peptide is given by formula IIIc: [ka] [In the formula, R 41’ , R 45’ , R 46’ and R 48’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0123] In one embodiment, the cyclic peptide is given by formula IIId: [ka] [In the formula, R41’ , R 45’ , R 46’ and R 48’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0124] In one embodiment, the cyclic peptide is given by formula IIIe: [ka] [In the formula, R 41’ , R 45’ , R 46’ and R 48’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0125] In one embodiment, the cyclic peptide is given by formula IIIf: [ka] [In the formula, R 41’ , R 45’ , R 46’ and R 48’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0126] In one embodiment, the cyclic peptide is given by formula IIIg: [ka] [In the formula, R 41’ , R 45’ , R 46’ and R 48’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0127] In one embodiment, the cyclic peptide is given by formula IIIh: [ka] [In the formula, R 41’ , R 45’ , R 46’ and R 48’ This is independently selected from optionally substituted phenyl compounds and optionally substituted 5-membered or 6-membered heteroaryl compounds. It is represented by [this].

[0128] In one embodiment, the cyclic peptide is selected from those listed in Tables 3 and 4 or any pharmaceutically acceptable salt thereof.

[0129] In one embodiment, the cyclic peptide disclosed herein is 1.0 × 10 -7 cm s -1 It has a cell permeability value exceeding 1.0 × 10. In one embodiment, the cyclic peptide disclosed herein has a cell permeability value exceeding 1.0 × 10. -6 cm s -1 It has a cell permeability value exceeding 1.0 × 10. In one embodiment, the cyclic peptide disclosed herein has a cell permeability value exceeding 1.0 × 10. -5 cm s -1 It has a cell permeability value exceeding 1.0 × 10. In one embodiment, the cyclic peptide disclosed herein has a cell permeability value exceeding 1.0 × 10. -4 cm s -1 It has a cell permeability value exceeding 1.0 × 10. In one embodiment, the cyclic peptide disclosed herein has a cell permeability value exceeding 1.0 × 10. -3 cm s -1 It has a cell permeability value exceeding 0.01 cm s. In one embodiment, the cyclic peptide disclosed herein has a cell permeability of 0.01 cm s. -1 It has a cell permeability value exceeding 0.1 cm s. In one embodiment, the cyclic peptide disclosed herein has a cell permeability of 0.1 cm s. -1 It has a cell permeability value exceeding 1.0 cm s. In one embodiment, the cyclic peptide disclosed herein has a cell permeability value exceeding 1.0 cm s. -1It has a cell permeability value exceeding [value]. In one embodiment, the cell permeability value of the cyclic peptide disclosed herein is determined by a Caco-2 assay. In one embodiment, the cell permeability value of the cyclic peptide disclosed herein is determined by an MDR1-MDCK assay.

[0130] In one embodiment, the cyclic peptide disclosed herein is 5.0 × 10 -8 It has a solubility greater than M. In one embodiment, the cyclic peptide disclosed herein is 5.0 × 10 -7 It has a solubility greater than M. In one embodiment, the cyclic peptide disclosed herein is 5.0 × 10 -6 It has a solubility greater than M. In one embodiment, the cyclic peptide disclosed herein is 5.0 × 10 -5 It has a solubility greater than M. In one embodiment, the cyclic peptide disclosed herein is 5.0 × 10 -4 It has a solubility greater than M. In one embodiment, the cyclic peptide disclosed herein is 5.0 × 10 -3 It has a solubility greater than M. In one embodiment, the cyclic peptide disclosed herein has a solubility greater than 0.05 M. In one embodiment, the cyclic peptide disclosed herein has a solubility greater than 0.5 M. In one embodiment, the cyclic peptide disclosed herein has a solubility greater than 5.0 M. In one embodiment, the solubility of the cyclic peptide disclosed herein is determined by a kinetic assay. In one embodiment, the solubility of the cyclic peptide disclosed herein is determined by an equilibrium solubility assay. In one embodiment, the solubility of the cyclic peptide disclosed herein is determined by a turbidity assay. In one embodiment, the solubility of the cyclic peptide disclosed herein is determined by a turbidimetry assay. In one embodiment, the solubility of the cyclic peptide disclosed herein is determined by a direct UV assay.

[0131] The compounds disclosed herein, in one embodiment, are in various isotope-enriched forms, for example, 2 H, 3 H,11 C, 13 C and / or 14 It may be used in a form enriched with C content. The deuterated form can be produced by the methods described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby extending the duration of action of the drug.

[0132] Unless otherwise specified, the compounds described herein are intended to include compounds that differ only by the presence of one or more isotope-enriched atoms. For example, substitution of hydrogen with deuterium or tritium or carbon 13 C or 14 Apart from substitution with carbon-enriched carbon, compounds having this structure are within the scope of the present invention.

[0133] The compounds of the present invention optionally contain one or more atoms constituting such compounds in non-natural atomic isotope ratios. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I) or carbon-14 ( 14 It can be labeled with isotopes such as C). 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 125All isotopic substitutions in I are taken into consideration. All isotopic variants of the cyclic peptides disclosed herein, whether radioactive or not, are included within the scope of the present invention.

[0134] In one embodiment, the compound disclosed herein is 1 Some or all of the H atoms 2 It is substituted with a hydrogen atom. Methods for synthesizing deuterium-containing compounds are known in this field, and include, as merely non-limiting examples, the following synthesis methods.

[0135] Deuterium-substituted compounds are synthesized using various methods, including those 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, 110 pp; 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.

[0136] Deuterated starting materials are readily available and are attached to the synthetic methods described herein for the synthesis of deuterium-containing compounds. Numerous deuterium-containing reagents and components are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0137] The cyclic peptides disclosed herein include, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of these compounds, as well as crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts and active metabolites of these compounds having the same type of activity, and mixtures thereof.

[0138] The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomers. The compounds shown herein include all diastereomers, enantiomers, and epimers, as well as suitable mixtures thereof. Separation of stereoisomers may be performed by chromatography, by forming diastereomers and separating them by recrystallization or chromatography, or by any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, incorporated herein by reference). Stereoiomers may also be obtained by stereoselective synthesis.

[0139] The methods and compositions described herein also 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 included within the scope of the present invention. Furthermore, the compounds described herein can exist in non-solvated and solvated forms with pharmaceutically acceptable solvents such as water and ethanol. The compounds shown herein in solvated forms are also considered to be disclosed herein.

[0140] The synthetic chemical transformations and methods useful for the synthesis of the compounds described herein are known in this field, including, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); TW Greene and PGM Wuts, 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).

[0141] The isolation and purification of the chemical substances and intermediates described herein may be carried out by any suitable separation or purification method, as desired, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography, or thick-layer chromatography, or a combination thereof. For specific procedures of suitable separation and isolation methods, please refer to the examples below. However, other equivalent separation or isolation methods may also be used.

[0142] The present invention is also intended to include in vivo metabolites of the disclosed compounds. Such products may, for example, originate from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, mainly by enzymatic treatment. Accordingly, the present invention includes compounds produced by a method comprising administering the compounds of the present invention to a mammal for a sufficient time to produce its metabolites. Such products are generally identified by administering the radiolabeled compounds of the present invention to an animal such as a rat, mouse, guinea pig, monkey, or human in a detectable dose to induce sufficient time for metabolism, and then isolating the conversion products from urine, blood, or other biological samples.

[0143] Pharmaceutical preparations The cyclic peptide of the present invention is formulated into some suitable pharmaceutical formulation. The pharmaceutical formulation of the present invention generally includes, but is not limited to, an active ingredient (e.g., the cyclic peptide disclosed herein) and one or more pharmaceutically acceptable additives or carriers, including inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants. In some embodiments, the pharmaceutically acceptable carrier or additive is selected from water, alcohol, glycerol, chitosan, alginic acid, chondroitin, vitamin E, mineral oil and dimethyl sulfoxide (DMSO).

[0144] Pharmaceutical formulations are provided in some appropriate form determined based on the route of administration. In one embodiment, the pharmaceutical composition disclosed herein may be formulated into a dosage form for administration to a subject. In one embodiment, the pharmaceutical composition is formulated for oral, intravenous, intra-arterial, aerosol, non-enteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and / or intraperitoneal administration. In one embodiment, the dosage form is formulated for oral administration. For example, the pharmaceutical composition may be formulated in the form of pills, tablets, capsules, inhalers, liquid suspensions, liquid emulsions, gels, or powders. In one embodiment, the pharmaceutical composition may be formulated as a unit dose in liquid, gel, semi-liquid, semi-solid, or solid form.

[0145] The amount of each cyclic peptide administered depends on the mammal being treated, the severity of the disorder or condition, the administration rate, the pharmacokinetics of the cyclic peptide, and the prescribing physician's judgment. In one embodiment, an effective dose is provided by pulse administration (i.e., administration of the compound for several days, followed by several days of rest).

[0146] In one embodiment, the present invention provides an orally administered pharmaceutical composition comprising at least one cyclic peptide disclosed herein and a pharmaceutical additive suitable for oral administration. The composition is in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In one embodiment, the composition further comprises a second agent.

[0147] In one embodiment, the present invention provides an orally administered solid pharmaceutical composition comprising (i) a cyclic peptide disclosed herein; and (ii) a pharmaceutical additive suitable for oral administration. In one embodiment, the composition further comprises (iii) a third or even a fourth agent. In one embodiment, each compound or agent is present in a therapeutically effective amount. In another embodiment, one or more compounds or agents are present in amounts less than or equal to a therapeutic amount, and the compounds or agents synergistically provide a therapeutically effective pharmaceutical composition.

[0148] The pharmaceutical compositions of the present invention, suitable for oral administration, may exist in individual dosage forms such as hard or soft capsules, cachets, lozenges, tablets, or liquids or aerosol sprays containing a predetermined amount of the active ingredient in powder or granule form, as well as as liquids or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil emulsions, or as dispersible powders or granules, syrups, or elixirs. Such dosage forms can generally be prepared by any compounding method that includes a step of binding the active ingredient to a carrier. Generally, compositions are prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a micronized solid carrier or both, and then, if necessary, molding the product into the desired form. For example, tablets may be prepared by compression or casting with one or more auxiliary ingredients, if desired. Compressed tablets can be prepared by mixing an active ingredient in a free-flowing form, such as powder or granules, with additives, optionally including but not limited to binders, lubricants, inert diluents, and / or surface-active or dispersing agents, and compressing the mixture in a suitable machine. Wet-molded tablets can be prepared by molding a mixture of powdered cyclic peptides moistened with an inert liquid diluent in a suitable machine.

[0149] In one embodiment, the present invention provides an injectable pharmaceutical composition comprising a cyclic peptide and a pharmaceutical additive suitable for injection, as disclosed herein. The amounts of the components and drugs in the composition are as described herein.

[0150] In one embodiment, the forms containing the cyclic peptides disclosed herein for administration by injection include aqueous or oil suspensions or emulsions using sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical media.

[0151] Aqueous solutions in saline solution are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Adequate fluidity is maintained, for example, by the use of coatings such as lecithin to maintain the required particle size in the case of dispersions, and by the use of surfactants. Microbial activity can be prevented by the use of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

[0152] Sterile injectable solutions are prepared by placing the required amount of the cyclic peptide disclosed herein into a suitable solvent containing various other components as listed above, as needed, and then sterilizing by filtration. Generally, dispersions are prepared by placing various sterile active ingredients into a sterile medium containing a basic dispersion medium and other necessary components from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, a preferred method of preparation is vacuum drying and freeze-drying, which produce a powder of the active ingredient and any additional desired components from a pre-filtered solution.

[0153] The pharmaceutical composition may also be prepared from the cyclic peptide described herein and one or more pharmaceutically acceptable additives suitable for transdermal, inhalation, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intrathecal administration. The preparation of such pharmaceutical compositions is well known in the art. 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 Drug Action, 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 (The Pharmaceutical Press, London, 1999).

[0154] The present invention also provides kits. A kit may comprise the cyclic peptide disclosed herein and one or more further agents in appropriate packaging, along with documentation that may include instructions for use, details of clinical trials, side effects, etc. Such a kit may also include information such as relevant literature, package inserts, clinical trial results, and / or summaries thereof, which demonstrate or prove the activity and / or benefits of the composition and / or describe dosing, administration, side effects, drug interactions, or other information useful to healthcare providers. Such information may be obtained from the results of various studies, e.g., studies using experimental animals, including in vivo models, and studies based on human clinical trials. The kit may further comprise other agents. In some embodiments, the cyclic peptide and agent disclosed herein are provided as separate compositions in separate containers within the kit. In some embodiments, the cyclic peptide and agent disclosed herein are provided as a single composition within the kit. Appropriate packaging and further equipment (e.g., measuring cups for liquid formulations, foil packaging to minimize exposure to air, etc.) are known in the art and may be included in the kit. The kits described herein may be offered, marketed, and / or advertised to healthcare providers, including physicians, nurses, pharmacists, and pharmacy officials. In some embodiments, the kits may also be marketed directly to consumers.

[0155] How to use In one embodiment, the present invention provides a method for inhibiting MDM2, comprising administering the cyclic peptide described herein to a subject requiring such inhibition. In another embodiment, the present invention provides a method for inhibiting both MDM2 and MDM4, comprising administering the cyclic peptide described herein to a subject requiring such inhibition.

[0156] In other embodiments, the present invention provides a method for treating a disease or disorder in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the cyclic peptide described herein. In one embodiment, the method for treating the disease or disorder comprises administering to the subject an MDM2 inhibitor. In one embodiment, the method for treating the disease or disorder comprises administering to the subject an MDM2 / MDM4 dual inhibitor. In one embodiment, the cyclic peptide disclosed herein is an MDM2 inhibitor. In one embodiment, the cyclic peptide disclosed herein is an MDM2 / MDM4 dual inhibitor.

[0157] In one embodiment, the disease or disorder is cancer. In one embodiment, cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. In one embodiment, the disease or disorder is associated with the proliferation of senescent cells. In one embodiment, the disease or disorder associated with the proliferation of senescent cells is selected from type 2 diabetes, Huntington's disease, non-alcoholic fatty liver disease, and hyperlipidemia. In one embodiment, the disease or disorder associated with the proliferation of senescent cells is selected from cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, lung diseases, eye diseases, ear diseases, kidney diseases, and skin diseases.

[0158] In further embodiments, methods for treating cancerous conditions are disclosed herein, wherein the cyclic peptide disclosed herein (e.g., an MDM2 inhibitor or an MDM2 / MDM4 dual inhibitor) is effective in one or more ways of inhibiting the proliferation of cancer cells, inhibiting the metastasis of cancer cells, reducing the severity or incidence of symptoms associated with the presence of cancer cells, and promoting an immune response against tumor cells. In one embodiment, the method comprises administering a therapeutically effective amount of the cyclic peptide disclosed herein to cancer cells. In one embodiment, the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. In one embodiment, the cyclic peptide disclosed herein is an MDM2 inhibitor. In one embodiment, the cyclic peptide disclosed herein is an MDM2 / MDM4 dual inhibitor. In one embodiment, the administration is performed in vitro. In one embodiment, the administration is performed in vivo.

[0159] The therapeutically effective amount of the cyclic peptide disclosed herein as used herein means an amount sufficient to act for an intended application, including but not limited to disease treatment, as defined herein. Also considered in the manner of the subject is the use of a sub-therapeutic amount of the cyclic peptide disclosed herein for the treatment of an intended disease condition.

[0160] The amount of the cyclic peptide disclosed herein administered will vary depending on the intended application (in vitro or in vivo) or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, and the method of administration, which can be readily determined by those skilled in the art.

[0161] In one embodiment, therapeutic efficacy is measured based on the treatment effect on proliferative disorders such as cancer. Generally, in relation to the treatment of proliferative disorders (e.g., cancer, whether benign or malignant), the therapeutic efficacy of the methods and compositions disclosed herein may be measured by the extent to which the methods and compositions promote inhibition of tumor cell proliferation, inhibition of 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 therapeutic efficacy are described herein. The appropriate combination of parameters for a particular situation may be established by the physician. The progress of the methods disclosed herein in cancer treatment (e.g., tumor size reduction or cancer cell eradication) can be confirmed using any appropriate method, such as methods currently used in etiology to track tumor size and cancer progression. The primary efficacy parameter used to evaluate cancer treatment with the methods and compositions disclosed herein is preferably tumor size reduction. Tumor size can be quantified using any appropriate technique, such as tumor volume estimation using available computer software, such as the FreeFlight software developed by Wake Forest University, which allows for measurement of dimensions or accurate estimation of tumor volume. Tumor size can be measured by tumor visualization, such as using CT, ultrasound, SPECT, spiral CT, MRI, or photography. In embodiments where the tumor is surgically removed after the completion of the treatment period, the presence and size of tumor tissue may be determined by gross analysis of the tissue to be removed and / or pathological analysis of the removed tissue.

[0162] In a preferred embodiment, as a result of the methods and compositions disclosed herein, tumor growth is stabilized (i.e., one or more tumors do not increase in size by more than 1%, 5%, 10%, 15%, or 20% and / or metastasize). In a preferred embodiment, the tumor is stabilized for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or longer. In a preferred embodiment, the tumor is stabilized for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In a preferred embodiment, the tumor is stabilized for at least about 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years or longer. Preferably, the methods disclosed herein reduce the tumor size 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 eradicated or reduced to below the detection level. In one embodiment, 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 longer after treatment. In one embodiment, the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer after treatment. In one embodiment, the subjects remain tumor-free for at least approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more after treatment.

[0163] In one embodiment, the effectiveness of the method disclosed herein in reducing tumor size can be determined by measuring the percentage of necrotic (i.e., lethal) tissue of the surgically excised tumor after the completion of the treatment period. In a further embodiment, the treatment is effective if the percentage of necrotic tissue of the excised 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 more (e.g., about 90%, 95%, or 100%). Most preferably, the percentage of necrotic tissue of the excised tissue is 100%, i.e., tumor tissue is absent or undetectable.

[0164] The effectiveness 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 novel tumors, detection of tumor antigens or markers (e.g., CEA, PSA, or CA-125), biopsy, surgical progression reduction (i.e., conversion of tumor surgical progression from unresectable to resectable), PET scanning, survival, disease progression-free survival, time to disease progression, and quality of life assessments such as Clinical Benefit Response Assessment, all of which may indicate overall cancer progression (or regression) in humans. Biopsy is particularly useful for detecting the eradication of cancer cells in tissue. Radioimmunodetection (RAID) is used for tumor localization and staging using serum levels of tumor-produced and / or associated markers (antigens) ("tumor markers" or "tumor-associated antigens") and may be useful as a pre-treatment diagnostic predictor, a post-treatment diagnostic indicator of recurrence, and a post-treatment indicator of treatment effectiveness. Tumor markers or tumor-associated antigens that can be evaluated as indicators of therapeutic efficacy include, but are not limited to, carcinoembryonic embryo 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), sialyl 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 this field. RAID technology, combined with endoscopic detection systems, can also efficiently differentiate small tumors from surrounding tissue (see, for example, U.S. Patents 4,932,412).

[0165] In a further preferred embodiment, cancer treatment in a human patient by the method disclosed herein is demonstrated by one or more of the following results: (a) complete disappearance of the tumor (i.e., complete response), (b) a reduction of approximately 25% to approximately 50% in tumor size at least 4 weeks after completion of the treatment period compared to the tumor size before treatment, (c) a reduction of at least approximately 50% in tumor size at least 4 weeks after completion of the treatment period compared to the tumor size before treatment, and (d) a reduction of at least 2% (e.g., approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%) in specific tumor-associated antigen levels approximately 4 to 12 weeks after completion of the treatment period compared to the tumor-associated antigen levels before treatment. A reduction of at least 2% in tumor-associated antigen levels is preferred, but any reduction in tumor-associated antigen levels demonstrates cancer treatment in a patient by the method disclosed herein. For example, in unresectable, locally advanced pancreatic cancer, treatment can be demonstrated by at least a 10% reduction in CA19-9 tumor-associated antigen levels 4–12 weeks after completion of treatment compared to CA19-9 levels before treatment. Similarly, in locally advanced rectal cancer, treatment can be demonstrated by at least a 10% reduction in CEA tumor-associated antigen levels 4–12 weeks after completion of treatment compared to CEA levels before treatment.

[0166] Regarding quality of life assessments such as Clinical Benefit Response Criteria, the therapeutic benefit of the procedure according to the present invention can be demonstrated by pain intensity, analgesic consumption, and / or Karnovski's Performance Scale score. In human patients, cancer treatment is demonstrated separately or in addition to the following: (a) a reduction of at least 50% in patient-reported pain intensity compared to pain intensity reported by the patient before treatment, for any four consecutive weeks within a 12-week period after treatment completion (e.g., a reduction of at least 60%, 70%, 80%, 90%, or 100%); (b) a reduction of at least 50% in patient-reported analgesic consumption compared to analgesic consumption reported by the patient before treatment, for any four consecutive weeks within a 12-week period after treatment completion (e.g., a reduction of at least 60%, 70%, 80%, 90%, or 100%); and / or (c) an increase of at least 20 points in patient-reported Karnovski performance scale score compared to Karnovski performance scale score reported by the patient before treatment, for any four consecutive weeks within a 12-week period after treatment completion (e.g., an increase of at least 30, 50, 70, or 90 points).

[0167] Treatment of proliferative disorders in human patients (e.g., cancer, whether benign or malignant) is preferably demonstrated by one or more of the results described above (any combination thereof), but other or additional results from the described studies and / or other studies may demonstrate the effectiveness of the treatment.

[0168] In one embodiment, tumor size is reduced as a result of the method disclosed herein, preferably without significant adverse events in the subject. Adverse events are classified or “staged” by the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP), where Grade 0 represents the least severe adverse side effect and Grade 4 represents the most severe adverse event. Preferably, the method disclosed herein results in the least severe adverse event, e.g., a Grade 0, Grade 1, or Grade 2 adverse event according to the CTEP / NCI stage. However, while reduction in tumor size is preferred as described herein, it is not necessary for the actual size of the tumor to be reduced, as it may not be reduced regardless of the eradication of tumor cells. Eradication of cancer cells is sufficient to achieve the therapeutic effect. Similarly, any reduction in tumor size is sufficient to achieve the therapeutic effect.

[0169] The detection, monitoring, and evaluation of various cancers in humans are further described in Cancer Facts and Figures 2001, American Cancer Society, New York, NY, and international patent application WO01 / 24684. Therefore, physicians can use standard tests to determine the effectiveness of various embodiments of the methods disclosed herein in cancer treatment. However, in addition to tumor size and spread, physicians may also consider the patient's quality of life and survival in evaluating the effectiveness of treatment.

[0170] In a certain embodiment, administration of the cyclic peptide disclosed herein improves therapeutic efficacy. The improvement in efficacy can be determined using any method known in the art, including but not limited to those described herein. In a certain embodiment, the improvement in therapeutic 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 an appropriate measure (e.g., tumor size reduction, tumor size stabilization period, metastatic event-free period, disease-free survival period). Improvements in efficacy can also be expressed as multipliers of improvement, such as at least approximately 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, 100x, 1000x, 10000x or more, using appropriate measures (e.g., tumor size reduction, duration of tumor size stability, duration of metastatic events, duration of disease-free survival).

[0171] Measuring the inhibition of the biological effects of MDM2 and / or MDM4 may involve performing assays on biological samples, such as samples from subjects. Any of the diverse samples may be selected depending on the assay. Examples of samples include, but are not limited to, blood samples (e.g., plasma or serum), exhaled condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0172] Subjects treated with the cyclic peptides disclosed herein may be monitored to determine the effectiveness of the treatment, and the treatment regimen may 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 exceeds or falls below a threshold, the dosage or frequency may be reduced or increased, respectively. The method may further include continuing the treatment if it is determined that the treatment is effective. The method may include maintaining, weakening, decreasing or discontinuing the dosage of the compound in the treatment if it is determined that the treatment is effective. The method may include increasing the dosage of the compound in the treatment if it is determined that the treatment is not effective. Alternatively, the method may include discontinuing the treatment if it is determined that the treatment is not effective. In some embodiments, treatment with the cyclic peptides disclosed herein is discontinued if the inhibition of the biological effect exceeds or falls below a threshold, such as a lack of response or adverse reaction. The biological effect may be a change in any of a variety of physiological indicators.

[0173] Generally, MDM2 inhibitors are compounds that inhibit one or more of the biological effects of MDM2. Examples of MDM2's biological effects include, but are not limited to, inhibition of p53 ubiquitination and p53 transcriptional activation. Such biological effects may be inhibited by approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.

[0174] Generally, MDM2 / MDM4 dual inhibitors are compounds that inhibit one or more of the biological effects of MDM2 and MDM4. Examples of the biological effects of MDM2 and MDM4 include, but are not limited to, inhibition of p53 ubiquitination and p53 transcriptional activation. Such biological effects may be inhibited by approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.

[0175] In some other embodiments, the methods of the subject of the present invention are useful for treating disease conditions associated with MDM2. Any disease condition directly or indirectly caused by abnormal activity or expression levels of MDM2 may be an intended disease condition. In some other embodiments, the methods of the subject of the present invention are useful for treating disease conditions associated with MDM2 and MDM4. Any disease condition directly or indirectly caused by abnormal activity or expression levels of MDM2 and MDM4 may be an intended disease condition. In some embodiments, the disease condition is a proliferative disorder described herein, including but not limited to cancer. In some embodiments, the disease condition is cancer. In some embodiments, cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myeloid leukemia.

[0176] In one embodiment, the compounds of the present invention are administered to treat conditions other than cancer. In one embodiment, the compounds of the present invention induce the lethality of senescent cells. In one embodiment, the induction of senescent cell lethality treats conditions associated with the proliferation of senescent cells. In one embodiment, the compounds of the present invention are administered to treat diseases or disorders associated with the proliferation of senescent cells. Examples of diseases or disorders 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.

[0177] Non-limited examples of cardiovascular diseases associated with the proliferation of senescent cells include, but are not limited to, atherosclerosis, angina pectoris, arrhythmias, cardiomyopathy, congestive heart failure, coronary artery disease, carotid artery disease, endocarditis, coronary thrombosis, myocardial infarction, hypertension, aortic aneurysm, cardiac diastolic dysfunction, hypercholesterolemia, hyperlipidemia, mitral valve prolapse, peripheral vascular disease, cardiac stress resistance, cardiofibrosis, cerebral aneurysm, and stroke.

[0178] Non-limited examples of inflammatory or autoimmune diseases associated with the proliferation of senescent cells include, but are not limited to, osteoarthritis, osteoporosis, inflammatory bowel disease, and herniated discs.

[0179] Non-limited examples of metabolic disorders associated with the proliferation of senescent cells include, but are not limited to, diabetes mellitus and metabolic syndrome.

[0180] Non-limited 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.

[0181] Non-exclusive examples of eye diseases include, but are not limited to, cataracts, macular degeneration, glaucoma, and keratoconus.

[0182] Non-limited examples of ear disorders associated with the proliferation of senescent cells include, but are not limited to, conductive hearing loss.

[0183] Non-limited examples of skin diseases associated with the proliferation of senescent cells include, but are not limited to, eczema, psoriasis, hyperpigmentation, impaired wound healing, alopecia, rashes, atopic dermatitis, urticaria, diseases and disorders associated with photosensitivity or photoaging, glabella, pruritus, dysesthesia, eczematous rash, eosinophilic dermatosis, reactive neutrophilic dermatosis, pemphigus, bullous pemphigoid, immunobullous dermatosis, fibrohistocytic proliferation of the skin, cutaneous lymphoma, and cutaneous lupus.

[0184] One embodiment intends a human subject, such as a subject diagnosed with having or being at risk of developing or acquiring a proliferative disorder. Another embodiment intends a non-human subject, such as a macaque, chimpanzee, gorilla, velvet monkey, orangutan, baboon, or other non-human primate, including non-human subjects that may be known in the art as preclinical models. Another embodiment intends a non-human subject that is a mammal, such as a mouse, rat, rabbit, pig, sheep, horse, cattle, goat, gerbil, hamster, guinea pig, or other mammal. Other embodiments also intend a subject or biological source that is a non-mammalian vertebrate, such as another higher vertebrate or a bird, amphibian, or reptile species or other subject or biological source. In one embodiment of the present invention, a transgenic animal is utilized. A transgenic animal is a non-human animal in which one or more of its cells are non-endogenous (i.e., heterogeneous) and contain nucleic acids that are present in the cell as extrachromosomal elements or integrated into its germline DNA (i.e., in most or all of the cell's genome sequence).

[0185] Combination therapy In one embodiment, disclosed herein is a method for further combination therapy, which, in addition to the cyclic peptide described herein, uses one or more secondary agents known to modulate other pathways, other components of the same pathway, or a group of overlapping target proteins. In one embodiment, such therapy includes, but is not limited to, a combination of a composition comprising the cyclic peptide described herein and one or more chemotherapeutic agents, therapeutic antibodies, immunotherapeutic agents, and radiotherapy to provide a synergistic or additive therapeutic effect, if desired.

[0186] In one embodiment, disclosed herein are methods and pharmaceutical compositions for inhibiting abnormal cell proliferation in mammals, comprising a combination of a certain amount of the cyclic peptide described herein and 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.

[0187] In one embodiment, disclosed herein is a method of using a combination of the cyclic peptide or pharmaceutical composition described herein with surgery, ionizing radiation, photodynamic therapy, or other tumor treatment approaches, including, for example, an implant used as a corticosteroid, hormone, or radiosensitizer. [Examples]

[0188] experiment Unless otherwise specified, all reagents were purchased from suppliers and used without further purification. Solvent drying by standard methods was used as needed. The following abbreviations are used in the experimental section: COMU = (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate; DBU = 1,8-diazabicyclo[5.4.0]undeca-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]pyridinium 3-oxoidhexafluorophosphate; HPLC = High-Performance Liquid Chromatography; MeOH = Methanol; N2 = Nitrogen Gas; 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 Double Minute 2 Homolog; HDM2 = Human Double Minute 2 Homolog; FAM = Fluorescein Amidite; MDM4 = Mouse Double Minute 4 Homolog; HDM4 = Human Double Minute 4 Homolog; FBS = Fetal Bovine Serum.

[0189] Cyclic peptide synthesis Step 1: Filling with 2-chlorotrityl resin Fmoc-Xaa (10 mmol) is processed in a vacuum desiccator using DrieRite. (登録商標) The mixture was dried overnight. The dried amino acids were dissolved in 50 mL of dried DCM containing 40 mmol of DIPEA dried with molecular sieves. The reaction mixture was subjected to ultrasonic treatment until Fmoc-Xaa was completely dissolved. 5 g of 2-chlorotrityl resin was added under a stream of N2, and the reaction mixture was shaken for 4 hours. The resin was treated with a 1:2:17 MeOH / DIPEA / DMF (15 mL) solution and shaken (3 × 15 mins). The resin was washed with DMF (3 × 15 mL), followed by DCM (3 × 15 mL). The degree of resin packing was calculated from UV quantification of Fmoc liberation after deprotection.

[0190] Step 2: Amino acid coupling Fmoc-Xaa (4 equivalents), DIPEA (6 equivalents), and HATU (3.8 equivalents) were added to the resin in DMF (2 mL), and the reaction mixture was shaken at room temperature for 1 hour. The resin was washed with DMF (3 × 3 mL), followed by DCM (3 × 3 mL).

[0191] Step 3: Fmoc deprotection on resin The resin was treated with a 20% 4-methyl-piperidine solution in DMF (3 mL) and shaken at room temperature for 20 minutes. Alternatively, the resin was treated with a 2% piperidine and 2% DBU solution in DMF (3 mL) and shaken twice for 10 minutes at room temperature. The resin was washed with DMF (3 × 3 mL) followed by DCM (3 × 3 mL).

[0192] Step 4: Peptoid coupling The resin was activated by shaking a 2:1 solution of 1 M bromoacetic acid / 0.5 M DIC in DMF for 20 minutes at room temperature. The resulting precipitate was allowed to settle, the supernatant was collected, and the deprotected resin was shaken with it at room temperature for 20 minutes. The resin was washed with DMF (3 × 3 mL) followed by DCM (3 × 3 mL). The resin was treated with a 1 M solution of amine in DMF and shaken at room temperature for 1 hour.

[0193] Step 5: Peptide cleavage To cleave the completed linear peptide, the resin was treated with 30% HFIP in 5 volumes of DCM and shaken for 1 hour. The resin was washed with 5 volumes of DCM. The resin was treated with 30% HFIP in 5 volumes of DCM and shaken for 30 minutes.

[0194] Step 6: Cyclization in COMU The dried linear peptide was dissolved in MeCN (2 mL) containing DIPEA (9 equivalents), and the resulting solution was added dropwise to a 1:10 MeCN / DCM solution containing COMU (4 equivalents) until the final concentration reached 1 mg of crude peptide / mL. The reaction mixture was monitored by LC-MS at room temperature for 16 hours, shaking until complete cyclization was achieved. The reaction mixture was concentrated under reduced pressure.

[0195] Step 7: Peptide Purification By-products of COMU cyclization were purified by mass-direction using a Waters HPLC system equipped with an Xbridge BEH C18 OBD 130Å 5μm, 10×250mm column, and eluted with H2O / MeCN modified with 0.1% FA. Peptide purity was analyzed by HPLC-MS using a Waters HPLC system equipped with a CORTECS T3 2.7μm 4.6×50 column and a Waters 3100 mass spectrometer, using a gradient with H2O / MeCN modified with 0.1% FA.

[0196] Fluorescence Polarization Assay 1 Human MDM2 (HDM2) 1-116 (20 μL) and FITC-labeled p53 (18-26) were distributed in 10 mM Tris, 50 mM NaCl, 0.01% Tween 20, and 1 mM DTT, pH 7.4, respectively, into opaque, black, 384-well plates. Compounds dissolved in DMSO were pin-transferred (approximately 200 nL) into the 384-well plates containing the MDM2 / p53 solution. After 10 minutes of incubation, fluorescence polarization was read using a Molecular Devices SpectraMax plate reader equipped with a Fluorescein FP cartridge. In addition to probe alone (positive control) and probe / MDM2 (negative control), titrated linear p53 (18-26) was included in all plates as an additional control. IC 50 The values ​​were fitted using Prism or Collaborative Drug Discovery.

[0197] Fluorescence Polarization Assay 2 50 nM and 10 nM human MDM2 (HDM2) 1-116 (20 μL) and FAM-labeled RFMDYWEGL-NH2 were partitioned into 10 mM Tris, 50 mM NaCl, 0.01% Tween 20, and 1 mM DTT, pH 7.4, respectively, into opaque, black, 384-well plates. Compounds dissolved in DMSO were pin-transferred (approximately 100-200 nL) into the 384-well plates containing the MDM2 / p53 solution. After 60 minutes of incubation, fluorescence polarization was read using a Molecular Devices SpectraMax plate reader equipped with a Fluorescein FP cartridge. In addition to probe alone (positive control) and probe / MDM2 (negative control), titrated linear p53 (18-26) was included in all plates as a further control. IC 50 The values ​​were fitted using Prism or Collaborative Drug Discovery.

[0198] Fluorescence Polarization Assay 2 Human MDM4 (HDM4) 1-114 (20 μL) and FAM-labeled RFMDYWEGL-NH2 (100 nM and 10 nM respectively) were distributed into 10 mM Tris, 50 mM NaCl, 0.01% Tween 20, and 1 mM DTT, pH 7.4, into opaque, black, 384-well plates. Compounds dissolved in DMSO were pin-transferred (approximately 100-200 nL) into 384-well plates containing MDM4 / p53 solution. After 60 minutes of incubation, fluorescence polarization was read using a Molecular Devices SpectraMax plate reader equipped with a Fluorescein FP cartridge. In addition to probe alone (positive control) and probe / MDM4 (negative control), titrated linear p53 (18-26) was included in all plates as a further control. IC 50 The values ​​were fitted using Prism or Collaborative Drug Discovery.

[0199] Cell fluorescence assay MOLM-13 cells were grown in a T75 flask in a suspension of RPMI medium supplemented with 10% fetal bovine serum (FBS) at 37°C under 5% CO2. 40 μL of MOLM-13 cells were seeded at a density of 1,500 cells / well in 10% FBS-supplemented RPMI medium into columns 1-22 of a black, clear-bottom, 384-well plate. Columns 23 and 24 were filled with 40 μL of medium as positive controls. Compounds dissolved in 100 nL of DMSO were pin-transferred into columns 3-22 of the 384-well plate. Columns 1 and 2 served as negative control wells. The plates were incubated for 72 hours at 37°C under 5% CO2. After incubation, cells were added to 10 μL of 2 mM resazurin in 10% FBS-supplemented RPMI medium and incubated for 3 hours. The fluorescence intensity was read using a Molecular Devices SpectraMax i3x plate reader (excitation wavelength = 535 nm, emission wavelength = 585 nm).

[0200] Parallel membrane permeability assay (PAMPA) A 96-well donor plate and a 96-well Teflon acceptor plate with a 0.45 μm hydrophobic Immobilon-P membrane support (Millipore) are used for the permeabilization assay. Donor wells are prepared by triplicating 150 μL of each cyclic peptide solution (10 μM in 5% DMSO / PBS, pH 7.4) into each well. A 1% (w / v) solution of lecithin in dodecane is prepared before use and subjected to ultrasonic treatment for 5 minutes. 5 μL of the dodecane lecithin solution is applied to the membrane support in the wells of the donor plate. The acceptor plate is prepared by adding 300 μL of 5% DMSO / PBS (pH 7.4) to each well. The donor plate is then placed on top of the acceptor plate so that the artificial membrane is in contact with the bottom of the buffer solution. The donor wells are covered, the system is covered with a glass evaporating dish, and left at room temperature for 10 hours. Place a damp paper towel inside the chamber to prevent evaporation.

[0201] Once the assay is complete, 100 μL from the donor and acceptor wells are dispensed into a 96-well sample plate and sealed. The samples are analyzed using a SIM-mode LC / MS detector, and the acceptor and donor concentrations are expressed as integrals under the m / z curve corresponding to the ESI+ mode (exact mass + protons) or the ESI- mode (exact mass - protons).

[0202] Using LC / MS peak integral, retain (E R Calculate the adjusted equilibrium value for ): E R =(P A V A +P D V D ) / (V A +V D ) Here, P A This is the peak integral of the acceptor, and V A The volume of the acceptor (cm³) 3 ) and P D This is the donor sample versus the standard peak, V D This is the volume of the donor tissue.

[0203] Calculate the transmittance percentage (%T) for each sample: %T=(P A / E R ) × 100 And the %T value is the time-independent Pe value: Pe=[(V A ×V D ) / (V0×A×t)]×ln(1-(%T / 100)) Convert to this, where V0 is the total volume (cm³). 3 ) and A is the accessible filter area of ​​the membrane (0.24 cm²). 2 ) where t is the incubation time (s). The mean %T and Pe values ​​are calculated for each compound from at least 3 data points, excluding excessively outlier permeability values. The standard deviation is calculated for the mean. Percent recovery is E R Therefore, for the sake of calculation, we assume there is no compound loss.

[0204] MOLM-13 mouse hybridization model 110 female nu / nu mice were given MOLM-13 cells (200 μL 1:1 PBS / Matrigel, 5 × 10⁶ cells). -6 The cells (or animal) were subcutaneously injected into the lower left flank. Mice were divided into eight treatment groups and administered the media specified in Table 1 (5% ethanol, 12.5% ​​Solutol HS, 12.5% ​​PEG300, and 70% 50 mM PBS), idasanuturin, or compound 35. [Table 1]

[0205] Mice were monitored for two weeks. Figure 1 shows the mean tumor volume change over time for intravenous compound 35 pair media. Figure 2 shows the tumor volume on day 13 after treatment with intravenous compound 35 pair media. Figure 3 shows the tumor volume change over time for each mouse treated with intravenous compound 35. Figure 4 shows the change in body weight over time for each mouse treated with intravenous compound 35.

[0206] Pharmacokinetic parameters of compound 35 Mice were intravenously treated with compound 35 (1 mg / kg), and plasma was collected at various time points to determine pharmacokinetic parameters. The mean plasma concentration changes over time are shown in Figure 5, and all obtained pharmacokinetic parameters are summarized in Table 2. [Table 2]

[0207] In one embodiment, the cyclic peptide described herein is the cyclic peptide shown in Table 3. [Table 3-1] [Table 3-2] [Table 3-3] *:A<1.0μM;1.0μM≦B<2.5μM;2.5μM≦C<5.0μM;5.0μM≦D **: SMILES string created from chemical structures in ChemDraw version 19.1.

[0208] In one embodiment, the cyclic peptide described herein is the cyclic peptide shown in Table 4. [Table 4-1] [Table 4-2] * :A<25.0nM;25.0nM≦B<50.0nM;50.0nM≦C<100.0nM;100.0nM≦D ** :A<50.0nM;50.0nM≦B<100.0nM;100.0nM≦C<150.0nM;150.0nM≦D Furthermore, the present invention encompasses the following aspects. 1. Nine to eleven amino acid residues independently selected from uncharged amino acid residues at physiological pH; First and second beta hairpin regions A cyclic peptide containing, 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 -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle), wherein the monocyclic carbocycle and monocyclic heterocycle are independently and optionally substituted; and At least three amino acid residues containing a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl compounds. Characterized by one of the following: Cyclic peptide. 2. The cyclic peptide of item 1, wherein the first beta-hairpin region contains two consecutive amino acid residues. 3. The first beta-hairpin region comprises two consecutive residues independently selected from L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe, and D-NMe-Val, where the phenyl group of L-NMe-Phe is -Hallo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide according to item 2, optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 4. The first beta-hairpin region comprises two consecutive residues independently selected from L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe, and D-NMe-Val, where the phenyl group of L-NMe-Phe is -Hallo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4A cyclic peptide of item 2 or 3, optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 5. The cyclic peptide of item 4, wherein the first beta-hairpin region comprises two consecutive residues independently selected from L-Pro, D-Pro, L-Aze, D-Pip, and D-NMe-Val. 6. The cyclic peptide described in item 5, where one of the two consecutive residues is D and the other is L. 7. The cyclic peptide of item 6, wherein the two consecutive amino acid residues are D-Pro and L-Pro. 8. The cyclic peptide of item 6, wherein the two consecutive amino acid residues are D-NMe-Val and L-Pro. 9. The two consecutive amino acid residues are D-Pro and L-NMe-Phe, where the phenyl group of L-NMe-Phe is -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide according to item 6, optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 10. The two consecutive amino acid residues are D-Pro and L-NMe-Phe, where the phenyl group of L-NMe-Phe is -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide of item 9, optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. 11. A cyclic peptide from any of items 1-10, wherein the second beta-hairpin region contains a second pair of consecutive amino acid residues. 12. The cyclic peptide of item 11, wherein the second beta-hairpin region comprises a second pair of residues independently selected from D-Pro, peptoid, DN-alkylated amino acids, and LN-alkylated amino acids. 13. The cyclic peptide of item 12, wherein the second beta-hairpin region comprises a second pair of residues independently selected from D-Pro, peptoid, and LN-alkylated amino acids. 14. The cyclic peptide of item 13, wherein the second pair of consecutive residues consists of a peptoid and an LN-alkylated amino acid. 15. The cyclic peptide of item 14, wherein the second pair of consecutive residues consists of L-NMe-Ala and N-(2-methoxyethyl)glycine. 16. The cyclic peptide of item 12, wherein the second pair of consecutive residues consists of one DN-alkylated amino acid and the other LN-alkylated amino acid. 17. The cyclic peptide of item 16, wherein the second pair of consecutive residues consists of one D-NMe-Ala and the other L-NMe-Ala. 18. The cyclic peptide of item 13, wherein one of the second pair of consecutive residues is a DN-alkylated amino acid and the other is a peptoid. 19. The cyclic peptide of item 18, wherein the second pair of consecutive residues consists of D-NMe-Ala and N-(2-methoxyethyl)glycine. 20. A cyclic peptide from any of items 1-19, wherein at least two consecutive amino acids separate the first beta-hairpin region from the second beta-hairpin region. 21. The cyclic peptide of item 20, wherein at least three consecutive amino acids separate the first beta-hairpin region from the second beta-hairpin region. 22. A cyclic peptide from any of items 1 to 21, having a molecular weight of 800 to 1300 Da. 23. The cyclic peptide of item 22, wherein the molecular weight of the cyclic peptide is 800-1200 Da. 24. The cyclic peptide of item 23, wherein the molecular weight of the cyclic peptide is 900-1200 Da. 25. A cyclic peptide according to any of items 1 to 24, comprising a ring independently selected from optionally substituted monocyclic carbocyclic rings and optionally substituted monocyclic heterocyclic rings, characterized by at least four amino acid residues in which at least one of the monocyclic carbocyclic rings and monocyclic heterocyclic rings is substituted. 26. The optionally substituted monocyclic carbocyclic ring is phenyl, and the optionally substituted monocyclic heterocyclic ring is a heteroaryl ring, where at least one phenyl or heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide of item 25, substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 27. The optionally substituted monocyclic carbocyclic ring is phenyl, and the optionally substituted monocyclic heterocyclic ring is a heteroaryl ring, where at least one phenyl or heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide of item 25 or 26, substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. 28. A cyclic peptide of any of items 25-27, wherein the optionally substituted monocyclic carbocyclic ring is phenyl, and the optionally substituted monocyclic heterocyclic ring is a heteroaryl ring, where at least one phenyl or heteroaryl ring is substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. 29. A cyclic peptide from any of items 25-28, independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, in which each heteroaryl ring may be substituted. 30. A cyclic peptide of any of items 1 to 24, characterized by at least four amino acid residues having a side chain selected from -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle), wherein the monocyclic carbocycle and monocyclic heterocycle are independently or optionally substituted. 31. A cyclic peptide of item 30, wherein each of at least four amino acids having side chains selected from -alkylene-(optionally substituted monocyclic carbon rings) and -alkylene-(optionally substituted monocyclic heterocycles) is not adjacent to one another. 32. A cyclic peptide of item 30 or 31, having side chains selected from -alkylene-(optionally substituted monocyclic carbon rings) and -alkylene-(optionally substituted monocyclic heterocycles), wherein two of at least four amino acids are adjacent to each other. 33. Each monocyclic carbocyclic ring is phenyl, and each monocyclic heterocyclic ring is a heteroaryl ring, where each phenyl and heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide of any of items 30-32, independently or optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 34. Each monocyclic carbocyclic ring is phenyl, and each monocyclic heterocyclic ring is a heteroaryl ring, where each phenyl and heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide of any of items 30-33, independently or optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. 35. A cyclic peptide of any of items 30-34, wherein each monocyclic carbocyclic ring is phenyl and each monocyclic heterocyclic ring is a heteroaryl ring, where each phenyl and heteroaryl ring is independently and optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. 36. A cyclic peptide of any of items 30-35, wherein each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, and each of these rings is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. 37. A cyclic peptide of any of items 1 to 24, characterized by at least three amino acid residues comprising a ring independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl. 38. Each phenyl and heteroaryl ring is a halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide of item 37, independently and optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 39. Each phenyl and heteroaryl ring is a halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide according to item 37 or 38, independently and optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. 40. A cyclic peptide of any of items 37-39, wherein each phenyl and heteroaryl ring is independently and optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. 41. A cyclic peptide of any of items 37-40, wherein each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, and each of these rings is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. 42. A cyclic peptide from any of items 1 to 41, wherein at least three of the main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. 43. The cyclic peptide of item 42, wherein four or five of the main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. 44. The cyclic peptide of item 43, wherein four of the main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. 45. The cyclic peptide of item 43, wherein five of the main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen atoms. 46. ​​A cyclic peptide of any of items 42-45, wherein one or more tertiary main chain nitrogen atoms are part of a heterocycloalkyl ring. 47. Having a C1-C6 alkyl substituent in which one or more tertiary nitrogen atoms are substituted by independently selected tertiary nitrogen atoms, where the substituents of the C1-C6 alkyl atoms are halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide of any of items 42-46, independently selected from alkyl, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 48. Having a C1-C6 alkyl substituent in which one or more tertiary nitrogen atoms are substituted by independently selected tertiary nitrogen atoms, where the substituents of the C1-C6 alkyl atoms are halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A cyclic peptide of any of items 42-47, independently selected from alkyl, -OBz, -OCH3, -OCF3, and -OCHF2. 49. A cyclic peptide of any of items 42-48, having a C1-C6 alkyl substituent in which one or more tertiary nitrogen atoms are substituted by independently selected tertiary nitrogen atoms, wherein the substituents of the C1-C6 alkyl atoms are independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2. 50. Each tertiary nitrogen independently [ka] It is expressed as follows, where R A -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 A C1-C6 alkyl group optionally substituted with one or more substituents independently selected from alkyl, -OBz, -OCH3, -OCF3, and -OCHF2, where, [ka] A cyclic peptide from items 42-49, where represents a binding site to an adjacent amino acid residue. 51. Each tertiary nitrogen independently [ka] It is expressed as follows, where R A is a C1-C6 alkyl which is optionally substituted with one or more substituents independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2, where, [ka] A cyclic peptide from items 42-50, where represents a binding site to an adjacent amino acid residue. 52. A cyclic peptide from any of items 1 to 51, wherein the cyclic peptide has 10 amino acid residues. 53. Equation I: [ka] [During the ceremony, R 1 , R 6 and R 8 is hydrogen, -(C1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon ring and 3-10 membered heterorings are halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 2 is hydrogen and C 1-6 Selected from alkyl groups; R 3 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Selected from alkylenes (3-10 membered heterocycles), where C 3-8 The carbon ring and 3-10 membered heterorings are halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2; and C 1-4 Alkyl is halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 4 is hydrogen or C 1-4 Alkyl or R 4 and R 14 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 5 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4Selected from alkylenes (3-10 membered heterocycles), where C 3-8 The carbon ring and 3-10 membered heterorings are halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2; and C 1-4 Alkyl is halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2; or R 5 and R 15 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 7 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-6 Selected from alkyl or R 7 and R 17 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 9 is hydrogen or C 1-6 Alkyl or R 9 and R 19 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 10 is hydrogen or C 1-4 Alkyl or R 10 and R 20 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 11 , R 12 , R 13 , R 16 and R 18Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected independently of alkyl; R 14 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 14 and R 4 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 15 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 15 and R 5 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 17 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 17 and R 7 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 19 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 19 and R 9 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; and R 20 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 20 and R 10 It combines with the atoms in between to form a 4- to 7-membered heterocycloalkyl group. A cyclic peptide represented by any of the terms 1 to 52. 54. Equation I: [ka] [During the ceremony, R 1 , R 6 and R 8 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon ring and 3-10 membered heterorings are halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; R 2 is hydrogen and C 1-6 Selected from alkyl groups; R 3 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C3-8 (Carbon ring) and -(C 1-4 Selected from alkylenes (3-10 membered heterocycles), where C 3-8 The carbon ring and 3-10 membered heterorings are halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2; and C 1-4 Alkyl is halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2; R 4 is hydrogen or C 1-4 Alkyl or R 4 and R 14 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 5 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Selected from alkylenes (3-10 membered heterocycles), where C 3-8 The carbon ring and 3-10 membered heterorings are halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2; and C 1-4 Alkyl is halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; or R 5 and R 15 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R7 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-6 Selected from alkyl or R 7 and R 17 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 9 is hydrogen or C 1-6 Alkyl or R 9 and R 19 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 10 is hydrogen or C 1-4 Alkyl or R 10 and R 20 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 11 , R 12 , R 13 , R 16 and R 18 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected independently of alkyl; R 14 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 14 and R 4 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 15Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 15 and R 5 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 17 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 17 and R 7 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 19 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 19 and R 9 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; and R 20 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 20 and R 10 It combines with the atoms in between to form a 4- to 7-membered heterocycloalkyl group. A cyclic peptide represented by any of items 1 to 53. 55. Formula II: [ka] [During the ceremony, R 21 , R 23 , R 26 and R 28 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbocyclic ring and the 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 24 is hydrogen or C 1-4 Alkyl or R 24 and R 34 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R25 is hydrogen or C 1-4 Alkyl or R 25 and R 35 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 30 is hydrogen or C 1-4 Alkyl or R 30 and R 40 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 22 , R 27 and R 29 is hydrogen and C 1-6 Selected independently of alkyl; R 31 , R 32 , R 33 , R 36 and R 38 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4Selected independently of alkyl; R 37 and R 39 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected independently of alkyl; R 34 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected from alkyl or R 34 and R 24 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 35 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected from alkyl or R 35 and R 25 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; and R 40 C is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. 1-4 Selected from alkyl or R 40 and R 30 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group. A cyclic peptide represented by any of the terms 1 to 54. 56. Formula II: [ka] [During the ceremony, R 21 , R 23 , R 26 and R 28 is hydrogen, -(C 1-4 Alkylene)-(C 3-8(Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbocyclic rings and 3- to 10-membered heterocycles are optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; R 24 is hydrogen or C 1-4 Alkyl or R 24 and R 34 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R25 is hydrogen or C 1-4 Alkyl or R 25 and R 35 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 30 is hydrogen or C 1-4 Alkyl or R 30 and R 40 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 22 , R 27 and R 29 is hydrogen and C 1-6 Selected independently of alkyl; R 31 , R 32 , R 33 , R 36 and R 38 C is optionally substituted with hydrogen; and one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Selected independently of alkyl; R 37 and R 39 C is optionally substituted with hydrogen; and one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Selected independently of alkyl; R 34C is optionally substituted with hydrogen; and one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Selected from alkyl or R 34 and R 24 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; R 35 C is optionally substituted with hydrogen; and one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Selected from alkyl or R 35 and R 25 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group; and R 40 C is optionally substituted with hydrogen; and one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2. 1-4 Selected from alkyl or R 40 and R 30 It combines with the atoms in between to form a 5-7 member heterocycloalkyl group. A cyclic peptide represented by any of the terms 1 to 55. 57. R 31 , R 32 , R 33 , R 36 and R 38 A cyclic peptide of item 56, where each of the atoms is a hydrogen atom. 58. R 34 , R 35 , R 37 , R 39 and R 40 A cyclic peptide of item 56 or 57, wherein at least four of its atoms are not hydrogen. 59. R 34 , R 35 , R 37 , R 39 and R 40 A cyclic peptide of item 58, in which four of the atoms are not hydrogen. 60. R 34 , R 35 , R 37, R 39 and R 40 A cyclic peptide of item 58, where the hydrogen is not hydrogen. 61. R 24 and R 34 , R 25 and R 35 and R 30 and R 40 A cyclic peptide of any of items 56-60, wherein at least one of the atoms integrates with an intermediate atom to form a 5-7 membered heterocycloalkyl group. 62. R 24 and R 34 The cyclic peptide of item 61, represented by the combination of an intermediate atom and an intermediate atom to form a 5-6 member heterocycloalkyl group. 63. R 25 and R 35 The cyclic peptide of item 61, represented by the combination of an intermediate atom and an intermediate atom to form a 5-6 member heterocycloalkyl group. 64. R 37 , R 39 and R 40 A cyclic peptide of any of items 56-63, wherein each of is selected from methyl and methoxyethyl. 65. R 35 , R 37 , R 39 and R 40 A cyclic peptide of any of items 56-62 or 64, wherein each of is selected from methyl and methoxyethyl. 66. R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 Alkyl or R 30 and R 40 A cyclic peptide of any of terms 56-63, represented by the combination of an intermediate atom and an intermediate atom to form a 5-7 membered heterocycloalkyl group. 67. R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 A cyclic peptide of item 66, which is alkyl. 68. R 40 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 2-4 A cyclic peptide of item 66 or 67, which is alkyl. 69. R 39 C is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 1-4 A cyclic peptide that is alkyl, one of the peptides listed in items 56-63. 70. R 22 , R 27 and R 29 C 1-6 A cyclic peptide from any of items 56-69, independently selected from alkyl groups. 71. R 22 , R 27 and R 29 A cyclic peptide of item 70, wherein is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl. 72. R 21 , R 23 , R 26 and R 28 ga-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 A cyclic peptide of any of items 56-71, wherein a carbon ring and a 3- to 10-membered heteroring are optionally substituted. 73. R 21 , R 23 , R 26 and R 28 -CH2-(C 3-8 A cyclic peptide of item 72, independently selected from a carbon ring and a -CH2- (3-10 membered heterocycle). 74. R 21 , R 23 , R 26 and R 28A cyclic peptide of item 73 is independently selected from phenylmethyl and pyridinylmethyl, where phenyl and pyridinyl are optionally substituted. 75. R 21 , R 23 , R 26 and R 28 but [ka] A cyclic peptide of item 74, independently selected from the above. 76. Compound is of formula IIa: [ka] A cyclic peptide represented by any of the terms 56-75. 77. Compound is given by formula IIb: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ The compound is independently selected from optionally substituted phenyl compounds and optionally substituted five- or six-membered heteroaryl compounds. The cyclic peptide of item 76, represented by [the specified formula]. 78. Formula III: [ka] [During the ceremony, R 41 , R 45 , R 46 and R 48 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon ring and 3-10 membered heterorings are halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 42 is hydrogen and C 1-6 Selected from alkyl groups; R 43 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl groups; R 44 is hydrogen or C 1-4 Alkyl or R 44 and R 54 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 47 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-6 Selected from alkyl or R 47 and R 57 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 49 is hydrogen or C 1-6 Alkyl or R 49 and R 59 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 50 is hydrogen or C 1-4 Alkyl or R 50 and R 60 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 51 , R 53 , R 56 and R58 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected independently of alkyl; R 52 and R 55 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected independently of alkyl; R 54 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 54 and R 44 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 57 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 57 and R 47 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 59 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2.1-4 Selected from alkyl or R 59 and R 49 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 60 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 Selected from alkyl or R 60 and R 50 It combines with the atoms in between to form a 4- to 7-membered heterocycloalkyl group. A cyclic peptide represented by any of the terms 1 to 54. 79. Formula III: [ka] [During the ceremony, R 41 , R 45 , R 46 and R 48 is hydrogen, -(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 The carbon ring and 3-10 membered heterorings are halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 Optionally substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2; R 42 is hydrogen and C 1-6 Selected from alkyl groups; R 43 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl groups; R 44 is hydrogen or C 1-4 Alkyl or R 44 and R 54 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 47 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-6 Selected from alkyl or R 47 and R 57 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 49 is hydrogen or C 1-6 Alkyl or R 49 and R 59 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 50 is hydrogen or C 1-4 Alkyl or R 50 and R 60 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 51 , R 53 , R 56 and R 58 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected independently of alkyl; R 52 and R 55Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected independently of alkyl; R 54 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 54 and R 44 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 57 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 57 and R 47 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 59 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 59 and R 49 It combines with the atoms in between to form a 4-7 member heterocycloalkyl group; R 60 Hydrogen; and halos, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 1-4 Selected from alkyl or R 60 and R 50 It combines with the atoms in between to form a 4- to 7-membered heterocycloalkyl group. A cyclic peptide represented by any of the terms 1-54 or 78. 80. R 51 , R 53 , R 56 and R 58 A cyclic peptide of item 79, where each of the atoms is a hydrogen atom. 81. R 52 , R 54 , R 55 , R 57 , R 59 and R 60 A cyclic peptide of item 79 or 80, wherein at least four of its atoms are not hydrogen. 82. R 52 , R 54 , R 55 , R 57 , R 59 and R 60 A cyclic peptide of item 81, in which four of the atoms are not hydrogen. 83. R 52 , R 54 , R 55 , R 57 , R 59 and R 60 A cyclic peptide of item 81, where the hydrogen is not hydrogen. 84. R 44 and R 54 and R 50 and R 60 A cyclic peptide according to any of items 79-83, wherein at least one of the atoms integrates with an intermediate atom to form a 4-7 membered heterocycloalkyl group. 85. R 44 and R 54 A cyclic peptide of item 84, in which one atom integrates with the intermediate atom to form the intermediate atom. 86. R 55 , R 59 and R 60A cyclic peptide of any of items 79-85, wherein each of is selected from methyl, ethyl, and methoxyethyl. 87. R 52 , R 55 , R 59 and R 60 A cyclic peptide of any of items 79-86, each of which is selected from methyl, ethyl, and methoxyethyl. 88. R 60 ga halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C is optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 2-4 Alkyl or R 50 and R 60 A cyclic peptide of any of the terms 79-85, represented by the combination of an intermediate atom and an interlocking atom to form a 4-7 membered heterocycloalkyl group. 89. R 60 ga halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 Alkyl or R 50 and R 60 A cyclic peptide of any of the terms 79-85 or 88, represented by the combination of an intermediate atom and an intervening atom to form a 4-7 membered heterocycloalkyl group. 90. R 60 ga halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 A cyclic peptide of item 89, which is alkyl. 91. R 59 ga halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C optionally substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, and -OCHF2 2-4 A cyclic peptide that is alkyl, one of the compounds listed in items 79-85. 92. R 42 , R 47 and R 49 C 1-6 A cyclic peptide from any of items 79-91, independently selected from alkyl groups. 93. R 42 , R 47 and R 49 A cyclic peptide of item 92, wherein is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl. 94. R 41 , R 45 , R 46 and R 48 ga-(C 1-4 Alkylene)-(C 3-8 (Carbon ring) and -(C 1-4 Alkylene)-(3-10 membered heteroring) is independently selected, where C 3-8 A cyclic peptide of any of items 79-93, in which a carbon ring and a 3- to 10-membered heterocycle are optionally substituted. 95. R 41 , R 45 , R 46 and R 48 -CH2-(C 3-8 A cyclic peptide of item 94, independently selected from a carbon ring and a -CH2- (3- to 10-membered heterocycle). 96. R 41 , R 45 , R 46 and R 48 A cyclic peptide of item 95, wherein is independently selected from phenylmethyl, pyridinylmethyl, and thiazolylmethyl, where phenyl, pyridinyl, and thiazolyl are optionally substituted. 97. R 41 , R 45 , R 46 and R 48 but [ka] A cyclic peptide of item 96, independently selected from the above. 98. Compound is of formula IIIa: [ka] A cyclic peptide represented by any of the terms 79-97. 99. Compound is formula IIIb: [ka] [In the formula, R 41’ , R 45’ , R 46’ and R 48’ The compound is independently selected from optionally substituted phenyl compounds and optionally substituted five- or six-membered heteroaryl compounds. The cyclic peptide of item 98, represented by [the specified formula]. 100. The cyclic peptide of item 1, wherein the cyclic peptide is selected from those in Tables 3 and 4 or any pharmaceutically acceptable salt thereof. 101. A pharmaceutical composition comprising any cyclic peptide from items 1 to 100 and a pharmaceutically acceptable additive. 102. A method for inhibiting AMDM2, comprising administering any of the cyclic peptides of items 1 to 100 to a subject requiring such inhibition. 103. A method for inhibiting AMDM2 and MDM4, comprising administering any cyclic peptide of items 1 to 100 to a subject requiring such inhibition. 104. A method for treating a disease or disorder in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of any cyclic peptide from items 1 to 100. 105. The method of paragraph 104, where the disease or disorder is cancer. 106. The method of item 105, wherein the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. 107. The method of paragraph 104, wherein the disease or disorder is associated with the proliferation of senescent cells. 108. The method of item 107, wherein the disease or disorder associated with the proliferation of senescent cells is selected from cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, lung diseases, eye diseases, ear diseases, kidney diseases and skin diseases. 109. A method for inducing the death of senescent cells in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of any cyclic peptide from items 1 to 100.

Claims

1. A cyclic peptide or a pharmaceutically acceptable salt thereof comprising the structure shown by the SMILES String in the following table. Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7

2. A pharmaceutical composition comprising the cyclic peptide of claim 1 and a pharmaceutically acceptable additive.

3. a) Inhibition of MDM2; or b) Inhibition of MDM2 and MDM4 A pharmaceutical composition according to claim 2 for the purpose of [the specified purpose].

4. A pharmaceutical composition according to claim 2 for the treatment of a disease or disorder in a subject requiring treatment; A pharmaceutical composition wherein the disease or disorder is cancer; or the disease or disorder is associated with the proliferation of senescent cells, and the disease or disorder associated with the proliferation of senescent cells is selected from cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, lung diseases, eye diseases, ear diseases, kidney diseases, and skin diseases.

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