Cell-permeable cyclic peptides and uses thereof

Abstract

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

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 193,383, filed May 26, 2021, the disclosure of which is incorporated herein by reference in its entirety. Summary of the Invention

[0002] overview Disclosed herein, in certain embodiments, are compounds, pharmaceutical compositions comprising the compounds, and the use of the compounds in disease treatment.Furthermore, the present invention relates to cyclic peptides, compositions, and uses thereof useful as MDM2 or dual MDM2 / MDM4 inhibitors in the treatment of diseases such as cancer.Furthermore, the present invention relates to cyclic peptides, compositions, and uses thereof useful as MDM2 or dual MDM2 / MDM4 inhibitors for inducing cell death of senescent cells, particularly for the treatment of diseases or disorders associated with the proliferation of senescent cells.

[0003] In one aspect, the present invention provides a method for producing a pharmaceutical composition comprising: 9 to 11 amino acid residues independently selected from amino acid residues that are uncharged at physiological pH; the first and second beta hairpin regions; at least one amino acid residue having a side chain containing a moiety selected from ether, ester, carbonate, amide, carbamate, and urea; and the following: at least four amino acid residues comprising rings independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles, wherein at least one of the monocyclic carbocycles and monocyclic heterocycles is substituted; at least 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 optionally substituted; and at least three amino acid residues containing rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl; The present invention provides a cyclic peptide, characterized by one of the following:

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

[0005] In some embodiments, the second beta hairpin region comprises a second two consecutive amino acid residues. In some embodiments, the second beta hairpin region comprises a second two consecutive residues independently selected from D-Pro, peptoids (e.g., sarcosine, N-isopropylglycine, N-benzylglycine, N-2-(methoxyethyl)glycine, etc.), DN-alkylated amino acids, and LN-alkylated amino acids. In some embodiments, the second beta hairpin region comprises a second two consecutive residues independently selected from D-Pro, peptoids, and LN-alkylated amino acids. In some embodiments, for the second two consecutive residues, one is a peptoid and the other is an LN-alkylated amino acid. In some embodiments, for the second two consecutive residues, one is L-NMe-Ala and the other is N-(2-methoxyethyl)glycine. In some embodiments, for the second two consecutive residues, one is a DN-alkylated amino acid and the other is an LN-alkylated amino acid. In some embodiments, for the second two consecutive residues, one is D-NMe-Ala and the other is L-NMe-Ala. In some embodiments, for the second two consecutive residues, one is a D-NMe-alkylated amino acid and the other is a peptoid. In some embodiments, for the second two consecutive residues, one is D-NMe-Ala and the other is N-(2-methoxyethyl)glycine.

[0006] In some embodiments, at least two contiguous amino acids separate the first and second beta hairpin regions, hi some embodiments, at least three contiguous amino acids separate the first and second beta hairpin regions.

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

[0008] In some embodiments, the cyclic peptide is characterized by at least four amino acid residues, comprising rings independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles, where at least one of the monocyclic carbocycles and monocyclic heterocycles is substituted. In some embodiments, the optionally substituted monocyclic carbocycles are phenyl and the optionally substituted monocyclic heterocycles are heteroaryl rings, where at least one of the phenyl or heteroaryl rings is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -CH3, -CH4, -CH5, -CH6, -CH7, -CH8, -CH9, -CH10, -CH11, -CH12, -CH13, -CH14, -CH15, -CH20, -CH30, -CH40, -CH50, -CH60, -CH70, -CH80, -CH90, -CH100, -CH110, -CH120, -CH130, -CH140, -CH150, -CH160, -CH170, -CH180, -CH190, -CH20, -CH30, -CH190, -CH100, -CH110, -CH120, -CH130, -CH140, -CH150, -CH160, -CH170, -CH180, -CH190, -CH190, -CH10 ... 1-4 It is substituted by one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. In some embodiments, the optionally substituted monocyclic carbocycle is a phenyl and the optionally substituted monocyclic heterocycle is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is substituted by one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole and imidazole, any of which may be substituted.

[0009] In some embodiments, the cyclic peptide is characterized by at least four amino acid residues with side chains selected from -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle), where the monocyclic carbocycle and the monocyclic heterocycle are independently optionally substituted.In some embodiments, each of the at least four amino acids with side chains selected from -alkylene-(optionally substituted monocyclic carbocycle) and -alkylene-(optionally substituted monocyclic heterocycle) are not adjacent to each other.In some embodiments, two of the at least four amino acids with side chains selected from -alkylene-(optionally substituted monocyclic carbocycle) and -alkylene-(optionally substituted monocyclic heterocycle) are adjacent to each other. In certain embodiments, each monocyclic carbocycle is a phenyl and each monocyclic heterocycle is a heteroaryl ring, wherein each phenyl and heteroaryl ring is independently optionally selected from halo, -SCH, -SOCH, -SOCH, -OH, -CN, -NO, -C 1-4 In some embodiments, each monocyclic carbocycle is phenyl and each monocyclic heterocycle is a heteroaryl ring, wherein each phenyl and heteroaryl ring is independently optionally substituted with one or more substituents independently selected from halo, -CH, -CF, -CHF, -OBz, -OCH, -OCF, and -OCHF. In some 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, -CH, -CF, -CHF, -OBz, -OCH, -OCF, and -OCHF.

[0010] In some embodiments, the cyclic peptide is characterized by at least three amino acid residues that contain rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl. In some embodiments, each phenyl and heteroaryl ring is independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 and 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 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, any of which is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2.

[0011] In some embodiments, at least three of the main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen. In some embodiments, four or five of the main chain nitrogen atoms are tertiary nitrogen. In some embodiments, four of the main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen. In some embodiments, five of the main chain nitrogen atoms of the cyclic peptide are tertiary nitrogen. In some embodiments, one or more of the tertiary main chain nitrogen atoms are part of a heterocycloalkyl ring. In some embodiments, one or more of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkyl ... 1-4In some embodiments, one or more of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected from each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each tertiary nitrogen is independently selected from [ka] or [ka] where R A is optionally halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C1-C6 alkyl substituted with one or more substituents independently selected from alkyl, -OBz, -OCH3, -OCF3 and -OCHF2, wherein [ka] indicates the point of attachment to the adjacent amino acid residue. In some embodiments, each tertiary nitrogen is independently [ka] or [ka] where R A is a C1-C6 alkyl optionally substituted with one or more substituents independently selected from halo, -OBz, -OCH3, -OCF3 and -OCHF2, where [ka] indicates the point of attachment to the adjacent amino acid residue.

[0012] In some embodiments, the cyclic peptide has 10 amino acid residues.

[0013] Provided herein, in another embodiment, is a cyclic peptide having Formula I: [ka] [During the ceremony, R 1 , R 3 and R 8 are independently hydrogen, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 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 each optionally is -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6Alkenyl and C 2-6 alkynyl; wherein the carbocycle and heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 2 and R 12 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 4 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; and 1-4 Alkyl is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 4 and R 14 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 5 is hydrogen or C 1-4 alkyl or R 5 and R 15 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 6 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; and 1-4 Alkyl is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 7 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 7 and R 17 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; 2 and R 7 at least one of which is not hydrogen or methyl; R 9 is hydrogen or C 1-4 alkyl or R 9 and R 19 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 10 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 10 and R 20 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 11 , R 13 , R 16 and R 18 are independently hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 12 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 12 and R 2 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 14 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 14 and R 4 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 15 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 15 and R 5 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 17 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 17 and R 7 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 19 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 19 and R 9 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 20 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 20 and R 10 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; and R 21is independently at each occurrence hydrogen; and each optionally represents halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 3-12 Carbocyclic ring, 3-12 membered heterocyclic ring, -O(C 1-10 alkyl), -O(C 2-10 alkenyl), -O(C 2-10 alkynyl), -O(C 3-8 C substituted with one or more substituents independently selected from -O(carbocyclic ring) and -O(3-10 membered heterocyclic ring) 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 is selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring. It is expressed by:

[0014] In one embodiment, the cyclic peptide has Formula II: [ka] [During the ceremony, R 21 , R 23 , R 26 and R 28 are independently hydrogen, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle 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 22 is hydrogen; and each optionally is -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl; wherein the carbocycle and heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 22 and R 32 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 24 is hydrogen or C 1-4 alkyl or R 24 and R 34 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 25 is hydrogen or C 1-4 alkyl or R 25 and R 35 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 27 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21)2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 27 and R 37 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; 22 and R 27 at least one of which is not hydrogen or methyl; R 29 is hydrogen or C 1-4 alkyl or R 29 and R 39 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 30 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 30 and R 40 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 31 , R 33 , R 36 and R 38 are independently hydrogen; and C optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl; R 32is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 32 and R 22 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 34 is hydrogen; and C optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl or R 34 and R 24 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 35 is hydrogen; and C optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl or R 35 and R 25 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 37 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 37 and R 27 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 39 is hydrogen; and C optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl or R 39 and R29 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 40 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 40 and R 30 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; and R 41 is independently at each occurrence hydrogen; and each optionally represents halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 3-12 Carbocyclic ring, 3-12 membered heterocyclic ring, -O(C 1-10 alkyl), -O(C 2-10 alkenyl), -O(C 2-10 alkynyl), -O(C 3-8 C substituted with one or more substituents independently selected from -O(carbocyclic ring) and -O(3-10 membered heterocyclic ring) 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 is selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring. It is expressed by:

[0015] In one embodiment, R 31 , R 33 , R 36 , R 37 and R 38 are each hydrogen.

[0016] In one embodiment, R 32 , R 34 , R 35 , R 39 and R 40At least four of R 32 , R 34 , R 35 , R 39 and R 40 In one embodiment, R 32 , R 34 , R 35 , R 39 and R 40 is not hydrogen.

[0017] In one embodiment, R 24 and R 34 , R 25 and R 35 and R 29 and R 39 At least one of R together with the intervening atoms forms a 5- to 7-membered heterocycloalkyl. 24 and R 34 and together with the intervening atoms form a 5- to 6-membered heterocycloalkyl. In some embodiments, R 25 and R 35 together with the atoms between them form a 5- to 6-membered heterocycloalkyl.

[0018] In one embodiment, R 32 , R 39 and R 40 Each of R is selected from methyl and methoxyethyl. 32 , R 34 , R 39 and R 40 Each of is selected from methyl and methoxyethyl.

[0019] In one embodiment, R 39 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; 2-4 alkyl or R 29 and R 39 and together with the intervening atoms form a 5- to 7-membered heterocycloalkyl. In some embodiments, R39 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; 2-4 It is an alkyl.

[0020] In one embodiment, R 40 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; 1-4 It is an alkyl.

[0021] In one embodiment, R 22 , R 27 and R 30 is independently C 1-6 In one embodiment, R 22 , R 27 and R 30 is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl.

[0022] In one embodiment, R 22 and R 27 is independently -C(O)R 41 , -C(O)N(R 41 )2, -N(R 41 )C(O)R 41 , -C(O)OR 41 , -OC(O)R 41 , -OC(O)N(R 41 )2, -N(R 41 )C(O)OR 41 , -OC(O)OR 41 and -N(R 41 )C(O)N(R 41 ) C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 22 HA-C(O)R 41 , -C(O)OR 41 , -OC(O)R 41 and -OC(O)OR 41C substituted with one or more substituents independently selected from 1-6 It is an alkyl.

[0023] In one embodiment, R 21 , R 23 , R 26 and R 28 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle and the 3- to 10-membered heterocycle are optionally substituted. In certain embodiments, R 21 , R 23 , R 26 and R 28 are independently -CH2-(C 3-8 In one embodiment, R 21 , R 23 , R 26 and R 28 is independently selected from phenylmethyl and pyridinylmethyl, where phenyl and pyridinyl are optionally substituted. In certain embodiments, R 21 , R 23 , R 26 and R 28 is independent [ka] is selected from.

[0024] In one embodiment, the cyclic peptide has the formula IIa: [ka] It is expressed by:

[0025] In one embodiment, the cyclic peptide has the formula IIb: [ka] [In the formula, R 21’ , R23’ , R 26’ and R 28’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0026] In some embodiments, the cyclic peptide has Formula III: [ka] [During the ceremony, R 41 , R 43 , R 44 and R 48 are independently hydrogen, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 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 each optionally is -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21)2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl; wherein the carbocycle and heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 42 and R 52 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 45 is hydrogen or C 1-4 alkyl or R 45 and R 55 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 46 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 47 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21, -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 47 and R 57 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; 42 and R 47 at least one of which is not hydrogen or methyl; R 49 is hydrogen or C 1-4 alkyl or R 49 and R 59 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 50 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 50 and R 60 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 51 , R 53 , R 56 and R 58 are independently hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 52 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 52and R 42 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 54 are independently hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 55 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 55 and R 45 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 57 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; or R 57 and R 47 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 59 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 59 and R 49 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 60is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 60 and R 50 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; and R 61 is independently at each occurrence hydrogen; and each optionally represents halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 3-12 Carbocyclic ring, 3-12 membered heterocyclic ring, -O(C 1-10 alkyl), -O(C 2-10 alkenyl), -O(C 2-10 alkynyl), -O(C 3-8 C substituted with one or more substituents independently selected from -O(carbocyclic ring) and -O(3-10 membered heterocyclic ring) 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 is selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring. It is expressed by:

[0027] In one embodiment, R 51 , R 53 , R 56 and R 58 are each hydrogen.

[0028] In one embodiment, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 At least four of R 52 , R 54 , R 55 , R57 , R 59 and R 60 In one embodiment, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 is not hydrogen.

[0029] In one embodiment, R 45 and R 55 and R 49 and R 59 At least one of R 1 , together with the intervening atoms, forms a 4- to 7-membered heterocycloalkyl. 45 and R 55 together with the atoms between them form a 4- to 6-membered heterocycloalkyl.

[0030] In one embodiment, R 54 , R 59 and R 60 Each of R is selected from methyl, ethyl, and methoxyethyl. 54 , R 57 , R 59 and R 60 Each of is selected from methyl, ethyl, and methoxyethyl.

[0031] In one embodiment, R 59 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 2-4 alkyl or R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 59 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2 2-4 It is an alkyl.

[0032] In one embodiment, R 60 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2 2-4 It is an alkyl.

[0033] In one embodiment, R 42 , R 47 and R 50 is independently C 1-6 In one embodiment, R 42 , R 47 and R 50 is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl.

[0034] In one embodiment, R 42 and R 47 is independently -C(O)R 61 , -C(O)N(R 61 )2, -N(R 61 )C(O)R 61 , -C(O)OR 61 , -OC(O)R 61 , -OC(O)N(R 61 )2, -N(R 61 )C(O)OR 61 , -OC(O)OR 61 and -N(R 61 )C(O)N(R 61 ) C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 42 HA-C(O)R 61 , -C(O)OR 61 , -OC(O)R 61 and -OC(O)OR61 C substituted with one or more substituents independently selected from 1-6 It is an alkyl.

[0035] In one embodiment, R 41 , R 43 , R 44 and R 48 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle and the 3- to 10-membered heterocycle are optionally substituted. In certain embodiments, R 41 , R 43 , R 44 and R 48 are independently -CH2-(C 3-8 In one embodiment, R 41 , R 43 , R 44 and R 48 is independently selected from phenylmethyl, pyridinylmethyl, and thiazolylmethyl, wherein phenyl, pyridinyl, and thiazolyl are optionally substituted. In certain embodiments, R 41 , R 43 , R 44 and R 48 is independent [ka] is selected from.

[0036] In one embodiment, the cyclic peptide has the formula IIIa: [ka] It is expressed by:

[0037] In one embodiment, the cyclic peptide has formula IIIb: [ka] [In the formula, R 41’ , R 43’ , R 44’ and R 48’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0038] In certain embodiments, the cyclic peptide is selected from those in Table 1 or a pharma- ceutically acceptable salt thereof.

[0039] In another aspect, the present invention provides a pharmaceutical composition comprising a cyclic peptide described herein and a pharma- ceutically acceptable excipient.

[0040] In another embodiment, the present invention provides a method of inhibiting MDM2, comprising administering to a subject in need of treatment a cyclic peptide described herein.

[0041] In another embodiment, the present invention provides a method of inhibiting MDM2 and MDM4 comprising administering to a subject in need of treatment a cyclic peptide described herein.

[0042] In another aspect, the present invention provides a method of treating a disease or disorder in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a cyclic peptide described herein.

[0043] In some embodiments, the disease or disorder is cancer.In some embodiments, the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myeloid leukemia.In some embodiments, the disease or disorder is associated with the proliferation of senescent cells.In some embodiments, the disease or disorder is selected from type 2 diabetes, Huntington's disease, alcoholic fatty liver disease and hyperlipidemia.In some embodiments, 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.

[0044] 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 through both E3 ubiquitin ligase activity and inhibition of p53 transcriptional activation. Furthermore, because disruption of the protein-protein interaction between p53 and MDM2 or MDM4 can lead to senescent cell death, the development of MDM2 and MDM4 inhibitors provides an opportunity for the treatment of diseases or disorders associated with the proliferation of senescent cells. A wide variety of diseases are associated with aging, including cardiovascular disease, inflammatory disease, autoimmune disease, metabolic disease, lung disease, eye disease, ear disease, kidney disease and skin disease. Specific examples include type 2 diabetes, Huntington's disease, alcoholic fatty liver disease and hyperlipidemia.

[0045] Cyclic peptides have emerged as potentially useful MDM2 and / or MDM4 inhibitors. Small molecule inhibitors of the MDM2 / p53 protein-protein interaction and / or the MDM4 / p53 protein-protein interaction are attractive as potential cancer therapeutics. Beta hairpin regions are often found in nature as a means of displaying residues essential for protein-protein recognition. These beta hairpin regions of natural proteins can be mimicked by carefully designed cyclic peptides, which may make them useful as inhibitors of difficult to access targets such as MDM2 and MDM4.

[0046] Despite their usefulness as therapeutic agents, the usefulness of cyclic peptides is limited by poor pharmacokinetics, particularly poor cell permeability, low solubility and high clearance. There is a need for MDM2 inhibitors and MDM2 / MDM4 dual inhibitors with excellent pharmacokinetics, including improved cell permeability, to treat diseases. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] The present invention provides cyclic peptides that overcome the pharmacokinetic barriers due to poor solubility and poor cell permeability. In particular, the present invention provides cyclic peptides that are optimized for enhanced cell permeability and solubility.

[0048] Disclosed herein are cyclic peptides useful as MDM2 inhibitors in some embodiments. In some embodiments, the cyclic peptides disclosed herein are useful as MDM2 / MDM4 dual inhibitors. In some embodiments, the cyclic peptides include 9-11 amino acids independently selected from amino acid residues that are uncharged at physiological pH, and at least one amino acid residue includes a side chain that includes an ether, ester, carbonate, amide, carbamate, and urea, and is selected from the first and second beta hairpin regions. In certain embodiments, the cyclic peptide is further characterized by one of the following: at least four amino acid residues comprising rings independently selected from an optionally substituted monocyclic carbocycle and an optionally substituted monocyclic heterocycle, where at least one of the monocyclic carbocycle and the monocyclic heterocycle is substituted; at least four amino acid residues having a side chain selected from -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle), where the monocyclic carbocycle and the monocyclic heterocycle are independently optionally substituted; and at least three amino acid residues comprising rings independently selected from an optionally substituted phenyl and an optionally substituted monocyclic heteroaryl.

[0049] In some embodiments, the cyclic peptides disclosed herein exhibit high cell permeability and potent inhibition of MDM2 in both biochemical and cellular assays. In some embodiments, the cyclic peptides disclosed herein exhibit high cell permeability and potent inhibition of MDM2 and MDM4 in both biochemical and cellular assays. In some embodiments, the cyclic peptides disclosed herein retain therapeutic potential for the treatment of cancer.

[0050] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0051] As used herein, the singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0052] The abbreviations of amino acids used herein are conventional and are as follows: 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 uncharged at physiological pH include, but are not limited to, alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0053] In an embodiment of the present invention, a cyclic peptide containing a certain number of amino acid residues is a cyclic peptide, where the backbone of the cyclic peptide contains the stated number of amino acid residues. In other words, each of the amino acid residues is in a ring. For example, for the purposes of the present invention, the following is considered to be a cyclic peptide containing 10 amino acid residues: [ka] As another example, the following would also be considered a cyclic peptide containing 10 amino acid residues rather than 11 amino acid residues: [ka]

[0054] "Consecutive" amino acid residues refer to endocyclic amino acids that are covalently linked in series with no intervening endocyclic atoms. The following is an example of two consecutive proline residues, where one is D and the other is L: [ka] In contrast, the following is an example of two non-consecutive proline residues: [ka]

[0055] When a number of contiguous amino acid residues, e.g., at least three contiguous amino acids, separate the first and second beta hairpin regions, the 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 contiguous 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 contiguous 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 the 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 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]

[0056] "Adjacent" residues are covalently bonded to one another via the N-terminus or C-terminus. Amino acid residues that are not adjacent to one another have at least one amino acid or other atom on both the N-terminus and C-terminus that separates them from the other. For example, the structure: [ka] For the valine residue is adjacent to a serine residue, but the valine is not adjacent to a cysteine ​​residue, and the serine residue is adjacent to both a valine and a cysteine ​​residue.

[0057] The term “C x-y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include groups containing x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight chain alkyl and branched chain alkyl groups, containing 1 to 6 carbons. x-y Alkylene refers to a substituted or unsubstituted alkylene chain containing x to y carbon atoms in the alkylene chain. For example, C 1-6 Alkylene may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which may be optionally substituted.

[0058] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight chain alkyl and branched chain alkyl groups. An alkyl group is a group having 1 to 12 carbon atoms (e.g., C 1-12 alkyl), e.g., 1 to 8 carbon atoms (C 1-8 alkyl) or 1 to 6 carbon atoms (C 1-6 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. The alkyl group is attached to the remainder of the molecule by a single bond. The alkyl group is optionally substituted with one or more substituents, such as those described herein.

[0059] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group, including straight or branched chain alkenyl groups containing at least one double bond. Alkenyl groups contain 2 to 12 carbon atoms (e.g., C 2-12 Examples of alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Alkenyl groups are optionally substituted with one or more substituents, such as those described herein.

[0060] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group, including straight or branched chain alkynyl groups containing at least one triple bond. Alkynyl groups are groups having 2 to 12 carbon atoms (e.g., C 2-12 Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups are optionally substituted with one or more substituents, such as those described herein.

[0061] "Haloalkyl" refers to an alkyl group that is 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.

[0062] The term "carbocycle" as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycles include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, 6-12 membered bridged rings and spirocyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated rings, unsaturated rings and aromatic rings. In an exemplary embodiment, an aromatic ring, such as phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane or cyclohexene. Bicyclic carbocycles include any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. Bicyclic carbocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems and 6-8 fused ring systems. Examples of carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl and naphthyl.

[0063] 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 3-10 membered monocyclic rings, 6-12 membered bicyclic rings and 6-12 membered bridged rings. Bicyclic heterocycles include any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In exemplary embodiments, an aromatic ring, such as pyridyl, can be fused with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems and 6-8 fused ring systems.

[0064] The term "heteroaryl" as used herein refers to an aromatic ring containing one or more heteroatoms. Examples of monocyclic heteroaryl rings are 5- to 6-membered rings in which the 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.

[0065] The term "ether" refers to a group of formula -OR, where R is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 R is selected from carbocycles and 3- to 10-membered heterocycles, and is optionally substituted with one or more substituents, such as those described herein.

[0066] The term "ester" refers to a group of formula -C(O)OR or -OC(O)R, where R is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 R is selected from carbocycles and 3- to 10-membered heterocycles, and is optionally substituted with one or more substituents, such as those described herein.

[0067] The term "carbonate" refers to a group of formula -OC(O)OR, where R is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 R is selected from carbocycles and 3- to 10-membered heterocycles, and is optionally substituted with one or more substituents, such as those described herein.

[0068] The term "amide" refers to a group of formula -C(O)N(R)2 or -N(R)C(O)R, where each R is independently hydrogen, 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C3-8 R is selected from carbocycles and 3- to 10-membered heterocycles, and is optionally substituted with one or more substituents, such as those described herein.

[0069] The term "carbamate" refers to a group of formula -OC(O)N(R)2 or -N(R)C(O)OR, where each R is independently hydrogen, 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 R is selected from carbocycles and 3- to 10-membered heterocycles, and is optionally substituted with one or more substituents, such as those described herein.

[0070] The term "urea" refers to a group of formula -N(R)C(O)N(R), where each R is independently hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 R is selected from carbocycles and 3- to 10-membered heterocycles, and is optionally substituted with one or more substituents, such as those described herein.

[0071] The term "substituted" refers to a moiety having a substituent replacing one or more carbon or substitutable heteroatoms, e.g., hydrogen of NH or NH2, of a compound. It is understood that "substituted" or "substituted with" includes potential conditions such as such substitution is in accordance with the permissible valence of the replacing atom and the substituent and the substitution results in a stable compound, i.e., a compound that does not naturally undergo transformation, such as by rearrangement, cyclization, elimination, etc. In some embodiments, substitution refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom, such as the replacement of two hydrogen atoms on one carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents are one or more and can be the same or different for appropriate organic compounds.

[0072] In some embodiments, the substituents may be any of the substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=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, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a)2, where t is 1 or 2; and each optionally includes alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R at may include alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, each of which may be substituted with 2, where t is 1 or 2; a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, where each R a is optionally, if valences permit, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a(where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2, where t is 1 or 2; b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain; each R c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0073] As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance. Each carrier must be "acceptable" in that it is compatible with the other ingredients of the formulation and is not harmful to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0074] As used herein, "treatment" or "treating" refers to an approach to obtain beneficial or desired results for a disease, disorder or condition, including, but not limited to, therapeutic benefit and / or preventive benefit. Therapeutic benefit may include, for example, eradication or improvement of the underlying disorder being treated. Therapeutic benefit may also include, for example, eradication or improvement of one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, regardless of whether the subject may still be suffering from the underlying disorder. In some embodiments, for preventive benefit, the composition is administered to a subject at risk of developing a particular disease or a subject who complains of one or more physiological symptoms of the disease, even if the disease may not yet be diagnosed. Treatment via administration of the compounds described herein does not require the involvement of a medical professional.

[0075] A "therapeutic benefit," as that term is used herein, includes the therapeutic benefits described above and / or prophylactic benefits. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting or reversing the progression of a disease or condition, or any combination thereof.

[0076] compound In one embodiment, the present invention provides a cyclic peptide. 9 to 11 amino acid residues independently selected from amino acid residues that are uncharged at physiological pH; the first and second beta hairpin regions; At least one amino acid residue selected from unnatural amino acids containing acyclic side chains: at least four amino acid residues comprising rings independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles, wherein at least one of the monocyclic carbocycles and monocyclic heterocycles is substituted; at least 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 optionally substituted; and at least three amino acid residues containing rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl; The present invention provides a cyclic peptide comprising:

[0077] In one embodiment, the present invention provides a cyclic peptide. 9 to 11 amino acid residues independently selected from amino acid residues that are uncharged at physiological pH; the first and second beta hairpin regions; at least one amino acid residue having a side chain containing a moiety selected from ether, ester, carbonate, amide, carbamate, and urea; and at least four amino acid residues comprising rings independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles, wherein at least one of the monocyclic carbocycles and monocyclic heterocycles is substituted; at least 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 optionally substituted; and at least three amino acid residues containing rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl; The present invention provides a cyclic peptide characterized by one or more of the following:

[0078] In some embodiments, the first beta hairpin region comprises two consecutive amino acid residues. In some embodiments, 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, wherein the phenyl group of L-NMe-Phe is optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 In some embodiments, 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, wherein the phenyl group of L-NMe-Phe is optionally substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, 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, wherein the phenyl group of L-NMe-Phe is optionally substituted with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The first beta hairpin region is substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2. In some embodiments, 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 some embodiments, for the two consecutive residues, one is D and the other is L. In some embodiments, the two consecutive amino acid residues are D-Pro and L-Aze. In some embodiments, the two consecutive amino acid residues are D-Pro and L-Pro. In some embodiments, the two consecutive amino acid residues are D-Pro and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally substituted with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4In one embodiment, the two consecutive amino acid residues are D-Pro and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally substituted with one or more substituents independently selected from 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, wherein the phenyl group of L-NMe-Phe is optionally substituted with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 The two consecutive amino acid residues are D-Pip and L-Pro. In some embodiments, the two consecutive amino acid residues are D-Pip and L-Aze. In some embodiments, the two consecutive amino acid residues are D-Pip and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally substituted with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 In one embodiment, the two consecutive amino acid residues are D-Pip and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe 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, wherein the phenyl group of L-NMe-Phe is optionally substituted with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 It is substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2. In some embodiments, the two consecutive amino acid residues are D-NMe-Val and L-Pro. In some embodiments, the two consecutive amino acid residues are D-NMe-Val and L-Aze. In some embodiments, the two consecutive amino acid residues are D-NMe-Val and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally substituted with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4In one embodiment, the two consecutive amino acid residues are D-NMe-Val and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe 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, wherein the phenyl group of L-NMe-Phe is optionally substituted with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 Substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2.

[0079] In some embodiments, the second beta hairpin region comprises a second two consecutive amino acid residues. In some embodiments, the second beta hairpin region comprises a second two consecutive residues independently selected from D-Pro, peptoids, D-N-alkylated amino acids, and LN-alkylated amino acids. In some embodiments, the second beta hairpin region comprises a second two consecutive residues independently selected from D-Pro, peptoids, and LN-alkylated amino acids. In some embodiments, for the second two consecutive residues, one is a peptoid and the other is a LN-alkylated amino acid. In some embodiments, for the second two consecutive residues, one is L-NMe-Ala and the other is N-(2-methoxyethyl)glycine. In some embodiments, for the second two consecutive residues, one is D-Pro and the other is a peptoid. In some embodiments, for the second two consecutive residues, one is D-Pro and the other is a LN-alkylated amino acid. In some embodiments, for the second two consecutive residues, one is D-Pro and the other is L-NMe-Ala. In some embodiments, for the second two consecutive residues, one is D-Pro and the other is N-(2-methoxyethyl)glycine. In some embodiments, for the second two consecutive residues, one is a DN-alkylated amino acid and the other is a LN-alkylated amino acid. In some embodiments, for the second two consecutive residues, one is D-NMe-Ala and the other is L-NMe-Ala. In some embodiments, for the second two consecutive residues, one is a DN-alkylated amino acid and the other is a peptoid. In some embodiments, for the second two consecutive residues, one is D-NMe-Ala and the other is N-(2-methoxyethyl)glycine.

[0080] In some embodiments, at least two consecutive amino acids separate the first beta hairpin region and the second beta hairpin region. In some embodiments, at least three consecutive amino acids separate the first beta hairpin region and the second beta hairpin region. In some embodiments, two consecutive amino acids separate the first beta hairpin region and the second beta hairpin region. In some embodiments, three consecutive amino acids separate the first beta hairpin region and the second beta hairpin region. In some embodiments, the number of consecutive amino acids between the first beta hairpin region and the second beta hairpin region refers to the number of amino acids starting from the C-terminus of the first beta hairpin region and ending at the N-terminus of the second beta hairpin region. In some embodiments, 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 certain embodiments, the number of contiguous 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, and contiguous 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, 3 contiguous amino acids starting from the C-terminus of the first beta hairpin region and ending at the N-terminus of the second beta hairpin region and 3 contiguous amino acids starting from the C-terminus of the second beta hairpin region and ending at the N-terminus of the first beta hairpin region.

[0081] In some embodiments, the molecular weight of the cyclic peptide is 800 to 1300 Da. In some embodiments, the molecular weight of the cyclic peptide is 800 to 1200 Da. In some embodiments, the molecular weight of the cyclic peptide is 900 to 1200 Da. In some embodiments, the molecular weight of the cyclic peptide is 800 to 900 Da. In some embodiments, the molecular weight of the cyclic peptide is 900 to 1000 Da. In some embodiments, the molecular weight of the cyclic peptide is 1000 to 1100 Da. In some embodiments, the molecular weight of the cyclic peptide is 1100 to 1200 Da. In some embodiments, the molecular weight of the cyclic peptide is 1200 to 1500 Da. In some embodiments, the molecular weight of the cyclic peptide is 1200 to 1400 Da. In some embodiments, the molecular weight of the cyclic peptide is 1100 to 1300 Da.

[0082] In some embodiments, a cyclic peptide, for example a cyclic peptide having 10 amino acid residues, comprises at least one amino acid residue having a side chain comprising a moiety selected from ether, ester, carbonate, amide, carbamate and urea. In some embodiments, a cyclic peptide comprises at least one amino acid residue having a side chain comprising a moiety selected from ether and ester. In some embodiments, a cyclic peptide comprises at least one amino acid residue having a side chain comprising an ether. In some embodiments, a cyclic peptide comprises at least one amino acid residue having a side chain comprising an ester. In some embodiments, a cyclic peptide comprises at least one amino acid residue having a side chain comprising a carbonate. In some embodiments, a cyclic peptide comprises at least one amino acid residue having a side chain comprising an amide. In some embodiments, a cyclic peptide comprises at least one amino acid residue having a side chain comprising a carbamate. In some embodiments, a cyclic peptide comprises at least one amino acid residue having a side chain comprising a urea. In some embodiments, a cyclic peptide comprises at least two amino acid residues having side chains comprising a moiety selected from ether, ester, carbonate, amide, carbamate and urea. In certain embodiments, the cyclic peptide comprises no more than two amino acid residues having a side chain comprising a moiety selected from ether, ester, carbonate, amide, carbamate, and urea.

[0083] In some embodiments, the cyclic peptide has at least four amino acid residues comprising a ring independently selected from an optionally substituted monocyclic carbocycle and an optionally substituted monocyclic heterocycle, where at least one of the monocyclic carbocycle and the monocyclic heterocycle is substituted.In some embodiments, the at least four amino acid residues comprising a ring independently selected from an optionally substituted monocyclic carbocycle and an optionally substituted monocyclic heterocycle are not adjacent to each other.In some embodiments, the cyclic peptide is characterized by four amino acid residues comprising a ring independently selected from an optionally substituted monocyclic carbocycle and an optionally substituted monocyclic heterocycle, where at least one of the monocyclic carbocycle and the monocyclic heterocycle is substituted.In some embodiments, the cyclic peptide is characterized by three amino acid residues comprising a ring independently selected from an optionally substituted monocyclic carbocycle and one amino acid residue comprising a ring independently selected from an optionally substituted monocyclic heterocycle. In certain embodiments, the optionally substituted monocyclic carbocycle is a phenyl and the optionally substituted monocyclic heterocycle is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is selected from the group consisting of halo, -SCH, -SOCH, -SOCH, -OH, -CN, -NO, -C, -C- ... 1-4 and substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In certain embodiments, the optionally substituted monocyclic carbocycle is a phenyl and the optionally substituted monocyclic heterocycle is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4It is substituted by one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2. In some embodiments, the optionally substituted monocyclic carbocycle is a phenyl and the optionally substituted monocyclic heterocycle is a heteroaryl ring, where at least one phenyl or heteroaryl ring is substituted by one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. In some embodiments, the optionally substituted monocyclic carbocycle is a phenyl and the optionally substituted monocyclic heterocycle is a heteroaryl ring, where at least one phenyl or heteroaryl ring is substituted by one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole and imidazole, any of which may be substituted.In some embodiments, the optionally substituted monocyclic carbocycle is phenyl, and the optionally substituted monocyclic heterocycle is pyridine, where each ring is independently optionally substituted.In some embodiments, the at least four amino acid residues comprising the rings 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.

[0084] In some embodiments, the cyclic peptide has at least four amino acid residues with side chains selected from -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle), where the monocyclic carbocycle and the monocyclic heterocycle are independently optionally substituted. In some embodiments, each of the at least four amino acids with side chains selected from -alkylene-(optionally substituted monocyclic carbocycle) and -alkylene-(optionally substituted monocyclic heterocycle) are not adjacent to each other. In some embodiments, two of the at least four amino acids with side chains selected from -alkylene-(optionally substituted monocyclic carbocycle) and -alkylene-(optionally substituted monocyclic heterocycle) are adjacent to each other. In some embodiments, each monocyclic carbocycle is a phenyl and each monocyclic heterocycle is a heteroaryl ring, where each phenyl and heteroaryl ring are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 and each monocyclic carbocycle is substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In certain embodiments, each monocyclic carbocycle is phenyl and each monocyclic heterocycle is a heteroaryl ring, wherein each phenyl and heteroaryl ring is independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4It is substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2. In some embodiments, the cyclic peptide is characterized by four amino acid residues having side chains independently selected from -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle), where the monocyclic carbocycle and the monocyclic heterocycle are independently optionally substituted. In some embodiments, the cyclic peptide is characterized by three amino acids having side chains independently selected from -alkylene-(monocyclic carbocycle) and one amino acid having side chain independently selected from -alkylene-(monocyclic heterocycle), where the monocyclic carbocycle and the monocyclic heterocycle are independently optionally substituted. In certain embodiments, each monocyclic carbocycle is a phenyl and each monocyclic heterocycle is a heteroaryl ring, wherein each phenyl and heteroaryl ring is independently optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In certain embodiments, each monocyclic carbocycle is a phenyl and each monocyclic heterocycle is a heteroaryl ring, wherein 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 some embodiments, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, any of which is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2.In some 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. In some embodiments, each monocyclic carbocycle is phenyl and each monocyclic heterocycle is pyridine, where each ring is independently optionally substituted. In some embodiments, the at least four amino acid residues having a side chain selected from -alkylene-(monocyclic carbocycle) and -alkylene-(monocyclic heterocycle) are independently selected from phenylalanine, 3-(3-pyridyl)alanine and 4-halophenylalanine.

[0085] In some embodiments, the cyclic peptide has at least three amino acid residues comprising rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl. In some embodiments, the at least three amino acid residues comprising rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl are not adjacent to each other. In some embodiments, the cyclic peptide is characterized by three amino acid residues comprising rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl. In some embodiments, the cyclic peptide is characterized by four amino acid residues comprising rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl. In some embodiments, the cyclic peptide is characterized by three amino acid residues comprising rings independently selected from optionally substituted phenyl and one amino acid residue comprising ring selected from optionally substituted monocyclic heteroaryl. In some embodiments, the cyclic peptide is characterized by three amino acid residues comprising rings independently selected from optionally substituted phenyl and one amino acid residue comprising ring selected from optionally substituted pyridine. In certain embodiments, each phenyl and heteroaryl ring is independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 In certain embodiments, each phenyl and heteroaryl ring is independently optionally substituted with one or more substituents selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In certain embodiments, each phenyl and heteroaryl ring is independently optionally substituted with halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4Substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each phenyl and heteroaryl ring is independently optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, 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 some embodiments, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, any of which is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, and imidazole, any of which is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, each heteroaryl ring is independently an optionally substituted pyridine. In certain embodiments, the at least three amino acid residues comprising rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl are independently selected from phenylalanine, 3-(3-pyridyl)alanine, and 4-halophenylalanine.

[0086] In some embodiments, at least three of the main chain nitrogen atoms of cyclic peptide are tertiary nitrogen.In some embodiments, four or five of the main chain nitrogen atoms are tertiary nitrogen.In some embodiments, four of the main chain nitrogen atoms of cyclic peptide are tertiary nitrogen.In some embodiments, five of the main chain nitrogen atoms of cyclic peptide are tertiary nitrogen.

[0087] In some embodiments, one or more of the tertiary main chain nitrogen atoms are part of heterocycloalkyl ring.When two or more tertiary main chain nitrogen atoms are part of heterocycloalkyl ring, these rings are different from each other.For example, when there are two tertiary main chain nitrogen atoms that are part of heterocycloalkyl ring, one nitrogen is part of the first proline moiety, and the second nitrogen is part of the second proline moiety.

[0088] In some embodiments, one tertiary main chain nitrogen atom is part of a heterocycloalkyl ring.In some embodiments, one tertiary main chain nitrogen atom is part of a first heterocycloalkyl ring, and the second tertiary main chain nitrogen atom is part of a second heterocycloalkyl ring.In some embodiments, one tertiary main chain nitrogen atom is part of a first heterocycloalkyl ring, the second tertiary main chain nitrogen atom is part of a second heterocycloalkyl ring, and the third tertiary main chain nitrogen atom is part of a third heterocycloalkyl ring.In some embodiments, one tertiary main chain nitrogen atom is part of a first heterocycloalkyl ring, the second tertiary main chain nitrogen atom is part of a second heterocycloalkyl ring, the third tertiary main chain nitrogen atom is part of a third heterocycloalkyl ring, and the fourth tertiary main chain nitrogen atom is part of a fourth heterocycloalkyl ring. In some embodiments, one tertiary main chain nitrogen atom is part of a first heterocycloalkyl ring, the second tertiary main chain nitrogen atom is part of a second heterocycloalkyl ring, the third tertiary main chain nitrogen atom is part of a third heterocycloalkyl ring, the fourth tertiary main chain nitrogen atom is part of a fourth heterocycloalkyl ring, and the fifth tertiary main chain nitrogen atom is part of a fifth heterocycloalkyl ring.

[0089] In certain embodiments, one or more of the tertiary nitrogens has an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituents are independently selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 In certain embodiments, one or more of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4In some embodiments, one or more of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, one or more of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3, and -OCHF2. In some embodiments, one of the tertiary nitrogens has an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. In some embodiments, one of the tertiary nitrogens has an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3 and -OCHF2. In some embodiments, two of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. In some embodiments, two of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3 and -OCHF2. In certain embodiments, three of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituents are independently selected from halo, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2.In some embodiments, three of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3 and -OCHF2. In some embodiments, four of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. In some embodiments, four of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituent is independently selected from halo, -OBz, -OCH3, -OCF3 and -OCHF2. In certain embodiments, five of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituents are independently selected from halo, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2. In certain embodiments, five of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituents are independently selected from halo, -OBz, -OCH3, -OCF3 and -OCHF2.

[0090] In certain embodiments, each tertiary nitrogen is independently [ka] or [ka] where R A is optionally halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C1-C6 alkyl substituted with one or more substituents independently selected from alkyl, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2, wherein [ka] indicates the point of attachment to the adjacent amino acid residue. In some embodiments, each tertiary nitrogen is independently [ka] or [ka] where R A is optionally halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 C1-C6 alkyl substituted with one or more substituents independently selected from alkyl, -OBz, -OCH3, -OCF3 and -OCHF2, wherein [ka] indicates the point of attachment to the adjacent amino acid residue. In some embodiments, each tertiary nitrogen is independently [ka] or [ka] where R A is a C1-C6 alkyl optionally substituted with one or more substituents independently selected from halo, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2, where [ka] indicates the point of attachment to the adjacent amino acid residue. In some embodiments, each tertiary nitrogen is independently [ka] or [ka] where R Ais a C1-C6 alkyl optionally substituted with one or more substituents independently selected from halo, -OBz, -OCH3, -OCF3 and -OCHF2, where [ka] indicates the point of attachment to the adjacent amino acid residue. In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] In some embodiments, one or more tertiary nitrogens are [ka] It is.

[0091] In some embodiments, the cyclic peptide has 8 amino acid residues. In some embodiments, the cyclic peptide has 9 amino acid residues. In some embodiments, the cyclic peptide has 10 amino acid residues. In some embodiments, the cyclic peptide has 11 amino acid residues. In some embodiments, the cyclic peptide has 12 amino acid residues.

[0092] Provided herein, in another embodiment, is a compound of formula I: [ka] [During the ceremony, R 1 , R 3 and R 8 are independently hydrogen, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8The carbocyclic and 3- to 10-membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 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 each optionally is -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl; wherein the carbocycle and heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 2 and R 12 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 4 is hydrogen, C 1-4Alkyl, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; and 1-4 Alkyl is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 4 and R 14 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 5 is hydrogen or C 1-4 alkyl or R 5 and R 15 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 6 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; and 1-4 Alkyl is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 7 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 7 and R 17 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; 2 and R 7 at least one of which is not hydrogen or methyl; R 9is hydrogen or C 1-4 alkyl or R 9 and R 19 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 10 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 10 and R 20 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 11 , R 13 , R 16and R 18 are independently hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 12 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 12 and R 2 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 14 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 14 and R 4 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 15 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 15 and R 5 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 17 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 17 and R 7 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 19 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 19 and R 9 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 20 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 20 and R 10 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; and R 21 is independently at each occurrence hydrogen; and each optionally represents halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 3-12 Carbocyclic ring, 3-12 membered heterocyclic ring, -O(C 1-10 alkyl), -O(C 2-10 alkenyl), -O(C 2-10 alkynyl), -O(C 3-8 C substituted with one or more substituents independently selected from -O(carbocyclic ring) and -O(3-10 membered heterocyclic ring) 1-10 Alkyl, C 2-10Alkenyl, C 2-10 Alkynyl, C 3-8 is selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring. It is a cyclic peptide represented by the formula:

[0093] In one embodiment, the cyclic peptide has Formula II: [ka] [During the ceremony, R 21 , R 23 , R 26 and R 28 are independently hydrogen, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle 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 22 is hydrogen; and each optionally is -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl; wherein the carbocycle and heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 22 and R 32 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 24 is hydrogen or C 1-4 alkyl or R 24 and R 34 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 25 is hydrogen or C 1-4 alkyl or R 25 and R 35 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 27 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21)2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 27 and R 37 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; 22 and R 27 at least one of which is not hydrogen or methyl; R 29 is hydrogen or C 1-4 alkyl or R 29 and R 39 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 30 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 30 and R 40 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 31 , R 33 , R 36 and R 38 are independently hydrogen; and C optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl; R 32 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 32 and R 22 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 34 is hydrogen; and C optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4alkyl or R 34 and R 24 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 35 is hydrogen; and C optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl or R 35 and R 25 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 37 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 37 and R 27 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 39 is hydrogen; and C optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl or R 39 and R 29 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 40 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 40 and R 30 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; and R 41is independently at each occurrence hydrogen; and each optionally represents halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 3-12 Carbocyclic ring, 3-12 membered heterocyclic ring, -O(C 1-10 alkyl), -O(C 2-10 alkenyl), -O(C 2-10 alkynyl), -O(C 3-8 C substituted with one or more substituents independently selected from -O(carbocyclic ring) and -O(3-10 membered heterocyclic ring) 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 is selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring. It is expressed by:

[0094] In one embodiment, R 31 is hydrogen. In some embodiments, R 37 is hydrogen. In some embodiments, R 33 is hydrogen. In some embodiments, R 36 is hydrogen. In some embodiments, R 38 is hydrogen. In some embodiments, R 31 and R 37 Each is hydrogen. In some embodiments, R 31 and R 33 Each is hydrogen. In some embodiments, R 31 and R 36 Each is hydrogen. In some embodiments, R 31 and R 38 Each is hydrogen. In some embodiments, R 37 and R 33 Each is hydrogen. In some embodiments, R 37 and R 36 Each is hydrogen. In some embodiments, R 37 and R 38 Each is hydrogen. In some embodiments, R 33 and R36 Each is hydrogen. In some embodiments, R 33 and R 38 Each is hydrogen. In some embodiments, R 36 and R 38 Each is hydrogen. In some embodiments, R 31 , R 37 and R 33 Each is hydrogen. In some embodiments, R 31 , R 37 and R 36 Each is hydrogen. In some embodiments, R 31 , R 37 and R 38 Each is hydrogen. In some embodiments, R 31 , R 33 and R 36 Each is hydrogen. In some embodiments, R 31 , R 33 and R 38 Each is hydrogen. In some embodiments, R 31 , R 36 and R 38 Each is hydrogen. In some embodiments, R 37 , R 33 and R 36 Each is hydrogen. In some embodiments, R 37 , R 33 and R 38 Each is hydrogen. In some embodiments, R 37 , R 36 and R 38 Each is hydrogen. In some embodiments, R 33 , R 36 and R 38 Each is hydrogen. In some embodiments, R 31 , R 37 , R 33 and R 36 Each is hydrogen. In some embodiments, R 31 , R 37 , R 33 and R 38 Each is hydrogen. In some embodiments, R 31 , R 33 , R 36and R 38 Each is hydrogen. In some embodiments, R 31 , R 37 , R 36 and R 38 Each is hydrogen. In some embodiments, R 37 , R 33 , R 36 and R 38 Each is hydrogen. In some embodiments, R 31 , R 37 , R 33 , R 36 and R 38 are each hydrogen.

[0095] In one embodiment, R 34 , R 35 , R 32 , R 39 and R 40 At least four of R 34 , R 35 , R 32 , R 39 and R 40 In one embodiment, R 34 , R 35 , R 32 and R 39 is not hydrogen. In some embodiments, R 34 , R 35 , R 32 and R 40 is not hydrogen. In some embodiments, R 35 , R 32 , R 39 and R 40 is not hydrogen. In some embodiments, R 34 , R 35 , R 39 and R 40 is not hydrogen. In some embodiments, R 34 , R 32 , R 39 and R 40 is not hydrogen. In some embodiments, R 34 , R 35 , R 32 , R 39 and R40 is not hydrogen.

[0096] In one embodiment, R 24 and R 34 , R 25 and R 35 and R 29 and R 39 At least one of R together with the intervening atoms forms a 5- to 7-membered heterocycloalkyl. 24 and R 34 , R 25 and R 35 and R 29 and R 39 At least two of R together with the intervening atoms form a 5- to 7-membered heterocycloalkyl. 24 and R 34 and together with the intervening atoms form a 5- to 6-membered heterocycloalkyl. In some embodiments, R 25 and R 35 and together with the intervening atoms form a 5- to 6-membered heterocycloalkyl. In some embodiments, R 29 and R 39 and together with the intervening atoms form a 5- to 6-membered heterocycloalkyl. In some embodiments, R 24 and R 34 and R 25 and R 35 and together with the intervening atoms form a 5- to 6-membered heterocycloalkyl. In some embodiments, R 24 and R 34 and R 29 and R 39 and together with the intervening atoms form a 5- to 6-membered heterocycloalkyl. In some embodiments, R 25 and R 35 and R 29 and R 39 and together with the intervening atoms form a 5- to 6-membered heterocycloalkyl. In some embodiments, R 24 and R 34 , R 25 and R 35 and R29 and R 39 together with the atoms between them form a 5- to 6-membered heterocycloalkyl.

[0097] In one embodiment, R 32 , R 39 and R 40 Each of R is selected from methyl and methoxyethyl. 34 , R 32 and R 40 Each of R is selected from methyl and methoxyethyl. 34 , R 32 and R 39 Each of R is selected from methyl and methoxyethyl. 34 , R 39 and R 40 Each of R is selected from methyl and methoxyethyl. 34 , R 32 , R 39 and R 40 Each of is selected from methyl and methoxyethyl.

[0098] In one embodiment, R 39 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 29 and R 39 and together with the intervening atoms form a 5- to 7-membered heterocycloalkyl. In some embodiments, R 39 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 29 and R 39 and together with the intervening atoms form a 5- to 7-membered heterocycloalkyl. In some embodiments, R 39is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; 2-4 alkyl or R 29 and R 39 and together with the intervening atoms form a 5- to 7-membered heterocycloalkyl. In some embodiments, R 39 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; 2-4 alkyl or R 29 and R 39 and together with the intervening atoms form a 5- to 7-membered heterocycloalkyl. In some embodiments, R 39 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2; 2-4 In one embodiment, R 39 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2; 2-4 In one embodiment, R 39 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; 2-4 In one embodiment, R 39 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; 2-4 In one embodiment, R 39 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5, and -OCH3; 2-4 In one embodiment, R 39is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3 and -OCH3; 2-4 In one embodiment, R 29 and R 39 together with the atoms between them form a 5- to 7-membered heterocycloalkyl.

[0099] In one embodiment, R 40 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2; 1-4 In one embodiment, R 40 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2; 1-4 In one embodiment, R 40 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; 1-4 In one embodiment, R 40 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; 1-4 In one embodiment, R 40 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5, and -OCH3; 1-4 In one embodiment, R 40 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3 and -OCH3; 1-4 In one embodiment, R 40 is optionally substituted with one or more substituents independently selected from -CHF2, -OBz, -SF5 and -OCHF2; 1-4 In one embodiment, R40 is optionally substituted with one or more substituents independently selected from -CHF2, -OBz ​​and -OCHF2; 1-4 It is an alkyl.

[0100] In one embodiment, R 22 , R 27 and R 30 is independently C 1-6 In one embodiment, R 22 , R 27 and R 30 is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, and t-butyl. 22 , R 27 and R 30 is selected from methyl, ethyl, i-propyl, and t-butyl. 22 is methyl. In some embodiments, R 30 is methyl. In some embodiments, R 22 and R 30 are each methyl.

[0101] In one embodiment, R 22 and R 27 is independently -C(O)R 41 , -C(O)N(R 41 )2, -N(R 41 )C(O)R 41 , -C(O)OR 41 , -OC(O)R 41 , -OC(O)N(R 41 )2, -N(R 41 )C(O)OR 41 , -OC(O)OR 41 and -N(R 41 )C(O)N(R 41 ) C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 22 HA-C(O)R 41 , -C(O)N(R 41 )2, -N(R 41 )C(O)R41 , -C(O)OR 41 , -OC(O)R 41 , -OC(O)N(R 41 )2, -N(R 41 )C(O)OR 41 , -OC(O)OR 41 and -N(R 41 )C(O)N(R 41 ) C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 22 HA-C(O)R 41 , -C(O)OR 41 , -OC(O)R 41 and -OC(O)OR 41 C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 22 -C(O)N(R 41 )2, -N(R 41 )C(O)R 41 , -OC(O)N(R 41 )2, -N(R 41 )C(O)OR 41 and -N(R 41 )C(O)N(R 41 ) C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 27 HA-C(O)R 41 , -C(O)N(R 41 )2, -N(R 41 )C(O)R 41 , -C(O)OR 41 , -OC(O)R 41 , -OC(O)N(R 41 )2, -N(R 41 )C(O)OR 41 , -OC(O)OR 41 and -N(R 41 )C(O)N(R 41 ) C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 27 HA-C(O)R 41, -C(O)OR 41 , -OC(O)R 41 and -OC(O)OR 41 C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 27 -C(O)N(R 41 )2, -N(R 41 )C(O)R 41 , -OC(O)N(R 41 )2, -N(R 41 )C(O)OR 41 and -N(R 41 )C(O)N(R 41 ) C substituted with one or more substituents independently selected from 1-6 It is an alkyl.

[0102] In one embodiment, R 21 , R 23 , R 26 and R 28 is independent -C 3-8 Carbocyclic ring, -3 to 10 membered heterocyclic ring, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle and the 3- to 10-membered heterocycle are optionally substituted. In certain embodiments, R 21 , R 23 , R 26 and R 28 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle and the 3- to 10-membered heterocycle are optionally substituted. In certain embodiments, R 21 , R 23 , R 26 and R 28 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle 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, -SF5, and -OCHF2. In certain embodiments, R 21 , R 23 , R 26 and R 28 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 In certain embodiments, the carbocycle and the 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halo, -OH, -CH, -CF, -CHF, -OBz, -OCH, and -OCHF. 21 , R 23 , R 26 and R 28 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 In certain embodiments, the carbocycle and the 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 21 , R 23 , R 26 and R 28 are independently -CH2-(C 3-8 In one embodiment, R 21 , R 23 , R 26 and R 28 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8In certain embodiments, the carbocycle and the 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halo, -OH, -CH, -CF, -SF, and -OCH. 21 , R 23 , R 26 and R 28 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 In certain embodiments, the carbocycle and the 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halo, -OH, -CH, -CF, and -OCH. 21 , R 23 , R 26 and R 28 is independently selected from phenylmethyl and pyridinylmethyl, where phenyl and pyridinyl are optionally substituted with one or more substituents independently selected from halo, -OH, -CH, -CF, -SF, and -OCH. 21 , R 23 , R 26 and R 28 is independently selected from phenylmethyl and pyridinylmethyl, where phenyl and pyridinyl are optionally substituted with one or more substituents independently selected from halo, -OH, -CH, -CF, and -OCH. 21 , R 23 , R 26 and R 28 is independent [ka] In one embodiment, R 21 teeth [ka] and R 23 , R 26 and R 28 is independent [ka] In one embodiment, R 21 teeth [ka] and R 23 teeth [ka] and R 26 and R 28 is independent [ka] In one embodiment, R 21 teeth [ka] and R 23 teeth [ka] and R 26 teeth [ka] and R 28 teeth [ka] It is.

[0103] In one embodiment, the cyclic peptide has the formula IIa: [ka] It is expressed by:

[0104] In one embodiment, the cyclic peptide has the formula IIb: [ka] [In the formula, R 21’, R 23’ , R 26’ and R 28’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0105] In one embodiment, R 21’ , R 23’ , R 26’ and R 28’ is independent [ka] In one embodiment, R 21’ teeth [ka] and R 23’ , R 26’ and R 28’ is independent [ka] In one embodiment, R 21’ teeth [ka] and R 23’ teeth [ka] and R 26’ and R 28’ is independent [ka] In one embodiment, R 21’ teeth [ka] and R 23’ teeth [ka] and R 26’ teeth [ka] and R 28’ teeth [ka] It is.

[0106] In one embodiment, the cyclic peptide has formula IIc: [ka] Formula IIc, [In the formula, R 21’ , R 23’ , R 26’ and R 28’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0107] In one embodiment, the cyclic peptide has the formula IId: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0108] In some embodiments, the cyclic peptide has the formula IIe: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0109] In one embodiment, the cyclic peptide has the formula IIf: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0110] In some embodiments, the cyclic peptide has the formula IIg: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0111] In some embodiments, the cyclic peptide has Formula III: [ka] [During the ceremony, R 41 , R 43 , R 44 and R 48 are independently hydrogen, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8The carbocyclic and 3- to 10-membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 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 each optionally is -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl; wherein the carbocycle and heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 42 and R 52 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 45 is hydrogen or C 1-4alkyl or R 45 and R 55 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 46 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 47 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 47 and R 57 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; 42 and R 47 at least one of which is not hydrogen or methyl; R 49 is hydrogen or C 1-4 alkyl or R 49 and R 59 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 50 are hydrogen; and each optionally represents halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 50 and R 60 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 51 , R 53 , R 56 and R 58 are independently hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 52 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 52 and R 42 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 54 are independently hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 55 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 55 and R 45 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 57 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; or R 57 and R 47 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 59 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 59 and R 49 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 60 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 60 and R 50 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; and R 61 is independently at each occurrence hydrogen; and each optionally represents halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 3-12 Carbocyclic ring, 3-12 membered heterocyclic ring, -O(C 1-10 alkyl), -O(C 2-10 alkenyl), -O(C 2-10 alkynyl), -O(C 3-8 C substituted with one or more substituents independently selected from -O(carbocyclic ring) and -O(3-10 membered heterocyclic ring) 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 is selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring. It is expressed by:

[0112] In one embodiment, R 51 is hydrogen. In some embodiments, R 53 is hydrogen. In some embodiments, R 56 is hydrogen. In some embodiments, R 58 is hydrogen. In some embodiments, R 51 and R 53 Each is hydrogen. In some embodiments, R 51 and R 56 Each is hydrogen. In some embodiments, R 51 and R 58 Each is hydrogen. In some embodiments, R 53 and R 56 Each is hydrogen. In some embodiments, R 53 and R 58 Each is hydrogen. In some embodiments, R 56 and R 58 Each is hydrogen. In some embodiments, R 51 , R 53 and R 56 Each is hydrogen. In some embodiments, R 51 , R 53 and R 58 Each is hydrogen. In some embodiments, R 51 , R 56 and R 58Each is hydrogen. In some embodiments, R 53 , R 56 and R 58 Each is hydrogen. In some embodiments, R 51 , R 53 , R 56 and R 58 are each hydrogen.

[0113] In one embodiment, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 At least four of R 52 , R 54 , R 55 , R 57 , R 59 and R 60 In one embodiment, R 52 , R 54 , R 55 and R 57 is not hydrogen. In some embodiments, R 52 , R 54 , R 55 and R 59 is not hydrogen. In some embodiments, R 52 , R 54 , R 55 and R 60 is not hydrogen. In some embodiments, R 52 , R 54 , R 57 and R 59 is not hydrogen. In some embodiments, R 52 , R 54 , R 57 and R 60 is not hydrogen. In some embodiments, R 52 , R 54 , R 59 and R 60 is not hydrogen. In some embodiments, R 52 , R 55 , R 57 and R 59 is not hydrogen. In some embodiments, R52 , R 55 , R 57 and R 60 is not hydrogen. In some embodiments, R 52 , R 55 , R 59 and R 60 is not hydrogen. In some embodiments, R 52 , R 57 , R 59 and R 60 is not hydrogen. In some embodiments, R 54 , R 55 , R 57 and R 59 is not hydrogen. In some embodiments, R 54 , R 55 , R 57 and R 60 is not hydrogen. In some embodiments, R 54 , R 55 , R 59 and R 60 is not hydrogen. In some embodiments, R 54 , R 57 , R 59 and R 60 is not hydrogen. In some embodiments, R 55 , R 57 , R 59 and R 60 is not hydrogen. In some embodiments, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 At least five of R are not hydrogen. 52 , R 54 , R 55 , R 57 , R 59 and R 60 In one embodiment, R 52 , R 54 , R 55 , R 57 and R 59 is not hydrogen. In some embodiments, R 52 , R 54 , R55 , R 57 and R 60 is not hydrogen. In some embodiments, R 52 , R 55 , R 57 , R 59 and R 60 is not hydrogen. In some embodiments, R 54 , R 55 , R 57 , R 59 and R 60 is not hydrogen. In some embodiments, R 52 , R 54 , R 55 , R 57 , R 59 and R 60 is not hydrogen.

[0114] In one embodiment, R 45 and R 55 , R 42 and R 52 , R 49 and R 59 and R 50 and R 60 At least one of R 1 , together with the intervening atoms, forms a 4- to 7-membered heterocycloalkyl. 45 and R 55 , R 42 and R 52 , R 49 and R 59 and R 50 and R 60 At least two of R together with the atoms between them form a 4- to 7-membered heterocycloalkyl. 45 and R 55 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 42 and R 52 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R50 and R 60 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 45 and R 55 and R 42 and R 52 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 45 and R 55 and R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 45 and R 55 and R 50 and R 60 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 42 and R 52 and R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 42 and R 52 and R 50 and R 60 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 49 and R 59 and R 50 and R 60 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 45 and R 55 , R 42 and R 52 and R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 45 and R 55 , R 42 and R 52 and R 50 and R 60and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 45 and R 55 , R 49 and R 59 and R 50 and R 60 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 42 and R 52 , R 49 and R 59 and R 50 and R 60 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 45 and R 55 , R 42 and R 52 , R 49 and R 59 and R 50 and R 60 together with the atoms between them form a 4- to 7-membered heterocycloalkyl.

[0115] In one embodiment, R 57 , R 54 and R 60 Each of R is selected from methyl, ethyl, and methoxyethyl. 57 , R 54 and R 59 Each of R is selected from methyl, ethyl, and methoxyethyl. 57 , R 59 and R 60 Each of R is selected from methyl, ethyl, and methoxyethyl. 54 , R 59 and R 60 Each of R is selected from methyl, ethyl, and methoxyethyl. 57 , R 54 , R 59 and R 60 Each of R is selected from methyl, ethyl, and methoxyethyl. 52, R 54 , R 57 , R 59 and R 60 Each of is selected from methyl, ethyl, and methoxyethyl.

[0116] In one embodiment, R 59 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CF3, -CHF2, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 2-4 alkyl or R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 59 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CF3, -CHF2, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2 2-4 alkyl or R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 59 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 2-4 alkyl or R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 59 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2 2-4alkyl or R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 59 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 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 59 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 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 59 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; 2-4 alkyl or R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 59 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; 2-4 alkyl or R 49 and R 59 and together with the intervening atoms form a 4- to 7-membered heterocycloalkyl. In some embodiments, R 59 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 2-4 In one embodiment, R59 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2 2-4 In one embodiment, R 59 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2; 2-4 In one embodiment, R 59 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2; 2-4 In one embodiment, R 59 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; 2-4 In one embodiment, R 59 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; 2-4 In one embodiment, R 59 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5, and -OCH3; 2-4 In one embodiment, R 59 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3 and -OCH3; 2-4 In one embodiment, R 49 and R 59 together with the atoms between them form a 4- to 7-membered heterocycloalkyl.

[0117] In one embodiment, R 60is optionally halo, -CF3, -CHF2, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 2-4 In one embodiment, R 60 is optionally halo, -CF3, -CHF2, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2 2-4 In one embodiment, R 60 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 2-4 In one embodiment, R 60 is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2 2-4 In one embodiment, R 60 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 In one embodiment, R 60 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 In one embodiment, R 60is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -SF5, and -OCHF2; 2-4 In one embodiment, R 60 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, and -OCHF2; 2-4 In one embodiment, R 60 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; 2-4 In one embodiment, R 60 is optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; 2-4 In one embodiment, R 60 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3, -SF5, and -OCH3; 2-4 In one embodiment, R 60 is optionally substituted with one or more substituents independently selected from halo, -OH, -CH3, -CF3 and -OCH3; 2-4 In one embodiment, R 60 is optionally substituted with one or more substituents independently selected from -CHF2, -OBz ​​and -OCHF2; 2-4 It is an alkyl.

[0118] In one embodiment, R 42 , R 47 and R 50 is independently C 1-6 In one embodiment, R 42 , R 47 and R 50 is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, and t-butyl.42 , R 47 and R 50 is selected from methyl, ethyl, i-propyl, and t-butyl. 47 is methyl. In some embodiments, R 42 is methyl, ethyl, i-propyl or t-butyl. 50 is methyl. In some embodiments, R 47 is methyl, R 42 is methyl, ethyl, i-propyl or t-butyl, R 50 is hydrogen. In some embodiments, R 47 is methyl, R 42 is methyl, R 50 is hydrogen. In some embodiments, R 47 is methyl, R 42 is ethyl, and R 50 is hydrogen. In some embodiments, R 47 is methyl, R 42 is i-propyl, R 50 is hydrogen. In some embodiments, R 47 is methyl, R 42 is t-butyl, R 50 is hydrogen. In some embodiments, R 47 is methyl, R 42 is methyl, ethyl, i-propyl or t-butyl, R 50 is methyl. In some embodiments, R 42 is methyl, R 47 is methyl, R 49 is methyl. In some embodiments, R 47 is methyl, R 42 is ethyl, and R 50 is methyl. In some embodiments, R 47 is methyl, R 42 is i-propyl, R 50 is methyl. In some embodiments, R 47 is methyl, R 42 is t-butyl, R 50is methyl.

[0119] In one embodiment, R 42 and R 47 is independently -C(O)R 61 , -C(O)N(R 61 )2, -N(R 61 )C(O)R 61 , -C(O)OR 61 , -OC(O)R 61 , -OC(O)N(R 61 )2, -N(R 61 )C(O)OR 61 , -OC(O)OR 61 and -N(R 61 )C(O)N(R 61 ) C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 42 HA-C(O)R 61 , -C(O)N(R 61 )2, -N(R 61 )C(O)R 61 , -C(O)OR 61 , -OC(O)R 61 , -OC(O)N(R 61 )2, -N(R 61 )C(O)OR 61 , -OC(O)OR 61 and -N(R 61 )C(O)N(R 61 ) C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 42 HA-C(O)R 61 , -C(O)OR 61 , -OC(O)R 61 and -OC(O)OR 61 C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 42 -C(O)N(R 61 )2, -N(R 61 )C(O)R 61 , -OC(O)N(R 61 )2, -N(R61 )C(O)OR 61 and -N(R 61 )C(O)N(R 61 ) C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 47 HA-C(O)R 61 , -C(O)N(R 61 )2, -N(R 61 )C(O)R 61 , -C(O)OR 61 , -OC(O)R 61 , -OC(O)N(R 61 )2, -N(R 61 )C(O)OR 61 , -OC(O)OR 61 and -N(R 61 )C(O)N(R 61 ) C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 47 HA-C(O)R 61 , -C(O)OR 61 , -OC(O)R 61 and -OC(O)OR 61 C substituted with one or more substituents independently selected from 1-6 In one embodiment, R 47 -C(O)N(R 61 )2, -N(R 61 )C(O)R 61 , -OC(O)N(R 61 )2, -N(R 61 )C(O)OR 61 and -N(R 61 )C(O)N(R 61 ) C substituted with one or more substituents independently selected from 1-6 It is an alkyl.

[0120] In one embodiment, R 41 , R 43 , R 44 and R 48 is independent -C 3-8 Carbocyclic ring, -3 to 10 membered heterocyclic ring, -(C1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle and the 3- to 10-membered heterocycle are optionally substituted. In certain embodiments, R 41 , R 43 , R 44 and R 48 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle and the 3- to 10-membered heterocycle are optionally substituted. In certain embodiments, R 41 , R 43 , R 44 and R 48 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle and 3- to 10-membered heterocycle are optionally independently selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 In certain embodiments, R is substituted with one or more substituents selected from alkyl, -OH, -CH, -CF, -CHF, -OBz, -OCH, -OCF, -SF, and -OCHF. 41 , R 43 , R 44 and R 48 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle and 3- to 10-membered heterocycle are optionally independently selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4In certain embodiments, R is substituted with one or more substituents selected from alkyl, -OH, -CH, -CF, -CHF, -OBz, -OCH, -OCF, and -OCHF. 41 , R 43 , R 44 and R 48 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle 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, -SF5, and -OCHF2. In certain embodiments, R 41 , R 43 , R 44 and R 48 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 In certain embodiments, the carbocycle and the 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halo, -OH, -CH, -CF, -CHF, -OBz, -OCH, and -OCHF. 41 , R 43 , R 44 and R 48 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 In certain embodiments, the carbocycle and the 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 41 , R 43 , R 44 and R 48 is independent - (C 1-4 Alkylene)-(C 3-8Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 In certain embodiments, the carbocycle and the 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, and -OCHF2. 41 , R 43 , R 44 and R 48 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 In certain embodiments, the carbocycle and the 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halo, -OH, -CH, -CF, -SF, and -OCH. 41 , R 43 , R 44 and R 48 is independent - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 In certain embodiments, the carbocycle and the 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from halo, -OH, -CH, -CF, and -OCH. 41 , R 43 , R 44 and R 48 are independently -CH2-(C 3-8 In one embodiment, R 41 , R 43 , R 44 and R 48 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. 41 , R43 , R 44 and R 48 is independent [ka] In one embodiment, R 48 teeth [ka] and R 44’ , R 43 and R 41 is independent [ka] In one embodiment, R 48 teeth [ka] and R 44 teeth [ka] and R 43 and R 41 is independent [ka] In one embodiment, R 48 teeth [ka] and R 44 teeth [ka] and R 43 teeth [ka] and R 41 teeth [ka] In one embodiment, R 48 teeth [ka] and R 44 teeth [ka] and R 43 and R 41 is independent [ka] In one embodiment, R 48 teeth [ka] and R 44 teeth [ka] and R 43 teeth [ka] and R 41 teeth [ka] It is.

[0121] In one embodiment, the cyclic peptide has the formula IIIa: [ka] It is expressed by:

[0122] In one embodiment, the cyclic peptide has formula IIIb: [ka] [In the formula, R 41 ', R 43’ , R 44’ and R 48’are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0123] In one embodiment, R 41 ', R 43’ , R 44’ and R 48’ is independent [ka] In one embodiment, R 48’ teeth [ka] and R 41 ', R 43’ and R 44’ is independent [ka] In one embodiment, R 48’ teeth [ka] and R 44’ teeth [ka] and R 41’ and R 43’ is independent [ka] In one embodiment, R 48’ teeth [ka] and R 44’ teeth [ka] and R 43’ teeth [ka] and R 41’ teeth [ka] In one embodiment, R 48’ teeth [ka] and R 44’ teeth [ka] and R 41’ and R 43’ is independent [ka] In one embodiment, R 48’ teeth [ka] and R 44’ teeth [ka] and R 43’ teeth [ka] and R 41’ teeth [ka] It is.

[0124] In one embodiment, the cyclic peptide has formula IIIc: [ka] [In the formula, R 41 ', R 43’ , R 44’ and R48’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0125] In one embodiment, the cyclic peptide has formula IIId: [ka] [In the formula, R 41 ', R 43’ , R 44’ and R 48’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0126] In some embodiments, the cyclic peptide has the formula IIIe: [ka] [In the formula, R 41 ', R 43’ , R 44’ and R 48’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0127] In one embodiment, the cyclic peptide has formula IIIf: [ka] [In the formula, R 41 ', R 43’ , R 44’ and R 48’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0128] In one embodiment, the cyclic peptide has formula IIIg: [ka] [In the formula, R 41 ', R 43’ , R 44’ and R 48’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0129] In one embodiment, the cyclic peptide has formula IIIh: [ka] [In the formula, R 41 ', R 43’ , R 44’ and R 48’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. It is expressed by:

[0130] In certain embodiments, the cyclic peptide is selected from those in Table 1 or a pharma- ceutically acceptable salt thereof.

[0131] In some embodiments, the cyclic peptides disclosed herein have a molecular weight of 1.0×10 -7 cm s -1 In some embodiments, the cyclic peptides disclosed herein have a cell permeability value of greater than 1.0×10 -6 cm s -1 In some embodiments, the cyclic peptides disclosed herein have a cell permeability value of greater than 1.0×10 -5 cm s -1 In some embodiments, the cyclic peptides disclosed herein have a cell permeability value of greater than 1.0×10 -4 cm s -1 In some embodiments, the cyclic peptides disclosed herein have a cell permeability value of greater than 1.0×10 -3 cm s -1In some embodiments, the cyclic peptides disclosed herein have a cell permeability value of greater than 0.01 cm s -1 In some embodiments, the cyclic peptides disclosed herein have a cell permeability value of greater than 0.1 cm s -1 In some embodiments, the cyclic peptides disclosed herein have a cell permeability value of greater than 1.0 cm s -1 In some embodiments, the cell permeability value of the cyclic peptides disclosed herein is determined by Caco-2 assay. In some embodiments, the cell permeability value of the cyclic peptides disclosed herein is determined by MDR1-MDCK assay.

[0132] In some embodiments, the cyclic peptides disclosed herein have a molecular weight of 5.0×10 -8 In some embodiments, the cyclic peptides disclosed herein have a solubility value of greater than 5.0×10 -7 In some embodiments, the cyclic peptides disclosed herein have a solubility value of greater than 5.0×10 -6 In some embodiments, the cyclic peptides disclosed herein have a solubility value of greater than 5.0×10 -5 In some embodiments, the cyclic peptides disclosed herein have a solubility value of greater than 5.0×10 -4 In some embodiments, the cyclic peptides disclosed herein have a solubility value of greater than 5.0×10 -3In some embodiments, the cyclic peptides disclosed herein have a solubility value of greater than 0.05M. In some embodiments, the cyclic peptides disclosed herein have a solubility value of greater than 0.5M. In some embodiments, the cyclic peptides disclosed herein have a solubility value of greater than 5.0M. In some embodiments, the solubility value of the cyclic peptides disclosed herein is determined by a kinetic solubility assay. In some embodiments, the solubility value of the cyclic peptides disclosed herein is determined by an equilibrium solubility assay. In some embodiments, the solubility value of the cyclic peptides disclosed herein is determined by a turbidimetric assay. In some embodiments, the solubility value of the cyclic peptides disclosed herein is determined by a turbidimetric assay. In some embodiments, the solubility value of the cyclic peptides disclosed herein is determined by a direct UV assay.

[0133] The compounds disclosed herein may, in some embodiments, be variously enriched, e.g. 2 H, 3 H, 11 C. 13 C and / or 14 It is used in a C-enriched isotopic form. Deuterated forms can be prepared 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 and thus extend the duration of action of the drug.

[0134] Unless otherwise specified, the compounds described herein are intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with 13 C or 14 Compounds having the present structure except for the replacement of a C-rich carbon are within the scope of this invention.

[0135] The compounds of the present invention optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be isotoped with, for example, deuterium ( 2 H), tritium (3 H), iodine-125( 125 I) or carbon-14( 14 The molecule may be labeled with an isotope such as 3C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br and 125 All isotopic substitutions at I are contemplated. All isotopic variations of the cyclic peptides disclosed herein, whether radioactive or not, are encompassed within the scope of the present invention.

[0136] In one embodiment, the compounds disclosed herein 1 Some or all of the H atoms 2 H atom is substituted. Methods for the synthesis of deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0137] Deuterium substituted compounds can be synthesized using a variety of methods, such as 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.

[0138] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Many deuterium-containing materials and building blocks can be purchased from chemical suppliers such as Aldrich Chemical Co.

[0139] The cyclic peptides disclosed herein also include crystalline and amorphous forms of these compounds, pharma- ceutically acceptable salts and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including hydrates), conformational polymorphs and amorphous forms of the compounds and mixtures thereof.

[0140] The compounds described herein may, in some cases, exist as diastereomers, enantiomers or other stereoisomeric forms. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms and the appropriate mixtures thereof. Separation of stereoisomers may be carried out by chromatography or formation of diastereomers and recrystallization or chromatographic separation or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, incorporated herein by reference). Stereoisomers may also be obtained by stereoselective synthesis.

[0141] The methods and compositions described herein encompass the use of amorphous forms as well as crystalline forms (also known as polymorphs). Similarly, active metabolites of these compounds having the same type of activity are within the scope of the present invention. Additionally, the compounds described herein may exist in unsolvated as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0142] Synthetic chemistry transformations and methods useful for the synthesis of the compounds described herein are known in the art and include, 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).

[0143] Isolation and purification of the chemicals and intermediates described herein can be carried out, if desired, by any suitable separation or purification method, such as, for example, filtration, extraction, crystallization, column chromatography, thin or thick layer chromatography, or a combination of these methods. Specific examples of suitable separation and isolation methods can be had by reference to the examples below. However, other equivalent separation or isolation methods can also be used.

[0144] The present invention is also intended to encompass the in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, and the like, of the administered compound, primarily by enzymatic processes. Thus, the present invention includes compounds produced by a process comprising administering a compound of the present invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering to an animal, such as a rat, mouse, guinea pig, monkey, or human, a detectable dose of a radiolabeled compound of the present invention, allowing sufficient time for metabolism, and withdrawing the conversion products from urine, blood, or other biological samples.

[0145] Pharmaceutical preparations The cyclic peptide of the present invention can be formulated into any suitable pharmaceutical formulation.The pharmaceutical formulation of the present invention typically comprises an active ingredient (e.g., the cyclic peptide disclosed herein) and one or more pharma- ceutically acceptable additives or carriers, including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers and adjuvants.In some embodiments, the acceptable carriers or additives for pharmaceutical formulations are selected from water, alcohol, glycerol, chitosan, alginate, chondroitin, vitamins, mineral oil and dimethylsulfoxide (DMSO).

[0146] The pharmaceutical preparation may be provided in any suitable form, which is determined based on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein may be formulated into a dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, pulmonary, transmucosal, inhalation and / or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral administration. For example, the pharmaceutical composition may be formulated into the form of a pill, tablet, capsule, inhalant, liquid suspension, liquid emulsion, gel or powder. In some embodiments, the pharmaceutical composition may be formulated as a unit dosage of liquid, gel, semi-liquid, semi-solid or solid form.

[0147] The amount of each cyclic peptide administered will depend on the mammal being treated, the severity of the disorder or condition, the rate of administration, the pharmacokinetics of the cyclic peptide, and the discretion of the prescribing physician, and in some embodiments, an effective dosage is provided in a pulsed regimen (i.e., administration of the compound on consecutive days followed by a rest period on consecutive days).

[0148] In some embodiments, the present invention provides a pharmaceutical composition for oral administration, comprising at least one cyclic peptide disclosed herein and pharmaceutical excipients suitable for oral administration.The composition is in the form of a solid, liquid, gel, semi-liquid or semi-solid.In some embodiments, the composition further comprises a second drug.

[0149] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration, comprising (i) a cyclic peptide disclosed herein; and (ii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises (iii) a third agent or even a fourth agent. In some embodiments, each compound or agent is present in a therapeutically effective amount. In other embodiments, one or more compounds or agents are present in a sub-therapeutic amount, and the compounds or agents act synergistically to provide a therapeutically effective pharmaceutical composition.

[0150] The pharmaceutical compositions of the present invention suitable for oral administration may be presented as separate dosage forms such as hard or soft capsules, cachets, troches, lozenges or tablets, or as liquids or aerosol sprays containing a predetermined amount of each of the active ingredients as a powder or granules, solutions or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions or dispersible powders or granules or syrups or elixirs. Such dosage forms typically include the step of bringing the active ingredients into association with carriers and can be prepared by any method of pharmacy. In general, the compositions are prepared by uniformly and intimately mixing the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired form. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compression, in a suitable device, of the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with additives including, but not limited to, binders, lubricants, inert diluents and / or surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered cyclic peptide moistened with an inert liquid diluent.

[0151] In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a cyclic peptide as disclosed herein and a pharmaceutical excipient suitable for injection, wherein the components and amounts of drugs in the composition are as described herein.

[0152] In some embodiments, the forms in which the cyclic peptides disclosed herein are formulated for administration by injection include aqueous or oily suspensions or emulsions using sesame oil, corn oil, cottonseed oil, or peanut oil, as well as the use of elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0153] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of a coating agent such as lecithin to maintain the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the growth of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0154] Sterile injectable solutions are prepared by incorporating the cyclic peptides disclosed herein in the required amount in a suitable solvent with various other ingredients as listed above, as needed, followed by filtration sterilization. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium and the other required ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, one preferred method of preparation is vacuum drying and freeze-drying technology, which produces a powder of the active ingredient and any additional desired ingredient from a previously sterile-filtered solution.

[0155] Pharmaceutical compositions may also be prepared from the cyclic peptides described herein and one or more pharma- ceutical acceptable excipients 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).

[0156] The present invention also provides kits. The kits may include the cyclic peptides disclosed herein and one or more additional agents in suitable packaging, along with written instructions for use, clinical trial results, a list of side effects, and the like. Such kits may also include information, such as bibliographic references, package inserts, clinical trial results and / or summaries thereof, that establish the activity and / or benefits of the composition and / or describe dosage, administration, side effects, drug interactions, or other information useful to medical practitioners. Such information may include the results of various studies, for example, studies using laboratory animals, including in vivo models, and studies based on human clinical trials. The kits may further include other agents. In some embodiments, the cyclic peptides disclosed herein and agents are provided as separate compositions in separate containers within the kit. In some embodiments, the cyclic peptides disclosed herein and agents are provided as one composition within a container of the kit. Suitable packaging and additional items for use (e.g., measuring cups for liquid formulations, foil wrapping to minimize exposure to air, etc.) are known in the art and may be included in the kit. The kits described herein may be provided, sold and / or recommended to healthcare professionals, including physicians, nurses, pharmacists, formulary personnel, etc. The kits may also, in some embodiments, be sold directly to consumers.

[0157] How to use In some embodiments, the invention provides methods of inhibiting MDM2 comprising administering to a subject in need of treatment a cyclic peptide described herein. In other embodiments, the invention provides methods of inhibiting MDM2 and MDM4 comprising administering to a subject in need of treatment a cyclic peptide described herein.

[0158] In another embodiment, the present invention provides a method for treating a disease or disorder in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a cyclic peptide described herein.In some embodiments, the method for treating a disease or disorder comprises administering to the subject an MDM2 inhibitor.In some embodiments, the method for treating a disease or disorder comprises administering to the subject an MDM2 / MDM4 dual inhibitor.In some embodiments, the cyclic peptide disclosed herein is an MDM2 inhibitor.In some embodiments, the cyclic peptide disclosed herein is an MDM2 / MDM4 dual inhibitor.

[0159] In some embodiments, the disease or disorder is cancer.In some embodiments, the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myeloid leukemia.In some embodiments, the disease or disorder is associated with the proliferation of senescent cells.In some embodiments, the disease or disorder is associated with the proliferation of senescent cells is selected from type 2 diabetes, Huntington's disease, alcoholic fatty liver disease and hyperlipidemia.In some embodiments, the disease or disorder is associated with the proliferation of senescent cells is selected from cardiovascular disease, inflammatory disease, autoimmune disease, metabolic disease, lung disease, eye disease, ear disease, kidney disease and skin disease.

[0160] In further embodiments, disclosed herein are methods of treating a cancer condition, wherein the cyclic peptides disclosed herein (e.g., MDM2 inhibitors or MDM2 / MDM4 dual inhibitors) are effective in one or more of inhibiting the proliferation of cancer cells, inhibiting metastasis of cancer cells, reducing the severity or incidence of symptoms associated with the presence of cancer cells, and enhancing immune response against tumor cells. In some embodiments, the method comprises administering to cancer cells a therapeutically effective amount of the cyclic peptides disclosed herein. In some embodiments, the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. In some embodiments, the cyclic peptides disclosed herein are MDM2 inhibitors. In some embodiments, the cyclic peptides disclosed herein are MDM2 / MDM4 dual inhibitors. In some embodiments, the administration is performed in vitro. In some embodiments, the administration is performed in vivo.

[0161] As used herein, a therapeutically effective amount of a cyclic peptide disclosed herein refers to an amount sufficient to perform the intended application, including, but not limited to, disease treatment, as defined herein. Also contemplated in the subject methods is the use of sub-therapeutic amounts of the cyclic peptides disclosed herein for the treatment of the intended disease state.

[0162] The amount of cyclic peptide disclosed herein to be administered will vary depending on the intended application (in vitro or in vivo) or the subject and disease state to be treated, e.g., the subject's weight and age, the severity of the disease state, the method of administration, etc., but can be readily determined by one of skill in the art.

[0163] In some embodiments, therapeutic efficacy is evaluated based on the effect of treating a proliferative disorder such as cancer. In general, the therapeutic efficacy of the methods and compositions disclosed herein for treating a proliferative disorder (e.g., cancer, benign or malignant) can be evaluated by the extent to which the methods and compositions promote the inhibition of tumor cell proliferation, inhibition of tumor angiogenesis, tumor cell eradication, tumor growth rate reduction and / or size reduction of at least one tumor. Several parameters are disclosed herein to be considered in determining therapeutic efficacy. The appropriate combination of parameters for a particular situation can be established by the clinician. The progress of the methods disclosed herein in treating cancer (e.g., tumor size reduction or cancer cell eradication) can be confirmed using any suitable method, such as the methods currently used in clinics 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 the reduction in tumor size. Tumor size can be quantified using any suitable technique, such as measuring size or estimating tumor volume using available computer software, such as FreeFlight software developed by Wake Forest University, which allows accurate estimation of tumor volume. Tumor size may be determined by tumor visualization using, for example, CT, ultrasound, SPECT, spiral CT, MRI, photography, etc. In embodiments in which the tumor is surgically removed after completion of the treatment period, the presence of tumor tissue and tumor size may be determined by gross analysis of the resected tissue and / or pathological analysis of the resected tissue.

[0164] In certain preferred embodiments, the methods and compositions disclosed herein result in stabilized tumor growth (i.e., one or more tumors do not increase in size by more than 1%, 5%, 10%, 15%, or 20% and / or do not metastasize). In certain embodiments, 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 more. In certain embodiments, 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 more. In certain embodiments, 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 more. Preferably, the methods disclosed herein reduce 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 eliminated or reduced to below the detection limit. In certain embodiments, the subject remains tumor-free (e.g., in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after treatment. In certain embodiments, the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months after treatment. In certain embodiments, the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years following treatment.

[0165] In some embodiments, the effectiveness of the methods disclosed herein in reducing tumor size can be determined by measuring the percentage of necrotic (i.e., dead) tissue of the surgically resected tumor after the completion of the treatment period.In some further embodiments, the treatment is therapeutically effective if the necrotic percentage of the resected 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 necrotic percentage of the resected tissue is 100%, i.e., no tumor tissue is present or detectable.

[0166] The efficacy of the methods disclosed herein can be determined by several secondary parameters. Examples of secondary parameters include, but are not limited to, detection of new tumors, detection of tumor antigens or markers (e.g., CEA, PSA, or CA-125), biopsy, surgical downstaging (i.e., conversion of the tumor from surgically unresectable to resectable), PET scans, quality of life assessments such as survival, disease-free survival, time to disease progression, and clinical benefit response assessments, all of which are intended to measure the overall progression (or regression) of cancer in humans. Biopsies are particularly useful for detecting eradication of cancer cells in tissue. Radioimmunodetection (RAID) is the localization and staging of tumors using serum levels of markers (antigens) produced by and / or associated with tumors ("tumor markers" or "tumor-associated antigens"), which can be useful as a pretreatment diagnostic predictive indicator, a posttreatment diagnostic indicator of recurrence, and a posttreatment indicator of therapeutic efficacy. Examples of tumor markers or tumor-associated antigens that can be evaluated as indicators of therapeutic efficacy include, but are not limited to, carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), CA-125, CA19-9, ganglioside molecules (e.g., GM2, GD2 and GD3), MART-1, heat shock proteins (e.g., gp96), 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 the art. RAID technology combined with endoscopic detection can also effectively distinguish small tumors from surrounding tissues (see, e.g., U.S. Pat. No. 4,932,412).

[0167] In further preferred embodiments, treatment of a human cancer patient with the methods disclosed herein is evidenced by one or more of the following outcomes: (a) complete disappearance of the tumor (i.e., complete response), (b) a reduction in tumor size of about 25% to about 50% for at least 4 weeks after completion of the treatment period compared to the tumor size before treatment, (c) a reduction in tumor size of at least about 50% for at least 4 weeks after completion of the treatment period compared to the tumor size before the treatment period, and (d) at least a 2% reduction in the level of a particular tumor-associated antigen (e.g., about a 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% reduction) for about 4 to 12 weeks after completion of the treatment period compared to the level of the tumor-associated antigen before the treatment period. Although at least a 2% reduction in the level of a tumor-associated antigen is preferred, any reduction in the level of a tumor-associated antigen is evidence of treatment of the cancer in the patient with the methods disclosed herein. For example, for unresectable, locally advanced pancreatic cancer, treatment may be evidenced by at least a 10% decrease in CA19-9 tumor associated antigen levels 4-12 weeks after completion of the treatment period, compared to the CA19-9 levels prior to the treatment period. Similarly, for locally advanced rectal cancer, treatment may be evidenced by at least a 10% decrease in CEA tumor associated antigen levels 4-12 weeks after completion of the treatment period, compared to the CEA levels prior to the treatment period.

[0168] With regard to quality of life assessments such as clinical benefit response criteria, the therapeutic benefit of treatment according to the invention may be demonstrated in terms of pain intensity, analgesic consumption and / or Karnofsky performance status score. Alternatively or additionally, treatment of a human cancer patient is evidenced by (a) at least a 50% reduction (e.g., at least a 60%, 70%, 80%, 90% or 100% reduction) in pain intensity reported by the patient, such as for any consecutive 4-week period in the 12-week period after completion of treatment, compared to the pain intensity reported by the patient prior to treatment; (b) at least a 50% reduction (e.g., at least a 60%, 70%, 80%, 90% or 100% reduction) in pain medication consumption reported by the patient, such as for any consecutive 4-week period in the 12-week period after completion of treatment, compared to the pain medication consumption reported by the patient prior to treatment; and / or (c) at least a 20-point increase (e.g., at least a 30-point, 50-point, 70-point or 90-point increase) in Karnofsky performance status score reported by the patient, such as for any consecutive 4-week period in the 12-week period after completion of the treatment, compared to the Karnofsky performance status score reported by the patient prior to the treatment period.

[0169] Treatment of a proliferative disorder (e.g., cancer, whether benign or malignant) in a human patient is desirably evidenced by one or more (any combination) of the above results, although alternative or additional results of the described tests and / or other tests may evidence treatment efficacy.

[0170] In some embodiments, tumor size is reduced as a result of the methods disclosed herein, preferably without significant adverse events in the subject. Adverse events are classified or "graded" by the National Cancer Institute's (NCI) Cancer Therapy Evaluation Program (CTEP), with grade 0 representing the least adverse side effects and grade 4 representing the most severe adverse events. Desirably, the methods disclosed herein are associated with minimal adverse events, e.g., grade 0, grade 1 or grade 2 adverse events, as graded by CTEP / NCI. However, as described herein, tumor size reduction, although preferred, is not essential, since the actual size of the tumor may not decrease, regardless of tumor cell eradication. Eradication of cancer cells is sufficient to achieve a therapeutic effect. Similarly, any reduction in tumor size is sufficient to achieve a therapeutic effect.

[0171] Detection, monitoring and grading of various human cancers are further described in Cancer Facts and Figures 2001, American Cancer Society, New York, NY, and International Patent Application WO01 / 24684. Thus, clinicians can use standard tests to determine the effectiveness of various embodiments of the methods disclosed herein in treating cancer. However, in addition to tumor size and spread, clinicians can also consider the quality of life and survival of the patient in assessing the effectiveness of treatment.

[0172] In some embodiments, administration of the cyclic peptides disclosed herein provides improved therapeutic efficacy. Improved efficacy can be measured using any method known in the art, including but not limited to those described herein. In some embodiments, improved therapeutic efficacy is 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 improvement using appropriate indicators (e.g., tumor size reduction, tumor size stability period, period free of metastatic events, disease-free survival period). Improved efficacy can also be expressed as a fold improvement, such as at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 1000-fold, 10000-fold or more, using appropriate indicators (e.g., tumor size reduction, time to stable tumor size, time free of metastatic events, disease-free survival).

[0173] Measuring the inhibition of the biological effect of MDM2 and / or MDM4 can include performing an assay on a biological sample, such as a sample from a subject. Depending on the assay, any of a variety of samples can be selected. Examples of samples include, but are not limited to, blood samples (e.g., plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0174] The subject treated with the cyclic peptides disclosed herein can be monitored to determine the effectiveness of treatment, and the treatment regimen can be adjusted based on the subject's physiological response to treatment. For example, when the inhibition of the biological effect of MDM2 and / or MDM4 inhibition exceeds or falls below a threshold, the dosage or frequency can be decreased or increased, respectively. The method further includes continuing the treatment if it is determined that the treatment is effective. The method can include maintaining, tapering, decreasing or stopping the dosage of the compound in the treatment if it is determined that the treatment is effective. The method can also include increasing the dosage of the compound in the treatment if it is determined that the treatment is not effective. Alternatively, the method can include stopping the treatment if it is determined that the treatment is not effective. In some embodiments, the 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 an adverse reaction. The biological effect can be a change in any of a variety of physiological indicators.

[0175] Generally, MDM2 inhibitors are compounds that inhibit one or more biological effects of MDM2. Examples of biological effects of MDM2 include, but are not limited to, inhibition of p53 ubiquitination and p53 transcriptional activation. Such biological effects can be inhibited by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

[0176] In general, MDM2 / MDM4 dual inhibitors are compounds that inhibit one or more biological effects of MDM2 and MDM4. Examples of biological effects of MDM2 and MDM4 include, but are not limited to, inhibition of p53 ubiquitination and p53 transcriptional activation. Such biological effects can be inhibited by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

[0177] In some other embodiments, the subject method is useful for treating disease conditions associated with MDM2. Any disease condition that is directly or indirectly derived from abnormal activity or expression level of MDM2 can be the intended disease condition. In some other embodiments, the subject method is useful for treating disease conditions associated with MDM2 and MDM4. Any disease condition that is directly or indirectly derived from abnormal activity or expression level of MDM2 and MDM4 can be the intended disease condition. In some embodiments, the disease condition is a proliferative disorder, including but not limited to cancer, as described herein. In some embodiments, the disease condition is cancer. In some embodiments, the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myeloid leukemia.

[0178] In some embodiments, the compounds of the present invention are administered to treat conditions other than cancer. In some embodiments, the compounds of the present invention induce cell death of senescent cells. In some embodiments, the induction of cell death of senescent cells treats conditions associated with the proliferation of senescent cells. In some embodiments, 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.

[0179] Non-limiting examples of cardiovascular diseases associated with senescent cell proliferation 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, cardiac fibrosis, cerebral aneurysm, and stroke.

[0180] Non-limiting 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.

[0181] Non-limiting examples of metabolic diseases associated with senescent cell proliferation include, but are not limited to, diabetes and metabolic syndrome.

[0182] Non-limiting examples of pulmonary 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.

[0183] Non-limiting examples of eye diseases include, but are not limited to, cataracts, macular degeneration, glaucoma, and keratoconus.

[0184] Non-limiting examples of ear diseases associated with senescent cell proliferation include, but are not limited to, conductive hearing loss.

[0185] Non-limiting examples of skin diseases associated with senescent cell proliferation include, but are not limited to, eczema, psoriasis, hyperpigmentation, impaired cutaneous wound healing, hair loss, rash, atopic dermatitis, urticaria, diseases and disorders associated with photosensitivity or photoaging, wrinkles, pruritus (itch), paresthesia, eczema, eosinophilic dermatosis, reactive neutrophilic dermatosis, pemphigus, pemphigoid, immune bullous dermatosis, cutaneous fibrohistiocytic proliferation, cutaneous lymphoma, and cutaneous lupus.

[0186] Some embodiments contemplate human subjects, such as subjects who have been diagnosed as having or at risk of developing or acquiring a proliferative disorder condition. Some other embodiments contemplate non-human subjects, such as non-human primates, such as macaques, chimpanzees, gorillas, green monkeys, orangutans, baboons, or other non-human primates, including non-human subjects that may be known in the art as preclinical models. Some other embodiments contemplate non-human subjects that are mammals, such as mice, rats, rabbits, pigs, sheep, horses, cows, goats, gerbils, hamsters, guinea pigs, or other mammals. Other embodiments are also contemplated in which the subject or biological source may be a non-mammalian vertebrate, such as other higher vertebrates or avian, amphibian, or reptile species, or other subjects or biological sources. In some embodiments of the invention, transgenic animals are used. A transgenic animal is a non-human animal in which one or more of the animal's cells contain a non-endogenous (i.e., heterologous) nucleic acid, either present in some of its cells as an extrachromosomal element or stably integrated into the germline DNA (i.e., most or all of the genomic sequence of its cells).

[0187] Combination Therapy In some embodiments, disclosed herein are methods of further combination therapy using, in addition to the cyclic peptides described herein, one or more second agents known to regulate other pathways of the target protein or other components of the same pathway or are an overlapping set of target proteins. In some embodiments, such therapy includes, but is not limited to, the combination of compositions including the cyclic peptides described herein and one or more chemotherapeutic agents, therapeutic antibodies, immunotherapeutic agents, and radiation treatments to provide synergistic or additive therapeutic effects, when desired.

[0188] In some embodiments, disclosed herein are methods and pharmaceutical compositions for inhibiting abnormal cell growth in a mammal, comprising a combination of an amount of a cyclic peptide described herein and an amount of an anti-cancer agent (e.g., a chemotherapeutic agent). Many chemotherapeutic agents are currently known in the art and can be used in combination with the cyclic peptides disclosed herein.

[0189] In some embodiments, disclosed herein are methods of using the cyclic peptides or pharmaceutical compositions described herein in combination with other tumor treatment approaches, including surgery, ionizing radiation, photodynamic therapy, or the use of, for example, corticosteroids, hormones, or implants as radiation sensitizers.

[0190] Exemplary Embodiments Embodiment I-1. 9 to 11 amino acid residues independently selected from amino acid residues that are uncharged at physiological pH; the first and second beta hairpin regions; at least one amino acid residue having a side chain comprising a moiety selected from ether, ester, carbonate, amide, carbamate, and urea; and the following: at least four amino acid residues comprising rings independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles, wherein at least one of the monocyclic carbocycles and monocyclic heterocycles is substituted; at least 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 optionally substituted; and at least three amino acid residues containing rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl; A cyclic peptide characterized by one of the following:

[0191] Embodiment I-2. The cyclic peptide of embodiment I-1, wherein the first beta hairpin region comprises two consecutive amino acid residues.

[0192] Embodiment I-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, wherein the phenyl group of L-NMe-Phe is optionally halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4 The cyclic peptide of embodiment I-2, substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2.

[0193] Embodiment I-4. The cyclic peptide of embodiment I-3, 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.

[0194] Embodiment I-5. The cyclic peptide of embodiment I-4, wherein for two consecutive residues, one is D and the other is L.

[0195] Embodiment I-6. The cyclic peptide of embodiment I-5, wherein the two consecutive amino acid residues are D-Pro and L-Pro.

[0196] Embodiment I-7. The cyclic peptide of embodiment I-5, wherein the two consecutive amino acid residues are D-NMe-Val and L-Pro.

[0197] Embodiment I-8. The two consecutive amino acid residues are D-Pro and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4The cyclic peptide of embodiment I-5, which is substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2.

[0198] Embodiment I-9. The cyclic peptide of any of embodiments I-1 to I-8, wherein the second beta hairpin region comprises a second two consecutive amino acid residues.

[0199] Embodiment I-10. The cyclic peptide of embodiment I-9, wherein the second beta hairpin region comprises a second two consecutive residues independently selected from D-Pro, a peptoid, a DN-alkylated amino acid, and a LN-alkylated amino acid.

[0200] Embodiment I-11. The cyclic peptide of embodiment I-10, wherein the second beta hairpin region comprises a second two consecutive residues independently selected from D-Pro, a peptoid, and a LN-alkylated amino acid.

[0201] Embodiment I-12. The cyclic peptide of embodiment I-11, wherein for the second two consecutive residues, one is a peptoid and the other is a LN-alkylated amino acid.

[0202] Embodiment I-13. The cyclic peptide of embodiment I-12, wherein for the second two consecutive residues, one is L-NMe-Ala and the other is N-(2-methoxyethyl)glycine.

[0203] Embodiment I-14. The cyclic peptide of embodiment I-10, wherein for the second two consecutive residues, one is a DN-alkylated amino acid and the other is a LN-alkylated amino acid.

[0204] Embodiment I-15. The cyclic peptide of embodiment I-14, wherein for the second two consecutive residues, one is D-NMe-Ala and the other is L-NMe-Ala.

[0205] Embodiment I-16. The cyclic peptide of embodiment I-11, wherein for the second two consecutive residues, one is a DN-alkylated amino acid and the other is a peptoid.

[0206] Embodiment I-17. The cyclic peptide of embodiment I-16, wherein for the second two consecutive residues, one is D-NMe-Ala and the other is N-(2-methoxyethyl)glycine.

[0207] Embodiment I-18. The cyclic peptide of any of embodiments I-1 to I-17, wherein at least two consecutive amino acids separate the first beta hairpin region and the second beta hairpin region.

[0208] Embodiment I-19. The cyclic peptide of embodiment I-18, wherein at least three contiguous amino acids separate the first beta hairpin region and the second beta hairpin region.

[0209] Embodiment I-20. A cyclic peptide according to any one of embodiments I-1 to I-19, wherein the molecular weight of the cyclic peptide is 800 to 1300 Da.

[0210] Embodiment I-21. The cyclic peptide of embodiment I-20, wherein the molecular weight of the cyclic peptide is 800 to 1200 Da.

[0211] Embodiment I-22. The cyclic peptide of embodiment I-21, wherein the molecular weight of the cyclic peptide is 900 to 1200 Da.

[0212] Embodiment I-23. A cyclic peptide according to any of embodiments I-1 to I-22, characterized by at least four amino acid residues comprising rings independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles, wherein at least one of the monocyclic carbocycles and monocyclic heterocycles is substituted.

[0213] Embodiment I-24. The optionally substituted monocyclic carbocycle is a phenyl and the optionally substituted monocyclic heterocycle is a heteroaryl ring, wherein at least one phenyl or heteroaryl ring is selected from the group consisting of halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 The cyclic peptide of embodiment I-23, substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2.

[0214] Embodiment I-25. The cyclic peptide of embodiment I-23 or I-24, wherein the optionally substituted monocyclic carbocycle is a phenyl and the optionally substituted monocyclic heterocycle is a heteroaryl ring, wherein 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.

[0215] Embodiment I-26. The cyclic peptide of any of embodiments I-23 to I-25, wherein each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole and imidazole, any of which may be substituted.

[0216] Embodiment I-27. A cyclic peptide of any of embodiments I-1 to I-22, characterized by at least 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 optionally substituted.

[0217] Embodiment I-28. The cyclic peptide of embodiment I-27, wherein each of the at least four amino acids having a side chain selected from -alkylene-(optionally substituted monocyclic carbocycle) and -alkylene-(optionally substituted monocyclic heterocycle) are not adjacent to one another.

[0218] Embodiment I-29. The cyclic peptide of embodiment I-27 or I-28, wherein two of the at least four amino acids having side chains selected from -alkylene-(optionally substituted monocyclic carbocycle) and -alkylene-(optionally substituted monocyclic heterocycle) are adjacent to one another.

[0219] Embodiment I-30. Each monocyclic carbocycle is a phenyl and each monocyclic heterocycle is a heteroaryl ring, wherein each phenyl and heteroaryl ring is independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 The cyclic peptide of any of embodiments I-27 to I-29, which is substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2.

[0220] Embodiment I-31. The cyclic peptide of any of embodiments I-27 to I-30, wherein each monocyclic carbocycle is a phenyl and each monocyclic heterocycle is a heteroaryl ring, wherein 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.

[0221] Embodiment I-32. The cyclic peptide of any of embodiments I-27 to I-31, wherein each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole and imidazole, any of which is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2.

[0222] Embodiment I-33. The cyclic peptide of any of embodiments I-1 to I-22, characterized in that at least three amino acid residues contain rings independently selected from optionally substituted phenyl and optionally substituted monocyclic heteroaryl.

[0223] Embodiment I-34. Each phenyl and heteroaryl ring is independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 The cyclic peptide of embodiment I-33, substituted with one or more substituents independently selected from alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2.

[0224] Embodiment I-35. The cyclic peptide of embodiment I-33 or I-34, wherein 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.

[0225] Embodiment I-36. The cyclic peptide of any of embodiments I-33 to I-35, wherein each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole and imidazole, any of which is optionally substituted with one or more substituents independently selected from halo, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3 and -OCHF2.

[0226] Embodiment I-37. The cyclic peptide of any of embodiments I-1 to I-36, wherein at least three of the backbone nitrogen atoms of the cyclic peptide are tertiary nitrogens.

[0227] Embodiment I-38. The cyclic peptide of embodiment I-37, wherein four or five of the main chain nitrogen atoms are tertiary nitrogens.

[0228] Embodiment I-39. The cyclic peptide of embodiment I-38, wherein four of the backbone nitrogen atoms of the cyclic peptide are tertiary nitrogens.

[0229] Embodiment I-40. The cyclic peptide of embodiment I-38, wherein five of the backbone nitrogen atoms of the cyclic peptide are tertiary nitrogens.

[0230] Embodiment I-41. The cyclic peptide of any of Embodiments I-37 to I-40, wherein one or more of the tertiary main chain nitrogen atoms is part of a heterocycloalkyl ring.

[0231] Embodiment I-42. One or more of the tertiary nitrogens has an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituents are independently selected from halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, -C 1-4 The cyclic peptide of any of embodiments I-37 to I-41, wherein -OCH3, -OCF3, -SF5 and -OCHF2 are selected from alkyl, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2.

[0232] Embodiment I-43. A cyclic peptide of any of embodiments I-37 to I-42, wherein one or more of the tertiary nitrogens have an optionally substituted C1-C6 alkyl substituent independently selected at each tertiary nitrogen, where the C1-C6 alkyl substituents are independently selected from halo, -OBz, -OCH3, -OCF3 and -OCHF2.

[0233] Embodiment I-44. Each tertiary nitrogen is independently [ka] or [ka] where R A optionally halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C 1-4C1-C6 alkyl substituted with one or more substituents independently selected from alkyl, -OBz, -OCH3, -OCF3 and -OCHF2, wherein [ka] The cyclic peptide of any of embodiments I-37 to I-43, wherein indicates the point of attachment to the adjacent amino acid residue.

[0234] Embodiment I-45. Each tertiary nitrogen is independently [ka] or [ka] where R A is a C1-C6 alkyl optionally substituted with one or more substituents independently selected from halo, -OBz, -OCH3, -OCF3 and -OCHF2, where [ka] The cyclic peptide of any of embodiments I-37 to I-44, wherein indicates the point of attachment to the adjacent amino acid residue.

[0235] Embodiment I-46. The cyclic peptide of any of embodiments I-1 to I-45, wherein the cyclic peptide has 10 amino acid residues.

[0236] Embodiment I-47. Formula I: [ka] [During the ceremony, R 1 , R 3 and R 8 are independently hydrogen, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8Carbocyclic and 3-10 membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 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 each optionally is -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl; wherein the carbocycle and heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 2 and R 12 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 4 is hydrogen, C 1-4Alkyl, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 Carbocyclic and 3-10 membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; and 1-4 Alkyl is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 4 and R 14 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 5 is hydrogen or C 1-4 alkyl or R 5 and R 15 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 6 is hydrogen, C 1-4 Alkyl, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 Carbocyclic and 3-10 membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; and 1-4 Alkyl is optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; R 7 are hydrogen; and each optionally is halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 7 and R 17 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; 2 and R 7 at least one of is not hydrogen or methyl; R 9is hydrogen or C 1-4 alkyl or R 9 and R 19 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 10 are hydrogen; and each optionally is halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 10 and R 20 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 11 , R 13 , R 16and R 18 are independently hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 12 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 12 and R 2 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 14 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 14 and R 4 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 15 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 15 and R 5 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 17 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 17 and R 7 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 19 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 19 and R 9 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 20 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 20 and R 10 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; and R 21 is independently at each occurrence hydrogen; and each optionally represents halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 3-12 Carbocyclic ring, 3-12 membered heterocyclic ring, -O(C 1-10 alkyl), -O(C 2-10 alkenyl), -O(C 2-10 alkynyl), -O(C 3-8 C substituted with one or more substituents independently selected from -O(carbocyclic ring) and -O(3-10 membered heterocyclic ring) 1-10 Alkyl, C 2-10Alkenyl, C 2-10 Alkynyl, C 3-8 is selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring. A cyclic peptide represented by:

[0237] Embodiment I-48. Formula II: [ka] [During the ceremony, R 21 , R 23 , R 26 and R 28 are independently hydrogen, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The carbocycle 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 22 is hydrogen; and each optionally is -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl; wherein the carbocycle and heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 22 and R 32 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 24 is hydrogen or C 1-4 alkyl or R 24 and R 34 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 25 is hydrogen or C 1-4 alkyl or R 25 and R 35 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 27 are hydrogen; and each optionally is halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21)2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 27 and R 37 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; 22 and R 27 at least one of is not hydrogen or methyl; R 29 is hydrogen or C 1-4 alkyl or R 29 and R 39 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 30 are hydrogen; and each optionally is halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 30 and R 40 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 31 , R 33 , R 36 and R 38 are independently hydrogen; and C optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl; R 32 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 32 and R 22 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 34 is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4alkyl or R 34 and R 24 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 35 is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl or R 35 and R 25 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 37 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 37 and R 27 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 39 is hydrogen; and optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2. 1-4 alkyl or R 39 and R 29 together with the intervening atoms form a 5- to 7-membered heterocycloalkyl; R 40 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 40 and R 30 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; and R 41is independently at each occurrence hydrogen; and each optionally represents halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 3-12 Carbocyclic ring, 3-12 membered heterocyclic ring, -O(C 1-10 alkyl), -O(C 2-10 alkenyl), -O(C 2-10 alkynyl), -O(C 3-8 C substituted with one or more substituents independently selected from -O(carbocyclic ring) and -O(3-10 membered heterocyclic ring) 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 is selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring. The cyclic peptide of embodiment I-47, represented by:

[0238] Embodiment I-49.R 31 , R 33 , R 36 , R 37 and R 38 The cyclic peptide of embodiment I-48, wherein each is hydrogen.

[0239] Embodiment I-50.R 32 , R 34 , R 35 , R 39 and R 40 The cyclic peptide of embodiment I-48 or 49, wherein at least four of are not hydrogen.

[0240] Embodiment I-51.R 32 , R 34 , R 35 , R 39 and R 40 The cyclic peptide of embodiment I-50, wherein four of are not hydrogen.

[0241] Embodiment I-52.R 32 , R 34 , R 35 , R 39and R 40 The cyclic peptide of embodiment I-50, wherein is not hydrogen.

[0242] Embodiment I-53.R 24 and R 34 , R 25 and R 35 and R 29 and R 39 The cyclic peptide of any of embodiments I-48 to I-52, wherein at least one of is taken together with the intervening atoms to form a 5- to 7-membered heterocycloalkyl.

[0243] Embodiment I-54.R 24 and R 34 The cyclic peptide of embodiment I-53, wherein together with the intervening atoms form a 5-6 membered heterocycloalkyl.

[0244] Embodiment I-55.R 25 and R 35 The cyclic peptide of embodiment I-53, wherein together with the intervening atoms form a 5-6 membered heterocycloalkyl.

[0245] Embodiment I-56.R 32 , R 39 and R 40 The cyclic peptide of any of embodiments I-48 to I-55, wherein each of is selected from methyl and methoxyethyl.

[0246] Embodiment I-57.R 32 , R 34 , R 39 and R 40 The cyclic peptide of any of embodiments I-48 to I-53, I-55 or I-56, wherein each of is selected from methyl and methoxyethyl.

[0247] Embodiment I-58.R 39 optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; 2-4 alkyl or R 29 and R39 The cyclic peptide of any of embodiments I-48 to I-55, wherein together with the intervening atoms form a 5- to 7-membered heterocycloalkyl.

[0248] Embodiment I-59.R 39 optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2; 2-4 The cyclic peptide of embodiment I-58, wherein the cyclic peptide is alkyl.

[0249] Embodiment I-60.R 40 optionally substituted with one or more substituents independently selected from halo, -OH, -OBz, -OCH3, -OCF3 and -OCHF2; 1-4 The cyclic peptide of any of embodiments I-48 to I-55, wherein R is alkyl.

[0250] Embodiment I-61.R 22 , R 27 and R 30 C 1-6 The cyclic peptide of any of embodiments I-48 to I-60, wherein the cyclic peptide is selected from alkyl.

[0251] Embodiment I-62.R 22 , R 27 and R 30 The cyclic peptide of embodiment I-61, wherein is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl.

[0252] Embodiment I-63.R 22 and R 27 is independent -C(O)R 41 , -C(O)N(R 41 )2, -N(R 41 )C(O)R 41 , -C(O)OR 41 , -OC(O)R 41 , -OC(O)N(R 41 )2, -N(R 41 )C(O)OR 41 , -OC(O)OR41 and -N(R 41 )C(O)N(R 41 ) C substituted with one or more substituents independently selected from 1-6 The cyclic peptide of any of embodiments I-48 to I-60, wherein the cyclic peptide is selected from alkyl.

[0253] Embodiment I-64.R 22 -C(O)R 41 , -C(O)OR 41 , -OC(O)R 41 and -OC(O)OR 41 C substituted with one or more substituents independently selected from 1-6 The cyclic peptide of embodiment I-63, wherein the cyclic peptide is alkyl.

[0254] Embodiment I-65.R 21 , R 23 , R 26 and R 28 Independently - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The cyclic peptide of any of embodiments I-48 to I-64, wherein the carbocycle and the 3- to 10-membered heterocycle are optionally substituted.

[0255] Embodiment I-66.R 21 , R 23 , R 26 and R 28 Independently, -CH2-(C 3-8 The cyclic peptide of embodiment I-65, wherein the cyclic peptide is selected from -CH2- (carbocycle) and -CH2- (3- to 10-membered heterocycle).

[0256] Embodiment I-67.R 21 , R 23 , R 26 and R 28 The cyclic peptide of embodiment I-66, wherein is independently selected from phenylmethyl and pyridinylmethyl, wherein phenyl and pyridinyl are optionally substituted.

[0257] Embodiment I-68.R 21 , R 23 , R 26 and R 28 Independent [ka] The cyclic peptide of embodiment I-67, selected from:

[0258] Embodiment I-69. The compound has the formula IIa: [ka] The cyclic peptide of any of embodiments I-48 to I-68, represented by:

[0259] Embodiment I-70. The compound has the formula IIb: [ka] [In the formula, R 21’ , R 23’ , R 26’ and R 28’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. The cyclic peptide of embodiment I-69, represented by:

[0260] Embodiment I-71. Formula III: [ka] [During the ceremony, R 41 , R 43 , R 44 and R 48 are independently hydrogen, -(C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8Carbocyclic and 3-10 membered heterocyclic rings are optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 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 each optionally is -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 alkynyl; wherein the carbocycle and heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 42 and R 52 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 45 is hydrogen or C 1-4alkyl or R 45 and R 55 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 46 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 47 are hydrogen; and each optionally is halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 47 and R 57 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; 42 and R 47 at least one of is not hydrogen or methyl; R 49 is hydrogen or C 1-4 alkyl or R 49 and R 59 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 50 are hydrogen; and each optionally is halo, C 1-4 Alkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -N(R 21 )C(O)OR 21 , -OC(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -S(O)R 21 , -S(O)2R 21 , -P(O)(OR 21 )2, -OP(O)(OR 21 )2, =O, =S, =N(R 21 ), C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10carbocycle and a 3- to 10-membered heterocycle; wherein the carbocycle and the heterocycle are independently optionally selected from halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 substituted with one or more substituents independently selected from alkyl, -OH, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5, and -OCHF2; or R 50 and R 60 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 51 , R 53 , R 56 and R 58 are independently hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 52 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 52 and R 42 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 54 are independently hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; R 55 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 55 and R 45 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 57 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl; or R 57 and R 47 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 59 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 59 and R 49 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; R 60 is hydrogen; and optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 1-4 alkyl or R 60 and R 50 together with the intervening atoms form a 4- to 7-membered heterocycloalkyl; and R 61 is independently at each occurrence hydrogen; and each optionally represents halogen, -OH, -CN, -NO2, -NH2, =O, =S, C 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 3-12 Carbocyclic ring, 3-12 membered heterocyclic ring, -O(C 1-10 alkyl), -O(C 2-10 alkenyl), -O(C 2-10 alkynyl), -O(C 3-8 C substituted with one or more substituents independently selected from -O(carbocyclic ring) and -O(3-10 membered heterocyclic ring) 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-8 is selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring. The cyclic peptide of embodiment I-47, represented by:

[0261] Embodiment I-72.R 51 , R 53 , R 56 and R 58 The cyclic peptide of embodiment I-71, wherein each is hydrogen.

[0262] Embodiment I-73.R 52 , R 54 , R 55 , R 57 , R 59 and R 60 The cyclic peptide of embodiment I-71 or I-72, wherein at least four of are not hydrogen.

[0263] Embodiment I-74.R 52 , R 54 , R 55 , R 57 , R 59 and R 60 The cyclic peptide of embodiment I-73, wherein four of are not hydrogen.

[0264] Embodiment I-75.R 52 , R 54 , R 55 , R 57 , R 59 and R 60 The cyclic peptide of embodiment I-73, wherein is not hydrogen.

[0265] Embodiment I-76.R 45 and R 55 and R 49 and R 59 The cyclic peptide of any of embodiments I-71 to I-75, wherein at least one of is taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl.

[0266] Embodiment I-77.R 45 and R 55 The cyclic peptide of embodiment I-76, wherein together with the intervening atoms form a 4- to 6-membered heterocycloalkyl.

[0267] Embodiment I-78.R 54 , R 59 and R 60 The cyclic peptide of any of embodiments I-71 to I-77, wherein each of is selected from methyl, ethyl, and methoxyethyl.

[0268] Embodiment I-79.R 54 , R 57 , R 59 and R 60 The cyclic peptide of any of embodiments I-71 to I-78, wherein each of is selected from methyl, ethyl, and methoxyethyl.

[0269] Embodiment I-80.R 59 optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 2-4 alkyl or R 49 and R 59 The cyclic peptide of any of embodiments I-71 to I-77, wherein together with the intervening atoms form a 4- to 7-membered heterocycloalkyl.

[0270] Embodiment I-81.R 59optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2 2-4 The cyclic peptide of embodiment I-80, wherein the cyclic peptide is alkyl.

[0271] Embodiment I-82.R 60 optionally halo, -SCH3, -SOCH3, -SO2CH3, -CN, -NO2, C 1-4 C substituted with one or more substituents independently selected from alkyl, -OH, -OBz, -OCH3, -OCF3 and -OCHF2 2-4 The cyclic peptide of any of embodiments I-71 to I-77, wherein R is alkyl.

[0272] Embodiment I-83.R 42 , R 47 and R 50 C 1-6 The cyclic peptide of any of embodiments I-71 to I-82, wherein:

[0273] Embodiment I-84.R 42 , R 47 and R 50 The cyclic peptide of embodiment I-83, wherein is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl.

[0274] Embodiment I-85.R 42 and R 47 is independent -C(O)R 61 , -C(O)N(R 61 )2, -N(R 61 )C(O)R 61 , -C(O)OR 61 , -OC(O)R 61 , -OC(O)N(R 61 )2, -N(R 61 )C(O)OR 61 , -OC(O)OR 61 and -N(R 61)C(O)N(R 61 ) C substituted with one or more substituents independently selected from 1-6 The cyclic peptide of any of embodiments I-71 to I-82, wherein:

[0275] Embodiment I-86.R 42 -C(O)R 61 , -C(O)OR 61 , -OC(O)R 61 and -OC(O)OR 61 C substituted with one or more substituents independently selected from 1-6 The cyclic peptide of embodiment I-85, wherein the cyclic peptide is alkyl.

[0276] Embodiment I-87.R 41 , R 43 , R 44 and R 48 Independently - (C 1-4 Alkylene)-(C 3-8 Carbocyclic) and -(C 1-4 alkylene)-(3- to 10-membered heterocycle), where C 3-8 The cyclic peptide of any of embodiments I-71 to I-86, wherein the carbocycle and the 3- to 10-membered heterocycle are optionally substituted.

[0277] Embodiment I-88.R 41 , R 43 , R 44 and R 48 Independently, -CH2-(C 3-8 The cyclic peptide of embodiment I-87, wherein the cyclic peptide is selected from -CH2- (carbocycle) and -CH2- (3- to 10-membered heterocycle).

[0278] Embodiment I-89.R 41 , R 43 , R 44 and R 48 The cyclic peptide of embodiment I-88, wherein is independently selected from phenylmethyl, pyridinylmethyl, and thiazolylmethyl, wherein phenyl, pyridinyl, and thiazolyl are optionally substituted.

[0279] Embodiment I-90.R 41 , R 43 , R 44 and R 48 Independent [ka] The cyclic peptide of embodiment I-89, selected from:

[0280] Embodiment I-91. The compound has formula IIIa: [ka] The cyclic peptide of any of embodiments I-71 to I-90, represented by:

[0281] Embodiment I-92. The compound has the formula IIIb: [ka] [In the formula, R 41’ , R 43’ , R 44’ and R 48’ are independently selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. The cyclic peptide of embodiment I-91, represented by:

[0282] Embodiment I-93. The cyclic peptide of embodiment I-1, wherein the cyclic peptide is selected from those in Table 1 or a pharma- ceutically acceptable salt.

[0283] Embodiment I-94. A pharmaceutical composition comprising any of the cyclic peptides of embodiments I-1 to I-93 and a pharma- ceutically acceptable excipient.

[0284] Embodiment I-95. A method of inhibiting MDM2 comprising administering to a subject in need of treatment a cyclic peptide of any of embodiments I-1 to I-93.

[0285] Embodiment I-96. A method of inhibiting MDM2 and MDM4 comprising administering to a subject in need of treatment a cyclic peptide of any of embodiments I-1 to I-93.

[0286] Embodiment I-97. A method for treating a disease or disorder in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a cyclic peptide of any of embodiments I-1 to I-93.

[0287] Embodiment I-98. The method of embodiment I-97, wherein the disease or disorder is cancer.

[0288] Embodiment I-99. The method of embodiment I-98, wherein the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.

[0289] Embodiment I-100. The method of embodiment I-97, wherein the disease or disorder is associated with the proliferation of senescent cells.

[0290] Embodiment I-101. The method of embodiment I-100, wherein the disease or disorder associated with the proliferation of senescent cells is selected from a cardiovascular disease, an inflammatory disease, an autoimmune disease, a metabolic disease, a pulmonary disease, an ocular disease, an otic disease, a renal disease and a skin disease.

[0291] Embodiment I-102. A method for inducing cell death of senescent cells in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a cyclic peptide of any of embodiments I-1 to I-93. EXAMPLES

[0292] experiment Unless otherwise stated, all reagents were used as purchased from commercial suppliers without further purification. Solvent drying by standard methods was performed when necessary. 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]undec-7-ene; DCM = dichloromethane; DMF = N,N-dimethylformamide; DIPEA = diisopropylethylamine; DMSO = dimethylsulfoxide; Fmoc = 9-fluorenylmethoxycarbonyl; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; HP LC = high performance liquid chromatography; MeOH = methanol; N2 = nitrogen gas; SPPS = solid phase peptide synthesis; FA = formic acid; Xaa = any amino acid; UV = ultraviolet; 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.

[0293] Cyclic Peptide Synthesis Step 1: Loading of 2-chlorotrityl resin Fmoc-Xaa (10 mmol) was (登録商標)The residue was dried overnight in a vacuum desiccator at 100° C. The dried amino acid was dissolved in dry DCM (50 mL) containing DIPEA (40 mmol) dried over molecular sieves. The reaction mixture was sonicated until Fmoc-Xaa was completely dissolved. 2-Chlorotrityl resin (5 g) was added under a stream of N2 and the reaction mixture was shaken for 4 h. The resin was treated with a 1:2:17 MeOH / DIPEA / DMF (15 mL) solution and shaken (3×15 min). The resin was washed with DMF (3×15 mL) followed by DCM (3×15 mL). The loading of the resin was calculated by UV quantification of Fmoc release after deprotection.

[0294] Step 2: Amino acid coupling Fmoc-Xaa (4 equiv.), DIPEA (6 equiv.) and HATU (3.8 equiv.) were added to the resin in DMF (2 mL) and the reaction mixture was shaken at room temperature for 1 h. The resin was washed with DMF (3×3 mL) followed by DCM (3×3 mL).

[0295] Step 3: Fmoc deprotection on resin The resin was treated with 20% 4-methyl-piperidine in DMF (3 mL) and shaken at room temperature for 20 min. Alternatively, the resin was treated with 2% piperidine and 2% DBU in DMF (3 mL) and shaken twice at room temperature for 10 min. The resin was washed with DMF (3×3 mL) followed by DCM (3×3 mL).

[0296] Step 4: Peptoid Coupling Activation was performed with a 2:1 solution of 1M bromoacetic acid / 0.5M DIC in DMF for 20 min with shaking at room temperature. The product was precipitated and the supernatant was collected and combined with the deprotected resin for 20 min with shaking at room temperature. The resin was washed with DMF (3 x 3 mL) followed by DCM (3 x 3 mL). The resin was treated with a 1M solution of the amine in DMF and shaken at room temperature for 1 h.

[0297] Step 5: Peptide cleavage To cleave the completed linear peptide, the resin was treated with 5 resin volumes of 30% HFIP in DCM and shaken for 1 hour. The resin was washed with 5 resin volumes of DCM. The resin was treated with 5 resin volumes of 30% HFIP in DCM and shaken for 30 minutes.

[0298] Step 6: Cyclization with COMU The dry linear peptide was dissolved in MeCN (2 mL) containing DIPEA (9 eq.) and the resulting solution was added dropwise to a 1:10 MeCN / DCM solution containing COMU (4 eq.) to a final concentration of 1 mg crude peptide / mL. The reaction mixture was shaken at room temperature for 16 h until complete cyclization was achieved as monitored by LCMS. The reaction mixture was concentrated under reduced pressure.

[0299] Step 7: Peptide purification COMU cyclization by-products were removed by mass directed purification on a Waters HPLC system equipped with an Xbridge BEH C18 OBD 130Å 5 μm, 10×250 mm column eluted with HO / MeCN modified with 0.1% FA. Peptide purity was analyzed by HPLC-MS on a Waters HPLC system equipped with a CORTECS T3 2.7 μm 4.6×50 and a Waters 3100 mass spectrometer with a gradient of HO / MeCN modified with 0.1% FA.

[0300] Fluorescence polarization assay 1 Human MDM2 (HDM2) 1-116 (20 μL) and FAM-labeled GGTSFAEYWNLLSP-NH2, 10 nM and 5 nM, respectively, in 10 mM Tris, 50 mM NaCl, 0.01% Tween 20 and 1 mM DTT, pH 7.4, were dispensed into an opaque, black 384-well plate. Compounds dissolved in DMSO were pin-transferred (approximately 100-200 nL) into the 384-well plate containing the MDM2 / p53 solution. After 60 min of incubation, fluorescence polarization was read on a Molecular Devices SpectraMax plate reader equipped with a Fluorescein FP cartridge. In addition to probe alone (positive control) and probe / MDM2 (negative control), a titration of linear p53 (18-26) was included in every plate as an additional control. IC 50 Values ​​were obtained using Prism or Collaborative Drug Discovery.

[0301] Fluorescence polarization assay 2 Human MDM4 (HDM4) 1-114 (20 μL) and FAM-labeled GGTSFAEYWNLLSP-NH2, 20 nM and 5 nM, respectively, in 10 mM Tris, 50 mM NaCl, 0.01% Tween 20 and 1 mM DTT, pH 7.4, were dispensed into an opaque, black 384-well plate. Compounds dissolved in DMSO were pin-transferred (approximately 100-200 nL) into the 384-well plate containing the MDM4 / p53 solution. After 60 min of incubation, fluorescence polarization was read on a Molecular Devices SpectraMax plate reader equipped with a Fluorescein FP cartridge. In addition to the probe alone (positive control) and probe / MDM4 (negative control), a titration of linear p53 (18-26) was added to all plates as an additional control. IC 50 Values ​​were obtained using Prism or Collaborative Drug Discovery.

[0302] Cytofluorescence Assay 1 MOLM-13 cells were grown in suspension in RPMI medium containing 10% fetal bovine serum (FBS) in T75 flasks at 37°C with 5% CO2. 40 μL of MOLM-13 cells were seeded in columns 1-22 of a white, flat-bottom, 384-well plate at a density of 1,000 cells / well in RPMI medium containing 10% FBS. Columns 23 and 24 were filled with 40 μL of medium as a positive control. 100 nL of compound dissolved in DMSO was pin-transferred into columns 3-22 of the 384-well plate. Columns 1 and 2 served as negative control wells. Plates were incubated for 72 hours at 37°C with 5% CO2. After incubation, cells were dosed with 10 μL of CellTiter-Glo® (Promega®). Fluorescence was read on a Molecular Devices SpectraMax i3x plate reader.

[0303] Cytofluorescence Assay 2 MV4-11 cells were grown in suspension in RPMI medium containing 10% fetal bovine serum (FBS) in T75 flasks at 37°C and 5% CO2. 40 μL of MV4-11 cells were seeded in columns 1-22 of a white, flat-bottom, 384-well plate at a density of 1,000 cells / well in RPMI medium containing 10% FBS. Columns 23 and 24 were filled with 40 μL of medium as a positive control. 100 nL of compound dissolved in DMSO was pin-transferred into columns 3-22 of the 384-well plate. Columns 1 and 2 served as negative control wells. Plates were incubated for 72 hours at 37°C and 5% CO2. After incubation, cells were dosed with 10 μL of CellTiter-Glo® (Promega®). Fluorescence was read on a Molecular Devices SpectraMax i3x plate reader.

[0304] Cytofluorescence Assay 3 WaGa cells were grown in suspension in RPMI medium containing 10% fetal bovine serum (FBS) in T75 flasks at 37°C with 5% CO2. 40 μL of WaGa cells were seeded in columns 1-22 of a white, flat-bottom, 384-well plate at a density of 1,000 cells / well in RPMI medium containing 10% FBS. Columns 23 and 24 were filled with 40 μL of medium as a positive control. 100 nL of compounds dissolved in DMSO were pin-transferred into columns 3-22 of the 384-well plate. Columns 1 and 2 served as negative control wells. Plates were incubated for 72 hours at 37°C with 5% CO2. After incubation, cells were dosed with 10 μL of CellTiter-Glo® (Promega®). Fluorescence was read on a Molecular Devices SpectraMax i3x plate reader.

[0305] Cytofluorescence Assay 4 MKL-1 cells were grown in suspension in RPMI medium containing 10% fetal bovine serum (FBS) in T75 flasks at 37°C and 5% CO2. 40 μL MKL-1 cells were seeded in columns 1-22 of a white, flat-bottom, 384-well plate at a density of 1,000 cells / well in RPMI medium containing 10% FBS. Columns 23 and 24 were filled with 40 μL of medium as a positive control. 100 nL of compound dissolved in DMSO was pin-transferred into columns 3-22 of the 384-well plate. Columns 1 and 2 were used as negative control wells. Plates were incubated for 72 hours at 37°C and 5% CO2. After incubation, 10 μL of CellTiter-Glo® (Promega®) was added to the cells. Fluorescence was read on a Molecular Devices SpectraMax i3x plate reader.

[0306] In certain embodiments, the cyclic peptides described herein are those described in Table 1. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] * :SMILES strings were generated from chemical structures in ChemDraw version 20.0. ** :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 **** :A<0.5μM;0.5μM≦B<1.0μM;1.0μM≦C<2.0μM;2.0μM≦D

[0307] Table 1a shows the chemical structures of each SMILES string in Table 1, generated using ChemDraw. [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13]

Table 14

Table 15

Table 16

Table 17

Claims

1. 9 to 11 amino acid residues independently selected from amino acid residues that are not charged at physiological pH; First and second beta-hairpin regions; At least 1 amino acid residue having a side chain containing a moiety selected from ether, ester, carbonate, amide, carbamate and urea; Comprising; and the following: At least 4 amino acid residues comprising a ring independently selected from a monocyclic carbocyclic ring optionally substituted and a monocyclic heterocyclic ring optionally substituted, wherein at least 1 of the monocyclic carbocyclic ring and the monocyclic heterocyclic ring is substituted; At least 4 amino acid residues having a side chain selected from -alkylene-(monocyclic carbocyclic ring) and -alkylene-(monocyclic heterocyclic ring), wherein the monocyclic carbocyclic ring and the monocyclic heterocyclic ring are independently optionally substituted; and At least 3 amino acid residues comprising a ring independently selected from phenyl optionally substituted and monocyclic heteroaryl optionally substituted A cyclic peptide characterized by one of.

2. The first beta-hairpin region contains 2 consecutive amino acid residues; Optionally, the 2 consecutive residues are independently selected from L-Pro, D-Pro, L-Aze, D-Pip, L-NMe-Phe and D-NMe-Val, wherein the phenyl group of L-NMe-Phe is optionally halo, -SCH3, -SOCH3, -SO2CH3, -OH, -CN, -NO2, C1-4 alkyl, -CH3, -CF3, -CHF2, -OBz, -OCH3, -OCF3, -SF5 and -OCHF2 Substituted with one or more substituents independently selected from; The cyclic peptide of Claim 1.

3. The cyclic peptide of Claim 2, wherein the first beta-hairpin region contains 2 consecutive residues independently selected from L-Pro, D-Pro, L-Aze, D-Pip and D-NMe-Val.

4. For 2 consecutive residues, one is D and the other is L; Optionally, the 2 consecutive amino acid residues are (a) D-Pro and L-Pro; (b) D-NMe-Val and L-Pro; or (c) D-Pro and L-NMe-Phe, wherein the phenyl group of L-NMe-Phe is optionally substituted with one or more substituents independently selected from halo, -SCH₃, -SOCH₃, -SO₂CH₃, -OH, -CN, -NO₂, C₁₋₄ alkyl, -CH₃, -CF₃, -CHF₂, -OBz, -OCH₃, -OCF₃, -SF₅ and -OCHF₂, The cyclic peptide of claim 3.

5. The second beta-hairpin region contains two consecutive amino acid residues; Optionally, the second beta-hairpin region contains two other consecutive residues independently selected from D-Pro, peptidomimetic, D-N-alkylated amino acid and L-N-alkylated amino acid, The cyclic peptide according to any one of claims 1 to 4.

6. (a) The two other consecutive residues are independently selected from D-Pro, peptidomimetic and L-N-alkylated amino acid; Optionally, for the two other consecutive residues, (i) one is a peptidomimetic and the other is an L-N-alkylated amino acid; Optionally one is L-NMe-Ala and the other is N-(2-methoxyethyl)glycine; or (ii) one is a D-N-alkylated amino acid and the other is a peptidomimetic, optionally one is D-NMe-Ala and the other is N-(2-methoxyethyl)glycine; or (b) For the two other consecutive residues, one is D-NMe-Ala and the other is an L-N-alkylated amino acid; Optionally one is D-NMe-Ala and the other is L-NMe-Ala, The cyclic peptide of claim 5.

7. At least two consecutive amino acids separate the first beta-hairpin region and the second beta-hairpin region; Optionally at least three consecutive amino acids separate the first beta-hairpin region and the second beta-hairpin region, The cyclic peptide of claim 1.

8. The molecular weight of the cyclic peptide is 800 - 1300 Da; 800 - 1200 Da; or 900 - 1200 Da, The cyclic peptide of claim 1.

9. A cyclic peptide according to claim 1, comprising a ring independently selected from optionally substituted monocyclic carbocycles and optionally substituted monocyclic heterocycles, wherein at least one of the monocyclic carbocycles and monocyclic heterocycles is substituted, and characterized by at least four amino acid residues.

10. The monocyclic carbocyclic ring optionally substituted is phenyl, the monocyclic heterocyclic ring optionally substituted is a heteroaryl ring, and each heteroaryl ring is independently selected from thiophene, thiazole, oxazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole and imidazole, any of which may be substituted, wherein at least one phenyl or heteroaryl ring is halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -OH, -CN, -NO ２ , C １－４ alkyl, -CH ３ , -CF ３ , -CHF ２ , -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted by one or more substituents independently selected from; optionally at least one phenyl or heteroaryl ring is halo, -CH 3, -CF 3, -CHF 2, -OBz, -OCH 3, -OCF 3 and -OCHF 2 The cyclic peptide of claim 9, which is substituted by one or more substituents independently selected from.

11. Formula I: 【Chemical 1】 〔Wherein, R １ 、R ３ and R ８ are independently hydrogen, -(C １－４ alkylene)-(C ３－８ carbocyclic ring) and -(C １－４ alkylene)-(3- to 10-membered heterocyclic ring), where the C ３－８ carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted with one or more substituents independently selected from halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -CH ３ , -CF ３ , -CHF ２ , -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ ; R ２ is hydrogen; and optionally each of -OR ２１ , -SR ２１ , -N(R ２１ ), ２ , -C(O)R ２１ , -C(O)N(R ２１ ), ２ , -N(R ２１ ),C(O)R ２１ , -C(O)OR ２１ , -OC(O)R ２１ , -OC(O)N(R ２１ ), ２ , -N(R ２１ ),C(O)OR ２１ , -OC(O)OR ２１ , -N(R ２１ ),C(O)N(R ２１ ), ２ , -S(O)R ２１ , -S(O) ２ R ２１ , -P(O)(OR ２１ ), ２ , -OP(O)(OR ２１ ), ２ , =O, =S, =N(R ２１ ), C ３－１０ is substituted with one or more substituents independently selected from carbocyclic rings and 3- to 10-membered heterocyclic rings; where the carbocyclic rings and heterocyclic rings are independently optionally halo, -SCH １－６ , -SOCH ２－６ , -SO ２－６ CH ３ , -CN, -NO ３ , C ２ alkyl, -OH, -CH ３ , -CF ２ , -CHF １－４ , -OBz, -OCH ３ , -OCF ３ , -SF ２ , -OCHF ３ and -OCHF ３ , and are substituted with one or more substituents independently selected therefrom; or R ５ and R ２ and R ２ and R １２ combines with the atom in between to form a 4- to 7-membered heterocycloalkyl; R ４ is selected from hydrogen, C １－４ alkyl, -(C １－４ alkylene)-(C ３－８ carbocyclic ring) and -(C １－４ alkylene)-(3- to 10-membered heterocyclic ring), where the C ３－８ carbocyclic ring and 3- to 10-membered heterocyclic ring are optionally substituted with one or more substituents independently selected from halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -CH ３ , -CF ３ , -CHF ２ , -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ and are substituted with one or more substituents independently selected from halo, -SCH １－４ , -SOCH ３ , -SO ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ ; or R ４ and R １４ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R ５ is hydrogen or C １－４ alkyl or R ５ and R １５ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R ６ is hydrogen, C １－４ alkyl, -(C １－４ alkylene)-(C ３－８ carbocyclic ring) and -(C １－４ alkylene)-(3- to 10-membered heterocyclic ring), where the C ３－８ carbocyclic ring and the 3- to 10-membered heterocyclic ring are optionally substituted with one or more substituents independently selected from halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -CH ３ , -CF ３ , -CHF ２ , -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ are substituted with one or more substituents independently selected therefrom; and the C １－４ alkyl is optionally substituted with one or more substituents independently selected from halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ are substituted with one or more substituents independently selected therefrom; R ７ is hydrogen; and optionally each halo, C １－４ alkyl, -OR ２１ -SR ２１ -N(R ２１ ) ２ -C(O)R ２１ -C(O)N(R ２１ ) ２ -N(R ２１ )C(O)R ２１ -C(O)OR ２１ -OC(O)R ２１ -OC(O)N(R ２１ ) ２ -N(R ２１ )C(O)OR ２１ -OC(O)OR ２１ -N(R ２１ )C(O)N(R ２１ ) ２ -S(O)R ２１ -S(O) ２ R ２１ -P(O)(OR ２１ ) ２ -OP(O)(OR ２１ ) ２ =O, =S, =N(R ２１ ), C ３－１０ alkyl, C １－６ carbon ring and one or more substituents independently selected from 3- to 10-membered heterocycles, where the carbon ring and heterocycles are optionally independently halo, -SCH ２－６ alkyl, C ２－６ alkenyl, C ３－１０ alkynyl, C ３ carbon ring and 3- to 10-membered heterocycles, where the carbon ring and heterocycles are independently optionally halo, -SCH ３ -SOCH ２ -SO ３ CH ２ -CN, -NO １－４ alkyl, -OH, -CH ３ -CF ３ -CHF ２ -OBz, -OCH ３ -OCF ３ -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected therefrom; or R ７ and R １７ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; wherein at least one of R ２ and R ７ is not hydrogen or methyl; R ９ is hydrogen or C １－４ alkyl or R ９ and R １９ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R １０ is hydrogen; and each optionally halo, C １－４ alkyl, -OR ２１ -SR ２１ -N(R ２１ ) ２ -C(O)R ２１ -C(O)N(R ２１ ) ２ -N(R ２１ )C(O)R ２１ -C(O)OR ２１ -OC(O)R ２１ -OC(O)N(R ２１ ) ２ -N(R ２１ )C(O)OR ２１ -OC(O)OR ２１ -N(R ２１ )C(O)N(R ２１ ) ２ -S(O)R ２１ -S(O) ２ R ２１ -P(O)(OR ２１ ) ２ -OP(O)(OR ２１ ) ２ =O, =S, =N(R ２１ ), C ３－１０ alkyl, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ carbon ring and 3- to 10-membered heterocycle are each independently selected; where the carbon ring and heterocycle are each optionally halo, -SCH ３ -, -SOCH ３ -, -SO ２ CH ３ -, -CN, -NO ２ , C １－４ alkyl, -OH, -CH ３ -, -CF ３ -, -CHF ２ -, -OBz, -OCH ３ -, -OCF ３ -, -SF ５ and -OCHF ２ substituted with one or more substituents independently selected therefrom; or R １０ and R ２０ together with the atoms intervening therebetween form a 4- to 7-membered heterocycloalkyl; R １１ 、 R １３ 、 R １６ and R １８ are independently hydrogen; and optionally halo, -SCH ３ 、 -SOC ３ 、 -SO ２ CH ３ 、 -CN, -NO ２ 、 C １－４ alkyl, -OH, -OBz, -OCH ３ 、 -OCF ３ 、 -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl; R １２ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected from C １－４ alkyl or R １２ and R ２ together with the atom(s) in between form a 4- to 7-membered heterocycloalkyl; R １４ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected from C １－４ alkyl or R １４ and R ４ together with the atom between them form a 4- to 7-membered heterocycloalkyl; R １５ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected from C １－４ alkyl or R １５ and R ５ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R １７ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected from C １－４ alkyl or R １７ and R ７ together with the atom between them form a 4- to 7-membered heterocycloalkyl; R １９ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl or R １９ and R ９ together with the atom between them form a 4- to 7-membered heterocycloalkyl; R ２０ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected from C １－４ alkyl or R ２０ and R １０ together with the atom between them form a 4- to 7-membered heterocycloalkyl; and R ２１ is, in each case independently, hydrogen; and optionally, in each case, halogen, -OH, -CN, -NO ２ , -NH ２ , =O, =S, C １－１０ alkyl, C ２－１０ alkenyl, C ２－１０ alkynyl, C １－１０ haloalkyl, C ３－１２ carbocyclic, 3- to 12-membered heterocyclic, -O(C １－１０ alkyl), -O(C ２－１０ alkenyl), -O(C ２－１０ alkynyl), -O(C ３－８ carbocyclic) and -O(3- to 10-membered heterocyclic), and is selected from C １－１０ alkyl, C ２－１０ alkenyl, C ２－１０ alkynyl, C ３－８ carbocyclic and 3- to 10-membered heterocyclic. ]] A cyclic peptide represented by.

12. Formula IIa: 【Chemical 2】 〔Wherein, R ２１ 、 R ２３ 、 R ２６ and R ２８ are independently selected from hydrogen, -(C １－４ alkylene)-(C ３－８ carbocyclic ring) and -(C １－４ alkylene)-(3- to 10-membered heterocyclic ring), where the C ３－８ carbocyclic ring and 3- to 10-membered heterocyclic ring are optionally substituted with one or more substituents independently selected from halo, -OH, -CH ３ , -CF ３ , -CHF ２ , -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ ; R ２２ is hydrogen; and optionally each of -OR ２１ , -SR ２１ , -N(R ２１ ) ２ , -C(O)R ２１ , -C(O)N(R ２１ ) ２ , -N(R ２１ )C(O)R ２１ , -C(O)OR ２１ , -OC(O)R ２１ , -OC(O)N(R ２１ ) ２ , -N(R ２１ )C(O)OR ２１ , -OC(O)OR ２１ , -N(R ２１ )C(O)N(R ２１ ) ２ , -S(O)R ２１ , -S(O) ２ R ２１ , -P(O)(OR ２１ ) ２ , -OP(O)(OR ２１ ) ２ , =O, =S, =N(R ２１ ), C ３－１０ alkyl, C １－６ alkenyl and C ２－６ alkynyl selected from; wherein the carbocycle and heterocycle are independently optionally halo, -SCH ２－６ , -SOCH ３ , -SO ３ CH ２ , -CN, -NO ３ , C ２ alkyl, -OH, -CH １－４ , -CF ３ , -CHF ３ , -OBz, -OCH ２ , -OCF ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from; or R ２２ and R ３２ forms a 4- to 7-membered heterocycloalkyl together with the atom in between; R ２４ is hydrogen or C １－４ alkyl or R ２４ and R ３４ together with the atoms in between form a 5- to 7-membered heterocycloalkyl; R ２５ is hydrogen or C １－４ alkyl or R ２５ and R ３５ together with the atoms in between form a 5- to 7-membered heterocycloalkyl; R ２７ is hydrogen; and each optionally halo, C １－４ alkyl, -OR ２１ -SR ２１ -N(R ２１ ) ２ -C(O)R ２１ -C(O)N(R ２１ ) ２ -N(R ２１ )C(O)R ２１ -C(O)OR ２１ -OC(O)R ２１ -OC(O)N(R ２１ ) ２ -N(R ２１ )C(O)OR ２１ -OC(O)OR ２１ -N(R ２１ )C(O)N(R ２１ ) ２ -S(O)R ２１ -S(O) ２ R ２１ -P(O)(OR ２１ ) ２ -OP(O)(OR ２１ ) ２ =O, =S, =N(R ２１ ), C ３－１０ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ carbon ring and 3- to 10-membered heterocycle, each independently selected; where the carbon ring and heterocycle are each optionally halo, -SCH ３－１０ -, -SOCH ３ -, -SO ３ CH ２ -, -CN, -NO ３ -, C ２ alkyl, -OH, -CH １－４ -, -CF ３ -, -CHF ３ -, -OBz, -OCH ２ -, -OCF ３ -, -OCF ３ -, -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected therefrom; or R ２７ and R ３７ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; wherein at least one of R ２２ and R ２７ is not hydrogen or methyl; R ２９ is hydrogen or C １－４ alkyl or R ２９ and R ３９ together with the atoms in between form a 5- to 7-membered heterocycloalkyl; R ３０ is hydrogen; and each optionally halo, C １－４ alkyl, -OR ２１ -SR ２１ -N(R ２１ ) ２ -C(O)R ２１ -C(O)N(R ２１ ) ２ -N(R ２１ )C(O)R ２１ -C(O)OR ２１ -OC(O)R ２１ -OC(O)N(R ２１ ) ２ -N(R ２１ )C(O)OR ２１ -OC(O)OR ２１ -N(R ２１ )C(O)N(R ２１ ) ２ -S(O)R ２１ -S(O) ２ R ２１ -P(O)(OR ２１ ) ２ -OP(O)(OR ２１ ) ２ =O, =S, =N(R ２１ ), C ３－１０ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ carbon ring and 3- to 10-membered heterocycle independently selected from; where the carbon ring and heterocycle are each optionally halo, -SCH ３－１０ -SOCH ３ -SOCH ３ -SO ２ CH ３ -CN, -NO ２ C １－４ alkyl, -OH, -CH ３ -CF ３ -CHF ２ -OBz, -OCH ３ -OCF ３ -SF ５ and -OCHF ２ substituted with one or more substituents independently selected therefrom; or R ３０ and R ４０ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R ３１ , R ３３ , R ３６ and R ３８ are independently hydrogen; and optionally halo, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl selected from; R ３２ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl or R ３２ and R ２２ together with the atom between them form a 4- to 7-membered heterocycloalkyl; R ３４ is hydrogen; and optionally halo, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl or R ３４ and R ２４ together with the atoms in between form a 5- to 7-membered heterocycloalkyl; R ３５ is hydrogen; and optionally halo, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl or R ３５ and R ２５ together with the atom(s) in between form a 5- to 7-membered heterocycloalkyl; R ３７ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected from C １－４ alkyl or R ３７ and R ２７ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R ３９ is hydrogen; and optionally halo, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl or R ３９ and R ２９ together with the atoms in between form a 5- to 7-membered heterocycloalkyl; R ４０ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl or R ４０ and R ３０ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; and R ４１ is in each case independently hydrogen; and optionally in each case halogen, -OH, -CN, -NO ２ , -NH ２ , =O, =S, C １－１０ alkyl, C ２－１０ alkenyl, C ２－１０ alkynyl, C １－１０ haloalkyl, C ３－１２ carbocyclic, 3- to 12-membered heterocyclic, -O(C １－１０ alkyl), -O(C ２－１０ alkenyl), -O(C ２－１０ alkynyl), -O(C ３－８ carbocyclic) and -O(3- to 10-membered heterocyclic), and is selected from C １－１０ alkyl, C ２－１０ alkenyl, C ２－１０ alkynyl, C ３－８ carbocyclic and 3- to 10-membered heterocyclic. ]] Represented by, and optionally by Formula IIb: [Chemical Formula 3] [wherein, R ２１’ , R ２３’ , R ２６’ and R ２８’ are independently selected from phenyl optionally substituted as desired and 5- or 6-membered heteroaryl optionally substituted as desired.] A cyclic peptide according to claim 11, represented by.

13. Formula III: 【Chemical Formula 4】 〔Wherein, R ４１ 、R ４３ 、R ４４ and R ４８ are independently hydrogen, -(C １－４ alkylene)-(C ３－８ carbocyclic ring) and -(C １－４ alkylene)-(3- to 10-membered heterocyclic ring), where C ３－８ carbocyclic ring and 3- to 10-membered heterocyclic ring are optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -CH ３ , -CF ３ , -CHF ２ , -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ are independently substituted with one or more substituents selected from; R ４２ is hydrogen; and each optionally is —OR ２１ , -SR ２１ , -N(R ２１ ) ２ , -C(O)R ２１ , -C(O)N(R ２１ ) ２ , -N(R ２１ )C(O)R ２１ , -C(O)OR ２１ , -OC(O)R ２１ , -OC(O)N(R ２１ ) ２ , -N(R ２１ )C(O)OR ２１ , -OC(O)OR ２１ , -N(R ２１ )C(O)N(R ２１ ) ２ , -S(O)R ２１ , -S(O) ２ R ２１ , -P(O)(OR ２１ ) ２ , -OP(O)(OR ２１ ) ２ , =O, =S, =N(R ２１ ), C ３－１０ C substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle １－６ Alkyl, C ２－６ Alkenyl and C ２－６ alkynyl; wherein the carbocycle and heterocycle are independently optionally selected from halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ Alkyl, -OH, -CH ３ , -CF ３ , -CHF ２ , -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ or R ４２ and R ５２ combines with the atom in between to form a 4- to 7-membered heterocycloalkyl; R ４５ is hydrogen or C １－４ alkyl, or R ４５ and R ５５ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R ４６ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl; R ４７ is hydrogen; and each optionally halo, C １－４ alkyl, -OR ２１ -SR ２１ -N(R ２１ ) ２ -C(O)R ２１ -C(O)N(R ２１ ) ２ -N(R ２１ )C(O)R ２１ -C(O)OR ２１ -OC(O)R ２１ -OC(O)N(R ２１ ) ２ -N(R ２１ )C(O)OR ２１ -OC(O)OR ２１ -N(R ２１ )C(O)N(R ２１ ) ２ -S(O)R ２１ -S(O) ２ R ２１ -P(O)(OR ２１ ) ２ -OP(O)(OR ２１ ) ２ =O, =S, =N(R ２１ ), C ３－１０ alkyl, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ a carbocycle and a 3- to 10-membered heterocycle are each independently selected; where the carbocycle and heterocycle are each optionally halo, -SCH ３ -, -SOCH ３ -, -SO ２ CH ３ -, -CN, -NO ２ , C １－４ alkyl, -OH, -CH ３ -, -CF ３ -, -CHF ２ -, -OBz, -OCH ３ -, -OCF ３ -, -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected therefrom; or R ４７ and R ５７ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; wherein at least one of R ４２ and R ４７ is not hydrogen or methyl; R ４９ is hydrogen or C １－４ alkyl or R ４９ and R ５９ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R ５０ is hydrogen; and each optionally halo, C １－４ alkyl, -OR ２１ -SR ２１ -N(R ２１ ) ２ -C(O)R ２１ -C(O)N(R ２１ ) ２ -N(R ２１ )C(O)R ２１ -C(O)OR ２１ -OC(O)R ２１ -OC(O)N(R ２１ ) ２ -N(R ２１ )C(O)OR ２１ -OC(O)OR ２１ -N(R ２１ )C(O)N(R ２１ ) ２ -S(O)R ２１ -S(O) ２ R ２１ -P(O)(OR ２１ ) ２ -OP(O)(OR ２１ ) ２ =O, =S, =N(R ２１ ), C ３－１０ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ selected from carbocycles and 3- to 10-membered heterocycles; where the carbocycles and heterocycles are each optionally halo, -SCH ３－１０ -SOCH ３ -SO ３ CH ２ -CN, -NO ３ , C ２ alkyl, -OH, -CH １－４ -CF ３ -CHF ３ -OBz, -OCH ２ -OCF ３ -OCF ３ -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected therefrom; or R ５０ and R ６０ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R ５１ 、 R ５３ 、 R ５６ and R ５８ are independently hydrogen; and optionally halo, -SCH ３ 、 -SOC H ３ 、 -SO ２ CH ３ 、 -CN, -NO ２ 、 C １－４ alkyl, -OH, -OBz, -OCH ３ 、 -OCF ３ 、 -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl; R ５２ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl or R ５２ and R ４２ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R ５４ is independently hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ and is substituted with one or more substituents independently selected from C １－４ alkyl; R ５５ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl or R ５５ and R ４５ together with the atom between them form a 4- to 7-membered heterocycloalkyl; R ５７ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ ; and is substituted with one or more substituents independently selected from C １－４ alkyl or R ５７ and R ４７ together with the atoms in between form a 4- to 7-membered heterocycloalkyl; R ５９ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ is substituted with one or more substituents independently selected from C １－４ alkyl or R ５９ and R ４９ together with the atom between them form a 4- to 7-membered heterocycloalkyl; R ６０ is hydrogen; and optionally halo, -SCH ３ , -SOCH ３ , -SO ２ CH ３ , -CN, -NO ２ , C １－４ alkyl, -OH, -OBz, -OCH ３ , -OCF ３ , -SF ５ and -OCHF ２ substituted with one or more substituents independently selected from C １－４ alkyl or R ６０ and R ５０ together with the atom between them form a 4- to 7-membered heterocycloalkyl; and R ６１ is in each case independently hydrogen; and optionally in each case halogen, -OH, -CN, -NO ２ , -NH ２ , =O, =S, C １－１０ alkyl, C ２－１０ alkenyl, C ２－１０ alkynyl, C １－１０ haloalkyl, C ３－１２ carbocyclic, 3- to 12-membered heterocyclic, -O(C １－１０ alkyl), -O(C ２－１０ alkenyl), -O(C ２－１０ alkynyl), -O(C ３－８ carbocyclic) and -O(3- to 10-membered heterocyclic) and is selected from C １－１０ alkyl, C ２－１０ alkenyl, C ２－１０ alkynyl, C ３－８ carbocyclic and 3- to 10-membered heterocyclic. ]] Represented by; R as desired ５１ R ５３ R ５６ and R ５８ The cyclic peptide according to claim 11, wherein each of R is hydrogen.

14. R ５２ , R ５４ , R ５５ , R ５７ , R ５９ and R ６０ and at least four of them are not hydrogen; Optionally, four of R52, R54, R55, R57, R59 and R60 are not hydrogen; or R52, R54, R55, R57, R59 and R60 are not hydrogen, A cyclic peptide according to claim 13.

15. R ４５ and R ５５ and R ４９ and R ５９ at least one of which combines with an atom in between to form a 4- to 7-membered heterocycloalkyl; Optionally, R45 and R55 together with the atoms in between form a 4- to 6-membered heterocycloalkyl, A cyclic peptide according to claim 13 or 14.