Cell-permeable cyclic peptides and uses thereof

A cyclic peptide represented by Formula I:

• wherein:
• R1, R3, and R8 are independently selected from hydrogen, —(C1-4 alkylene)-(C3-8carbocycle), and —(C1-4 alkylene)-(3-10 membered heterocycle), wherein the C3-8carbocycle and 3-10 membered heterocycle are optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4alkyl, —OH, —CH3, —CF3, —CHF2, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2;
• R2 is selected from hydrogen;
• and C1-6alkyl, C2-6alkenyl, and C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from —OR21, —SR21, —N(R21)2, —C(O)R21, —C(O)N(R21)2, —N(R21)C(O)R21, —C(O)OR21, —OC(O)R21, —OC(O)N(R21)2, —N(R21)C(O)OR21, —OC(O)OR21, —N(R21)C(O)N(R21)2, —S(O)R21, —S(O)2R21, —P(O)(OR21)2, —OP(O)(OR21)2, ═O, ═S, ═N(R21), C3-10 carbocycle, and 3- to 10-membered heterocycle;
• wherein the carbocycle and heterocycle are independently optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4alkyl, —OH, —CH3, —CF3, —CHF2, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2;
• or R2 and R12 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• R4 is selected from hydrogen, C1-4 alkyl, —(C1-4alkylene)-(C3-8carbocycle), and —(C1-4alkylene)-(3-10 membered heterocycle), wherein the C3-8 carbocycle and 3-10 membered heterocycle are optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4alkyl, —OH, —CH3, —CF3, —CHF2, —OBz, —OCH3, —OCF3, —SF 5, and —OCHF2;
• and wherein the C1-4alkyl is optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4 alkyl, —OH, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2;
• or R4 and R14 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• R5 is hydrogen or C1-4 alkyl, or R5 and R15 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• R6 is selected from hydrogen, C1-4 alkyl, —(C1-4alkylene)-(C3-8carbocycle), and —(C1-4alkylene)-(3-10 membered heterocycle), wherein the C3-8 carbocycle and 3-10 membered heterocycle are optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4alkyl, —OH, —CH3, —CF3, —CHF2, —OBz, —OCH3, —OCF3, —SF 5, and —OCHF2;
• and wherein the C1-4alkyl is optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4 alkyl, —OH, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2;
• R7 is selected from hydrogen;
• and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halo, C1-4alkyl, —OR21, —SR21, —N(R21)2, —C(O)R21, —C(O)N(R21)2, —N(R21)C(O)R21, —C(O)OR21, —OC(O)R21, —OC(O)N(R21)2, (R21)C(O)OR21, —OC(O)OR21, —N(R21)C(O)N(R21)2, —S(O)R21, S(O)2R21, —P(O)(OR21)2, —OP(O)(OR21)2, ═O, ═S, ═N(R21), C3-10 carbocycle, and 3- to 10-membered heterocycle;
• wherein the carbocycle and heterocycle are independently optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4alkyl, —OH, —CH3, —CF3, —CHF2, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2;
• or R7 and R17 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• wherein at least one of R2 and R7 is not hydrogen or methyl;
• R9 is hydrogen or C1-4 alkyl, or R9 and R19 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• R10 is selected from hydrogen;
• and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halo, C1-4alkyl, —OR21, —SR21, —N(R21)2, —C(O)R21, —C(O)N(R21)2, —N(R21)C(O)R21, —C(O)OR21, —OC(O)R21, —OC(O)N(R21)2, —N(R21)C(O)OR21, —OC(O)OR21, —N(R21)C(O)N(R21)2, —S(O)R21, —S(O)2R21, —P(O)(OR21)2, —OP(O)(OR21)2, ═O, ═S, ═N(R21), C3-10 carbocycle, and 3- to 10-membered heterocycle;
• wherein the carbocycle and heterocycle are independently optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4alkyl, —OH, —CH3, —CF3, —CHF2, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2;
• or It m and R20 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• R11, R13, R16 and R18 are independently selected from hydrogen;
• and C1-4alkyl optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4 alkyl, —OH, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2;
• R12 is selected from hydrogen;
• and C1-4alkyl optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4 alkyl, —OH, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2, or R12 and R2 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• R14 is selected from hydrogen;
• and C1-4alkyl optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4 alkyl, —OH, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2, or R14 and R4 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• R15 is selected from hydrogen;
• and C1-4alkyl optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4 alkyl, —OH, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2, or R15 and R5 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• R17 is selected from hydrogen;
• and C1-4alkyl optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4 alkyl, —OH, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2, or R1 7 and R7 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• R19 is selected from hydrogen;
• and C1-4alkyl optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4 alkyl, —OH, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2 or R19 and R9 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• R20 is selected from hydrogen;
• and C1-4alkyl optionally substituted with one or more substituents independently selected from halo, —SCH3, —SOCH3, —SO2CH3, —CN, —NO2, C1-4 alkyl, —OH, —OBz, —OCH3, —OCF3, —SF5, and —OCHF2, or R20 and R10 are taken together with the intervening atoms to form a 4- to 7-membered heterocycloalkyl;
• and
• R21 is independently selected at each occurrence from hydrogen;
• and C1-10 alkyl, C2-10alkenyl, C2-10 alkynyl, C3-8 carbocycle, and 3-10 membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO2, —NH2, ═O, ═S, C2-10alkenyl, C2-10alkynyl, C1-10haloalkyl, C3-12 carbocycle, 3- to 12-membered heterocycle, —O(C1-10alkyl), —O(C2-10alkenyl), —O(C2-10alkynyl), —O(C3-8carbocycle), and —O(3-10 membered heterocycle).