Peptidomimetic macrocycles

A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c, wherein the peptidomimetic macrocycle has the formula:

• or a pharmaceutically-acceptable salt thereof,
• wherein:
• each A, C, and D is independently an amino acid;
• each B is independently an amino acid,
• [—NH-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-];
• each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);
• each R1 and R2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
• or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;
• each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
• each L and L′ is independently a macrocycle-forming linker of the formula -L1-L2-;
• each L1 and L2 and L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4-K-R4—]n, each being optionally substituted with R5;
• each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
• each K is independently O, S, SO, SO2, CO, CO2, or CONR3;
• each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R7 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
• each R8 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
• each v is independently an integer from 1-1000;
• each w is independently an integer from 3-1000;
• u is an integer from 1-10;
• each x, y and z is independently an integer from 0-10;
• and
• each n is independently an integer from 1-5.

A peptidomimetic macrocycle of Formula:

• or pharmaceutically-acceptable salt thereof
• wherein:
• each of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xa10 is independently an amino acid, wherein at least three of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 are the same amino acids as the amino acid at the corresponding position of the sequence Phe3-X4-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12 (SEQ ID NO:
• 8) or Phe3-X4-Glu5-Tyr6-Trp7-Ala8-Gln9-Leu10/Cba10-X11-Ala12 (SEQ ID NO:
• 9), wherein each X4 and X11 is independently an amino acid;
• each D is independently an amino acid;
• each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);
• R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
• or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;
• each L or L′ is independently a macrocycle-forming linker;
• each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SO2R6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
• R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
• R8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
• v is an integer from 1-1000;
• and
• w is an integer from 3-1000.

A method of preparing a composition comprising a peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof of Formula (Ia):

• or pharmaceutically-acceptable salt thereof,
• comprising an amino acid sequence which is about 60% to about 100% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c, the method comprising treating a compound of Formula (II) or pharmaceutically-acceptable salt thereof
• with a catalyst to result in the compound of Formula (Ia) or pharmaceutically-acceptable salt thereof,
• wherein in the compound of Formula (Ia) or pharmaceutically-acceptable salt thereof and in the compound of Formula (II) or pharmaceutically-acceptable salt thereof
• each A, C, and D is independently an amino acid;
• each B is independently an amino acid [—NH-L3-SO2—], or [—NH-L3-];
• each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);
• each R1 and R2 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halogen;
• or forms a macrocycle-forming linker L′ connected to the alpha position of one of the D or E amino acids;
• each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
• each L′ is independently a macrocycle-forming linker of the formula -L1-L2-;
• each L1, L2 and L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4-K-R4—]n, each being optionally substituted with R5;
• each R4 and R4′ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
• each K is independently O, S, SO, SO2, CO, CO2, or CONR3;
• each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R6 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
• each R7 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
• each R8 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
• each v is independently an integer from 1-1000;
• each w is independently an integer from 3-1000;
• u is an integer from 1-10;
• each x, y and z is independently an integer from 0-10;
• each n is independently an integer from 1-5;
• each o is independently an integer from 1 to 15;
• each p is independently an integer from 1 to 15;
• (E) indicates a trans double bond or an E-double bond;
• and
• one or more of A, B, and C, has a side chain bearing a protecting group.