Macrocyclic compounds and methods of use thereof

A macrocyclic compound, or a pharmaceutically acceptable salt thereof, wherein the macrocyclic compound is a compound of formula (I):

• wherein:
• X1 is a VHL binding motif having the formula-X1A—X1B—X1C—;
• X1B is an L-hydroxyproline or an L-fluorohydroxyproline;
• X1A is selected from the group consisting of L-Tle, L-bMe-Ile, L-Tle-Tria, NMe-L-Tle-Tria, L-Tle-Tria-CyP, L-Val, L-Ala, L-Abu, L-Pen, L-Cha, L-Cpa, L-Cba, L-bMe2AllylGly, L-AdaGly and L-ThpGly;
• X1C is selected from the group consisting of D-MTPG, D-BiPhe, D-Ala, Aib, D-Bta, L-Bta, D-bMtpg, L-bMtpg, D-MtPhe, L-BiPhe, L-Tyr(O-Me), D-bBiPhe, D-bRMeBiPhe, D-bSMeBiPhe, D-Phe(4Br), D-Phe(4Cl), D-Phe(4F), D-Phe(4CN) and D-Phe(4I);
• -L2C-L2B-L2A-X2-L1A-L1B-L1C- is selected from the group consisting of
• wherein
• the carbonyl group of L1C and the amino group of L2C are linked to X1;
• R52A and R52B are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, —CH2-phenyl, —CH2-biphenyl, —CH2-pyridyl, —CH2—CH2—C(O)—NH2 and —(CH2)n15—R111, wherein n15 is an integer from 1 to 4 and R111 is —NH2, N3, or —C(O)—NH2;
• R53 is hydrogen, C(O)NH2, —[CH2]n16—NH2—, or —[C(O)NH—CH2]n17—C(O)NH2—, wherein n16 and n17 are each independently an integer from 1 to 3;
• R54 is hydrogen or unsubstituted C1-C6 alkyl;
• L11 is a bond or a substituted or unsubstituted alkylene;
• and
• R11 is hydrogen, an unsubstituted C1-5 alkyl or a protecting group.