Rapafucin derivative compounds and methods of use thereof

Inventors

Liu, Jun • Hong, Sam • Ullman, Brett R. • Semple, Joseph E. • YAMAMOTO, Kana • Kumar, Puneet • Sadagopan, Magesh • Schmitt, Jennifer C.

Assignees

Rapafusyn Research And Developement Inc • Rapafusyn Pharmaceuticals Inc • Johns Hopkins University

Abstract

The present disclosure provides macrocyclic compounds inspired by the immunophilin ligand family of natural products FK506 and rapamycin. The generation of a Rapafucin library of macrocyles that contain FK506 and rapamycin binding domains should have great potential as new leads for developing drugs to be used for treating diseases.

Core Innovation

The invention relates to a macrocyclic compound according to Formula (XII), or a pharmaceutically acceptable salt or stereoisomer thereof. The compound includes Ring A, Ring B, Ring C, Ring E, a resin, an oligonucleotide domain D, and an Effector Domain having Formula (XIIa). The structure is defined by multiple variable groups, including J, R6, RN, R', Lb, Lc, and La through L8, with linkage selections and substitution patterns specified across the macrocyclic framework.

Ring A is defined as a 5-10 membered aryl substituted with 1-17 substituents selected from halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, alkylthio, oxo, amino, alkylamino, and dialkylamino, with optional heteroaryl or heterocycloalkyl alternatives. Ring B is defined as a 4-10 membered heterocycloalkyl optionally substituted with 1-10 substituents, and Ring C is defined as a 5-6 membered heteroaryl optionally substituted with 1-4 substituents including Lb-J-Lc-D. Ring E is defined as phenyl or a 5-6 membered heteroaryl or heterocycloalkyl.

The Effector Domain is defined by Formula (XIIa), in which each of k_a through k_i is independently 0 or 1 and each of X_a through X_i is independently a bond, sulfur-containing linkage, or substituted or unsubstituted alkylene, alkenylene, or alkynylene. The disclosure also includes tagged macrocyclic compounds and macrocyclic compound libraries, including conjugation of Formula (XII) macrocycles with a compound of Formula (XIV) and library sizes on the order of 10^2 to 10^10.

Claims Coverage

The material includes one independent claim, clm-00001, defining a macrocyclic compound according to Formula (XII), including pharmaceutically acceptable salt or stereoisomer forms, with a resin-linked oligonucleotide domain D, multiple ring systems, and a parameterized Effector Domain of Formula (XIIa). It also discloses tagged macrocyclic compounds and macrocyclic compound libraries.

The claim coverage centers on a Formula (XII) macrocyclic compound with a resin-linked oligonucleotide domain D, defined ring systems and linkages, and an Effector Domain of Formula (XIIa) governed by k and X parameters, with additional disclosure of tagged macrocyclic compounds and libraries.

Stated Advantages

Documented Applications