Rapafucin derivative compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11066416-B2
Application number	US-201916590087-A
Country	US
Kind code	B2
Filing date	Oct 1, 2019
Priority date	Feb 4, 2016
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

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.

First claim

What is claimed is:

1. A macrocyclic compound according to Formula (XII):

or a pharmaceutically acceptable salt or stereoisomer thereof
wherein
Ring A is a 5-10 membered aryl substituted with 1-17 substituents independently selected from the group consisting of halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, alkylthio, oxo, amino, alkylamino, dialkylamino,

 or heteroaryl or heterocycloalkyl, optionally substituted with 1-17 substituents, each of the substituent is independently selected from the group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, alkylthio, oxo, amino, alkylamino, dialkylamino,

 wherein

 is a resin;
J is independently at each occurrence selected from the group consisting of —C(O)NR 6 —,

R 6 is each hydrogen, alkyl, arylalkyl

R N is aryl, alkyl, or arylalkyl;
R′ is hydrogen, alkyl, arylalkyl, or haloalkyl;
D is independently at each occurrence an oligonucleotide;
L b and L c are independently at each occurrence selected from the group consisting of bond, —O—, —S—, —OC(O)—, —C(O)O—, —(CH 2 ) n C(O)—, —(CH 2 ) n C(O)C(O)—, —(CH 2 ) n NR 5 C(O)C(O)—, —NR 5 (CH 2 ) n C(O)C(O)—, optionally substituted (CH 2 ) n C 1-6 alkylene (CH 2 ) n —, optionally substituted (CH 2 ) n C(O)C 1-6 alkylene (CH 2 ) n —, optionally substituted (CH 2 ) n NR 5 C 1-6 alkylene (CH 2 ) n —, optionally substituted (CH 2 ) n C(O)NR 5 C 1-6 alkylene (CH 2 ) n —, optionally substituted (CH 2 )nNR 5 C(O)C 1-6 alkylene (CH 2 ) n —, optionally substituted (CH 2 ) n C(O)OC 1-6 alkylene (CH 2 ) n —, optionally substituted (CH 2 ) n OC(O)C 1-6 alkylene (CH 2 ) n —, optionally substituted (CH 2 ) n OC 1-6 alkylene (CH 2 ) n —, optionally substituted (CH 2 ) n NR 5 C 1-6 alkylene (CH 2 )n-, optionally substituted (CH 2 ) n —S—C 1-6 alkylene (CH 2 ) n —, and optionally substituted (CH 2 CH 2 O) n ; wherein each alkylene is optionally substituted with 1 or 2 groups independently selected from the group consisting of halo, hydroxy, haloalkyl, haloalkoxy, alkyl, alkoxy, amino, carboxyl, cyano, nitro, NHFmoc;
each R 5 is independently hydrogen, alkyl, arylalkyl,

 or and

R N is aryl, alkyl, or arylalkyl; X is O, S or NR 8 , R 8 is hydrogen, hydroxy, OR 9 , NR 10 R 11 alkyl, arylalkyl,

 wherein R N is aryl, alkyl, or arylalkyl; wherein R 9 , R 10 and R 11 are each independently hydrogen or alkyl; V 1 and V 2 are each independently

 W is

 Ring B is a 4-10 membered heterocycloalkyl, optionally substituted with 1-10 substituents, each of which is selected from the group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, alkylthio, oxo, amino, alkylamino, dialkylamino, arylalkyl,

 wherein R 12 is aryl, alkyl, or arylalkyl; R 13 is hydrogen, hydroxy, OR 16 , NR 17 R 18 , alkyl, arylalkyl,

 R N is aryl, alkyl, or arylalkyl; R 14 and R 15 is each independently hydrogen, hydroxy, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, arylalkyl, or heteroaryl; Z is bond,

 R 16 and R 17 are each independently selected from the group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, cycloalkyl, cyano, alkylthio, amino, alkylamino, and dialkylamino; K is O, CHR 18 , CR 18 , N, or and NR 18 , wherein R 18 is hydrogen or alkyl;
L a , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 and L 8 are each independently a bond, —O—, —NR 19 —, —SO—, —SO 2 —, (CH 2 ) n —,

 or a linking group selected from Table 1; Ring C is a 5-6 membered heteroaryl, optionally substituted with 1-4 substituents, each of which is independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, alkylthio, amino, alkylamino, dialkylamino and L b -J-L c -D; wherein each R 19 , R 20 , and R 21 is independently is selected from the group consisting of hydrogen, hydroxy, OR 22 , NR 23 R 24 , alkyl, arylalkyl,

 wherein R N is aryl, alkyl, or arylalkyl; wherein R 22 , R 23 , and R 24 are each independently hydrogen or alkyl;
n is 0, 1, 2, 3, 4, 5 or 6; and
the Effector Domain has Formula (XIIa):

each k a , k b , k c , k d , k e , k f , k g , k h , and k i is independently 0 or 1;
each X a , X b , X c , X d , X e , X f , X g , X h , and X i is independently a bond, —S—, —S—S—, —S(O)—, —S(O) 2 —, substituted or unsubstituted —(C 1 -C 3 ) alkylene-, —(C 2 -C 4 ) alkenylene-, —(C 2 -C 4 ) alkynylene-, or

Ring E is phenyl or a 5-6 heteroaryl or heterocycloalkyl; wherein each w is independently 0, 1, or 2; each R 1 , R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 1i , and R 4 is independently hydrogen, alkyl, arylalkyl or NR 25 , wherein R 25 is hydrogen, hydroxy, OR 26 , NR 27 R 28 , alkyl, arylalkyl,

 wherein R N is aryl, alkyl, or arylalkyl; wherein R 26 , R 27 , and R 28 are each independently hydrogen or alkyl; each R 2 , R 3 , R 2a , R 3a , R 2b , R 3b , R 2c , R 3c , R 2d , R 3d , R 2e , R 3e , R 2f , R 3f , R 2g , R 3g , R 2h , R 3h , R 2i , and R 3i is independently selected from the group consisting of hydrogen, halo, amino, cyano, nitro, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl and

Assignees

• Univ Johns Hopkins
• Rapafusyn Pharmaceuticals Inc

Inventors

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

Classifications

• C07D498/14 Primary

  Ortho-condensed systems · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07F9/3258

  the ester moiety containing a substituent or a structure which is considered as characteristic · CPC title