Stabilization of amyloidogenic immunoglobulin light chains

Patent metadata

Field	Value
Publication number	US-11945806-B2
Application number	US-202017593812-A
Country	US
Kind code	B2
Filing date	Mar 29, 2020
Priority date	Mar 29, 2019
Publication date	Apr 2, 2024
Grant date	Apr 2, 2024

Abstract

In immunoglobulin light chain amyloidosis (AL), the unique antibody light chain (LC) protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. For treating AL patients, such as those with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, provided herein are small molecule compounds of Formula Ia, Formula Ib, and Formula II that are kinetic stabilizers of the native dimeric structure of full-length LCs, which compounds can slow or stop the amyloidogenicity cascade at its origin.

First claim

We claim:

1. A method of stabilizing an immunoglobulin light chain dimer in a native conformation thereof, comprising contacting the dimer and an effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof:

wherein
A is

X 1 is O or NR 0 ;
X 2 is selected from the group consisting of a bond, NR 12 , O, C(O), C(O)NR 11 , and CR 12 R 11 ;
X 3 is O or NR 13 ;
W is

m is an integer selected from 1, 2, 3, 4, 5, and 6;
n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
p is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
r is an integer selected from 0, 1, 2, and 3;
Z 1 is selected from the group consisting of
H,
C 1 -C 6 -alkyl,
C 3 -C 8 -cycloalkyl,
3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
C 2 -C 6 -alkenyl,
C 3 -C 8 -cycloalkenyl,
3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
C 6 -C 10 -aryl,
5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
—(C 1 -C 6 -alkyl)(C 6 -C 10 -aryl),
—(C 1 -C 6 -alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S,
halogen,
NR 16 NR 17 ,
COOR 18 ;
OR 18 ,
NR 16 SO 2 R 18 ,
NR 16 COR 18 ,
X 4 (CR 21 R 22 ) a CONR 16 R 17 ,
X 4 (CR 21 R 22 ) a COOR 18 ,
X 4 (CR 21 R 22 ) a COR 18 ,
X 4 (CR 21 R 22 ) a NR 16 R 17 ,
X 4 (CR 21 R 22 ) a OR 18 ,
SO 2 NR 16 R 17 ,
X 4 (CR 21 R 22 ) a NR 16 COR 18 ,
C(N═R 23 )NR 24 OH, and

wherein
X 4 is a bond, O, or NR 0 ; and
a is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

Z 2 is selected from the group consisting of
H,
C 1 -C 6 -alkyl,
C 3 -C 8 -cycloalkyl,
3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
C 2 -C 6 -alkenyl,
C 2 -C 6 -alkynyl,
C 3 -C 8 -cycloalkenyl,
3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
C 6 -C 10 -aryl,
5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
—(C 1 -C 6 -alkyl)(C 6 -C 10 -aryl),
—(C 1 -C 6 -alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S,
CN,
OR 18 and
NR 19 R 20 ;

Ar 1 is a divalent moiety selected from
C 6 -C 10 -arylene and
5- to 10-membered heteroarylene wherein 1-4 heteroaryl members are independently selected from N, O, and S;

R 1 is selected from the group consisting of
H,
C 1 -C 6 -alkyl,
C 3 -C 8 -cycloalkyl,
3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
C 2 -C 6 -alkenyl,
C 3 -C 8 -cycloalkenyl,
3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
C 6 -C 10 -aryl,
5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
—(C 1 -C 6 -alkyl)(C 6 -C 10 -aryl),
—(C 1 -C 6 -alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S,
OH,
(CR 21 R 22 ) b OR 18 where b is an integer selected from 0, 1, 2, 3, 4, 5, and 6,
halogen, and
(C 1 -C 6 )haloalkyl;

R 2 , R 3 , and R 4 are independently selected from the group consisting of
H,
C 1 -C 6 -alkyl,
—(C 1 -C 6 -alkyl)(C 6 -C 10 -aryl),
OH,
(CR 21 R 22 ) b OR 18 ,
halogen,
C 3 -C 8 -cycloalkyl,
3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
C 2 -C 6 -alkenyl,
C 3 -C 8 -cycloalkenyl,
3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
C 6 -C 10 -aryl,
5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
—(C 1 -C 6 -alkyl)(C 6 -C 10 -aryl), and
—(C 1 -C 6 -alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S;

R 0 , R 5 -R 13 and R 18 -R 22 are independently selected from the group consisting of H,
C 1 -C 6 -alkyl,
C 1 -C 6 -haloalkyl,
C 3 -C 8 -cycloalkyl,
3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
C 2 -C 6 -alkenyl,
C 2 -C 6 -alkynyl,
C 3 -C 8 -cycloalkenyl,
3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
C 6 -C 10 -aryl,
5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
—(C 1 -C 6 -alkyl)(C 6 -C 10 -aryl), and
—(C 1 -C 6 -alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S;

R 16 and R 17 are independently selected from the group consisting of H,
C 1 -C 6 -alkyl,
C 3 -C 8 -cycloalkyl,
3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
C 2 -C 6 -alkenyl,
C 3 -C 8 -cycloalkenyl,
3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
C 6 -C 10 -aryl,
5- to 10-membered heteroaryl 4 wherein 1-4 heteroaryl members are independently selected from N, O, and S,
—(C 1 -C 6 -alkyl)(C 6 -C 10 -aryl),
—(C 1 -C 6 -alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S,
C(O)OR 18 ,
C(O)R 18 , and
SO 2 R 18 ;

R 16 and R 17 , together with the atoms to which they are bound, optionally are a 3- to 8-membered ring wherein ring members are selected from C, O and N;
R 19 and R 20 , together with the atoms to which they are bound, optionally are a 3- to 8-membered ring;
R 21 and R 22 , together with the atoms to which they are bound, optionally are a 3- to 8-membered ring.

2. A method of treatment of light chain amyloidosis in a patient, comprising administering to the patient an effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof:

wherein

A is
X 1 is O or NR 0 ;
X 2 is selected from the group consisting of a bond, NR 12 , O, C(O), C(O)NR 11 , and CR 12 R 11 ;
X 3 is O or NR 13
W is

m is an integer selected from 1, 2, 3, 4, 5, and 6;
n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
p is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
r is an integer selected from 0, 1, 2, and 3;
Z 1 is selected from the group consisting of
H,
C 1 -C 6 -alkyl,
C 3 -C 8 -cycloalkyl,
3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
C 2 -C 6 -alkenyl,
C 3 -C 8 -cycloalkenyl,
3- t

Assignees

• Scripps Research Inst

Inventors

• Kelly Jeffery W
• Morgan Gareth John
• Lok Yan Nicholas
• Petrassi Hank Michael James

Classifications

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07C255/30

  containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same unsaturated acyclic carbon skeleton · CPC title

• C07C311/39

  having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom · CPC title

• C07C317/24

  having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton · CPC title

• C07D207/06

  with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms · CPC title