Modulators of THR-β and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12180192-B2
Application number	US-202117330232-A
Country	US
Kind code	B2
Filing date	May 25, 2021
Priority date	May 8, 2019
Publication date	Dec 31, 2024
Grant date	Dec 31, 2024

Abstract

Disclosed herein are compounds of Formula I:

TL-L a -CE-HD  (I)

or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, where i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; ii) CE is a moiety of Formula IV; iii) HD is a moiety of Formula V or VI; where the substituents are as defined herein. Disclosed are also pharmaceutical compositions comprising the above compounds, and methods of treating disease by administering or contact a patient with one or more of the above compounds.

First claim

What is claimed is:

1. A compound of Formula I′:
TL-L a -CE-HD  (I′)

or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId:

wherein:
each of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , and Q 8 , is independently nitrogen or —CR b —, wherein each R b is independently hydrogen, halogen, or lower alkyl;
R 1 is hydrogen, an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, —CN, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in a ring structure;
R 2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or —CN;
R 3 is hydrogen or lower alkyl;
R 4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in a ring structure; and
R 5 is hydroxy, NH 2 , alkylamino, alkanoylamino, or alkylsulfonylamino;
or R 4 and R 5 taken together along with the carbon atoms to which they are attached form a five- or six-membered optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic group, or optionally substituted heteroaryl group;
or R 4 and R 5 taken together along with the carbon atoms to which they are attached form a seven to eleven membered, optionally substituted spirocyclic ring or a seven to eleven membered, optionally substituted spiro-heterocyclic ring;
Alk is hydrogen or an optionally substituted alkyl; and
R 11 is an aryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a heteroaryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a bicyclic ring system; or a bicyclic heterocyclic ring system;
ii) CE is a moiety of Formula IV

wherein:
each of R 6 and R 7 is independently selected from halogen or lower alkyl;
R 8 is selected from hydrogen or lower alkyl;
or R 6 is selected from halogen and lower alkyl, and R 7 and R 8 taken together, along with the carbon atoms to which they are attached, form a 4-, 5- or 6-membered non-aromatic carbocyclic ring;
Q 7 is —CR c —, wherein R c is hydrogen;
(TL) denotes the point where the moiety of Formula IV connects to TL-L a -; and
(HD) denotes the point where the moiety of Formula IV connects to —HD;
iii) HD is a moiety of Formula V:

wherein:
R 9 is —(C(R d ) 2 ) n −N(R d ) 2 ; wherein
each R d is independently hydrogen or optionally substituted lower alkyl; and
each n is 0; and
L a is —(C(R a ) 2 ) z —; oxygen; or sulfur; wherein each R a is a hydrogen; and z is 1.

2. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
TL is a moiety of Formula IIIb:

3. The compound of claim 2 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 6 alkyl; C 2 -C 10 alkenyl; a non-aromatic C 3 -C 12 carbocyclic ring; a C 6 -C 10 aryl group; a 3- to 6-membered heterocycloalkyl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a five- to ten-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; or a (heterocycloalkyl)alkyl group; and R 4 is optionally substituted with one to five R g independently selected from the group consisting of hydroxy, halogen, CN, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 6 -C 10 aralkoxy, or two R g together with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen.

4. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
TL is a moiety of Formula IIIa:

5. The compound of claim 4 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein TL is a moiety of Formula IIIaa:

wherein each R g is independently C 1 -C 6 alkyl or the two R g together with the atom(s) to which they are attached form a 3- to 6-membered non-aromatic carbocyclic group.

6. The compound of claim 4 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein TL is a moiety of Formula IIIab:

wherein R g is C 1 -C 6 alkyl.

7. The compound of claim 4 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein TL is a moiety of Formula IIIac:

wherein R g is C 1 -C 6 alkyl.

8. The compound of claim 4 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein TL is a moiety of Formula IIIad:

wherein each R g is independently hydrogen or C 1 -C 6 alkyl.

9. The compound of claim 4 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt wherein:
R 4 is C 1 -C 6 alkyl; C 2 -C 10 alkenyl; a non-aromatic C 3 -C 12 carbocyclic ring, a C 6 -C 10 aryl group; a 3- to 6-membered heterocycloalkyl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a five- to ten-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic

Assignees

• Aligos Therapeutics Inc

Inventors

• Vandyck Koen
• Raboisson Pierre Jean-Marie Bernard
• Mcgowan David
• Deval Jerome

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/12 Primary

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