HTT modulators for treating Huntington's disease

Patent metadata

Field	Value
Publication number	US-12281116-B2
Application number	US-202217988340-A
Country	US
Kind code	B2
Filing date	Nov 16, 2022
Priority date	Nov 17, 2021
Publication date	Apr 22, 2025
Grant date	Apr 22, 2025

Abstract

Provided herein are certain compounds useful as HTT modulators. Such compound are useful in the treatment of Huntington's disease.

First claim

What is claimed is:

1. A compound of Formula I:

or an isotopically enriched analog, pharmaceutically acceptable salt, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein:
X 1 , X 2 , X 3 , and X 4 are CR 4 or N, wherein at least two but no more than three of X 1 , X 2 , X 3 , and X 4 are N;
each R 4 is independently hydrogen, halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxy;

Y 1 is CR 5 ;
R 5 is C 1-6 alkoxy substituted with C 2-6 alkynyl, aryl, C 1-6 alkoxy, heteroaryl, heterocyclyl, or cyano;

Y 2 is absent, CR 6 , or N;
R 6 is hydrogen, cyano, halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 haloalkoxy, heterocyclyl, —NH 2 , —NHR 17 , or —N(R 17 ) 2 , and optionally substituted on an available nitrogen atom with C 1-6 alkyl or C 1-6 haloalkyl; and

Y 3 is CR 3 or N;
R 3 is hydrogen, cyano, halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 haloalkoxy, heterocyclyl, —NH 2 , —NHR 17 , or —N(R 17 ) 2 , and optionally substituted on an available nitrogen atom with C 1-6 alkyl or C 1-6 haloalkyl;
each R 17 is independently C 1-4 alkyl, or two R 17 join, with any intervening atoms, to form a 3- to 6-membered heterocyclyl;

each of Z 1 and Z 2 is C or N;
Ring A and Ring B together form a 9- or 10-membered bicyclic heteroaryl containing 1 to 3 ring nitrogen atoms;
Ring B contains 1 to 3 heteroatoms independently selected from N, O, and S, and is optionally substituted on available carbon atom(s) with 1 to 3 substituents independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy, and optionally substituted on an available nitrogen atom with C 1-6 alkyl or C 1-6 haloalkyl;

R 1 is -L 1 -R 11 , wherein L 1 is —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 12 )—, —C 1-3 alkylene-, —O—C 1-3 alkylene-, —N(R 12 )—C 1-3 alkylene-, or absent, and R 11 is C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, heteroaryl, or heterocyclyl, wherein R 11 is optionally substituted with 1 to 4 R 13 groups;
R 12 is hydrogen or C 1-6 alkyl;
each R 13 is independently selected from halo, cyano, hydroxy, C 1-6 alkyl optionally substituted with R 16 , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-10 cycloalkyl optionally substituted with R 16 , C 3-10 cycloalkyl-C 1-6 alkyl optionally substituted with R 16 , C 6-10 aryl optionally substituted with R 16 , C 6-10 aryl-C 1-6 alkyl optionally substituted with R 16 , heteroaryl optionally substituted with R 16 , heteroaryl-C 1-6 alkyl optionally substituted with R 16 , heterocyclyl optionally substituted with R 16 , heterocyclyl-C 1-6 alkyl optionally substituted with R 16 , OR 14 , —NH 2 , —NHR 14 , —N(R 14 ) 2 , —C 1-6 alkylene-NH 2 , —C 1-6 alkylene-NHR 14 , —C 1-6 alkylene-N(R 14 ) 2 , —C(O)R 15 , —C(O)OR 15 , —C(O)NHR 15 , —C(O)N(C 1-4 alkyl)R 15 , —S(O) 2 R 15 , —S(O)R 15 , —NHC(O)R 15 , —N(C 1-4 alkyl)C(O)R 15 , —NHS(O)R 15 , —N(C 1-4 alkyl)S(O)R 15 , —NHS(O) 2 R 15 , and —N(C 1-4 alkyl)S(O) 2 R 15 ,
each R 14 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, heteroaryl, and heterocyclyl; and each R 14 is optionally substituted with one to six halo, C 1-3 alkyl, C 1-3 alkoxy, C 3-10 cycloalkyl, or —NHSO 2 -aryl-N(CH 3 ) 2 ;
each R 15 is independently hydrogen, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, heteroaryl, or heterocyclyl;
each R 16 is independently halo, cyano, hydroxy, —NH 2 , —NHR 21 , —N(R 21 ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, OR 21 , or C 3-10 cycloalkyl;
each R 21 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, heteroaryl, heterocyclyl, and —CH 2 C(O)NHR 22 ; and each R 21 is optionally substituted with one to six halo or C 1-3 alkoxy and R 22 is C 1-6 alkyl substituted with heterocycylyl and N 3 ; and

R 2 is hydrogen or C 1-6 alkyl.

2. The compound of claim 1 , of Formula Ia, Formula Ib, or Formula Ic:

or an isotopically enriched analog, pharmaceutically acceptable salt, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

3. The compound of claim 1 , of Formula IIa:

or an isotopically enriched analog, pharmaceutically acceptable salt, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein R 8 is hydrogen, halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

4. The compound of claim 1 , of Formula IIb:

or an isotopically enriched analog, pharmaceutically acceptable salt, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein R 10 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl.

5. The compound of claim 1 , of Formula IIIa, Formula IIIb, or Formula IIIc:

or an isotopically enriched analog, pharmaceutically acceptable salt, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein R 8 is hydrogen, halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

6. The compound of claim 1 , wherein R 11 is heterocyclyl optionally substituted with 1 to 4 groups independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heteroaryl, heterocyclyl, heterocyclyl-C 1-6 alkyl, —NH 2 , —NHR 14 , —N(R 14 ) 2 , —C 1-6 alkylene-NH 2 , —C 1-6 alkylene-NHR 14 , —C 1-6 alkylene-N(R 14 ) 2 , and —C(O)OR 15 ; wherein each R 14 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, and heterocyclyl, and each R 14 is optionally substituted with one to three halo; and wherein R 15 is C 1-6 alkyl.

7. The compound of claim 1 , wherein R 11 is

wherein Ring C is a 3- to 10-membered heterocyclyl containing 0, 1 or 2 additional ring nitrogen atoms optionally substituted with 1 to 4 R 13 groups.

8. The compound of claim 7 , wherein Ring C is a 5- to 10-membered spirobicyclic heterocyclyl containing one additional ring nitrogen atom optionally substituted with 1 to 4 R 13 groups.

9. The compound of claim 1 , wherein R 3 is halo.

10. The compound of claim 1 , wherein R 3 is hydrogen.

11. The compound of claim 1 , wherein each R 4 is hydrogen.

12. The compound of claim 1 , wherein R 2 is hydrogen.

13. The compound of claim 1 , wherein L 1 is absent.

14. The compound of claim 1 , wherein Y 2 is CR 6 .

15. The compound of claim 1 , wherein Y 3 is CR 3 .

16. A compound selected from:

or an isotopically enriched analog, pharmaceutically acceptable salt, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

17. A pharmaceutical composition comprising the compound of claim 1 , or an isotopically enriched analog, pharmaceutically acceptable salt, tautomer, stereoisomer, or a

Assignees

• Chdi Foundation Inc

Inventors

• Liu Longbin
• Dominguez Celia
• Plotnikov Nikolay V
• Haughan Alan
• Stott Andrew
• Cosgrove Brett
• Clissold Cole
• Vater Huw
• Spencer Jonathan
• ESMIEU William
• Malagu Karine
• Chambers Mark

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title