Granted Patent B2

US 12,281,116 · App. 17/988,340 · Granted Apr 22, 2025

Inventors: Longbin Liu (Thousand Oaks, CA); Celia Dominguez (Los Angeles, CA); Nikolay V. Plotnikov (Los Angeles, CA); Alan Haughan (Saffron Walden, GB); Andrew Stott (Saffron Walden, GB); Brett Cosgrove (Saffron Walden, GB); Cole Clissold (Saffron Walden, GB); Huw Vater (Saffron Walden, GB); Jonathan Spencer (Saffron Walden, GB); William Esmieu (Saffron Walden, GB); Karine Malagu (Saffron Walden, GB); Mark Chambers (Saffron Walden, GB)

Assignee: CHDI Foundation, Inc.

C07D471/10A61K45/06C07D403/14C07D405/14C07D413/14C07D471/04

Abstract

Claims (46)

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 mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient.

18. A method for treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .

19. A method for treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 in combination with a second active agent.

Assignments (3)

Continuity (2)

References Cited (72)