Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
The present disclosure relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula: where R 1 , R 2 , R 3 , R 4 , R 4′ , X 1 , Y 1 , Y 2 , Y 3 , Y 4 , n, and m are described herein.
1. A compound of Formula (Id):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 1 -C 6 ) alkyl substituted with R 8 ;
each R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 3 -C 8 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 20 ; or
two R 3 together when on adjacent carbons form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three R 20 ; or
two R 3 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one to three R 20 ; or
two R 3 together when attached to the same carbon atom form a 3- to 7-membered spiroheterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to three R 20 ; or
two R 3 together when on adjacent carbons form a (C 6 -C 14 ) aryl ring optionally substituted with one to three R 20 ; or two R 3 together when on adjacent carbons form a 5- or 6-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S optionally substituted with one to three R 20 ;
R 6 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen other than Cl, CN, NO 2 , —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 8 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 13 ;
R 8 is —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl optionally substituted with one to three R 9 ;
each R 9 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 8 ) cycloalkyl, 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —(C 0 -C 3 )-alkylene-(C 6 -C 14 ) aryl, —(C 0 -C 3 )-alkylene-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —NH 2 , —OH, —C(O)R 23 , —C(O)NR 23 R 24 , —NR 23 C(O)R 24 , —NR 23 R 24 , —S(O) q R 23 , —S(O) q NR 23 R 24 , —NR 23 S(O) q R 24 , oxo, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)((C 6 -C 14 ) aryl) 2 , —SiMe 3 , —SF 5 , —O—(C 6 -C 14 ) aryl, CN, or —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 19 ;
each R 13 is independently D, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 3 -C 8 ) cycloalkyl, 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 6 -C 14 ) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O-3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 3 -C 8 ) cycloalkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 26 R 27 , —S(O) q NR 26 R 27 , NR 26 R 27 , —NR 26 C(O)NR 26 R 27 , —NR 26 C(O)OR 27 , —NR 26 S(O) q R 27 , —NR 26 C(O)R 27 , halogen, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)((C 6 -C 14 ) aryl) 2 , —SiMe 3 , or —SF 5 , wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 15 ;
each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
each R 19 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —NR 26 C(O)R 27 , —NR 26 S(O) q R 27 , C(O)R 26 , —C(O)NR 26 R 27 , —NR 26 R 27 , —S(O) q R 26 , —S(O) q NR 26 R 27 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)((C 6 -C 14 ) aryl) 2 , —SiMe 3 , —SF 5 , —OH, or CN;
each R 20 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —NH 2 , or CN;
each R 23 and R 24 is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 8 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one to three R 25 ;
each R 26 and R 27 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 8 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one to three substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, —NH 2 , (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2 or 3;
q is independently at each occurrence 0, 1, or 2;
provided that the compound is further characterized by any one or more of the following:
i. R 6 is (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 5 -C 8 ) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 13 ; or
ii. each R 13 is independently (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 3 -C 8 ) cycloalkyl, 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O-3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are substituted with one to three R 15 .
2. The compound of claim 1 , wherein n is 1.
3. The compound of claim 1 , wherein m is 0.
4. The compound of claim 3 , wherein n is 1.
5. The compound of claim 4 , wherein R 2 is 3-butyl.
6. The compound of claim 5 , wherein R 8 is —(C 0 )-alkylene-(C 6 ) aryl.
7. The compound of claim 6 , wherein R 8 is —(C 0 )-alkylene-(C 6 ) aryl unsubstituted with R 9 .
8. The compound of claim 7 , wherein R 6 is H.
9. The compound of claim 7 , wherein R 6 is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen other than Cl, CN, NO 2 , or —NH 2 .
10. The compound of claim 7 , wherein
R 6 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen other than Cl, CN, NO 2 , —NH 2 , —NHC(O)(C 1 -C 6 ) alkyl, wherein the alkyl is optionally substituted with one to three R 13 ;
each R 13 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein in the alkyl or heterocycloalkyl are optionally substituted with one to three R 15 ; and
each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN.
11. The compound of claim 7 , wherein R 6 is —NHC(O)(C 1 -C 6 ) alkyl.
12. The compound of claim 11 , wherein the alkyl of R 6 is substituted with one R 13 .
13. The compound of claim 12 , wherein
R 13 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —OH, —NH 2 , 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl or heterocycloalkyl are optionally substituted with one to three R 15 ; and
each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN.
14. The compound of claim 13 , wherein R 13 is a 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the heterocycloalkyl is optionally substituted with one to three R 15 .
15. The compound of claim 14 , wherein R 13 is a 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the heterocycloalkyl is optionally substituted with one to three R 15 .
16. The compound of claim 15 , wherein R 13 is a piperazinyl and R 15 is (C 1 -C 6 ) alkyl.
17. A compound of Formula (Id):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 1 -C 6 ) alkyl substituted with R 8 ;
R 6 is —NHC(O)(C 1 -C 6 ) alkyl, wherein the alkyl is substituted with R 13 ;
R 8 is —(C 0 -C 4 )-alkylene-(C 6 ) aryl;
each R 13 is independently (C 6 -C 14 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 3 -C 8 ) cycloalkyl, 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 6 ) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O-5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 5 -C 6 ) cycloalkyl, wherein in the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are substituted with one to three R 15 ;
each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
m is 0; and
n is 1.
18. The compound of claim 17 , wherein
R 2 is (C 3 ) alkyl;
R 13 is a piperazinyl;
R 6 is —NHC(O)(C 2 ) alkyl, wherein the alkyl is substituted with one R 15 ; and
R 15 is methyl.
19. A compound of Formula (Id):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is (C 1 -C 6 ) alkyl substituted with one R 8 ;
R 6 is —NHC(O)(C 1 -C 6 ) alkyl substituted with one R 13 ;
R 8 is —(C 0 )-alkylene-(C 6 ) aryl;
R 13 is 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, substituted with one to three R 15 ;
each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —C(O)(C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, —OH, or CN;
m is 0; and
n is 1.
20. The compound of claim 19 , wherein
R 13 is a piperazinyl substituted with one R 15 ;
R 15 is methyl; and
R 2 is (C 3 ) alkyl.