Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors

Patent metadata

Field	Value
Publication number	US-9840491-B2
Application number	US-201615015571-A
Country	US
Kind code	B2
Filing date	Feb 4, 2016
Priority date	Feb 5, 2015
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

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.

First claim

The invention claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, and tautomer thereof,
wherein:
X 1 is C, S, or S(O);
Y 1 is N or CH;
Y 2 is N or CR 5 ;
Y 3 is N or CR 6 ;
Y 4 is N or CR 7 ;
R 1 is H, —OH, —SH, —NH 2 , or F;
R 2 is (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, 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, or —NR 10 R 11 , wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three 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 4 and R 4′ are independently H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or CN;
R 5 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, halogen, NO 2 , or CN, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one to three R 12 ;
R 6 is H, D, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, 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 7 is H, (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, 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, —N((C 1 -C 6 ) alkyl)-(C 6 -C 14 ) aryl, —NH—(C 6 -C 14 ) aryl, —N((C 1 -C 6 ) alkyl)-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or —NH-5- or 6-membered heteroaryl 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 14 ;
wherein R 5 , R 6 , and R 7 are not all simultaneously H;
each R 8 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, —(C 1 -C 3 )-alkylene-O—(C 1 -C 6 ) alkyl, —(C 0 -C 4 )-alkylene-(C 6 -C 14 ) aryl, —(C 0 -C 4 )-alkylene-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 3 -C 10 ) cycloalkyl, 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —(C 0 -C 4 )-alkylene-O—(C 6 -C 14 ) aryl, —(C 0 -C 4 )-alkylene-O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C 3 -C 8 ) cycloalkyl, —S-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —C(O)R 21 , —CO(O)R 21 , —C(O)NR 21 R 22 , —S(O) q R 21 , —S(O) q NR 21 R 22 , —NR 21 S(O) q R 22 , —(C 0 -C 3 )-alkylene-NR 21 R 22 , —NR 21 C(O)R 22 , —NR 21 C(O)C(O)R 22 , —NR 21 C(O)NR 21 R 22 , —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)((C 6 -C 14 ) aryl) 2 , —SiMe 3 , —SF 5 , or —OR 21 , wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R 9 ; or
two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one to three R 9 ; or two R 8 together when on adjacent atoms form a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to three R 9 ; or two R 8 together when on adjacent atoms form a (C 6 -C 14 ) aryl ring optionally substituted with one to three R 9 ; or two R 8 together when on adjacent atoms 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 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 ;
R 10 and R 11 are independently H, (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 17 ; or
R 10 and R 11 together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to three R 17 ;
each R 12 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, CN, —C(O)(C 1 -C 6 ) alkyl, —S(O) q (C 1 -C 6 ) alkyl, —NH 2 , (C 1 -C 6 ) alkylamino, or di(C 1 -C 6 ) alkylamino;
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

Assignees

• Forma Therapeutics Inc

Inventors

• Ioannidis Stephanos
• Talbot Adam Charles
• Follows Bruce
• Buckmelter Alexandre Joseph
• Wang Minghua
• Campbell Ann-Marie
• Lancia Jr David R

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title