Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors

Patent metadata

Field	Value
Publication number	US-2016229864-A1
Application number	US-201615015563-A
Country	US
Kind code	A1
Filing date	Feb 4, 2016
Priority date	Feb 5, 2015
Publication date	Aug 11, 2016
Grant date	—

Abstract

The 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 5 , R 5′ , X 1 , X 2 , n, and m are described herein.

First claim

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof,
wherein:
X 1 is C, S, or S(O);
X 2 is

R 1 is H, —OH, —SH, —NH 2 , or F;
R 2 is (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, heterocycloalkyl, —NR 10 R 11 , or —OR 10 , wherein the alkyl is substituted with one or more R 8 , and wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 8 ;
each R 3 is independently at each occurrence selected from D, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 20 ; or
two R 3 together when on adjacent carbons form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more 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 or more R 20 ; or two R 3 together when attached to the same carbon atom form a spiroheterocycloalkyl optionally substituted with one or more R 20 ; or two R 3 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 20 ; or two R 3 together when on adjacent carbons form an heteroaryl ring optionally substituted with one or more R 20 ;
R 4 is H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 12 ;
R 5 and R 5′ 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 6 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 , (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 14 ;
R 7 is H, D, (C 1 -C 6 ) alkyl, halogen, CN, NO 2 , (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 16 ; or
R 6 and R 7 together with the atoms to which they are attached form a (C 3 -C 8 )cycloalkyl optionally substituted with one or more R 16 ;
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-aryl, —(C 0 -C 4 )-alkylene-heteroaryl, (C 3 -C 10 ) cycloalkyl, heterocycloalkyl, —(C 0 -C 4 )-alkylene-O-aryl, —(C 0 -C 4 )-alkylene-O-heteroaryl, —O—(C 3 -C 8 )cycloalkyl, —S-heteroaryl, —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)(aryl) 2 , —SiMe 3 , —SF 5 , or —OR 21 , wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 9 ; or
two R 8 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 9 ; or two R 8 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more 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, heterocycloalkyl, (C 6 -C 14 ) aryl, heteroaryl, —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)(aryl) 2 , —SiMe 3 , —SF 5 , —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 26 ;
R 10 and R 11 are independently H, (C 1 -C 6 ) alkyl, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 18 ; or
R 10 and R 11 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 18 ;
each R 12 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, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —C(O)O(C 1 -C 6 ) alkyl, —C(O)NR 27 R 28 , —S(O) q NR 27 R 28 , —NR 27 R 28 , —NR 27 C(O)NR 27 R 28 , —NR 27 C(O)OR 28 , —NR 27 S(O) q R 28 , —NR 27 C(O)R 28 , halogen, —P(O)((C 1 -C 6 ) alkyl) 2 , —P(O)(aryl) 2 , —SiMe 3 , or —SF 5 , wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 13 ; or
two R 12 together when on adjacent atoms form a (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 13 ; or two R 12 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more 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, —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, (C 6 -C 14 ) aryl, heteroaryl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C 3 -C 8 )cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R 29 ;
each R 14 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, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more 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 16 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 , —OH, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 ) alkylamino, (C 6 -C 14 ) aryl, heteroaryl, (C 5 -C 8 ) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more

Assignees

• Forma Therapeutics Inc

Inventors

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

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title