Thienopyridine carboxamides as ubiquitin-specific protease inhibitors

Patent metadata

Field	Value
Publication number	US-10913753-B2
Application number	US-201716077407-A
Country	US
Kind code	B2
Filing date	Feb 13, 2017
Priority date	Feb 12, 2016
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

Abstract

The disclosure relates to inhibitors of USP28 and/or USP25 useful in the treatment of cancers, inflammation, autoimmune diseases, and infectious diseases, having the Formula:

where R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ , R 6 , R 7 , X, m, and n are described herein.

First claim

The invention claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof,
wherein:
X is N or CR 7 ;
R 1 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, —CN, or —NR 9 R 10 ;
R 2 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, or —NR 11 R 12 ;
R 3 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, or —NR 13 R 14 ;
wherein at least one of R 1 , R 2 , or R 3 is not H;
or R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 15 ;
or R 2 and R 3 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 15 ;
R 4 is H, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) haloalkyl;
R 5 is H, (C 1 -C 6 ) alkyl, halogen, or (C 1 -C 6 ) haloalkyl;
R 5′ is H, (C 1 -C 6 ) alkyl, halogen, or (C 1 -C 6 ) haloalkyl; or
R 4 and R 5 together with the carbon atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring;
R 6 is —(C 0 -C 3 ) alkylene-C(O)OH, —(C 0 -C 3 ) alkylene-heterocycloalkyl, —O-heterocycloalkyl, —(C 0 -C 3 ) alkylene-aryl, —(C 0 -C 3 ) alkylene-heteroaryl or —N(R 8 )-(C 0 -C 3 ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R 16 ;
each R 7 is independently at each occurrence H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —OH, —CN, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl is optionally substituted with one or more (C 1 -C 6 ) alkoxy or —OH, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R 17 ; or
R 6 and R 7 together when on adjacent atoms form a (C 4 -C 8 ) cycloalkyl ring optionally substituted with one or more R 18 ; or R 6 and R 7 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 18 ; R 6 and R 7 together when on adjacent atoms form an aryl ring optionally substituted with one or more R 18 ; or R 6 and R 7 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R 18 ; or
two R 7 together when on adjacent atoms form a (C 4 -C 8 ) cycloalkyl ring; or two R 7 together when on adjacent atoms form a heterocycloalkyl ring; two R 7 together when on adjacent atoms form an aryl ring; or two R 7 together when on adjacent atoms form a heteroaryl ring;
R 8 is H or (C 1 -C 6 ) alkyl;
each R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is independently H, (C 1 -C 6 ) alkyl, or —C(O)(C 1 -C 6 ) alkyl;
each R 15 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, or —OH;
each R 16 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, (C 1 -C 6 ) hydroxyalkyl, halogen, (C 3 -C 8 ) cycloalkyl, —C(O)NR 21 R 22 , —S(O) 2 (C 1 -C 6 ) alkyl, —OH, or —NR 19 R 20 , wherein the alkyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkoxy, OH, and heterocycloalkyl; or
two R 16 together when attached to the same carbon can form —C═(O) when R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, —O-heterocycloalkyl, or

—N(R 8 )-(C 0 -C 3 ) alkylene-heterocycloalkyl; or two R 16 together when attached to the same atom form a (C 3 -C 8 ) spirocycloalkyl optionally substituted with one or more R 23 when R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, —O-heterocycloalkyl, or
—N(R 8 )-(C 0 -C 3 ) alkylene-heterocycloalkyl; or two R 16 together when attached to the same atom form a (C 3 -C 8 ) spiroheterocycloalkyl optionally substituted with one or more R 23 when R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, —O-heterocycloalkyl, or
—N(R 8 )-(C 0 -C 3 ) alkylene-heterocycloalkyl; or two R 16 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R 23 ; or two R 16 together when on adjacent atoms form a heteroaryl ring optionally substituted with one or more R 23 ; or two R 16 together with the atoms to which they are attached can form a bridged heterocycloalkyl ring optionally substituted with one or more R 23 when R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, —O-heterocycloalkyl, or —N(R 8 )-(C 0 -C 3 ) alkylene-heterocycloalkyl;
each R 17 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, cycloalkyl, heterocycloalkyl, or

—C(O)-heterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkoxy and —OH;
each R 18 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, —CN, —C(O)OH, or —C(O)O(C 1 -C 6 ) alkyl;
each R 19 and R 20 is independently H, (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, —CH 2 C(O)NH 2 , —S(O) 2 (C 1 -C 6 ) alkyl, —S(O) 2 (C 6 -C 10 ) aryl or —C(O)(C 1 -C 6 ) alkyl;
each R 21 and R 22 is independently H or (C 1 -C 6 ) alkyl;
each R 23 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, or halogen; or
two R 23 together when attached to the same carbon form —C═(O);
m is 1 or 2; and
n is 0, 1, 2, or 3.

2. The compound of claim 1 , wherein R 1 is (C 1 -C 6 ) alkyl, R 2 is H or (C 1 -C 6 ) alkyl, or R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 15 ; and R 3 is H.

3. The compound of claim 1 , having the structure of Formula (Id):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, and tautomer thereof.

4. The compound of claim 1 , wherein R 4 , R 5 , and R 5′ are each independently chosen from H or (C 1 -C 6 ) alkyl.

5. The compound of claim 1 , wherein R 4 and R 5 are each independently chosen from H or CH 3 , and R 5′ is H.

6. The compound of claim 1 , wherein R 6 is —(C 0 -C 3 ) alkylene -heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 17 .

7. The compound of claim 1 , wherein X is CH.

8. The compound of claim 3 , wherein R 1 is (C 1 -C 6 ) alkyl, R 2 is H or (C 1 -C 6 ) alkyl, or R 1 and R 2 together form a (C 4 -C 8 ) cycloalkyl optionally substituted with one or more R 15 ; R 3 is H; R 4 , R 5 , and R 5′ are each independently chosen from H or (C 1 -C 6 ) alkyl; and R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 17 .

9. The compound of claim 8 , wherein R 1 is CH 3 , R 2 is H; R 3 is H; R 4 , R 5 , and R 5′ are each independently chosen from H or CH 3; and R 6 is —(C 0 -C 3 ) alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more R 17 .

10. The compound of claim 9 , wherein R 4 , R 5 , and R 5′ are each H.

Assignees

• Forma Therapeutics Inc
• Valo Early Discovery Inc

Inventors

• Guerin David Joseph
• Bair Kenneth W
• Caravella Justin A
• Ioannidis Jr Stephanos
• Lancia Jr David R
• Li Hongbin
• Mischke Steven
• Ng Pui Yee
• Richard David
• Schiller Shawn E R
• Shelekhin Tatiana
• Wang Zhongguo

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title