Inhibiting ubiquitin specific peptidase 30

Patent metadata

Field	Value
Publication number	US-11247987-B2
Application number	US-201816753439-A
Country	US
Kind code	B2
Filing date	Oct 5, 2018
Priority date	Oct 6, 2017
Publication date	Feb 15, 2022
Grant date	Feb 15, 2022

Abstract

The present disclosure relates to chemical entities useful as inhibitors of Ubiquitin Specific Protease 30 (USP30), pharmaceutical compositions comprising the chemical entities, and methods of using the chemical entities. The chemical entities as disclosed herein can be useful in the treatment of a disease, disorder, or condition involving mitochondrial dysfunction, including neurodegenerative diseases, motor neuron diseases, metabolic disorders, and cancers, among other ailments. Chemical entities disclosed herein include compounds of Formula (II):wherein A, R2, R3, R4, Ra, Rc, Rd, Re, Rf, and m are defined herein.

First claim

The invention claimed is:

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
A is N or CR b ;
R a is hydrogen;
R b is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 ) alkyl optionally substituted with one or more R 5 , and (C 1 -C 6 ) alkoxy optionally substituted with one or more R 5 ; or
R b and X together form a (C 3 -C 6 ) spirocyclic cycloalkyl or (C 3 -C 6 ) spirocyclic heterocycloalkyl;
each of R c , R d , R e and R f is independently selected from the group consisting of hydrogen and (C 1 -C 6 ) alkyl optionally substituted with one or more R 5 ;
R 2 is selected from the group consisting of C(O)N(X) and N(X)C(O);
X is independently chosen from hydrogen, alkyl, and heteroalkyl, wherein the alkyl and heteroalkyl can optionally cyclize with R 3 ;
R 3 is selected from the group consisting of (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) heteroalkyl, aryl having 1 to 3 aromatic rings and optionally substituted with 1 or 2 R groups, and heteroaryl having 1 to 3 aromatic rings and optionally substituted with 1 or 2 R groups;
R 4 is independently chosen from alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, cycloalkoxy, heteroalkoxy, haloalkoxy, carboxyalkyl, heterocarboxyalkyl, cyclic, heterocyclic, aryl, and heteroaryl, wherein any rings are optionally substituted with 1 or 2 Y groups;
R 5 is selected from the group consisting of hydrogen, halogen, OH, (C 1 -C 3 ) alkyl, and (C 1 -C 3 ) alkoxy;
R is independently chosen from hydrogen, OH, CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocycloalkyl, (C 3 -C 6 ) cycloalkyloxy, and (C 1 -C 6 ) alkoxyalkyl;
Y is independently chosen from hydrogen, OH, CN, N(X) 2 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) heteroalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocycloalkyl, (C 5 -C 8 ) aryl, (C 4 -C 8 ) heteroaryl, and (C 4 -C 8 ) heteroaryl substituted with (C 1 -C 3 ) alkyl; and
m is 0, 1, or 2.

2. The compound of claim 1 , wherein each of R c , R d , R e , and R f is independently selected from the group consisting of hydrogen and (C 1 -C 6 ) alkyl.

3. The compound of claim 1 , wherein R 3 is aryl having 1 to 3 aromatic rings and optionally substituted with 1 or 2 R groups or heteroaryl having 1 to 3 aromatic rings and optionally substituted with 1 or 2 R groups.

4. The compound of claim 3 , wherein R 4 is cycloalkyl optionally substituted with 1 or 2 Y groups or aryl optionally substituted with 1 or 2 Y groups.

5. The compound of claim 4 , wherein R 4 is cycloalkyl optionally substituted with 1 or 2 Y groups.

6. The compound of claim 3 , wherein R 3 is heteroaryl having 1 aromatic ring containing two heteroatoms and optionally substituted with 1 or 2 R groups.

7. The compound of claim 6 , wherein R 3 is a thiazole ring.

8. The compound of claim 6 , wherein R 4 is cycloalkyl optionally substituted with 1 or 2 Y groups.

9. The compound of claim 1 , wherein the compound is of Formula (III):

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 , wherein X is hydrogen.

11. The compound of claim 9 , wherein each of R c , R d , R e , and R f is hydrogen.

12. The compound of claim 11 , wherein R 3 is aryl having 1 to 3 aromatic rings and optionally substituted with 1 or 2 R groups or heteroaryl having 1 to 3 aromatic rings and optionally substituted with 1 or 2 R groups.

13. The compound of claim 12 , wherein R 3 is heteroaryl having 1 aromatic ring containing two heteroatoms and optionally substituted with 1 or 2 R groups.

14. The compound of claim 13 , wherein R 3 is a thiazole ring.

15. The compound of claim 13 , wherein R 4 is cycloalkyl optionally substituted with 1 or 2 Y groups.

16. The compound of claim 12 , wherein R 4 is cycloalkyl optionally substituted with 1 or 2 Y groups or aryl optionally substituted with 1 or 2 Y groups.

17. The compound of claim 16 , wherein R 4 is cycloalkyl optionally substituted with 1 or 2 Y groups.

18. The compound of claim 9 , wherein m is 0.

19. The compound of claim 1 , wherein each of R c , R d , R e , and R f is hydrogen.

20. The compound of claim 19 , wherein R b is selected from the group consisting of hydrogen and (C 1 -C 6 ) alkyl groups.

21. The compound of claim 1 , wherein R b is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 ) alkyl groups, and (C 1 -C 6 ) alkoxy groups.

22. The compound of claim 1 , wherein the compound is selected from:

Compound 1-1

trans-3-(cyanoamino)-N-[5- (oxan-4-yl)-1,3-thiazol-2- yl]cyclobutane-1- carboxamide;

Compound 2-1

3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)azetidine-1-carboxamide;

Compound 3-1

5-phenyl-N-[(trans)-3- (cyanoamino)cyclobutyl]- 1,3-thiazole-2-carboxamide;

Compound 4-1

5-phenyl-N-[(cis)-3- (cyanoamino)cyclobutyl]- 1,3-thiazole-2-carboxamide;

Compound 5-1

cis-3-(cyanoamino)-N-(1- phenyl-1H-pyrazol-4- yl)cyclobutane-1- carboxamide;

Compound 5-2

cis-3-(cyanoamino)-N-(1- phenyl-1H-pyrazol-3- yl)cyclobutane-1- carboxamide;

Compound 5-3

Assignees

• Forma Therapeutics Inc

Inventors

• Caravella Justin
• Han Bingsong
• Liu Cuixian
• Ioannidis Stephanos
• Buckmelter Alexandre Joseph
• Richard David James
• Martin Matthew W
• Mischke Steven
• Mente Scot

Classifications

• C07D231/40

  Acylated on said nitrogen atom · CPC title

• C07C261/04 Primary

  Cyanamides (unsubstituted cyanamide C01C3/16) · CPC title

• C07D261/04

  having one double bond between ring members or between a ring member and a non-ring member · CPC title

• C07D295/185

  from aliphatic carboxylic acids · CPC title

• C07D263/48

  Nitrogen atoms not forming part of a nitro radical · CPC title