Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease

Patent metadata

Field	Value
Publication number	US-11560366-B2
Application number	US-202017075400-A
Country	US
Kind code	B2
Filing date	Oct 20, 2020
Priority date	Oct 21, 2019
Publication date	Jan 24, 2023
Grant date	Jan 24, 2023

Abstract

Disclosed herein are compounds which inhibit the kinase activity of dual leucine zipper (DLK) kinase (MAP3K12), pharmaceutical compositions, and methods of treatment of DLK-mediated diseases, such as neurological diseases that result from traumatic injury to central nervous system and peripheral nervous system neurons (e.g. stroke, traumatic brain injury, spinal cord injury), or that result from a chronic neurodegenerative condition (e.g. Alzheimer's disease, frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar ataxia, progressive supranuclear palsy, Lewy body disease, Kennedy's disease, and other related conditions), from neuropathies resulting from neurological damage (chemotherapy-induced peripheral neuropathy, diabetic neuropathy, and related conditions) and from cognitive disorders caused by pharmacological intervention (e.g. chemotherapy induced cognitive disorder, also known as chemobrain).

First claim

What is claimed is:

1. A compound of Formula (I′)

or a salt thereof wherein:
R 1 is chosen from alkyl and cycloalkyl, either of which is optionally substituted with one or more R 4 ;
R 2 is chosen from fluoro and NR 5a R 5b ;
R 3 is chosen from trifluoromethyl and trifluoromethoxy;
R 4 is halo;
R 5a and R 5b combine to form alkylene which, together to the intervening nitrogen, forms a monocyclic heterocycloalkyl which is optionally substituted with one or more R 6 ; and
each R 6 is independently chosen from cyano, halo, and hydroxyl
provided that R 2 is not a morpholine.

2. The compound of claim 1 having Formula (II):

or a salt thereof wherein:
R 1 is chosen from alkyl and cycloalkyl, either of which is optionally substituted with one or more R 4 ;
R 3 is chosen from methoxy and trifluoromethoxy; and
R 4 is halo.

3. The compound of claim 1 having Formula (III′):

or a salt thereof wherein:
R 1 is chosen from alkyl and cycloalkyl, either of which is optionally substituted with one or more R 4 ;
R 3 is chosen from methoxy and trifluoromethoxy;
R 4 is halo;
R 5a and R 5b combine to form alkylene which, together to the intervening nitrogen, forms a monocyclic heterocycloalkyl which is optionally substituted with one or more R 6 ; and
each R 6 is independently chosen from cyano, halo, and hydroxyl
provided R 5a and R 5b when combined do not form a morpholine group.

4. The compound as recited in claim 1 wherein each R 6 is fluoro.

5. The compound as recited in claim 3 , wherein the monocyclic heterocycloalkyl formed by R 5a , R 5b and the intervening nitrogen comprise exactly one —CF 2 —.

6. The compound as recited in claim 5 , wherein the monocyclic heterocycloalkyl formed by R 5a , R 5b and the intervening nitrogen is chosen from 3,3-difluoropiperidin-1-yl and 4,4-difluoropiperidin-1-yl.

7. The compound as recited in claim 6 , wherein the monocyclic heterocycloalkyl formed by R 5a , R 5b and the intervening nitrogen is 4,4-difluoropiperidin-1-yl.

8. The compound as recited in claim 3 , wherein R 1 is chosen from C 1-6 alkyl and C 3-7 cycloalkyl, either of which is optionally substituted with one, two, or three R 4 .

9. The compound as recited in claim 8 , wherein each R 4 is halo.

10. The compound as recited in claim 8 , wherein R 1 is chosen from isopropyl, trifluoromethyl, and cyclopropyl.

11. The compound as recited in claim 1 , wherein the compound is chosen from:

or a salt thereof.

12. A pharmaceutical composition comprising a compound as recited in claim 1 , or a salt thereof, together with a pharmaceutically acceptable carrier.

13. A method of inhibition of DLK comprising contacting DLK with a compound, or a salt thereof, as recited in claim 1 .

14. A method of treatment of a DLK-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited claim 1 , or a salt thereof, to a patient in need thereof.

15. The method as recited in claim 14 wherein said disease is a neurological disease.

16. The method as recited in claim 15 wherein said neurological disease results from traumatic injury to central nervous system or peripheral nervous system neurons.

17. The method as recited in claim 16 wherein said traumatic injury is chosen from stroke, traumatic brain injury, and spinal cord injury.

18. The method as recited in claim 15 wherein said neurological disease results from a chronic neurodegenerative condition.

19. The method as recited in claim 18 wherein said chronic neurodegenerative condition is chosen from Alzheimer's disease, frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar ataxia, progressive supranuclear palsy, Lewy body disease, and Kennedy's disease.

20. The method as recited in claim 15 wherein said neurological disease results from a neuropathy resulting from neurological damage.

21. The method as recited in claim 20 wherein said neurological damage is chosen from chemotherapy-induced peripheral neuropathy and diabetic neuropathy.

22. The method as recited in claim 15 wherein said disease is a cognitive disorder.

23. The method as recited in claim 22 wherein said cognitive disorder is caused by pharmacological intervention.

24. A method of treatment of a DLK-mediated disease comprising the administration of:
a. a therapeutically effective amount of a compound as recited in claim 1 , or a salt thereof; and
b. another therapeutic agent.

Assignees

• Univ Texas

Inventors

• Soth Michael J
• Le Kang
• Jones Philip
• Cross Jason

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title