US Patent No. 10,428,057

BICYCLO[1.1.1]PENTANE INHIBITORS OF DUAL LEUCINE ZIPPER (DLK) KINASE FOR THE TREATMENT OF DISEASE


Patent No. 10,428,057
Issue Date October 01, 2019
Title Bicyclo[1.1.1]pentane Inhibitors Of Dual Leucine Zipper (dlk) Kinase For The Treatment Of Disease
Inventorship Michael J. Soth, Sugar Land, TX (US)
Gang Liu, Sugar Land, TX (US)
Kang Le, Sugar Land, TX (US)
Jason Cross, Pearland, TX (US)
Philip Jones, Houston, TX (US)
Assignee Board of Regents, The University of Texas System, Austin, TX (US)

Claim of US Patent No. 10,428,057

1. A method of treating a disease selected from the group consisting ofchemotherapy-induced cognitive deficits (CICD),
chemotherapy-induced cognitive impairment (CICI),
chemotherapy-induced peripheral neuropathy (CIPN),
diabetic neuropathy,
Alzheimer's disease,
amyotrophic lateral sclerosis,
frontotemporal dementia,
Huntington's disease,
Kennedy's disease,
Lewy body disease,
Parkinson's disease,
progressive supranuclear palsy,
spinocerebellar ataxia,
traumatic brain injury (TBI), and
traumatic injury to the central nervous system or peripheral nervous system neurons,
the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
X1 is selected from C or N;
X2 is selected from C or N;
exactly one of X1 and X2 is N;
X3 is N;
X4 and X5 are C;
X1, X2, X3, X4, and X5 form a five membered heteroaryl;
R1 is selected from alkyl, cycloalkyl, or heterocycloalkyl, any of which is optionally substituted with one to three R5 groups;
R2 is H or is selected from alkyl, amino, aryl, cycloalkyl, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, or sulfonylalkyl, any of which is optionally substituted with one to three R6 groups;
R3 is selected from H, alkyl, (alkoxy)alkyl, (arylalkoxy)alkyl, (heteroarylalkoxy)alkyl, cyano, cycloalkyl, halo, haloalkoxy, or haloalkyl;
R4 is (NR4a)2, wherein each R4a is independently selected from hydrogen, C1-4alkyl, or C1-4haloalkyl;
or R3 and R4 together with the atoms to which they are attached form a 5- or 6-membered heteroaryl or heteroalkyl ring, optionally substituted with one to three R7 groups;
each R5 and R6 is independently selected from C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C1-4-alkylthio, C1-4haloalkylthio, aryl, heteroaryl, C3-7cycloalkyl, C3-7heterocycloalkyl, (aryl)C1-4alkyl, (heteroaryl)C1-4alkyl, (C3-7cycloalkyl)C1-4alkyl, (C3-7heterocycloalkyl)C1-4alkyl, (ethenyl)C1-4alkyl, (ethynyl)C1-4alkyl, (aryl)C1-4alkoxy, (heteroaryl)C1-4alkoxy, (C3-7cycloalkyl)C1-4alkoxy, (C3-7heterocycloalkyl)C1-4alkoxy, (aryl)C1-4alkylthio, (heteroaryl)C1-4alkylthio, (C3-7cycloalkyl)C1-4alkylthio, (C3-7heterocycloalkyl)C1-4alkylthio, amino, halo, hydroxy, cyano, or oxo; and
each R7 is independently selected from C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, aryl, heteroaryl, C3-7cycloalkyl, C3-7heterocycloalkyl, (aryl)C1-4alkyl, (heteroaryl)C1-4alkyl, (C3-7cycloalkyl)C1-4alkyl, (C3-7heterocycloalkyl)C1-4alkyl, halo, hydroxy, cyano, or oxo.