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

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).

1 .- 51 . (canceled) 
     
     
         52 . A method of treatment of a DLK-mediated disease comprising the administration of a therapeutically effective amount of a compound of structural Formula I 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 X 1  is selected from C and N; 
 X 2  is selected from C and N; 
 exactly one of X 1  and X 2  is N; 
 X 3  is N; 
 X 4  and X 5  are C; 
 X 1 , X 2 , X 3 , X 4 , and X 5  form a five membered heteroaryl; 
 R 1  is selected from alkyl, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one to three R 5  groups; 
 R 2  is H or is selected from alkyl, amino, aryl, cycloalkyl, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, and sulfonylalkyl, any of which is optionally substituted with one to three R 6  groups; 
 R 3  is selected from H, alkyl, (alkoxy)alkyl, (arylalkoxy)alkyl, (heteroarylalkoxy)alkyl, cyano, cycloalkyl, halo, haloalkoxy, and haloalkyl; 
 R 4  is N(R 4a ) 2 , wherein each R 4a  is independently selected from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl; 
 or R 3  and R 4  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 R 7  groups; 
 each R 5  and R 6  is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1-4 haloalkylthio, aryl, heteroaryl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, (aryl)C 1-4 alkyl, (heteroaryl)C 1-4 alkyl, (C 3-7 cycloalkyl)C 1-4 alkyl, (C 3-7 heterocycloalkyl)C 1-4 alkyl, (ethenyl)C 1-4 alkyl, (ethynyl)C 1-4 alkyl, (aryl)C 1-4 alkoxy, (heteroaryl)C 1-4 alkoxy, (C 3-7 cycloalkyl)C 1-4 alkoxy, (C 3-7 heterocycloalkyl)C 1-4 alkoxy, (aryl)C 1-4 alkylthio, (heteroaryl)C 1-4 alkylthio, (C 3-7 cycloalkyl)C 1-4 alkylthio, (C 3-7 heterocycloalkyl)C 1-4 alkylthio, amino, halo, hydroxy, cyano, and oxo; and 
 each R 7  is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, aryl, heteroaryl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, (aryl)C 1-4 alkyl, (heteroaryl)C 1-4 alkyl, (C 3-7 cycloalkyl)C 1-4 alkyl, (C 3-7 heterocycloalkyl)C 1-4 alkyl, halo, hydroxy, cyano, and oxo; 
 to a patient in need thereof. 
 
     
     
         53 . The method of  claim 52 , wherein said disease is a neurological disease or a cognitive disorder. 
     
     
         54 . The method of  claim 53 , wherein said neurological disease results from a traumatic injury chosen from stroke and spinal cord injury. 
     
     
         55 . The method of  claim 53 , wherein said neurological disease results from a chronic neurodegenerative condition. 
     
     
         56 . The method of  claim 53 , wherein said neurological disease results from a neuropathy resulting from neurological damage. 
     
     
         57 . The method of  claim 53 , wherein said cognitive disorder is caused by pharmacological intervention. 
     
     
         58 . A method of treatment of cancer and reducing the development of a chemotherapy-induced neurological disorder, comprising the administration of a chemotherapeutic drug together with a compound of structural Formula I 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 X 1  is selected from C and N; 
 X 2  is selected from C and N; 
 exactly one of X 1  and X 2  is N; 
 X 3  is N; 
 X 4  and X 5  are C; 
 X 1 , X 2 , X 3 , X 4 , and X 5  form a five membered heteroaryl; 
 R 1  is selected from alkyl, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one to three R 5  groups; 
 R 2  is H or is selected from alkyl, amino, aryl, cycloalkyl, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, and sulfonylalkyl, any of which is optionally substituted with one to three R 6  groups; 
 R 3  is selected from H, alkyl, (alkoxy)alkyl, (arylalkoxy)alkyl, (heteroarylalkoxy)alkyl, cyano, cycloalkyl, halo, haloalkoxy, and haloalkyl; 
 R 4  is N(R 4a ) 2 , wherein each R 4a  is independently selected from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl; 
 or R 3  and R 4  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 R 7  groups; 
 each R 5  and R 6  is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1-4 haloalkylthio, aryl, heteroaryl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, (aryl)C 1-4 alkyl, (heteroaryl)C 1-4 alkyl, (C 3-7 cycloalkyl)C 1-4 alkyl, (C 3-7 heterocycloalkyl)C 1-4 alkyl, (ethenyl)C 1-4 alkyl, (ethynyl)C 1-4 alkyl, (aryl)C 1-4 alkoxy, (heteroaryl)C 1-4 alkoxy, (C 3-7 cycloalkyl)C 1-4 alkoxy, (C 3-7 heterocycloalkyl)C 1-4 alkoxy, (aryl)C 1-4 alkylthio, (heteroaryl)C 1-4 alkylthio, (C 3-7 cycloalkyl)C 1-4 alkylthio, (C 3-7 heterocycloalkyl)C 1-4 alkylthio, amino, halo, hydroxy, cyano, and oxo; and 
 each R 7  is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, aryl, heteroaryl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, (aryl)C 1-4 alkyl, (heteroaryl)C 1-4 alkyl, (C 3-7 cycloalkyl)C 1-4 alkyl, (C 3-7 heterocycloalkyl)C 1-4 alkyl, halo, hydroxy, cyano, and oxo. 
 
     
     
         59 . A method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound of structural Formula I 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 X 1  is selected from C and N; 
 X 2  is selected from C and N; 
 exactly one of X 1  and X 2  is N; 
 X 3  is N; 
 X 4  and X 5  are C; 
 X 1 , X 2 , X 3 , X 4 , and X 5  form a five membered heteroaryl; 
 R 1  is selected from alkyl, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one to three R 5  groups; 
 R 2  is H or is selected from alkyl, amino, aryl, cycloalkyl, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, and sulfonylalkyl, any of which is optionally substituted with one to three R 6  groups; 
 R 3  is selected from H, alkyl, (alkoxy)alkyl, (arylalkoxy)alkyl, (heteroarylalkoxy)alkyl, cyano, cycloalkyl, halo, haloalkoxy, and haloalkyl; 
 R 4  is N(R 4a ) 2 , wherein each R 4a  is independently selected from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl; 
 or R 3  and R 4  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 R 7  groups; 
 each R 5  and R 6  is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1-4 haloalkylthio, aryl, heteroaryl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, (aryl)C 1-4 alkyl, (heteroaryl)C 1-4 alkyl, (C 3-7 cycloalkyl)C 1-4 alkyl, (C 3-7 heterocycloalkyl)C 1-4 alkyl, (ethenyl)C 1-4 alkyl, (ethynyl)C 1-4 alkyl, (aryl)C 1-4 alkoxy, (heteroaryl)C 1-4 alkoxy, (C 3-7 cycloalkyl)C 1-4 alkoxy, (C 3-7 heterocycloalkyl)C 1-4 alkoxy, (aryl)C 1-4 alkylthio, (heteroaryl)C 1-4 alkylthio, (C 3-7 cycloalkyl)C 1-4 alkylthio, (C 3-7 heterocycloalkyl)C 1-4 alkylthio, amino, halo, hydroxy, cyano, and oxo; and 
 each R 7  is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, aryl, heteroaryl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, (aryl)C 1-4 alkyl, (heteroaryl)C 1-4 alkyl, (C 3-7 cycloalkyl)C 1-4 alkyl, (C 3-7 heterocycloalkyl)C 1-4 alkyl, halo, hydroxy, cyano, and oxo; 
 wherein the effect is chosen from decrease of neurons, reduction in cerebral atrophy, improved neurological function, improved cognition, and improved mental performance.