INHIBITORS OF DUAL LEUCINE ZIPPER (DLK) KINASE FOR THE TREATMENT OF DISEASE
원문보기
IPC분류정보
국가/구분
United States(US) Patent
공개
국제특허분류(IPC7판)
C07D-498/04
C07D-405/14
A61K-031/4439
C07D-401/04
A61K-031/5377
C07D-487/04
A61K-031/4985
A61K-031/5383
A61K-031/553
C07D-401/14
A61K-031/496
C07D-491/048
C07D-413/14
출원번호
US-0688554
(2017-08-28)
공개번호
US-0057507
(2018-03-01)
발명자
/ 주소
SOTH, Michael J.
JONES, Philip
RAY, James
LIU, Gang
LE, Kang
CROSS, Jason
출원인 / 주소
SOTH, Michael J.
인용정보
피인용 횟수 :
0인용 특허 :
0
초록▼
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 ner
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).
대표청구항▼
1. A compound of structural Formula I: or a salt or ester thereof, wherein: R1 is selected from H, halo, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, cycloalkoxy, haloalkoxy, and halocycloalkoxy;R2 is selected from H, halo, C1-4 alkyl, and C1-4 alkoxy;R3 and R4 are independently selected f
1. A compound of structural Formula I: or a salt or ester thereof, wherein: R1 is selected from H, halo, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, cycloalkoxy, haloalkoxy, and halocycloalkoxy;R2 is selected from H, halo, C1-4 alkyl, and C1-4 alkoxy;R3 and R4 are independently selected from H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, and haloalkyl, any of which is optionally substituted with one to three R7 groups; or R3 and R4 together, in combination with the intervening atoms, form a ring containing atoms selected from C, N, and O, said ring being optionally substituted with one to three R7 groups;R5 is selected from H, halo, C1-4 alkyl, and C1-4 alkoxy;R6a and R6b are independently selected from H and C1-4 alkyl;R7 is selected from acyl, alkoxy, alkyl, amino, cyano, halo, haloalkyl, haloalkoxy, hydroxyl, sulfonylalkyl, sulfonamidoalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroaryl, any of which is optionally substituted with one to three R8 groups; andR8 is selected from C1-4 alkyl, C1-4 alkoxy, halo, hydroxy, oxo, hydroxyalkyl, amino, carboxyl, cyano, C3-6 cycloalkyl, heterocycloalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, aryl, and heteroaryl; or two R8, in combination with the intervening atoms, form a 4-7 membered ring consisting of atoms selected from C, N, and O, said ring being optionally substituted with one to three groups selected from amino, halo, and hydroxy. 2. The compound of claim 1, or a salt or ester thereof, wherein: R3 and R4 are independently selected from H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, and haloalkyl, any of which is optionally substituted with one to three R7 groups; 3. The compound of claim 2, wherein R1 is trifluoromethyl. 4. The compound of claim 3, wherein R2 and R5 are H. 5. The compound of claim 4, wherein R6a and R6b are H. 6. The compound of claim 5, wherein R3 is selected from bicyclo[3.1.0]hexan-6-yl and 3-azabicyclo[3.1.0]hexan-6-yl, and is optionally substituted with one or more R7 groups. 7. The compound of claim 6, wherein R4 is selected from bicyclo[3.1.0]hexan-6-yl and 3-azabicyclo[3.1.0]hexan-6-yl, and is optionally substituted with one or more R7 groups. 8. The compound of claim 2, wherein the compound has the structural formula III: or a salt or ester thereof, wherein: R1 is selected from H, halo, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, cycloalkoxy, haloalkoxy, and halocycloalkoxy;R2 is selected from H, halo, C1-4 alkyl, and C1-4 alkoxy;R3 is selected from H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, and haloalkyl, any of which is optionally substituted with one to three R7a groups;R5 is selected from H, halo, C1-4 alkyl, and C1-4 alkoxy;R6a and R6b are independently selected from H and C1-4 alkyl;R7a is selected from acyl, alkoxy, alkyl, amino, cyano, halo, haloalkyl, haloalkoxy, hydroxyl, sulfonylalkyl, sulfonamidoalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroaryl, any of which is optionally substituted with one to three R8 groups; andR7b is selected from H, acyl, alkyl, sulfonylalkyl, sulfonamidoalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroaryl, any of which is optionally substituted with one to three R8 groups; andR8 is selected from C1-4alkyl, C1-4 alkoxy, halo, hydroxy, oxo, hydroxyalkyl, amino, carboxyl, cyano, C3-6 cycloalkyl, heterocycloalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, aryl, and heteroaryl; or two R8, in combination with the intervening atoms, form a 4-7 membered ring consisting of atoms selected from C, N, and O, said ring being optionally substituted with one to three groups selected from amino, halo, and hydroxy. 9. The compound of claim 8, wherein the 7-azabicyclo[3.1.0]heptane ring has exo stereochemistry. 10. The compound of claim 9, wherein R1 is trifluoromethyl. 11. The compound of claim 10, wherein R2 and R5 are H. 12. The compound of claim 11, wherein R6a and R6b are H. 13. The compound of claim 1, or a salt or ester thereof, wherein R3 and R4 together, in combination with the intervening atoms, form a ring, which is optionally substituted with one to three R7 groups. 14. The compound of claim 1, having structural formula IV: or a salt or ester thereof, wherein: Y is selected from O, N(R7b), and CH(R7b);R7a is selected from H, acyl, alkoxy, alkyl, amino, cyano, halo, haloalkyl, haloalkoxy, hydroxyl, sulfonylalkyl, sulfonamidoalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroaryl, any of which is optionally substituted with one to three R8 groups; andR7b is selected from H, acyl, alkyl, sulfonylalkyl, sulfonamidoalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroaryl, any of which is optionally substituted with one to three R8 groups; andR8 is selected from C1-4 alkyl, C1-4 alkoxy, halo, hydroxy, oxo, alkoxy, hydroxyalkyl, amino, carboxyl, cyano, C3-6 cycloalkyl, heterocycloalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, aryl, and heteroaryl; or two R8, in combination with the intervening atoms, form a 4-7 membered ring consisting of atoms selected from C, N, and O, said ring being optionally substituted with one to three groups selected from amino, halo, and hydroxy. 15. The compound of claim 2, wherein the compound has the structural formula V: or a salt or ester thereof, wherein: R1 is selected from H, halo, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, cycloalkoxy, haloalkoxy, and halocycloalkoxy;R2 is selected from H, halo, C1-4 alkyl, and C1-4 alkoxy;R3 is selected from H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, and haloalkyl, any of which is optionally substituted with one to three R7b groups;R5 is selected from H, halo, C1-4 alkyl, and C1-4 alkoxy;R6a and R6b are independently selected from H and C1-4 alkyl;R7a and R7b are independently selected from acyl, alkoxy, alkyl, amino, halo, hydroxyl, sulfonylalkyl, sulfonamidoalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, and heteroaryl, any of which is optionally substituted with one to three R8 groups; andR8 is selected from C1-4 alkyl, C1-4 alkoxy, halo, hydroxy, oxo, hydroxyalkyl, amino, carboxyl, cyano, C3-6 cycloalkyl, heterocycloalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, aryl, and heteroaryl; or two R8, in combination with the intervening atoms, form a 4-7 membered ring consisting of atoms selected from C, N, and O, said ring being optionally substituted with one to three groups selected from amino, halo, and hydroxy. 16. The compound of claim 15, wherein the bicyclo[3.1.0]heptane ring has exo stereochemistry. 17. The compound of claim 16, wherein R7a is selected from alkyl, cycloalkyl, and heterocycloalkyl, and is optionally substituted with one to three R8 groups. 18. The compound of claim 17, wherein R7a is selected from piperazin-1-yl, morpholin-1-yl, 1,4-diazepan-1-yl, and 1,4-oxazepan-4-yl, and is optionally substituted with one or two R8 groups. 19. The compound of claim 18, wherein R1 is trifluoromethyl. 20. The compound of claim 19, wherein R2 and R5 are H. 21. The compound of claim 20, wherein R6a and R6b are H. 22. The compound of claim 21, wherein R8 is selected from C1-4 alkyl, C1-4 alkoxy, halo, hydroxy, oxo, hydroxyalkyl, amino, carboxyl, cyano, C3-6 cycloalkyl, heterocycloalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, aryl, and heteroaryl. 23. The compound of claim 22, wherein R8 is selected from C1-4 alkyl, C1-4 alkoxy, halo, hydroxy, oxo, hydroxyalkyl, C3-6 cycloalkyl, heterocycloalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy. 24. The compound of claim 23, wherein R8 is selected from C1-4 alkyl and C1-4 haloalkyl. 25. The compound of claim 24, wherein R7a is selected from: 26. The compound of claim 1, wherein the compound is chosen from: or a salt or ester thereof. 27. The compound of claim 1, wherein the compound has the structural formula chosen from: or a salt or ester thereof. 28. A compound as recited in claim 1 for use as a medicament. 29. A compound as recited in claim 1 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of DLK. 30. A compound as recited in claim 1 for use in the treatment of a disease mediated by DLK kinase. 31. The compound as recited in claim 30, wherein said disease results from traumatic injury to central nervous system or peripheral nervous system neurons. 32. The compound as recited in claim 31, wherein said traumatic injury is chosen from stroke, traumatic brain injury, and spinal cord injury. 33. The compound as recited in claim 30, wherein said disease results from a chronic neurodegenerative condition. 34. The compound as recited in claim 33, wherein said 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, chemotherapy-induced peripheral neuropathy, diabetic neuropathy and Kennedy's disease. 35. The compound as recited in claim 30, wherein said disease results from a neuropathy resulting from neurological damage. 36. The compound as recited in claim 35, wherein said neurological damage is chosen from chemotherapy-induced peripheral neuropathy and diabetic neuropathy. 37. A compound as recited in claim 1 for the use in the treatment of a cognitive disorder. 38. The compound as recited in claim 37, wherein said cognitive disorder is caused by pharmacological intervention. 39. A pharmaceutical composition comprising a compound as recited in claim 1 together with a pharmaceutically acceptable carrier. 40. A method of inhibition of DLK comprising contacting DLK with a compound as recited in claim 1. 41. A method of treatment of a DLK-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in claim 1 to a patient in need thereof. 42. The method as recited in claim 41 wherein said disease is a neurological disease. 43. The method as recited in claim 42, wherein said neurological disease results from traumatic injury to central nervous system or peripheral nervous system neurons. 44. The method as recited in claim 43, wherein said traumatic injury is chosen from stroke, traumatic brain injury, and spinal cord injury. 45. The method as recited in claim 42, wherein said neurological disease results from a chronic neurodegenerative condition. 46. The method as recited in claim 45, 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. 47. The method as recited in claim 42, wherein said neurological disease results from a neuropathy resulting from neurological damage. 48. The method as recited in claim 47, wherein said neurological damage is chosen from chemotherapy-induced peripheral neuropathy and diabetic neuropathy. 49. The method as recited in claim 41 wherein said disease is a cognitive disorder. 50. The method as recited in claim 49 wherein said cognitive disorder is caused by pharmacological intervention 51. 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; andb. another therapeutic agent. 52. The method as recited in claim 51, wherein said DLK-mediated disease is a cognitive disorder caused by pharmacological intervention. 53. The method as recited in claim 52, wherein said cognitive disorder is chemotherapy-induced cognitive disorder. 54. A method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as recited in claim 1 to a patient, wherein the effect is chosen from decrease loss of neurons, reduction in cerebral atrophy, improved neurological function, improved cognition, and improved mental performance.
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