Heterocyclic compounds and their use for the treatment of neurodegenerative tauopathies
The present invention is directed to triazolopyrimidine, phenylpyrimidine, pyridopyridazine, and pyridotriazine compounds which are microtubule-stabilizing compounds and their use in the treatment of neurodegenerative disorders, in particular, tauopathies, such as for example, Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, progressive supranuclear palsy (PSP), and corticobasal degeneration. In addition, the compounds of the invention may be useful for other diseases where tau pathology is a comorbidity or where microtubule function is compromised, for example, schizophrenia, Parkinson's disease (PD), PD with dementia, Lewy body disease with dementia, and amyotrophic lateral sclerosis.
1. A method of treating a neurodegenerative disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula II:
wherein
R 1 is H, Cl, F, or Br;
R 2 is C 1-6 alkyl or substituted C 1-6 alkyl;
R 3 is H; or R 2 and R 3 , together with the N atom to which they are attached, form a heterocycloC 3-6 alkyl;
R 4 is H, Cl, F, or Br;
R 5 is H, Cl, F, or Br;
R 6 is F, Cl, Br, —N 3 , —OC 1-6 alkyl, —OC 1-6 alkyleneOH, —OC 1-6 alkylene-halo,
—OC 1-6 alkyleneNR 7 R 8 , —OC 1-6 substituted-alkyleneNR 7 R 8 , or
—OC 3-6 cycloalkyleneNR 7 R 8 , wherein R 7 and R 8 are each independently H,
C 1-6 alkyl, substituted C 1-6 alkyl, —C(O)C 1-6 alkyl, or aryl; or R 7 and R 8 together form a heterocyclic ring;
or a stereochemical isomer thereof;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein R 1 is Cl.
3. The method of claim 1 , wherein R 2 is C 1-6 alkyl.
4. The method of claim 3 , wherein R 2 is methyl, ethyl, propyl, or isopropyl.
5. The method of claim 1 , wherein R 2 is substituted C 1-6 alkyl.
6. The method of claim 5 , wherein R 2 is —CH(CH 3 )(CF 3 ).
7. The method of claim 5 , wherein R 2 is —CH 2 (CF 3 ).
8. The method of claim 1 , wherein R 3 is H.
9. The method of claim 1 , wherein R 4 is F.
10. The method of claim 1 , wherein R 5 is F.
11. The method of claim 1 , wherein R 3 , R 4 , and R 5 are each F.
12. The method of claim 1 , wherein R 6 is F.
13. The method of claim 1 , wherein R 6 is —OC 1-6 alkyleneNR 7 R 8 .
14. The method of claim 13 , wherein R 6 is —O—CH 2 CH 2 CH 2 —N(CH 3 ) 2 or —O—CH 2 CH 2 CH 2 —NH(CH 3 ).
15. The method of claim 1 , wherein R 6 is OC 1-6 cycloalkyleneNR 7 R 8 .
16. The method of claim 15 , wherein R 6 is
17. The method of claim 1 , wherein R 6 is —OC 1-6 alkyl.
18. The method of claim 1 , wherein R 6 is —OC 1-6 alkyleneOH.
19. The method of claim 1 , wherein R 6 is —OC 1-6 alkylene-halo.
20. The method of claim 1 , wherein R 6 is —OC 1-6 substituted-alkyleneNR 7 R 8 .
21. The method of claim 20 , wherein R 7 is H.
22. The method of claim 20 , wherein R 8 is C 1-6 alkyl.
23. The method of claim 20 , wherein R 8 is substituted C 1-6 alkyl.
24. The method of claim 23 , wherein the alkyl is substituted with CF 3 .
25. The method of claim 20 , wherein R 8 is —C(O)C 1-6 alkyl.
26. The method of claim 20 , wherein R 8 is aryl.
27. The method of claim 1 , wherein the compound of formula II is
R 1
R 2
R 3
R 4
R 5
R 6
Cl
H
H
F
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
F
Cl
—CH(CH 3 )CF 3 (R)
H
F
F
F
Cl
—CH(CH 3 )CF 3 (S,R)
H
F
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
—OCH 2 CH 2 CH 2 NHCH 3
Cl
—CH(CH 3 )CF 3 (R)
H
F
F
—OCH 2 CH 2 CH 2 NHCH 3
Cl
—CH(CH 3 )CF 3 (S,R)
H
F
F
—OCH 2 CH 2 CH 2 NHCH 3
Cl
H
H
F
F
—OCH 2 CH 2 CH 2 NHCH 3
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
—OCH 2 CH 2 CH 2 N(CH 3 ) 2
Cl
—CH(CH 3 )CF 3 (R)
H
F
F
—OCH 2 CH 2 CH 2 N(CH 3 ) 2
Cl
—CH(CH 3 )CF 3 (S,R)
H
F
F
—OCH 2 CH 2 CH 2 N(CH 3 ) 2
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (R)
H
F
F
Cl
—CH(CH 3 )CF 3 (S,R)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
Cl
—CH(CH 3 )CF 3 (S)
H
F
F
28. The method of claim 1 , wherein the neurodegenerative disease is characterized by a tauopathy or compromised microtubule function in the brain of the patient.
29. The method of claim 1 , wherein the neurodegenerative disease is Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, progressive supranuclear palsy (PSP), corticobasal degeneration, Parkinson's disease (PD), PD with dementia, Lewy body disease with dementia, or amyotrophic lateral sclerosis.
30. The method of claim 1 , wherein the neurodegenerative disease is traumatic brain injury or post traumatic stress disorder.
31. The method of claim 1 , wherein the neurodegenerative disease is schizophrenia.
32. The method of claim 30 , wherein the traumatic brain injury is repetitive traumatic brain injury or chronic traumatic encephalopathy.