COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVE DISEASES AND CARDIOMYOPATHY
Disclosed herein inter alia are compositions and methods useful in the treatment neurodegenerative diseases and cardiomyopathy, and for modulating the activity of PINK1.
1 . A compound having the formula:
wherein
Y is NR 3 or CR 3a R 3b ;
L 1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R 2 is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3a and R 3b are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
wherein if R 2 is hydrogen, then -L 1 -R 1 is not hydrogen,
2 . The compound of claim 1 , wherein L 1 is a bond or substituted or unsubstituted alkylene.
3 .- 13 . (canceled)
14 . The compound of claim 1 , wherein R 1 is substituted or unsubstituted iso-pentenyl, substituted or unsubstituted hexenyl, substituted or unsubstituted propenyl, substituted or unsubstituted ethenyl, substituted or unsubstituted pentenyl, substituted or unsubstituted butenyl, substituted or unsubstituted 2-methylbut-1-enyl, substituted or unsubstituted 3-methylbut-1-enyl, substituted or unsubstituted 2-methylbut-2-enyl, substituted or unsubstituted 1-pentenyl, cis-2-pentenyl, or substituted or unsubstituted trans-2-pentenyl.
15 . The compound of claim 1 , wherein R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
16 .- 20 . (canceled)
21 . The compound of claim 1 having the formula:
wherein,
Ring A is substituted or unsubstituted furanyl, substituted or unsubstituted thiofuranyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, or substituted or unsubstituted triazolyl;
Ring B is substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, or substituted or unsubstituted pyridinyl; and
Ring C is substituted or unsubstituted tetrahydrofuranyl, or substituted or unsubstituted tetrahydropyranyl;
R 20 is independently halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, substituted or unsubstituted monophosphate, substituted or unsubstituted diphosphate, substituted or unsubstituted triphosphate, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
22 . (canceled)
23 . The compound of claim 1 , wherein the compound has the formula:
24 .- 26 . (canceled)
27 . The compound claim 1 , wherein R 2 has the formula:
wherein,
R 4 and R 5 are independently be hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O) NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R 6 is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted phosphate, substituted or unsubstituted monophosphate, substituted or unsubstituted diphosphate, or substituted or unsubstituted triphosphate.
28 .- 30 . (canceled)
31 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .
32 . A method of treating a neurodegenerative disease or a cardiomyopathy in a patient comprising administering a compound of formula:
wherein
Y is NR 3 or CR 3a R 3b ;
L 1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
R 1 is hydrogen, oxo, halogen, —CX 3 , —CN, —SO 2 Cl, —SO—R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC(O)NHNH 2 , —NHC(O)NR 7 R 8 , —NR 7 R 8 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —N(R 7 )C(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3a and R 3b are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —Cl 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O) NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , ONH 2 , —NHC(O)NHNH 2 , —NHC(O) NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; where R 7 and R 8 are bonded to the same nitrogen atom, they may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
m and v are independently 1 or 2;
n is independently an integer from 0 to 4;
X is independently —Cl, —Br, —I, or —F.
33 . The method of claim 32 , wherein said compound is administered in a therapeutically effective amount to said patient.
34 .- 45 . (canceled)
46 . The method of claim 32 , wherein R 1 is substituted or unsubstituted iso-pentenyl, substituted or unsubstituted hexenyl, substituted or unsubstituted propenyl, substituted or unsubstituted ethenyl, substituted or unsubstituted pentenyl, substituted or unsubstituted butenyl, substituted or unsubstituted 2-methylbut-1-enyl, substituted or unsubstituted 3-methylbut-1-enyl, substituted or unsubstituted 2-methylbut-2-enyl, substituted or unsubstituted 1-pentenyl, cis-2-pentenyl, or substituted or unsubstituted trans-2-pentenyl.
47 . The method of claim 32 , wherein R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
48 .- 52 . (canceled)
53 . The method of claim 32 , having the formula:
wherein,
Ring A is substituted or unsubstituted furanyl, substituted or unsubstituted thiofuranyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, or substituted or unsubstituted triazolyl;
Ring B is substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, or substituted or unsubstituted pyridinyl; and
Ring C is substituted or unsubstituted tetrahydrofuranyl, or substituted or unsubstituted tetrahydropyranyl;
R 20 is independently halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, substituted or unsubstituted monophosphate, substituted or unsubstituted diphosphate, substituted or unsubstituted triphosphate, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
54 . (canceled)
55 . The method of claim 32 , wherein said compound has the formula:
56 .- 58 . (canceled)
59 . The method of claim 32 , wherein R 2 has the formula:
wherein,
R 4 and R 5 are independently be hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O) NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R 6 is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted phosphate, substituted or unsubstituted monophosphate, substituted or unsubstituted diphosphate, or substituted or unsubstituted triphosphate
60 . (canceled)
61 . The method of claim 32 , wherein said compound is administered to treat a neurodegenerative disease in the patient.
62 . (canceled)
63 . (canceled)
64 . The method of claim 61 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis.
65 . The method of claim 64 , wherein the neurodegenerative disease is Parkinson's Disease.
66 . The method of claim 32 , wherein said compound is administered to treat a cardiomyopathy in the patient.
67 .- 69 . (canceled)
70 . A method of increasing the level of activity of PINK1 in a cell by contacting the cell with a neo-substrate of PINK1.
71 . (canceled)