Substituted imidazo[1,2-b]pyridazine derivatives, pharmaceutical compositions, and methods of use as β-secretase inhibitors
View Patent ↗The present invention provides substituted imidazo[1,2-b]pyridazine derivatives, pharmaceutically acceptable salts thereof, and tautomers of any of the foregoing, where such compounds inhibit β-site amyloid precursor protein-cleaving enzyme (BACE), which may be useful in the treatment of diseases in which BACE is involved, such as Alzheimer's disease. The invention also provides pharmaceutical compositions comprising any of these compounds and the use of any of these compounds and compositions in the treatment of diseases, disorders, or conditions in which BACE is involved.
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein
R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of:
a) —H,
b) -halogen,
c) —C 1-6 alkyl,
d) —C 3-10 cycloalkyl,
e) —C 1-4 alkylene-C 3-10 cycloalkyl,
f) -heterocyclyl,
g) —C 1-4 alkylene-heterocyclyl,
h) -phenyl,
i) —C 1-4 alkylene-phenyl,
j) -heteroaryl,
k) —C 1-4 alkylene-heteroaryl,
l) -cyano,
m) —CF 3 ,
n) —OCF 3 ,
o) —O—R a ,
p) —S(O) w —R a ,
q) —S(O) 2 O—R a ,
r) —NR a R b ,
S) —C(O)—R a ,
t) —C(O)—O—R a ,
u)—OC(O)—R a ,
v) —C(O)NR a R b ,
w) —NR a C(O)R b ,
x) —OC(O)NR a R b ,
y) —NR a C(O)OR b , and
z) —NR a C(O)NR a R b ,
where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R z ;
R 5 is hydrogen, —C 1-6 alkyl, or —C 1-4 alkylene-C 3-10 cycloalkyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R z ;
R 6 is hydrogen, —C 1-6 alkyl, or —C 1-4 alkylene-C 3-10 cycloalkyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R z ;
R 7 is:
a) —H,
b) -halogen,
c) —C 1-6 alkyl,
d) —C 3-10 cycloalkyl,
e) —C 1-4 alkylene-C 3-10 cycloalkyl,
f) -heterocyclyl,
g) —C 1-4 alkylene-heterocyclyl,
h) -phenyl,
i) —C 1-4 alkylene-phenyl,
j) -heteroaryl,
k) —C 1-4 alkylene-heteroaryl,
l) -cyano,
m) —CF 3 ,
n) —OCF 3 ,
o) —O—R c ,
p) —S(O) w —R c ,
q) —S(O) 2 O—R c ,
r) —NR c R d ,
s) —C(O)—R c ,
t) —C(O)—O—R c ,
u)—OC(O)—R c ,
v) —C(O)NR c R d ,
w) —NR c C(O)R d ,
x)—OC(O)NR c R d ,
y) —NR c C(O)OR d ,
z) —NR c C(O)NR c R d ,
aa) —O—C 1-6 alkylene-O—R c , or
bb) —O—C 1-6 alkylene-NR c R d ,
where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R y ;
R 8 and R 9 are each independently selected from the group consisting of:
a) —H,
b) -halogen,
c) —C 1-6 alkyl,
d) —C 3-10 cycloalkyl,
e) —C 1-4 alkylene-C 3-10 cycloalkyl,
f) -heterocyclyl,
g) —C 1-4 alkylene-heterocyclyl,
h) -phenyl,
i) —C 1-4 alkylene-phenyl,
j) -heteroaryl,
k) —C 1-4 alkylene-heteroaryl,
l) -cyano,
m) —CF 3 ,
n) —OCF 3 ,
o) —O—R a ,
p) —S(O) w —R a ,
q) —S(O) 2 O—R a ,
r) —NR a R b ,
s) —C(O)—R a ,
t) —C(O)—O—R a ,
u)—OC(O)—R a ,
v) —C(O)NR a R b ,
w) —NR a C(O)R b ,
x) —OC(O)NR a R b ,
y) —NR a C(O)OR b , and
z) —NR a C(O)NR a R b ,
where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R z ;
R a and R b are independently selected from the group consisting of hydrogen, —C 1-6 alkyl, —C 3-10 cycloalkyl, heterocyclyl, phenyl, heteroaryl, —C 1-4 alkylene-C 3-10 cycloalkyl, —C 1-4 alkylene-heterocyclyl, —C 1-4 alkylene-phenyl, and —C 1-4 alkylene-heteroaryl, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R z ; or, if R a and R b are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, 2-oxo-pyrrolidin-1-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-oxazolidin-3-yl, 2-oxo-thiazolidin-3-yl, 3-oxo-isoxazolidin-2-yl, 3-oxo-isothiazolidin-3-yl, 2-oxo-piperidin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-morpholin-4-yl, 3-oxo-thiomorpholin-4-yl, 2-oxo-azepan-1-yl, 1H-pyrrol-1-yl, 3-pyrrolin-1-yl, imidazol-1-yl, 2-imidazolin-1-yl, 1H-pyrazol-1-yl, 2-pyrazolin-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, and tetrazol-1-yl, where each ring is optionally substituted one or more times with substituents independently selected from R z ;
R c and R d are independently selected from the group consisting of hydrogen, —C 1-6 alkyl, —C 3-10 cycloalkyl, heterocyclyl, phenyl, heteroaryl, —C 1-4 alkylene-C 3-10 cycloalkyl, —C 1-4 alkylene-heterocyclyl, —C 1-4 alkylene-phenyl, and —C 1-4 alkylene-heteroaryl, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R y ; or, if R c and R d are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, 2-oxo-pyrrolidin-1-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-oxazolidin-3-yl, 2-oxo-thiazolidin-3-yl, 3-oxo-isoxazolidin-2-yl, 3-oxo-isothiazolidin-3-yl, 2-oxo-piperidin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-morpholin-4-yl, 3-oxo-thiomorpholin-4-yl, 2-oxo-azepan-1-yl, 1H-pyrrol-1-yl, 3-pyrrolin-1-yl, imidazol-1-yl, 2-imidazolin-1-yl, 1H-pyrazol-1-yl, 2-pyrazolin-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, and tetrazol-1-yl, where each ring is optionally substituted one or more times with substituents independently selected from R y ;
R e and R f are independently selected from the group consisting of hydrogen, —C 1-6 alkyl, —C 3-10 cycloalkyl, heterocyclyl, phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, —C 1-4 alkylene-C 3-10 cycloalkyl, —C 1-4 alkylene-heterocyclyl, —C 1-4 alkylene-phenyl, and —C 1-4 alkylene-heteroaryl, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, naphthyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from the group consisting of halogen, methyl, ethyl, isopropyl, —CF 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , —OCH 2 CF 3 ; or, if R e and R f are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, 2-oxo-pyrrolidin-1-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-oxazolidin-3-yl, 2-oxo-thiazolidin-3-yl, 3-oxo-isoxazolidin-2-yl, 3-oxo-isothiazolidin-3-yl, 2-oxo-piperidin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-morpholin-4-yl, 3-oxo-thiomorpholin-4-yl, 2-oxo-azepan-1-yl, 1H-pyrrol-1-yl, 3-pyrrolin-1-yl, imidazol-1-yl, 2-imidazolin-1-yl, 1H-pyrazol-1-yl, 2-pyrazolin-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, and tetrazol-1-yl, where each ring is optionally substituted one or more times with substituents independently selected from the group consisting of halogen, methyl, ethyl, isopropyl, —CF 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , —OCH 2 CF 3 ;
R y is
a) -halogen,
b) —NR e R f ,
c) —O—R e ,
d) —S—R e ,
e) —S(O) 2 —R e ,
f) -cyano,
g) —C(O)—R e ,
h) —C(O)—O—R e ,
i) —C(O)NR e R f ,
j)—C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen and —OH,
k) -heterocyclyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen and —OH,
l) —C 3-10 cycloalkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen and —OH,
m) —CF 3 ,
n) —OCF 3 ,
o) -phenyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen and —OH, or
p) -heteroaryl; optionally substituted one or more times with substituents selected independently from the group consisting of halogen and —OH;
R z is
a) -halogen,
b) —NR e R f ,
c) —O—R e ,
d) —S—R e ,
e) —S(O) 2 —R e ,
f) -cyano,
g) —C(O)—R e ,
h) —C(O)—O—R e ,
i) —C(O)NR e R f ,
j) —C 1-6 alkyl, optionally substituted one or more times with halogen,
k) -heterocyclyl, optionally substituted one or more times with halogen,
l) —C 3-10 cycloalkyl, optionally substituted one or more times with halogen,
m) —CF 3 ,
n) —OCF 3 ,
o) -phenyl, optionally substituted one or more times with halogen, or
p) -heteroaryl; optionally substituted one or more times with halogen; and
w is an integer from 0 to 2;
wherein at least one of R 2 and R 3 is not —H;
or, if R 5 is —H, a tautomer of any of the foregoing.
2. The compound of claim 1 , wherein R 1 , R 3 , and R 4 are —H.
3. The compound of claim 2 , wherein R 5 is —H.
4. The compound of claim 3 , wherein R 6 is —H.
5. The compound of claim 4 , wherein R 8 and R 9 are —H.
6. The compound of claim 5 , wherein R 2 is —O—CH 2 -phenyl, phenyl, cyclopentyl, or cyclohexyl, where the phenyl, cyclopentyl, and cyclohexyl moieties are optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —CF 3 , —O—CF 3 , —CH 3 , and —OCH 3 .
7. The compound of claim 6 , wherein R 2 is phenyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —CF 3 , —O—CF 3 , —CH 3 , and —OCH 3 .
8. The compound of claim 7 , wherein R 7 is —O—C 1-6 alkylene-O—R C , where R c is —C 1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen and —OH, and the alkylene is optionally substituted one or more times with halogen.
9. The compound of claim 7 , wherein R 7 is —O—C 1-6 alkylene-O—R c , where R c is —H, and the alkylene is optionally substituted one or more times with halogen.
10. The compound of claim 9 , wherein R 7 is —O—C 1-6 alkylene-OH.
11. The compound of claim 1 , wherein the compound is 6-Methoxy-imidazo[1,2-b]pyridazine-2-carboxylic acid [6-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein the compound is 6-(2-Methoxy-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein the compound is 6-(2-Dimethylamino-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein the compound is 6-(2-Morpholin-4-yl-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein the compound is 6-((1S,3S)-3-Hydroxy-cyclopentyloxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , wherein the compound is 6-((R)-2-Hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , wherein the compound is 6-((S)-2-Hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , wherein the compound is 6-(2-Hydroxy-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the compound is 6-(2-Hydroxy-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , wherein the compound is 6-(2-Hydroxy-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 , wherein the compound is 6-((S)-2-Hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-yl]-amide or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, excipient, or diluent.