US 2011/0237570 A1 · SUBSTITUTED IMIDAZO[1,2-B]PYRIDAZINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE AS BETA-SECRETASE INHIBITORS

Abstract

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.

A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein
R1, R2, R3, and R4 are each independently selected from the group consisting of:
a) —H,
b) -halogen,
c) —C1-6 alkyl,
d) —C3-10 cycloalkyl,
e) —C1-4 alkylene-C3-10 cycloalkyl,
f) -heterocyclyl,
g) —C1-4 alkylene-heterocyclyl,
h) -phenyl,
i) —C1-4 alkylene-phenyl,
j) -heteroaryl,
k) —C1-4 alkylene-heteroaryl,
l) -cyano,
m) —CF3,
n) —OCF3,
o) —O—Ra,
p) —S(O)w—Ra,
q) —S(O)2O—Ra,
r) —NRaRb,
S) —C(O)—Ra,
t) —C(O)—O—Ra,
u) —OC(O)—Ra,
v) —C(O)NRaRb,
w) —NRaC(O)Rb,
x) —OC(O)NRaRb,
y) —NRaC(O)ORb, and
z) —NRaC(O)NRaRb,
where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;
R5 is hydrogen, —C1-6 alkyl, or —C1-4 alkylene-C3-10 cycloalkyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rz.
R6 is hydrogen, —C1-6 alkyl, or —C1-4 alkylene-C3-10 cycloalkyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rz.
R7 is:
a) —H,
b) -halogen,
c) —C1-6 alkyl,
d) —C3-10 cycloalkyl,
e) —C1-4 alkylene-C3-10 cycloalkyl,
f) -heterocyclyl,
g) —C1-4alkylene-heterocyclyl,
h) -phenyl,
i) —C1-4 alkylene-phenyl,
j) -heteroaryl,
k) —C1-4 alkylene-heteroaryl,
l) -cyano,
m) —CF3,
n) —OCF3,
o) —O—Rc,
p) —S(O)w—Rc,
q) —S(O)2O—Rc,
r) —NRcRd,
s) —C(O)—Rc,
t) —C(O)—O—Rc,
u) —OC(O)—Rc,
v) —C(O)NRcRd,
w) —NRcC(O)Rd,
x) —OC(O)NRcRd,
y) —NRcC(O)ORd,
z) —NRcC(O)NRcRd,
aa) —O—C1-6 alkylene-O—Rc, or
bb) —O—C1-6 alkylene-NRcRd,
where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Ry;
R8 and R9 are each independently selected from the group consisting of:
a) —H,
b) -halogen,
c) —C1-6 alkyl,
d) —C3-10 cycloalkyl,
e) —C1-4 alkylene-C3-10 cycloalkyl,
f) -heterocyclyl,
g) —C1-4 alkylene-heterocyclyl,
h) -phenyl,
i) —C1-4 alkylene-phenyl,
j) -heteroaryl,
k) —C1-4 alkylene-heteroaryl,
l) -cyano,
m) —CF3,
n) —OCF3,
o) —O—Ra,
p) —S(O)w—Ra,
q) —S(O)2O—Ra,
r) —NRaRb,
s) —C(O)—Ra,
t) —C(O)—O—Ra,
u) —OC(O)—Ra,
v) —C(O)NRaRb,
w) —NRaC(O)Rb,
x) —OC(O)NRaRb,
y) —NRaC(O)ORb, and
z) —NRaC(O)NRaRb,
where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;
Ra and Rb are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C3-10 cycloalkyl, heterocyclyl, phenyl, heteroaryl, —C1-4alkylene-C3-10cycloalkyl, —C1-4 alkylene-heterocyclyl, —C1-4 alkylene-phenyl, and —C1-4 alkylene-heteroaryl, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;
or, if Ra and Rb 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 Rz;
Rc and Rd are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C3-10 cycloalkyl, heterocyclyl, phenyl, heteroaryl, —C1-4 alkylene-C3-10 cycloalkyl, —C1-4 alkylene-heterocyclyl, —C1-4 alkylene-phenyl, and —C1-4 alkylene-heteroaryl, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Ry;
or, if Rc and Rd 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 Ry;
Re and Rf are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C3-10 cycloalkyl, heterocyclyl, phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, —C1-4 alkylene-C3-10 cycloalkyl, —C1-4 alkylene-heterocyclyl, —C1-4 alkylene-phenyl, and —C1-4 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, —CF3, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCH2CF3;
or, if Re and Rf 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, —CF3, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCH2CF3;
Ry is
a) -halogen,
b) —NReRf,
c) —O—Re,
d) —S—Re,
e) —S(O)2—Re,
f) -cyano,
g) —C(O)—Re,
h) —C(O)—O—Re,
i) —C(O)NReRf,
j) —C1-6 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) —C3-10 cycloalkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen and —OH,
m) —CF3,
n) —OCF3,
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;
Rz is
a) -halogen,
b) —NReRf,
c) —O—Re,
d) —S—Re,
e) —S(O)2—Re,
f) -cyano,
g) —C(O)—Re,
h) —C(O)—O—Re,
i) —C(O)NReRf,
j) —C1-6 alkyl, optionally substituted one or more times with halogen,
k) -heterocyclyl, optionally substituted one or more times with halogen,
l) —C3-10 cycloalkyl, optionally substituted one or more times with halogen,
m) —CF3,
n) —OCF3,
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 R2 and R3 is not —H;
or, if R5 is —H, a tautomer of any of the foregoing.

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Substituted imidazo[1,2-b]pyridazine derivatives, pharmaceutical compositions, and methods of use as beta-secretase inhibitors

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Substituted imidazo[1,2-b]pyridazine derivatives, pharmaceutical compositions, and methods of use as beta-secretase inhibitors

Life of this patent

Abstract

Claims19