Compounds inhibiting leucine-rich repeat kinase enzyme activity
The present invention is directed to substituted certain reversed indazole compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R9, and A are as defined herein, which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which LRRK-2 kinase is involved.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein R 1 is pyrazolyl, wherein said pyrazolyl is optionally substituted with one to three substituents independently selected from the group consisting of:
a) halo,
b) cyano,
c) hydroxyl,
d) oxo,
e) C 1-3 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl and NR c R d ,
f) OC 1-3 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl, NR c R d , and aryl,
g) C 3-8 cycloalkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl and NR c R d ,
h) aryl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl, S(O) m NR c R d , C(O)NR c R d and NR c R d ,
i) heteroaryl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl, S(O) m NR c R d , C(O)NR c R d and NR c R d ,
j) C 4-8 cycloalkenyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl and NR c R d ;
R 2 and R 3 are taken together with the atoms to which they are shown attached to form a morpholinyl group, a piperazinyl group, a piperidinyl group, an azetidinyl group, or a pyrrolidinyl group, wherein each said group is optionally substituted with from 1 to 4 substituents selected from the group consisting of:
a) halo,
b) oxo,
c) OR 5 ,
d) NR c R d ,
e) S(O) m R 5 ,
f) S(O) m R 7 ,
f) R 5 ,
g) R 6 ,
h) R 7 ,
i) (C═O)R 5 ,
j) (C═O)OR 5 and
k) (C═O)R 7 ;
R 4 is selected from the group consisting of: hydrogen, halo, cyano, OR 5 , aryl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, and C 1-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OC 1-3 alkyl, NR c R d and hydroxy;
R 5 is selected from the group consisting of hydrogen or C 1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of:
a) halo,
b) hydroxyl,
c) OC 1-6 alkyl,
d) NR c R d ,
e) (C═O)NR c R d ,
f) S(O) m R 8 ,
g) S(O) m R 7 ,
h) R 7 , and
i) OR 7 ;
R 6 is C 1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;
or R 5 and R 6 can be taken together with the atoms to which they are attached to form a 3 to 8 membered carbocyclic, aryl wherein said carbocyclic, and aryl are optionally substituted with one to three substituents independently selected from the group consisting of:
a) halo,
b) oxo,
c) cyano,
d) hydroxyl,
e) C 1-3 alkyl, which is optionally substituted with one to three halo,
f) C 3-8 cycloalkyl,
g) OC 1-3 alkyl, which is optionally substituted with one to three halo, and
h) OC 3-8 cycloalkyl;
R 7 is selected from the group consisting of C 3-8 cycloalkyl, C 4-8 cycloalkenyl, and aryl, wherein said cycloalkyl, cycloalkenyl, and aryl groups are optionally substituted with one to three substituents independently selected from the group consisting of:
a) halo,
b) cyano,
c) hydroxyl,
d) oxo,
e) C 1-3 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl and NR c R d ,
f) OC 1-3 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl, NR c R d , aryl and heteroaryl,
g) C 3-8 cycloalkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl and NR c R d ,
h) aryl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl, S(O) m NR c R d , C(O)NR c R d and NR c R d ,
i) C 4-8 cycloalkenyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC 1-3 alkyl and NR c R d ;
R 8 is hydrogen or C 1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of:
a) halo,
b) cyano,
c) hydroxyl,
d) OC 1-3 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo and NR e R f , and
e) C 3-8 cycloalkyl;
R 9 is selected from the group consisting of:
a) C 1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo,
b) halo,
c) cyano,
d) hydroxyl, and
e) OC 1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo;
R a is selected from the group consisting of hydrogen and C 1-6 alkyl;
R b is selected from the group consisting of hydrogen and C 1-6 alkyl;
R C is selected from the group consisting of:
a) hydrogen,
b) C 1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, aryl, NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , OC 1-6 alkyl, and C 3-8 cycloalkyl;
R d is selected from the group consisting of:
a) hydrogen,
b) C 3-8 cycloalkyl,
c) C 1-3 alkyl,
d) (C═O)C 1-3 alkyl,
e) aryl, and
wherein said cycloalkyl, alkyl, and aryl groups are each optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, R 8 , SO 2 R 8 , OC 1-6 alkyl and C 3-8 cycloalkyl;
R e is selected from the group consisting of hydrogen and C 1-3 alkyl;
R f is selected from the group consisting of hydrogen and C 1-3 alkyl; and
m is an integer from zero to two.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H and R 9 is selected from the group consisting of H and halo.
3. The compound of claim 2 wherein R 1 is pyrazolyl, wherein said pyrazolyl is optionally substituted with one to three substituents independently selected from the group consisting of: alkyl, alkoxy, halo, cyano, hydroxyl, and oxo.
4. A compound, or a pharmaceutically acceptable salt thereof, said compound selected from the group consisting of:
5. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.