Compounds inhibiting leucine-rich repeat kinase enzyme activity

1. A compound of the formula:

wherein X 1 , X 2 and X 3 are each independently selected from the group consisting of a bond or CR e R f ;

Y is O, CR a R b or NR c ;

Z is O, CR a R b or NR c ;

R 1 is selected from the group consisting of hydrogen and C 1-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, hydroxyl, NR c R d , OR 5 and (C═O)OR 5 ;

R 2 is selected from the group consisting of hydrogen and C 1-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of:

a) halo,

b) cyano,

c) R 5 ,

d) R 7 ,

e) OR 5 , and

f) NR c R d ;

R 3 is selected from the group consisting of:

a) hydrogen,

b) C 1-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 5 and NR c R d ,

c) C 3-8 cycloalkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 5 and NR c R d ,

d) heterocyclyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, oxo, R 5 , OR 5 and NR c R d ,

e) heteroaryl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, oxo, R 5 , OR 5 and NR c R d ;

f) C 4-8 cycloalkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR 5 and NR c R d ,

g) (C═O)R 7 ,

h) (C═O)R 5 ,

i) S(O) m R 5 , and

j) S(O) m R 7 ;

or R 2 and R 3 can be taken together with the atoms to which they are attached to form a 3 to 8 membered heterocyclic ring, wherein said ring may contain from one to three heteroatoms selected from N, O and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, and which ring is optionally substituted with one to four substituents each independently selected from the group consisting of:

a) halo,

b) oxo,

c) cyano,

d) OR 5 ,

e) NR c R d ,

f) SO 3 H,

g) S(O) m R 5 ,

h) S(O) m R 7

i) R 5 ,

j) R 6 ,

k) R 7 ,

l) (C═O)R 5 ,

m) (C═O)OR 5 ,

n) (C═O)R 7 , and

o) (C═O)NR c R d ;

R 4 is selected from the group consisting of hydrogen, halo, cyano, OR 5 , aryl, heteroaryl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, C 4-8 heterocycloalkyl 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 hydroxyl;

R 5 is selected from the group consisting of hydrogen and 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 ,

g) S(O) m R 8 ,

h) S(O) m R 7 ,

i) R 7 , and

j) 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 4 to 8 membered heterocyclic, 3 to 8 membered carbocyclic, aryl or heteroaryl ring, wherein said heterocyclic and heteroaryl rings may contain from one to three heteroatoms selected from N, O and S, wherein said heterocyclic, carbocyclic, aryl and heteroaryl rings 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 4-8 heterocyclyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, aryl or heteroaryl, wherein said heterocyclyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl 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, heterocyclyl, 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, heterocyclyl, 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, heterocyclyl, 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, heterocyclyl, 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, heterocyclyl, OC 1-3 alkyl, S(O) m NR c R d , C(O)NR c R d and NR c R d ,

j) heterocyclyl, 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 ,

k) C 4-8 cycloalkenyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, heterocyclyl, 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, and halo, and

e) C 3-8 cycloalkyl;

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 and

b) C 1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, heteroaryl, 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 3-6 heterocyclyl,

d) C 1-3 alkyl,

e) (C═O)C 1-3 alkyl,

f) aryl, and

g) heteroaryl;

wherein said cycloalkyl, heterocyclyl, alkyl, aryl and heteroaryl 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,

or R c and R d can be taken together with the atoms to which they are attached to form a 3 to 8 membered heterocyclic ring, wherein said ring may contain from one to three heteroatoms selected from N, O and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, and which ring is optionally substituted with one to four substituents each independently selected from the group consisting of halo, cyano, hydroxyl, C 1-3 alkyl and OC 1-3 alkyl;

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;

m is an integer from zero to two,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein X 1 , X 2 and X 3 are each a bond, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 wherein Y is O or CR a R b and

Z is O or CR a R b ; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 wherein R 1 is selected from the group consisting of: hydrogen and C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 wherein R 4 is selected from the group consisting of: hydrogen and halo, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 wherein R 2 and R 3 can be taken together with the atoms to which they are attached to form a 3 to 8 membered heterocyclic ring, wherein said ring may contain from one to three heteroatoms selected from N, O and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, and which ring is optionally substituted with one to four substituents each independently selected from the group consisting of:

a) halo,

b) oxo,

c) cyano,

d) OR 5 ,

e) NR c R d ,

f) SO 3 H,

g) S(O) m R 5 ,

h) S(O) m R 7

i) R 5 ,

j) R 6 ,

k) R 7 ,

l) (C═O)R 5 ,

m) (C═O)OR 5 ,

n) (C═O)R 7 , and

o) (C═O)NR c R d ;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 wherein R 2 and R 3 can be taken together with the atoms to which they are attached to form a 6 membered heterocyclic ring, wherein said ring may contain from one to three heteroatoms selected from N, O and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, and which ring is optionally substituted with one to four substituents each independently 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 ,

g) R 5 ,

h) R 6 ,

i) R 7 ,

j) (C═O)R 5 ,

k) (C═O)OR 5 , and

l) (C═O)R 7 ;

or a pharmaceutically acceptable salt thereof.

8. A compound selected from

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

10. A method for the treatment of Parkinson's Disease comprising administering a compound of claim 1 , or a pharmaceutical composition thereof, to a patient in need thereof.