Compounds inhibiting leucine-rich repeat kinase enzyme activity

Patent metadata

Field	Value
Publication number	US-2016009681-A1
Application number	US-201414772525-A
Country	US
Kind code	A1
Filing date	Feb 27, 2014
Priority date	Mar 4, 2013
Publication date	Jan 14, 2016
Grant date	—

Abstract

The present invention is directed to indazole compounds 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 LRRK2 kinase is involved.

First claim

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 2 ,
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, halo and NR c R d , 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,

Assignees

• Miller Michael
• Basu Kallol
• Mong Duane
• Scott Jack
• Liu Hong
• Dai Xing
• Stamford Andrew
• Poirier Marc
• Tempest Paul
• Merck Sharp & Dohme

Inventors

• Miller Michael
• Basu Kallol
• Demong Duane
• Scott Jack
• Liu Hong
• Dai Xing
• Stamford Andrew
• Poirier Marc
• Tempest Paul

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D495/08

  Bridged systems · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D491/08

  Bridged systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title