Compounds inhibiting leucine-rich repeat kinase enzyme activity

Patent metadata

Field	Value
Publication number	US-9416126-B2
Application number	US-201414772290-A
Country	US
Kind code	B2
Filing date	Feb 27, 2014
Priority date	Mar 4, 2013
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

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 LRRK-2 kinase is involved.

First claim

The invention claimed is:

1. A compound of the formula:

wherein R 1 is selected from the group consisting of:
a) hydrogen,
b) halo,
c) cyano,
d) hydroxyl,
e) C 2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano and R 5 ;
f) OC 2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano and R 5 ;
g) R 5 ,
h) OR 5 ,
i) R 7 ,
j) S(O) m R 5 ,
k) S(O) m R 7 ,
l) (C═O)R 7 ,
m) (C═O)R 5 ,
n) (C═O)OR 5 , and
o) NR c R d ;

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;
or R 1 and R 4 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) R 5 , and
e) R 7
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 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 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 , 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, 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 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, 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, ar

Assignees

• Merck Sharp & Dohme

Inventors

• Miller Michael
• Basu Kallol
• Demong Duane
• Scott Jack
• Li Wei
• Harris Joel
• Stamford Andrew
• Poirier Marc
• Tempest Paul

Classifications

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A61K31/505

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title