Compounds inhibiting leucine-rich repeat kinase enzyme activity

Patent metadata

Field	Value
Publication number	US-9718818-B2
Application number	US-201414912761-A
Country	US
Kind code	B2
Filing date	Aug 18, 2014
Priority date	Aug 22, 2013
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

The present invention is directed to azaindazole 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

What is claimed:

1. A compound of the formula: I:

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) aryl, wherein said aryl is optionally substituted with one to three substituents independently selected from the group consisting of:
halo,
cyano,
hydroxyl,
oxo,
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 ,
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,
C 3-8 cycloalkyl, which 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 ,
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 ,
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 ,
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 , and
C 4-8 cycloalken, 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 ,

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 ,
o) NR c R d and

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 z is selected from the group consisting of hydrogen and C 1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , OC 1-6 alkyl and C 3-8 cycloalkyl;
A is CH or N;
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 or heteroaryl 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 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 and 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 subs

Assignees

• Merck Sharp & Dohme
• Demong Duane
• Greshock Thomas J
• Chang Ronald K
• Dai Xing
• Liu Hong
• Mccauley John A
• Li Wei
• Basu Kallol
• Scott Jack D
• Miller Michael

Inventors

• Demong Duane
• Greshock Thomas J
• Chang Ronald K
• Dai Xing
• Liu Hong
• Mccauley John A
• Li Wei
• Basu Kallol
• Scott Jack D
• Miller Michael

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title