N-heteroaryl indazole derivatives as LRRK2 inhibitors, pharmaceutical compositions, and uses thereof

Patent metadata

Field	Value
Publication number	US-12030872-B2
Application number	US-201917286870-A
Country	US
Kind code	B2
Filing date	Oct 25, 2019
Priority date	Oct 31, 2018
Publication date	Jul 9, 2024
Grant date	Jul 9, 2024

Abstract

The present invention is directed to substituted certain N-heteroaryl indazole derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , X, Y, and Z are as defined herein, which are potent inhibitors of LRRK2 kinase and may be useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease and other diseases and disorders described herein. 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 diseases, such as Parkinson's disease, in which LRRK-2 kinase is involved.

First claim

The invention claimed is:

1. A compound having a structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
X is selected from N, C—H, C—F, and C—Cl;
Y is selected from N, C—H, C—F, and C—Cl;
R 1 is selected from H, F, Cl, CN, —(C 1 -C 3 )alkyl, —O(C 1 -C 3 )alkyl, —(C 1 -C 3 )haloalkyl, —O(C 1 -C 3 )haloalkyl, and —(C 3 -C 6 )cycloalkyl;
R 2 is a moiety selected from:

wherein:
q is 1, 2, or 3;
r is 1 or 2;
t is 1 or 2;
Z is selected from O and N(R 2N );
R 2N is selected from H, (C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl-OH, (C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, C(O)O(C 1 -C 6 )alkyl, C(O)NH 2 , C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, oxetanyl which is optionally substituted with R 2A , furanyl which is optionally substituted with 1 or 2 groups selected from OH and R 2A , pyranyl which is optionally substituted with 1 or 2 groups selected from OH and R 2A , and

each R 2A is independently selected from H and —(C 1 -C 4 )alkyl;
R 3 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH;
R 3A is selected from H and CN;
R 4 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH;
ring A is 5-membered heteroaryl group comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S;
R 5 is selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl substituted with (C 1 -C 4 )alkyl, S(O) 2 (C 3 -C 6 )cycloalkyl, C(O)N(R 5A ) 2 , C(O)OR 5A , phenyl, heteroaryl, heterocycloalkyl and

 and
each R 5A is independently selected from H and —(C 1 -C 4 )alkyl; and
R 5B is selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, CN, S(O) 2 (C 3 -C 6 )cycloalkyl, C(O)N(R 5A ) 2 , and C(O)OR 5A .

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein ring A is selected from pyrazolyl, triazolyl, thiazolyl, oxazolyl, and oxadiazolyl;
R 5 is selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl substituted with (C 1 -C 4 )alkyl, S(O) 2 (C 3 -C 6 )cycloalkyl, C(O)N(R 5A ) 2 , C(O)OR 5A , phenyl, heteroaryl, heterocycloalkyl, and

R 5A is selected from H and —(C 1 -C 4 )alkyl; and
R 5B is selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, CN, C(O)N(R 5A ) 2 , and C(O)OR 5A .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is:

wherein:
R 2N is selected from H,

 —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , and —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl;
R 2A is selected from H and —(C 1 -C 4 )alkyl;
R 2B is selected from H and OH;
R 3 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH; and
R 4 is selected from H, F, Cl, —(C 1 -C 4 )alkyl, —(C 1 -C 6 )haloalkyl, and —(C 1 -C 6 )alkyl-OH.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is a moiety selected from:

wherein R 3A is selected from H and CN.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is:

wherein:
R 2N is selected from

 H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , and —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl;
R 2A is selected from H and —(C 1 -C 4 )alkyl;
R 2B is selected from H and OH;
R 3 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH; and
R 4 is selected from H, F, Cl, —(C 1 -C 4 )alkyl, —(C 1 -C 6 )haloalkyl, and —(C 1 -C 6 )alkyl-OH.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is a moiety selected from:

wherein:
q is 1, 2, or 3;
r is 1 or 2;
Z is 0 or NR 2N ;
R 2N is selected from

 H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, C(O)O(C 1 -C 6 )alkyl, C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , and —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl;
R 2A is selected from H and —(C 1 -C 4 )alkyl; and
R 2B is selected from H and OH.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is a moiety selected from:

wherein:
R 2N is selected from

 H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N((C 1 -C 6 )alkyl) 2 , and —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl;
R 2A is selected from H and —(C 1 -C 4 )alkyl;
R 2B is selected from H and OH;
R 3 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH; and
R 4 is selected from H, F, Cl, (C 1 -C 4 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH;
In an alternative of each of the preceding embodiments, in Formula (I):
R 2 is a moiety selected from:

wherein:
R 2N is selected from

 H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkyl-CN, —S(O) 2 (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-S(O) 2 (C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N(

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Simov Vladimir
• Kaplan William P
• Acton Iii John J
• Ardolino Michael J
• Chen Joanna L
• Fuller Peter H
• Gunaydin Hakan
• Li Derun
• Liu Ping
• Logan Kaitlyn Marie
• Methot Joey
• Morriello Gregori J
• Neelamkavil Santhosh F
• Torres Luis
• Yan Xin
• Zhou Hua

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D417/04

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

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D413/04

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

• C07D409/14

  containing three or more hetero rings · CPC title