2-aminoquinazolines as LRRK2 inhibitors, pharmaceutical compositions, and uses thereof

Patent metadata

Field	Value
Publication number	US-12570640-B2
Application number	US-202118041849-A
Country	US
Kind code	B2
Filing date	Sep 1, 2021
Priority date	Sep 2, 2020
Publication date	Mar 10, 2026
Grant date	Mar 10, 2026

Abstract

The present invention is directed to certain 2-aminoquinzaoline derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein R 1 , R 3 , R 4 , X 1 , and X 2 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 such diseases in which LRRK-2 kinase is involved.

First claim

What is claimed:

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

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is N or CH;
X 2 is N or CR 2 ;
R1 is selected from:

R 2 is selected from H, C 1-6 alkyl, and Cl,
R 3 is selected from H, Cl, CN, and C 1-6 alkyl;
R 4 represents NRR′, or an N-linked C 4-10 heterocyclyl, said heterocyclyl optionally substituted with 1 to 3 groups of R d ,
each R represents H, or C 1-6 alkyl;
R′ is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, and C 4-10 heterocyclyl, said alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1 to 3 groups of R e ;
R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkylOR, C 1-3 haloalkyl, —(CH 2 )nC4-10 heterocyclyl, —(CH 2 )nC3-10 cycloalkyl, —(CH 2 )nC5-10 heteroaryl, said alkyl, cycloalkyl, heteroaryl, and heterocyclyl are optionally substituted with 1 to 3 groups of R c ;
R a and R b are independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-3 haloalkyl, —(CH 2 )nC5-10 heteroaryl, and C 3-6 cycloalkyl, or
R 5 and R a in (i) and (ii) of R 1 can combine with the nitrogen and carbon atoms to which they are attached, respectively, to form a six membered ring;
R c is selected from OR, halogen, (CH 2 ) n CN, C 1-3 haloalkyl, C 1-6 alkyl, C 1-6 alkylOR, C 1-3 haloalkyl, and C 4-10 heterocyclyl, said alkyl and heterocyclyl are optionally substituted with 1 to 3 groups of C 1-6 alkyl or CN;
R d is selected from oxo, OR, C 1-6 alkyl, C 1-6 alkylOR, CH 2 CF 3 , C 4-10 heterocyclyl, —(CH 2 )nC3-10 cycloalkyl, C(O) C 1-6 alkyl, and NRR, said alkyl, heterocyclyl and cycloalkyl are optionally substituted with 1 to 3 groups of R e ;
R c is selected from OR, C 1-6 alkyl, CN, and fluorine; and
Each n is independently 1, 2, 3, or 4.

2 . The compound according to claim 1 wherein X 1 is N, X 2 is CH.

3 . The compound according to claim 1 wherein R 1 is structural formula (i).

4 . The compound according to claim 1 wherein R 1 is structural formula (ii).

5 . The compound according to claim 1 wherein R 1 is structural formula (iii).

6 . The compound according to claim 1 wherein R 1 is structural formula (iv).

7 . The compound according to claim 1 wherein R 1 is selected from structural formula (v), and (vi).

8 . The compound according to claim 1 wherein R 5 of R 1 is selected from the group consisting of CH 3 , CH 2 CH 3 , CH 2 CHF 2 , (CH 2 ) 2 F, CH 2 CF 3 , CHF 2 , (CH 2 ) n C(CH 3 ) 3 , CH 2 C(CH 3 ) 2 OH, CH 2 CH(OH)CH 2 C(CH 3 ) 2 OH, C(CH 3 ) 2 CN, (CH 2 ) 2 CN, (CH 2 ) n cyclopropyl, (CH 2 ) n cyclobutyl, (CH 2 ) n cyclopentyl, (CH 2 ) n cyclohexyl, (CH 2 ) n oxetanyl, azetidinyl, piperazinyl, piperidinyl, oxanyl, bicyclopentanyl, dihydropyrrolopyrazolo, azaspiroheptanyl, and tetrahydropyrazolopyridinyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, piperazinyl, piperidinyl, oxanyl, bicyclopentanyl, dihydropyrrolopyrazolo, azaspiroheptanyl, and tetrahydropyrazolopyridinyl are optionally substituted with 1 to 3 groups of R c .

9 . The compound of claim 1 wherein R 3 is selected from the group consisting of hydrogen, chlorine, CN and methyl.

10 . The compound of claim 1 wherein R 4 is selected from the group consisting of N-linked piperazinyl, oxetanylpiperidinyl, pyrrolidinyl, azetidinyl, diazaspirononanyl, piperidinyl, azabicyclohexanyl, dihydrotriazolopyrazinyl, diazabicycloheptanyl, azabicycloheptanyl, azabicyclooctanyl, pyrrolopyridinyl, oxazolidinonyl, azaspirodecanyl, pyrazolopyridinyl, oxaazaspirodecanonyl, azabicycloheptanonyl, azaspiroheptanyl, diazaspiroheptanyl, piperazinonyl, piperazinyltetrahydrofuranyl, oxazolidinonyl, and azabicycloheptanonyl, said group optionally substituted with 1 to 3 groups of R d selected from C 1-6 alkyl, CH 2 (CH 3 ) 2OH, OH, OCH 3 , CH 2 OH, CH 2 CF 3 , N(CH 3 ) 2 , (CH 2 ) 2 CN, C(O)CH 3 , oxo, cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl, said alkyl, cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl are optionally substituted with 1 to 3 groups of R e .

11 . The compound according to claim 1 wherein R 4 is NRR′ selected from the group consisting of N(CH 3 ) 2, NHCH 3 , NHCH 2 CH 3 , NHCH(CH 3 ) 2, NHCH 2 cyclopropyl, and N(CH 3 ) oxetanyl.

12 . The compound according to claim 1 wherein R a and R b are independently selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl, isopropyl, t-butyl, CF 3 , CHF 2 , cyclopropyl, and C(CH 3 ) 2 -triazolyl.

13 . The compound according to claim 12 wherein at least one of R a and R b is hydrogen and the other is selected from the group consisting of chlorine, methyl, CF 3 , CHF 2 , and cyclopropyl.

14 . The compound according to claim 1 represented by structural Formula II:

or a pharmaceutically acceptable salt thereof, wherein R a and R b are independently selected from the group consisting of hydrogen, chlorine, methyl, CF 3 , CHF 2 , and cyclopropyl, R 3 is selected from the group consisting of CH 3 , chlorine, fluorine, bromine, hydrogen, and CN, R 4 is selected from the group consisting of

wherein R d is selected from the group consisting of C 1-6 alkyl, CH 2 (CH 3 ) 2 OH, OH, OCH 3 , CH 2 OH, CH 2 CF 3 , N(CH 3 ) 2 , (CH 2 ) 2 CN, C(O)CH 3 , cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl, said alkyl, cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl are optionally substituted with 1 to 3 groups of R e , and R 5 is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2F, CH 2 CF 3 , CHF 2 , CH 2 C(CH 3 ) 2 OH, (CH 2 ) n cyclopropyl, (CH 2 ) n oxetanyl, piperazinyl, piperidinyl, and bicyclopentanyl, said cyclopropyl, oxetanyl, piperazinyl, piperidinyl, and bicyclopentanyl are optionally substituted with 1 to 3 groups of R c .

15 . The compound according to claim 1 represented by structural Formula III:

or a pharmaceutically acceptable salt thereof, wherein R a and R b are independently selected from the group consisting of hydrogen, chlorine, methyl, CF 3 , CHF 2 , and cyclopropyl, R 3 is selected from the group consisting of CH 3 , chlorine, fluorine bromine, hydrogen, and CN, R 4 is selected from the group consisting of

wherein R d is selected from the group consisting of C 1-6 alkyl, CH 2 (CH 3 ) 2 OH, OH, OCH 3 , CH 2 OH, CH 2 CF 3 , N(CH 3 ) 2 , (CH 2 ) 2 CN, C(O)CH 3 , cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl, said alkyl, cyclopropyl, cyclopentanyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, and tetrahydrofuranyl are optionally substituted with 1 to 3 groups of R e , and R 5 is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2 F, CH 2

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Acton Iii John J
• Chau Ryan
• Fuller Peter H
• Gulati Anmol
• Johnson Rebecca Elizabeth
• Kattar Solomon
• Keylor Mitchell H
• Li Derun
• Margrey Kaila A
• Morriello Gregori J
• Yan Xin

Classifications

• C07D498/08

  Bridged systems · CPC title

• C07D491/107

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

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/08

  Bridged systems · CPC title