IP Library › Granted Patent US 12,516,039

Granted Patent B2

US 12,516,039 · App. 18/248,407 · Granted Jan 6, 2026

N-linked isoquinoline amides as LRRK2 inhibitors, pharmaceutical compositions, and uses thereof

Inventors: Peter H. Fuller (Ashland, MA); Anmol Gulati (Watertown, MA); Solomon D. Kattar (Wakefield, MA); Mitchell H. Keylor (Malden, MA); Kaila A. Margrey (Cambridge, MA); Xin Yan (Newton Highlands, MA)

Assignee: Merck Sharp & Dohme LLC

C07D405/12 C07D217/22 C07D401/04 C07D401/14 C07D405/14 C07D409/14 C07D413/04 C07D471/04 C07D471/08

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Quick Facts

Patent No.: US 12,516,039
App. No.: 18/248,407
Granted: Jan 6, 2026
Kind: B2

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Abstract

The present invention is directed to certain 2-aminoquinzaoline derivatives of Formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , and R 3 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.

Claims (611)

1 . A compound of structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from monocyclic or bicyclic C 3-8 carbocycle, said carbocycle optionally interrupted by an oxygen atom and optionally substituted with 1 to 3 groups selected from C 1-6 alkyl, (CH 2 ) n OC 1-6 alkyl, CN, C 1-3 haloalkyl, C 3-10 heteroaryl, C 3-10 heterocyclyl, and halogen, said heteroaryl and heterocyclyl optionally substituted with 1 to 3 groups selected from C 1-6 alkyl, CF 3 , and CN;

R 2 is selected from hydrogen, C 1-6 alkyl, OC 1-6 alky, C 3-6 cycloalkyl, and halogen;

R 3 is selected from N-linked oxo-oxazolidinyl, oxoazabicycloheptanyl, azabicycloheptanyl, piperidinyl, tetrahydropyrazolopyridinyl, azaspiroheptanyl, and piperazinyl said N-linked oxazolidinyl, oxazolidinonyl, oxoazabicycloheptanyl, piperidinyl, tetrahydropyrazolopyridinyl, azaspiroheptanyl, and piperazinyl unsubstituted or substituted with 1 to 3 groups independently selected from C 1-6 alkyl, OC 1-6 alkyl, OH, halogen, CN, azetidinyl, wherein said piperazinyl is further substituted at available nitrogen atom with a group independently selected from C 1-6 alkyl, oxetanyl, azetidinyl, and tetrahydrofuranyl, said oxetanyl, azetidinyl, and tetrahydrofuranyl unsubstituted or substituted with 1 to 2 groups independently selected from C 1-6 alkyl, OC 1-6 alkyl, halogen, CN, and OH and n is selected from 0 to 3, provided that when R 1 is cyclopropyl and R 2 is halogen, then R 3 is not oxo-oxazolidinyl.

2 . The compound according to claim 1 wherein R 1 is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heptanyl, octanyl, tetrahydrofuranyl, tetrahydropyranyl, spirohexanyl, spiropentanyl, spirooctanyl, bicyclopentanyl, oxabicyclohexanyl, oxaspiroheptanyl, oxaspirooctanyl, and oxaspirononanyl, or a pharmaceutically acceptable salt thereof.

3 . The compound according to claim 1 wherein R 1 is selected from substituted or unsubstituted oxabicyclohexanyl, oxaspiroheptanyl, oxaspirooctanyl, and oxaspirononanyl or a pharmaceutically acceptable salt thereof.

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

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

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

7 . The compound according to claim 1 wherein R 3 is selected from substituted or unsubstituted N-linked oxo-oxazolidinyl, or a pharmaceutically acceptable salt thereof.

8 . The compound according to claim 1 wherein R 3 is substituted or unsubstituted N-linked oxoazabicycloheptanyl, azaspiroheptany or azabicycloheptanyl, or a pharmaceutically acceptable salt thereof.

9 . The compound according to claim 1 wherein R 3 is substituted or unsubstituted N-linked piperazinyl, piperidinyl, or a pharmaceutically acceptable salt thereof.

10 . The compound according to claim 1 wherein R 3 is substituted N-linked piperazinyl wherein the substitution is on the available nitrogen atom.

11 . The compound according to claim 1 wherein R 3 is substituted or unsubstituted N-linked tetrahydropyrazolopyridinyl.

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

or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are as described herein, p is 0 or 1, X is N, O, or CH, R 5 is selected from C 1-6 alkyl, OC 1-6 alkyl, OH, CN, and halogen, R 7 is selected from hydrogen, C 1-6 alkyl and ═O, and R 6 is selected from

1) R 4 , when X is N, p is 1 and R 7 is hydrogen or C 1-6 alkyl,

2) Absent, when X is O, p is 0, and R 7 is ═O, and

3) Hydrogen, C 1-6 alkyl, or OH, when X is CH, p is 1, and R 7 is hydrogen or C 1-6 alkyl, wherein when p is 0 (or absent) a five membered ring is present and when p is 1 a six membered ring is present, and R 4 is selected from C 1-6 alkyl, oxetanyl and tetrahydrofuranyl said oxetanyl and tetrahydrofuranyl unsubstituted or substituted with 1 to 2 groups independently selected from C 1-6 alkyl, OC 1-6 alkyl, and OH.

13 . The compound according to claim 12 wherein p is 1 and X is N or CH.

14 . The compound according to claim 12 wherein p is 0 and X is O.

15 . The compound according to claim 12 represented by structural Formula III:

or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from C 1-6 alkyl, OC 1-6 alkyl, OH, CN, and halogen, R 1 is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heptanyl, octanyl, tetrahydrofuranyl, tetrahydropyranyl, spirohexanyl, spiropentanyl, bicyclopentanyl, oxabicyclohexanyl, oxabicycloheptanyl, oxaspiroheptanyl, oxaspirooctanyl, and oxaspirononanyl, R 2 is hydrogen, methyl, chlorine, or fluorine, and R 4 is selected from methyl, ethyl, propyl, oxetanyl, tetrahydrofuranyl, said oxetanyl and tetrahydrofuranyl unsubstituted or substituted with 1 to 2 groups independently selected from C 1-6 alkyl, OC 1-6 alkyl and OH.

16 . The compound according to claim 1 represented by structural Formula IV:

or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are as described and R 3a is selected from the group consisting of:

wherein R 5 is selected from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, OH, CN, and halogen.

17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from:

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide,

(3R,4R)-N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide,

(3S,4S)-N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide,

N-(7-chloro-6-(4-(4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide,

(3R,4R)-N-(7-chloro-6-(4-(4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide,

(3S,4S)-N-(7-chloro-6-(4-(4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide,

N-(7-fluoro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide,

(3R,4R)-N-(7-fluoro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide,

(3S,4S)-N-(7-fluoro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.3]hexane-1-carboxamide,

(1R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.3]hexane-1-carboxamide,

(1R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.3]hexane-1-carboxamide,

(1S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.3]hexane-1-carboxamide,

(1S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.3]hexane-1-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide,

(1R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide,

(1R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide,

(1S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide,

(1S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide,

N-(7-chloro-6-(4-((3S,4S or 3R, 4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.5]octane-1-carboxamide,

(1R,3S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.5]octane-1-carboxamide,

(1R,3S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.5]octane-1-carboxamide,

(1R,3R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.5]octane-1-carboxamide,

(1R,3R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.5]octane-1-carboxamide,

(1S,3S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.5]octane-1-carboxamide,

(1S,3S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.5]octane-1-carboxamide,

(1S,3R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.5]octane-1-carboxamide o

(1S,3R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.5]octane-1-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6,6-difluorospiro[2.5]octane-1-carboxamide,

(1R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6,6-difluorospiro[2.5]octane-1-carboxamide,

(1R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6,6-difluorospiro[2.5]octane-1-carboxamide,

(1S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6,6-difluorospiro[2.5]octane-1-carboxamide,

(1S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6,6-difluorospiro[2.5]octane-1-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5,5-dimethyltetrahydrofuran-3-carboxamide,

(R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5,5-dimethyltetrahydrofuran-3-carboxamide,

(R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5,5-dimethyltetrahydrofuran-3-carboxamide,

(S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5,5-dimethyltetrahydrofuran-3-carboxamide,

(S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5,5-dimethyltetrahydrofuran-3-carboxamide,

N-(7-chloro-6-(1-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-4-yl)isoquinolin-3-yl)-2,2-dimethyltetrahydrofuran-3-carboxamide,

(R)-N-(7-chloro-6-(1-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-4-yl)isoquinolin-3-yl)-2,2-dimethyltetrahydrofuran-3-carboxamide,

(R)-N-(7-chloro-6-(1-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-4-yl)isoquinolin-3-yl)-2,2-dimethyltetrahydrofuran-3-carboxamide,

(S)-N-(7-chloro-6-(1-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-4-yl)isoquinolin-3-yl)-2,2-dimethyltetrahydrofuran-3-carboxamide,

(S)-N-(7-chloro-6-(1-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-4-yl)isoquinolin-3-yl)-2,2-dimethyltetrahydrofuran-3-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-2-(methoxymethyl)cyclobutane-1-carboxamide,

(1R,2S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-2-(methoxymethyl)cyclobutane-1-carboxamide,

(1R,2S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-2-(methoxymethyl)cyclobutane-1-carboxamide,

(1R,2R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-2-(methoxymethyl)cyclobutane-1-carboxamide,

(1R,2R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-2-(methoxymethyl)cyclobutane-1-carboxamide,

(1S,2S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-2-(methoxymethyl)cyclobutane-1-carboxamide,

(1S,2S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-2-(methoxymethyl)cyclobutane-1-carboxamide,

(1S,2R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-2-(methoxymethyl)cyclobutane-1-carboxamide,

(1S,2R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-2-(methoxymethyl)cyclobutane-1-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-7-oxaspiro[3.5]nonane-1-carboxamide,

(R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-7-oxaspiro[3.5]nonane-1-carboxamide,

(R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-7-oxaspiro[3.5]nonane-1-carboxamide,

(S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-7-oxaspiro[3.5]nonane-1-carboxamide,

(S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-7-oxaspiro[3.5]nonane-1-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide or

(S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

N-{7-chloro-6-[(3S)-4-hydroxyoxolan-3-yl)-3-methylpiperazin-1-yl]isoquinolin-3-yl}-6-oxaspiro[2.5]octane-1-carboxamide,

(R)-N-{7-chloro-6-[(3S)-4-(3R,4R)-4-hydroxyoxolan-3-yl)-3-methylpiperazin-1-yl]isoquinolin-3-yl}-6-oxaspiro[2.5]octane-1-carboxamide,

(R)-N-{7-chloro-6-[(3S)-4-(3S,4S)-4-hydroxyoxolan-3-yl)-3-methylpiperazin-1-yl]isoquinolin-3-yl}-6-oxaspiro[2.5]octane-1-carboxamide,

(S)-N-{7-chloro-6-[(3S)-4-(3R,4R)-4-hydroxyoxolan-3-yl)-3-methylpiperazin-1-yl]isoquinolin-3-yl}-6-oxaspiro[2.5]octane-1-carboxamide or

(S)-N-{7-chloro-6-[(3S)-4-(3S,4S)-4-hydroxyoxolan-3-yl)-3-methylpiperazin-1-yl]isoquinolin-3-yl}-6-oxaspiro[2.5]octane-1-carboxamide,

N-(7-chloro-6-(4-(4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide or

(S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.4]heptane-1-carboxamide,

(1R,3R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.4]heptane-1-carboxamide,

(1R,3R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.4]heptane-1-carboxamide,

(1R,3S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.4]heptane-1-carboxamide,

(1R,3S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.4]heptane-1-carboxamide,

(1S,3R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.4]heptane-1-carboxamide,

(1S,3R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.4]heptane-1-carboxamide,

(1S,3S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.4]heptane-1-carboxamide,

(1S,3S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-5-oxaspiro[2.4]heptane-1-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.2]pentane-1-carboxamide,

(R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.2]pentane-1-carboxamide,

(R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.2]pentane-1-carboxamide,

(S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.2]pentane-1-carboxamide or

(S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.2]pentane-1-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-4,4-difluorospiro[2.2]pentane-1-carboxamide,

(1R,3R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-4,4-difluorospiro[2.2]pentane-1-carboxamide,

(1R,3R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-4,4-difluorospiro[2.2]pentane-1-carboxamide,

(1R,3S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-4,4-difluorospiro[2.2]pentane-1-carboxamide,

(1R,3S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-4,4-difluorospiro[2.2]pentane-1-carboxamide,

(1S,3R)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-4,4-difluorospiro[2.2]pentane-1-carboxamide,

(1S,3R)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-4,4-difluorospiro[2.2]pentane-1-carboxamide,

(1S,3S)-N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-4,4-difluorospiro[2.2]pentane-1-carboxamide or

(1S,3S)-N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-4,4-difluorospiro[2.2]pentane-1-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.3]hexane-5-carboxamide,

N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.3]hexane-5-carboxamide or

N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)spiro[2.3]hexane-5-carboxamide,

N-(7-chloro-6-(4-((3S,4S or 3R, 4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxamide,

N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxamide or

N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxamide,

N-(7-chloro-6-(4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl) bicyclo[1.1.1]pentane-1-carboxamide,

N-(7-chloro-6-(4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl) bicyclo[1.1.1]pentane-1-carboxamide or

N-(7-chloro-6-(4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl) bicyclo[1.1.1]pentane-1-carboxamide,

N-(7-chloro-6-((S)-4-(4-hydroxy-3-methyltetrahydrofuran-3-yl)-3-methylpiperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(R)-N-(7-chloro-6-((S)-4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)-3-methylpiperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(R)-N-(7-chloro-6-((S)-4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)-3-methylpiperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(S)-N-(7-chloro-6-((S)-4-((3R,4R)-4-hydroxy-3-methyltetrahydrofuran-3-yl)-3-methylpiperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide or

(S)-N-(7-chloro-6-((S)-4-((3S,4S)-4-hydroxy-3-methyltetrahydrofuran-3-yl)-3-methylpiperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

N-(7-chloro-6-(4-(3-ethyl-4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(R)-N-(7-chloro-6-(4-((3R,4R)-3-ethyl-4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(R)-N-(7-chloro-6-(4-((3S,4S)-3-ethyl-4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

(S)-N-(7-chloro-6-(4-((3R,4R)-3-ethyl-4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide or

(S)-N-(7-chloro-6-(4-((3S,4S)-3-ethyl-4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl)isoquinolin-3-yl)-6-oxaspiro[2.5]octane-1-carboxamide,

N-[7-fluoro-6-[4-[4-hydroxy-3-methyl-tetrahydrofuran-3-yl]piperazin-1-yl]-3-isoquinolyl]-2-(2-pyridyl)cyclopropanecarboxamide,

(1R,2R)-N-[7-fluoro-6-[4-[(3R,4R)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]piperazin-1-yl]-3-isoquinolyl]-2-(2-pyridyl)cyclopropanecarboxamide,

(1R,2R)-N-[7-fluoro-6-[4-[(3S,4S)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]piperazin-1-yl]-3-isoquinolyl]-2-(2-pyridyl)cyclopropanecarboxamide,

(1S,2S)-N-[7-fluoro-6-[4-[(3R,4R)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]piperazin-1-yl]-3-isoquinolyl]-2-(2-pyridyl)cyclopropanecarboxamide,

(1S,2S)-N-[7-fluoro-6-[4-[(3S,4S)-4-hydroxy-3-methyl-tetrahydrofuran-3-yl]piperazin-1-yl]-3-isoquinolyl]-2-(2-pyridyl)cyclopropanecarboxamide,