JP2014504362A5

JP2014504362A5 -

Info

Publication number: JP2014504362A5
Application number: JP2013542113A
Authority: JP
Filing date: 2011-11-29
Publication date: 2015-01-15

Claims

A method of identifying a patient or subject suffering from or at risk of developing Parkinson's disease, comprising determining the level of S1292 autophosphorylation in said subject, wherein the elevated level Is correlated with the risk of developing Parkinson's disease or the risk of developing Parkinson's disease.

The method of claim 1, further comprising obtaining or obtaining an LRRK2-containing sample from a subject.

3. The method of claim 2, further comprising measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the subject sample.

4. The method of claim 3, further comprising comparing the amount or level of S1292 autophosphorylation in the subject sample with the amount or level of S1292 autophosphorylation in one or more control samples.

A method of predicting the sensitivity of a subject to an LRRK2 modulator, or the effect of an LRRK2 modulator for the treatment of Parkinson's disease, comprising determining the level of S1292 autophosphorylation in said subject, wherein said level of S1292 self is increased. A method wherein phosphorylation correlates with the effect of the inhibitor for the treatment of the disease.

6. The method of claim 5, further comprising obtaining or obtaining a first LRRK2-containing sample from a subject.

7. The method of claim 6, further comprising administering an LRRK2 modulator to the subject.

8. The method of claim 7, further comprising obtaining or obtaining a second LRRK2-containing sample from the subject after administering the LRRK2 modulator to the subject.

9. The method of claim 8, further comprising measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the first subject sample.

10. The method of claim 9, further comprising measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the second subject sample.

11. The method of claim 10, further comprising comparing the amount or level of S1292 autophosphorylation in the first subject sample with the amount or level of S1292 autophosphorylation in the second subject sample.

Said LRRK2 modulator is of formula I:

Or a pharmaceutically acceptable salt thereof.
(In the above formula,
m is 0-3;
X is: —NR ^a —; —O—; or —S (O) _r — (r is 0-2, R ^a is hydrogen or C _1-6 alkyl);
R ¹ is: C _1-6 alkyl; halo-C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; Hydroxy-C _1-6 alkyl; amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _1-6 alkyl or C _3-6 cycloalkyl optionally substituted with halo; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); tetrahydropyranyl; tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl Oxetanyl; or oxetane-C _1-6 alkyl;
Or R ¹ and R ^a together with the atoms to which they are attached may contain further heteroatoms selected from O, N and S and are substituted with oxo, halo or C _1-6 alkyl 3 Can form ˜6-membered rings;
R ² is: halo; C _1-6 alkoxy; cyano; C _2-6 alkynyl; C _2-6 alkenyl; halo-C _1-6 alkyl; halo-C _1-6 alkoxy; C _3-6 cycloalkyl (C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); C _3-6 cycloalkyl-C _1-6 alkyl (C _3-6 cycloalkyl moiety is substituted with C _1-6 alkyl) Tetrahydrofuranyl-C _1-6 alkyl; acetyl; oxetanyl; or oxetane-C _1-6 alkyl;
R ³ is: —OR ⁴ ; halo; cyano; C _1-6 alkyl; halo-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted with C _1-6 alkyl; C _3-6 cyclo Alkyl-C _1-6 alkyl (C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl); tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 alkyl; oxetanyl; or oxetane-C _{1- 6} alkyl;
R ⁴ is: hydrogen; C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _1-6 alkyl or C _3-6 optionally substituted with halo C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted with C _1-6 alkyl or halo); tetrahydrofuranyl; tetrahydrofuranyl-C _1-6 Alkyl; oxetanyl; or oxetane-C _1-6 alkyl;
R ⁵ is: hydrogen; or C _1-6 alkyl;
n is 0 or 1;
R ⁶ is: hydrogen; _{C 1-6} alkyl; _{C 1-6} alkoxy -C _1-6 alkyl; hydroxy -C _1-6 alkyl; amino -C _1-6 alkyl; _{C 3-6} cycloalkyl; _{C 3- 6} cycloalkyl-C _1-6 alkyl; heterocyclyl; or heterocyclyl-C _1-6 alkyl; C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyl, heterocyclyl and heterocyclyl-C _1- each ₆ alkyl: _{C 1-6} alkyl; halo -C _1-6 alkyl; _{C 1-6} alkoxy; halo -C _1-6 alkoxy; hydroxy; hydroxyalkyl -C _1-6 alkyl; halo; nitrile; _{C 1 -6} alkyl - carbonyl; _{C 1-6} alkyl - sulfonyl; _{C 3-6} cycloalkyl; _{C 3-6} cycloalkyl -C _1-6 alkyl; _{C 3-6} cycloalkyl - carbonyl; amino; or f It may be substituted with one, two, three or four groups independently selected from Roshikuriru; or two groups form a ring of 5 or 6 membered together with the atoms to which they are attached obtain;
Or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 3- to 7-membered ring which may contain further heteroatoms selected from O, N and S (O) _n and, it: _{C 1-6} alkyl; halo -C _1-6 alkyl; _{C 1-6} alkoxy; halo -C _1-6 alkoxy; hydroxy; _{C 1-6} alkoxy -C _1-6 alkyl; hydroxy -C _{1 -6} alkyl; halo, nitrile; _{C 1-6} alkyl - carbonyl; _{C 1-6} alkyl - sulfonyl; _{C 3-6} cycloalkyl; _{C 3-6} cycloalkyl -C _1-6 alkyl; _{C 3-6} cycloalkyl -Carbonyl; amino; or may be substituted with 1, 2, 3 or 4 groups independently selected from heterocyclyl; or the two groups may be 5- or 6-membered rings with the atoms to which they are attached. And R ⁷ is: halo; C _1-6 alkyl; C _1-6 alkoxy; halo-C _1-6 alkyl; or halo-C _1-6 alkoxy).

Said LRRK2 modulator is of formula II

Or a pharmaceutically acceptable salt thereof.
(In the above formula,
X is: —NR ^a —; or —O— (R ^a is hydrogen or C _1-6 alkyl);
R ¹ is: C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; halo-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; hydroxy-C _1-6 alkyl; Amino-C _1-6 alkyl; C _1-6 alkylsulfonyl-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted one or more times with C _1-6 alkyl; C _3-6 cycloalkyl -C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times with C _1-6 alkyl); a heterocyclyl optionally substituted one or more times with R ⁷ ; or R ⁷ is heterocyclyl-C _1-6 alkyl optionally substituted one or more times;
Or X and R ¹ are both C _1-6 alkyl; C _1-6 alkoxy-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ ; or C _3-6 Forming a cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times by R ⁶ );
Or R ¹ and R ^a together with the atoms to which they are attached may form a 3-6 membered heterocycle that may be substituted one or more times with R ⁷ ;
R ² is: _{C 1-6} alkyl; halo; _{C 1-6} alkoxy; cyano; _{C 2-6} alkynyl; _{C 2-6} alkenyl; halo -C _1-6 alkyl; halo -C _1-6 alkoxy; ^{R 6} C _3-6 cycloalkyl optionally substituted one or more times by: C _3-6 cycloalkyl-C _1-6 alkyl (wherein the C _3-6 cycloalkyl moiety is substituted one or more times by R ⁶ -OR ^b (R ^b is C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ , or C _3-6 cycloalkyl-C _1-6 alkyl) (C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ); or —C (O) —R ^c (R ^c is C _1-6 alkyl, C _1-6 alkoxy, Amino, or heterocyclyl optionally substituted one or more times by R ⁷ );
R ³ is: hydrogen; C _1-6 alkyl; halo-C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; hydroxy-C _1-6 alkyl; C _1-6 alkoxy-C _1-6 Alkyl; cyano-C _1-6 alkyl; C _1-6 alkylsulfonyl; C _1-6 alkylsulfonyl C _1-6 alkyl; amino-C _1-6 alkyl; _optionally substituted one or more times by R ⁶ C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl (the C _3-6 cycloalkyl moiety may be substituted one or more times by R ⁶ ); C _3-6 cycloalkyl- Sulfonyl (C _3-6 cycloalkyl moiety may be substituted one or more times with R ⁶ ); Heterocyclyl optionally substituted one or more times with R ⁷ ; Heterocyclyl-C _1-6 alkyl (heterocyclyl moiety) one or more in R ⁷ is May be substituted); with R ⁸ may be substituted one or more times aryl; aryl -C _1-6 alkyl (the aryl moiety may be substituted one or more times by R ^8); R Heteroaryl optionally substituted one or more times by ⁸ ; heteroaryl-C _1-6 alkyl (the heteroaryl moiety may be substituted one or more times by R ⁸ ); or —Y—C (O ) -R ^d ;
Y is C _2-6 alkylene or a bond;
R ^d is C _1-6 alkyl, C _1-6 alkoxy, amino, C _1-6 alkyl-amino, di-C _1-6 alkyl-amino, halo-C _1-6 alkyl-amino, di-halo-C _1-6 alkyl-amino, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, hydroxy, C _1-6 alkoxy-C _1-6 alkyl, cyano-C _1-6 alkyl, C _1-6 alkyl Sulfonyl C _1-6 alkyl, amino-C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ , C _3-6 cycloalkyl-C _1-6 alkyl (C _{3 The -6} cycloalkyl moiety may be substituted one or more times by R ⁶ ), a heterocyclyl optionally substituted one or more times by R ⁷ , or a heterocyclyl-C _1-6 alkyl (in the heterocyclyl moiety R ⁷⁾ . (It may be substituted one or more times) Yes;
R ⁴ is: hydrogen; C _1-6 alkyl; halo; cyano; halo-C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; C _1-6 alkoxy; C _1-6 alkoxy-C _{1 -6} alkyl; hydroxy-C _1-6 alkyl; C _3-6 cycloalkyl optionally substituted one or more times with R ⁶ ; C _3-6 cycloalkyl-C _1-6 alkyl (C _3-6 cyclo The alkyl moiety may be substituted one or more times with R ⁶ ); or —Y—C (O) —R ^d ;
R ⁵ is: hydrogen; or C _1-6 alkyl;
Each R ⁶ is independently: C _1-6 alkyl; halo-C _1-6 alkyl; C _1-6 alkoxy; oxo; cyano; halo; or Y—C (O) —R ^d ;
Each R ⁷ is independently: C _1-6 alkyl; halo-C _1-6 alkyl; halo; oxo; C _1-6 alkoxy; C _1-6 alkylsulfonyl; C _1-6 alkoxy-C _1-6 alkyl Cyano; —YC (O) —R ^d ; heterocyclyl; heterocyclyl-C _1-6 alkyl; C _3-6 cycloalkyl; C _3-6 cycloalkyl-C _1-6 alkyl; or C _3-6 cyclo; And each R ⁸ is independently: oxo; C _1-6 alkyl; halo-C _1-6 alkyl; halo; C _1-6 alkyl-sulfonyl; C _1-6 alkoxy; C _1-6 alkoxy -C _1-6 alkyl; cyano; Hetoeryclyl; heterocyclyl -C _1-6 ^{alkyl; -Y-C (O) -R} d; C 3-6 cycloalkyl, _{C 3-6} cycloalkyl -C _1-6 alkyl , or _{C 3-6} cycloalkyl - scan It is a Honiru).

A method of identifying a subject suffering from Parkinson's disease or a subject at risk of developing Parkinson's disease, comprising:
Obtaining or obtaining an LRRK2 containing sample from a subject;
Measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in a subject sample; and the amount or level of S1292 autophosphorylation in a subject sample to determine the amount or level of S1292 autophosphorylation in one or more control samples Comparing to an amount or level.

A method of determining a subject responsive to treatment with an LRRK2 modulator comprising:
Obtaining or obtaining a first LRRK2 containing sample from a subject;
Administering an LRRK2 modulator to the subject;
Obtaining or obtaining a second LRRK2 containing sample from the subject after administering the LRRK2 modulator to the subject;
Measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the first subject sample;
Measuring, monitoring or otherwise detecting the amount or level of S1292 autophosphorylation in the second subject sample; and the amount or level of S1292 autophosphorylation in the first subject sample Comparing to the amount or level of phosphorylation.

An assay for screening compounds and compositions for inhibition of LRRK2 activity comprising:
A method comprising exposing LRRK2 or a fragment thereof to a potential inhibitory compound; and detecting the level or amount of phosphorylation associated with S1292 on LRRK2.