Aminopyrimidine derivatives as LRRK2 modulators

摘要

Compounds of the formula I:;
or pharmaceutically acceptable salts thereof,

wherein A, X, R1, R2, R3 and R4 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease.

主权项

1. A compound of formula I: or pharmaceutically acceptable salts thereof, wherein:
A is a five- or six-membered saturated or unsaturated ring that includes one or two heteroatoms selected from O, N and S, which is substituted once with R5, and which is optionally substituted one, two or three times with R6;X is: —NRa—; —O—; or —S(O)r— wherein r is from 0 to 2 and Ra is hydrogen or C1-6alkyl;R1 is: C1-6alkyl; C1-6alkenyl; C1-6alkynyl; halo-C1-6alkyl; C1-6alkoxy-C1-6alkyl; hydroxy-C1-6alkyl; amino-C1-6alkyl; C1-6alkylsulfonyl-C1-6alkyl; C3-6cycloalkyl optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl portion is optionally substituted with C1-6alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C1-6alkyl; oxetanyl; or oxetan-C1-6alkyl;or R1 and Ra together with the atoms to which they are attached may form a three to six membered ring that may optionally include an additional heteroatom selected from O, N and S, and which is substituted with oxo, halo or C1-6alkyl;R2 is: halo; C1-6alkoxy; cyano; C1-6alkynyl; C1-6alkenyl; halo-C1-6alkyl; halo-C1-6alkoxy; C3-6cycloalkyl wherein the C3-6cycloalkyl portion is optionally substituted with C1-6alkyl; C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl portion is optionally substituted with C1-6alkyl; tetrahydrofuranyl; tetrahydrofuranyl-C1-6alkyl; acetyl; oxetanyl; or oxetan-C1-6alkyl;one of R3 and R4 is: halo; or C1-6alkoxy, and the other is hydrogen;R5 is; oxo; C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkyl-C1-6alkyl; or —C(O)—NRbRc wherein Rb and Rc each independently is hydrogen or —C1-6alkyl, or Rb and Rc together with the atoms to which they are attached may form a heterocyclyl group that optionally includes an additional heteroatom selected from 0, N and S and which is optionally substituted one or more times with R6; andeach R6 is independently: C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkyl-C1-6alkyl; halo; halo-C1-6alkyl; hydroxy-C1-6alkyl; C1-6alkoxy-C1-6alkyl; heterocyclyl; oxo; or —C(O)—NRbRc.