Fluorine-18 and carbon-11 labeled radioligands for positron emission tomography (pet) imaging for lrrk2

A LRRK2 PET ligand precursor compounds of formula IV:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is:
• C1-6alkyl;
• halo-C1-6alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• halo-C1-6alkyl;
• C1-6alkoxy-C1-6alkyl;
• hydroxy-C1-6alkyl;
• amino-C1-6alkyl;
• C1-6alkylsulfonyl-C1-6alkyl;
• C3-6cycloalkyl optionally substituted with C1-6alkyl or halo;
• C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl portion is optionally substituted with C1-6alkyl;
• tetrahydropyranyl;
• tetrahydrofuranyl;
• tetrahydro furanyl-C1-6alkyl;
• oxetanyl;
• or oxetan-C1-6alkyl;
• R2 is:
• halo;
• C1-6alkoxy;
• cyano;
• C2-6alkynyl;
• C2-6alkenyl;
• 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;
• R5 is:
• hydrogen;
• or C1-6alkyl;
• R6 is:
• hydrogen;
• C1-6alkyl;
• C1-6alkoxy-C1-6alkyl;
• hydroxy-C1-6alkyl;
• amino-C1-6alkyl;
• C3-6cycloalkyl;
• C3-6cycloalkyl-C1-6alkyl;
• heterocyclyl;
• or heterocyclyl-C1-6alkyl;
• wherein the C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, heterocyclyl and heterocyclyl-C1-6alkyl each may be optionally substituted with one, two, three or four groups independently selected from:
• C1-6alkyl;
• halo-C1-6alkyl;
• C1-6alkoxy;
• halo-C1-6alkoxy;
• hydroxy;
• hydroxy-C1-6alkyl;
• halo;
• nitrile;
• C1-6alkyl-carbonyl;
• C1-6alkyl-sulfonyl;
• C3-6cycloalkyl;
• C3-6cycloalkyl-C1-6alkyl;
• C3-6cycloalkyl-carbonyl;
• amino;
• or heterocyclyl;
• or two of the groups together with the atoms to which they are attached may form a five or six-membered ring;
• or R5 and R6 together with the nitrogen atom to which they are attached form a three- to seven-membered ring that optionally includes an additional heteroatom selected from O, N and S(O)n, and which is optionally substituted with one, two, three or four groups independently selected from:
• C1-6alkyl;
• halo-C1-6alkyl;
• C1-6alkoxy;
• halo-C1-6alkoxy;
• hydroxy;
• C1-6alkoxy-C1-6alkyl;
• hydroxy-C1-6alkyl;
• halo, nitrile;
• C1-6alkyl-carbonyl;
• C1-6alkyl-sulfonyl;
• C3-6cycloalkyl;
• C3-6cycloalkyl-C1-6alkyl;
• C3-6cycloalkyl-carbonyl;
• amino;
• or heterocyclyl;
• or two of the groups together with the atoms to which they are attached may form a five or six-membered ring;
• and
• R7 is:
• halo;
• C1-6alkyl;
• C1-6alkoxy;
• halo-C1-6alkyl;
• or halo-C1-6alkoxy.

A method of preparing a LRRK2 PET ligand of formula h:

• the method comprising:
• reacting a compound of formula f
• with a radiolabeled alkylating agent g
• R*-L
• to provide the radiolabeled aminopyrimidine compound of formula h:
• wherein:
• R1 is:
• C1-6alkyl;
• halo-C1-6alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• halo-C1-6alkyl;
• C1-6alkoxy-C1-6alkyl;
• hydroxy-C1-6alkyl;
• amino-C1-6alkyl;
• C1-6alkylsulfonyl-C1-6alkyl;
• C3-6cycloalkyl optionally substituted with C1-6alkyl or halo;
• C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl portion is optionally substituted with C1-6alkyl;
• tetrahydropyranyl;
• tetrahydrofuranyl;
• tetrahydro furanyl-C1-6alkyl;
• oxetanyl;
• or oxetan-C1-6alkyl;
• R2 is:
• halo;
• C1-6alkoxy;
• cyano;
• C2-6alkynyl;
• C2-6alkenyl;
• 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;
• R5 is:
• hydrogen;
• or C1-6alkyl;
• R6 is:
• hydrogen;
• C1-6alkyl;
• C1-6alkoxy-C1-6alkyl;
• hydroxy-C1-6alkyl;
• amino-C1-6alkyl;
• C3-6cycloalkyl;
• C3-6cycloalkyl-C1-6alkyl;
• heterocyclyl;
• or heterocyclyl-C1-6alkyl;
• wherein the C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, heterocyclyl and heterocyclyl-C1-6alkyl each may be optionally substituted with one, two, three or four groups independently selected from:
• C1-6alkyl;
• halo-C1-6alkyl;
• C1-6alkoxy;
• halo-C1-6alkoxy;
• hydroxy;
• hydroxy-C1-6alkyl;
• halo;
• nitrile;
• C1-6alkyl-carbonyl;
• C1-6alkyl-sulfonyl;
• C3-6cycloalkyl;
• C3-6cycloalkyl-C1-6alkyl;
• C3-6cycloalkyl-carbonyl;
• amino;
• or heterocyclyl;
• or two of the groups together with the atoms to which they are attached may form a five or six-membered ring;
• or R5 and R6 together with the nitrogen atom to which they are attached form a three- to seven-membered ring that optionally includes an additional heteroatom selected from O, N and S(O)n, and which is optionally substituted with one, two, three or four groups independently selected from:
• C1-6alkyl;
• halo-C1-6alkyl;
• C1-6alkoxy;
• halo-C1-6alkoxy;
• hydroxy;
• C1-6alkoxy-C1-6alkyl;
• hydroxy-C1-6alkyl;
• halo, nitrile;
• C1-6alkyl-carbonyl;
• C1-6alkyl-sulfonyl;
• C3-6cycloalkyl;
• C3-6cycloalkyl-C1-6alkyl;
• C3-6cycloalkyl-carbonyl;
• amino;
• or heterocyclyl;
• or two of the groups together with the atoms to which they are attached may form a five or six-membered ring;
• R7 is:
• halo;
• C1-6alkyl;
• C1-6alkoxy;
• halo-C1-6alkyl;
• or halo-C1-6alkoxy;
• R* is C1-6alkyl with a F18 or 11C atom thereon;
• and
• L is a leaving group.