Myeloperoxidase imaging agents

A method of diagnosing a disease or disorder associated with abnormal myeloperoxidase activity in a subject, comprising:

• i) administering to the subject a compound of Formula I:
• or a pharmaceutically acceptable salt thereof, wherein:
• L1 is selected from the group consisting of a bond, —C(O)—, —C(O)O—, —C(O) NRa1—, —C(O)(C1-6 alkylene)-, and —C(O)(C1-6 alkyleneoxy)-;
• R1 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from OH, halo, C1-6 alkoxy, and C1-6 haloalkyl;
• L2 is selected from the group consisting of —(C1-6 alkylene)-(C3-10 cycloalkylene)-, —(C1-6 alkylene)-(C6-10 arylene)-, —(C1-6 alkylene)-(4-10 membered heterocycloalkylene)-, —(C1-6 alkylene)-(5-10 membered heteroarylene)-, —C(O)—, —C(O)O—, —C(O) NRa2—, —C(O)(C1-6 alkylene)-, and —C(O)(C1-6 alkyleneoxy)-;
• R2 is selected from the group consisting of C1-6 alkoxy, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each C1-6 alkoxy, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from OH, halo, C1-6 alkoxy, and C1-6 haloalkyl;
• L3 is selected from the group consisting of a bond, —C(O)—, —C(O)O—, —C(O)(C1-6 alkylene)-, —C(O)(C1-6 alkyleneoxy)-, —C(O)N(Ra3) (C1-6 alkylene)-, —C(O)N(Ra3) (C1-6 alkylene)-di(C1-6 alkyl) amino, and —C(O)N(Ra3) (C1-6 alkyleneoxy)-;
• R3 is selected from the group consisting of C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and —C(O)N(Ra3) (C1-6 haloalkoxy), wherein each C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from OH, halo, and C1-6 haloalkyl;
• R4 is H;
• and
• each Ra1, Ra2, and Ra3 is independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
• ii) waiting a time sufficient to allow the compound to accumulate at a cell or tissue site associated with the disease;
• and
• iii) imaging the cell or tissue with an imaging technique.

A method of detecting myeloperoxidase activity in a subject, the method comprising:

• i) administering to the subject a compound of Formula I:
• or a pharmaceutically acceptable salt thereof, wherein:
• L1 is selected from the group consisting of a bond, —C(O)—, —C(O)O—, —C(O) NRa1—, —C(O)(C1-6 alkylene)-, and —C(O)(C1-6 alkyleneoxy)-;
• R1 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from OH, halo, C1-6 alkoxy, and C1-6 haloalkyl;
• L2 is selected from the group consisting of —(C1-6 alkylene)-(C3-10 cycloalkylene)-, —(C1-6 alkylene)-(C6-10 arylene)-, —(C1-6 alkylene)-(4-10 membered heterocycloalkylene)-, —(C1-6 alkylene)-(5-10 membered heteroarylene)-, —C(O)—, —C(O)O—, —C(O) NRa2—, —C(O)(C1-6 alkylene)-, and —C(O)(C1-6 alkyleneoxy)-;
• R2 is selected from the group consisting of C1-6 alkoxy, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each C1-6 alkoxy, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from OH, halo, C1-6 alkoxy, and C1-6 haloalkyl;
• L3 is selected from the group consisting of a bond, —C(O)—, —C(O)O—, —C(O)(C1-6 alkylene)-, —C(O)(C1-6 alkyleneoxy)-, —C(O)N(Ra3) (C1-6 alkylene)-, —C(O)N(Ra3) (C1-6 alkylene)-di(C1-6 alkyl) amino, and —C(O)N(Ra3) (C1-6 alkyleneoxy)-;
• R3 is selected from the group consisting of C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and —C(O)N(Ra3) (C1-6 haloalkoxy), wherein each C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from OH, halo, and C1-6 haloalkyl;
• R4 is H;
• and
• each Ra1, Ra2, and Ra3 is independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
• ii) imaging the subject with an imaging technique.

A method of monitoring treatment of a disease or disorder associated with abnormal myeloperoxidase activity in a subject, the method comprising:

• i) administering to the subject a compound of Formula I:
• or a pharmaceutically acceptable salt thereof, wherein:
• L1 is selected from the group consisting of a bond, —C(O)—, —C(O)O—, —C(O) NRa1—, —C(O)(C1-6 alkylene)-, and —C(O)(C1-6 alkyleneoxy)-;
• R1 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from OH, halo, C1-6 alkoxy, and C1-6 haloalkyl;
• L2 is selected from the group consisting of —(C1-6 alkylene)-(C3-10 cycloalkylene)-, —(C1-6 alkylene)-(C6-10 arylene)-, —(C1-6 alkylene)-(4-10 membered heterocycloalkylene)-, —(C1-6 alkylene)-(5-10 membered heteroarylene)-, —C(O)—, —C(O)O—, —C(O) NRa2—, —C(O)(C1-6 alkylene)-, and —C(O)(C1-6 alkyleneoxy)-;
• R2 is selected from the group consisting of C1-6 alkoxy, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein each C1-6 alkoxy, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from OH, halo, C1-6 alkoxy, and C1-6 haloalkyl;
• L3 is selected from the group consisting of a bond, —C(O)—, —C(O)O—, —C(O)(C1-6 alkylene)-, —C(O)(C1-6 alkyleneoxy)-, —C(O)N(Ra3) (C1-6 alkylene)-, —C(O)N(Ra3) (C1-6 alkylene)-di(C1-6 alkyl) amino, and —C(O)N(Ra3) (C1-6 alkyleneoxy)-;
• R3 is selected from the group consisting of C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and —C(O)N(Ra3) (C1-6 haloalkoxy), wherein each C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, or 4 substituents independently selected from OH, halo, and C1-6 haloalkyl;
• R4 is H;
• and
• each Ra1, Ra2, and Ra3 is independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
• ii) imaging the subject with an imaging technique;
• iii) administering to the subject a therapeutically effective amount of a therapeutic compound to treat the disease or disorder;
• iv) imaging the cell or tissue in the subject with an imaging technique;
• and
• v) comparing the image of step i) and the image of step iv).