Treatment of chronic headaches

A method for the treatment of migraine, trigeminal autonomic cephalalgias, medication overuse headache, or post-traumatic headache, the method comprising:

• administering a selective agonist for the human adenosine A3 receptor (A3 AR) subtype to a patient in need thereof, wherein the selective agonist for the human adenosine A3 receptor subtype is a compound of Formula (I):
• wherein:
• X is selected from NHR1, CH3, and CH═C(Ra)(Rb) wherein Ra and Rb are independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C6-C14 aryl;
• Y is N or CH;
• R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C3-C8 cycloalkyl, C6-C14 aryl C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 dicycloalkyl C1-C6 alkyl, C7-C12 bicycloalkyl, C7-C12 bicycloalkyl C1-C6 alkyl, C7-C14 tricycloalkyl C1-C6 alkyl, C6-C14 aryl, C6-C14 aryl C1-C6 alkyl, C6-C14 diaryl C1-C6 alkyl, C6-C14 aryl C1-C6 alkoxy, heterocyclyl C1-C6 alkyl, heterocyclyl, 4-[[[4-[[[(2-amino C1-C6 alkyl) amino]-carbonyl]-C1-C6 alkyl]anilino]carbonyl]C1-C6 alkyl]C6-C14 aryl, and C6-C14 aryl C3-C8 cycloalkyl, wherein the aryl or heterocyclyl portion of R1 is optionally substituted with one or more substituents selected from halo, amino, hydroxyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C14 aryloxy, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, carboxy C1-C6 alkyl, carboxy C2-C6 alkenyl, carboxy C2-C6 alkynyl, aminocarbonyl C1-C6 alkyl, aminocarbonyl C2-C6 alkenyl, aminocarbonyl C2-C6 alkynyl, and any combination thereof;
• and the alkyl or cycloalkyl portion of R1 is optionally substituted with one or more substituents selected from halo, amino, alkyl, alkoxy, aryloxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aminocarbonylalkoxy, and arylalkoxy, and any combination thereof;
• R2 is selected from C6-C12 aryl, C3-C8 cycloalkyl, heteroaryl, and metallocenyl, wherein the aryl group is substituted with one or more substituents selected from trifluoromethyl, hydroxyalkyl, alkoxy, sulfonyloxy, carboxyalkyl, sulfonyloxyalkyl, arylcarbonyl, and any combination thereof, wherein the heteroaryl group is optionally substituted with one or more substituents selected from halo, trifluoromethyl, amino, alkyl, hydroxyalkyl, aryl, benzo, alkoxy, hydroxyl, carboxyl, sulfonyloxy, carboxyalkyl, sulfonyloxyalkyl, alkylcarbonyl, arylcarbonyl, and any combination thereof;
• R3 and R4 are independently selected from hydrogen, hydroxyl, amino, mercapto, ureido, C1-C6 alkyl carbonylamino, hydroxy C1-C6 alkyl, and hydrazinyl;
• R5 is selected from C1-C3 alkyl aminocarbonyl, di(C1-C3 alkyl) aminocarbonyl, C1-C3 alkylthio C1-C3 alkyl, halo C1-C3 alkyl, hydrazinyl, amino C1-C3 alkyl, hydroxy C1-C3 alkyl, C3-C6 cycloalkylamino, hydroxylamino, and C2-C3 alkenyl;
• and
• R6 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, and C1-C6 aminoalkyl;
• or a pharmaceutically acceptable salt thereof.