Substituted imidazo[1,2-c]quinazolines as A2A antagonists
Disclosed are compounds having the structure of Formula I, or a pharmaceutically acceptable salt of any thereof: wherein: “Z” and R 1 are defined herein, which compounds are believed suitable for use in selectively antagonizing the A2a receptors, for example, those found in high density in the basal ganglia. Such compounds and pharmaceutical formulations are believed to be useful in treatment or management of neurodegenerative diseases, for example, Parkinson's disease, or movement disorders arising from use of certain medications used in the treatment or management of Parkinson's disease.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
Z′ is CH 2 -phenyl, wherein the phenyl is optionally substituted with one or two R 2a substituents;
each R 2a is independently halogen, C 1-5 alkyl, CH 2 -piperazin-1-yl, CH 2 -phenyl, C(O)R 2i , N(R 2c ) 2 , OH, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 1-(acetyl)piperazin-4-yl, morpholin-4-yl, phenyl, pyridinyl, pyrazin-2-yl, pyrimidinyl, benzo[c][1,2,5]oxadiazol-4-yl, or benzo[c][1,2,5]oxadiazol-5-yl;
wherein each C 1-5 alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of F, OH, and morpholin-4-yl;
wherein each pyrrolidin-1-yl and piperidin-1-yl is optionally and independently substituted with one R 2d substituent;
wherein each piperazin-1-yl is optionally and independently substituted with one R 2e substituent;
wherein each phenyl is optionally and independently substituted with one R 2b substituent; and
wherein each pyridinyl is optionally and independently substituted with one R g substituent;
each R 2b is independently OCH 3 or 4-[CH(CH 3 )morpholin-4-yl];
each R 2c is independently H or CH 3 ;
each R 2d is independently morpholin-4-yl;
each R 2e is independently CH 2 C(O)CH 3 , phenyl, pyrimidin-2-yl, or benzo[d]oxazol-2-yl, wherein each phenyl is optionally and independently substituted with one R 2f substituent;
each R 2f is independently OCH 2 CH 2 OCH 3 ;
each R g is independently F, CF 3 , or morpholin-4-yl; and
each R 2i is independently NH—CH 2 CH 2 -morpholin-4-yl, NH—CH 2 CH(morpholin-4-yl)(pyridin-3-yl), NH-(1,1-cyclopropylene)-phenyl, NH-phenyl, NH-pyridinyl, NH-(1-methylbenzo [d]imidazol-2-ye, or 5-(CH 2 -morpholin-4-yl)-1,3,4-oxadiazol-2-yl.
2. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
3. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of claim 2 , or a pharmaceutically acceptable salt thereof.
4. A method for inhibiting adenosine signaling in tumor immunosuppression in a patient, wherein the method comprises administering to the patient in need thereof an effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof.
5. A method for treating a central nervous system disorder in a patient, wherein the method comprises administering to the patient in need thereof an effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof.