Phenoxy-substituted pyrimidines as opioid receptor modulators

A method for treating mild to severe pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I

• wherein
• R1 is selected from the group consisting of phenyl, pyridinyl, and thiazolyl;
• wherein R1 is optionally substituted with one to two substituents independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, hydroxy, fluoro, chloro, bromo, and cyano;
• in addition, R1 is optionally substituted with amino, C1-4alkylamino, di(C1-4alkyl)amino, aminocarbonyl, C1-4alkylaminocarbonyl, or di(C1-4alkyl)aminocarbonyl;
• Y is O, S, NH, vinyl, ethynyl or S(O);
• R2 is a substituent selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluoro, chloro, bromo, and hydroxy;
• Ra is hydrogen or methyl;
• R3 is selected from the group consisting of pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridin-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl, morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-amino-propyl, 8-aza-bicyclo [3.2.1]octanyl, 1-aza-bicyclo[2.2.2]octanyl, guanidinyl-ethyl, 4-(imidazol-1-yl)-phenylmethyl, 2-(methylamino)-ethyl, 2-diethylamino-ethyl, 4-diethylamino-but-2-yl, piperidin-3-yl, piperidin-4-yl, and pyrrolidin-3-yl;
• and wherein piperidin-3-yl is optionally substituted at a carbon atom with phenyl;
• and wherein pyrrolidin-2-yl of pyrrolidin-2-ylmethyl, pyrrolidin-3-yl, piperidin-3-yl, and piperidin-4-yl are optionally substituted at a nitrogen atom with methyl, phenylmethyl, phenethyl, or methylcarbonyl;
• and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.