Pyrimidine-based compounds useful as GSK-3 inhibitors

A compound of formula I:

• 258
• or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
• B is an optionally substituted 5-6 membered monocyclic or 8-10 membered bicyclic aromatic ring, wherein said monocyclic or bicyclic ring has 0-4 heteroatoms selected from oxygen, sulfur or nitrogen;
• Q is a C1-4 alkylidene chain, wherein each methylene unit of said Q is substituted by R2 and R2′, and up to two non-adjacent methylene units of said Q are optionally and independently replaced by —SO2 or —C(═O);
• Ring C is selected from a phenyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C optionally has one or two ortho substituents independently selected from —R1, any substitutable carbon position on Ring C is independently substituted by —R5, or two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or —R8;
• R1 is selected from -halo, —CN, —NO2, T-V-R6, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C1-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or —R8, said C1-6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;
• each R2 is independently selected from H, —OH, C1-10 aliphatic;
• (C1-10 aliphatic)-NH-(C1-10 aliphatic);
• —O—(C1-10 aliphatic);
• —NH2, —NH(C1-10 aliphatic), —N(C1-10 aliphatic)2, —C(═O)R, aryl, or heteroaryl, wherein said aliphatic, aryl, or heteroaryl is optionally substituted;
• R is selected from an optionally substituted group selected from C1-10 aliphatic, aryl, aralkyl, heteroaryl, or heteroaralkyl;
• each R2′ is independently selected from H or an optionally substituted C1-10 aliphatic group;
• RX and RY are independently selected from T—R3, or RX and RY are taken together with their intervening atoms to form a fused, partially saturated or aromatic, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by RX and RY is substituted by oxo or T-R3, and any substitutable nitrogen on said ring formed by RX and RY is substituted by R4;
• T is a valence bond or a C1-4 alkylidene chain;
• R3 is selected from —R′, -halo, —OR′, —C(═O)R′, —CO2R′, —COCOR′, —COCH2COR′, —NO2, —CN, —S(O)R′, —S(O)2R′, —SR′, —N(R4)2, —CON(R7)2, —SO2N(R7)2, —OC(═O)R′, —N(R7)COR′, —N(R7)CO2(optionally substituted C1-6aliphatic), —N(R4)N(R4)2, —C═NN(R4)2, —C═N—OR′, —N(R7)CON(R7)2, —N(R7)SO2N(R7)2, —N(R4)SO2R, or —OC(═O)N(R7)2;
• each R′ is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
• each R4 is independently selected from —R7, —COR7, —CO2(C1-6 aliphatic), —CON(R7)2, or —SO2R7, or two R4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;
• each R5 is independently selected from —R′, halo, —OR′, —C(═O)R′, —CO2R′, —COCOR′, —NO2, —CN, —S(O)R′, —SO2R′, —SR′, —N(R4)2, —CON(R4)2, —SO2N(R4)2, —OC(═O)R′, —N(R4)COR′, —N(R4)CO2(optionally substituted C1-6 aliphatic), —N(R4)N(R4)2, —C═NN(R4)2, —C═N—OR′, —N(R4)CON(R4)2, —N(R4)SO2N(R4)2, —N(R4)SO2R′, or —OC(═O)N(R4)2, or R5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;
• V is —O—, —S—, —SO—, —SO2—, —N(R6)SO2—, —SO2N(R6)—, —N(R6)—, —CO—, —CO2—, —N(R6)CO—, —N(R6)C(O)O—, —N(R6)CON(R6)—, —N(R6)SO2N(R6)—, —N(R6)N(R6)—, —C(O)N(R6)—, —OC(O)N(R6)—, —C(R6)2O—, —C(R6)2S—, —C(R6)2SO—, —C(R6)2SO2—, —C(R6)2SO2N(R6)—, —C(R6)2N(R6)—, —C(R6)2N(R6)C(O)—, —C(R6)2N(R6)C(O)O—, —C(R6)═NN(R6)—, —C(R6)═N—O—, —C(R6)2N(R6)N(R6)—, —C(R6)2N(R6)SO2N(R6)—, or —C(R6)2N(R6)CON(R6)—;
• each R6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
• each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
• and
• each R8 is independently selected from an optionally substituted C1-4 aliphatic group, —OR6 , —SR6, —COR6, —SO2R6, —N(R6)2, —N(R6)N(R6)2, —CN, —NO2, —CON(R6)2, or —CO2R6.