Pyrrole-2, 5dione derivatives and their used as GSK-3 inhibitors

A compound of Formula I

• where:
• Ar is benzofur-7-yl optionally substituted in the phenyl ring with R8 and R9, or 2,3-dihydrobenzofur-7-yl optionally substituted in the phenyl ring with R8 and R9 and in the dihydrofuryl ring with C1-C4 alkyl;
• G is independently at each occurrence hydroxy, NR11R12, or piperidin-4-yl;
• R2 is hydrogen, C1-C4 alkyl, —(CH2)m-G, tetrahydropyran-4-yl, 4-(NR4R5)cyclo-hex-1-yl, 4-hydroxycyclohex-1-yl, 2-azabicyclo[3.2.1]oct-5-yl, the moiety
• the moiety
• cyclohexan-1-on-4-yl, pyridin-4-yl;
• and R3 is hydrogen, halo, C1-C4 alkyl, or cyclopropyl;
• R4 hydrogen and R5 is hydrogen or C1-C4 alkyl, or R4 and R5 taken together with nitrogen to which they are attached form a pyrrolidine ring;
• R6 is hydrogen, benzyl, —CO2(C1-C4 alkyl), —C(O)—(C1-C4 alkyl)n-NR14R15, —C(O)tetrahydropyran-4-yl, —C(O)morpholin-4-yl, —CH2-tetrahydropyran-4-yl, an amino acid residue, —C(O)pyridin-2-yl, —C(O)pyridin-3-yl, —C(O)pyridin-4-yl, —C(O)pyrimidin-5-yl, C1-C4 alkyl, —C(O)pyrazin-2-yl, or —CO2—(C1-C4 alkyl)-(C1-C4 alkoxy);
• R8 is —NHCO2(C1-C4 alkyl), —NHSO2(C1-C4 alkyl), halo, amino, —O—(CH2)m-G, —NHC(O)(C1-C4 alkyl), C1-C4 alkoxy, hydroxy, —O—R10, C1-C4 alkyl, C1-C4 alkylthio, or —(CH2)m-G;
• R9 is halo;
• R10 is piperidin-3-yl, piperidin-4-yl, or pyrrolidin-3-yl;
• R11 and R12 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, cyclopropylmethyl, benzyl, or, taken together with the nitrogen to which they are attached form a piperidine, 4-hydroxypiperidine, 4-(C1-C4 alkyl)piperidine, N—(R13)-piperazine, or morpholine ring;
• R13 is hydrogen, C(O)—(C1-C4 alkyl), or C1-C4 alkyl;
• R14 and R15 are independently hydrogen or C1-C4 alkyl;
• R16 is independently at each occurrence hydrogen, geminal dimethyl, geminal diethyl, a spiro-fused C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with hydroxy;
• and R17 represents hydrogen, C1-C4 alkyl, or geminal dimethyl, provided that the total number of carbon atoms between R16 and R17 does not exceed five;
• m is independently at each occurrence 2, 3, 4, or 5;
• n is independently at each occurrence 0 or 1;
• or a pharmaceutically acceptable salt thereof, subject to the following provisos:
• i) when G is hydroxy, no more than two of R1a, R2, or R8 may be —(CH2)m-G, or —O—(CH2)m-G;
• and
• ii) when G is NR11R12, no more than one of R1a, R2, or R8 may be —(CH2)m-G, or —O—(CH2)m-G.