Phosphoinositide 3-kinase inhibitor compounds and methods of use

A compound selected from Formula Ic and Formula Id:

• and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
• X is O or S;
• R1 is a group of formula:
• R2 is selected from H, F, Cl, Br, I, C6-C20 aryl, C1-C20 heteroaryl, C1-C6 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl;
• R3 is a monocyclic heteroaryl group selected from pyridyl, isoxazolyl, imidazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, furanyl, thienyl, triazolyl, tetrazolyl, where the monocyclic heteroaryl group is optionally substituted with one or more groups selected from F, Cl, Br, I, —CN, —NR10R11, —C(O)R10, —NR10C(O)R11, —N(C(O)R11)2, —NR10C(O)NR10R11, —NR12SO2R10, —NO2, —SR10, —C(═O)OR10, —C(═O)NR10R11, C6-C20 aryl, C1-C12 alkyl and (C1-C12 alkyl)-OR10;
• R4 and R5 form, together with the N atom to which they are attached, a group selected from piperazine, piperidine, pyrrolidine, oxazolidinone, morpholine, thiomorpholine, diazepan and 2,5-diaza-bicyclo[2,2,1]-heptane, which group is optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, CF3, —NO2, oxo, —C(═Y)R10, —C(═Y)OR10, —C(═Y)NR10R11, —(CR14R15)nNR10R11, —(CR14R15)nNR12SO2R10, —(CR14R15)nOR10, —NR10R11, —NR12C(═Y)R10, —NR12C(═Y)OR11, —NR12C(═Y)NR10R11, —NR12SO2R10, ═NR12, OR10, —OC(═Y)R10, —OC(═Y)OR10, —OC(═Y)NR10R11, —OS(O)2(OR10), —OP(═Y)(OR10)(OR11), —OP(OR10)(OR11), SR10, —S(O)R10, —S(O)2—(C1-C6 alkyl)-S(O)2R10, —S(O)2R10, —S(O)2NR10R11, —S(O)(OR10), —S(O)2(OR10), —SC(═Y)R10, —SC(═Y)OR10, —SC(═Y)NR10R11, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, and C1-C20 heteroaryl;
• or one of R4 and R5 is C1-C6 alkyl, —(C1-C6 alkyl)q-(C2-C20) heterocyclyl, or —(C1-C6 alkyl)q-OR10 and the other is a piperazine, piperidine, pyrrolidine, sulfonylpyran, —(C1-C6 alkyl)-(C2-C20) heterocyclyl group, or —(C1-C6 alkyl)-(C1-C20) heteroaryl group, wherein said piperazine, piperidine, pyrrolidine, sulfonylpyran, heterocyclyl, or heteroaryl group is unsubstituted or substituted by C1-C6 alkyl, —(C1-C6 alkyl)q-OR10 or —S(O)2R10;
• R10, R11 and R12 are independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, or C1-C20 heteroaryl,
• or R10 and R11 together with the nitrogen to which they are attached optionally form a C3-C20 heterocyclic ring optionally containing one or more additional ring atoms selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, (CH2)nOR10, NR10R11, CF3, F, Cl, Br, I, SO2R10, C(═O)R10, NR12C(═Y)R11, C(═Y)NR10R11, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl and C1-C20 heteroaryl;
• R14 and R15 are independently selected from H, C1-C12 alkyl, or —(CH2)n-aryl,
• or R14 and R15 together with the atoms to which they are attached form a saturated or partially unsaturated C3-C12 carbocyclic ring,
• R30 is H or C1-C6 alkyl;
• mor is a morpholine group optionally substituted with one or more groups selected from F, Cl, Br, I, —C(C1-C6 alkyl)2NR10R11, —(CR14R15)nNR10R11, —(CR14R15)nNR12C(═Y)R10, (CR14R15)nNR12S(O)2R10, —CH(OR10)R10, —(CR14R15)nOR10, —(CR14R15)nS(O)2R10, (CR14R15)nS(O)2NR10R11, —C(═Y)R10, —C(═Y)OR10, —C(═Y)NR10R11, —C(═Y)NR12OR10, —C(═O)NR12S(O)2R10, —C(═O)NR12(CR14R15)mNR10R11, —NO2, —NR10R11, —NR12C(═Y)R11, —NR12C(═Y)OR11, —NR12C(═Y)NR10R11, —NR12S(O)2R10, —NR12SO2NR10R11, —S(O)2R10, —S(O)2NR10R11, —SC(═Y)R10, —SC(═Y)OR10, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, or C1-C20 heteroaryl;
• where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, CF3, —NO2, oxo, —C(═Y)R10, —C(═Y)OR10, —C(═Y)NR10R11, —(CR14R15)nNR10R11, —(CR14R15)nNR12SO2R10, —(CR14R15)nOR10, —NR10R11, —NR12C(═Y)R10, —NR12C(═Y)OR11, —NR12C(═Y)NR10R11, —NR12SO2R10, ═NR12, OR10, —OC(═Y)R10, —OC(═Y)OR10, —OC(═Y)NR10R11, —OS(O)2(OR10), —OP(═Y)(OR10)(OR11), —OP(OR10)(OR11), SR10, —S(O)R10, —S(O)2R10, —S(O)2NR10R11, —S(O)(OR10), —S(O)2(OR10), —SC(═Y)R10, —SC(═Y)OR10, —SC(═Y)NR10R11, optionally substituted C1-C12 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C12 carbocyclyl, optionally substituted C2-C20 heterocyclyl, optionally substituted C6-C20 aryl, and optionally substituted C1-C20 heteroaryl;
• Y is O, S, or NR12;
• each q is independently 0 or 1;
• m is 0 or 1;
• and
• n is 1, 2, 3, 4, 5, or 6;
• with the provisos that:
• (i) when in Formula (Ic) mor is unsubstituted morpholino, X is S, R1 is a (4-methylsulfonylpiperazin-1-yl)methyl group and R2 is H, then R3 is not a group selected from imidazolyl which is unsubstituted or substituted with one CH3 group, pyrimidinyl which is unsubstituted and pyridinyl which is unsubstituted or substituted with one F group;
• (ii) when in Formula (Ic) mor is unsubstituted morpholino, X is S, R1 is a (4-methylpiperazin-1-yl)methyl group and R2 is H, then R3 is not pyridinyl which is substituted by one OH group;
• and
• (iii) when in Formula (Id) mor is unsubstituted morpholino, X is S, R1 is a (4-methylsulfonylpiperazin-1-yl)methyl group and R2 is H, then R3 is not a group selected from pyridinyl which is unsubstituted and pyrimidinyl which is unsubstituted or substituted by one —OCH3 or —N(CH3)2 group.