US 2008/0076758 A1 · Pharmaceutical compounds

Abstract

Compounds of Formulae Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia and Ib for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

A compound which is a fused pyrimidine of formula (Ia) or (Ib):

wherein
X is O or S;
R1 is a group of formula:
R2 is H, halo or C1-C6 alkyl
R4 and R5 form, together with the N atom to which they are attached, a group selected from piperazine, piperidine, pyrrolidine, oxazolidinone, diazepan and 2,5-diaza-bicyclo[2,2,1]-heptane, which group is unsubstituted or substituted by -[(alk)q-NR]r—S(O)2-(alk)q-Z or —C(O)-(alk)q-S(O)2Z wherein Z is R10 or —NR11R12, or by unsubstituted C1-C6 alkyl hydroxyl-C1-C6 alkyl, oxo (═O), -(alk)q-OR, —C(O)—C(R′)2—N(R)2, —C(R)2—C(O)—N(R)2, —C(O)—(NR)q-(alk)q-OR, —C(O)-cyclyl, —C(O)R, —C(O)OR, —C(O)-Tet or —NR13R14;
or one of R4 and R5 is C1-C6 alkyl, -(alk)q-Heterocyclyl or -(alk)q-OR and the other is a piperazine, piperidine, pyrrolidine, sulphonylpyran or -(alk)q-Heterocyclyl group, wherein said piperazine, piperidine, pyrrolidine, sulphonylpyran or Heterocyclyl is unsubstituted or substituted by C1-C6 alkyl, -(alk)q-OR or —S(O)2R10;
R is H or C1-C6 alkyl which is unsubstituted;
each R′ is, independently, H or C1-C6 alkyl which is unsubstituted, or the two groups R′ form, together with the C atom to which they are attached, a cyclyl group;
R10 is H, cyclyl, C1-C6 alkyl which is unsubstituted or CF3;
R11 and R12 are each independently selected from H, C1-C6 alkyl which is unsubstituted and -(alk)q-OR, or R11 and R12 together form, with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group containing 0 or 1 additional heteroatoms selected from O, N and S;
R13 and R14 are each independently selected from C1-C6 alkyl, —S(O)2R10, and -(alk)q-OR;
Tet is a tetrahydrofuranyl or tetrahydropyranyl group, which group is unsubstituted or substituted;
Heterocyclyl is a 5- or 6-membered saturated N-containing heterocyclic group containing 0 or 1 additional heteroatoms selected from O, N and S;
Cyclyl is a C3-C6 cycloalkyl group;
each q is independently 0 or 1;
r is 0 or 1;
alk is C1-C6 alkylene;
and
R3 is selected from:
(a) a group of the following formula:
wherein B is a phenyl ring which is unsubstituted or substituted, and Z is selected from H, —OR, —SR, CH2OR, —CO2R, CF2OH, CH(CF3)OH, C(CF3)2OH, —(CH2)qOR, —(CH2)qNR2, —C(O)N(R)2, —NR2, —NRC(O)R, —S(O)mN(R)2, —OC(O)R, OC(O)N(R)2, —NRS(O)mR, —NRC(O)N(R)2, CN, halogen and —NO2, wherein each R is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl and a 5- to 12-membered aryl or heteroaryl group, the group being unsubstituted or substituted, m is 1 or 2 and q is 0, 1 or 2;
(b) a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from O and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted;
and
(c) a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined above;
or a pharmaceutically acceptable salt thereof;
with the provisos that:
(i) when X in formula (Ia) is S, then R3 is other than an indole or 3-hydroxyphenyl group;
(ii) when X in formula (Ib) is S, then R3 is other than an indole group;
(iii) in formula (Ia) only, when X is S and R2 is H and R3 is indazol-4-yl, then R4 and R5 do not form:
(i) piperazine which is unsubstituted or substituted by a group selected from methyl, —S(O)2Me, —S(O)2 NMe2, -alk-OH, -alk-OMe, —S(O)2-alk-NMe2, and —S(O)2-alk-morpholino;
or (ii) piperidine which is substituted by a group selected from —S(O)2 Me, —C(O)—NR-(alk)q-OR, —NMe-S(O)2-Me, methyl, piperidine and —NR13R14 wherein one of R13 and R14 is -(alk)q-OR.

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Pharmaceutical compounds

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Abstract

Claims33