US 8,802,670 B2Granted

Pharmaceutical compounds

AssigneesF. Hoffmann-La Roche AG, Genentech, Inc.

InventorsAdrian Folkes, Stephen Shuttleworth, Irina Chuckowree, Sally Oxenford, Nan Chi Wan, Georgette Castanedo, Richard Goldsmith, Janet Gunzner, Tim Heffron, Simon Mathieu, Alan Olivero, Daniel P. Sutherlin, Bing-Yan Zhu

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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.

Claims12

Dependent claims

A compound which is fused pyrimidine of formula (Ib′):

wherein
X is O or S;
Y is N or —CH—;
R2 is H, halo or C1-C6 alkyl;
each R′ is, independently, H, C1-C6 alkyl or hydroxy-C1-C6 alkyl, or two groups R′ on the same carbon atom form an oxo (═O) group;
or when Y is N, two groups R′ on different carbon atoms together form a —CH2— bridgehead;
each R″ is, independently, H or C1-C6 alkyl, or two groups R″ on the same carbon atom form an oxo (═O) group;
Z is R10 or -(alk)q-NR11R12;
R10 is H, a C3-C6 cycloalkyl group, 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;
q is 0 or 1;
r is 0 or 1;
alk is C1-C6 alkylene;
and
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 bicyclic and which is unsubstituted or substituted;
and
(c) 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.

18 more elements

A compound which is a fused pyrimidine of formula (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 bicyclic and which is unsubstituted or substituted;
and
(c) 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 proviso that:
(i) when X in formula (Ib) is S, then R3 is other than an indole group.

24 more elements

A compound selected from:

2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine;
(3-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)phenyl)methanol;
2-(1H-indazol-4-yl)-6-((4-N,N-dimethylaminosulfonylpiperidin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-methylsulfonylpiperidin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine;
4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-2-yl]-isoquinoline;
3-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-2-yl]-quinoline;
2-(1H-Indazol-4-yl)-6-((S)-4-methanesulfonyl-3-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine;
2-(1H-Indazol-4-yl)-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine;
2-(1H-Indazol-4-yl)-6-((R)-4-methanesulfonyl-3-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine;
2-(1H-Indazol-4-yl)-6-((2S,6R)-4-methanesulfonyl-2,6-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine;
2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl]-methyl-(1-methyl-piperidin-4-yl)-amine;
2-{4-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl]-piperazin-1-yl}-N,N-dimethyl-acetamide;
2-{4-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl]-piperazin-1-yl}-N-methyl-isobutyramide;
2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-5-methyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine;
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one;
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxy-2-methylpropan-1-one;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methoxyethanone;
(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-amino-2-methylpropan-1-one;
(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-aminocyclopropyl)methanone;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-aminoethanone;
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-aminopropan-1-one;
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-aminopropan-1-one;
and
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(methylsulfonyl)ethanone;
6-((4-methylsulfonylpiperazin)1-yl)methyl)-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin)5-yl)thieno[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-[((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinofuro[2,3-d]pyrimidine;
6-((4-isopropylsulfonylpiperazin-1-yl)methyl)-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3-d]pyrimidine;
6-(6-((4-methylsulfonylpiperazin)1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-3H-imidazo[4,5-b]pyridine;
(S)-2-hydroxy-1-(4-((4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propan-1-one;
(S)-2-hydroxy-1-(4-((4-morpholino-2-(quinolin-3-yl)thieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propan-1-one;
2-methyl-6-(6((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-3H-imidazo[4,5-b]pyridine;
(S)-2-hydroxy-1-(4-((2-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propan-1-one;
6-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)imidazo[1,2-a]pyrimidine;
2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine;
2-(1H-benzo[d]imidazol-5-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine;
2-(2-methyl-1H-benzo[d]imidazol-5-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine;
4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)benzene-1,2-diamine;
4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-2-(pyrido[2,3-b]pyrazin-7-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine;
4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine;
4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-2-(1H-pyrazolo[3,4-c]pyridin-4-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine;
4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-2-(5,6,7,8-tetrahydroquinolin-3-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine;
and
N,1-dimethyl-N-((4-morpholino-2-(quinolin-3-yl)thieno[2,3-d]pyrimidin-6-yl)methyl)piperidin-4-amine;
and the pharmaceutically acceptable salts thereof.

46 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/789,468Filed 24 Apr 2007 · us provisional application
Priority: 26 Apr 2006
Published: US 2008/0076758 A127 Mar 2008
Granted: 12 Aug 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification23 codes

A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
A61K 31/551
Having seven-membered rings, e.g. azelastine, pentylenetetrazole: having two nitrogen atoms, e.g. dilazep
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 3/00
Drugs for disorders of the metabolism