Pharmaceutical compounds

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

wherein

X is O or S;

Y is N or —CH—;

R 2 is H, halo or C 1 -C 6 alkyl;

each R′ is, independently, H, C 1 -C 6 alkyl or hydroxy-C 1 -C 6 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 —CH 2 — bridgehead;

each R″ is, independently, H or C 1 -C 6 alkyl, or two groups R″ on the same carbon atom form an oxo (═O) group;

Z is R 10 or -(alk) q -NR 11 R 12 ;

R 10 is H, a C 3 -C 6 cycloalkyl group, C 1 -C 6 alkyl which is unsubstituted, or CF 3 ;

R 11 and R 12 are each independently selected from H, C 1 -C 6 alkyl which is unsubstituted and -(alk) q -OR, or R 11 and R 12 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 C 1 -C 6 alkylene; and

and R 3 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, CH 2 OR, —CO 2 R, CF 2 OH, CH(CF 3 )OH, C(CF 3 ) 2 OH, —(CH 2 ) q OR, —(CH 2 ) q NR 2 , —C(O)N(R) 2 , —NR 2 , —NRC(O)R, —S(O) m N(R) 2 , —OC(O)R, OC(O)N(R) 2 , —NRS(O) m R, —NRC(O)N(R) 2 , CN, halogen and —NO 2 , wherein each R is independently selected from H, C 1 -C 6 alkyl, C 3 -C 10 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.

2. A compound which is a fused pyrimidine of formula (Ib):

wherein

X is O or S;

R 1 is a group of formula:

R 2 is H, halo or C 1 -C 6 alkyl

R 4 and R 5 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) 2 Z wherein Z is R 10 or —NR 11 R 12 , or by unsubstituted C 1 -C 6 alkyl, hydroxyl-C 1 -C 6 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 —NR 13 R 14 ;

or one of R 4 and R 5 is C 1 -C 6 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 C 1 -C 6 alkyl, -(alk) q -OR or —S(O) 2 R 10 ;

R is H or C 1 -C 6 alkyl which is unsubstituted;

each R′ is, independently, H or C 1 -C 6 alkyl which is unsubstituted, or the two groups R′ form, together with the C atom to which they are attached, a cyclyl group;

R 10 is H, cyclyl, C 1 -C 6 alkyl which is unsubstituted or CF 3 ;

R 11 and R 12 are each independently selected from H, C 1 -C 6 alkyl which is unsubstituted and -(alk) q -OR, or R 11 and R 12 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;

R 13 and R 14 are each independently selected from C 1 -C 6 alkyl, —S(O) 2 R 10 , 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 C 3 -C 6 cycloalkyl group;

each q is independently 0 or 1;

r is 0 or 1;

alk is C 1 -C 6 alkylene; and

R 3 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, CH 2 OR, —CO 2 R, CF 2 OH, CH(CF 3 )OH, C(CF 3 ) 2 OH, —(CH 2 ) q OR, —(CH 2 ) q NR 2 , —C(O)N(R) 2 , —NR 2 , —NRC(O)R, —S(O) m N(R) 2 , —OC(O)R, OC(O)N(R) 2 , —NRS(O) m R, —NRC(O)N(R) 2 , CN, halogen and —NO 2 , wherein each R is independently selected from H, C 1 -C 6 alkyl, C 3 -C 10 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 R 3 is other than an indole group.

3. A compound which is a fused pyrimidine of formula (Ib):

wherein

X is O or S;

R 1 is a group of formula:

R 2 is H, halo or C 1 -C 6 alkyl

R 4 and R 5 form, together with the N atom to which they are attached, a group selected from piperazine, 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) 2 Z wherein Z is R 10 or —NR 11 R 12 , or by unsubstituted C 1 -C 6 alkyl, —C(O)—C(R′) 2 —N(R) 2 , —C(O)-cyclyl, —C(O)R, —C(O)-Tet or —NR 13 R 14 ; or one of R 4 and R 5 is C 1 -C 6 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 C 1 -C 6 alkyl, -(alk) q -OR or —S(O) 2 R 10 ;

R is H or C 1 -C 6 alkyl which is unsubstituted;

each R′ is, independently, H or C 1 -C 6 alkyl which is unsubstituted, or the two groups R′ form, together with the C atom to which they are attached, a cyclyl group;

R 10 is H, cyclyl, C 1 -C 6 alkyl which is unsubstituted or CF 3 ;

R 11 and R 12 are each independently selected from H, C 1 -C 6 alkyl which is unsubstituted and -(alk) q -OR, or R 11 and R 12 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;

R 13 and R 14 are each independently selected from C 1 -C 6 alkyl, —S(O) 2 R 10 , 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 C 3 -C 6 cycloalkyl group;

each q is independently 0 or 1;

r is 0 or 1;

alk is C 1 -C 6 alkylene; and

R 3 is 1H-indazol-4-yl;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 2 wherein R 1 is (4-methylsulfonylpiperazin-1-yl)methyl.

5. A compound according to claim 2 wherein R 2 is H.

6. A compound according to claim 2 wherein R 3 is selected from:

where W is CR 10 or N; each R 10 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 acyl, —C(O)NR′R″, —S(O) t NR′R″, aryl, heteroaryl, sulphonyl and halogen; R′ and R″ are each independently H or C 1 -C 6 alkyl; and t is 1 or 2.

7. A compound according to claim 2 wherein R 3 is 1H-indazol-4-yl.

8. 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.

9. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound as claimed in claim 2 .

10. A composition according to claim 9 , further comprising a chemotherapeutic agent.

11. A composition according to claim 9 which is formulated for oral administration.

12. A kit comprising:

(a) a first pharmaceutical composition comprising a compound as defined in claim 2 ;

(b) a second pharmaceutical composition that comprises a compound having anti-hyperproliferative activity;

and

(c) instructions for the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need thereof; wherein said first and second pharmaceutical compositions are contained in separate containers.