Fused tricyclic heterocycles useful for treating hyper-proliferative disorders

1. A compound selected from Formula Ia and Formula Ib

where

X is O or S;

R 1 is in each instance independently selected from H, C 1 –C 6 alkyl, benzoyl, and C(O)R A ;

R A is in each instance independently H, (C 1 –C 6 )alkoxy, NR B R B , or

(C 1 –C 6 )alkyl, said alkyl being optionally substituted with OH, ═O, (C 1 –C 3 )alkoxy, C(O)R B , halo or NR B R B ;

R B is in each instance independently H, (C 3 –C 6 )cycloalkyl, or

(C 1 –C 6 )alkyl, said alkyl being optionally substituted with

OH, ═O, halo, (C 1 –C 6 )alkoxy, NH(C 1 –C 3 )alkyl, N[(C 1 –C 3 )alkyl] 2 , NC(O)(C 1 –C 3 )alkyl or phenyl,

and where R B , when it is attached to a N atom, is in each instance (C 1 –C 4 )alkyl, then the 2 (C 1 –C 4 )alkyl groups, taken together with the N atom to which they are attached, may be joined together to form a saturated ring,

and where R B and R B together with the N to which they are attached may form a morpholinyl ring or a piperazinyl ring optionally substituted on the available N atom with (C 1 –C 6 )alkyl, said alkyl being optionally substituted with OH, ═O, NH 2 , NH(C 1 –C 3 )alkyl, N[(C 1 –C 3 )alkyl] 2 , or (C 1 –C 6 )alkoxy,

and with the proviso that when R B is attached to S(O) or to S(O) 2 , it cannot be H;

R 2 is selected from

phenyl and naphthyl, each optionally substituted with 1, 2, or 3 substitutents each independently selected from

OH, CN, NO 2 , (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, (C 3 –C 6 )cycloalkyl, halo, halo(C 1 –C 6 )alkyl, halo(C 1 –C 6 )alkoxy, C(O)R A , C(O)NR B R B , NR B R B , NH[(C 1 –C 6 )alkyl] 0-1 S(O) 2 R B , NH[(C 1 –C 6 )alkyl] 0-1 C(O)R A , and NH[(C 1 –C 6 )alkyl] 0-1 C(O)OR B ,

a heterocycle selected from a six membered heterocycle, a five membered heterocycle and a fused bicyclic heterocycle, each heterocycle being optionally substituted with 1, 2 or 3 substitutents each independently selected from

OH, CN, NO 2 , (C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkyl, (C 1 –C 6 )alkoxy, halo, halo(C 1 –C 6 )alkyl, halo(C 1 –C 6 )alkoxy, C(O)R A , C(O)NR B R B , NR B R B , NH[(C 1 –C 6 )alkyl] 0-1 S(O) 2 R B , NH[(C 1 –C 6 )alkyl] 0-1 C(O)R A , and NH[(C 1 –C 6 )alkyl] 0-1 C(O)OR B ,

R 3 and R 4 are each independently selected from H, halo, OH, CN, (C 1 –C 3 )alkoxy, (C 1 –C 3 )alkyl, halo(C 1 –C 3 )alkoxy and halo(C 1 –C 3 )alkyl with the proviso that when X in Formula Ib is S, then R 4 cannot be (C 1 –C 3 )alkyl;

B is a 5 or 6 membered cyclic moiety being optionally substituted with 1 or 2 subsituents each independently selected from ═O, OH, N oxide, halo, halo(C 1 –C 6 )alkyl, halo(C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyl, (C 1 –C 3 )alkylphenyl, (C 1 –C 6 )alkoxy, C(O)R A , C(O)OR B , C(O)NR B R B , NR B R B , NH[(C 1 –C 6 )alkyl] 0-1 S(O) 2 R B , and NH[(C 1 –C 6 )alkyl] 0-1 C(O)R A ;

or a pharmaceutically acceptable salt or ester thereof.

2. A compound of claim 1 comprising a compound of Formula Ia.

3. A compound of claim 1 comprising a compound of Formula Ib.

4. A compound of claim 2 where R 2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted.

5. A compound of claim 2 where at least one R 1 is H.

6. A compound of claim 2 where B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

7. A compound of claim 2 where R 2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted, and B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

8. A compound of claim 6 where R 2 is optionally substituted with 1 or 2 substituents and R 3 and R 4 are each independently selected from H, OH, Cl, F, CN, CH 3 , OCH 3 , CF 3 and OCF 3 .

9. A compound of claim 7 where optionally substituted B, contains no unsaturation other than the shared double bond which is part of the phenyl ring from which B is fused to.

10. A compound of claim 9 where B is substituted with ═O, OH, Cl, F, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, NR B R B , CF 3 or OCF 3 .

11. A compound of claim 3 where R 2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted.

12. A compound of claim 3 where at least one R 1 is H.

13. A compound of claim 3 where B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

14. A compound of claim 3 where R 2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted, and B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

15. A compound of claim 13 where R 2 is optionally substituted with 1 or 2 substituents and R 3 and R 4 are each independently selected from H, OH, Cl, F, CN, CH 3 , OCH 3 , CF 3 and OCF 3 .

16. A compound of claim 14 where optionally substituted B, contains no unsaturation other than the shared double bond which is part of the phenyl ring from which B is fused to.

17. A compound of claim 16 where B is substituted with ═O, OH, Cl, F, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, NR B R B , CF 3 or OCF 3 .

18. A composition comprising a compound of Formula Ia or Formula Ib.

19. A composition of claim 18 comprising a compound of Formula Ia.

20. A composition of claim 18 comprising a compound of Formula Ib.

21. A composition of claim 19 where R 2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted.

22. A composition of claim 21 where at least one R 1 is H.

23. A composition of claim 21 where B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

24. A composition of claim 20 where R 2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted.

25. A composition of claim 24 where at least one R 1 is H.

26. A composition of claim 24 where B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.