Benzofuran and benzothiophene derivatives useful in the treatment of hyper-proliferative disorders

1. A compound of Formula I

wherein

X is selected from O and S;

R 1 is selected from H, (C 1 -C 6 )alkyl, C(O)(C 1 -C 6 )alkyl, and benzoyl;

R 2 is selected from

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

OH, CN, NO 2 , (C 1 -C 6 )alkyl, (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 ,

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 substituents each independently selected from

OH, CN, NO 2 , (C 1 -C 6 )alkyl, (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 A is in each instance independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, NR B R B , or

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

R B is in each instance independently H, (C 3 -C 6 )cycloalkyl, and

(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 , and NC(O)(C 1 -C 3 )alkyl,

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 , (C 1 -C 6 )alkoxy, NH(C 1 -C 3 )alkyl, or N[(C 1 -C 3 )alkyl] 2 ,

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

R 3 is selected from from H, OH, CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, halo(C 1 -C 3 )alkyl, and halo(C 1 -C 3 )alkoxy;

R 4 is selected from

piperonyl,

Y where

Y is a heterocycle optionally substituted with 1, 2, or 3 substituents each independently selected from

═O, N-oxide, H, CN, NO 2 , halo, halo(C 1 -C 6 )alkyl, OH, halo(C 1 -C 6 )alkoxy, C(O)OR B , C(NH)NR B R B , NR B R B , S(O) 0-2 R B , S(O) 2 NR B R B ,

(C 1 -C 6 )alkoxy, said alkoxy being optionally substituted with 1 or 2 substituents selected from OH, NR B R B , and (C 1 -C 3 )alkoxy,

NR C R C where

 R C is selected from R B , C(O)R B , and S(O) 2 R B ,

C(O)R D where

 R D is selected from R A , (C 3 -C 6 )cycloalkyl, Z and N[(C 1 -C 3 )alkyl]Z where

 Z is in each instance a heterocycle independently optionally substituted with

 CN, ═O, OH, N-oxide, NO 2 , halo, (C 1 -C 6 )alkoxy, halo(C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkyl, S(O) 2 R B , S(O) 2 NR B R B , NR B R B , C(O)R A , and (C 1 -C 6 )alkyl,

said alkyl being optionally substituted with OH, C(O)R B , (C 1 -C 3 )alkoxy and NR B R B ;

NR B R E where

 R E is selected from C(O)R A , C(O)R B , S(O) 2 R B , S(O) 2 NR B R B and C(O)[(C 1 -C 6 )alkyl]Z where Z is optionally substituted as described above,

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

 CN, OH, ═O, halo, (C 1 -C 6 )alkoxy, C(O)R A , NR B R B , NR C R C , NR B R E , C(NH)NR B R B , S(O) 0-2 R B , S(O) 2 NR B R B , C(O)R B C(O)OR B , Z, C(O)Z, and C(O)N[(C 1 -C 3 )alkyl]Z, where Z in each instance is independently optionally substituted as described above,

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

OH, CN, NO 2 , halo, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, C(O)OR B , C(NH)NR B R B , NR B R B , S(O) 0-2 R B , S(O) 2 NR B R B , Z, C(O)Z where Z is in each instance optionally substituted as described above,

(C 1 -C 6 )alkoxy, said alkoxy being optionally substituted with 1 or 2 substituents selected from OH, NR B R B , and (C 1 -C 3 )alkoxy,

NR C R C where

R C is selected from R B , C(O)R B , and S(O) 2 R B ,

C(O)R D where

R D is selected from R A , (C 3 -C 6 )cycloalkyl, and N[(C 1 -C 3 )alkyl]Z where Z is optionally substituted as described above,

NR B R E where

R E is selected from C(O)R A , C(O)R B , S(O) 2 R B , S(O) 2 NR B R B and C(O)[(C 1 -C 6 )alkyl]Z where Z is optionally substituted as described above,

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

CN, OH, ═O, halo, (C 1 -C 6 )alkoxy, C(O)R A , NR B R B , NR B R E , C(NH)NR B R B , S(O) 0-2 R B , S(O) 2 NR B R B , C(O)R B C(O)OR B , Z, C(O)Z, and C(O)N[(C 1 -C 3 )alkyl]Z, where Z in each instance is independently optionally substituted as described above;

R 5 and R 6 are each independently selected from H, OH, CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy,

halo, halo(C 1 -C 3 )alkyl, and halo(C 1 -C 3 )alkoxy;

or a pharmaceutically acceptable salt or ester thereof.

2. A compound of claim 1 wherein X is O.

3. A compound of claim 1 wherein X is S.

4. A compound of claim 2 wherein 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 wherein R 4 is selected from Y and phenyl, each being optionally substituted.

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

7. A compound of claim 5 wherein R 4 is selected from phenyl and Y where Y is selected from a 5 membered heterocyclic ring and pyridine, each cyclic moiety being optionally substituted.

8. A compound of claim 6 wherein R 2 and R 4 are each independently optionally substituted with 1 or 2 substituents, and R 3 , R 5 and R 6 are each independently selected from H, OH, Cl, F, CN, CH 3 , OCH 3 , CF 3 and OCF 3 .

9. A compound of claim 8 wherein R 1 is selected from H and (C 1 -C 6 -)alkyl.

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

11. A compound of claim 3 wherein R 4 is selected from Y and phenyl, each being optionally substituted.

12. A compound of claim 3 wherein R 2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted, and R 4 is selected from Y and phenyl, each being optionally substituted.

13. A compound of claim 11 wherein R 4 is selected from phenyl and Y where Y is selected from a 5 membered heterocyclic ring and pyridine, each cyclic moiety being optionally substituted.

14. A compound of claim 12 wherein R 2 and R 4 are each independently optionally substituted with 1 or 2 substituents, and R 3 , R 5 and R 6 are each independently selected from H, OH, Cl, F, CN, CH 3 , OCH 3 , CF 3 and OCF 3 .

15. A compound of claim 14 wherein R 1 is selected from H and (C 1 -C 6 -)alkyl.

16. A compound selected from

(3-Amino-6-phenyl-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone,

(3-Amino-6-pyridin-3-yl-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone,

[3-Amino-6-(3-nitro-phenyl)-benzofuran-2-yl]-(2,4-dichloro-phenyl)-methanone,

[3-Amino-6-(3-amino-phenyl)-benzofuran-2-yl]-(2,4-dichloro-phenyl)-methanone,

3-[3-Amino-2-(2,4-dichloro-benzoyl)benzofuran-6-yl]-benzonitrile,

N-{3-[3-Amino-2-(2,4-dichloro-benzoyl)-benzofuran-6-yl]-phenyl}-methanesulfonamide,

N-{3-[3-Amino-2-(2,4-dichloro-benzoyl)-benzofuran-6-yl]-phenyl)-acetamide,

[3-Amino-6-(2-methyl-pyridin-3-yl)-benzofuran-2-yl]-(2,4-dichloro-phenyl)-methanone,

5-[3-Amino-2-(2,4-dichloro-benzoyl)-benzofuran-6-yl]-nicotinamide,

3-[3-Amino-2-(2,4-dichloro-benzoyl)-benzofuran-6-yl]-benzenesulfonamide,

(3-Amino-5-fluoro-6-pyridin-3-yl-benzofuran-2-yl}-(2,4-dichloro-phenyl)-methanone,

{3-Amino-6-[3-((S-2,3-dihydroxy-propylamino)-phenyl]-benzofuran-2-yl}-(2,4-dichloro-phenyl)-methanone,

3-[3-Amino-2-(2,4-dichloro-benzoyl)-benzofuran-6-yl]-N-methyl-benzamide,

[3-Amino-6-(1-methyl-1H-imidazol-4-yl)-benzofuran-2-yl]-(2,4-dichloro-phenyl)-methanone,

3-[3-Amino-2-(2-chloro-4-fluoro-benzoyl)-benzofuran-6-yl]-benzamide,

2-{3-[3-Amino-2-2,4-dichloro-benzoyl)-benzofuran-6-yl]-phenyl}acetamide,

[3-Amino-6-(2-methyl-thiazol-4-yl)-benzofuran-2-yl]-(2,4-dichloro-phenyl)-methanone,

N-{3-[3-Amino-2-(2,4-dichloro-benzoyl)-benzofuran-6-yl]-benzyl}-Methanesulfonamide,

N-{3-[3-Amino-2-(2,4-dichloro-benzoyl)-benzofuran-6-yl]-benzyl}-acetamide,

[3-Amino-6-(2-methyl-oxazolyl)benzofuran-2-yl]-(2-methoxy-phenyl)-methanone,

[3-Amino-6-(3-fluoro-5-nitro-phenyl)-benzofuran-2-yl]-(2,4-dichloro-phenyl)-methanone,

[3-Amino-6-(3-methanesulfonyl-phenyl)-benzofuran-2-yl]-(2,4-dichloro-phenyl)-methanone,

[3-Amino-6-(2-fluoro-pyridin-3-yl)-benzofuran-2-yl]-(2,4-dichloro-phenyl)-methanone, and

[3-Amino-6-(2-methylamino-pyridin-3-yl)-benzofuran-2-yl]-(2,4-dichloro-phenyl)-methanone.

17. A composition comprising a compound of Formula I.

18. A composition according to claim 17 where X is O.

19. A composition according to claim 17 where X is S.

20. A composition according to claim 18 where R 2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted, and R 4 is selected from Y and phenyl, each being optionally substituted.

21. A composition according to claim 19 where R 2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted, and R 4 is selected from Y and phenyl, each being optionally substituted.