IP Library › Granted Patent US 7,951,819

Granted Patent B2

US 7,951,819 · App. 12/298,325 · Granted May 31, 2011

Imidazo[4, 5-B]pyridin-2-one and oxazolo[4, 5-B] pyridin-2-one compounds and analogs thereof as cancer therapeutic compounds

Assignees: Cancer Research Technology Limited; The Institute of Cancer Research: Royal Cancer Hospital; Astex Therapeutics Limited

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Quick Facts

Patent No.: US 7,951,819
App. No.: 12/298,325
Granted: May 31, 2011
Kind: B2

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Abstract

The present invention pertains to certain imidazo[4,5-b]pyridin-2-one and oxazolo[4,5 b]pyridin-2-one compounds and analogs thereof, which, inter alia, inhibit RAF (e.g., B RAF) activity, inhibit cell proliferation, treat cancer, etc. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit RAF (e.g., B-RAF) activity, to inhibit receptor tyrosine kinase (RTK) activity, to inhibit cell proliferation, and in the treatment of diseases and conditions that are ameliorated by the inhibition of RAF, RTK, etc., proliferative conditions such as cancer (e.g., colorectal cancer, melanoma), etc.

Claims (110)

1. A compound selected from compounds of the following formula and pharmaceutically acceptable salts thereof:

wherein:

J is independently —NR N1 —;

R N1 is independently —H, aliphatic saturated C 1-3 alkyl, or aliphatic C 2-3 alkenyl;

R N2 is independently —H, aliphatic saturated C 1-3 alkyl, or aliphatic C 2-3 alkenyl;

Y is independently —CH═;

Q is independently —O—;

each of R P1 , R P2 , R P5 , and R P4 is independently —H, -Me, —CF 3 , —OH, —OMe, —F, or —Cl;

the group A-L- is independently:

A-NR N —C(═O)—NR N —;

A-CH 2 —NR N —C(═O)—NR N —;

A-NR N —C(═O)—NR N —CH 2 —;

A-NR N —C(═O)—;

A-CH 2 —NR N —C(═O)—;

A-NR N —C(═O)—CH 2 —;

A-CH 2 —NR N —C(═O)—CH 2 —;

A-CH 2 —CH 2 —NR N —C(═O)—;

A-NR N —C(═O)—CH 2 —CH 2 —;

A-NR N —C(═O)—CH 2 —NR N —;

A-NR N —CH 2 —NR N —C(═O)—;

A-C(═O)—NR N —;

A-CH 2 —C(═O)—NR N —;

A-C(═O)—NR N —CH 2 —;

A-CH 2 —C(═O)—NR N —CH 2 —;

A-CH 2 —CH 2 —C(═O)—NR N —;

A-C(═O)—NR N —CH 2 —CH 2 —;

A-NR N —CH 2 —C(═O)—NR N —

A-C(═O)—NR N —CH 2 —NR N —

A-C(═O)—CH 2 —NR N —;

A-C(═O)—CH 2 —NR N —CH 2 —;

A-C(═O)—CH 2 —CH 2 —NR N —;

A-CH 2 —C(═O)—CH 2 —NR N —;

A-NR N —CH 2 —C(═O)—;

A-NR N —CH 2 —C(═O)—CH 2 —;

A-NR N —CH 2 —CH 2 —C(═O)—; or

A-CH 2 —NR N —CH 2 —C(═O)—;

each R N is independently —H, saturated aliphatic C 1-3 alkyl, or aliphatic C 2-3 alkenyl;

A is independently C 5-14 heteroaryl, and is independently unsubstituted or substituted with one or more groups selected from: —C(═O)OH, —C(═O)OMe, —C(═O)OEt, —C(═O)O(iPr), —C(═O)O(tBu), —C(═O)O(cPr), —C(═O)OCH 2 CH 2 OH, —C(═O)OCH 2 CH 2 OMe, —C(═O)OCH 2 CH 2 OEt, —C(═O)OPh, —C(═O)OCH 2 Ph, —(C═O)NH 2 , —(C═O)NMe 2 , —(C═O)NEt 2 , —(C═O)N(iPr) 2 , —(C═O)N(CH 2 CH 2 OH) 2 , —(C═O)-morpholino, —(C═O)NHPh, —(C═O)NHCH 2 Ph, —C(═O)H, —(C═O)Me, —(C═O)Et, —(C═O)(tBu), —(C═O)-cHex, —(C═O)Ph, —(C═O)CH 2 Ph, —F, —Cl, —Br, —I, —CN, —NO 2 , —OH, —OMe, —OEt, —O(iPr), —O(tBu), —OPh, —OCH 2 Ph, —OCF 3 , —OCH 2 CF 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OMe, —OCH 2 CH 2 OEt, —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 NMe 2 , —OCH 2 CH 2 N(iPr) 2 , —OPh-Me, —OPh-OH, —OPh-OMe, —OPh-F, —OPh-Cl, —OPh-Br, —OPh-I, —SH, —SMe, —SEt, —SPh, —SCH 2 Ph, —OC(═O)Me, —OC(═O)Et, —OC(═O)(iPr), —OC(═O)(tBu), —OC(═O)(cPr), —OC(═O)CH 2 CH 2 OH, —OC(═O)CH 2 CH 2 OMe, —OC(═O)CH 2 CH 2 OEt, —OC(═O)Ph, —OC(═O)CH 2 Ph, —OC(═O)NH 2 , —OC(═O)NHMe, —OC(═O)NMe 2 , —OC(═O)NHEt, —OC(═O)NEt 2 , —OC(═O)NHPh, —OC(═O)NCH 2 Ph, —NH 2 , —NHMe, —NHEt, —NH(iPr), —NMe 2 , —NEt 2 , —N(iPr) 2 , —N(CH 2 CH 2 OH) 2 , —NHPh, —NHCH 2 Ph, piperidino, piperazino, morpholino, —NH(C═O)Me, —NH(C═O)Et, —NH(C═O)nPr, —NH(C═O)Ph, —NHC(═O)CH 2 Ph, —NMe(C═O)Me, —NMe(C═O)Et, —NMe(C═O)Ph, —NMeC(═O)CH 2 Ph, —NH(C═O)NH 2 , —NH(C═O)NHMe, —NH(C═O)NHEt, —NH(C═O)NPh, —NH(C═O)NHCH 2 Ph, —NH(C═S)NH 2 , —NH(C═S)NHMe, —NH(C═S)NHEt, —NH(C═S)NPh, —NH(C═S)NHCH 2 Ph, —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 Ph, —NHSO 2 PhMe, —NHSO 2 CH 2 Ph, —NMeSO 2 Me, —NMeSO 2 Et, —NMeSO 2 Ph, —NMeSO 2 PhMe, —NMeSO 2 CH 2 Ph, —SO 2 Me, —SO 2 CF 3 , —SO 2 Et, —OSO 2 Ph, —SO 2 PhMe, —SO 2 CH 2 Ph, —OSO 2 Me, —OSO 2 CF 3 , —OSO 2 Et, —OSO 2 Ph, —OSO 2 PhMe, —OSO 2 CH 2 Ph, —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NHEt, —SO 2 NMe 2 , —SO 2 NEt 2 , —SO 2 -morpholino, —SO 2 NHPh, —SO 2 NHCH 2 Ph, —CH 2 Ph, —CH 2 Ph-Me, —CH 2 Ph-OH, —CH 2 Ph-F, —CH 2 Ph-Cl, -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-NH 2 , -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe, -cPr, -cHex, —CH═CH 2 , —CH 2 —CH═CH 2 , —CF 3 , —CHF 2 , —CH 2 F, —CCl 3 , —CBr 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 OH, —CH 2 OMe, —CH 2 OEt, —CH 2 NH 2 , —CH 2 NMe 2 , —CH 2 CH 2 OH, —CH 2 CH 2 OMe, —CH 2 CH 2 OEt, —CH 2 CH 2 CH 2 NH 2 , and —CH 2 CH 2 NMe 2 .

2. A compound according to claim 1 , wherein the group A-L- is independently A-NR N —C(═O)—NR N —, A-C(═O)—NR N —, or A-NR N —C(═O)—.

3. A compound according to claim 1 , wherein each of the groups R N is independently —H or -Me.

4. A compound according to claim 2 , wherein each of the groups R N is independently —H or -Me.

5. A compound according to claim 1 , wherein the group A-L- is independently A-NH—C(═O)—NH—, A-C(═O)—NH—, or A-NH—C(═O)—.

6. A compound according to claim 1 , wherein the group A-L- is independently A-NH—C(═O)—NH—.

7. A compound according to claim 1 , wherein the group A-L- is independently A-C(═O)—NH—.

8. A compound according to claim 1 , wherein the group A-L- is independently A-NH—C(═O)—.

9. A compound according to claim 1 , wherein R N1 is independently —H or -Me; and R N2 is independently —H or -Me.

10. A compound according to claim 1 , wherein R N1 is independently —H; and R N2 is independently —H.

11. A compound according to claim 5 , wherein R N1 is independently —H or -Me; and R N2 is independently —H or -Me.

12. A compound according to claim 5 , wherein R N1 is independently —H; and R N2 is independently —H.

13. A compound according to claim 1 , wherein each of R P1 , R P2 , R P5 , and R P4 is independently —H, -Me, —CF 3 , —F, or —Cl.

14. A compound according to claim 5 , wherein each of R P1 , R P2 , R P5 , and R P4 is independently —H, -Me, —CF 3 , —F, or —Cl.

15. A compound according to claim 11 , wherein each of R P1 , R P2 , R P5 , and R P4 is independently —H, -Me, —CF 3 , —F, or —Cl.

16. A compound according to claim 12 , wherein each of R P1 , R P2 , R P5 , and R P4 is independently —H, -Me, —CF 3 , —F, or —Cl.

17. A compound according to claim 1 , wherein each of R P1 , R P2 , R P5 , and R P4 is independently —H.

18. A compound according to claim 5 , wherein each of R P1 , R P2 , R P5 , and R P4 is independently —H.

19. A compound according to claim 11 , wherein each of R P1 , R P2 , R P5 , and R P4 is independently —H.

20. A compound according to claim 12 , wherein each of R P1 , R P2 , R P5 , and R P4 is independently —H.

21. A compound according to claim 1 , wherein A is independently monocyclic C 5-6 heteroaryl, and is independently unsubstituted or substituted.

22. A compound according to claim 1 , wherein A is independently: pyrrolyl, pyridinyl, furanyl, thienyl, benzothienyl, oxazolyl, isoxazolyl, thiadiazolyl, benzothiadiazolyl, oxadiazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or tetrazolyl; and is independently unsubstituted or substituted.

23. A compound according to claim 1 , wherein A is independently pyrazolyl, and is independently unsubstituted or substituted.

24. A compound according to claim 5 , wherein A is independently pyrazolyl, and is independently unsubstituted or substituted.

25. A compound according to claim 11 , wherein A is independently pyrazolyl, and is independently unsubstituted or substituted.

26. A compound according to claim 12 , wherein A is independently pyrazolyl, and is independently unsubstituted or substituted.

27. A compound according to claim 15 , wherein A is independently pyrazolyl, and is independently unsubstituted or substituted.

28. A compound according to claim 16 , wherein A is independently pyrazolyl, and is independently unsubstituted or substituted.

29. A compound according to claim 19 , wherein A is independently pyrazolyl, and is independently unsubstituted or substituted.

30. A compound according to claim 20 , wherein A is independently pyrazolyl, and is independently unsubstituted or substituted.

31. A compound according to claim 1 , wherein A is independently unsubstituted or substituted with one or more groups selected from: —C(═O)OH, —C(═O)OMe, —C(═O)OEt, —C(═O)O(iPr), —C(═O)O(tBu), —(C═O)NH 2 , —(C═O)NMe 2 , —(C═O)NEt 2 , —(C═O)N(iPr) 2 , —(C═O)-morpholino, —F, —Cl, —Br, —I, —CN, —NO 2 , —OH, —OMe, —OEt, —O(iPr), —O(tBu), —OPh, —OCH 2 Ph, —OCF 3 , —OC(═O)Me, —OC(═O)Et, —OC(═O)(iPr), —OC(═O)(tBu), —NH 2 , —NHMe, —NHEt, —NH(iPr), —NMe 2 , —NEt 2 , —N(iPr) 2 , piperidino, piperazino, morpholino, —NH(C═O)Me, —NH(C═O)Et, —NH(C═O)nPr, —CH 2 Ph, —CH 2 Ph-Me, —CH 2 Ph-OH, —CH 2 Ph-F, —CH 2 Ph-Cl, -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-NH 2 , -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe, and —CF 3 .

32. A compound according to claim 1 , wherein A is:

wherein:

R PY is independently saturated C 1-7 alkyl; and

R N3 is independently phenyl, and is independently unsubstituted or substituted with one or more groups selected from —F, —Cl, —Br, —I, —OMe, —OCF 3 , -Me, and —CF 3 .

33. A compound according to claim 15 , wherein A is:

wherein:

R PY is independently saturated C 1-7 alkyl; and

R N3 is independently phenyl, and is independently unsubstituted or substituted with one or more groups selected from —F, —Cl, —Br, —I, —OMe, —OCF 3 , -Me, and —CF 3 .

34. A compound according to claim 19 , wherein A is:

wherein:

R PY is independently saturated C 1-7 alkyl; and

R N3 is independently phenyl, and is independently unsubstituted or substituted with one or more groups selected from —F, —Cl, —Br, —I, —OMe, —OCF 3 , -Me, and —CF 3 .

35. A compound according to claim 1 , wherein A is:

wherein: