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Claims for Patent: 7,351,834

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Claims for Patent: 7,351,834

Title:.omega.-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
Abstract:This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.
Inventor(s): Riedl; Bernd (Wuppertal, DE), Dumas; Jacques (Orange, CT), Khire; Uday (Hamden, CT), Lowinger; Timothy (Hyogo, JP), Scott; William (Guilford, CT), Smith; Roger A. (Madison, CT), Wood; Jill E. (Hamden, CT), Monahan; Mary-Katherine (Hamden, CT), Natero; Reina (Hamden, CT), Renick; Joel (Milford, CT), Sibley; Robert (North Haven, CT)
Assignee: Bayer Pharmaceuticals Corporation (West Haven, CT)
Application Number:09/889,227
Patent Claims: 1. A compound of Formula I: A--D--B (I) or a pharmaceutically acceptable salt thereof, wherein D is --NH--C(O)--NH--, A is a substituted moiety of the formula: --L--M--L.sup.1, wherein L is phenyl, optionally substituted by halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of C.sub.1-C.sub.5 linear or branched alkyl, C.sub.1-C.sub.5 linear or branched haloalkyl up to perhaloalkyl and C.sub.1-C.sub.3 alkoxy L.sup.1 is selected from pyridinyl substituted by --C(O)R.sub.x, and optionally substituted with 1-3 additional substituents independently selected from the group consisting of R.sup.7 and halogen; wherein R.sub.x is NR.sub.aR.sub.b and R.sub.a and R.sub.b are A) independently a) hydrogen, b) C.sub.1-C.sub.10 alkyl, c) C.sub.6 aryl, d) pyridinyl e) substituted C.sub.1-10 alkyl, f) substituted C.sub.6 aryl, g) substituted pyridinyl h) -phenylpiperazine(pyridinyl), i) -phenylmorpholinyl, j) -ethylmorpholinyl, k) -ethylpiperidyl, l) -methyl pyrrolidinyl, m) -methyl tetrahydrofuryl, or n) --C.sub.2H.sub.4NH(phenyl); where when R.sub.a and R.sub.b are a substituted group, they are substituted by a) halogen up to per halo, b) hydroxy, c) --N(CH.sub.3).sub.2, d) C.sub.1-C.sub.10 alkyl, e) C.sub.1-C.sub.10 alkoxy, f) halosubstituted C.sub.1-6 alkyl, or g) --OSi(Pr-i).sub.3; or B) R.sub.a and R.sub.b together form piperazine or a substituted piperazine with substituents selected from the group consisting of a) halogen, b) hydroxy, c) C.sub.1-10 alkyl, d) pyridinyl e) C.sub.1-10 alkoxy, f) C.sub.6 aryl, g) halo substituted C.sub.6 aryl, and h) N-(4-acetylphenyl); M is selected from the group consisting of oxygen and sulfur; and B is phenyl, substituted with 1-3 substituents independently selected from the group consisting of halogen and R.sup.7, and R.sup.7 is (a) C.sub.1-C.sub.6 linear or branched alkyl, optionally substituted with 1-3 halogen substituents; or (b) C.sub.1-C.sub.6 linear or branched alkoxy.

2. A compound as in claim 1 wherein M is oxygen.

3. A compound as in claim 1 wherein the cyclic structures of B and L bound directly to D are substituted in the ortho position by hydrogen.

4. A compound of claim 1 wherein B of Formula I is phenyl, substituted with 1-3 substituents independently selected from the group consisting of chlorine, C.sub.1-C.sub.6 alkoxy or up to per halo substituted C.sub.1-C.sub.6 alkyl.

5. A compound of claim 2 wherein B of Formula I is phenyl, substituted with 1-3 substituents independently selected from the group consisting of chlorine, C.sub.1-C.sub.6 alkoxy, or substituted C.sub.1-C.sub.6 alkyl, substituted by one or more halogen substituents.

6. A compound of claim 3 wherein B of Formula I is phenyl, substituted 1 to 3 times by 1 or more substituents selected from the group consisting of chlorine, C.sub.1-C.sub.6 alkoxy or up to per halo substituted C.sub.1-C.sub.6 alkyl.

7. A compound of claim 1, wherein L is phenyl, optionally substituted by halogen up to perhalo.

8. A compound of claim 1, wherein L is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of halogen and C.sub.1-C.sub.3 alkoxy.

9. A compound of claim 3, wherein M is --O--.

10. A compound of claim 6 wherein M is --O--.

11. A compound of claim 7 wherein M is --O--.

12. A compound of claim 8 wherein M is --O--.

13. A compound of claim 1 wherein L.sup.1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, halogen and C.sub.1-C.sub.6 alkoxy.

14. A compound of claim 2 wherein L.sup.1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, halogen and C.sub.1-C.sub.6 alkoxy.

15. A compound of claim 9 wherein L.sup.1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, halogen and C.sub.1-C.sub.6 alkoxy.

16. A compound of claim 10 wherein L.sup.1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, halogen and C.sub.1-C.sub.6 alkoxy.

17. A compound of claim 11 wherein L.sup.1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, halogen and C.sub.1-C.sub.6 alkoxy.

18. A compound of claim 12 wherein L.sup.1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, halogen and C.sub.1-C.sub.6 alkoxy.

19. A compound of claim 2 wherein R.sub.a and R.sub.b are independently hydrogen or C.sub.1-C.sub.6 alkyl.

20. A compound of claim 9 wherein R.sub.a and R.sub.b are independently hydrogen or C.sub.1-C.sub.6 alkyl.

21. A compound of claim 10 wherein R.sub.a and R.sub.b are independently hydrogen or C.sub.1-C.sub.6 alkyl.

22. A compound of claim 11 wherein R.sub.a and R.sub.b are independently hydrogen or C.sub.1-C.sub.6 alkyl.

23. A compound of claim 12 wherein R.sub.a and R.sub.b are independently hydrogen or C.sub.1-C.sub.6 alkyl.

24. A compound of Formula I: A--D--B (I) or a pharmaceutically acceptable salt thereof, wherein D is --NH--C(O)--NH--, A is of the formula: --L--M--L.sup.1, wherein L is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C.sub.1-C.sub.5 linear or branched alkyl, C.sub.1-C.sub.5 linear or branched haloalkyl up to perhalo, C.sub.1-C.sub.3 alkoxy and halogen; L.sup.1 is pyridinyl, substituted by --C(O)R.sub.x; wherein R.sub.x is NR.sub.aR.sub.b and R.sub.a and R.sub.b are independently hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.6 aryl, pyridinyl, substituted C.sub.1-10 alkyl, substituted C.sub.6 aryl, or substituted pyridinyl, where R.sub.a and R.sub.b are a substituted group, they are substituted by halogen up to per halo; and M is selected from the group consisting of oxygen and sulfur and B is phenyl, substituted with 1-3 substituents independently selected from the group consisting of R.sup.7 and halogen; and R.sup.7 is (a) C.sub.1-C.sub.6 linear or branched alkyl, optionally substituted with 1-3 halogen substituents; or (b) C.sub.1-C.sub.6 linear or branched alkoxy.

25. A compound of Formula I: A--D--B (I) or a pharmaceutically acceptable salt thereof, wherein D is --NH--C(O)--NH--, A is of the formula: --L--M--L.sup.1, L is phenyl, M is --O--, L.sup.1 is pyridinyl substituted by --C(O)R.sub.x, wherein R.sub.x is NR.sub.aR.sub.b and R.sub.a and R.sub.b are independently hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.6 aryl, pyridinyl, substituted C.sub.1-10 alkyl, substituted C.sub.6 aryl, or substituted pyridinyl where R.sub.a and R.sub.b are a substituted group, they are substituted by halogen up to per halo, and B is a phenyl group substituted by trifluoromethyl or tert-butyl, and optionally additional substituents selected from the group consisting of halogen up to per halo, and W.sub.n where n is 0-3, and each W is independently selected from the group consisting of C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy, C.sub.6 aryl, pyridinyl, and substituted C.sub.1-C.sub.10 alkyl, substituted by one or more substituents independently selected from the group consisting of halogen up to per halo.

26. A compound as in claim 24 wherein the cyclic structures of B and L bound directly to D are substituted in the ortho position by hydrogen.

27. A compound as in claim 25 wherein the cyclic structures of B and L bound directly to D are substituted in the ortho position by hydrogen.

28. A compound as in claim 24 wherein substituents for B, are selected from the group consisting of up to per halo substituted C.sub.1-C.sub.6 alkyl and halogen.

29. A compound as in claim 25 wherein the optional substituents for B are selected from the group consisting of up to per halo substituted C.sub.1-C.sub.6 alkyl and halogen.

30. A pharmaceutically acceptable salt of a compound of formula I of claim 1 which is a) a basic salt of an organic acid or inorganic acid which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid; or b) an acid salt of an organic or inorganic base containing an alkali metal cation, an alkaline earth metal cation, an ammonium cation, an aliphatic substituted ammonium cation or an aromatic substituted ammonium cation.

31. A pharmaceutically acceptable salt of a compound of claim 24 which is a) a basic salt of an organic acid or inorganic acid which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid; or b) an acid salt of an organic or inorganic base containing an alkali metal cation, an alkaline earth metal cation, an ammonium cation, an aliphatic substituted ammonium cation or an aromatic substituted ammonium cation.

32. A pharmaceutically acceptable salt of a compound of claim 25 which is a) a basic salt of an organic acid or inorganic acid which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid; or b) an acid salt of an organic or inorganic base containing an alkali metal cation, an alkaline earth metal cation, an ammonium cation, an aliphatic substituted ammonium cation or an aromatic substituted ammonium cation.

33. A compound of claim 1 wherein the optional substituents on L.sup.1 are selected from the group consisting of methyl, trifluoromethyl, methoxy, Cl and F.

34. A compound of claim 1 wherein the substituents of B and L are independently selected from the group consisting of methyl, trifluoromethyl, tert-butyl, methoxy, Cl, and F.

35. A compound of Formula I: A--D--B (I) or a pharmaceutically acceptable salt thereof, wherein D is --NH--C(O)--NH--, A is a substituted moiety of the formula: --L--M--L.sup.1, wherein L is phenyl, optionally substituted with chlorine or methyl substituents; L.sup.1 is pyridinyl, substituted with --C(O)NR.sup.aR.sup.b; wherein R.sup.a and R.sup.b independently are a) hydrogen b) methyl; c) ethyl; or d) propyl B is phenyl, substituted by tert-butyl or trifluoromethyl and optionally substituted with additional substituents independently selected from the group consisting of a) halogen, or b) methoxy.

36. A compound of claim 35 where L has no optional substituents.

37. A compound of claim 35 where R.sup.a is hydrogen and R.sup.b is methyl.

38. A compound of claim 35 where B is substituted by trifluoromethyl and chlorine or bromine.

39. A compound which is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyr- idyloxy)phenyl)urea of the formula X ##STR00186## or a pharmaceutically acceptable salt thereof.

40. A compound of claim 39 which is a pharmaceutically acceptable salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyr- idyloxy)phenyl)urea that is a basic salt of an organic acid or an inorganic acid which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid.

41. A compound of claim 39 which is a tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyr- idyloxy)phenyl)urea.
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