ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors

• US 7,351,834 B1
• Filed: 01/12/2000
• Issued: 04/01/2008
• Est. Priority Date: 01/13/1999
• Status: Expired due to Term

• Current Assignee: Bayer Healthcare LLC (Bayer AG)
• Original Assignee: Bayer Pharmaceuticals Corporation (Bayer AG)
• Inventors: Lowinger, Timothy, Monahan, Mary-Katherine, Dumas, Jacques, Natero, Reina, Smith, Roger A., Renick, Joel, Wood, Jill E., Riedl, Bernd, Khire, Uday, Scott, William, Sibley, Robert
• Primary Examiner(s): DESAI, RITA J
• Application Number:
  US09/889,227
• Time in Patent Office: 3,002 Days
• Field of Search: 546/290, 546/300, 546/329, 546/346, 544/242, 544/298, 544/309, 544/329, 544/358, 564/48, 564/52, 564/53, 564/55, 564/63, 514/256, 514/345, 514/351, 514/357, 514/482, 514/588, 514/596, 514/247, 514/277
• US Class Current: 546/290
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 251/48 with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 275/28 having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• CPC Class Codes: C07C 275/30 being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 275/32 being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 275/36 with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
• CPC Class Codes: C07C 275/40 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/22 with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/46 with an oxygen atom in position 1
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/79 Acids; Esters
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 295/12 substituted by singly or doubly bound nitrogen atoms nitro radicals C07D295/06
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 295/135 : with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/18 : by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 295/192 : from aromatic carboxylic acids
• CPC Class Codes: C07D 307/14 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links

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.

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—

L¹,

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 C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl up to perhaloalkyl and C₁-C₃ alkoxy L¹ is selected from pyridinyl substituted by —

C(O)R_x, and

optionally substituted with 1-3 additional substituents independently selected from the group consisting of R⁷ and halogen;

wherein R_x is NR_aR_b and R_a and R_b are

A) independently

a) hydrogen,

b) C₁-C₁₀ alkyl,

c) C₆ aryl,

d) pyridinyl

e) substituted C_1-10 alkyl,

f) substituted C₆ aryl,

g) substituted pyridinyl

h) -phenylpiperazine(pyridinyl),

i) -phenylmorpholinyl,

j) -ethylmorpholinyl,

k) -ethylpiperidyl,

l) -methyl pyrrolidinyl,

m) -methyl tetrahydrofuryl,

or

n) —

C₂H₄NH(phenyl);

where when R_a and R_b are a substituted group, they are substituted by

a) halogen up to per halo,

b) hydroxy,

c) —

N(CH₃)₂,

d) C₁-C₁₀ alkyl,

e) C₁-C₁₀ alkoxy,

f) halosubstituted C_1-6 alkyl, or

g) —

OSi(Pr-i)₃;

or

B) R_a and R_b together form piperazine or a substituted piperazine with substituents selected from the group consisting of

a) halogen,

b) hydroxy,

c) C_1-10 alkyl,

d) pyridinyl

e) C_1-10 alkoxy,

f) C₆ aryl,

g) halo substituted C₆ 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 R⁷,

and R⁷ is

(a) C₁-C₆ linear or branched alkyl, optionally substituted with 1-3 halogen substituents;

or

(b) C₁-C₆ 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, C₁-C₆ alkoxy or up to per halo substituted C₁-C₆ 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, C₁-C₆ alkoxy, or substituted C₁-C₆ 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, C₁-C₆ alkoxy or up to per halo substituted C₁-C₆ 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 C₁-C₃ 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 L¹ is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C₁-C₆ alkyl, halogen and C₁-C₆ alkoxy.

14. A compound of claim 2 wherein L¹ is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C₁-C₆ alkyl, halogen and C₁-C₆ alkoxy.

15. A compound of claim 9 wherein L¹ is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C₁-C₆ alkyl, halogen and C₁-C₆ alkoxy.

16. A compound of claim 10 wherein L¹ is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C₁-C₆ alkyl, halogen and C₁-C₆ alkoxy.

17. A compound of claim 11 wherein L¹ is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C₁-C₆ alkyl, halogen and C₁-C₆ alkoxy.

18. A compound of claim 12 wherein L¹ is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C₁-C₆ alkyl, halogen and C₁-C₆ alkoxy.

19. A compound of claim 2 wherein R_a and R_b are independently hydrogen or C₁-C₆ alkyl.

20. A compound of claim 9 wherein R_a and R_b are independently hydrogen or C₁-C₆ alkyl.

21. A compound of claim 10 wherein R_a and R_b are independently hydrogen or C₁-C₆ alkyl.

22. A compound of claim 11 wherein R_a and R_b are independently hydrogen or C₁-C₆ alkyl.

23. A compound of claim 12 wherein R_a and R_b are independently hydrogen or C₁-C₆ alkyl.

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.

33. A compound of claim 1 wherein the optional substituents on L¹ 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.

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—

L¹, wherein

L is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl up to perhalo, C₁-C₃ alkoxy and halogen;

L¹ is pyridinyl, substituted by —

C(O)R_x;

wherein R_x is NR_aR_b and R_a and R_b are independently

hydrogen,

C₁-C₁₀ alkyl,

C₆ aryl,

pyridinyl, substituted C_1-10 alkyl,

substituted C₆ aryl, or

substituted pyridinyl,

where R_a and R_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 R⁷ and halogen;

and R⁷ is

(a) C₁-C₆ linear or branched alkyl, optionally substituted with 1-3 halogen substituents;

or

(b) C₁-C₆ linear or branched alkoxy.

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.

28. A compound as in claim 24 wherein substituents for B, are selected from the group consisting of up to per halo substituted C₁-C₆ alkyl and halogen.

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.

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—

L¹,

L is phenyl,

M is —

O—

,

L¹ is pyridinyl substituted by —

C(O)R_x,

wherein R_x is NR_aR_b and R_a and R_b are independently

hydrogen,

C₁-C₁₀ alkyl,

C₆ aryl,

pyridinyl,

substituted C_1-10 alkyl,

substituted C₆ aryl, or

substituted pyridinyl

where R_a and R_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_n where n is 0-3, and each W is independently selected from the group consisting of

C₁-C₁₀ alkyl,

C₁-C₁₀ alkoxy,

C₆ aryl,

pyridinyl,

and substituted C₁-C₁₀ alkyl, substituted by one or more substituents independently selected from the group consisting of halogen up to per halo.

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.

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 C₁-C₆ alkyl and halogen.

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.

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—

L¹,

wherein L is phenyl, optionally substituted with chlorine or methyl substituents;

L¹ is pyridinyl, substituted with —

C(O)NR^aR^b;

wherein R^a and R^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^a is hydrogen and R^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-pyridyloxy)phenyl)urea of the formula X

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-pyridyloxy)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-pyridyloxy)phenyl)urea.