Aryl ureas as kinase inhibitors
This invention relates to new aryl ureas and methods for their synthesis. The inventive compounds are useful in the treatment of (i) raf mediated diseases, for example, cancer, (ii) p38 mediated diseases such as inflammation and osteoporosis, and (iii) VEGF mediated diseases such as angiogenesis disorders.
1. A dispersible powder which comprises a compound of formula (I),
wherein,
Y is OR 1 or NHR 2 ,
Hal is chlorine or bromine,
R 1 is H or C 1 -C 6 alkyl,
R 2 is H, OH, CH 3 or CH 2 OH,
Z 1 and Z 2 are each H or OH, wherein only one of Z 1 or Z 2 can be OH,
X 1 to X 7 are each, independently, H, OH or O(CO)C 1 -C 4 alkyl, and
n is 1,
or a salt thereof, or an isolated stereoisomer thereof.
2. A dispersible powder of claim 1 wherein in formula (I), Y is NHR 2 and R 2 is H or CH 3 .
3. A dispersible powder of claim 1 wherein in formula (I),
a) X 1 to X 7 are each H, or
b) Z 1 and Z 2 are each H.
4. A dispersible powder of claim 1 wherein in formula (I),
a) X 1 to X 7 are each H, or
b) Z 1 is H and Z 2 is OH or Z 1 is OH and Z 2 is H, or
c) X 1 to X 7 and Z 1 are each H and Z 2 is OH or
d) X 1 to X 7 and Z 2 are each H and Z 1 is OH.
5. A dispersible powder of claim 1 , wherein in formula (I), at least one of X 1 to X 7 is OH or O(CO)C 1 -C 4 alkyl.
6. A dispersible powder of claim 1 , wherein in formula (I), Y is NHR 2 and R 2 is CH 2 OH or OH.
7. A dispersible powder of claim 1 wherein in formula (I), Y is OH.
8. A dispersible powder of claim 1 , wherein in formula (I), Z 1 is H and Z 2 is OH or Z 1 is OH and Z 2 is H.
9. A dispersible powder of claim 3 , wherein in formula (I), X 1 to X 7 are each H.
10. A dispersible powder of claim 1 which comprises a compound selected from the group consisting of:
4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methyl-2-pyridine carboxamide 1-oxide,
4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-hydroxymethyl-2-pyridine carboxamide 1-oxide,
4-{4-[({[4-bromo-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methyl-2-pyridine carboxamide 1-oxide,
4-{4-[({[4-bromo-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-hydroxymethyl-2-pyridine carboxamide 1-oxide,
4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-2-pyridine carboxamide 1-oxide,
4-{4-[({[4-bromo-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-2-pyridine carboxamide 1-oxide, salts thereof and stereoisomers thereof.
11. A dispersible powder which comprises a compound of formula (II) or a salt or stereoisomer thereof,
wherein,
Y is OR 1 or NHR 2 ,
Hal is chlorine or bromine,
R 1 is H or C 1 -C 6 alkyl,
R 2 is H, OH, CH 3 or CH 2 OH,
Z 1 and Z 2 are each H or OH, wherein only one of Z 1 or Z 2 is OH,
X 4 to X 7 are each, independently, H, OH or O(CO)C 1 -C 4 alkyl, and
n is 1.
12. A dispersible powder of claim 11 , wherein in formula (II), Z 1 and Z 2 are each H.
13. A dispersible powder of claim 12 , wherein in formula (II), at least one of X 4 to X 7 is OH.
14. A dispersible powder of claim 12 , wherein in formula Y is NHR 2 and R 2 is H or CH 3 .
15. A dispersible powder of claim 11 , wherein in formula (II) Y is NHR 2 and R 2 is OH.
16. A dispersible powder of claim 11 , wherein in formula (II), at least one of X 4 to X 7 is OH.
17. A dispersible powder which comprises a compound of formula (III), or a salt or isolated stereoisomer thereof,
wherein,
Y is OR 1 or NHR 2 ,
Hal is chlorine or bromine,
R 1 is H or C 1 -C 6 alkyl,
R 2 is H, OH, CH 3 or CH 2 OH,
Z 1 and Z 2 are each H or OH, wherein only one of Z 1 or Z 2 can be OH, and
n is 1.
18. A dispersible powder of claim 17 , wherein in formula (III), n is 1 and Z 1 and Z 2 are each H.
19. A dispersible powder of claim 18 , wherein in formula (III), Y is NHR 2 and R 2 is H or CH 3 .
20. A dispersible powder which comprises a compound of formula (III), or a salt or isolated stereoisomer thereof,
wherein,
Y is OR 1 or NHR 2 ,
Hal is chlorine or bromine,
R 1 is H or C 1 -C 6 alkyl,
R 2 is H, OH, CH 3 or CH 2 OH,
n is 0 and Z 1 is H and Z 2 is OH or Z 1 is OH and Z 2 is H.
21. A dispersible powder of claim 20 , wherein in formula (III), Y is NHR 2 and R 2 is H or CH 3 .
22. A dispersible powder of claim 17 , wherein in formula Y is OH.
23. A dispersible powder which comprises a compound of formula (I),
wherein,
Y is —NHOH,
Hal is chlorine or bromine,
Z 1 and Z 2 are each H,
X 1 to X 7 are each, H, and
n is 0 or 1
or a salt thereof, or an isolated stereoisomer thereof.
24. A dispersible powder of claim 23 , wherein n is 1.
25. A dispersible powder of claim 24 , wherein n is 0.
26. A dispersible powder of claim 25 , wherein in formula (I), X 1 to X 7 are each H.
27. A dispersible powder of claim 25 , wherein in formula (I), Z 1 is H and Z 2 is OH or Z 1 is OH and Z 2 is H.
28. A dispersible powder of claim 25 , wherein in formula (I), at least one of X 1 to X 7 is OH or O(CO)C 1 -C 4 alkyl.