Substituted pyrimidine derivatives useful in the treatment of cancer and other disorders

1. A compound of formula (I), a salt thereof, an oxidized derivative thereof, wherein one or more of the nitrogens are substituted with a hydroxy group, or a diastereoisomeric form thereof, either as an isolated stereoisomer or in a mixture of stereoisomers

wherein

A is pyrimidine,

optionally substituted with 1 to 3 substituents which are independently R 1 , OR 1 , S(O) p R 1 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , halogen, hydroxy, amino, cyano, or nitro;

B is phenyl, naphthyl, or pyridyl, optionally substituted with 1 to 4 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, or nitro;

L is a bridging group which is:

(a) —(CH 2 ) m —O—(CH 2 ) l —,

(b) —(CH 2 ) m —(CH 2 ) l —,

(c) —(CH 2 ) m —C(O)—(CH 2 ) l —,

(d) —(CH 2 ) m —NR 3 —(CH 2 ) l —,

(e) —(CH 2 ) m —NR 3 C(O)—(CH 2 ) l —,

(f) —(CH 2 ) m —S—(CH 2 ) l —, or

(g) —(CH 2 ) m C(O)NR 3 —(CH 2 ) l —, where the integers m and l are independently selected from 0-4 and for —(CH 2 ) m —(CH 2 ) l — m and l cannot both be 0;

M is a pyridine or pyrimidine ring, optionally substituted with 1-3 substituents which are independently selected from:

(1) C 1 -C 5 linear or branched alkyl;

(2) C 1 -C 5 linear or branched haloalkyl;

(3) C 1 -C 3 alkoxy;

(4) hydroxy;

(5) amino;

(6) C 1 -C 3 alkylamino;

(7) C 1 -C 6 dialkylamino;

(8) halogen;

(9) nitro;

(10) C(O) NR 4 R 5 ;

(11) C(O)OR 4 ;

(12) C(O)R 4 ;

(13) CN;

(14) C(S)NR 4 R 5 ;

(15a) C(O)NR 7 —NR 4 R 5 ;

(15b) C(O)NR 7 —R 4 —C(O)NR 4 R 5 ;

(16) tetrazolyl;

(17) imidazolyl;

(18) imidazoline-2-yl;

(19) 1,3,4-oxadiazoline-2-yl;

(20) 1,3-thiazoline-2-yl;

(21) 5-thioxo-4,5-dihydro-1,3,4-thiazoline-2-yl;

(22) 5-oxo-4,5-dihydro-1,3,4-oxadiazoline-2-yl; or

(23) a group of the formula

each of R 1 , R 2 , R 3 , R 4 and R 5 is independently

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl,

(c) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or

(d) —(CH 2 ) q —X.

where the substituent X is a 5 or 6 membered heterocyclic ring, containing at least one atom selected from oxygen, nitrogen and sulfur, which is saturated, partially saturated, or aromatic, or a 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from the group consisting of O, N and S;

R 2 , R 3 , R 4 and R 5 may, independently, additionally include phenyl or C 1 -C 3 phenyl-alkyl;

R 4 and R 5 may optionally be taken together to form a 5 or 6 membered aliphatic ring, which may be interrupted by an atom selected from N, O or S which is optionally substituted with 1-3 substituents which are independently C 1 -C 5 linear or branched alkyl, up to perhalo substituted C 1 -C 5 linear or branched alkyl, C 1 -C 3 alkoxy, hydroxy, oxo, carboxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, or nitro;

R 6 is independently:

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl,

(c) cyano,

(d) nitro,

(e) up to per-halo substituted C 1 -C 5 linear or branched alkyl, or

(f) —C(O)R 7 , where R 7 is C 1 -C 5 linear, branched, or cyclic alkyl;

R 7 is hydrogen, or C 1 -C 5 linear, branched, or cyclic alkyl;

the variable q is an integer 1, 2, 3, or 4 and the variable p is an integer 0, 1, or 2.

2. A compound of claim 1 wherein B is phenyl, optionally substituted with 1-4 substituents which are independently C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 3 alkoxy, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 6 dialkylamino, halogen, cyano, or nitro.

3. A compound of claim 1 or 2 where L is —O— or —S—.

4. A compound of claim 1 , where M is pyridine, optionally substituted with 1-3 substituents which are independently selected from the groups

(1) C 1 -C 5 linear or branched alkyl;

(2) C 1 -C 5 linear or branched haloalkyl;

(3) C 1 -C 3 alkoxy;

(4) hydroxy;

(5) amino;

(6) C 1 -C 3 alkylamino;

(7) C 1 -C 6 dialkylamino;

(8) halogen;

(9) nitro;

(10) C(O) NR 4 R 5 ;

(11) C(O)O R 4 ;

(12) C(O) R 4 ;

(13) CN,

(15a) C(O)NR 7 —NR 4 R 5 ; or

(15b) C(O)NR 7 —R 4 —C(O)NR 4 R 5 .

5. A compound of claim 1 where R 6 is independently:

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl, or

(c) cyano or

(d) nitro.

6. A compound of claim 1 where R 6 is independently:

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl, or

(c) cyano.

7. A compound of claim 1 of formula (III), a salt thereof, an oxidized derivative thereof, wherein one or more of the nitrogens are substituted with a hydroxy group, or a diastereoisomeric form thereof, either as an isolated stereoisomer or in a mixture of stereoisomers,

wherein

Ra is R 1 , OR 1 or cyano;

and B, L and M are as defined in claim 1 .

8. A compound of claim 1 of formula (IV), a salt thereof, an oxidized derivative thereof, wherein one or more of the nitrogens are substituted with a hydroxy group, or a diastereoisomeric form thereof, either as an isolated stereoisomer or in a mixture of stereoisomers,

wherein

Ra is R 1 , OR 1 or cyano;

each Rc is independently hydrogen, halogen, C 1 -C 3 linear or branched alkyl, C 1 -C 3 linear or branched haloalkyl, C 1 -C 3 alkoxy or hydroxy;

and

L and M are as defined in claim 1 .

9. A compound of claim 1 of formula (V), a salt thereof, an oxidized derivative thereof, wherein one or more of the nitrogens are substituted with a hydroxy group, or a diastereoisomeric form thereof, either as an isolated stereoisomer or in a mixture of stereoisomers,

wherein

Ra is R 1 , OR 1 or cyano;

each Rc is independently hydrogen, halogen, C 1 -C 3 linear or branched alkyl, C 1 -C 3 linear or branched haloalkyl, C 1 -C 3 alkoxy or hydroxy;

and M is as defined in claim 1 .

10. A compound as in claim 8 or 9 wherein M is pyridine.

11. A compound as in claim 8 or 9 where in M is pyridine substituted by C(O) NR 4 R 5 or CN.

12. A compound as in claim 8 or 9 where in M is pyridine substituted by C(O) NR 4 R 5 .

13. A compound as in claim 8 or 9 where in M is pyridine substituted by C(O) NHCH 3 or C(O)NH 2 .

14. A compound of formula (II), a salt thereof, an oxidized derivative thereof, wherein one or more of the nitrogens are substituted with a hydroxy group, or a diastereoisomeric form thereof, either as an isolated stereoisomer or mixture of stereoisomers,

wherein

Ra is R 1 , OR 1 or cyano

each Rc is independently hydrogen, halogen, C 1 -C 3 linear or branched alkyl, C 1 -C 3 linear or branched haloalkyl, C 1 -C 3 alkoxy or hydroxy;

Rb is

(1) C 1 -C 5 linear or branched alkyl;

(2) C 1 -C 5 linear or branched haloalkyl;

(3) C 1 -C 3 alkoxy;

(4) hydroxy;

(5) amino;

(6) C 1 -C 3 alkylamino;

(7) C 1 -C 6 dialkylamino;

(8) halogen;

(9) nitro;

(10) C(O) NR 4 R 5 ;

(11) C(O)OR4;

(12) C(O)R 4 ;

(13) CN;

(14) C(S)NR 4 R 5 ;

(15) C(O)NR 7 —R 4 C(O)N R 4 R 5 ; or

(16) hydrogen;

R 1 is hydrogen or C 1 -C 5 linear, branched, or cyclic alkyl,

each of R 4 and R 5 is independently

(a) hydrogen,

(b) C 1 -C 5 linear, branched, or cyclic alkyl or

(c) phenyl, and

R 7 is hydrogen, or C 1 -C 5 linear, branched, or cyclic alkyl.

15. A compound of claim 14 wherein Rb is

C 1 -C 5 linear or branched alkyl;

C 1 -C 3 alkoxy;

halogen;

C(O) NR 4 R 5 ;

CN;

C(S)NR 4 R 5 or C(O)NR 7 —R 4 C(O)N R 4 R 5 .

16. A compound of claim 14 wherein Rb is C 1 -C 5 linear or branched alkyl; halogen; C(O) NR 4 R 5 or CN.

17. A compound of claim 14 , 15 or 16 wherein Rc is independently hydrogen or fluorine.

18. A compound of claim 14 wherein Rb is C(O) NR 4 R 5 or CN.

19. A compound of claim 14 wherein Rb is C(O) NR 4 R 5 .

20. A compound of claim 14 wherein Rb is C(O) NHCH 3 or C(O) NH 2 .

21. A compound of claim 1 which is:

4-{3-fluoro-4-[3-(6-trifluoromethylpyrimidin-4-yl)ureido]phenoxy}pyridine-2-carboxylic acid methylamide,

4-{4-[3-(6-trifluoromethyl-pyrimidin-4-yl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide,

4-{4-[3-(6-trifluoromethylpyrimidin-4-yl)ureido]phenoxy}-2-methylpyridine,

1-[2-Fluoro-4-(2-methylpyridin-4-yloxy)phenyl]-3-(6-trifluoromethylpyrimid-in-4-yl)urea,

1-(6-tert-Butylpyrimidin-4-yl)-3-[4-(2-cyanopyridin-4-yloxy)-2-fluoropheny-l]urea,

4-{3-fluoro-4-[3-(6-tert-butylpyrimidin-4-yl)ureido]phenoxy}pyridine-2-carboxylic acid methylamide,

4-{4-[3-(6-tert-Butylpyrimidin-4-yl)ureido]-3-fluorophenoxy}pyridine-2-carboxylic acid amide,

4-{4-[3-(6-tert-Butylpyrimidin-4-yl)ureido]phenoxy}pyridine-2-carbothioic acid amide,

4-{3-fluoro-4-[3-(6-methoxypyrimidin-4-yl)ureido]phenoxy}pyridine-2-carboxylic acid methylamide, or

4-{4-[3-(6-Phenylpyrimidin-4-yl)ureido]phenoxy}pyridine-2-carbothioic acid amide.