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Claims for Patent: 7,262,203

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Claims for Patent: 7,262,203

Title:Pyrimidineamines as angiogenesis modulators
Abstract:Pyrimidine derivatives, which are useful as VEGFR2 inhibitors are described herein. The described invention also includes methods of making such pyrimidine derivatives as well as methods of using the same in the treatment of hyperproliferative diseases.
Inventor(s): Boloor; Amogh (Lubbock, TX), Cheung; Mui (Durham, NC), Davis; Ronda (Durham, NC), Harris; Philip Anthony (Durham, NC), Hinkle; Kevin (Durham, NC), Mook, Jr.; Robert Anthony (Durham, NC), Stafford; Jeffery Alan (San Diego, CA), Veal; James Marvin (Durham, NC)
Assignee: SmithKline Beecham Corporation (Philadelphia, PA)
Application Number:11/383,229
Patent Claims: 1. A compound of Formula (I): ##STR00124## or a salt thereof: wherein: D is ##STR00125## X.sub.1 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 hydroxyalkyl; X.sub.2 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C(O)R.sup.1, or aralkyl; X.sub.3 is hydrogen or halogen; X.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, heteroaralkyl, cyanoalkyl, --(CH.sub.2).sub.pC.dbd.CH(CH.sub.2).sub.tH, --(CH.sub.2).sub.pC.ident.C(CH.sub.2).sub.tH, or C.sub.3-C.sub.7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is C--R, wherein R is hydrogen, halogen, or cyano; Q.sub.1 is hydrogen, halogen, C.sub.1-C.sub.2 haloalkyl, C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy, or C.sub.1-C.sub.2 haloalkoxy; Q.sub.2 is A.sup.1 or A.sup.2; Q.sub.3 is A.sup.1 when Q.sub.2 is A.sup.2 and Q.sub.3 is A.sup.2 when Q.sub.2 is A.sup.1; wherein A.sup.1 is hydrogen, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, --OR.sup.1, and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl, NR.sup.3R.sup.4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R.sup.1 is C.sub.1-C.sub.4 alkyl; R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl, --S(O).sub.2R.sup.5, and --C(O)R.sup.5; R.sup.5 is C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.7 cycloalkyl; and when Z is oxygen then Z.sup.1 is S(O).sub.2 and when D is ##STR00126## then X.sub.2 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C(O)R.sup.1, or aralkyl.

2. A compound as claimed in claim 1 wherein D is ##STR00127##

3. A compound as claimed in claim 1 wherein D is ##STR00128##

4. A compound of claim 1 wherein D is ##STR00129##

5. A compound of formula (II): ##STR00130## or a salt thereof: wherein: X.sub.1 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 hydroxyalkyl; X.sub.2 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C(O)R.sup.1, or aralkyl; X.sub.3 is hydrogen or halogen; X.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, heteroaralkyl, cyanoalkyl, --(CH.sub.2).sub.pC.dbd.CH(CH.sub.2).sub.tH, --(CH.sub.2).sub.pC.dbd.C(CH.sub.2).sub.tH, or C.sub.3-C.sub.7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is C--R, wherein R is hydrogen, halogen, or cyano; Q.sub.1 is hydrogen, halogen, C.sub.1-C.sub.2 haloalkyl, C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy, or C.sub.1-C.sub.2 haloalkoxy; Q.sub.2 is A.sup.1 or A.sup.2; Q.sub.3 is A.sup.1 when Q.sub.2 is A.sup.2 and Q.sub.3 is A.sup.2 when Q.sub.2 is A.sup.1; wherein A.sup.1 is hydrogen, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, --OR.sup.1, and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH.sub.2NR.sup.2and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4alkyl, NR.sup.3R.sup.4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R.sup.1 is C.sub.1-C.sub.4alkyl; R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl, --S(O).sub.2R.sup.5, and --C(O)R.sup.5; R.sup.5 is C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.7 cycloalkyl; and when Z is oxygen then Z.sup.1 is S(O).sub.2.

6. A compound of Formula (III): ##STR00131## or a salt thereof: wherein: X.sub.1 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 hydroxyalkyl; X.sub.2 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or C(O)R.sup.1; X.sub.3 is hydrogen or halogen; X.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, heteroaralkyl, cyanoalkyl, --(CH.sub.2).sub.pC.dbd.CH(CH.sub.2).sub.tH, --(CH.sub.2).sub.pC.ident.C(CH.sub.2).sub.tH, or C.sub.3-C.sub.7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is C--R, wherein R is hydrogen, halogen, or cyano; Q.sub.1 is hydrogen, halogen, C.sub.1-C.sub.2 haloalkyl, C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy, or C.sub.1-C.sub.2 haloalkoxy; Q.sub.2 is A.sup.1 or A.sup.2; Q.sub.3 is A.sup.1 when Q.sub.2 is A.sup.2 and Q.sub.3 is A.sup.2 when Q.sub.2 is A.sup.1; wherein A.sup.1 is hydrogen, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, --OR.sup.1, and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl, NR.sup.3R.sup.4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R.sup.1 is C.sub.1-C.sub.4 alkyl; R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl, --S(O).sub.2R.sup.5, and --C(O)R.sup.5; R.sup.5 is C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.7 cycloalkyl; and when Z is oxygen then Z.sup.1 is S(O).sub.2.

7. A compound of Formula (IV): ##STR00132## or a salt thereof: wherein: X.sub.1 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 hydroxyalkyl; X.sub.2 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, or C(O)R.sup.1, or aralkyl; X.sub.3 is hydrogen or halogen; X.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, heteroaralkyl, cyanoalkyl, --(CH.sub.2).sub.pC.dbd.CH(CH.sub.2).sub.tH, --(CH.sub.2).sub.pC.ident.C(CH.sub.2).sub.tH, or C.sub.3-C.sub.7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is C--R, wherein R is hydrogen, halogen, or cyano; Q.sub.1 is hydrogen, halogen, C.sub.1-C.sub.2 haloalkyl, C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy, or C.sub.1-C.sub.2 haloalkoxy; Q.sub.2 is A.sup.1 or A.sup.2; Q.sub.3 is A.sup.1 when Q.sub.2 is A.sup.2and Q.sub.3 is A.sup.2 when Q.sub.2 is A.sup.1; wherein A.sup.1 is hydrogen, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, --OR.sup.1, and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH.sub.2 NR.sup.2and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl, NR.sup.3R.sup.4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R.sup.1 is C.sub.1-C.sub.4 alkyl; R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl, --S(O).sub.2R.sup.5, and --C(O)R.sup.5; R.sup.5 is C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.7 cycloalkyl; and when Z is oxygen then Z.sup.1 is S(O).sub.2.

8. A compound as claimed in claim 1, wherein X.sub.1 is hydrogen or C.sub.1-4 alkyl.

9. A compound as claimed in claim 1, wherein X.sub.1 is methyl or ethyl.

10. A compound as claimed in claim 1, wherein X.sub.1 is methyl.

11. A compound as claimed in claim 1, wherein X.sub.2 is hydrogen or C.sub.1-4 alkyl.

12. A compound as claimed in claim 1, wherein X.sub.2 is hydrogen or methyl.

13. A compound as claimed in claim 1, wherein X.sub.2 is hydrogen.

14. A compound as claimed in claim 1, wherein X.sub.2 is methyl.

15. A compound as claimed in claim 1, wherein X.sub.3 is halogen.

16. A compound as claimed in claim 1, wherein X.sub.3 is hydrogen.

17. A compound as claimed in claim 1, wherein X.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, cyanoalkyl, or --(CH.sub.2).sub.pC.ident.C(CH.sub.2).sub.tH.

18. A compound as claimed in claim 1, wherein X.sub.4 is hydrogen, methyl, ethyl, isopropyl, cyanomethyl, or --(CH.sub.2).sub.pC.ident.C(CH.sub.2).sub.tH, wherein p is 1 and t is 0.

19. A compound as claimed in claim 1, wherein X.sub.4 is methyl.

20. A compound as claimed in claim 1, wherein X.sub.1 is methyl or ethyl, X.sub.2 is hydrogen or methyl, X.sub.3 is hydrogen or halogen, and X.sub.4 is hydrogen, methyl, ethyl, isopropyl, cyanomethyl, or --(CH.sub.2).sub.pC.ident.C(CH.sub.2).sub.tH, wherein p is 1 and t is 0.

21. A compound as claimed in claim 1, wherein X.sub.1 is methyl, X.sub.2 is hydrogen, X.sub.3 is hydrogen, and X.sub.4 is methyl.

22. A compound as claimed in claim 1, wherein X.sub.1 is methyl, X.sub.2 is methyl, X.sub.3 is hydrogen, and X.sub.4 is methyl.

23. A compound as claimed in claim 1, wherein D is: ##STR00133## and X.sub.1 is methyl, X.sub.2 is hydrogen, X.sub.3 is hydrogen, and X.sub.4 is methyl.

24. A compound as claimed in claim 1, wherein D is ##STR00134## and X.sub.1 is methyl, X.sub.2 is methyl, X.sub.3 is hydrogen, and X.sub.4 is methyl.

25. A compound as claimed in claim 1, wherein W is C--R wherein R is H, F, Cl, or CN.

26. A compound as claimed in claim 1, wherein W is C--F, or C--H.

27. A compound as claimed in claim 1, wherein Q.sub.1 is hydrogen, halogen, C.sub.1-C.sub.2 alkyl or C.sub.1-C.sub.2 alkoxy.

28. A compound as claimed in claim 1, wherein Q.sub.1 is hydrogen.

29. A compound as claimed in claim 1, wherein Q.sub.1 is chlorine.

30. A compound as claimed in claim 1, wherein Q.sub.1 is methyl.

31. A compound as claimed in claim 1, wherein Q.sub.1 is methoxy.

32. A compound as claimed in claim 1, wherein Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2.

33. A compound as claimed in claim 1, wherein Q.sub.2 is A.sup.2 and Q.sub.3 is A.sup.1.

34. A compound as claimed in claim 1, wherein Q.sub.2 is A.sup.2 and Q.sub.3 is A.sup.1, wherein A.sup.1 is hydrogen, halogen, or C.sub.1-C.sub.3 haloalkyl and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4 and wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen or C.sub.1-C.sub.4alkyl.

35. A compound as claimed in claim 1, wherein Q.sub.2 is A.sup.2 and Q.sub.3 is A.sup.1, wherein A.sup.1 is hydrogen or chlorine and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z.sup.1 is S(O).sub.2; and Z.sup.2 is C.sub.1-C.sub.4 alkyl.

36. A compound as claimed in claim 1, wherein Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2, wherein A.sup.1 is hydrogen, halogen, or C.sub.1-C.sub.3 alkyl and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4, and wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen or C.sub.1-C.sub.4 alkyl.

37. A compound as claimed in claim 1, wherein Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2, wherein A.sup.1 is hydrogen, methyl, or chlorine and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3; Z.sup.1 is S(O).sub.2; and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4, wherein R.sup.3 and R.sup.4 are each independently selected from hydrogen or C.sub.1-C.sub.4 alkyl.

38. A compound as claimed in claim 1, wherein X.sub.1 is hydrogen or C.sub.1-4 alkyl; X.sub.2 is hydrogen or C.sub.1-4 alkyl; X.sub.3 is hydrogen or halogen; and X.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, cyanoalkyl, or --(CH.sub.2).sub.pC.ident.C(CH.sub.2).sub.tH; W is C--R wherein R is H, F, Cl, or CN; Q.sub.1 is hydrogen, halogen, C.sub.1-C.sub.2 alkyl or C.sub.1-C.sub.2 alkoxy; and Q.sub.2 is A.sup.2 and Q.sub.3 is A.sup.1, wherein A.sup.1 is hydrogen, halogen, or C.sub.1-C.sub.3 haloalkyl and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2 or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4 and wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen or C.sub.1-C.sub.4alkyl.

39. A compound as claimed in claim 1, wherein X.sub.1 is hydrogen or C.sub.1-4 alkyl; X.sub.2 is hydrogen or C.sub.1-4 alkyl; X.sub.3 is hydrogen or halogen; and X.sub.4 is hydrogen, C.sub.1-C.sub.4 alkyl, cyanoalkyl, or --(CH.sub.2).sub.pC.ident.C(CH.sub.2).sub.tH; W is C--R wherein R is H, F, Cl, or CN; Q.sub.1 is hydrogen, halogen, C.sub.1-C.sub.2 alkyl or C.sub.1-C.sub.2 alkoxy; and Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2, wherein A.sup.1 is hydrogen, halogen, or C.sub.1-C.sub.3 haloalkyl and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4, and wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen or C.sub.1-C.sub.4alkyl.

40. A compound as claimed in claim 1, wherein X.sub.1 is methyl or ethyl; X.sub.2 is hydrogen or methyl; X.sub.3 is hydrogen; and X.sub.4 is hydrogen, methyl, ethyl, isopropyl, cyanomethyl, or --(CH.sub.2).sub.pC.ident.C(CH.sub.2).sub.tH, wherein p is 1 and t is 0; W is C--H or C--F; Q.sub.1 is hydrogen, chlorine, methyl, or methoxy; Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2, wherein A.sup.1 is hydrogen, methyl, or chlorine and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4, and wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from H or C.sub.1-C.sub.4 alkyl.

41. A compound as claimed in claim 1, wherein X.sub.1 is methyl; X.sub.2 is hydrogen; X.sub.3 is hydrogen; and X.sub.4 is methyl; W is C--H; Q.sub.1 is hydrogen, chlorine, methyl, or methoxy; Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2, wherein A.sup.1 is hydrogen, methyl, or chlorine and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4, and wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen or C.sub.1-C.sub.4 alkyl.

42. A compound as claimed in claim 1, wherein X.sub.1 is methyl; X.sub.2 is methyl; X.sub.3 is hydrogen; and X.sub.4 is methyl; W is C--H; Q.sub.1 is hydrogen, chlorine, methyl, or methoxy; Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2, wherein A.sup.1 is hydrogen, methyl, or chlorine and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4, and wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen or C.sub.1-C.sub.4 alkyl.

43. A compound as claimed in claim 1, wherein X.sub.1 is methyl; X.sub.2 is hydrogen; X.sub.3 is hydrogen; and X.sub.4 is methyl; W is C--F; Q.sub.1 is hydrogen, chlorine, or methoxy; Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2.sub.1, wherein A.sup.1 is hydrogen, methyl, or chlorine and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4, and wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen or C.sub.1-C.sub.4 alkyl.

44. A compound as claimed in claim 1, wherein D is: ##STR00135## and X.sub.1 is methyl; X.sub.2 is hydrogen; X.sub.3 is hydrogen; and X.sub.4 is methyl; W is C--H; Q.sub.1 is hydrogen, methyl, chlorine, or methoxy; Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2, wherein A.sup.1 is hydrogen, methyl, or chlorine and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4, and wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen or C.sub.1-C.sub.4 alkyl.

45. A compound as claimed in claim 1, wherein D is ##STR00136## and X.sub.1 is methyl; X.sub.2 is methyl; X.sub.3 is hydrogen; and X.sub.4 is methyl; W is C--H; Q.sub.1 is hydrogen, chlorine, methyl, or methoxy; Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2, wherein A.sup.1 is hydrogen, methyl, or chlorine and A.sup.2 is the group defined by -(Z).sub.m-(Z.sup.1)-(Z.sup.2), wherein Z is CH.sub.2 and m is 0, 1, 2, or 3, or Z is NR.sup.2 and m is 0 or 1, or Z is CH.sub.2NR.sup.2 and m is 0 or 1; Z.sup.1 is S(O).sub.2, S(O), or C(O); and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4, and wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen or C.sub.1-C.sub.4 alkyl.

46. A compound selected from the group consisting of: N.sup.2-[5-(ethylsulfonyl)-2-methoxyphenyl]-5-fluoro-N.sup.4-methyl-N.sup- .4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; 3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)-4-methoxy-N-methylbenzenesulfonamide; 5-fluoro-N.sup.4-methyl-N.sup.4-(3-methyl-1H-indazol-6-yl)-N.sup.2-{3-[(m- ethylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; 3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)-N-isopropylbenzenesulfonamide; 5-fluoro-N.sup.2-[5-(isopropylsulfonyl)-2-methoxyphenyl]-N.sup.4-methyl-N- .sup.4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N-[5-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}a- mino)-2-methylphenyl]methanesulfonamide; 5-fluoro-N.sup.4-methyl-N.sup.4-(3-methyl-1H-indazol-6-yl)-N.sup.2-[4-(me- thylsulfonyl)phenyl]-2,4-pyrimidinediamine; N.sup.4-(3-ethyl-1H-indazol-6-yl)-5-fluoro-N.sup.4-methyl-N.sup.2(-methyl- -N.sup.2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; 4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)benzenesulfonamide; N.sup.4-ethyl-5-fluoro-N.sup.2-[2-methoxy-5-(methylsulfonyl)phenyl]-N.sup- .4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; [4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}ami- no)phenyl]-N-methylmethanesulfonamide; 5-fluoro-N.sup.2-{3-[(isopropylsulfonyl)methyl]phenyl}-N.sup.4-methyl-N.s- up.4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; 3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)-4-methoxybenzamide; 4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)-3-methoxybenzenesulfonamide; 3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzene- sulfonamide; N.sup.2-[5-(ethylsulfonyl)-2-methoxyphenyl]-N.sup.4-methyl-N.sup.4-(3-met- hyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N.sup.4-methyl-N.sup.4-(3-methyl-1H-indazol-6-yl)-N.sup.2-{3-[(methylsulf- onyl)methyl]phenyl}-2,4-pyrimidinediamine; N-isopropyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}a- mino)benzenesulfonamide; N-cyclopropyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl- }amino)benzenesulfonamide; N.sup.4-ethyl-N.sup.2-[5-(ethylsulfonyl)-2-methoxyphenyl]-N.sup.4-(3-meth- yl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phen- yl]methanesulfonamide; N.sup.2-{3-[(isopropylsulfonyl)methyl]phenyl}-N.sup.4-methyl-N.sup.4-(3-m- ethyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N.sup.2-{4-[(isopropylsulfonyl)methyl]phenyl}-N.sup.4-methyl-N.sup.4-(3-m- ethyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N.sup.2-[5-(isobutylsulfonyl)-2-methoxyphenyl]-N.sup.4-(3-methyl-1H-indaz- ol-6-yl)-2,4-pyrimidinediamine; N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phen- yl]acetamide; N-[3-({4-[ethyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)pheny- l]acetamide; N.sup.2-(2-methoxy-5-{[(5-methyl-3-isoxazolyly)methyl]sulfonyl}phenyl)-N.- sup.4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; 4-methoxy-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)ben- zenesulfonamide; N.sup.2-[5-(isopropylsulfonyl)-2-methoxyphenyl]-N.sup.4-methyl-N.sup.4-(3- -methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N.sup.2-[5-(ethylsulfonyl)-2-methoxyphenyl]-N.sup.4-isopropyl-N.sup.4-(3-- methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N.sup.4-(1H-indazol-6-yl)-N.sup.4-methyl-N.sup.2-{3-[(methylsulfonyl)meth- yl]phenyl}-2,4-pyrimidinediamine; N.sup.4-(1,3-dimethyl-1H-indazol-6-yl)-N.sup.4-methyl-N.sup.2-{3-[(methyl- sulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; N.sup.4-(2,3-dimethyl-2H-indazol-6-yl)-N.sup.4-methyl-N.sup.2-{3-[(methyl- sulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; N.sup.4-(2,3-dimethyl-2H-indazol-6-yl)-N.sup.2-[5-(ethylsulfonyl)-2-metho- xyphenyl]-N.sup.4-methyl-2,4-pyrimidinediamine; 1-[4-methoxy-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)- phenyl]-1-propanone; 4-methoxy-N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}- amino)phenyl]benzenesulfonamide; 4-methoxy-N-methyl-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}- amino)benzenesulfonamide; [(3-methyl-1H-indazol-6-yl)(2-{4-[(methylsulfonyl)methyl]anilino}-4-pyrim- idinyl)amino]acetonitrile; [{2-[5-(ethylsulfonyl)-2-methoxyanilino]-4-pyrimidinyl}(3-methyl-1H-indaz- ol-6-yl)amino]acetonitrile; [(3-methyl-1H-indazol-6-yl)(2-{3-[(methylsulfonyl)methyl]anilino}-4-pyrim- idinyl)amino]acetonitrile; 4-methoxy-N-methyl-3-({4-[methyl (3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; 4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzami- de; 3-methoxy-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}- amino)benzenesulfonamide; N.sup.4-ethynyl-N.sup.4-(3-methyl-1H-indazol-6-yl)-N.sup.2-{3-[(methylsul- fonyl)methyl]phenyl}-2,4-pyrimidinediamine; 3-({4-[(3-methyl-1H-indazol-6-yl)(2-propynyl)amino]-2-pyrimidinyl}amino)b- enzenesulfonamide; 4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzene- sulfonamide; N.sup.4-methyl-N.sup.4-(3-methyl-1H-indazol-6-yl)-N.sup.2-[3-(methylsulfo- nyl)phenyl]-2,4-pyrimidinediamine; 4-methoxy-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}ami- no)benzenesulfonamide; N.sup.2-[5-(ethylsulfonyl)-2-methoxyphenyl]-N.sup.4-(3-methyl-1H-indazol-- 6-yl)-2,4-pyrimidinediamine; 3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzami- de; N.sup.2-[4-(ethylsulfonyl)phenyl]-N.sup.4-methyl-N.sup.4-(3-methyl-1H-- indazol-6-yl)-2,4-pyrimidinediamine; N-[4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benz- yl]ethanesulfonamide; N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benz- yl]methanesulfonamide; 2-chloro-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)benzenesulfonamide; 2-chloro-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)benzenesulfonamide; 4-chloro-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)benzenesulfonamide; 3-methyl-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)benzenesulfonamide; 2-methyl-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)benzenesulfonamide; 4-methyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amin- o)benzenesulfonamide; N.sup.4-methyl-N.sup.4-(3-methyl-1H-indazol-6-yl)-N.sup.2-[3-(methylsulfi- nyl)phenyl]-2,4-pyrimidinediamine; N.sup.2-[2-fluoro-5-(methylsulfonyl)phenyl]-N.sup.4-methyl-N.sup.4-(3-met- hyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N.sup.2-[2-methoxy-5-(methylsulfonyl)phenyl]-N.sup.4-methyl-N.sup.4-(3-me- thyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; 3-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)b- enzenesulfonamide; 2-[4-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amin- o)phenyl]ethanesulfonamide; 3-({4-[[3-(hydroxymethyl)-2-methyl-2H-indazol-6-yl](methyl)amino]pyrimidi- n-2-yl}amino)benzenesulfonamide; 3-({4-[(1,2-dimethyl-1H-benzimidazol-5-yl)(methyl)amino]pyrimidin-2-yl}am- ino)benzenesulfonamide, 3-({4-[(2-benzyl-1-methyl-1H-benzimidazol-5-yl)(methyl)amino]pyrimidin-2-- yl}amino)benzenesulfonamide; 3-({4-[(2-ethyl-3-methyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}ami- no)benzenesulfonamide; and 3-({4-[[2-(3-chlorobenzyl)-3-methyl-2H-indazol-6-yl](methyl)amino]pyrimid- in-2-yl}amino)benzenesulfonamide; or a salt thereof.

47. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in claim 1, or a salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.

48. The pharmaceutical composition of claim 47, further comprising at least one additional anti-neoplastic agent.

49. The pharmaceutical composition of claim 47, further comprising an additional agent which inhibits angiogenesis.

50. A method of treating a disorder in a mammal, said disorder being characterized by inappropriate angiogenesis, wherein the disorder is a proliferative retinopathy, comprising: administering to said mammal a therapeutically effective amount of a compound as claimed in claim 1, or a salt thereof.
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