Claims for Patent: 7,262,203

Summary 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):	Amogh Boloor, Mui Cheung, Ronda Davis, Philip Anthony Harris, Kevin Hinkle, Robert Anthony Mook, Jr., Jeffery Alan Stafford, James Marvin Veal
Assignee:	Novartis AG, SmithKline Beecham Corp
Application Number:	US11/383,229
Patent Claims:	1. A compound of Formula (I): or a salt thereof: wherein: D is X1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl; X2 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C(O)R1, or aralkyl; X3 is hydrogen or halogen; X4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, heteroaralkyl, cyanoalkyl, —(CH2)pC═CH(CH2)tH, —(CH2)pC≡C(CH2)tH, or C3-C7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is C—R, wherein R is hydrogen, halogen, or cyano; Q1 is hydrogen, halogen, C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 alkoxy, or C1-C2 haloalkoxy; Q2 is A1 or A2; Q3 is A1 when Q2 is A2 and Q3 is A2 when Q2 is A1; wherein A1 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OR1, and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl, NR3R4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R1 is C1-C4 alkyl; R2, R3, and R4 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, —S(O)2R5, and —C(O)R5; R5 is C1-C4 alkyl, or C3-C7 cycloalkyl; and when Z is oxygen then Z1 is S(O)2 and when D is then X2 is C1-C4 alkyl, C1-C4 haloalkyl, C(O)R1, or aralkyl. 2. A compound as claimed in claim 1 wherein D is 3. A compound as claimed in claim 1 wherein D is 4. A compound of claim 1 wherein D is 5. A compound of formula (II): or a salt thereof: wherein: X1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl; X2 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C(O)R1, or aralkyl; X3 is hydrogen or halogen; X4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, heteroaralkyl, cyanoalkyl, —(CH2)pC═CH(CH2)tH, —(CH2)pC═C(CH2)tH, or C3-C7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is C—R, wherein R is hydrogen, halogen, or cyano; Q1 is hydrogen, halogen, C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 alkoxy, or C1-C2 haloalkoxy; Q2 is A1 or A2; Q3 is A1 when Q2 is A2 and Q3 is A2 when Q2 is A1; wherein A1 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OR1, and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH2NR2and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4alkyl, NR3R4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R1 is C1-C4alkyl; R2, R3, and R4 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, —S(O)2R5, and —C(O)R5; R5 is C1-C4 alkyl, or C3-C7 cycloalkyl; and when Z is oxygen then Z1 is S(O)2. 6. A compound of Formula (III): or a salt thereof: wherein: X1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl; X2 is C1-C4 alkyl, C1-C4 haloalkyl, or C(O)R1; X3 is hydrogen or halogen; X4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, heteroaralkyl, cyanoalkyl, —(CH2)pC═CH(CH2)tH, —(CH2)pC≡C(CH2)tH, or C3-C7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is C—R, wherein R is hydrogen, halogen, or cyano; Q1 is hydrogen, halogen, C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 alkoxy, or C1-C2 haloalkoxy; Q2 is A1 or A2; Q3 is A1 when Q2 is A2 and Q3 is A2 when Q2 is A1; wherein A1 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OR1, and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl, NR3R4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R1 is C1-C4 alkyl; R2, R3, and R4 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, —S(O)2R5, and —C(O)R5; R5 is C1-C4 alkyl, or C3-C7 cycloalkyl; and when Z is oxygen then Z1 is S(O)2. 7. A compound of Formula (IV): or a salt thereof: wherein: X1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl; X2 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C(O)R1, or aralkyl; X3 is hydrogen or halogen; X4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, heteroaralkyl, cyanoalkyl, —(CH2)pC═CH(CH2)tH, —(CH2)pC≡C(CH2)tH, or C3-C7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is C—R, wherein R is hydrogen, halogen, or cyano; Q1 is hydrogen, halogen, C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 alkoxy, or C1-C2 haloalkoxy; Q2 is A1 or A2; Q3 is A1 when Q2 is A2and Q3 is A2 when Q2 is A1; wherein A1 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OR1, and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH2 NR2and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl, NR3R4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R1 is C1-C4 alkyl; R2, R3, and R4 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, —S(O)2R5, and —C(O)R5; R5 is C1-C4 alkyl, or C3-C7 cycloalkyl; and when Z is oxygen then Z1 is S(O)2. 8. A compound as claimed in claim 1, wherein X1 is hydrogen or C1-4 alkyl. 9. A compound as claimed in claim 1, wherein X1 is methyl or ethyl. 10. A compound as claimed in claim 1, wherein X1 is methyl. 11. A compound as claimed in claim 1, wherein X2 is hydrogen or C1-4 alkyl. 12. A compound as claimed in claim 1, wherein X2 is hydrogen or methyl. 13. A compound as claimed in claim 1, wherein X2 is hydrogen. 14. A compound as claimed in claim 1, wherein X2 is methyl. 15. A compound as claimed in claim 1, wherein X3 is halogen. 16. A compound as claimed in claim 1, wherein X3 is hydrogen. 17. A compound as claimed in claim 1, wherein X4 is hydrogen, C1-C4 alkyl, cyanoalkyl, or —(CH2)pC≡C(CH2)tH. 18. A compound as claimed in claim 1, wherein X4 is hydrogen, methyl, ethyl, isopropyl, cyanomethyl, or —(CH2)pC≡C(CH2)tH, wherein p is 1 and t is 0. 19. A compound as claimed in claim 1, wherein X4 is methyl. 20. A compound as claimed in claim 1, wherein X1 is methyl or ethyl, X2 is hydrogen or methyl, X3 is hydrogen or halogen, and X4 is hydrogen, methyl, ethyl, isopropyl, cyanomethyl, or —(CH2)pC≡C(CH2)tH, wherein p is 1 and t is 0. 21. A compound as claimed in claim 1, wherein X1 is methyl, X2 is hydrogen, X3 is hydrogen, and X4 is methyl. 22. A compound as claimed in claim 1, wherein X1 is methyl, X2 is methyl, X3 is hydrogen, and X4 is methyl. 23. A compound as claimed in claim 1, wherein D is: and X1 is methyl, X2 is hydrogen, X3 is hydrogen, and X4 is methyl. 24. A compound as claimed in claim 1, wherein D is and X1 is methyl, X2 is methyl, X3 is hydrogen, and X4 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 Q1 is hydrogen, halogen, C1-C2 alkyl or C1-C2 alkoxy. 28. A compound as claimed in claim 1, wherein Q1 is hydrogen. 29. A compound as claimed in claim 1, wherein Q1 is chlorine. 30. A compound as claimed in claim 1, wherein Q1 is methyl. 31. A compound as claimed in claim 1, wherein Q1 is methoxy. 32. A compound as claimed in claim 1, wherein Q2 is A1 and Q3 is A2. 33. A compound as claimed in claim 1, wherein Q2 is A2 and Q3 is A1. 34. A compound as claimed in claim 1, wherein Q2 is A2 and Q3 is A1, wherein A1 is hydrogen, halogen, or C1-C3 haloalkyl and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl or NR3R4 and wherein R2, R3, and R4 are each independently selected from hydrogen or C1-C4alkyl. 35. A compound as claimed in claim 1, wherein Q2 is A2 and Q3 is A1, wherein A1 is hydrogen or chlorine and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z1 is S(O)2; and Z2 is C1-C4 alkyl. 36. A compound as claimed in claim 1, wherein Q2 is A1 and Q3 is A2, wherein A1 is hydrogen, halogen, or C1-C3 alkyl and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl or NR3R4, and wherein R2, R3, and R4 are each independently selected from hydrogen or C1-C4 alkyl. 37. A compound as claimed in claim 1, wherein Q2 is A1 and Q3 is A2, wherein A1 is hydrogen, methyl, or chlorine and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3; Z1 is S(O)2; and Z2 is C1-C4 alkyl or NR3R4, wherein R3 and R4 are each independently selected from hydrogen or C1-C4 alkyl. 38. A compound as claimed in claim 1, wherein X1 is hydrogen or C1-4 alkyl; X2 is hydrogen or C1-4 alkyl; X3 is hydrogen or halogen; and X4 is hydrogen, C1-C4 alkyl, cyanoalkyl, or —(CH2)pC≡C(CH2)tH; W is C—R wherein R is H, F, Cl, or CN; Q1 is hydrogen, halogen, C1-C2 alkyl or C1-C2 alkoxy; and Q2 is A2 and Q3 is A1, wherein A1 is hydrogen, halogen, or C1-C3 haloalkyl and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2 or C(O); and Z2 is C1-C4 alkyl or NR3R4 and wherein R2, R3, and R4 are each independently selected from hydrogen or C1-C4alkyl. 39. A compound as claimed in claim 1, wherein X1 is hydrogen or C1-4 alkyl; X2 is hydrogen or C1-4 alkyl; X3 is hydrogen or halogen; and X4 is hydrogen, C1-C4 alkyl, cyanoalkyl, or —(CH2)pC≡C(CH2)tH; W is C—R wherein R is H, F, Cl, or CN; Q1 is hydrogen, halogen, C1-C2 alkyl or C1-C2 alkoxy; and Q2 is A1 and Q3 is A2, wherein A1 is hydrogen, halogen, or C1-C3 haloalkyl and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl or NR3R4, and wherein R2, R3, and R4 are each independently selected from hydrogen or C1-C4alkyl. 40. A compound as claimed in claim 1, wherein X1 is methyl or ethyl; X2 is hydrogen or methyl; X3 is hydrogen; and X4 is hydrogen, methyl, ethyl, isopropyl, cyanomethyl, or —(CH2)pC≡C(CH2)tH, wherein p is 1 and t is 0; W is C—H or C—F; Q1 is hydrogen, chlorine, methyl, or methoxy; Q2 is A1 and Q3 is A2, wherein A1 is hydrogen, methyl, or chlorine and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl or NR3R4, and wherein R2, R3, and R4 are each independently selected from H or C1-C4 alkyl. 41. A compound as claimed in claim 1, wherein X1 is methyl; X2 is hydrogen; X3 is hydrogen; and X4 is methyl; W is C—H; Q1 is hydrogen, chlorine, methyl, or methoxy; Q2 is A1 and Q3 is A2, wherein A1 is hydrogen, methyl, or chlorine and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl or NR3R4, and wherein R2, R3, and R4 are each independently selected from hydrogen or C1-C4 alkyl. 42. A compound as claimed in claim 1, wherein X1 is methyl; X2 is methyl; X3 is hydrogen; and X4 is methyl; W is C—H; Q1 is hydrogen, chlorine, methyl, or methoxy; Q2 is A1 and Q3 is A2, wherein A1 is hydrogen, methyl, or chlorine and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl or NR3R4, and wherein R2, R3, and R4 are each independently selected from hydrogen or C1-C4 alkyl. 43. A compound as claimed in claim 1, wherein X1 is methyl; X2 is hydrogen; X3 is hydrogen; and X4 is methyl; W is C—F; Q1 is hydrogen, chlorine, or methoxy; Q2 is A1 and Q3 is A2 1, wherein A1 is hydrogen, methyl, or chlorine and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl or NR3R4, and wherein R2, R3, and R4 are each independently selected from hydrogen or C1-C4 alkyl. 44. A compound as claimed in claim 1, wherein D is: and X1 is methyl; X2 is hydrogen; X3 is hydrogen; and X4 is methyl; W is C—H; Q1 is hydrogen, methyl, chlorine, or methoxy; Q2 is A1 and Q3 is A2, wherein A1 is hydrogen, methyl, or chlorine and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl or NR3R4, and wherein R2, R3, and R4 are each independently selected from hydrogen or C1-C4 alkyl. 45. A compound as claimed in claim 1, wherein D is and X1 is methyl; X2 is methyl; X3 is hydrogen; and X4 is methyl; W is C—H; Q1 is hydrogen, chlorine, methyl, or methoxy; Q2 is A1 and Q3 is A2, wherein A1 is hydrogen, methyl, or chlorine and A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl or NR3R4, and wherein R2, R3, and R4 are each independently selected from hydrogen or C1-C4 alkyl. 46. A compound selected from the group consisting of: N2-[5-(ethylsulfonyl)-2-methoxyphenyl]-5-fluoro-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; 3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-4-methoxy-N-methylbenzenesulfonamide; 5-fluoro-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; 3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-N-isopropylbenzenesulfonamide; 5-fluoro-N2-[5-(isopropylsulfonyl)-2-methoxyphenyl]-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N-[5-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-2-methylphenyl]methanesulfonamide; 5-fluoro-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-N2-[4-(methylsulfonyl)phenyl]-2,4-pyrimidinediamine; N4-(3-ethyl-1H-indazol-6-yl)-5-fluoro-N4-methyl-N2(-methyl-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; 4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; N4-ethyl-5-fluoro-N2-[2-methoxy-5-(methylsulfonyl)phenyl]-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; [4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]-N-methylmethanesulfonamide; 5-fluoro-N2-{3-[(isopropylsulfonyl)methyl]phenyl}-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; 3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-4-methoxybenzamide; 4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-3-methoxybenzenesulfonamide; 3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; N2-[5-(ethylsulfonyl)-2-methoxyphenyl]-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; N-isopropyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; N-cyclopropyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; N4-ethyl-N2-[5-(ethylsulfonyl)-2-methoxyphenyl]-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]methanesulfonamide; N2-{3-[(isopropylsulfonyl)methyl]phenyl}-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N2-{4-[(isopropylsulfonyl)methyl]phenyl}-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N2-[5-(isobutylsulfonyl)-2-methoxyphenyl]-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]acetamide; N-[3-({4-[ethyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]acetamide; N2-(2-methoxy-5-{[(5-methyl-3-isoxazolyly)methyl]sulfonyl}phenyl)-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; 4-methoxy-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; N2-[5-(isopropylsulfonyl)-2-methoxyphenyl]-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N2-[5-(ethylsulfonyl)-2-methoxyphenyl]-N4-isopropyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N4-(1H-indazol-6-yl)-N4-methyl-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; N4-(1,3-dimethyl-1H-indazol-6-yl)-N4-methyl-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; N4-(2,3-dimethyl-2H-indazol-6-yl)-N4-methyl-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; N4-(2,3-dimethyl-2H-indazol-6-yl)-N2-[5-(ethylsulfonyl)-2-methoxyphenyl]-N4-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-pyrimidinyl)amino]acetonitrile; [{2-[5-(ethylsulfonyl)-2-methoxyanilino]-4-pyrimidinyl}(3-methyl-1H-indazol-6-yl)amino]acetonitrile; [(3-methyl-1H-indazol-6-yl)(2-{3-[(methylsulfonyl)methyl]anilino}-4-pyrimidinyl)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)benzamide; 3-methoxy-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; N4-ethynyl-N4-(3-methyl-1H-indazol-6-yl)-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine; 3-({4-[(3-methyl-1H-indazol-6-yl)(2-propynyl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; 4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-N2-[3-(methylsulfonyl)phenyl]-2,4-pyrimidinediamine; 4-methoxy-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; N2-[5-(ethylsulfonyl)-2-methoxyphenyl]-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; 3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzamide; N2-[4-(ethylsulfonyl)phenyl]-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N-[4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzyl]ethanesulfonamide; N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzyl]methanesulfonamide; 2-chloro-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; 2-chloro-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; 4-chloro-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; 3-methyl-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; 2-methyl-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; 4-methyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide; N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-N2-[3-(methylsulfinyl)phenyl]-2,4-pyrimidinediamine; N2-[2-fluoro-5-(methylsulfonyl)phenyl]-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; N2-[2-methoxy-5-(methylsulfonyl)phenyl]-N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine; 3-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide; 2-[4-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)phenyl]ethanesulfonamide; 3-({4-[[3-(hydroxymethyl)-2-methyl-2H-indazol-6-yl](methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide; 3-({4-[(1,2-dimethyl-1H-benzimidazol-5-yl)(methyl)amino]pyrimidin-2-yl}amino)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}amino)benzenesulfonamide; and 3-({4-[[2-(3-chlorobenzyl)-3-methyl-2H-indazol-6-yl](methyl)amino]pyrimidin-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.