Details for Patent: 7,858,626

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 (La Jolla, CA), Cheung; Mui (Wayne, PA), Davis-Ward; Ronda Gayle (North Little Rock, AR), Harris; Philip Anthony (Wayne, PA), Hinkle; Kevin (Phoenixville, PA), Lauderman; Christopher P. (Durham, NC), Mook, Jr.; Robert Anthony (Chapel Hill, NC), Stafford; Jeffery Alan (San Diego, CA), Veal; James Marvin (Apex, NC)
Assignee:	GlaxoSmithKline LLC (Philadelphia, PA)
Filing Date:	Jul 30, 2007
Application Number:	11/830,024
Claims:	1. A compound of formula (II): ##STR00124## or a salt thereof, wherein: X.sub.1 is methyl or ethyl; X.sub.2 is hydrogen or methyl; X.sub.3 is hydrogen; X.sub.4 is hydrogen, methyl, or ethyl; W is N; Q.sub.1 is hydrogen, chlorine, or methoxy; 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, 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, and Z.sup.2 is C.sub.1-C.sub.4 alkyl or NR.sup.3R.sup.4; and R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen and C.sub.1-C.sub.4 alkyl. 2. A compound as claimed in claim 1 wherein X.sub.1 is methyl. 3. A compound as claimed in claim 1 wherein X.sub.2 is hydrogen. 4. A compound as claimed in claim 1 wherein X.sub.2 is methyl. 5. A compound as claimed in claim 1 wherein X.sub.4 is methyl. 6. 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. 7. 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. 8. A compound as claimed in claim 1 wherein Q.sub.1 is hydrogen. 9. A compound as claimed in claim 1 wherein Q.sub.1 is chlorine. 10. A compound as claimed in claim 1 wherein Q.sub.1 is methoxy. 11. A compound as claimed in claim 1 wherein Q.sub.2 is A.sup.1 and Q.sub.3 is A.sup.2. 12. A compound as claimed in claim 1 wherein Q.sub.2 is A.sup.2 and Q.sub.3 is A.sup.1. 13. 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; Z.sup.1 is S(O).sub.2; and Z.sup.2 is C.sub.1-C.sub.4 alkyl. 14. 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).sub.4Z.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 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. 15. A compound as claimed in claim 1 selected from the group consisting of: N.sup.2-(3-methyl-1H-indazol-6-yl)-N.sup.4-{3-[(methylsulfonyl)methyl- ]phenyl}-1,3,5-triazine-2,4-diamine trifluoroacetate; N.sup.2-methyl-N.sup.2-(3-methyl-1H-indazol-6-yl)-N.sup.4-4-{3-[(methylsu- lfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diamine; N.sup.2-[5-(ethylsulfonyl)-2-methoxyphenyl]-N.sup.4-methyl-N.sup.4-(3-met- hyl-1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine; N-[2-methyl-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-1,3,5-triazin-2- -yl}amino)phenyl]methanesulfonamide; N.sup.2-methyl-N.sup.2-(3-methyl-1H-indazol-6-yl)-N.sup.4-[3-(methylsulfo- nyl)phenyl]-1,3,5-triazine-2,4-diamine; 3-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-1,3,5-triazin-2-yl}am- ino)benzenesulfonamide; and 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-1,3,5-triazin-2-yl}am- ino)-2-methylbenzenesulfonamide; or a salt thereof. 16. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients. 17. The pharmaceutical composition of claim 16, further comprising at least one additional agent that is an anti-neoplastic agent. 18. The pharmaceutical composition of claim 16, further comprising an additional agent that inhibits angiogenesis. 19. A method of treating a disorder in a mammal, said disorder being characterized by inappropriate angiogenesis, wherein said disorder is selected from the group consisting of colon cancer and breast cancer, comprising administering to said mammal a therapeutically effective amount of a compound as claimed in claim 1. 20. A compound as claimed in claim 1, wherein X.sub.1 is methyl, X.sub.2 is hydrogen, X.sub.3 is hydrogen, X.sub.4 is methyl, and Q.sub.1 is hydrogen.