Details for Patent: 8,440,681

Title:	2-biphenylamino-4-aminopyrimidine derivatives as kinase inhibitors
Abstract:	The invention provides novel pyrimidine derivatives of formula (1) and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of insulin-like growth factor (IGF-1R) or anaplastic lymphoma kinase (ALK). ##STR00001##
Inventor(s):	Marsilje; Thomas H. (San Diego, CA), Lu; Wenshuo (San Diego, CA), Chen; Bei (San Diego, CA), He; Xiaohui (San Diego, CA), Bursulaya; Badry (Escondido, CA), Lee; Christian Cho-Hua (San Diego, CA)
Assignee:	IRM LLC (Hamilton, BM)
Filing Date:	Aug 27, 2008
Application Number:	12/675,379
Claims:	1. A compound of Formula (1): ##STR00129## or a pharmaceutically acceptable salt thereof; wherein R.sup.1a is halo, C.sub.1-6 alkyl, or a halo-substituted C.sub.1-6 alkyl; R.sup.1b is H; R.sup.2 is a C.sub.6-10 carbocyclic, or a 5-10 membered heteroaryl or 5-7 membered heterocyclic ring each having 1-3 heteroatoms selected from N, O and S; each of which is optionally substituted with C.sub.1-6 alkyl, -L-Y, -L-C(O)O.sub.0-1--(CR.sub.2).sub.q--R.sup.8 or -L-C(O)--NRR.sup.8; R.sup.3 is H or CO(R.sup.7) wherein R.sup.7 is C.sub.1-6 alkyl; R.sup.4 is H; R.sup.5 and R.sup.6 are independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, each of which may be optionally substituted with halo, amino or hydroxyl groups; or R.sup.5 and R.sup.6 are independently halo, nitro, cyano, OR.sup.8, O(CR.sub.2).sub.p--OR.sup.8, -L-NR(R.sup.8), -L-NR(CR.sub.2).sub.pOR.sup.8, -L-NR--(CR.sub.2).sub.q--C(O)R.sup.9, -L-Y, -L-C(O)O.sub.0-1--(CR.sub.2).sub.q--R.sup.8, -L-C(O)--NRR.sup.8, -L-C(O)--NR--(CR.sub.2).sub.p--NRR.sup.8, -L-C(O)NR(CR.sub.2).sub.pOR.sup.8, -L-C(O)--(CR.sub.2).sub.q--NR--C(O)--R.sup.9, -L-C(O)NR(CR.sub.2).sub.pSR.sup.8, -L-C(O)NR(CR.sub.2).sub.pS(O).sub.1-2R.sup.9, -L-S(O).sub.2R.sup.9, -L-S(O).sub.2NRR.sup.8, -L-S(O).sub.2NR(CR.sub.2).sub.pNR(R.sup.8), -L-S(O).sub.2NR(CR.sub.2).sub.pOR.sup.8; alternatively, two adjacent R.sup.5 groups together with the carbon atoms they are attached to may form a 9-14 membered ring; R.sup.8 and R.sup.9 are independently (CR.sub.2).sub.9Y or C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, each of which may be optionally substituted with halo, amino or hydroxyl; or R.sup.8 is H; each R is H or C.sub.1-6 alkyl; Y is a C.sub.3-12 carbocyclic ring, C.sub.6-10 aryl or a 5-10 membered heteroaryl or heterocyclic ring, each having 1-4 heteroatoms selected from N, O and S; wherein Y is optionally substituted with 1-3 C.sub.1-6 alkyl; L is (CR.sub.2).sub.1-4 or a bond; m is 2-4; p is 1-4; and n and q are independently 0-4. 2. The compound of claim 1, wherein said compound is of Formula (2A) or (2B): ##STR00130## wherein one of R.sup.5a, R.sup.5b and R.sup.5c is H and the others and R.sup.6 are independently C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, each of which may be optionally substituted with halo, amino or hydroxyl groups; or R.sup.5a, R.sup.5b, R.sup.5c and R.sup.6 are independently halo, nitro, cyano. OR.sup.8, O(CR.sub.2).sub.p--OR.sup.8, -L-NR(R.sup.8), -L-NR(CR.sub.2).sub.pOR.sup.8, -L-NR-L-C(O)R.sup.9, -L-Y, -L-C(O)O.sub.0-1--(CR.sub.2).sub.q--R.sup.8, -L-C(O)--NRR.sup.8, -L-C(O)--NR--(CR.sub.2).sub.p--NRR.sup.8, -L-C(O)NR(CR.sub.2).sub.pOR.sup.8, -L-C(O)--(CR.sub.2).sub.q--NR--C(O)--R.sup.9, -L-C(O)NR(CR.sub.2).sub.pSR.sup.8, -L-C(O)NR(CR.sub.2).sub.pS(O).sub.1-2R.sup.9, -L-S(O).sub.2R.sup.9, -L-S(O).sub.2NRR.sup.8, -L-S(O).sub.2NR(CR.sub.2).sub.pNR(R.sup.8), -L-S(O).sub.2NR(CR.sub.2).sub.pOR.sup.8; wherein L is (CR.sub.2).sub.1-4 or a bond; R.sup.8 and R.sup.9 are independently (CR.sub.2).sub.9Y or C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, each of which may be optionally substituted with halo, amino or hydroxyl; or R.sup.8 is H; each R is H or C.sub.1-6 alkyl; Y is a C.sub.3-12 carbocyclic ring, C.sub.6-10 aryl or a 5-10 membered heteroaryl or heterocyclic ring, each having 1-4 heteroatoms selected from N, O and S; wherein Y is optionally substituted with 1-3 C.sub.1-6 alkyl groups; p is 1-4; and q is 0-4. 3. The compound of claim 2, wherein R.sup.5b is H; R.sup.5a and R.sup.5c are independently halo, hydroxyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo-substituted C.sub.1-6 alkyl or halo-substituted C.sub.1-6 alkoxy; and R.sup.6 is C.sub.1-6 alkyl, -L-NR-L-C(O)R.sup.9, -L-C(O)O.sub.0-1--(CR.sub.2).sub.q--R.sup.8, -L-C(O)--NRR.sup.8, -L-S(O).sub.2R.sup.9 or -L-S(O).sub.2NRR.sup.8. 4. The compound of claim 2, wherein R.sup.5c is H; and R.sup.5a and R.sup.5b are independently halo, hydroxyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo-substituted C.sub.1-6 alkyl or halo-substituted C.sub.1-6 alkoxy. 5. The compound of claim 1, wherein R.sup.2 is pyrazolyl, pyrrolyl, thiophenyl, pyrimidinyl, isoxazolyl, pyridyl, azepan-2-onyl, thiazolyl, imidazolyl, isoxazolyl, indazolyl, quinolinyl, or bicycle[2.2.1]hept-5-enyl, each of which is optionally substituted with 1-2 R.sup.6 groups. 6. The compound of claim 1, wherein said compound is selected from the group consisting of ##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.