发明名称 |
Kinase inhibitors, prodrug forms thereof and their use in therapy |
摘要 |
The invention provides kinase inhibitors of Formula I:;wherein either:(1) R1 is H, and
(a) R2 is (3-chlorobenzyl)oxy-and R3 is chloro;(b) R2 and R3, together with the carbon atoms to which they are attached, form 1-(3-fluorobenzyl)-1H-pyrazole;(c) R2 is 2-pyridinylmethoxy and R3 is chloro;(d) R2 and R3 are both chloro;(e) R2 is chloro and R1 is bromo;(f) R2 and R3 are both bromo;(g) R2 is fluoro and R3 is ethynyl;(h) R2 is chloro and R3 is ethynyl;(i) R2 is bromo and R3 is ethynyl;(j) other than when R1 is in the 3-position in combination with R3, in the 4-position, R2 is bromo and R3 is fluoro;(k) R2 is 2-pyridinylmethoxy and R3 is fluoro; or(l) R2 is 2-pyridinylmethoxy and R1 is bromo; or(2) at least one of R1, R2 and R3 is selected from benzyloxy, 3-chlorobenzyloxy and 2-pyridinylmethoxy and when at least one of R1, R2 and R3 is not benzyloxy, 3-chlorobenzyloxy or 2-pyridinylmethoxy, each of the others is independently selected from H, halogen, and C2-C4 alkynyl, with the proviso that when one of R1, R2 and R3 is benzyloxy or 2-pyridinylmethoxy, the other two of R1, R2 and R3 are not H; or(3) two of R1, R2 and R3, together with the carbon atoms to which they are attached, form 1-(3-fluorobenzyl)-1H-pyrazole; and the other is selected from H, halogen and C2-C4 alkynyl.;Also provided are reductive prodrugs, comprising a kinase inhibitor as defined above and a reductive trigger linked directly or indirectly to a nitrogen of the kinase inhibitor. Further provided are pharmaceutical compositions, comprising the kinase inhibitors or the prodrugs, and the use of such compositions in therapy, in particular for treating cancer. |
申请公布号 |
US9101632(B2) |
申请公布日期 |
2015.08.11 |
申请号 |
US201013390398 |
申请日期 |
2010.09.02 |
申请人 |
AUCKLAND UNISERVICES LIMITED |
发明人 |
Smaill Jeffrey Bruce;Patterson Adam Vorn;Lu Guo-Liang;Lee Ho Huat;Ashoorzadeh Amir;Anderson Robert Forbes;Wilson William Robert;Denny William Alexander;Hsu Huai-Ling Annie;Maroz Andrej;Jamieson Stephen Michael Frazer;Mowday Alexandra Marie;Carlin Kendall Marie |
分类号 |
A61K31/519;A61P35/00;C07D471/04 |
主分类号 |
A61K31/519 |
代理机构 |
Kilpatrick Townsend & Stockton LLP |
代理人 |
Kilpatrick Townsend & Stockton LLP |
主权项 |
1. A compound of Formula III: wherein: X is a negatively charged counterion; and either (1) R1 is H, and
(a) R2 is (3-chlorobenzyl)oxy-and R3 is chloro;(b) R2 and R3, together with the carbon atoms to which they are attached, form 1-(3-fluorobenzyl)-1H-pyrazole;(c) R2 is 2-pyridinylmethoxy and R3 is chloro;(d) R2 and R3 are both chloro;(e) R2 is chloro and R3 is bromo;(f) R2 and R3 are both bromo;(g) R2 is fluoro and R3 is ethynyl;(h) R2 is chloro and R3 is ethynyl;(i) R2 is bromo and R3 is ethynyl;(j) other than when R2 is in the 3-position in combination with R3 in the 4-position, R2 is bromo and R3 is fluoro;(k) R2 is 2-pyridinylmethoxy and R3 is fluoro; or(l) R2 is 2-pyridinylmethoxy and R3 is bromo; or (2) at least one of R1, R2 and R3 is selected from the group consisting of benzyloxy, 3-chlorobenzyloxy and 2-pyridinylmethoxy and when at least one of R1, R2 and R3 is not benzyloxy, 3-chlorobenzyloxy or 2-pyridinylmethoxy, each of the other of R1, R2 and R3 is independently selected from the group consisting of H, halogen, and C2-C4 alkynyl, with the proviso that when one of 1, R2 and R3 is benzyloxy or 2-pyridinylmethoxy, the other two of R1, R2 and R3 re not H; or (3) two of R1, R2 and R3, together with the carbon atoms to which they are attached, form 1-(3-fluorobenzyl)-1H-pyrazole, and the other of R1, R2 and R3 is selected from the group consisting of H, halogen and C2-C4 alkynyl; (4) two of R1, R2 and R3, together with the carbon atoms to which they are attached, form 1-(3-fluorobenzyl)-1H-pyrazole, and the other of R1, R2 and R3 is selected from the group consisting of H, halogen and C2-C4 alkynyl;
R4 is selected from the group consisting of H, methyl, ethyl, trifluoromethyl, —CN, —CONH2 and propyn-1-yl; andR5 is C1-C6 alkyl;or a pharmaceutically acceptable salt or solvate thereof. |
地址 |
Auckland NZ |