Macrocyclic derivatives for the treatment of proliferative diseases 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO2013132376 A1 2013-09-12 [WO2013132376] / 2013-09-12
申请号/申请日
2013WO-IB51391 / 2013-02-20
发明人
BAILEY SIMON;BURKE BENJAMIN JOSEPH;COLLINS MICHAEL RAYMOND;CUI JINGRONG JEAN;DEAL JUDITH GAIL;HOFFMAN ROBERT LOUIS;HUANG QINHUA;JOHNSON TED WILLIAM;KANIA ROBERT STEVEN;KATH JOHN CHARLES;LE PHUONG THI QUY;MCTIGUE MICHELE ANN;PALMER;
申请人
PFIZER;
主分类号
IPC分类号
A61K-031/4353A61P-035/00C07D-491/08C07D-491/18C07D-498/08C07D-498/18C07D-498/22C07D-513/18
摘要
(WO2013132376) The invention relates to compounds of formula (Phi) as further defined herein and to the pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to the uses thereof.  The compounds and salts of the present invention inhibit anaplastic lymphoma kinase (ALK) and/or EML4-ALK and are useful for treating or ameliorating abnormal cell proliferative disorders, such as cancer.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2012US-61607485 2012-03-06 2013US-61759307 2013-01-31
主权利要求
(WO2013132376) 1. A compound of the formula (I) wherein: X is selected from the group consisting of -(CR(5)R(6))[q]O(CR(5)R(6))[r], -(CR(5)R(6))[q]N(R(1))(CR(5)R(6))[r], -(CR(5)R(6))[q]C(0)N(R(1))(CR(5)R(6))[r]- and -(CR(5)R(6))[q]N(R(1))C(0)(CR(5)R(6))[r]; Y and Z are each independently N or CH, with the proviso that when Y is N, Z is CH and when Z is N, Y is CH; A is a ring selected from C[6]-Ci[2] aryl and 5-6 membered heteroaryl; R(1) is selected from the group consisting of hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl, wherein each hydrogen on said Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-C[12] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(2) is independently selected from the group consisting of halogen, C-|-C[6] alkyl, C[2]- C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-C[12] aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, -S(0)[t]R(7), -S(0)[2]NR(7)R(8), -S(0)[2]OR(7), -N0[2], -(CR(5)R(6))[q]NR(7)R(8), - N(CR(5)R(6))(CR(5)R(6))[q]NR(7)R(8), -OR(7), -0(CR(5)R(6))(CR(5)R(6))[q]OR(7), -0(CR(5)R(6))(CR(5)R(6))[q]R(7), -CN, -C(0)R(7), -OC(0)R(7), -0(CR(5)R(6))[q]R(7), -NR(7)C(0)R(8), -(CR(5)R(6))[q]C(0)OR(7), -(CR(5)R(6))[q]NR(7)R(8), -C(=NR(7))NR(7)R(8), -NR(7)C(0)NR(7)R(8), -NR(7)S(0)[2]R(8) and -(CR(5)R(6))[q]C(0)NR(7)R(8); wherein each hydrogen on said C C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, - NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -OR(9), -CN, -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); R(3) and R(4) are each independently selected from hydrogen, Ci-C[6] alkyl and C[3]-C[6] cycloalkyi, wherein each hydrogen on Ci-C[6] alkyl and C[3]-C[6] cycloalkyi may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(5) and R(6) is independently selected from the group consisting of hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) and -C(0)NR(9)R(10); wherein each hydrogen on said Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, Cs- Ce cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(7) and R(8) is independently selected from the group consisting of hydrogen, C-|-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-C[12] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl, wherein each hydrogen on said Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -OR(9), -CN, -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(9) and R(10) is independently selected from hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]- C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; each q is independently 0, 1, 2 or 3; each r is independently 0, 1, 2 or 3; and each t is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 2. A compound of the formula (V) A is a ring selected from C[6]-Ci[2] aryl and 5-6 membered heteroaryl; R(1) is selected from the group consisting of hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl, wherein each hydrogen on said Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(2) is independently selected from the group consisting of halogen, Ci-C[6] alkyl, C[2]- C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, -S(0)[t]R(7), -S(0)[2]NR(7)R(8), -S(0)[2]OR(7), -N0[2], -(CR(5)R(6))[q]NR(7)R(8), - N(CR(5)R(6))(CR(5)R(6))[q]NR(7)R(8), -OR(7), -0(CR(5)R(6))(CR(5)R(6))[q]OR(7), -0(CR(5)R(6))(CR(5)R(6))[q]R(7), -CN, -C(0)R(7), -OC(0)R(7), -0(CR(5)R(6))[q]R(7), -NR(7)C(0)R(8), -(CR(5)R(6))[q]C(0)OR(7), -(CR(5)R(6))[q]NR(7)R(8), -C(=NR(7))NR(7)R(8), -NR(7)C(0)NR(7)R(8), -NR(7)S(0)[2]R(8) and -(CR(5)R(6))[q]C(0)NR(7)R(8); wherein each hydrogen on said C C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, - NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -OR(9), -CN, -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); R(3) and R(4) are each independently selected from hydrogen, Ci-C[6] alkyl and C[3]-C[6] cycloalkyi, wherein each hydrogen on Ci-C[6] alkyl and C[3]-C[6] cycloalkyi may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(5) and R(6) is independently selected from the group consisting of hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) and -C(0)NR(9)R(10); wherein each hydrogen on said Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]- C[6] cycloalkyl, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(7) and R(8) is independently selected from the group consisting of hydrogen, C-|-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-C[12] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl, wherein each hydrogen on said Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -OR(9), -CN, -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(9) and R(10) is independently selected from hydrogen, C^Ce alkyl, C[2]-C[6] alkenyl, C[2]- C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-C[12] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl; p is 0, 1, 2, 3 or 4; each q is independently 0, 1, 2 or 3; each r is independently 0, 1, 2 or 3; and each t is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 3. A compound of the formula (VI) (VI) wherein: A is a ring selected from C[6]-Ci[2] aryl and 5-6 membered heteroaryl; R(1) is selected from the group consisting of hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl, wherein each hydrogen on said Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(2) is independently selected from the group consisting of halogen, C Ce alkyl, C[2]- C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, -S(0)[t]R(7), -S(0)[2]NR(7)R(8), -S(0)[2]OR(7), -N0[2], -(CR(5)R(6))[q]NR(7)R(8), - N(CR(5)R(6))(CR(5)R(6))[q]NR(7)R(8), -OR(7), -0(CR(5)R(6))(CR(5)R(6))[q]OR(7), -0(CR(5)R(6))(CR(5)R(6))[q]R(7), -CN, -C(0)R(7), -OC(0)R(7), -0(CR(5)R(6))[q]R(7), -NR(7)C(0)R(8), -(CR(5)R(6))[q]C(0)OR(7), -(CR(5)R(6))[q]NR(7)R(8), -C(=NR(7))NR(7)R(8), -NR(7)C(0)NR(7)R(8), -NR(7)S(0)[2]R(8) and -(CR(5)R(6))[q]C(0)NR(7)R(8); wherein each hydrogen on said C C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-C[12] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, - NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -OR(9), -CN, -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); R(3) and R(4) are each independently selected from hydrogen, C-|-C[6] alkyl and C[3]-C[6] cycloalkyi, wherein each hydrogen on C Ce alkyl and C[3]-C[6] cycloalkyi may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(5) and R(6) is independently selected from the group consisting of hydrogen, CrC[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) and -C(0)NR(9)R(10); wherein each hydrogen on said CrC[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, Cs- Ce cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(7) and R(8) is independently selected from the group consisting of hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl, wherein each hydrogen on said Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -OR(9), -CN, -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(9) and R(10) is independently selected from hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]- C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl; p is 0, 1, 2, 3 or 4; each q is independently 0, 1, 2 or 3; each r is independently 0, 1, 2 or 3; and each t is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 8), -S(0)[2]OR(7), -N0[2], -(CR(5)R(6))[q]NR(7)R(8), - N(CR(5)R(6))(CR(5)R(6))[q]NR(7)R(8), -OR(7), -0(CR(5)R(6))(CR(5)R(6))[q]OR(7), -0(CR(5)R(6))(CR(5)R(6))[q]R(7), -CN, -C(0)R(7), -OC(0)R(7), -0(CR(5)R(6))[q]R(7), -NR(7)C(0)R(8), -(CR(5)R(6))[q]C(0)OR(7), -(CR(5)R(6))[q]NR(7)R(8), -C(=NR(7))NR(7)R(8), -NR(7)C(0)NR(7)R(8), -NR(7)S(0)[2]R(8) and -(CR(5)R(6))[q]C(0)NR(7)R(8); wherein each hydrogen on said C C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, - NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -OR(9), -CN, -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); R(3) is Ci-C[6] alkyl or C[3]-C[6] cycloalkyi and R(4) is hydrogen, wherein each hydrogen on said Ci-C[6] alkyl or C[3]-C[6] cycloalkyi may be independently optionally substituted by halogen, -OH, - NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(5) and R(6) is independently selected from the group consisting of hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(1).deg., -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) and -C(0)NR(9)R(10); wherein each hydrogen on said Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]- C[6] cycloalkyl, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(7) and R(8) is independently selected from the group consisting of hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl, wherein each hydrogen on said C-|-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-C[12] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -OR(9), -CN, -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(9) and R(10) is independently selected from hydrogen, C-|-C[6] alkyl, C[2]-C[6] alkenyl, C[2]- C[6] alkynyl, C[3]-C[6] cycloalkyl, C[6]-C[12] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl; p is 0, 1, 2, 3 or 4; each q is independently 0, 1, 2 or 3; each r is independently 0, 1, 2 or 3; and each t is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof. R(1) is selected from the group consisting of hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl, wherein each hydrogen on said Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(2) is independently selected from the group consisting of halogen, Ci-C[6] alkyl, C[2]- C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, -S(0)[t]R(7), -S(0)[2]NR(7)R(8), -S(0)[2]OR(7), -N0[2], -(CR(5)R(6))[q]NR(7)R(8), - N(CR(5)R(6))(CR(5)R(6))[q]NR(7)R(8), -OR(7), -0(CR(5)R(6))(CR(5)R(6))[q]OR(7), -0(CR(5)R(6))(CR(5)R(6))[q]R(7), -CN, -C(0)R(7), -OC(0)R(7), -0(CR(5)R(6))[q]R(7), -NR(7)C(0)R(8), -(CR(5)R(6))[q]C(0)OR(7), -(CR(5)R(6))[q]NR(7)R(8), -C(=NR(7))NR(7)R(8), -NR(7)C(0)NR(7)R(8), -NR(7)S(0)[2]R(8) and -(CR(5)R(6))[q]C(0)NR(7)R(8); wherein each hydrogen on said C C[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-C[12] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, - NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -OR(9), -CN, -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); R(3) is C Ce alkyl or C[3]-C[6] cycloalkyi and R(4) is hydrogen, wherein each hydrogen on said Ci-C[6] alkyl or C[3]-C[6] cycloalkyi may be independently optionally substituted by halogen, -OH, - NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(5) and R(6) is independently selected from the group consisting of hydrogen, C Ce alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) and -C(0)NR(9)R(10); wherein each hydrogen on said CrC[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, Cs- Ce cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(7) and R(8) is independently selected from the group consisting of hydrogen, CrC[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl, wherein each hydrogen on said CrC[6] alkyl, C[2]-C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic and 5-6 membered heteroaryl may be independently optionally substituted by halogen, -OH, -NH[2], -S(0)[t]R(9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -NO[2], -OR(9), -CN, -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(1).deg. or -C(0)NR(9)R(10); each R (9) and R(10) is independently selected from hydrogen, Ci-C[6] alkyl, C[2]-C[6] alkenyl, C[2]- C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, and 5-6 membered heteroaryl; p is 0, 1, 2, 3 or 4; each q is independently 0, 1, 2 or 3; each r is independently 0, 1, 2 or 3; and each t is independently 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 9), -S(0)[2]NR(9)R(10), -S(0)[2]OR(9), -N0[2], -CN, -OR(9), -C(0)R(9), -OC(0)R(9), -NR(9)C(0)R(10), -C(0)OR(9), -C(=NR(9))NR(9)R(10), -NR(9)C(0)NR(9)R(10), -NR(9)S(0)[2]R(10) or -C(0)NR(9)R(10); each R(2) is independently selected from the group consisting of halogen, C Ce alkyl, C[2]- C[6] alkenyl, C[2]-C[6] alkynyl, C[3]-C[6] cycloalkyi, C[6]-Ci[2] aryl, 3-12 membered heteroalicyclic, 5-6 membered heteroaryl, -S(0)[t]R(7), -S(0)[2]NR(7)R(
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state=2013-02-20   Application number in the designated or member state=2014JP-0560470 Corresponding cc:  Designated or member state=JP Corresponding pat: JP2015510879  Publication stage code in the designated or member state=A  Publication date in the designated or member state=2015-04-13   Publication number in the designated or member state=JP2015510879    Event publication date=2014-09-05  Event code=WO/ENP  Event type=Entry into national phase  Entry into the national phase in: Corresponding cc:  Designated or member state=JP     Event publication date=2015-11-25  Event code=JP/STCHG  Patent Status changed by the national office Corresponding cc:  Designated or member state=JP  LEGAL DETAILS FOR DESIGNATED STATE KR20140137414  Actual or expected expiration date=2033-02-20    Legal state=ALIVE    Status=GRANTED   Corresponding cc:  Designated or member state=KR Corresponding appl: KR20147027905  Application date in the designated or member state=2013-02-20   Application number in 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date=2033-02-20    Legal state=ALIVE    Status=GRANTED   Corresponding cc:  Designated or member state=ZA Corresponding appl: ZA201406244  Application date in the designated or member state=2014-08-25   Application number in the designated or member state=2014ZA-0006244 Corresponding cc:  Designated or member state=ZA Corresponding pat: ZA201406244  Publication stage code in the designated or member state=B  Publication date in the designated or member state=2015-05-27   Publication number in the designated or member state=ZA201406244    Event publication date=2015-05-27  Event code=ZA/STCHG  Patent Status changed by the national office Corresponding cc:  Designated or member state=ZA
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