发明名称 Macrocyclic FLT3 kinase inhibitors
摘要 The present invention relates to macrocylic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of FLT3 (FMS-Related Tyrosine kinase 3). Moreover, the present invention provides processes for the preparation of the disclosed compounds, as well as methods of using them, for instance as a medicine, in particular for the treatment of cell proliferative disorders, such as cancer.;
申请公布号 US9090630(B2) 申请公布日期 2015.07.28
申请号 US201214347750 申请日期 2012.09.28
申请人 Oncodesign S.A. 发明人 Blom Petra Marcella Francoise;Hoflack Jan Marie Cyriel Jozef
分类号 C07D471/22;C07D487/18;C07D498/18 主分类号 C07D471/22
代理机构 Dinsmore & Shohl LLP 代理人 Dinsmore & Shohl LLP
主权项 1. A compound of Formula I or a stereoisomer, tautomer, racemic, pharmaceutically acceptable salt, or N-oxide form thereof, Wherein A1 and A2 are selected from C and N; wherein when A1 is C, then A2 is N; and wherein when A2 is C, then A1 is N; R1 and R7 are each independently selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR9R10, —(C═O)—R4, —SO2—R4, —CN, —NR9—SO2—R4, —C3-6cycloalkyl, and -Het6; wherein each of said C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —NR11R12, —O—C1-6alkyl, and —S—C1-6alkyl; R2 is selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —(C═O)—C1-6alkyl, —(C═O)—O—C1-6alkyl, —(C═O)—NR27R28, -Het3, —(C═O)-Het3, —SO2—C1-6alkyl, and —C3-6cycloalkyl; wherein each of said C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C1-6alkyl, —S—C1-6alkyl, -Het3, —Ar2, and —NR13R14; R3 is selected from —H, -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —(C═O)—C1-6alkyl, —(C═O)—O—C1-6alkyl, -Het2, —C3-6cycloalkyl —(C═O)-Het2, —(C═O)—NR29R30, and —SO2—C1-6alkyl; wherein each of said C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C1-6alkyl, —S—C1-6alkyl, —NR15R16, -Het2, and —Ar3; R4 is independently selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR17R18, and -Het4; R5 is selected from —H —C1-6alkyl, and —C3-6cycloalkyl; wherein each of said C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —OC1-6alkyl, —SC1-6alkyl, -Het5, and —NR31R32; R6 is selected from —H, —OH, -halo, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NR33R34, and -Het8; R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, and R34 are each independently selected from —H, —O, —C1-6alkyl, and Het1; wherein each of said C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C1-6alkyl, —S—C1-6alkyl, —NR35R36, -Het7, and —Ar4; R35 and R36 are each independently selected from —H, —O, and C1-6alkyl; wherein each of said C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —O—C1-6alkyl, and —S—C1-6alkyl; X1 is selected from —C1-6alkyl-, —O—C1-6alkyl-, —S—C1-6alkyl-, —(C═O)—, —NR3—(C═O)—, —C1-6alkyl-NR3—(C═O)—, —NR3—(C═O)—NR35—, —NR3—C1-6alkyl-, —NR3—, and —NR3—SO2—; wherein each of said C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, and —NR23R24; X2 is selected from —C1-6 alkyl-, —O—C1-6 alkyl-, —S—C1-6alkyl-, —(C═O)—, —NR2—(C═O)—, —NR2—C1-6alkyl-, —NR2—, and —SO2—NR2—; wherein each of said C1-6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, —OH, —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, and —NR25R26; Y is selected from a direct bond, —CHR6—, —O—, —S—, and —NR5—; Ar2, Ar3, and Ar4 are each independently a 5- or 6-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; wherein each of said Ar2, Ar3, and Ar4 is optionally and independently substituted with from 1 to 3 substituents selected from —NR19R20, —C1-6alkyl, —O—C1-6alkyl, and —S—C1-6alkyl; Het1, Het2, Het3, Het4, Het5, Het6, Het7 and Het8 are each independently a 5- or 6-membered monocyclic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each heterocycle is optionally substituted with from 1 to 3 substituents selected from —C1-6alkyl, —OC1-6alkyl, —SC1-6alkyl, and —NR21R22; wherein each of said C1-6alkyl is optionally and independently substituted with from 1 to 3 -halo; Z1, Z2, Z3, Z4 and Z5 are each independently selected from C and N; and m and n are each independently 1, 2, 3, or 4.
地址 Dijon Cedex FR