US 11,926,619 B2
Certain pladienolide compounds and methods of use
Gregg F. Keaney, Lexington, MA (US); John Wang, Andover, MA (US); Baudouin Gerard, Belmont, MA (US); Kenzo Arai, Ibaraki (JP); Xiang Liu, Winchester, MA (US); Guo Zhu Zheng, Lexington, MA (US); Kazunobu Kira, Ibaraki (JP); Lisa A. Marcaurelle, Arlington, MA (US); Marta Nevalainen, Weymouth, MA (US); Ming-Hong Hao, Quincy, MA (US); Morgan Welzel O'Shea, Arlington, MA (US); Parcharee Tivitmahaisoon, Boston, MA (US); Sudeep Prajapati, Somerville, MA (US); Tuoping Luo, Newton, MA (US); Nicholas C. Gearhart, Durango, CO (US); Jason T. Lowe, East Bridgewater, MA (US); Yoshihiko Kotake, Ibaraki (JP); Satoshi Nagao, Ibaraki (JP); Regina Mikie Kanada Sonobe, İbaraki (JP); Masayuki Miyano, İbaraki (JP); Norio Murai, Ibaraki (JP); Andrew Cook, Stow, MA (US); Shelby Ellery, Boston, MA (US); Atsushi Endo, Andover, MA (US); James Palacino, Wellesley, MA (US); and Dominic Reynolds, Stoneham, MA (US)
Assigned to Eisai R & D Management Co., Ltd., Tokyo (JP)
Appl. No. 17/045,952
Filed by EISAI R&D MANAGEMENT CO., LTD., Tokyo (JP)
PCT Filed Apr. 8, 2019, PCT No. PCT/US2019/026313
§ 371(c)(1), (2) Date Oct. 7, 2020,
PCT Pub. No. WO2019/199667, PCT Pub. Date Oct. 17, 2019.
Claims priority of provisional application 62/814,843, filed on Mar. 6, 2019.
Claims priority of provisional application 62/814,838, filed on Mar. 6, 2019.
Claims priority of provisional application 62/679,653, filed on Jun. 1, 2018.
Claims priority of provisional application 62/655,021, filed on Apr. 9, 2018.
Prior Publication US 2021/0163456 A1, Jun. 3, 2021
Int. Cl. C07D 407/12 (2006.01); A61K 31/365 (2006.01); A61K 31/4427 (2006.01); A61K 31/497 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01); C07D 313/00 (2006.01); C07D 405/12 (2006.01); C07D 405/14 (2006.01); C07D 407/06 (2006.01); C07D 407/14 (2006.01); C07D 413/12 (2006.01); C07D 417/12 (2006.01); C07D 487/08 (2006.01); C07D 487/10 (2006.01); C07D 491/107 (2006.01)
CPC C07D 407/06 (2013.01) [A61K 45/06 (2013.01); A61P 35/00 (2018.01); C07D 313/00 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 413/12 (2013.01); C07D 417/12 (2013.01); C07D 487/08 (2013.01); C07D 487/10 (2013.01); C07D 491/107 (2013.01)] 18 Claims
 
1. A compound of Formula

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or a pharmaceutically acceptable salt thereof,
wherein:
n is chosen from 0, 1, 2 or 3;
R1 is chosen from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, —NR9R10,

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 groups,

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 groups,

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 groups,

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 groups,

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 groups,

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 groups,

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 groups, and

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 groups;
R9 is chosen from hydrogen, —NR11R12 groups, C1-C8 alkyl groups, —(C1-C6 alkyl)-CO2H groups, C3-C8 cycloalkyl groups, and heterocyclyl groups, wherein the —NR11R12 groups, C1-C8 alkyl groups, C3-C8 cycloalkyl groups, and heterocyclyl groups may be unsubstituted or substituted from 1-3 times with a group independently chosen from C1-C8 alkyl groups, —(C1-C8 alkyl)-CO2H groups, hydroxy, halogen groups, and C1-C8 alkoxy groups, and wherein the heterocyclyl group is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently chosen from O, N, and S or a bicyclic heterocycle;
R10 is chosen from hydrogen and C1-C8 alkyl groups;
one of either R2 or R3 is chosen from hydrogen and C1-C8 alkyl groups, and the other is chosen from hydrogen, —OR10, —OC(O)R10, —OC(O)R10, and C1-C8 alkyl groups;
R4 is chosen from hydrogen and hydroxy;
R5 and R6 are each independently chosen from C1-C8 alkyl groups;
R7 and R8 are each independently chosen from hydrogen, hydroxy, C1-C8 alkoxy groups, and C1-C8 alkyl groups; and
Y is chosen from phenyl, thiophenyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl, wherein Y may be unsubstituted or substituted from 1-3 times with groups independently chosen from oxo groups, C1-C8 alkyl groups, C3-C5 cycloalkyl groups, hydroxy C1-C8 alkyl groups, C1-C8 alkoxy groups, methoxy C1-C8 alkyl groups, —NR11R12 groups,

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 wherein R11 and R12 are each independently chosen from hydrogen and C1-C6 alkyl groups;
wherein if:
Y is

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R1 is a

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 group,
R2 is OR10 and R10 is hydrogen,
R3 is a C1-C6 alkyl group,
R4 is hydroxy,
R5 and R6 are each a C1-C6 alkyl group, and
one of R7 and R8 is hydrogen and the other is a C1-C6 alkyl group,
then R9 is not a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing one N; and
wherein if:
Y is

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R1 is a

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 group,
R2 is OR10 and R10 is hydrogen,
R3 is a C1-C6 alkyl group,
R4 is hydroxy,
R5 and R6 are each a C1-C6 alkyl group, and
one of R7 and R8 is hydrogen and the other is a C1-C6 alkyl group,
then R9 is not a C1-C6 alkyl group or a C3-C8 cycloalkyl group.