US 12,268,665 B2
Combination of immunotherapies with MDM2 inhibitors
Dajun Yang, Suzhou (CN); Yifan Zhai, Suzhou (CN); Douglas Dong Fang, Suzhou (CN); and Qiuqiong Tang, Suzhou (CN)
Assigned to ASCENTAGE PHARMA (SUZHOU) CO., LTD, Suzhou (CN)
Appl. No. 16/618,794
Filed by ASCENTAGE PHARMA (SUZHOU) CO., LTD., Suzhou (CN)
PCT Filed Aug. 7, 2019, PCT No. PCT/CN2019/099664
§ 371(c)(1), (2) Date Dec. 2, 2019,
PCT Pub. No. WO2020/030016, PCT Pub. Date Feb. 13, 2020.
Claims priority of provisional application 62/853,069, filed on May 27, 2019.
Claims priority of application No. PCT/CN2018/099280 (WO), filed on Aug. 8, 2018; application No. PCT/CN2018/124866 (WO), filed on Dec. 28, 2018; and application No. PCT/CN2019/073720 (WO), filed on Jan. 29, 2019.
Prior Publication US 2022/0175725 A1, Jun. 9, 2022
Int. Cl. A61K 31/407 (2006.01); A61K 39/395 (2006.01); A61P 35/00 (2006.01)
CPC A61K 31/407 (2013.01) [A61K 39/3955 (2013.01); A61P 35/00 (2018.01)] 13 Claims
 
1. A method of treating liver cancer- or colon cancer, comprising administering to a subject in need thereof:
a) an effective amount of a modulator of an immune checkpoint molecule; wherein the modulator of the immune checkpoint molecule is an anti-PD-1 antibody; and
b) an effective amount of a MDM2 inhibitor, wherein the MDM2 inhibitor is represented by the following formula:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein

OG Complex Work Unit Chemistry
is selected from the group consisting of

OG Complex Work Unit Chemistry
B is a C4-7 carbocyclic ring;
R1 is H, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORa, or NRaRb;
n is 0, 1, or 2;
R2, R3, R4, R5, R7, R8, R9, and R10, independently, are selected from the group consisting of H, F, Cl, CH3, and CF3;
R6 is

OG Complex Work Unit Chemistry
Ra is hydrogen or substituted or unsubstituted C1-4 alkyl;
Rb is hydrogen or substituted or unsubstituted C1-4 alkyl;
Rc and Rd are substituents on one carbon atom of ring B, wherein
Re is H, C1-3 alkyl, C1-3 alkylene-ORa, ORa, or halo;
Rd is H, C1-3 alkyl, C1-3 alkylene-ORa, ORa, or halo; or
Rc and Rd are taken together with the carbon to which they are attached to form a 4 to 6-membered Spiro substituent, optionally containing an oxygen atom; and
Re is —C(═O) ORa, —C(═O) NRaRb, or —C(═O) NHSO2CH3.