Combination of immunotherapies with mdm2 inhibitors
AssigneeAscentage Pharma (Suzhou) Co., Ltd.
InventorsDajun YANG, Yifan ZHAI, Douglas Dong FANG, Qiuqiong TANG
Life of this patent
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Abstract
Disclosed herein are combination therapies comprising an effective amount of a modulator of the immune checkpoint molecule; and an effective amount of a MDM2 inhibitor.
Claims43
A method of treating cancer, comprising administering to a subject in need thereof:
- a) an effective amount of a modulator of an immune checkpoint molecule;
- and
- b) an effective amount of a MDM2 inhibitor, wherein the MDM2 inhibitor is represented by the following formula:
- or a pharmaceutically acceptable salt thereof, wherein
- is selected from the group consisting of
- 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
- 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
- Rc 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
- Re 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.
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A pharmaceutical composition comprising
- a) an effective amount of a modulator of an immune checkpoint molecule;
- and
- b) an effective amount of a MDM2 inhibitor, wherein the MDM2 inhibitor is represented by the following formula:
- or a pharmaceutically acceptable salt thereof, wherein
- is selected from the group consisting of
- 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
- 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
- Rc 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.
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A pharmaceutical composition comprising a MDM2 inhibitor of the following structure
- or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in a solid dose form.
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A method for treating hyper-progression in a patient receiving anti-PD-1/PD-L1 therapy for the treatment of cancer, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a MDM2 inhibitor, wherein the MDM2 inhibitor is
- or a pharmaceutically acceptable salt thereof.
85-88. (canceled)
A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a MDM2 inhibitor, wherein the method comprises at least one 28-day treatment cycle, wherein MDM2 inhibitor is administrated orally every other day for the first consecutive 3-weeks of the treatment cycle and is not administered during the forth week of the treatment cycle, wherein the therapeutically effective amount is from about 100 mg to about 200 mg of MDM2 inhibitor.
90-104. (canceled)
Dependencies are inferred from the claim text.