EZH2 inhibitors for treating lymphoma
AssigneeEpizyme, Inc.
InventorsHeike Keilhack, Sarah Kathleen Knutson, Danielle Johnston Blackwell
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Abstract
The present disclosure relates to compositions comprising inhibitors of human histone methyltransferase EZH2 and one or more other therapeutic agents, particularly anticancer agents such as prednisone, and methods of combination therapy for administering to subjects in need thereof for the treatment of cancer.
Claims14
A method for treating a germinal center-derived lymphoma in a subject in need thereof comprising administering a therapeutically effective amount of an EZH2 inhibitor and a therapeutically effective amount of a standard of care agent, wherein the EZH2 inhibitor is of Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- R701 is H, F, OR707, NHR707, —(C≡C)—(CH2)n7—R708, phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C1-3 alkyl, OH, O—C1-6 alkyl, NH—C1-6 alkyl, and, C1-3 alkyl substituted with C3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C1-6 alkyl and NH—C1-6 alkyl is optionally substituted with hydroxyl, O—C1-3 alkyl or NH—C1-3 alkyl, each of the O—C1-3 alkyl and NH—C1-3 alkyl being optionally further substituted with O—C1-3 alkyl or NH—C1-3 alkyl;
- each of R702 and R703 independently is H, halo, C1-4 alkyl, C1-6 alkoxyl or C6-C10 aryloxy, each optionally substituted with one or more halo;
- each of R704 and R705 independently is C1-4 alkyl;
- R706 is cyclohexyl substituted by N(C1-4 alkyl)2 wherein one or both of the C1-4 alkyl is optionally substituted with C1-6 alkoxy;
- or R706 is tetrahydropyranyl;
- R707 is C1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C1-4 alkoxy, amino, mono- or di-C1-4 alkylamino, C3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C1-3 alkyl;
- R708 is C1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C1-6 alkyl;
- and
- n7 is 0, 1, or 2;
- and
- wherein the standard of care agent is selected from Alisertib, Enzastaurin, Vemurafenib, Ruxolitinib, Fedratinib, Tofacitinib, OG-L002, and GSK J4.
A method for treating Primary Mediastinal Large B-Cell Lymphoma (PMBCL) in a subject in need thereof comprising a step of administering a therapeutically effective amount of an EZH2 inhibitor and a therapeutically effective amount of a standard of care agent, wherein the EZH2 inhibitor is of Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- R701 is H, F, OR707, NHR707, —(C≡C)—(CH2)n7—R708, phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C1-3 alkyl, OH, O—C1-6 alkyl, NH—C1-6 alkyl, and, C1-3 alkyl substituted with C3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C1-6 alkyl and NH—C1-6 alkyl is optionally substituted with hydroxyl, O—C1-3 alkyl or NH—C1-3 alkyl, each of the O—C1-3 alkyl and NH—C1-3 alkyl being optionally further substituted with O—C1-3 alkyl or NH—C1-3 alkyl;
- each of R702 and R703 independently is H, halo, C1-4 alkyl, C1-6 alkoxyl or C6-C10 aryloxy, each optionally substituted with one or more halo;
- each of R704 and R705 independently is C1-4 alkyl;
- R706 is cyclohexyl substituted by N(C1-4 alkyl)2 wherein one or both of the C1-4 alkyl is optionally substituted with C1-6 alkoxy;
- or R706 is tetrahydropyranyl;
- R707 is C1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C1-4 alkoxy, amino, mono- or di-C1-4 alkylamino, C3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C1-3 alkyl;
- R708 is C1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C1-6 alkyl;
- and
- n7 is 0, 1, or 2;
- and
- wherein the standard of care agent is selected from Alisertib, Enzastaurin, Vemurafenib, Ruxolitinib, Fedratinib, Tofacitinib, OG-L002, and GSK J4.
Dependencies are inferred from the claim text.