SHMT inhibitors
AssigneeThe Trustees of Princeton University
InventorsJoshua D. Rabinowitz, Hahn Kim, Gregory S. Ducker, Jonathan M. Ghergurovich
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Abstract
The present invention relates to a method for the treatment of cancer or an autoimmune disorder, comprising the administration of a serine hydroxymethyltransferase (SHMT) inhibitor, and in particular the administration of pyrazolopyran compounds of Formula (VI) as presently described, wherein the compounds are capable of inhibiting a mammalian SHMT, such as human SHMT1 and/or SHMT2. The treatment method further comprises the optional administration of an additional agent as a rescue therapy to reduce toxicity, wherein said agent may be chosen from formate, a formate salt, folinic acid, formate ester, or leucovorin.
Claims23
A method for treating cancer, comprising administering to a mammalian subject in need thereof an effective amount of a serine hydroxymethyl transferase (SHMT) inhibitor, and an anti-folate compound.
A method for treating cancer, comprising administering to a mammalian subject in need thereof an effective amount of a serine hydroxymethyl transferase (SHMT) inhibitor, an anti-folate compound and a rescue therapy, wherein the rescue therapy comprises formate, formate salt, formate ester, or leucovorin.
A method for treating a hematological malignancy, comprising administering to a mammalian subject in need thereof an effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt thereof:
- wherein:
- R0, R1 and R2 are each independently selected from —H, halogen, hydroxyl, nitro, nitrile, —SOR11, —S(O)2R11, —S(O)2NR10R12, —OR11, —OC(O)R12, —C(O)OR12, —C(O)R11, —C(O)NR10R12, —NR10R12, —N(R12)C(O)R11, —NS(O)2R11, —NS(O)2R12, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C6 haloalkoxy;
- R3 is selected from isopropyl, cyclopropyl, or cyclobutyl;
- R4 is selected from —H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl;
- R5, R6 and R7 are each independently selected from —H, —C(O)R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl, or R5 is selected from any of the foregoing and R6 and R7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-6 membered ring;
- each occurrence of R11 is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- and
- each occurrence of R10 and R12 is each independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
A method for treating a hematological malignancy, comprising administering to a mammalian subject in need thereof an effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt thereof:
- wherein:
- R0, R1 and R2 are each independently selected from —H, halogen, hydroxyl, nitro, nitrile, —SOR11, —S(O)2R11, —S(O)2NR10R12, —OR11, —OC(O)R12, —C(O)OR12, —C(O)R11, —C(O)NR10R12, —NR10R12, —N(R12)C(O)R11, —NS(O)2R12, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C6 haloalkoxy;
- R3 is selected from halogen, hydroxyl, nitro, nitrile, —SOR11, —S(O)2R11, —S(O)2NR10R12, —OR11, —OC(O)R12, —C(O)OR12, —C(O)R11, —C(O)NR10R12, —NR10R12, —N(R12)C(O)R11, —NS(O)2R12, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C1-C6 haloalkoxy;
- R4 is selected from —H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl;
- R5, R6 and R7 are each independently selected from —H, —C(O)R11, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl, or R5 is selected from any of the foregoing and R6 and R7 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-6 membered ring;
- each occurrence of R11 is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- and
- each occurrence of R10 and R12 is each independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Dependencies are inferred from the claim text.