Hydrazone and diacyl hydrazine compounds and methods of use
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsAdrian Wiestner, Yihong Ye, Qiuyan Wang, William C. Trenkle, Bidhan A. Shinkre
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Abstract
Disclosed herein are novel hydrazone and diacyl hydrazine derivatives that are inhibitors of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Also disclosed are hydrazone and diacyl hydrazine derivatives as potent and selective inhibitors of the p97 ATPase. These agents provide useful tools for the study of protein degradation and other processes involving p97. Methods of treating diseases or disorders for which p97 inhibition and/or ER stress induction is an effective treatment with certain hydrazone and diacyl hydrazine derivatives are also disclosed.
Claims20
A compound of the formula
- or a pharmaceutically acceptable salt thereof;
- wherein
- Ar1 is
- where G is O, N, or S, and R6 is nitro, cyano, —PO4, —CHO, or —COOH;
- and
- Ar1 is optionally substituted with one or more substituents independently chosen from cyano, C1-C2alkyl, C1-C2alkoxy, mono- and di-(C1-C2)alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
- X1 is CR1 or N;
- X2 is CR2 or N;
- X3 is CR3 or N;
- X4 is CR4 or N;
- wherein
- is not unsubstituted or substituted phenyl, unsubstituted pyridyl, or unsubstituted pyridazine, or 2-methylbenzo[d]thiazole, and no more than 2 of X1-X4 are N;
- R1 to R4 are independently chosen from hydrogen, halogen, hydroxyl, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C4)alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
- and
- One of the following three conditions may be present:
- R1 and R2 may be taken together to form a 6-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S, which carbocyclic or heterocyclic R1/R2 ring is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C4)alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
- R2 and R3 may be taken together to form a 6-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S, which carbocyclic or heterocyclic R2/R3 ring is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C4)alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
- R3 and R4 may be taken together to form a 6-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S, which carbocyclic or heterocyclic R3/R4 ring is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C4)alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
- and
- R5 is hydrogen, halogen, hydroxyl, amino, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, mono- or di-(C1-C4)alkylamino, C1-C2haloalkyl, or C1-C2haloalkoxy.
A method of treating mantle cell lymphoma, leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer in a subject comprising providing to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the formula
- where
- Ar1 is
- where G is O, N, or S, and R6 is nitro, cyano, —PO4, —CHO, or —COOH;
- and
- Ar1 is optionally substituted with one or more substituents independently chosen from cyano, C1-C2alkyl, C1-C2alkoxy, mono- and di-(C1-C2)alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
- X1 is CR1 or N;
- X2 is CR2 or N;
- X3 is CR3 or N;
- X4 is CR4 or N;
- wherein
- is not unsubstituted or substituted phenyl, unsubstituted pyridyl, or unsubstituted pyridazine, or 2-methylbenzo[d]thiazole, and no more than 2 of X1-X4 are N;
- R1 to R4 are independently chosen from hydrogen, halogen, hydroxyl, amino, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C4)alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
- One of the following three conditions may be present:
- R1 and R2 may be taken together to form a 6-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S, which carbocyclic or heterocyclic R1/R2 ring is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C4)alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
- R2 and R3 may be taken together to form a 6-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S, which carbocyclic or heterocyclic R2/R3 ring is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C4)alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
- R3 and R4 may be taken together to form a 6-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S, which carbocyclic or heterocyclic R3/R4 ring is substituted with 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, mono- and di-(C1-C4)alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
- and
- R5 is hydrogen, halogen, hydroxyl, amino, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, mono- or di-(C1-C4)alkylamino, C1-C2haloalkyl, or C1-C2haloalkoxy.
Dependencies are inferred from the claim text.