Compositions and methods for the treatment of cancer
AssigneeDuke University
InventorsDennis J. Thiele, Bushu Dong, Alexander M. Jaeger, Philip F. Hughes, Timothy Haystead, Jiyong Hong
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Abstract
This disclosure relates to compounds, pharmaceutical compositions comprising them, and methods of using the compounds and compositions for treating diseases related to Heat Shock Transcription Factor 1 (HSF1) activity and/or function. More particularly, this disclosure relates to methods of inhibiting HSF1 activity with these compounds and pharmaceutical compositions thereof, and methods of treating diseases associated with HSF1 activity and/or function, such as cancer.
Claims35
A method of treating disease associated with an elevated HSF1 activity in a subject in need thereof, the method comprising administering to the subject an effective amount of an HSF1 inhibiting compound having the structure of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- ring A1 is C1-C6alkyl, C3-C6cycloalkyl, C6-C10aryl, heteroaryl, or 3- to 10-membered heterocycloalkyl;
- each optionally substituted with 1-5 substituents independently selected from the group consisting of R1a, —OR1a, —OC(O)R2a, —NR2aR2b, —S(O)1-2R2a, —SO2NR2aR2b, —NR2aSO2R2b, —C(O)R2b, —C(O)OR2a, —C(O)NR2aR2b, —NR2aC(O)R2b, —NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;
- L1 is selected from —(CH2)mNR1—, —(CH2)mS—, —(CH2)mO—, —C(O)—, —C(O)O—, —C(O)NR1—, —C(═NR1)—, —CR2═N—, C1-C6alkyl, C2-C6alkenyl, C2-C6heteroalkyl, C3-C6cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl;
- each optionally substituted with 1-5 substituents independently selected from the group consisting of R1a, —OR1a, —OC(O)R2a, —NR2aR2b, —S(O)1-2R2a, —SO2NR2aR2b, —NR2aSO2R2b, —C(O)R2b, —C(O)OR2a, —C(O)NR2aR2b, —NR2aC(O)R2b, —NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;
- L2 is absent or selected from —C(O)—, —C(═NR1)—, —S—, —O—, —C(O)O—, —C(O)NR1—, —(CH2)mNR1—, —S(O)—, —SO2—, C1-C6alkyl, C2-C6alkenyl, C2-C6heteroalkyl, C3-C6cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl;
- each optionally substituted with 1-5 substituents independently selected from the group consisting of R1a, —OR1a, —OC(O)R2a, —NR2aR2b, —S(O)1-2R2a, —SO2NR2aR2b, —NR2aSO2R2b, —C(O)R2b, —C(O)OR2a, —C(O)NR2aR2b, —NR2aC(O)R2b, —NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;
- L3 is absent or selected from —(CH2)nNR1—, —(CH2)nS—, —(CH2)nO—, —C(O)—, —C(O)NR1—, —NHC(O)NH—, —N═CR2—, C1-C6alkyl, C2-C6alkenyl, C2-C6heteroalkyl, C3-C6cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl;
- each optionally substituted with 1-5 substituents independently selected from the group consisting of R1a, —OR1a, —OC(O)R2a, —NR2aR2b, —S(O)1-2R2a, —SO2NR2aR2b, —NR2aSO2R2b, —C(O)R2b, —C(O)OR2a, —C(O)NR2aR2b, —NR2aC(O)R2b, —NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;
- and
- ring A2 is a C3-C6cycloalkyl, C6-C10aryl, heteroaryl, or 3- to 10-membered heterocycloalkyl;
- each optionally substituted with 1-5 substituents independently selected from the group consisting of R1a, —OR1a, —OC(O)R2a, —NR2aR2b, —S(O)1-2R2a, —SO2NR2aR2b, —NR2aSO2R2b, —C(O)R2b, —C(O)OR2a, —C(O)NR2aR2b, —NR2aC(O)R2b, —NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;
- wherein
- each R1 is independently selected from hydrogen;
- hydroxy;
- cyano;
- substituted or unsubstituted C1-C6alkyl;
- substituted or unsubstituted C2-C6alkenyl;
- substituted or unsubstituted C1-C6heteroalkyl;
- substituted or unsubstituted C3-C6cycloalkyl;
- substituted or unsubstituted C6-C10aryl;
- substituted or unsubstituted 5 to 10 membered heteroaryl and substituted or unsubstituted 3-10 membered heterocycloalkyl;
- each R2 is independently selected from hydrogen;
- halogen;
- cyano;
- nitro;
- substituted or unsubstituted C1-C6alkyl;
- substituted or unsubstituted C2-C6alkenyl;
- substituted or unsubstituted C1-C6heteroalkyl;
- substituted or unsubstituted C3-C6cycloalkyl;
- substituted or unsubstituted C6-C10aryl;
- substituted or unsubstituted 5 to 10 membered heteroaryl and substituted or unsubstituted 3-10 membered heterocycloalkyl;
- each R1a is independently selected from unsubstituted C1-C6alkyl;
- C1-C6alkyl substituted with halogen, amine, cyano, oxo, or nitro;
- C2-C6alkene;
- C2-C6alkenyl;
- unsubstituted C3-C6 cycloalkyl;
- C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- unsubstituted C6-C10aryl;
- C6-C10aryl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- unsubstituted heteroaryl;
- heteroaryl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- unsubstituted 3- to 10-membered heterocycloalkyl;
- and 3- to 10-membered heterocycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- R2a and R2b are each independently selected from hydrogen, hydroxy, cyano, —COOH;
- —C(O)(OC1-C6alkyl);
- unsubstituted C1-C6alkyl;
- C1-C6alkyl substituted with halogen, amine, cyano, oxo, or nitro;
- C2-C6alkene;
- C2-C6alkenyl;
- unsubstituted C3-C6 cycloalkyl;
- C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- unsubstituted C6-C10aryl;
- C6-C10aryl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- unsubstituted heteroaryl;
- heteroaryl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- unsubstituted 3- to 10-membered heterocycloalkyl;
- and 3- to 10-membered heterocycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- m is an integer in the range of 0-3;
- and
- n is an integer in the range of 0-3.
The method of claim 0, wherein A1 is C3-C6cycloalkyl, C6-C10aryl, heteroaryl, or 3- to 10-membered heterocycloalkyl;
- each optionally substituted with 1-5 substituents independently selected from the group consisting of R1a, —OR1a, —OC(O)R2a, —NR2aR2b, —S(O)1-2R2a, —SO2NR2aR2b, —NR2aSO2R2b, —C(O)R2b, —C(O)OR2a, —C(O)NR2aR2b, —NR2aC(O)R2b, —NR2aC(O)OR2b, halogen, cyano, oxo, and nitro.
3-4. (canceled)
The method of claim 0, wherein A1 is selected from phenyl, cyclohexyl, pyridine, diazine, diazole, triazole, benzo(c)[1,2,5]oxadiazole, or thiophene;
- each optionally substituted with 1-5 substituents independently selected from the group consisting of R1a, —OR1a, —OC(O)R2a, —NR2aR2b, —S(O)1-2R2a, —SO2NR2aR2b, —NR2aSO2R2b, —C(O)R2b, —C(O)OR2a, —C(O)NR2aR2b, —NR2aC(O)R2b, —NR2aC(O)OR2b, halogen, cyano, oxo, and nitro.
6-10. (canceled)
(canceled)
(canceled)
16-18. (canceled)
20-22. (canceled)
24-31. (canceled)
33-45. (canceled)
(canceled)
(canceled)
(canceled)
The method of claim 0, wherein the disease is a cancer selected from the group consisting of breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, liver cancer, bladder cancer, hepatoma, colorectal cancer, uterine cervical cancer, endometrial carcinoma, salivary gland carcinoma, mesothelioma, kidney cancer, vulval cancer, pancreatic cancer, thyroid cancer, hepatic carcinoma, skin cancer, melanoma, brain cancer, neuroblastoma, myeloma, head and neck cancer, leukemia (including but not limited to acute lymphoblastic leukemia and acute myeloid leukemia), sarcoma, carcinoma, stromal cancer, testicular cancer, neurofibroma, hepatocellular carcinoma, lymphoma, Ewing sarcoma and peripheral neuroepithelioma.
The method of claim 06, wherein the cancer is prostate cancer
(canceled)
A compound having the structure of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- ring A1 is a C6-C10aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 3- to 10-membered heterocycloalkyl;
- each substituted with one or more substituents selected from halogen, cyano, nitro, —COOH, C1-C6alkyl, halogenated C1-C6alkyl, —R1a, —NHCOC1-C6alkyl, and —OS(O2)OH;
- ring A2 is a C6-C10aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 3- to 10-membered heterocycloalkyl;
- each substituted with one or more substituents selected from halogen, cyano, nitro, —COOH, C1-C6alkyl, halogenated C1-C6alkyl, —R1a, —NHCOC1-C6alkyl, —S(O2)CF3, —NHC(O)CH3, —OS(O2)OH;
- or —COO(C1-8 alkyl);
- L1-L2-L3- represents a bond, —NR1—R3—NR1—, —S—, —O—, —C(O)—, —C(O)O—, —C(O)NR1—, —CR2═N—NHCO—, C1-C6alkyl, or 3-10 membered heterocycloalkyl;
- wherein
- each R1 is independently selected from hydrogen;
- hydroxy, cyano;
- C1-C6alkyl;
- C3-C6cycloalkyl;
- C6-C10aryl;
- 5- to 10-membered heteroaryl;
- and 3- to 10-membered heterocycloalkyl;
- each R2 is independently selected from hydrogen;
- halogen;
- cyano;
- nitro;
- C1-C6alkyl;
- C3-C6cycloalkyl;
- C6-C10aryl;
- 5- to 10-membered heteroaryl;
- and 3- to 10-membered heterocycloalkyl;
- R3 is selected from —C(O)—, —C(═N—CN)—, —C(═NH)—, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C6-C10aryl, substituted unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3-10 membered heterocycloalkyl;
- and
- each R1a is independently selected from unsubstituted C1-C6alkyl;
- C1-C6alkyl substituted with halogen, amine, cyano, oxo, or nitro;
- C2-C6alkene;
- C2-C6alkenyl;
- unsubstituted C3-C6 cycloalkyl;
- C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- unsubstituted C6-C10aryl;
- C6-C10aryl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- unsubstituted heteroaryl;
- heteroaryl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro;
- unsubstituted 3- to 10-membered heterocycloalkyl;
- and 3- to 10-membered heterocycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro.
59-64. (canceled)
66-99. (canceled)
The compound of claim 18, wherein the compound is selected from the group consisting of:
101-109. (canceled)
Dependencies are inferred from the claim text.