Methods for the treatment of cancer

Abstract

Methods for treating cancer in a subject in need thereof by administration of a compound of Formula (I) are described herein. The methods may treat cancer by degrading heat shock factor 1 (HSF1), arresting tumor growth, treatment of malignant bone marrow, the selective killing of malignant bone marrow, etc.

Description

METHODS FOR THE TREATMENT OF CANCERCross-Reference To Related Applications

[0001] This application claims priority to United States Provisional Application No. 63 / 646,420 titled “METHODS FOR THE TREATMENT OF CANCER” filed May 13, 2024, the entire contents of which are incorporated by reference herein.Field of the Invention

[0002] This disclosure relates to compounds, pharmaceutical formulations comprising them, and methods of using the compounds and compositions for treating cancer.Background of the disclosure

[0003] Therapies to prevent cancer cell survival, invasion and migration would be a major therapeutic breakthrough. Recent work has uncovered a critical role for the mammalian stress-responsive transcription factor, HSF1, in cancer cell initiation, proliferation, survival, invasion and metastasis. Furthermore, HSF1 was discovered as one of six metastasispromoting genes in malignant melanoma. HSF1 is normally activated by cellular stresses that cause protein misfolding, activating the expression of protein chaperones that protect cells from protein damage. In many distinct cancers, however, HSF1 protein abundance and activity are dramatically elevated and HSF1 drives a program of gene expression that regulates pathways to support tumor cell initiation, growth, survival, invasion and metastasis, in both tumor cells and the stromal tissue.

[0004] HSF1 itself is not an oncogene, but a broad range of cancer cells have a "nononcogene addiction" to the pro-survival, pro-proliferative, pro-invasive and pro-metastatic functions of HSFI. Indeed, in melanoma, breast, hepatocellular carcinoma, prostate cancer and other cancers, HSFI levels, and in particular nuclear HSFI levels, inversely correlate with patient survival. In melanoma and other cancers, HSFI protein levels are dramatically elevated, in part due to decreased levels of the F Box protein Fbxw7, which normally targets HSFI for ubiquitin-mediated proteasomal degradation. Other mechanisms underlying the increase in HSFI levels and activity, and particularly increased nuclear HSFI levels, in a broad range of cancers are possible. Moreover, silencing of HSFI expression by RNAi, shRNA, CRISPR-Cas9 or inactivation of the HSFI gene by deletion in cultured cancer cells in vitro, or in mice, results in a marked reduction in cancer cell invasion and metastasis and in increased survival of mouse cancer models. While numerous reports have indicated thatHSF1 is a promising therapeutic target in cancer, HSF1 inhibitors are not available for use in the clinic. Therefore, there exists a need to identify novel HSF1 inhibitors.SUMMARY OF THE INVENTION

[0005] Provided herein are methods for treating cancer in a subject in need thereof. The method generally comprises administering a composition comprising a compound having the formula:wherein Al is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro; each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen.

[0006] In some embodiments, the ring Al is selected from the group consisting of

[0007] In some aspects, the ring Al has the formula:some aspects, the ring Al has the formula:

[0008] In some embodiments, A2 is selected from the group consisting of:

[0009] In some aspects, the ring A2 has the formula:

[0010] In some embodiments, the compound has the formulasome embodiments, the compound hasthe formulasome embodiments, the compound has the formula. In some embodiments, the compound has the formulaIn some embodiments, the compoundembodiments, the compound has the formula. In some embodiments, thesome embodiments, the compound has the formula

[0011] In some embodiments, at least one of R3aor R4ais cyano.

[0012] In some aspects, the compound is:

[0013] In some embodiments, each R3ais independently selected from the group consisting of hydrogen, unsubstituted Ci-Ce alkyl, Ci-Ce alkyl substituted with halogen, unsubstituted Ci- Ce cycloalkyl, — (unsubstituted Ci-Ce alkyl) — N(un substituted Ci-Ce alkyl)2, — O —(unsubstituted Ci-Ce alkyl), — O — (unsubstituted Ci-Ce alkyl) — (3- to 10-membered heterocycloalkyl), — S(O)2(Ci-Ce alkyl substituted with halogen), — S(O)2(unsubstituted Ci- Ce alkyl), halogen, cyano, and nitro. In some aspects, each R3ais independently selected from the group consisting of hydrogen, cyano, and halogen.

[0014] In some embodiments, each R4ais independently selected from the group consisting of hydrogen, unsubstituted Ci-Ce alkyl, Ci-Ce alkyl substituted with halogen, unsubstituted Ci- Ce cycloalkyl, 3- to 10-membered heterocycloalkyl, — (unsubstituted Ci-Ce alkyl) — (3- to 10- membered heterocycloalkyl), — (unsubstituted Ci-Ce alkyl) — N(un substituted Ci-Ce alkyl)2, — O — (unsubstituted Ci-Ce alkyl), — O — (unsubstituted Ci-Ce alkyl) — (3- to 10-membered heterocycloalkyl), — S(O)2(Ci-Ce alkyl substituted with halogen), — S(O)2(unsubstituted Ci- Ce alkyl), — NHS(O)2(unsubstituted Ci-Ce alkyl), halogen, cyano, and nitro. In some aspects, each R4ais independently selected from the group consisting of hydrogen, cyano, halogen, — S(O)2(Ci-Ce alkyl substituted with halogen), and — S(O)2(unsubstituted Ci-Ce alkyl).

[0015] In some examples, the compound is:In some examples, the compound is:In some examples, the compound is:In some examples, the compound is:

[0016] In some embodiments, the compound has a half-life of greater than 500 minutes, greater than 750 minutes, greater than 1000 minutes, greater than 1250 minutes, or greater than 1500 minutes after administration.

[0017] In some embodiments, the administration comprises oral administration. In some aspects, the compound has a Tmax of 3.33 ± 0.25 hours as a result of the administration. In some aspects, the compound has a Tmax of 2.67 ± 0.25 hours as a result of the administration. In some aspects, the compound has a half life of 10.3 hours ± 15% as a result of the administration. In some aspects, the compound has a half life of 6.47 hours ± 15% as a result of the administration. In some aspects, the compound has a Cmaxof 2520 ng / mL ± 15% as a result of the administration of a dose of about 0.1 to about 1 mg / kg of the compound. In some aspects, the compound has a Cmaxof 1070 ng / mL ± 15% as a result of the administration of a dose of about 0.1 to about 1 mg / kg of the compound. In some aspects, the compound has a AUCo-oo of 39600 ng / mL h ± 15% as a result of the administration of a dose of about 0.1 to about 1 mg / kg of the compound. In some aspects, the compound has a AUCo-® of 15900 ng / mL h ± 15% as a result of the administration of a dose of about 0.1 to about 1 mg / kg of the compound. In some aspects, the compound has a bioavailability from 60% ± 15% to 100% ± 5% as a result of the administration. In some aspects, the compound has a bioavailability from 60% ± 15% to 80% ± 15%. In some aspects, the compound has a bioavailability from 80% ± 5% to 100% ± 5%.

[0018] In some embodiments, the administration comprises intravenous administration. In some aspects, the compound has a half life of 8.23 hours ± 15% as a result of the administration. In some aspects, the compound has a half life of 6.62 hours ± 15% as a result of the administration. In some aspects, the compound has a Cmaxof 1040 ng / mL ± 15% as a result of the administration of a dose of about 0.01 to about 0.2 mg / kg of the compound. In some aspects, the compound has a Cmaxof 276 ng / mL ± 15% as a result of the administrationof a dose of about 0.01 to about 0.2 mg / kg of the compound. In some aspects, the compound has a AUCo-oo of 8120 ng / mL h ± 15% as a result of the administration of a dose of about 0.01 to about 0.2 mg / kg of the compound. In some aspects, the compound has a AUCo-® of 3170 ng / mL h ± 15% as a result of the administration of a dose of about 0.01 to about 0.2 mg / kg of the compound.

[0019] In some embodiments, the administration results in degradation of nuclear HSF1. In some aspects, nuclear HSF1 is degraded by greater than 50% in less than 20 hours, less than 10 hours, or less than 5 hours.

[0020] In some embodiments, the cancer is prostate cancer. In some aspects, the administration results in reduction of 22RV1 prostate tumor growth as compared to a vehicle control. In some aspects, the administration results in reduction of 22RV1 prostate tumor growth by at least 500%, at least 1000%, at least 1500%, at least 2000%, at least 2500%, or at least 3000%.

[0021] In some embodiments, the cancer is leukemia. In some aspects, administration of the composition results in a reduction in cell count of human AML bone marrow cells as compared to a vehicle control. In some examples, the reduction is 2xl06cells or more.

[0022] In some embodiments, the compound is administered at a concentration from about 0.01 mg / kg body weight of the subject to about 5 mg / kg body weight of the subject, such as about 0.01 mg / kg to about 2.5 mg / kg, about 0.05 mg / kg to about 2 mg / kg, or about 0.08 mg / kg to about 1.6 mg / kg.

[0023] In some embodiments, the subject is human.

[0024] In some embodiments, 2-15% of hCD45+cells remain 5 days, 10 days, 15 days, 20 days, 25 days, or greater than 25 days after administration. In some embodiments, median tumor volume decreases by at least 5 mm3to at least 100 mm3at least 5 days, 10 days, 15 days, 20 days, or at least 25 days after administration. In some embodiments, median tumor volume decreases by at least 5 mm3to at least 10 mm3at least 5 days, 10 days, 15 days, 20 days, or at least 25 days after administration.

[0025] Further provided herein is a method for degrading HSF1 in a subject in need thereof, the method comprising administering a composition comprising a compound having the formula:wherein Al is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro; each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen.

[0026] In some embodiments, the percentage of HSF1 is degraded at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more within an hour after administration. In some embodimetns, the percentage of HSF1 is degraded at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more within five hours after administration. In some embodiments, the percentage of HSF1 is degraded at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more within ten hours after administration. In some embodiments, the percentage of HSF1 is degraded at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more within fifteen hours after administration. In some embodiments, the percentage of HSF1 is degraded at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more within twenty hours after administration. In some embodiments, the percentage of HSF1 degraded is substantially similar to the line indicated with circles, denoted as Nuclear HSF1 Degradation, in FIG. 2.

[0027] In some embodiments, HSF1 resynthesis occurs from about 18 to about 32 hours, about 20 to about 30 hours, about 22 to about 26 hours, or about 23 to about 25 hours after administration. In some embodiments, HSF1 synthesis is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% of full potential by 25 hours after administration. In some embodiments, HSF1 synthesis is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% of full potential by 30 hours after administration. In some embodiments, HSF1 synthesis is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 85%, 90% or more of full potential by 40 hours after administration. In some embodiments, HSF1 synthesis is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 85%, 90% or more of full potential by 50 hours after administration. In some embodiments, HSF1 synthesis is at least 75%, 85%, 90% or more of full potential by 60 hours after administration.

[0028] Further provided herein is a method of degrading HSF1 in a subject in need thereof, the method comprising administering a composition comprising a compound having the formula:wherein Al is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen, and having a half-life (Ti / 2)(min) greater than 40, 50, 75, 100, 200, 300, 500, 700, 900, 1,000, or more.

[0029] Further provided herein is a method for arresting tumor growth or decreasing tumor size in a subject in need thereof, the method comprising administering a composition comprising a compound having the formulawherein Al is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen.

[0030] Further provided herein is a method for treating malignant bone marrow in a subject in need thereof, the method comprising administering a composition comprising a compound having the formulawherein Al is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen.

[0031] Further provided herein is a method for selective killing of malignant bone marrow in a subject in need thereof, the method comprising administering a composition comprising a compound having the formulawherein Al is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The accompanying drawings are included to provide a further understanding of the compositions and methods of the disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiment s) of the disclosure and, together with the description, serve to explain the principles and operation of the disclosure.

[0033] FIG. 1 shows the degradation of nuclear HSF1 after administration of Compound A and Compound 6. As shown in the Figure, Compound 6 achieves a superior degradation profile as compared to Compound A.

[0034] FIG. 2 shows the degradation and resynthesis of HSF1 after administration of Compound 6 followed by a washout of Compound 6 at 24 hours.

[0035] FIG. 3 shows the change in expression of HSF1 target genes HSPA4L, DNAJB1, SPTN1, and CDH1 at 24 hours after administration of Compound 6.

[0036] FIG. 4 shows the serum concentration of Compound 6 after oral administration to a mouse.

[0037] FIG. 5 shows the concentration of Compounds 6, A, and B after intravenous administration to a mouse.

[0038] FIG. 6 shows the concentration of Compounds 6, A, and B after oral administration to a mouse.

[0039] FIG. 7 shows the concentration of Compound 6 after intravenous administration and after oral administration to a rat.

[0040] FIG. 8 shows the arrest of 22RV1 prostate tumor growth after oral administration of a vehicle control, oral administration of compound 6, and intra peritoneal administration of compound A.

[0041] FIG. 9A shows the percentage of hCD45+cells remaining after intra peritoneal administration of Compound A as compared to a vehicle control. The data shows the selective killing of malignant bone marrow in acute myeloid leukemia patient derived xenograft.FIG. 9B shows the killing of human acute myeloid leukemia bone marrow cells after oral administration of increasing doses of compound 6.DETAILED DESCRIPTION OF THE INVENTION

[0042] Before the disclosed processes and materials are described, it is to be understood that the aspects described herein are not limited to specific embodiments, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.I. Composition

[0043] The compounds of the present disclosure have the general formula of Formula I:(Formula I).

[0044] The ring Al may be selected from the group consisting of:

[0045] In some embodiments, the ring Al may have the formula

[0046] Each R3aof ring Al may be independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, —NR2aC(O)OR2b, halogen, cyano, oxo, and nitro, with the proviso that at least one of R3ais H. In some aspects, at least one R3aof ring Al is cyano.

[0047] Rlaand Rlbmay each be independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-C6 alkene; C2-C6 alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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.

[0048] R2aand R2bmay each be independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-C6 alkene; C2-C6 alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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.

[0049] The ring A2 may be selected from the group consisting of:

[0050] In some embodiments, the ring A2 may have the formula

[0051] Each R4aof ring A2 may be independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro, with the proviso that at least one of R4ais H. In some aspects, at least one R4aof ring Al is cyano.

[0052] Rlaand Rlbmay each be independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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.

[0053] R2aand R2bmay each be independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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.

[0054] In some embodiments, the compound of Formula I may have the formula:

[0055] In some aspects, each R3aof ring Al may be independently selected from the group consisting of hydrogen, unsubstituted Ci-Ce alkyl, Ci-Ce alkyl substituted with halogen, unsubstituted Ci-Ce cycloalkyl, — (unsubstituted Ci-Ce alkyl) — N(unsubstituted Ci-Ce alkyl)2, — O — (unsubstituted Ci-Ce alkyl), — O — (unsubstituted Ci-Ce alkyl) — (3- to 10-membered heterocycloalkyl), — S(O)2(Ci-Ce alkyl substituted with halogen), — S(O)2(unsubstituted Ci- Ce alkyl), halogen, cyano, and nitro. In some examples, each R3amay be independently selected from the group consisting of hydrogen, cyano, and halogen.

[0056] In some aspects, each R4aof ring A2 is independently selected from the group consisting of hydrogen, unsubstituted Ci-Ce alkyl, Ci-Ce alkyl substituted with halogen, unsubstituted Ci-Ce cycloalkyl, 3- to 10-membered heterocycloalkyl, — (unsubstituted Ci-Ce alkyl) — (3- to 10-membered heterocycloalkyl), — (unsubstituted Ci-Ce alkyl) — N(unsubstituted Ci-Ce alkyl)2, — O — (unsubstituted Ci-Ce alkyl), — O — (unsubstituted Ci-Ce alkyl) — (3- to 10-membered heterocycloalkyl), — S(O)2(Ci-Ce alkyl substituted with halogen), — S(O)2(unsubstituted Ci-Ce alkyl), — NHS(O)2(unsubstituted Ci-Ce alkyl), halogen, cyano, and nitro. In some examples, each R4amay be independently selected from the group consisting of hydrogen, cyano, halogen, — S(O)2(Ci-Ce alkyl substituted with halogen), and — S(O)2(unsubstituted Ci-Ce alkyl).

[0057] In some aspects, the compound may be one of the following compounds, wherein each X is independently selected from the group consisting of H, methyl, halogen, cyano, AND hydroxyl:

[0058] In some examples, the compound of Formula I may be:

[0059] In some preferred examples, the compound of Formula I is:

[0060] In certain embodiments, the compounds and / or compositions of the disclosure inhibit the activity and / or function of human HSF1. The activity is not limited to a particular type of HSF. In some embodiments, the HSF1 is HSF1, HSF2, or HSF4. The compounds and / or compositions are not limited by the manner in which they result in HSF1 inhibition. In some embodiments, HSF1 inhibition includes, but is not limited to, inhibition of HSF 1 homo- trimerization, inhibition of HSF 1 target gene expression (e.g., Heat Shock Elements), inhibition of HSF 1 target protein expression (e.g., Heat Shock Proteins), inhibition of HSF 1- mediated genome-wide transcriptional regulation, and / or inhibition of protein chaperone activity (e.g., decreased protein folding, decreased protein solubilization, protein degradation). In certain embodiments, the inhibition of the activity and / or function of HSF 1 is by binding of the compound directly to HSF1. For example, in certain embodiments, the binding of the compound stabilizes the HSF1 protein. In certain embodiments, the binding of the compound destabilizes the HSF1 protein. In certain embodiments, the compound is a compound of Formula I.

[0061] In some embodiments, the binding of the compound increases the melting temperature of the HSF1 protein by at least 1 °C when compared with the melting temperature of the HSF1 protein prior to binding. In some embodiments, the binding of the compound increases the melting temperature of the HSF1 protein by at least about 0.5, about 1, about 1.5, about 2, about 3, about 3.5, about 4, about 4.5, about 5, or about 5.5 °C when compared with the melting temperature of the HSF1 protein prior to binding. In some embodiments, the binding of the compound increases the melting temperature of the HSF 1 protein by no greater than about 0.5, about 1, about 1.5, about 2, about 3, about 3.5, about 4, about 4.5, about 5, or about 5.5 °C when compared with the melting temperature of the HSF1 protein prior to binding. In some embodiments, the binding of the compound increases the melting temperature of the HSF1 protein by about 0.5, about 1, about 1.5, about 2, about 3, about 3.5, about 4, about 4.5,about 5, about 5.5, about 6, about 10, or at any intermediate value spanned by the range herein.

[0062] In some embodiments, the binding of the compound decreases the melting temperature of the HSF1 protein by at least 1 °C when compared with the melting temperature of the HSF1 protein prior to binding. In some embodiments, the binding of the compound decreases the melting temperature of the HSF1 protein by at least about 0.5, about 1, about 1.5, about 2, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about6.5, about 7, about 7.5, about 8, about 9, about 10, about 12.5, or about 15 °C when compared with the melting temperature of the HSF1 protein prior to binding. In some embodiments, the binding of the compound decreases the melting temperature of the HSF1 protein by no greater than about 0.5, about 1, about 1.5, about 2, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 9, about 10, about12.5, or about 15 °C when compared with the melting temperature of the HSF1 protein prior to binding. In some embodiments, the binding of the compound decreases the melting temperature of the HSF1 protein by about 0.5, about 1, about 1.5, about 2, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 10, or at any intermediate value spanned by the range herein.Isomers / Stereoisomers

[0063] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.Labeled compounds

[0064] In some embodiments, the compounds described herein exist in their isotopically- labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical formulations. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.

[0065] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0066] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical formulations.

[0067] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0068] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, y -hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenyl acetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0069] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l -carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0070] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI-4 alkyl)4, and the like.

[0071] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0072] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical formulations.

[0073] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed duringthe processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Tautomers

[0074] In some situations, the compounds of the present disclosure may exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.II. Pharmaceutical Formulations

[0075] Further provided herein are pharamceutical compositions that include one or more compounds described in Section I above.

[0076] The compounds described in Section I may be administered as pharmaceutical formulations by any one of the following routes: oral, systemic (e.g., intranasal, suppository, intrapulmonary), or parenteral (e.g., intramuscular, intravenous, intrathecal, or intraperitoneal) administration. Preferably, the compound is administered as a pharmaceutical formulation orally, intravenously, or via inhalation. Pharmaceutical formulations may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, liposomes, exosomes, nanoparticles, or any other appropriate compositions.

[0077] The pharmaceutical formulations comprise a compound as described in Section I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of the disclosure. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. A "pharmaceutically acceptable excipient and / or carrier" or "diagnostically acceptable excipient and / or carrier" includes but is not limited to sterile distilled water, saline, phosphate buffered solutions, amino acid-based buffers, or bicarbonate buffered solutions. An excipient selected and the amount of excipient used will depend upon the mode of administration. In a non-limiting example, the at least one pharmaceutically acceptable excipient includes DMSOand (2-hydroxypropyl)-P-cyclodextrin. In another non-limiting example, the pharmaceutical formulation comprises DMSO and 15% (2-hydroxypropyl)-P-cyclodextrin in water in a ratio of 5:95.

[0078] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0079] Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

[0080] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).

[0081] The amount of the compound described in Section I in a pharmaceutical formulation of the present disclosue can vary within the full range employed by those skilled in the art. Typically, the pharamceutical formulation may contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of the present disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the pharmaceutical formulation may contain from about 0.01 wt% to about 1 wt%, about 0.01 wt% to about 5 wt%, about 0.01 wt% to about 10 wt%, about 0.01 wt% to about 20 wt%, about 0.01 wt% to about 30 wt%, about 0.01 wt% to about 40 wt%, about 0.01 wt% to about 50 wt%, about 0.01 wt% to about 60 wt%, about 0.01 wt% to about 70 wt%, about 0.01 wt% to about 80 wt%, about 0.01 wt% to about 90 wt%, about 0.01 wt% to about 95 wt%, about 0.01 wt% to about 99 wt%, about 0.01 wt% to about 99.99 wt%, about 1 wt% to about 99.99 wt%, about 5 wt% to about 99.99 wt%, about 10 wt% to about 99.99 wt%, about 20 wt% to about 99.99 wt%, about 30 wt% to about 99.99 wt%, about 40 wt% to about 99.99 wt%, about 50 wt% to about 99.99 wt%, about 60 wt% to about 99.99 wt%, about 70 wt% to about 99.99 wt%, about 80 wt% to about 99.99 wt%, about 90 wt% to about 99.99 wt%, about 95 wt% to about 99.99 wt%, or from about 99 wt% to about 99.99 wt% of a compound of the present disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present in the pharmaceutical formulation at a level from about 1-80 wt %.

[0082] The compounds of the present disclosure described in Section I may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of the present invention, or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical formulation in unit dosage form containing such other drugs and the compound of the present invention is preferred. The combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.

[0083] Accordingly, the pharmaceutical formulations of the present invention may also include those that contain one or more other active ingredients, in addition to a compound of the present disclosure.

[0084] The above combinations include combinations of a compound as described in Section I not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present disclosure may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical formulation containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical formulations of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of the present invention. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.

[0085] In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of a compound described herein may optionally be given continuously;alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0086] Once improvement of the patient's conditions has occurred, a maintenance dose may be administered if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In some embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0087] In some embodiments of the present disclosure, the compounds / compositions are administered alone, while in some other embodiments, the compounds / compositions are preferably present in a pharmaceutical formulation / composition comprising at least one active ingredient / agent, as defined above, together with a solid support or alternatively, together with one or more pharmaceutically acceptable carriers and / or excipients. Optionally, such pharmaceutical formulations / compositions may also comprise other therapeutic agents. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not injurious to the subject.

[0088] Contemplated formulations include those suitable oral, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) and pulmonary administration. In some embodiments, formulations are conveniently presented in unit dosage form and are prepared by any method known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association (e.g„ mixing) the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary, shaping the product.

[0089] Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, wherein each preferably contains a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. In other embodiments, the active ingredient is presented as a bolus, electuary, or paste, etc.

[0090] In some embodiments, tablets comprise at least one active ingredient and optionally one or more accessory agents / carriers are made by compressing or molding the respective agents. In some embodiments, compressed tablets are prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets are made by molding in a suitable machine a mixture of the powdered compound (e.g., active ingredient) moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

[0091] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. In some embodiments, the formulations are presented / formulated in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0092] Preferred unit dosage formulations are those containing a daily dose or unit, daily subdose, as herein above-recited, or an appropriate fraction thereof, of an agent. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents. It also is intended that the agents, compositions and methods of this invention be combined with other suitable compositions and therapies. Still other formulations optionally include food additives (suitable sweeteners,flavorings, colorings, etc.), phytonutrients (e.g., flax seed oil), minerals (e.g., Ca, Fe, K, etc.), vitamins, and other acceptable compositions (e.g., conjugated linoleic acid), extenders, and stabilizers, etc.

[0093] In some embodiments, the compounds of the present disclosure are provided in unsolvated form or are in non-aqueous solutions (e.g., ethanol). The compounds may be generated to allow such formulations through the production of specific crystalline polymorphs compatible with the formulations.

[0094] In other embodiments, the present disclosure provides instructions for administering said compound to a subject. In certain embodiments, the present disclosure provides instructions for using the compositions contained in a kit for the treatment of cancer (e.g., a cancer characterized by the activation and / or overexpression of HSF) providing dosing, route of administration, decision trees for treating physicians for correlating patient-specific characteristics with therapeutic courses of action.

[0095] Yet another aspect of the present disclosure provides all that is disclosed and illustrated herein.III. Methods

[0096] One aspect of the disclosure provides methods of treating cancer. Such methods include administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure as described in Section I or a pharmaceutical formulation of the present disclosure as described in Section II.

[0097] As is known in the art, a cancer is generally considered as uncontrolled cell growth. The methods of the present invention can be used to treat any cancer, and any metastases thereof, that is characterized by the activation and / or overexpression of HSF 1. Examples include, but are not limited to, 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, various types of 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, and combinations thereof.

[0098] In some embodiments, the cancer is leukemia, non- small cell lung cancer, colon cancer, CNS cancer, ovarian cancer, renal cancer, breast cancer, prostate cancer and melanoma. In some embodiments, the cancer is prostate cancer or melanoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is leukemia.

[0099] Effective amounts of a compound, composition and / or pharmaceutical formulation as provided herein can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject). The compositions may also be administered multiple times at these dosages. The optimal dosage and treatment regime for a particular patient can readily be determined by one skilled in the art of medicine by monitoring the patient for signs of disease and adjusting the treatment accordingly.

[0100] In some embodiments, the compound of the present disclosure may be administered at a concentration from about 1 mg / kg body weight of the subject to about 20 mg / kg body weight of the subject. For example, the compound of the present disclosure may be administered at a concentration from about 1 mg / kg to about 2 mg / kg, about 1 mg / kg to about 4 mg / kg, about 1 mg / kg to about 6 mg / kg, about 1 mg / kg to about 8 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 12 mg / kg, about 1 mg / kg to about 14 mg / kg, about 1 mg / kg to about 16 mg / kg, about 1 mg / kg to about 18 mg / kg, about 1 mg / kg to about 20 mg / kg, about 2 mg / kg to about 20 mg / kg, about 4 mg / kg to about 20 mg / kg, about 6 mg / kg to about 20 mg / kg, about 8 mg / kg to about 20 mg / kg, about 10 mg / kg to about 20 mg / kg, about 12 mg / kg to about 20 mg / kg, about 14 mg / kg to about 20 mg / kg, about 16 mg / kg to about 20 mg / kg, about 18 mg / kg to about 20 mg / kg, about about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, or about 10 mg / kg to about 15 mg / kg. In some additional examples, the compound of the present disclosure may be administered at a concentration of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg.

[0101] It is contemplated that the compounds, compositions and / or pharmaceutical formulations of the disclosure can be administered to subjects or individuals susceptible to or at risk of developing pathological growth of target cells and correlated conditions (e.g., at risk of developing a cancer). When the compounds, compositions and / or pharmaceuticalformulations is administered to a subject such as a mouse, a rat or a human patient, the compounds, compositions and / or pharmaceutical formulations can be added to a pharmaceutically acceptable carrier and / or excipient and systemically administered to the subject. To determine patients that can be beneficially treated, a tissue sample may be removed from the patient and the cells assayed for sensitivity to the agent.

[0102] The compounds, compositions and / or pharmaceutical formulations may be administered orally, intranasally, parenterally or by inhalation therapy, and may take the form of tablets, lozenges, granules, capsules, pills, ampoules, suppositories or aerosol form. They may also take the form of suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders. In addition to an agent of the present invention, the pharmaceutical formulations may also contain other pharmaceutically active compounds or a plurality of compounds of the invention.

[0103] More particularly, a compound, composition and / or pharmaceutical formulation according to the present disclosure, also referred to herein as the active ingredient, may be administered for therapy by any suitable route including, but not limited to, oral, parenteral (including, but not limited to, subcutaneous, intramuscular, intravenous and intradermal) and pulmonary. It is also appreciated that the preferred route varies with the condition and age of the recipient, and the disease being treated. Preferably, the administration is performed orally, intravenously, or via inhalation.

[0104] Ideally, the compounds, compositions and / or pharmaceutical formulations should be administered to achieve peak concentrations of the active compound at sites of disease. This may be achieved, for example, by the intravenous injection of the agent, optionally in saline, or orally administered, for example, as a tablet, capsule or syrup containing the active ingredient.

[0105] Desirable blood levels of the composition may be maintained by a continuous infusion to provide a therapeutic amount of the active ingredient within disease tissue. The use of operative combinations is contemplated to provide therapeutic combinations requiring a lower total dosage of each component agent than may be required when each individual therapeutic compound or drug is used alone, thereby reducing adverse effects.

[0106] Therapeutic amounts are empirically determined and vary with the pathology being treated, the subject being treated and the efficacy and toxicity of the compounds, compositions and / or pharmaceutical formulations. When delivered to an animal, the method isuseful to further confirm efficacy of the compounds, compositions and / or pharmaceutical formulations.

[0107] In some embodiments, in vivo administration is effective in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations are carried out with the dose level and pattern being selected by the treating physician.

[0108] An effective amount of the compounds, compositions and / or pharmaceutical formulations described herein may be given in one dose, but is not restricted to one dose. Thus, the administration can be two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more, administrations of the composition. Where there is more than one administration in the present methods, the administrations can be spaced by time intervals of one minute, two minutes, three, four, five, six, seven, eight, nine, ten, or more minutes, by intervals of about one hour, two hours, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 hours, and so on. In the context of hours, the term "about" means plus or minus any time interval within 30 minutes. The administrations can also be spaced by time intervals of one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, and combinations thereof. The methods of the present disclosure are not limited to dosing intervals that are spaced equally in time, but encompass doses at nonequal intervals, such as a priming schedule consisting of administration at 1 day, 4 days, 7 days, and 25 days, just to provide a non-limiting example.

[0109] An effective amount for a particular subject / patient may vary depending on factors such as the condition being treated, the overall health of the patient, the route and dose of administration and the severity of side effects. Guidance for methods of treatment and diagnosis is available (see, e.g., Maynard, et al. (1996) A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, Fla.; Dent (2001) Good Laboratory and Good Clinical Practice, Urch Publ., London, UK).

[0110] In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similarutilities. Therapeutically effective amounts of compounds of the disclosure as described in Section I may range from about 0.01 to about 5 mg per kg subject body weight per day, which can be administered in single or multiple doses. As a non-limiting example, the therapeutically effective dose may range from about 0.01 mg / kg to about 0.05 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.01 mg / kg to about 0.25 mg / kg, about 0.01 mg / kg to about 0.5 mg / kg, about 0.01 mg / kg to about 0.75 mg / kg, about 0.01 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 1.5 mg / kg, about 0.01 mg / kg to about 2 mg / kg, about 0.01 mg / kg to about 2.5 mg / kg, about 0.01 mg / kg to about 3 mg / kg, about 0.01 mg / kg to about 3.5 mg / kg, about 0.01 mg / kg to about 4 mg / kg, about 0.01 mg / kg to about 4.5 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.05 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.25 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 5 mg / kg, about 0.75 mg / kg to about 5 mg / kg, about 1 mg / kg to about 5 mg / kg, about 1.5 mg / kg to about 5 mg / kg, about 2 mg / kg to about 5 mg / kg, about 2.5 mg / kg to about 5 mg / kg, about 3 mg / kg to about 5 mg / kg, about 3.5 mg / kg to about 5 mg / kg, about 4 mg / kg to about 5 mg / kg, about 4.5 mg / kg to about 5 mg / kg, about 0.05 mg / kg to about 2 mg / kg, about 0.05 mg / kg to about 1 mg / kg, or about 0.05 mg / kg to about 0.5 mg / kg.[OHl] For oral administration, the compositions may be provided in the form of tablets containing about 1.0 to about 750 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, and 750 milligrams of the active ingredient. The actual amount of the compound of the present disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.

[0112] A dosing schedule of, for example, once / week, twice / week, three times / week, four times / week, five times / week, six times / week, seven times / week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, and the like, is available for the methods provided herein. The dosing schedules encompass dosing for a total period of time of, for example, one week, two weeks, three weeks, four weeks, five weeks, six weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, and twelve months.

[0113] Provided are cycles of the above dosing schedules. The cycle may be repeated about, e.g., every seven days; every 14 days; every 21 days; every 28 days; every 35 days; 42 days; every 49 days; every 56 days; every 63 days; every 70 days; and the like. An interval of non-dosing can occur between a cycle, where the interval can be about, e.g., seven days; 14 days; 21 days; 28 days; 35 days; 42 days; 49 days; 56 days; 63 days; 70 days; and the like. In this context, the term "about" means plus or minus one day, plus or minus two days, plus or minus three days, plus or minus four days, plus or minus five days, plus or minus six days, or plus or minus seven days.

[0114] The present disclosure also includes methods involving co-administration of the compounds, compositions and / or pharmaceutical formulations described herein with one or more additional active agents (e.g., additional chemotherapeutic / anti -cancer agents, biological agents, chemical agents, radiation, and the like). Methods for co-administration with an additional therapeutic agent are well known in the art (Hardman, et al. (eds.) (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, New York, N.Y.; Poole and Peterson (eds.) (2001) Pharmacotberapeutics for Advanced Practice:A Practical Approach, Lippincott, Williams & Wilkins, Phila., Pa.; Chabner and Longo (eds.) (2001) Cancer Chemotherapy and Biotherapy, Lippincott, Williams & Wilkins, Phila., Pa.).

[0115] In one embodiment, the present disclosure provides methods for enhancing prior art therapies and / or pharmaceutical formulations by co-administering a compound, composition and / or pharmaceutical formulation according to the present disclosure. The pharmaceutical formulations and modes of administration may be any of those described above. In addition, the two or more co-administered chemotherapeutic / anti-cancer agents, chemical agents, biological agents or radiation may each be administered using different modes or different formulations. Co-administration need not refer to administration at the same time in an individual, but rather may include administrations that are spaced by hours or even days, weeks, or longer, as long as the administration of multiple therapeutic agents is the result of a single treatment plan. By way of example, the co-administration may comprise administering the compounds, compositions and / or pharmaceutical formulations according to the present disclosure before, after, or at the same time as the one or more additional therapeutics. In one possible treatment schedule, the compounds, compositions and / or pharmaceutical formulations of the present disclosure may be given as an initial dose in a multi-day protocol, with one or more additional therapeutics given on later administration days; or the one or more additional therapeutics are given as an initial dose in a multi-day protocol, with the compounds, compositions and / or pharmaceutical formulations of the present disclosure given on later administration days. On another hand, one or more additional therapeutic agents and the compounds, compositions and / or pharmaceutical formulations of the present disclosure maybe administered on alternate days in a multi -day protocol. In still another example, a mixture of one or more additional therapeutics and the compounds, compositions and / or pharmaceutical formulations of the present disclosure may be administered to reduce the presence of cancer in the subject. This is not meant to be a limiting list of possible administration protocols.

[0116] Formulations of therapeutic agents may be prepared for storage by mixing with physiologically acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y.).

[0117] Another aspect of the disclosure provides a method for arresting tumor growth in a subject in need thereof by administering a compound as described in Section I. In a subject with a tumor, the administration may result in a median tumor volume decrease of at least 5 mm3(i.e., 5 mm3or greater) to at least 100 mm3at least 5 days, 10 days, 15 days, 20 days, or at least 25 days after administration. For example, the administration may result in a median tumor volume decrease of at least 5 mm3, at least 10 mm3, at least 20 mm3, at least 30 mm3, at least 40 mm3, at least 50 mm3, at least 60 mm3, at least 70 mm3, at least 80 mm3, at least 90 mm3, or at least 100 mm3at least 5 days, 10 days, 15 days, 20 days, or at least 25 days after administration.

[0118] Another aspect of the disclosure provides a method for reducing hCD45+cells in a subject in need thereof by administering a compound as described in Section I. The administration may result in the reduction of hCD45+cells in the subject, such that 2-15% of the hCD45+cells remain after 5 days, after 10 days, after 15 days, after 20 days, after 25 days, or greater than 25 days after administration, as shown in FIG. 9A. For example, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% of the hCD45+cells remain after 5 days, after 10 days, after 15 days, after 20 days, after 25 days, or greater than 25 days after administration.Il l

[0119] The administration may result in the degradation of nuclear HSF1 in the subject, as shown in FIG. 1 and FIG. 2. Nuclear HSF1 may be degraded by greater than 50%, greater than 60%, greater than 70%, or greater than 80% in the subject in less than 20 hours, less than 10 hours, or less than 5 hours after administration.

[0120] Another aspect of the disclosure provides a method for the selective killing of malignant cells in a subject in need thereof by administering a compound as described in Section I. The administration may result in the reduction of 22RV1 prostate tumor growth as compared to a vehicle control, as shown in FIG. 8. The reduction of 22RV1 prostate tumor growth may be at least 500%, at least 1000%, at least 1500%, at least 2000%, at least 2500%, or at least 3000%.

[0121] The administration may result in the reduction of the cell count of human AML bone marrow cells as compared to a vehicle control, as shown in FIG. 9B. The reduction in cell count may be 2xl06cells or more, such as about 5xl06cells or more, IxlO7cells or more, IxlO8cells or more, and so on.

[0122] The compound described in Section I compound may have a half-life in the subject of greater than 500 minutes, greater than 750 minutes, greater than 1000 minutes, greater than 1250 minutes, or greater than 1500 minutes after administration of the compound. The halflife may be measured from the serum of the subject using methods known to those having ordinary skill in the art.

[0123] When administered orally, the compound may have a Tmax in serum from about 2 hours to about 8 hours as a result of the administration. For example, the compound may have a Tmax from 2 ± 0.25 hours to 3 ± 0.25 hours, 2 ± 0.25 hours to 4 ± 0.25 hours, 2 ± 0.25 hours to 5 ± 0.25 hours, 2 ± 0.25 hours to 6 ± 0.25 hours, 2 ± 0.25 hours to 7 ± 0.25 hours, 2 ± 0.25 hours to 8 ± 0.25 hours, 3 ± 0.25 hours to 8 ± 0.25 hours, 4 ± 0.25 hours to 8 ± 0.25 hours, 5 ± 0.25 hours to 8 ± 0.25 hours, 6 ± 0.25 hours to 8 ± 0.25 hours, or 7 ± 0.25 to 8 ± 0.25 hours as a result of the administration. The compound may have a Tmax of 2 ± 0.25 hours, 2.5 ± 0.25 hours, 3 ± 0.25 hours, 3.5 ± 0.25 hours, 4 ± 0.25 hours, 4.5 ± 0.25 hours, 5 ± 0.25 hours, 5.5 ± 0.25 hours, 6 ± 0.25 hours, 6.5 ± 0.25 hours, 7 ± 0.25 hours, 7.5 ± 0.25 hours, or 8 ± 0.25 hours as a result of the administration. In some non-limiting examples, the componund has a Tmaxof 3.33 ± 0.25 hours or 2.67 ± 0.25 hours as a result of the administration.

[0124] When administered orally, the compound may have a half life in serum from about 4 hours ± 15% to about 20 hours ± 15% as a result of the administration. For example, thecompound may have a half life from 4 hours ± 15% to 6 hours ± 15%, 4 hours ± 15% to 8 hours ± 15%, 4 hours ± 15% to 10 hours ± 15%, 4 hours ± 15% to 12 hours ± 15%, 4 hours ± 15% to 16 hours ± 15%, 4 hours ± 15% to 18 hours ± 15%, 4 hours ± 15% to 20 hours ± 15%, 6 hours ± 15% to 20 hours ± 15%, 8 hours ± 15% to 20 hours ± 15%, 10 hours ± 15% to 20 hours ± 15%, 12 hours ± 15% to 20 hours ± 15%, 14 hours ± 15% to 20 hours ± 15%, 16 hours ± 15% to 20 hours ± 15%, or 18 hours ± 15% to 20 hours ± 15% as a result of the administration. The compound may have a half life of 4 hours ± 15%, 5 hours ± 15%, 6 hours ± 15%, 7 hours ± 15%, 8 hours ± 15%, 9 hours ± 15%, 10 hours ± 15%, 11 hours ± 15%, 12 hours ± 15%, 13 hours ± 15%, 14 hours ± 15%, 15 hours ± 15%, 16 hours ± 15%, 17 hours ± 15%, 18 hours ± 15%, 19 hours ± 15%, or 20 hours ± 15% as a result of the administration. In some non-limiting examples, the compound may have a half life of 10.3 hours ± 15% or 6.47 hours ± 15%.

[0125] When administered orally at a dose of about 0.1 to about 1 mg / kg, the compound may have a Cmax in serum from 700 ng / mL ± 15% to 3500 ng / mL ± 15% as a result of the administration. For example, when orally administered at a dose of [x], the compound may have a Cmax in serum from 700 ng / mL ± 15% to 1000 ng / mL ± 15%, 700 ng / mL ± 15% to 1500 ng / mL ± 15%, 700 ng / mL ± 15% to 2000 ng / mL ± 15%, 700 ng / mL ± 15% to 2500 ng / mL ± 15%, 700 ng / mL ± 15% to 3000 ng / mL ± 15%, 700 ng / mL ± 15% to 3500 ng / mL ± 15%, 1000 ng / mL ± 15% to 3500 ng / mL ± 15%, 1500 ng / mL ± 15% to 3500 ng / mL ± 15%, 2000 ng / mL ± 15% to 3500 ng / mL ± 15%, 2500 ng / mL ± 15% to 3500 ng / mL ± 15%, or 3000 ng / mL ± 15% to 3500 ng / mL ± 15% as a result of the administration. When orally administered at a dose of about 0.1 to about 1 mg / kg, the compound may have a Cmax in serum of 700 ng / mL ± 15%, 800 ng / mL ± 15%, 900 ng / mL ± 15%, 1000 ng / mL ± 15%, 1100 ng / mL ± 15%, 1200 ng / mL ± 15%, 1300 ng / mL ± 15%, 1400 ng / mL ± 15%, 1500 ng / mL ± 15%, 1600 ng / mL ± 15%, 1700 ng / mL ± 15%, 1800 ng / mL ± 15%, 1900 ng / mL ± 15%, 2000 ng / mL ± 15%, 2100 ng / mL ± 15%, 2200 ng / mL ± 15%, 2300 ng / mL ± 15%, 2400 ng / mL ± 15%, 2500 ng / mL ± 15%, 2600 ng / mL ± 15%, 2700 ng / mL ± 15%, 2800 ng / mL ± 15%, 2900 ng / mL ± 15%, 3000 ng / mL ± 15%, 3100 ng / mL ± 15%, 3200 ng / mL ± 15%, 3300 ng / mL ± 15%, 3400 ng / mL ± 15%, or 3500 ng / mL ± 15%. In some non-limiting examples, the compound may have a Cmax in serum of 2520 ng / mL ± 15% or 1070 ng / mL ± 15% when orally administered at a dose of about 0.1 to about 1 mg / kg.

[0126] When administered orally at a dose of about 0.1 to about 1 mg / kg, the compound may have a AUCo-® in serum from 10000 ng / mL h ± 15% to 45000 ng / mL h ± 15%. For example,when administered orally at a dose of about 0.1 to about 1 mg / kg, the compound may have a AUCo-oo in serum from 10000 ng / mL h ± 15% to 15000 ng / mL h ± 15%, 10000 ng / mL h ± 15% to 20000 ng / mL h ± 15%, 10000 ng / mL h ± 15% to 25000 ng / mL h ± 15%, 10000 ng / mL h ± 15% to 30000 ng / mL h ± 15%, 10000 ng / mL h ± 15% to 35000 ng / mL h ± 15%, 10000 ng / mL h ± 15% to 40000 ng / mL h ± 15%, 10000 ng / mL h ± 15% to 45000 ng / mL h ± 15%, 15000 ng / mL h ± 15% to 45000 ng / mL h ± 15%, 20000 ng / mL h ± 15% to 45000 ng / mL h ± 15%, 25000 ng / mL h ± 15% to 45000 ng / mL h ± 15%, 30000 ng / mL h ± 15% to 45000 ng / mL h ± 15%, 35000 ng / mL h ± 15% to 45000 ng / mL h ± 15%, or 40000 ng / mL h ± 15% to 45000 ng / mL h ± 15% as a result of the administration. When orally administered at a dose of about 0.1 to about 1 mg / kg, the compound may have a AUCo-® in serum of 10000 ng / mL h ± 15%, 15000 ng / mL h ± 15%, 20000 ng / mL h ± 15%, 25000 ng / mL h ± 15%, 30000 ng / mL h ± 15%, 35000 ng / mL h ± 15%, 40000 ng / mL h ± 15%, or 45000 ng / mL h ± 15% as a result of the administration. In some non-limiting examples, the compound may have a AUCo-® in serum of 39600 ng / mL h ± 15% or 15900 ng / mL h ± 15% when orally administered at a dose of about 0.1 to about 1 mg / kg.

[0127] When administered orally, the compound may have a bioavailability from 60% ± 15% to 100% ±15%. For example, the compound may have a bioavailability from 60% ± 15% to 70% ± 15%, 60% ± 15% to 80% ± 15%, 60% ± 15% to 90% ± 15%, 60% ± 15% to 100% ± 15%, 70% ± 15% to 100% ± 15%, 80% ± 15% to 100% ± 15%, 90% ± 15% to 100% ± 15%, 70% ± 15% to 90% ± 15%, 60% ± 5% to 70% ± 5%, 60% ± 5% to 80% ± 5%, 60% ± 5% to 90% ± 5%, 60% ± 5% to 100% ± 5%, 70% ± 5% to 100% ± 5%, 80% ± 5% to 100% ± 5%, 90% ± 5% to 100% ± 5%, or 70% ± 5% to 90% ± 5%. The compound may have a bioavailability of 60 ± 15%, 65 ± 15%, 70 ± 15%, 75 ± 15%, 80 ± 15%, 85 ± 15%, 90 ± 15%, 95 ± 15%, 100 ± 15%, 60 ± 5%, 65 ± 5%, 70 ± 5%, 75 ± 5%, 80 ± 5%, 85 ± 5%, 90 ± 5%, 95 ± 5%, or 100 ± 5%.

[0128] When administered intravenously, the compound may have a half life in serum from about 4 hours ± 15% to about 20 hours ± 15% as a result of the administration. For example, the compound may have a half life from 4 hours ± 15% to 6 hours ± 15%, 4 hours ± 15% to 8 hours ± 15%, 4 hours ± 15% to 10 hours ± 15%, 4 hours ± 15% to 12 hours ± 15%, 4 hours ± 15% to 16 hours ± 15%, 4 hours ± 15% to 18 hours ± 15%, 4 hours ± 15% to 20 hours ± 15%, 6 hours ± 15% to 20 hours ± 15%, 8 hours ± 15% to 20 hours ± 15%, 10 hours ± 15% to 20 hours ± 15%, 12 hours ± 15% to 20 hours ± 15%, 14 hours ± 15% to 20 hours ± 15%, 16 hours ± 15% to 20 hours ± 15%, or 18 hours ± 15% to 20 hours ± 15% as a result of theadministration. The compound may have a half life of 4 hours ± 15%, 5 hours ± 15%, 6 hours ± 15%, 7 hours ± 15%, 8 hours ± 15%, 9 hours ± 15%, 10 hours ± 15%, 11 hours ± 15%, 12 hours ± 15%, 13 hours ± 15%, 14 hours ± 15%, 15 hours ± 15%, 16 hours ± 15%, 17 hours ± 15%, 18 hours ± 15%, 19 hours ± 15%, or 20 hours ± 15% as a result of the administration. In some non-limiting examples, the compound may have a half life of 8.23 hours ± 15% or 6.62 hours ± 15%.

[0129] When administered intravenously at a dose of about 0.01 to about 0.2 mg / kg, the compound may have a Cmax in serum from 100 ng / mL ± 15% to 1500 ng / mL ± 15% as a result of the administration. For example, when administered intravenously at a dose of about 0.01 to about 0.2 mg / kg, the compound may have a Cmax in serum from 100 ng / mL ± 15% to 250 ng / mL ± 15%, 100 ng / mL ± 15% to 500 ng / mL ± 15%, 100 ng / mL ± 15% to 750 ng / mL ± 15%, 100 ng / mL ± 15% to 1000 ng / mL ± 15%, 100 ng / mL ± 15% to 1250 ng / mL ± 15%, 100 ng / mL ± 15% to 1500 ng / mL ± 15%, 250 ng / mL ± 15% to 1500 ng / mL ± 15%, 500 ng / mL ± 15% to 1500 ng / mL ± 15%, 750 ng / mL ± 15% to 1500 ng / mL ± 15%, 1000 ng / mL ± 15% to 1500 ng / mL ± 15%, or 1250 ng / mL ± 15% to 1500 ng / mL ± 15% as a result of the administration. When administered intravenously at a dose of about 0.01 to about 0.2 mg / kg, the compound may have a Cmax in serum of 100 ng / mL ± 15%, 200 ng / mL ± 15%, 300 ng / mL ± 15%, 400 ng / mL ± 15%, 500 ng / mL ± 15%, 600 ng / mL ± 15%, 700 ng / mL ± 15%, 800 ng / mL ± 15%, 900 ng / mL ± 15%, 1000 ng / mL ± 15%, 1100 ng / mL ± 15%, 1200 ng / mL ± 15%, 1300 ng / mL ± 15%, 1400 ng / mL ± 15%, or 1500 ng / mL ± 15% as a result of the administration. In some non-limiting examples, the compound may have a Cmax in serum of 1040 ng / mL ± 15% or 276 ng / mL ± 15% when administered intravenously at a dose of about 0.01 to about 0.2 mg / kg.

[0130] When administered intravenously at a dose of about 0.01 to about 0.2 mg / kg, the compound may have a AUC.., in serum from 1000 ng / mL h ± 15% to 10000 ng / mL h ± 15% as a result of the administration. For example, the compound may have a AUCo-® in serum from 1000 ng / mL h ± 15% to 2500 ng / mL h ± 15%, 1000 ng / mL h ± 15% to 5000 ng / mL h ± 15%, 1000 ng / mL h ± 15% to 7500 ng / mL h ± 15%, 1000 ng / mL h ± 15% to 10000 ng / mL h ± 15%, 2500 ng / mL h ± 15% to 10000 ng / mL h ± 15%, 5000 ng / mL h ± 15% to 10000 ng / mL h ± 15%, or 7500 ng / mL h ± 15% to 10000 ng / mL h ± 15% as a result of the administration. When administered intravenously at a dose of about 0.01 to about 0.2 mg / kg, the compound may have a AUCo-® in serum of 1000 ng / mL h ± 15%, 2000 ng / mL h ± 15%, 3000 ng / mL h ± 15%, 4000 ng / mL h ± 15%, 5000 ng / mL h ± 15%, 6000 ng / mL h ± 15%,7000 ng / mL h ± 15%, 8000 ng / mL h ± 15%, 9000 ng / mL h ± 15%, or 10000 ng / mL h ± 15% as a result of the administration. In some non-limiting examples, the compound may have a AUCo-oo in serum of 8120 ng / mL h ± 15% or 3170 ng / mL h ± 15% when administered intravenously at a dose of about 0.01 to about 0.2 mg / kg.

[0131] In some embodiments, the methods may further include diagnosing the subject with cancer. Methods of diagnosing cancer are generally known to those having ordinary skill in the art.Combination Therapy

[0132] In some cases, a compound described herein is administered in combination with a second anti-cancer agent. Examples of anti -cancer agents for use in combination with a compound of the disclosure (e.g., of Formula I) include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).

[0133] Other anti-cancer agents that can be employed in combination with a compound of the disclosure (e.g., of Formula I) include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinantinterleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-la; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

[0134] Other anti-cancer agents that can be employed in combination with a compound of the disclosure (e.g., of Formula I) include: 20-epi-l, 25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara- CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide;bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionicgonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N- substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; Rn retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B 1 ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfm; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate;triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

[0135] Yet other anticancer agents that can be employed in combination with a compound of the disclosure (e.g., of Formula I) include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0136] Examples of natural products useful in combination with a compound of the disclosure (e.g., of Formula I) include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).

[0137] Examples of alkylating agents that can be employed in combination with a compound of the disclosure (e.g., of Formula I) include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

[0138] Examples of hormones and antagonists useful in combination with a compound as described in Section I include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer includeplatinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide).

[0139] Examples of anti -cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with an irreversible EGFR tyrosine kinase inhibitor compound include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongi statin 1, Spongi statin 2, Spongi statin 3, Spongi statin 4, Spongi statin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21 -hydroxy epothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR- 112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR- 258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC- 106969), T- 138067 (Tularik, also known as T-67, TL- 138067 and TI- 138067), COBRA- 1 (Parker Hughes Institute, also known as DDE-261 and WHL261), H10 (Kansas State University), Hl 6 (Kansas State University), Oncocidin Al (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3- BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1 AABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)- Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A- 318315 (Abbott), HTI-286 (also known as SPA- 110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY- 007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0140] In some cases, a compound described herein (e.g., a compound of Formula I) is administered in combination with TNF-alpha and / or TNF -related apoptosis-inducing ligand (TRAIL). TRAIL shows homology to other members of the TNF-alpha family of proteins. In some cases, a compound described herein (e.g., a compound of Formula I) is administered in combination with a TNF-alpha modulator and / or a TNF-alpha analogue (e.g., lenalidomide, revlimid, CC-5013; CC-4047, ACTIMID, thalidomide and the like). In some cases, a compound described herein (e.g., a compound of Formula I) is administered in combination with an adjuvant, hormone therapy, immunotherapy or any combination thereof.Definitions

[0141] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0142] Articles "a" and "an" are used herein to refer to one or to more than one (i.e. at least one) of the grammatical object of the article. By way of example, "an element" means at least one element and can include more than one element.

[0143] " About" is used to provide flexibility to a numerical range endpoint by providing that a given value may be "slightly above" or "slightly below" the endpoint without affecting thedesired result. Unless otherwise noted, “about” may be defined as ± 15% of the endpoint, ± 10% of the endpoint, ± 7% of the endpoint, or ± 5% of the endpoint.

[0144] The use herein of the terms "including," "comprising," or "having," and variations thereof, is meant to encompass the elements listed thereafter and equivalents thereof as well as additional elements. Embodiments recited as "including," "comprising," or "having," certain elements are also contemplated as "consisting essentially of and "consisting of those certain elements. As used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations where interpreted in the alternative ("or").

[0145] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. For example, if a concentration range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highest value enumerated are to be considered to be expressly stated in this disclosure.

[0146] Terms used herein may be preceded and / or followed by a single dash, or a double dash, “=”, to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond or a pair of single bonds in the case of a spiro-substituent. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read “left to right” with reference to the chemical structure referred to unless a dash indicates otherwise. For example, arylalkyl, arylalkyl-, and -alkylaryl indicate the same functionality.

[0147] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety can refer to a monovalent radical (e.g. CH3-CH2-), in some circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene). All atoms are understood to have their normal number of valences for bond formation (z.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).Nitrogens in the presently disclosed compounds can be hypervalent, e.g., an N-oxide or tetrasubstituted ammonium salt. On occasion a moiety may be defined, for example, as -B-(A)a, wherein a is 0 or 1. In such instances, when a is 0 the moiety is -B and when a is 1 the moiety is -B-A.

[0148] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3- methyl-1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l -pentyl, 3-methyl-l- pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1 -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cio alkyl, a C1-C9 alkyl, a Ci-Cs alkyl, a C1-C7 alkyl, a Ci-Ce alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0149] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3- butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In someembodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0150] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0151] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0152] “Alkoxy” refers to a radical of the formula -ORa where Rais an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may beoptionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0153] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0154] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0155] “Cycloalkyl” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0156] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atomss. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0157] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogen atoms. In some embodiments, the alkyl is substituted with one, two, or three halogen atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogen halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluorom ethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.

[0158] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0159] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0160] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0161] “Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl comprises 1 or 2 heteroatoms selected from nitrogen and oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl), from two to eight carbon atoms (C2-C8heterocycloalkyl), from two to six carbon atoms (C2-C6 heterocycloalkyl), from two to five carbon atoms (C2-C5 heterocycloalkyl), or two to four carbon atoms (C2-C4 heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1, 1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran- 1-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0162] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl isoptionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0163] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1- oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0164] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a subject (e.g. a mammal, such as a human), either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0165] “ Treatment” of a subject (e.g. a mammal, such as a human) includes any type of intervention used in an attempt to alter the natural course of the subject. In some embodiments, treatment includes administration of a pharmaceutical formulation, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen, e.g., cancer does not metastasize and the like) or alleviation of the condition (e.g., reduction in tumor size, remission of cancer, absence of symptoms of autoimmune disease and the like). In other embodiments, treatment also includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected to be suffering from a condition described herein).

[0166] As used herein, “subject”, “individual” and “patient” are used interchangeably, and may refer to a mammal such as a human. None of the terms imply that a medical professional is required for the administration of the compounds disclosed herein.EXAMPLES

[0167] The methods of use and preparation of the compounds of the disclosure is illustrated further by the following examples, which are not to be construed as limiting the disclosure in scope or spirit to the specific procedures and compounds described in them.Comparative Example 1: Preparation of l-(4-chloro-3-nitrophenyl)-3-(4- fluorophenyl)urea

[0168] 1 -fluoro-4-isocyanatobenzene (1.0 equiv) and 4-chl oro-3 -nitroaniline (1.0 equiv) were dissolved in di chloromethane (each 0.5 M) and stirred gently at 25°C for 48 hours. l-(4- chloro-3-nitrophenyl)-3-(4-fluorophenyl)urea was collected by filtration, washed with dichloromethane, and dried under vacuum.1H NMR: (Chloroform-t / , 400 MHz) 5 7.96 (d, J = 2.5 Hz, 1H), 7.69 (dd, J = 8.4, 2.4 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.35 (dd, J = 8.8, 4.7 Hz, 2 H), 6.99 (t, J = 8.6 Hz, 2H).Comparative Example 2: Preparation of l-[4-chloro-3-(trifluoromethylsulfonyl)phenyl]- 3-(4-fluorophenyl)urea

[0169] Step 1 : Preparation of 2-chloro-5-nitro-benzenediazonium: To a solution of 2-chloro- 5 -nitro-aniline (6.92 g, 40.10 mmol, 1 eq) in EtOH (12 mL) was added HBF4 (17.61 g, 80.20 mmol, 12.4 mL, 40% purity, 2 eq and t-BuONO (8.27 g, 80.20 mmol, 9.54 mL, 2 eq) at 0 °C drop-wise slowly. After addition, the mixture was stirred at 25 °C for 2 hours. The mixture was quenched by addition of diisopropylether (100 mL) at 20 °C, filtered. The filtered cake was washed with diisopropylether (50 mL*3), dried in vaccum afford the crude product 2- chloro- 5 -nitro-benzenedi azonium (7.5 g, crude) as a yellow solid which was used into the next step without further purification.

[0170] Step 2: Preparation of l-chloro-4-nitro-2-(trifluoromethylsulfonyl)benzene: A mixture of 2-chl oro-5 -nitro-benzenedi azonium (3.4 g, 18.42 mmol, 1 eq), sodium trifluoromethanesulfmate (8.62 g, 55.27 mmol, 8.62 mL, 3 eq), CU2O (263.60 mg, 1.84 mmol, 188.29 uL, 0.1 eq) was degassed and purged with N2 for 3 times, and then DMSO (120 mL) was added by syringe. The mixture was stirred at 25 °C for 12 hr under N2 atmosphere. The mixture was diluted with EtOAc (150 mL) at 20 °C, washed with H2O (10 mL*3), brine (10 mL), dried overNa2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petr oleum ether gradient @ 75 mL / min) the compound l-chloro-4-nitro-2- (trifluoromethylsulfonyl)benzene (0.35 g, 1.21 mmol, 6.56% yield) as light-yellow oil.

[0171] Step 3: Preparation of 4-chloro-3-(trifluoromethylsulfonyl)aniline: To a solution of 1- chloro-4-nitro-2-(trifluoromethylsulfonyl)benzene (0.5 g, 1.73 mmol, 1 eq) in EtOH (10 mL) / H2O (2 mL) was added Fe (964.12 mg, 17.26 mmol, 10 eq) and NH4CI (461.74 mg, 8.63 mmol, 5 eq) under N2 atmosphere. After addition, the mixture was heated to 75 °C and stirred at 75 °C for 6 hours. The mixture was cooled to 25 °C and filtered, and the filter cake was washed with MeOH (10 mL*2). The filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient@ 36 mL / min) to afford the compound 4-chloro-3-(trifluoromethylsulfonyl)aniline (73.28% purity, 0.34 g) as yellow oil with purity 73.28% on LCMS.

[0172] Step 4: Preparation of l-[4-chloro-3-(trifluoromethylsulfonyl)phenyl]-3-(4- fhiorophenyl)urea: To a solution of 4-fluoroaniline (25.68 mg, 231.10 pmol, 22.14 uL, 1.2 eq) in THF (5 mL) was added triphosgene (22.86 mg, 77.03 pmol, 0.4 cv / )and DIPEA (49.78 mg, 385.16 pmol, 67.09 uL, 2 eq) at 0 °C. After addition, the mixture was stirred at 0 °C for 2 hours and then 4-chloro-3-(trifluoromethylsulfonyl)aniline (0.05 g, 192.58 pmol, 1 eq was added. The mixture was warmed to 25 °C and stirred for 10 hours. The mixture was quenched by addition of H2O (10 mL) at 0 °C, extracted with EtOAc (10 mL*2). The combined organic layers were washed with H2O (10 mL), dried over ISfeSCU and filtered. The filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by pre- HPLC (column: HUAPU C8 Extreme BDS 150*30 5u;mobile phase: [water(0.04%HCl)- ACN];B%: 40%-75%,l lmin) to afford the compound 1 -[4-chl oro-3 - (trifluoromethylsulfonyl)phenyl]-3-(4-fluorophenyl)urea (0.0162 g, 40.48 pmol, 21.02% yield, 99.13% purity) as an off-white solid with purity 99.13% on LCMS.1H NMR: (400 MHz, MeOD) 5 8.53 (s, 1H), 7.97 (m, 1H), 7.74 (m, 1H), 7.51 (m, 2H), 7.11 (m, 2H).Example 1.

[0173] The melting temperature (ATm) for purified recombinant human HSF1 (HSF1 DNA binding domain) was determined in the presence of HSF1 degrader compounds shown in Table 1 and compared to the solvent DMSO. Sypro orange dye was added to the HSF1 DBD (5 micromolar final concentration) in buffer, mixed and distributed to wells in 384 well microtiter plates. HSF1 degrader compound (12.5micromolar) or DMSO solvent was added to three replicate wells per compound concentration, mixed and plates loaded into a Quant Studio thermocycler and run on a temperature gradient from 25°C to 85°C with increments of 0.5°C steps. Melting curves were obtained and analyzed using the ThermoFisher Shift Software 1.4 fitted with a Boltzmann equation to determine the change in melting temperature of the protein in the presence of DMSO as compared to compound. The difference in the melting temperature under these two conditions was assigned as the change in melting temperature of ATm. Results are shown in Table 2.Table 1

[0174] Next, cell viability of C4-2 prostate cancer cells was determined. C4-2 prostate cancer cells were grown in RMPI-1640 (no L-glutamine, Gibco 21870076) supplemented with 10% fetal bovine albumin (non-heat-inactivated, Cytiva Hyclone SH30071.03). C4-2 prostate cancer cell proliferation at 37°C, 5% CO2 was assessed to determine the IC50 (concentration at which 50% of cell proliferation was inhibited) for each compound. A 9-point dilution series was used to assess the ability of each compound to inhibit the growth of C4-2 prostate cancer cells over a 48-hour period, as compared to negative control solvent, DMSO. Cell proliferation was measured by the Cell Titre Gio assay using 384 well microtiter plate reader to quantitate luminescence. The IC50 was determined from the values obtained. Results are shown in Table 2.

[0175] Next, the change in heat shock protein gene expression in C4-2 prostate cancer cells was determined. C4-2 prostate cancer cells were grown in RMPI-1640 (no L-glutamine, Gibco 21870076) supplemented with 10% fetal bovine albumin (non-heat-inactivated, Cytiva Hyclone SH30071.03). To quantitatively measure the inhibition of HSF1 activity in C4-2 prostate cancer cells, compounds or DMSO were added to triplicate C4-2 cell cultures for 2 hours. HSF1 activity was then stimulated with the Hsp90 inhibitor SNX-2112 (100 nM) for an additional 5 hr at 37°C in the presence of HSF1 degrader compounds or DMSO. Total RNA was extracted, converted to cDNA and used in qPCR assays to quantify the change in HSF1 target gene transcript expression (HSPA4L equals Hsp70, HSPB1 equals Hsp27 andDNAJB1 equals Hsp40) as compared to GAPDH internal control gene, and then compared to DMSO negative control. The results are shown in Table 2.

[0176] Next, the microsome stability in rats was determined for select compounds from Table 1. Test compounds are incubated with rat liver microsomes supplemented with cofactors at 37°C. Typical conditions were a compound concentration of 1 pM and 5 sampling time-points (0, 5, 15, 30 and 45 minutes), in duplicate. At each time-point, the reactions were terminated by the addition of organic solvent. The samples were centrifuged and the parent compound concentration was evaluated by LC-MS / MS measurements. Control compounds were included with well-established stability when incubated with rat microsomes. Multiple time points were used to determine % parent compound remaining at each time point and to calculate the T1 / 2 for each compound in rat liver microsomes. A higher T1 / 2 indicates increased compound stability in microsomes. The results are shown in Table 2.Table 2Example 2: Preparation of l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4- cyanophenyl)urea (Compound 6)Step C Compound 63

[0177] Step A: To a stirred solution of 2-chloro-5-nitroaniline (10.0 g, 0.058 mol) in EtOH (40 mL) was added tert-butyl nitrite (12.0 g, 0.12 mol) and fluoroboric acid (50 wt. % in H2O) (21.27 g, 0.12 mol) dropwise at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 2 hours. After completion, MTBE (100 mL) was added to the mixture. The precipitant was filtered and dried in vacuo to give the diazonium salt (12.5 g, 0.046 mol, yield: 79.3 %) as a yellow solid. LC-MS (ESI+): m / z 184.0 (M+H)+.

[0178] Then sodium trifluoromethanesulfmate (17.49 g, 0.11 mol) and CU2O (0.53 g, 0.0037 mol) were added to the diazonium salt (10.0 g, 0.037 mol) in DMSO (100 mL). The reaction mixture was stirred at 25 °C for 13 hours. The reaction mixture was quenched with H2O (100 mL), extracted with EA (3*80 mL). The organic layer was washed with brine (2*80 mL) and concentrated in vacuo. The residue was purified by column chromatography (silica gel PE / EA=9 / 1) to afford l-chloro-4-nitro-2-((trifluoromethyl)sulfonyl)benzene(L7 g, 0.0059 mol, yield: 15.9%) as yellow oil.

[0179] Step B: To a stirred solution of l-chloro-4-nitro-2-((trifluoromethyl)sulfonyl)benzene (1.7 g, 5.9 mol) in EtOH (17 mL) and H2O (3.5 mL) was added Fe (3.29 g, 58.75 mmol) andNH4CI (1.56 g, 29.43 mmol). The reaction mixture was warmed to 65 °C and stirred for 5hours. After completion, the resulting mixture was filtered, and the filtrate was concentrated in vacuo to afford crude product. The residue was purified by column chromatography (silica gel PE / EA=10: 1-3: 1) to afford 4-chl oro-3 -((trifluoromethyl)sulfonyl)aniline( 1.2 g, 4.62 mmol, yield: 15.9%) as yellow oil. LC-MS (ESI+): m / z 260.0(M+H)+.

[0180] Step C: A mixture of 4-chloro-3-((trifluoromethyl)sulfonyl)aniline (1.2 g, 4.62 mmol) and 4-isocyanatobenzonitrile (0.67 g, 4.65 mmol) in DCM (15 mL) was stirred at room temperature for 17 hours. Then the mixture was refluxed at 55 °C for 5 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel PE / EA=9: 1) to afford crude product. The residue was recrystallized by MTBE to give l-(4- chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4-cyanophenyl)urea (520 mg, 1.29 mol, yield, 27.9%). LC-MS (ESI+): m / z 404.0(M+H)+. *H NMR (400 MHz, DMSO) 5 9.62 (s, 1H), 9.46 (s, 1H), 8.59 (d, J= 2.5 Hz, 1H), 7.91 (dd, J= 8.8, 2.6 Hz, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.76 (d, J= 8.7 Hz, 2H), 7.67 (d, J= 8.8 Hz, 2H).Example 3: Preparation of l-(4-chloro-3-nitrophenyl)-3-(3-cyanophenyl)urea(Compound 1)

[0181] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in di chloromethane (5 mL) was added 3 -aminobenzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (29.6 mg, 0.09 mmol, yield: 37.2%). LC-MS (ESI+): m / z 317.2 (M+H)+. 'HNMR (400 MHz, DMSO-t / e) d 9.46 (s, 1H), 9.28 (s, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.73-7.68 (m, 3H), 7.55-7.47 (m, 2H).Example 4: Preparation of l-(4-chloro-3-nitrophenyl)-3-(4-cvanophenyl)urea (Compound 2)

[0182] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-aminobenzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (28.8 mg, 0.09 mmol, yield: 36.2%). LC-MS (ESI+): m / z 317.2 (M+H)+. 'HNMR (400 MHz, DMSO-t / e) d 9.45 (s, 1H), 9.43 (s, 1H), 8.30 (s, 1H), 7.77-7.74 (m, 2H), 7.70-7.64 (m, 4H).Example 5: Preparation of l-(4-chloro-3-nitrophenyl)-3-(4-cyano-3- (trifluoromethyl)phenyl)urea (Compound 3)

[0183] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-amino-2-(trifluoromethyl)benzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered and the filter cake was washed by dichloromethane. The residue was further purified by Prep- HPLC to give the desired compound (36.3 mg, 0.09 mmol, yield: 37.6%). LC-MS (ESI+): m / z 385.2 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.81 (s, 1H), 9.62 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.07-8.04 (m, 1H), 7.83-7.80 (m, 1H), 7.69 (s, 2H).Example 6: Preparation of l-(4-chloro-3-nitrophenyl)-3-(4-cyano-3- methoxyphenyl)urea (Compound 4)

[0184] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-amino-2-methoxybenzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (37.5 mg, 0.11 mmol, yield: 43.2%). LC-MS (ESI+): m / z 347.2 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.46 (s, 2H), 8.32 (s, 1H), 7.68-7.67 (m, 2H), 7.63-7.61 (m, 1H), 7.52 (s, 1H), 7.07-7.05 (m, 1H), 3.89 (s, 3H).Example 7: Preparation of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4- cyanophenyl)urea (Compound 5)

[0185] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-aminobenzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (35.1 mg, 0.10 mmol, yield: 28.6%). LC-MS (ESI+): m / z 340.0 (M+H)+. 'HNMR (400 MHz, DMSO-t / e) d 9.42 (s, 1H), 9.39 (s, 1H), 8.11 (s, 1H), 7.76-7.74 (d, J=8.8, 2H), 7.67-7.66 (m, 2H), 7.65-7.63(d, J=8.8, 2H).Example 8: Preparation of l-(4-cyanophenyl)-3-(l,l-dioxidobenzo[b]thiophen-6-yl)urea (Compound 7)

[0186] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 5-aminobenzo[Z>]thiophene 1,1-dioxide (144.8 mg, 0.80 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (28.0 mg, 0.08 mmol, yield: 22.9%). LC-MS (ESI+): m / z 326.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.47 (s, 1H), 9.45 (s, 1H), 8.06 (s, 1H), 7.79-7.77 (d, J=8.8, 2H), 7.68-7.66 (d, J=8.8, 2H), 7.60-7.58(m, 2H), 7.54- 7.52 (m, 1H), 7.27-7.25 (m, 1H).Example 9: Preparation of l-(benzo[c][l,2,5]thiadiazol-5-yl)-3-(4-cyanophenyl)urea (Compound 8)

[0187] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added benzo[c]][l,2,5]thiadiazol-5-amine at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (70.0 mg, 0.23 mmol, yield: 65.7%). LC-MS (ESI+): m / z 296.1 (M+H)+. ‘H NMR (400 MHz, DMSO-t / 6) d 9.43 (s, 1H), 9.38 (s, 1H), 8.33 (s, 1H), 8.03-8.01 (d, J=8.8, 1H), 7.77-7.75(d, J=8.8, 2H), 7.71-7.68(d, J=8.8, 2H), 7.65-7.62 (m, 1H).Example 10: Preparation of l-(benzofuran-5-yl)-3-(4-cyanophenyl)urea (Compound 9)

[0188] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added benzofuran-5-amine at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (55.0 mg, 0.19 mmol, yield: 54.3%). LC-MS (ESI+): m / z 278.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / e) d 9.20 (s, 1H), 8.87 (s, 1H), 7.96 (s, 1H), 7.84-7.83 (m, 1H), 7.74-7.72 (d, J=8.8, 2H), 7.66-7.63 (d, J=8.8, 2H), 7.54-7.51 (d, J=8.8, 1H), 7.30-7.28 (dd, J=8.8, 1H), 6.93 (s, 1H).Example 11: Preparation of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-cyano-3- methoxyphenyl)urea (Compound 10)

[0189] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-amino-2-methoxybenzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (50.0 mg, 0.13 mmol, yield: 44.8%). LC-MS (ESI+): m / z 370.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.42 (s, 1H), 9.36 (s, 1H), 8.11 (s, 1H), 7.68-7.61 (m, 3H), 7.52 (s, 1H), 7.09-7.06 (m, 1H), 3.90 (s, 3H).Example 12: Preparation of l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4- cyano-3-methoxyphenyl)urea (Compound 11)1 Step A Compound 11

[0190] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-amino-2-methoxybenzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (27.5 mg, 0.06 mmol, yield: 20.7%). LC-MS (ESI+): m / z 434.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.74 (s, 1H), 9.58 (s, 1H), 8.59 (s, 1H), 7.92-7.89 (m, 1H), 7.85-7.83 (d, .7=8.8, 1H), 7.63-7.61 (d, 7=8.8, 1H), 7.50 (s, 1H), 7.09-7.06, (m, 1H), 3.89 (s, 3H).Example 13: Preparation of l-(4-cyano-3-methoxyphenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (Compound 12)

[0191] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 5-aminobenzo[Z>]thiophene 1,1-dioxide (144.8 mg, 0.80 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (35.4 mg, 0.1 mmol, yield: 34.5%). LC-MS (ESH): m / z 356.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.51 (s, 1H), 9.48 (s, 1H), 8.09 (s, 1H), 7.64-7.52 (m, 5H), 7..27-7.26 (m, 1H), 7.08-7.05 (m, 1H), 3.91 (s, 3H).Example 14: Preparation of l-(benzo[c][l,2,5]thiadiazol-5-yl)-3-(4-cyano-3- methoxyphenyl)urea (Compound 13)

[0192] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added benzo[c]][l,2,5]thiadiazol-5-amine at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (30.0 mg, 0.09 mmol, yield: 31%). LC-MS (ESI+): m / z 326.1 (M+H)+. ‘H NMR (400 MHz, DMSO-t / 6) d 10.04 (s, 2H), 8.35 (s, 1H), 8.04-8.02 (d, J=8.8, 1H), 7.63-7.61 (d, J=8.8, 2H), 7.55 (s, 1H), 7.09-7.06 (d, J=8.4, 1H), 3.91 (s, 3H).Example 15: Preparation of l-(4-cyano-3-methoxyphenyl)-3-(3a,7a-dihydrobenzofuran- 5-yl)urea (Compound 14)DCM / 25 C / 12h1 Step A Compound 14

[0193] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added benzofuran-5-amine at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (31.4 mg, 0.10 mmol, yield: 34.5%). LC-MS (ESI+): m / z 308.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / e) d 9.23 (s, 1H), 8.89 (s, 1H), 7.97-7.96 (d, J=2.0, 1H), 7.86-7.86 (d, J=2.0, 1H), 7.60-7.52 (m, 3H), 7.30-7.27 (m, 1H), 7.04-7.02 (m, 1H), 6.94 (s, 1H), 3.89 (s, 3H).Example 16: Preparation of l,3-bis(4-cyano-3-(trifluoromethyl)phenyl)urea (Compound 15)

[0194] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-amino-2-(trifluoromethyl)benzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep- HPLC to give the desired compound (49.8 mg, 0.12 mmol, yield: 46.2%). ’H NMR (400 MHz, DMSO-t / e) d 9.97 (s, 2H), 8.20 (s, 2H), 8.09-8.07 (d, J=8.8, 2H), 7.85-7.83 (dd, J=8.8, 2H).Example 17: Preparation of l,3-bis(4-cyanophenyl)urea (Compound 16)

[0195] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-aminobenzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (53.9 mg, 0.20 mmol, yield: 57.1%). LC-MS (ESI+): m / z 263.0 (M+H)+. 'HNMR (400 MHz, DMSO-t / e) d 9.40 (s, 2H), 7.77-7.75 (dd, J=6.8, 4H), 7.66-7.63 (dd, J=6.8, 4H).Example 18: Preparation of l-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4- fluorophenyl)urea (Compound 17)

[0196] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-amino-2-(trifluoromethyl)benzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep- HPLC to give the desired compound (19.3 mg, 0.06 mmol, yield: 16.6%). LC-MS (ESI+): m / z 324.0 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.71 (s, 1H), 9.15 (s, 1H), 8.22 (s, 1H), 8.06-8.04 (d, .7=8.4, 1H), 7.80-7.77 (dd, 7=6.8, 1H), 7.52-7.50 (m, 2H), 7.19-7.15 (m, 2H).Example 19: Preparation of l-(4-cyanophenyl)-3-(4-fluorophenyl)urea (Compound 18)

[0197] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-aminobenzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (53.4 mg, 0.20 mmol, yield: 55.5%). LC-MS (ESL): m / z 256.1 (M+H)+. 'HNMR (400 MHz, DMSO-7) d 9.23 (s, 1H), 8.92 (s, 1H), 7.74-7.72 (d, 7=8.4, 2H), 7.64-7.62 (d, 7=8.4, 2H), 7.49-7.45 (m, 2H), 7.17-7.12 (m, 2H).Example 20: Preparation of l-(4-cyano-3-(trifluoromethyl)phenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (Compound 19)1 Step A Compound 19

[0198] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 5-aminobenzo[Z>]thiophene 1,1-dioxide (144.8 mg, 0.80 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep-HPLC to give the desired compound (35.0 mg, 0.08 mmol, yield: 29.0%). LC-MS (ESI+): m / z 394.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.84 (s, 1H), 9.60 (s, 1H), 8.23 (s, 1H), 8.09-8.05 (m, 2H), 7.84 (s, 1H), 7.66-7.59 (m, 2H), 7.55-7.53 (m, 1H), 7.29-7.27 (m, 1H).Example 21: Preparation of l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4- cyano-3-(trifluoromethyl)phenyl)urea (Compound 20)

[0199] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-amino-2-trifluoromethyl)benzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep- HPLC to give the desired compound (50.1 mg, 0.10 mmol, yield: 38.5%). LC-MS (ESI+): m / z 472.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.87 (s, 1H), 9.82 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 8.07-8.05 (d, J=8.8, 1H), 7.97-7.94 (m, 1H), 7.86-7.84 (d, J=8.8, 2H).Example 22: Preparation of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-cyano-3- (trifluoromethyl)phenyl)urea (Compound 21)

[0200] Step A: To a stirred solution of compound 1 (50.0 mg, 0.25 mmol) in dichloromethane (5 mL) was added 4-amino-2-(trifluoromethyl)benzonitrile at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purified by Prep- HPLC to give the desired compound (30.2 mg, 0.07 mmol, yield: 26.9%). LC-MS (ESI+): m / z 408.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.77 (s, 1H), 9.51 (s, 1H), 8.19 (s, 1H), 8.08-8.03 (m, 2H), 7.82 (s, 1H), 7.68-7.62 (m, 2H).Example 23: Preparation of l-(4-cyano-3-cyclopropylphenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (Compound 22)toluene, 100 °CStep-C Compound 22

[0201] Step A: To a stirred solution of 2-bromo-4-nitrobenzonitrile (700 mg, 3.08 mmol) in toluene (5 mL) was added cyclopropylboronic acid (794 mg, 9.25 mmol), K3PO4 (1.3 g, 6.16 mmol), tricyclohexyl phosphine (43 mg, 0.154 mmol) and Pd(OAc)2 (17.3 mg, 0.077 mmol).The reaction mixture was stirred at 100 °C overnight under nitrogen atmosphere. After completion, the reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 5% - 30%) to give 2-cyclopropyl-4-nitrobenzonitrile (460 mg, 2.44 mmol, yield: 79.3 %) as a light yellow solid.

[0202] Step B: To a stirred solution of 2-cyclopropyl-4-nitrobenzonitrile (460 mg, 2.44 mmol) in MeOH (10 mL) was added P / C (50 mg, 10% palladium on carbon) at room temperature. The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at room temperature for 1 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (PE / EtOAc = 5% - 33%) to give 4-amino-2- cyclopropylbenzonitrile (280 mg, 1.77 mmol, yield: 72.7%) as a yellow oil. LC-MS (ESI+): 159.1.

[0203] Step C: To a stirred solution of 6-aminobenzo[Z>]thiophene 1,1 -di oxide (641.5 mg, 3.54 mmol) in THF (30 mL) was added triphosgene (420.2 mg, 1.42 mmol) and DIPEA (977 mg, 7.08 mmol) at 0 °C. After addition, the mixture was stirred at 0 °C for 2 hours and then 4-amino-2-cyclopropylbenzonitrile (280 mg, 1.77 mmol) was added. The mixture was warmed to room temperature and stirred for 10 hours. The mixture was quenched by H2O (10 mL) at 0°C and extracted with EtOAc (10 mL*2). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CH3CN / H2O = 5% - 80%) to give l-(4-cyano-3-cyclopropylphenyl)-3-(l,l-dioxidobenzo[b]thiophen-6- yl)urea (10 mg, 0.027 mmol, yield: 1.5%) as a white solid. LC-MS (ESI+): m / z 366.1 (M+H)+. 'H NMR (400 MHz, DMSO-t / 6) d 9.40 (s, 1H), 9.17 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.60-7.49 (m, 4H), 7.23 (d, J= 6.8, 1H), 7.06 (d, J= 8.8, 1H), 2.12 (m, 1H), 1.08-1.05 (m, 2H), 0.78-0.75 (m, 2H).Example 24: Preparation of l-(4-cyano-3-cyclopentylphenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (Compound 23)Step-C Compound 23

[0204] Step A: A mixture of 2-bromo-4-nitrobenzonitrile (300 mg, 1.32 mmol), 2- (cyclopent-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (512 mg, 2.64 mmol), Pd(PPhs)4 (150 mg, 0.13 mmol) and K2CO3 (546 mg, 3.96 mmol) in dioxane (5 mL) and water (0.5 mL) was degassed with nitrogen. The mixture was heated to 80°C and stirred for 16 hours under nitrogen atmosphere. After completion, the reaction was cooled to room temperature, diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give 2-(cyclopent-l-en-l-yl)-4-nitrobenzonitrile (200 mg, 0.93 mmol, yield: 70.5 %) as a white solid.

[0205] Step B: To a stirred solution of 2-(cyclopent-l-en-l-yl)-4-nitrobenzonitrile (200 mg, 0.93 mmol) in MeOH (5 mL) was added Pd / C (20 mg, 10% palladium on carbon) at room temperature. The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at room temperature for 2 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 :1) to give 4-amino-2- cyclopentylbenzonitrile (100 mg, 0.54 mmol, yield: 58.1 %) as a colorless oil.

[0206] Step C: To a solution of 6-aminobenzo[b]thiophene 1,1-dioxide (150 mg, 0.83 mmol) and DIPEA (209 mg, 1.62 mmol) in DCM (4 mL) was added triphosgene (80 mg, 0.27 mmol) under nitrogen atmosphere at 0°C. After addition, the reaction mixture was stirred at this temperature for 2 hours, then a solution of 4-amino-2-cyclopentylbenzonitrile (100 mg, 0.54 mmol) in THF (1 mL) was added to the solution. The reaction was warmed to room temperature and stirred for 16 hours. After completion, the reaction mixture was filtered and the filter cake was washed by dichloromethane. The residue was purified by Prep-HPLC to give l-(4-cyano-3-cyclopentylphenyl)-3-(l,l-dioxidobenzo[b] thiophen-6-yl)urea (40 mg, 0.102 mmol, yield: 18.9 %) as a white solid. LC-MS (ESI+): m / z 394.2 (M+H)+. *H NMR (400 MHz, DMSO-t / e) d 9.42-9.40 (m, 2H), 8.05 (s, 1H), 7.70-7.68 (m, 2H), 7.59 - 7.50 (m, 3H), 7.44 - 7.41 (m, 1H), 7.25 - 7.23 (m, 1H), 3.36-3.25 (m, 1H), 2.09-2.04 (m, 2H), 1.84- 1.78 (m, 2H), 1.74-1.69 (m, 2H), 1.64-1.56 (m, 2H).Example 25: Preparation of l-(4-cyano-3-methylphenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (Compound 24)p

[0207] Step A: To a solution of 6-aminobenzo[b]thiophene 1,1 -di oxide (150 mg, 0.83 mmol) and DIPEA (178 mg, 1.38 mmol) in DCM (3 mL) was added triphosgene (83 mg, 0.28 mmol) under nitrogen atmosphere at 0 °C. After addition, the reaction mixture was stirred at this temperature for 2 hours, then a solution of 4-amino-2-methylbenzonitrile (91 mg, 0.69 mmol) in THF (0.5 mL) was added. The reaction was warmed to room temperature and stirred for 16 hours. After completion, the reaction mixture was filtered, and the filter cake was washed with di chloromethane. The residue was purified by Prep-HPLC to give l-(4- cyano-3-methylphenyl)-3-(l,l-dioxidobenzo[b]thiophen-6-yl)urea (7 mg, 0.021 mmol, yield: 3.0 %) as a white solid. LC-MS (ESI+): m / z 340.1 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) d 9.43 (s, 1H), 9.37 (s, 1H), 8.07-8.05 (m, 1H), 7.69-7.67 (d, J= 8.8, 1H), 7.59-7.55 (m, 3H), 7.52-7.50 (m, 1H), 7.47-7.44 (m, 1H), 7.26-7.23 (m, 1H), 2.45 (s, 3H).Example 26: Preparation of l-(6-cyanopyridin-3-yl)-3-(l,l-dioxidobenzo[b]thiophen-6- yl)urea (Compound 28)Step-A Compound 28

[0208] Step A: To a solution of 6-aminobenzo[b]thiophene 1,1 -di oxide (150 mg, 0.83 mmol) and DIPEA (178 mg, 1.38 mmol) in DCM (3 mL) was added triphosgene (83 mg, 0.28 mmol) under nitrogen atmosphere at 0°C. After addition, the reaction mixture was stirred at this temperature for 2 hours, then a solution of 5-aminopicolinonitrile (100 mg, 0.7 mmol) in THF (0.5 mL) was added. The reaction was warmed to room temperature and stirred for 16 hours. After completion, the reaction mixture was filtered, and the filter cake was washed with dichloromethane. The residue was purified by Prep-HPLC to give the desired compound (15 mg, 0.046 mmol, yield: 6.7 %). LC-MS (ESI+): m / z 327.1 (M+H)+. 'H NMR (400 MHz, DMSO-ifc) d 10.43 (s, 1H), 10.09 (s, 1H), 8.78-8.77 (m, 1H), 8.25-8.21 (m, 1H), 8.12 (s, 1H), 7.85-7.80 (d, J= 8.8, 1H), 7.69-7.64 (m, 1H), 7.63-7.58 (d, J= 6.8, 1H), 7.59-7.54 (d, J= 8.4, 1H), 7.31-7.26 (d, J= 7.2, 1H).Example 27: Preparation of l-(5-cyanopyridin-2-yl)-3-(l,l-dioxidobenzo[b]thiophen-6- yl)urea (Compound 29)Step-A Compound 29

[0209] Step A: To a solution of 6-aminobenzo[b]thiophene 1,1 -di oxide (150 mg, 0.83 mmol) and DIPEA (178 mg, 1.38 mmol) in DCM (3 mL) was added triphosgene (83 mg, 0.28 mmol) under nitrogen atmosphere at 0°C. After addition, the reaction mixture was stirred at this temperature for 2 hours, then a solution of 6-aminonicotinonitrile (95 mg, 0.7 mmol) in THF (0.5 mL) was added. The reaction was warmed to room temperature and stirred for 16hours. After completion, the reaction mixture was filtered, and the filter cake was washed with dichloromethane. The residue was purified by Prep-HPLC to give the desired compound (15 mg, 0.046 mmol, yield: 6.7 %). LC-MS (ESI+): m / z 327.1 (M+H)+. 'HNMR (400 MHz, DMSO-i / ,) d 10.43 (s, 1H), 10.09 (s, 1H), 8.79-8.77 (m, 1H), 8.26-8.20 (m, 1H), 8.12 (s, 1H), 7.86-7.81 (d, J= 8.8, 1H), 7.69-7.64 (m, 1H), 7.63-7.60 (d, J= 6.8, 1H), 7.59-7.56 (d, J= 8.4, 1H), 7.30-7.26 (d, J= 7.2, 1H).Example 28: Preparation of l-(6-cyanopyridin-2-yl)-3-(l,l-dioxidobenzo[b]thiophen-6- yl)urea (Compound 30)Step-A Compound 30

[0210] Step A: To a solution of 6-aminobenzo[b]thiophene 1,1 -di oxide (150 mg, 0.83 mmol) and DIPEA (178 mg, 1.38 mmol) in DCM (3 mL) was added triphosgene (83 mg, 0.28 mmol) under nitrogen atmosphere at 0°C. After addition, the reaction mixture was stirred at this temperature for 2 hours, then a solution of 6-aminopicolinonitrile (100 mg, 0.7 mmol) in THF (0.5 mL) was added. The reaction was warmed to room temperature and stirred for 16 hours. After completion, the reaction mixture was filtered and the filter cake was washed with dichloromethane. The residue was purified by Prep-HPLC to give the desired compound (40 mg, 0.123 mmol, yield: 14.5 %). LC-MS (ESI+): m / z 327.2 (M+H)+. 'HNMR (400 MHz, DMSO-i / ,) d 9.90 (s, 1H), 9.80 (s, 1H), 8.16-8.10 (m, 1H), 8.09 (s, 1H), 8.04-7.99 (m, 1H), 7.70-7.66 (d, J= 7.6, 1H), 7.62-7.57 (m, 1H), 7.56-7.54 (m, 2H), 7.28-7.24 (d, J= 6.8, 1H).Example 29: Preparation of l-(4-cyano-3-ethylphenyl)-3-(l,l-dioxidobenzo[b]thiophen- 6-yl)urea (Compound 25)

[0211] Step A: To a stirred solution of 2-bromo-4-nitrobenzonitrile (300 mg, 1.32 mmol) in 1,4-dioxane (5 mL) was added tributyl(vinyl)stannane (1.26 g, 3.96 mmol), NaOAc (359 mg, 2.64 mmol) and Pd(PPhs)4 (152.5 mg, 0.132 mmol). The reaction mixture was stirred at 100°C overnight under nitrogen atmosphere. After completion, the reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 5% - 30%) to give 4-nitro-2- vinylbenzonitrile (200 mg, 1.15 mmol, yield: 87%) as a light yellow solid.

[0212] Step B: To a stirred solution of 4-nitro-2-vinylbenzonitrile (200 mg, 1.15 mmol) in MeOH (5 mL) was added P / C (20 mg, 10% palladium on carbon) at room temperature. The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at room temperature for 1 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (PE / EtOAc = 5% - 30%) to give 4-amino-2-ethylbenzonitrile (100 mg, 0.68 mmol, yield: 59.6%) as a yellow oil. LC-MS (ESI+): 147.1(M+H)+.

[0213] Step C: To a stirred solution of 6-aminobenzo[Z>]thiophene 1,1-dioxide (247.9 mg, 1.37 mmol) in THF (10 mL) was added triphosgene (162.6 mg, 0.55 mmol) and DIPEA (378 mg, 2.74 mmol) at 0°C. After addition, the mixture was stirred at 0 °C for 2 hours and then 5-amino-2-ethylbenzonitrile (100 mg, 0.68 mmol) was added. The mixture was warmed to room temperature and stirred for 10 hours. The mixture was quenched by H2O (10 mL) at 0°C and extracted with EtOAc (10 mL*2). The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (CH3CN / H2O = 5% - 80%) to give l-(4-cyano-3-ethylphenyl)-3-(l,l-dioxidobenzo[Z>]thiophen-6-yl)urea (5 mg, 0.014 mmol, yield: 2.1%) as a white solid. LC-MS (ESI+): m / z 354.2 (M+H)+. 'HNMR (400 MHz, DMSO- f,) d 9.49 (s, 1H), 9.26 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.66-7.42 (m, 5H), 7.25 (d, J= 7.2, 1H), 2.76 (q, J =7.6, 2H), 1.22 (t, J= 7.6, 3H).Example 30: Preparation of l-(4-cyano-3-isopropylphenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (Compound 26)

[0214] Step A: To a stirred solution of 2-bromo-4-nitrobenzonitrile (400 mg, 1.76 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was added 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)- 1,3,2-dioxaborolane (600.0 mg, 3.52 mmol), K2CO3 (729.0 mg, 5.28 mmol) and Pd(PPh3)4 (203.0 mg, 0.17 mmol). The reaction mixture was stirred at 100°C overnight under nitrogen atmosphere. After completion, the reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 5% - 30%) to give 4-nitro-2-(prop-l-en-2-yl)benzonitrile (130 mg, 0.69 mmol, yield: 39.2 %) as a light yellow solid.

[0215] Step B: To a stirred solution of 4-nitro-2-(prop-l-en-2-yl)benzonitrile (130 mg, 0.69 mmol) in MeOH (5 mL) was added P / C (20 mg, 10% palladium on carbon) at room temperature. The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at room temperature for 1 h. After completion, the mixture was filtered and the filtrate was concentrated to give 4-amino-2-isopropylbenzonitrile (100 mg, 0.62 mmol, yield: 90.5%) as a yellow oil. LC-MS (ESI+): 161.1(M+H)+.

[0216] Step C: To a stirred solution of 6-aminobenzo[Z>]thiophene 1,1-dioxide (112.2 mg, 0.62 mmol) in THF (10 mL) was added triphosgene (61.3 mg, 0.20 mmol) and DIPEA (160.0 mg, 1.24 mmol) at 0°C. After addition, the mixture was stirred at 0°C for 2 hours and then 4-amino-2-isopropylbenzonitrile (100 mg, 0.62 mmol) was added. The mixture was warmed to room temperature and stirred for 16 hours. The mixture was quenched by H2O (10 mL) at 0°C and extracted with EtOAc (10 mL*3). The combined organic layers were washed with H2O and brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give l-(4-cyano-3-isopropylphenyl)-3- (l,l-dioxidobenzo[b]thiophen-6-yl)urea (8.0 mg, 0.02 mmol, yield: 3.5%) as a white solid. LC-MS (ESI+): m / z 368.2 (M+H)+. 'H NMR (400 MHz, DMSO-t / 6) d 9.45 (s, 2H), 8.06 (s, 1H), 7.71-7.66 (m, 2H), 7.61-7.58 (m, 2H), 7.54-7.51 (m, 1H), 7.48-7.45 (m, 1H), 7.26-7.25 (m, 1H), 3.22-3.19 (m, 1H), 1.28-1.27 (m, 6H).Example 31: Preparation of l-(3-(tert-butyl)-4-cyanophenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (Compound 27)

[0217] Step A: A solution of 2-(tert-butyl)aniline (1.0 g, 6.7 mmol) in AC2O (10 mL) was stirred at room temperature and stirred for 2 hours. After completion, the reaction mixture was poured into water (100 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by gel silica (PE / EA = 4 / 1) to give N-(2-(tert-butyl)phenyl)acetamide (800.0 mg, 4.1 mmol, yield: 61.1%) as a white solid.

[0218] Step B: Concentrated sulfuric acid (15 mL) was cooled to 0° C and N-(2-(tert- butyl)phenyl)acetamide (500.0 mg, 2.6 mmol) was added in several portions. After addition, KNO3 (290.0 mg, 2.8 mmol) was added. The reaction mixture was warmed to r.t and stirred overnight. The reaction mixture was poured into ice-water (100 mL) and extracted with EA(30 mL*3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give N-(2-(tert-butyl)-4-nitrophenyl)acetamide (500.0 mg, 2.1 mmol, yield: 80.7%) as a yellow solid.

[0219] Step C: To a solution of N-(2-(tert-butyl)-4-nitrophenyl)acetamide (500.0 mg, 2.1 mmol) in THF (10 mL) was added KOH (356.0 mg, 6.3 mmol) and H2O (10 mL). The mixture was stirred at r.t for 2h. The mixture was poured into water (30 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 2-(tert-butyl)-4-nitroaniline (400.0 mg, crude) as a yellow solid. LC-MS (ESI+): m / z 195.1 (M+H)+.

[0220] Step D: A solution of CuCN (360. 0 mg, 4.0 mmol) in DMSO (10 mL) was stirred at 60 °C for 30 min under nitrogen atmosphere, then t-BuNO (418. 0 mg, 4.0 mmol) was added, followed by 2-(tert-butyl)-4-nitroaniline (400.0 mg, crude) in DMSO (5 mL). The reaction mixture was stirred at 60 °C for 3h. The mixture was poured into ice-water (60 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by gel silica (PE / EA = 10 / 1) to give 2-(tert-butyl)-4-nitrobenzonitrile (200.0 mg, 1.0 mmol, yield: 47.6%) as a yellow solid.

[0221] Step E: A solution of 2-(tert-butyl)-4-nitrobenzonitrile (200.0 mg, 1.0 mmol) in EA (10 mL) was added Pd / C(20.0 mg, 10% palladium on carbon). The mixture was stirred at r.t under H2 atmosphere for 2h. After completion, the mixture was filtered and the filtrate was concentrated to give 4-amino-2-(tert-butyl)benzonitrile (150.0 mg, 0.86 mmol, yield: 86.0 %) as an oil. LC-MS (ESI+): m / z 175.1 (M+H)+.

[0222] Step F: To a stirred solution of 6-aminobenzo[b]thiophene 1,1-dioxide (100.0 mg, 0.55 mmoL) in 5 mL of dry DCM was added a solution of triphosgene (55.7 mg, 0.18 mmol) in 3 mL of DCM. The resulting mixture was stirred at 0°C for 3 hours and then treated with 4-amino-2-(tert-butyl)benzonitrile (96.0 mg, 0.55 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated and the residue was purified by Prep-HPLC to give l-(3-(tert-butyl)-4-cyanophenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (20 mg, 0.05 mmol, yield: 9.4%). LC-MS (ESI+): m / z 382.2 (M+H)+. 'H NMR (400 MHz, DMSO-t / 6) d 9.47 (s, 1H), 9.27 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.64-7.61 (m, 1H), 7.58-7.56 (m, 2H), 7.51-7.48 (m, 2H), 7.24-7.22 (m, 1H), 1.44 (s, 9H).Example 32: Preparation of l-(5-cyanopyrazin-2-yl)-3-(l,l-dioxidobenzo[b]thiophen-6- yl)urea (Compound 31)Step-B Compound 31

[0223] Step A: A mixture of 5-aminopyrazine-2-carbonitrile (100 mg, 0.83 mmol) in THF (2 mL) and DCM (2 mL) was added pyridine (198 mg, 2.5 mmol) under nitrogen atmosphere. After addition, the reaction mixture was stirred for 20 min, then a solution of phenyl carb onochlori date (393 mg, 2.5 mmol) in THF (0.5 mL) was added. The reaction mixture was heated to 50°C and stirred for 4 hours. After completion, the reaction mixture was cooled to room temperature, diluted with water (10 ml) and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give phenyl (5-cyanopyrazin-2-yl)carbamate (200 mg, 0.83 mmol, yield: 99.9 %) as a yellow solid which will be used directly for next step without further purification.

[0224] Step B: A mixture of phenyl (5-cyanopyrazin-2-yl)carbamate (100 mg, 0.83 mmol) and 6-aminobenzo[b]thiophene 1,1 -di oxide (151 mg, 0.83 mmol) in THF (5 mL) was added TEA (248 mg, 2.45 mmol). After addition, the reaction mixture was heated to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to room temperature and concentrated. The residue was further purified by Prep-HPLC to give l-(5-cyanopyrazin- 2-yl)-3-(l,l-dioxidobenzo[b]thiophen-6-yl)urea (20 mg, 0.061 mmol, yield: 7.3 %) as a white solid. LC-MS (ESI+): m / z 328.1 (M+H)+. *H NMR (400 MHz, DMSO-t / 6) d 10.37 (s, 1H),10.01 (s, 1H), 9.19-9.17 (m, 1H), 8.90-8.88 (m, 1H), 8.10 (s, 1H), 7.68-7.55 (m, 3H), 7.30- 7.28 (d, J= 6.8, 1H).Example 33: Preparation of l-(6-cyanopyridin-2-yl)-3-(l,l-dioxidobenzo[b]thiophen-6- yl)urea (Compound 32)Step-B Compound 32

[0225] Step A: A mixture of 5-aminopyradine-2-carbonitrile (100 mg, 0.83 mmol) in THF (2 mL) and DCM (2 mL) was added pyridine (198 mg, 2.5 mmol) under nitrogen atmosphere. After addition, the reaction mixture was stirred for 20 min, then a solution of phenyl carb onochlori date (393 mg, 2.5 mmol) in THF (0.5 mL) was added. The reaction mixture was heated to 50°C and stirred for 4 hours. After completion, the reaction mixture was cooled to room temperature, diluted with water (10 ml) and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give phenyl (5-cyanopyradin-2-yl)carbamate (200 mg, 0.83 mmol, yield: 99.9 %) as a yellow solid which will be used directly for next step without further purification.

[0226] Step B: A mixture of phenyl (5-cyanopyradin-2-yl)carbamate (100 mg, 0.83 mmol) and 6-aminobenzo[b]thiophene 1,1 -di oxide (151 mg, 0.83 mmol) in THF (5 mL) was added TEA (248 mg, 2.45 mmol). After addition, the reaction mixture was heated to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to room temperature and concentrated. The residue was further purified by Prep-HPLC to give the desired product (20 mg, 0.061 mmol, yield: 14.5 %) as a white solid. LC-MS (ESI+): m / z 328.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) 3 9.89 (s, 1H), 9.83 (s, 1H), 9.11-9.09 (m, 2H), 8.05 (s, 1H), 7.65 -7.53 (m, 3H), 7.28-7.26 (d, J= 6.8, 1H).Example 34: Preparation of l-(5-cyanopyrimidin-2-yl)-3-(l,l-dioxidobenzo[b]thiophen- 6-yl)urea (Compound 33)Step-B Compound 33

[0227] Step A: A mixture of 2-aminopyradine-5-carbonitrile (100 mg, 0.83 mmol) in THF (2 mL) and DCM (2 mL) was added pyridine (198 mg, 2.5 mmol) under nitrogen atmosphere. After addition, the reaction mixture was stirred for 20 min, then a solution of phenyl carb onochlori date (393 mg, 2.5 mmol) in THF (0.5 mL) was added. The reaction mixture was heated to 50°C and stirred for 4 hours. After completion, the reaction mixture was cooled to room temperature, diluted with water (10 ml) and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give phenyl (5-cyanopyradin-2-yl)carbamate (200 mg, 0.83 mmol, yield: 99.9 %) as a yellow solid which will be used directly for next step without further purification.

[0228] Step B: A mixture of phenyl (5-cyanopyrimidin-2-yl)carbamate (100 mg, 0.83 mmol) and 6-aminobenzo[b]thiophene 1,1 -di oxide (151 mg, 0.83 mmol) in THF (5 mL) was added TEA (248 mg, 2.45 mmol). After addition, the reaction mixture was heated to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to room temperature and concentrated. The residue was further purified by Prep-HPLC to give the desired product (5 mg, yield: 5 %). LC-MS (ESI+): m / z 328.1 (M+H)+.‘HNMR (400 MHz, DMSO-t / 6) d11.44 (s, 1H), 11.04 (s, 1H), 9.11-9.19 (m, 2H), 8.15 (s, 1H), 7.85-7.83 (m, 1H), 7.60-7.56 (m, 2H), 7.29-7.27 (m, 1H).Example 35: Preparation of l-(5-cyanofuran-2-yl)-3-(l,l-dioxidobenzo[b]thiophen-5- yl)urea (Compound 34)0°C-20°C, 12hCompound 34Step-B

[0229] Step A: To a stirred solution of 5-nitrofuran-2-carbonitrile (100 mg, 0.724 mmol) in THF (5 mL) and water (1 mL) was added Fe (200 mg, 3.62 mmol) and NH4CI (770 mg, 7.24 mmol), then the mixture was heated to 60°C and stirred for 2 hours. After completion, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo to give 5-aminofuran-2-carbonitrile (70 mg, yield: 90 %) as a yellow oil. LC-MS (ESI+): m / z 109.03 (M+H)+.

[0230] Step B: To a stirred solution of 5-aminobenzo[b]thiophene 1,1-dioxide (100 mg, 0.640 mmol) in DCM (10 mL) was added triphosgene (76 mg, 0.259 mmol) and DIEA (143 mg, 1.30 mmol) at 0°C. The reaction mixture was stirred at this temperature for 2 hours, then 5-aminofuran-2-carbonitrile (70 mg, 0.647 mmol) was added. The mixture was warmed to room temperature and stirred for 12 hours. After completion, the reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC to give l-(5-cyanofuran-2- yl)-3-(l,l-dioxidobenzo[b]thiophen-5-yl)urea (4 mg, yield: 4 %) as a white solid. LC-MS (ESI+): m / z 316.1 (M+H)+. 'H NMR (400 MHz, DMSO-t / 6) d 10.51 (s, 1H), 9.63 (s, 1H), 8.03 (s, 1H), 7.61-7.57 (m, 3H), 7.53-7.50 (m, 1H), 6.30-6.29 (m, 1H), 6.30 (s, 1H).Example 36: Preparation of l-(5-cyanothiophen-2-yl)-3-(l,l-dioxidobenzo[b]thiophen-5- yl)urea (Compound 35)Step A Compound 35

[0231] Step A: To a stirred solution of 5-aminothiophene-2-carbonitrile (100.0 mg, 0.80 mmol) in DCM (5 mL) was added triphosgene (79.1 mg, 0.26 mmol) and DIPEA (206.4 mg, 1.60 mmol) at 0°C. After addition, the mixture was stirred at 0°C for 2 hours and then 6- aminobenzo[Z>]thiophene 1,1-dioxide (144.8 mg, 0.80 mmol) was added. The mixture was warmed to room temperautre and stirred for 16 hours. The mixture was concentrated and the residue was purified by Prep-HPLC to give l-(5-cyanothiophen-2-yl)-3-(l,l- dioxidobenzo[b]thiophen-5-yl)urea (12.0 mg, 0.038 mmol, yield: 4.7%) as a white solid. LC- MS (ESI+): m / z 332.1 (M+H)+. *H NMR (400 MHz, DMSO-t / 6) d 10.89 (s, 1H), 9.71 (s, 1H), 8.00 (s, 1H), 7.72-7.71 (m, 1H), 7.68-7.66 (m, 1H), 7.60-7.58 (m, 1H), 7.54-7.52 (m, 1H), 7.28-7.26 (m, 1H), 6.73-6.72 (m, 1H).Example 37: Preparation of l-(4-cyanophenyl)-3-(3-nitrophenyl)urea (Compound 36)Step-A Compound 36

[0232] Step A: To a stirred solution of 4-isocyanatobenzonitrile (100 mg, 0.69 mmol) in dichloromethane (2 mL) was added 3 -nitroaniline (95 mg, 0.69 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered and the filter cake was washed by di chloromethane. The residue was purified by Prep-HPLC to give l-(4- cyanophenyl)-3-(3-nitrophenyl)urea (30 mg, 0.11 mmol, yield: 16.0 %) as a white solid. LC- MS (ESI+): m / z 283.2 (M+H)+. *H NMR (400 MHz, DMSO-t / 6) d 9.43 (s, 1H), 9.40 (s, 1H), 8.57-8.54 (m, 1H), 7.88 -7.85 (m, 1H), 7.78 -7.73 (m, 3H), 7.70-7.65 (m, 2H), 7.61-7.57 (m, 1H).Example 38: Preparation of l-(4-cyanophenyl)-3-(3-(trifluoromethyl)phenyl)urea (Compound 37)

[0233] Step A: To a stirred solution of 4-isocyanatobenzonitrile (100 mg, 0.69 mmol) in dichloromethane (2 mL) was added 3-(trifluoromethyl)aniline (95 mg, 0.69 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was purified by Prep-HPLC to give the desired product (60 mg, 0.21 mmol, yield: 30.4 %). LC-MS (ESI+): m / z 306.1 (M+H)+. ‘H NMR (400 MHz, DMSO-t / 6) d 9.35 (s, 1H), 9.25 (s, 1H), 8.02 (s, 1H), 7.79-7.74 (d, J= 8.8, 2H), 7.68-7.65 (m, 2H), 7.65-7.61 (d, J= 8.4, 1H), 7.58-7.54 (d, J= 7.6, 1H), 7.38-7.35 (d, J= 7.6, 1H).Example 39: Preparation of l-(4-cyanophenyl)-3-(3- ((trifluoromethyl)sulfonyl)phenyl)urea (Compound 38)

[0234] Step A: To a stirred solution of 4-isocyanatobenzonitrile (100 mg, 0.69 mmol) in dichloromethane (2 mL) was added 3-((trifluoromethyl)sulfonyl)aniline (95 mg, 0.69 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was purified by Prep-HPLC to give the desired product (50 mg, 0.14 mmol, yield: 20.3 %). LC-MS (ESI+): m / z 370.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.57 (s, 1H), 9.46 (s, 1H), 8.48 (s, 1H), 7.91-7.88 (m, 1H), 7.81-7.74 (m, 4H), 7.70-7.66 (d, J= 8.8, 2H).Example 40: Preparation of N-(3-(3-(4-cyanophenyl)ureido)phenyl)methanesulfonamide (Compound 39)Step-A Compound 39

[0235] Step A: To a stirred solution of 4-isocyanatobenzonitrile (100 mg, 0.69 mmol) in dichloromethane (2 mL) was added N-3-(aminophenyl)methanesulfonamide (100 mg, 0.72 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was purified by Prep-HPLC to give the desired product (35 mg, 0.106 mmol, yield: 19.6%) as a white solid. LC-MS (ESH): m / z 331.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.79 (s, 1H), 9.18 (s, 1H), 8.99 (s, 1H), 7.77-7.64 (m, 4H), 7.40 (s, 1H), 7.26 (d, J= 5.6, 2H), 6.88-6.86 (m, 1H), 3.38 (s, 3H).Example 41: Preparation of l-(4-cyanophenyl)-3-(8-oxo-5,6,7,8-tetrahydronaphthalen- 2-yl)urea (Compound 41)ep-Compound 41

[0236] Step A: To a stirred solution of 4-isocyanatobenzonitrile (100 mg, 0.69 mmol) in dichloromethane (2 mL) was added 7-amino-3,4-dihydronaphthalen-l(2H)-one (95 mg, 0.7 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was purified by Prep-HPLC to give the desired product (50 mg, 0.164 mmol, yield: 26.4%) as a brown solid. LC-MS (ESI+): m / z 306.2 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 922 (s, 1H), 9.03 (s, 1H), 8.04-8.00 (d, J= 2.4, 1H), 7.76-7.60 (m, 5H), 7.33-7.30 (d, J= 8.8, 1H), 2.92-2.89 (m, 2H), 2.62-2.59 (m, 2H), 2.06-2.04 (m, 2H).Example 42: Preparation of l-(3-(lH-tetrazol-5-yl)phenyl)-3-(4-cyanophenyl)urea (Compound 43)Compound 43

[0237] Step A: To a stirred solution of 4-isocyanatobenzonitrile (100 mg, 0.69 mmol) in dichloromethane (2 mL) was added 3-(lH-l,2,4-triazol-5-yl)aniline (95 mg, 0.7 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was purified by Prep-HPLC to give the desired product (8 mg, 0.0262 mmol, yield: 4.2%) as a white solid. LC-MS (ESI+): m / z 306.2 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.40 (s, 1H), 9.26 (s, 1H), 8.30 (s, 1H), 8.29-7.53 (m, 7H).Example 43: Preparation of l-(l-acetylindolin-6-yl)-3-(4-cyanophenyl)urea (Compound 44)Step-A Compound 44

[0238] Step A: To a stirred solution of 4-isocyanatobenzonitrile (100 mg, 0.69 mmol) in dichloromethane (2 mL) was added l-(6-aminoindolin-l-yl)ethan-l-one (100 mg, 0.68 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was purified by Prep-HPLC to give the desired product (50 mg, yield: 22.5 %) as a yellow solid. LC-MS (ESI+): m / z 321.2 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.02 (s, 1H), 8.93 (s, 1H), 8.08 (s, 1H), 7.72-7.70 (d, J=8.8, 2H), 7.62-7.60 (d, J=8.8, 2H), 7.28-7.25 (m, 1H), 7.13-7.11 (m, 1H), 4.10-4.06 (t, .7=8.8, 2H), 3.09-3.04 (t, J=8.8, 2H), 2.15 (s, 3H).Example 44: Preparation of l-(4-cyanophenyl)-3-(3-oxo-2,3-dihydro-lH-inden-5-yl)urea (Compound 46)Step-ACompound 46

[0239] Step A: To a stirred solution of 4-isocyanatobenzonitrile (100 mg, 0.69 mmol) in dichloromethane (2 mL) was added 16-amino-2,3-dihydro-lH-inden-l-one (100 mg, 0.72 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was purified by Prep-HPLC to give the desired product (20 mg, yield: 30 %) as a yellow solid. LC-MS (ESI+): m / z 292.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.53 (s, 1H), 9.33 (s, 1H), 7.85 (s, 1H), 7.75-7.73 (m, 2H), 7.65-7.61 (m, 3H), 7.52-7.50 (d, J=8.4, 1H), 3.05-3.02 (m, 2H), 2.65-2.63 (m, 2H).Example 45: Preparation of l-(4-cyanophenyl)-3-(5,5-dioxidodibenzo[b,d]thiophen-3- yl)urea (Compound 40)

[0240] Step A: To a stirred solution of 4-isocyanatobenzonitrile (200 mg, 1.38 mmol) in dichloromethane (5 mL) was added dibenzo[b,d]thi ophen-3 -amine (274.5 mg, 1.38 mmol) at room temperature and stirred for 12 hours. The reaction mixture was filtered, and the filter cake was washed with DCM to give l-(4-cyanophenyl)-3-(dibenzo[b,d]thi ophen-3 -yl)urea (200 mg, 0.58 mmol, yield: 42.0%) as a white solid. LC-MS (ESI+): m / z 344.1 (M+H)+.

[0241] Step B: A solution of l-(4-cyanophenyl)-3-(dibenzo[b,d]thiophen-3-yl)urea (200 mg, 0.58 mmol) in AcOH (10 mL) was added NaBOs LEO (268.0 mg, 1.74 mmol). After addition, the mixture was heated to 60 °C and stirred for 6h. After completion, the mixture was cooled to room temperature and concentrated. The residue was purified by Prep-HPLC to give l-(4-cyanophenyl)-3-(5,5-dioxidodibenzo[b,d]thiophen-3-yl)urea (4.0 mg, 0.01 mmol, yield: 1.7%). LC-MS (ESL): m / z 376.1 (M+H)+. 'H NMR (400 MHz, DMSO-t / 6) d 9.56-9.51 (m, 2H), 8.16 (s, 1H), 8.11-8.07 (m, 2H), 7.95-7.93 (m, 1H), 7.79-7.75 (m, 3H), 7.70-7.76 (m, 3H), 7.59-7.56 (m, 1H).Example 46: Preparation of l-(4-cyanophenyl)-3-(l,l-dioxidothiochroman-6-yl)urea (Compound 45)

[0242] Step A: A solution of 4-nitrobenzenethiol (2.5 g, 16.13 mmol) in 10% aqueous solution of KOH (30 mL) was added 3-bromopropanoic acid (2.45 g, 16.13 mmol), and the solution was refluxed for 5 hours. After completion, the reaction mixture was cooled to room temperature and washed with EA. The aqueous layer was treated with 6N HC1 to PH < 3. The resulting precipitate was collected by filtration, washed with water and dried to give 3-((4- nitrophenyl)thio)propanoic acid (3.0 g, 13.21 mmol, yield: 82 %).

[0243] Step B: A solution of 3-((4-nitrophenyl)thio)propanoic acid (1.5 g, 6.6 mmol) in thionyl chloride (10 mL) was refluxed for 4 hours. After completion, the reaction mixture was cooled to room temperature and evaporated to dryness. The residue was dissolved in anhydrous dichloromethane (5 mL), then AlCh was added (1.32 g, 9.9 mmol) and the reaction mixture was stirred for 4 hours at room temperature under nitrogen atmosphere. After completion, the reaction was quenched by water (10 mL) and extracted twice with DCM (10 mL *3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 20 %) to give 6-nitrothiochroman-4-one (1.0 g, 4.78 mmol, yield: 72.5 %) as a white solid.

[0244] Step C: To a stirred solution of 6-nitrothiochroman-4-one (300 mg, 1.43 mmol) in TFA (10 mL) was added EbSiH (500 mg, 4.3 mmol) and stirred at 60°C for 2 hours. After completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 25%) to give 6-nitrothiochromane (230 mg, 1.18 mmol, yield: 82 %) as a white solid.

[0245] Step D: To a stirred solution of 6-nitrothiochromane (230 mg, 1.18 mmol) in AcOH (5 mL) was added NaBCL / EEO (494.5 mg, 5.9 mmol) and stirred at 60°C for 1 hour. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 35%) to give 6-nitrothiochromane 1,1-dioxide (150 mg, 0.66 mmol, yield: 55.9 %) as a white solid.

[0246] Step E: To a stirred solution of 6-nitrothiochromane 1,1-dioxide (150 mg, 0.66 mmol) in MeOH (5 mL) was added P / C (15 mg, 10% palladium on carbon). The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at r.t. for 1 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (PE / EtOAc = 40 %) to give 6- aminothiochromane 1, 1-dioxide (62 mg, 0.31 mmol, yield: 47.6 %) as a white solid. LC-MS (ESI+): 198.2.

[0247] Step F: To a stirred solution of 6-aminothiochromane 1, 1-dioxide (62 mg, 0.31 mmol) in dichloromethane (5 mL) was added 4-isocyanatobenzonitrile (45 mg, 0.31 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was further purifiedby reverse phase column chromatography (CH3CN / H2O = 5% - 80%) to give l-(4- cyanophenyl)-3-(l,l-dioxidothiochroman-6-yl)urea (10 mg, 0.029 mmol, yield: 9.3 %) as a white solid. LC-MS (ESI+): m / z 342.1 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.36 (s, 1H), 9.27 (s, 1H), 7.78-7.66 (m, 5H), 7.51-7.49 (m, 2H), 3.48-3.45 (m, 2H), 3.01-2.98 (m, 2H), 2.34-2.31 (m, 2H).Example 47: Preparation of l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4- cyano-3-(2- (dimethylamino)ethyl)phenyl)urea (Compound 47)Step BCompound 47

[0248] Step A: To a stirred solution of 4-amino-2-(2-(dimethylamino)ethyl)benzonitrile (100 mg, 0.528 mmol) in THF (3 mL) was added pyridine (0.1 ml) and phenyl carb onochlori date (100 mg, 0.634 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was concentrated in vacuo to give phenyl (4-cyano-3-(2- (dimethylamino)ethyl)phenyl)carbamate (100 mg, yield: 60 %) as a white solid. LC-MS (ESI+): m / z 310.4 (M+H)+.

[0249] Step B: To a stirred solution of phenyl (4-cyano-3-(2- (dimethylamino)ethyl)phenyl)carbamate (100 mg, 0.323 mmol) in THF (3 mL) was added 4- chloro-3-((trifluoromethyl)sulfonyl)aniline (84 mg, 0.323 mmol) and TEA (65 mg, 0.646 mmol) at room temperature. The reaction mixture was heated to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to r.t and concentrated in vacuo. The residue was purified by Prep-HPLC to give l-(4-chl oro-3 - ((trifluoromethyl)sulfonyl)phenyl)-3-(4-cyano-3-(2-(dimethylamino)ethyl)phenyl)urea (5 mg, yield: 5 %) as a white solid. LC-MS (ESI+): m / z 475.3 (M+H)+. 'HNMR (400 MHz, DMSO- tZ6) d 9.90 (s, 1H), 9.63 (s, 1H), 8.60-8.59 (m, 1H), 7.87-7.84 (m, 2H), 7.69-7.67 (m, 1H), 7.61 (s, 1H), 7.50-7.48 (m, 1H), 2.92-2.89 (m, 2H), 2.61-2.57 (m, 2H), 2Example 48: Preparation of l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4- cyano-3- (morpholinomethyl)phenyl)urea (Compound 48)Compound 48

[0250] Step A: To a stirred solution of 4-amino-2-(morpholinomethyl)benzonitrile (80 mg, 0.368 mmol) in THF (1.5 mL) was added phenyl carb onochlori date (70 mg, 0.441 mmol) and pyridine (0.05 ml) and stirred at room temperature for 12 hours. After completion, the reaction mixture was concentrated in vacuo to give phenyl (4-cyano-3- (morpholinomethyl)phenyl)carbamate (80 mg, 0.294 mmol, yield: 80 %) as a white solid.

[0251] Step B: To a stirred solution of phenyl phenyl (4-cyano-3- (morpholinomethyl)phenyl)carbamate (50 mg, 0.148 mmol) in THF (3 mL) was added 4- chloro-3-((trifluoromethyl)sulfonyl)aniline (46 mg, 0.178 mmol) and TEA (65 mg, 0.646 mmol). The reaction mixture was heated to 65°C and stirred for 12 hours. After completion, the reaction mixture was cooled to r.t and concentrated in vacuo. The residue was purified by Prep-HPLC to give l-(4-chl oro-3 -((trifluoromethyl)sulfonyl)phenyl)-3 -(4-cyano-3- (morpholinomethyl)phenyl)urea (10 mg, 0.021 mmol, yield: 14 %) as a white solid. LC-MS (ESI+): m / z 503.3 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 10.70 (s, 1H), 10.30 (s, 1H), 8.68 (s, 1H), 8.05 (s, 1H), 7.92-7.72 (m, 3H), 7.70-7.68 (m, 1H), 4.52-4.42 (m, 2H), 4.02- 3.89 (m, 2H), 3.88-3.84 (m, 2H), 3.26-3.29 (m, 4H).Example 49: Preparation of l-(4-cyano-3-(2-morpholinoethyl)phenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (Compound 55)ompoun

[0252] Step A: A mixture of 2-bromo-4-nitrobenzonitrile (1 g, 4.41 mmol), (E)-(2- ethoxyvinyl)boronic acid (768 mg, 6.62 mmol), Pd2(dba)s (403 mg, 0.44 mmol), tricyclohexyl phosphine (246 mg, 0.88 mmol) and KF (767 mg, 13.22 mmol) in dioxane (15 mL) and water (3 mL) was degassed with nitrogen. The mixture was heated to 100°C and stirred for 2 hours under nitrogen atmosphere. After completion, the reaction was cooled to r.t, diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give (E)-2- (2-ethoxyvinyl)-4-nitrobenzonitrile (900 mg, 4.13 mmol, yield: 93.7 %) as a white solid.

[0253] Step B: To a stirred solution of (E)-2-(2-ethoxyvinyl)-4-nitrobenzonitrile (900 mg, 4.13 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction solution was stirred at r.t for 2 h. After completion, the mixture was concentrated to afford 4-nitro-2-(2- oxoethyl)benzonitrile (600 mg, 3.16 mmol, yield: 76.5 %) as yellow oil which was used directly for next step without further purification.

[0254] Step C: A solution of 4-nitro-2-(2-oxoethyl)benzonitrile (600 mg, 3.16 mmol) and morpholine (637 mg, 7.32 mmol) in DCE (10 mL) was added AcOH (1 mL). After addition, the reaction solution was stirred for 2 hours, then NaBH(OAc)3 (1.55 g, 7.31 mmol) was added to the solution. The mixture was stirred at r.t for 2 hours. After completion, the reaction was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 : 1) to give 2-(2-morpholinoethyl)-4-nitrobenzonitrile (500 mg, 1.92 mmol, yield: 60.8 %) as a yellow solid.

[0255] Step D: To a stirred solution of 2-(2-morpholinoethyl)-4-nitrobenzonitrile (500 mg, 1.92 mmol) in MeOH (8 mL) was added Pd / C (50 mg, 10% palladium on carbon). The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at r.t for 2 h. After completion, the mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 :2) to give 4-amino-2-(2-morpholinoethyl)benzonitrile (400 mg, 1.73 mmol, yield: 90.1 %) as a white solid.

[0256] Step E: A mixture of 4-amino-2-(2-morpholinoethyl)benzonitrile (100 mg, 0.43 mmol) in THF (2 mL) was added pyridine (102 mg, 1.29 mmol) under nitrogen atmosphere. After addition, the reaction mixture was stirred for 20 min, then a solution of phenyl carb onochlori date (393 mg, 2.5 mmol) in THF (0.5 mL) was added to the reaction mixture. The reaction mixture was heated to 50°C and stirred for 4 hours. After completion, the reaction was cooled to room temperature, diluted with water (10 ml) and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give phenyl (4-cyano-3-(2- morpholinoethyl)phenyl)carbamate (150 mg, 0.43 mmol, yield: 99.9 %) as a yellow solid which was used directly for next step without further purified.

[0257] Step F: To a mixture of phenyl (4-cyano-3-(2-morpholinoethyl)phenyl)carbamate (150 mg, 0.43 mmol) and 6-aminobenzo[b]thiophene 1,1-dioxide (78 mg, 0.43 mmol) in THF (3 mL) was added TEA (130 mg, 1.29 mmol). After addition, the reaction mixture was heated to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to r.t and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give l-(4- cyano-3-(2-morpholinoethyl)phenyl)-3- (l,l-dioxidobenzo[b]thiophen-6-yl)urea (30 mg, 0.068 mmol, yield: 15.8 %) as a white solid. LC-MS (ESI+): m / z 439.4 (M+H)+. *H NMR (400 MHz, DMSO-t / e) d 9.49 (s, 1H), 9.43 (s, 1H), 8.07 (s, 1H), 7.72-7.69 (d, J= 8.8, 1H), 7.65-7.63 (m, 1H), 7.60-7.56 (m, 2H), 7.54-7.51 (d, J= 8.0, 1H), 7.51-7.46 (m, 1H), 7.27- 7.24 (d, J= 6.8, 1H), 3.61-3.58 (m, 4H), 2.94-2.89 (m, 2H), 2.59-2.54 (m, 2H), 2.46-2.43 (m, 4H).Example 50: l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4-cyano-3-(2- morpholinoethyl)phenyl)urea (Compound 49)ompoun

[0258] Step A: A mixture of 2-bromo-4-nitrobenzonitrile (1 g, 4.41 mmol), (E)-(2- ethoxyvinyl)boronic acid (768 mg, 6.62 mmol), Pd2(dba)s (403 mg, 0.44 mmol), tri cyclohexyl phosphine (246 mg, 0.88 mmol) and KF (767 mg, 13.22 mmol) in dioxane (15 mL) and water (3 mL) was degassed with nitrogen. The mixture was heated to 100°C and stirred for 2 hours under nitrogen atmosphere. After completion, the reaction was cooled to r.t, diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residuewas purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give (E)-2- (2-ethoxyvinyl)-4-nitrobenzonitrile (900 mg, 4.13 mmol, yield: 93.7 %) as a white solid.

[0259] Step B: To a stirred solution of (E)-2-(2-ethoxyvinyl)-4-nitrobenzonitrile (900 mg, 4.13 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction solution was stirred at r.t for 2 h. After completion, the mixture was concentrated to afford 4-nitro-2-(2- oxoethyl)benzonitrile (600 mg, 3.16 mmol, yield: 76.5 %) as yellow oil which was used directly for next step without further purification.

[0260] Step C: A solution of 4-nitro-2-(2-oxoethyl)benzonitrile (600 mg, 3.16 mmol) and morpholine (637 mg, 7.32 mmol) in DCE (10 mL) was added AcOH (1 mL). After addition, the reaction solution was stirred for 2 hours, then NaBH(OAc)3 (1.55 g, 7.31 mmol) was added to the solution. The mixture was stirred at r.t for 2 hours. After completion, the reaction was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 : 1) to give 2-(2-morpholinoethyl)-4-nitrobenzonitrile (500 mg, 1.92 mmol, yield: 60.8 %) as a yellow solid.

[0261] Step D: To a stirred solution of 2-(2-morpholinoethyl)-4-nitrobenzonitrile (500 mg, 1.92 mmol) in MeOH (8 mL) was added Pd / C (50 mg, 10% palladium on carbon). The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at r.t for 2 h. After completion, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 :2) to give 4-amino-2-(2-morpholinoethyl)benzonitrile (400 mg, 1.73 mmol, yield: 90.1 %) as a white solid.

[0262] Step E: A mixture of 4-amino-2-(2-morpholinoethyl)benzonitrile (100 mg, 0.43 mmol) in THF (2 mL) was added pyridine (102 mg, 1.29 mmol) under nitrogen atmosphere. After addition, the reaction mixture was stirred for 20 min, then a solution of phenyl carb onochlori date (393 mg, 2.5 mmol) in THF (0.5 mL) was added to the reaction mixture. The reaction mixture was heated to 50°C and stirred for 4 hours. After completion, the reaction was cooled to room temperature, diluted with water (10 ml) and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give phenyl (4-cyano-3-(2-morpholinoethyl)phenyl)carbamate (150 mg, 0.43 mmol, yield: 99.9 %) as a yellow solid which was used directly for next step without further being purified.

[0263] Step F: To a stirred solution of phenyl (4-cyano-3-(2- morpholinoethyl)phenyl)carbamate (100 mg, 0.323 mmol) in THF (3 mL) was added 4- chloro-3-((trifluoromethyl)sulfonyl)aniline (84 mg, 0.323 mmol) and TEA (65 mg, 0.646 mmol) at room temperature. The reaction mixture was heated to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to r.t and concentrated in vacuo. The residue was purified by Prep-HPLC to give the desired product (12 mg, 0.023 mmol, yield: 5.3 %). LC-MS (ESI+): m / z 517.4 (M+H)+. *H NMR (400 MHz, DMSO-t / 6) d 9.77 (s, 1H), 9.51 (s, 1H), 8.62-8.60 (m, 1H), 7.92-7.87 (m, 1H), 7.86-7.83 (d, J= 8.4, 1H), 7.71-7.68 (d, J= 8.4, 1H), 7.65-7.63 (d, J= 2.0, 1H), 7.51-7.46 (m, 1H), 3.60-3.57 (m, 4H), 2.93-2.88 (m, 2H), 2.58-2.54 (m, 2H), 2.46-2.43 (m, 4H).Example 51: Preparation of l-(4-cyanophenyl)-3-(4-(2-(dimethylamino)ethyl)-3- ((trifluoromethyl)sulfonyl)phenyl)urea (Compound 50)

[0264] Step A: A solution of compound 2-(4-nitro-2- ((trifluoromethyl)sulfonyl)phenyl)acetaldehyde (100 mg, 0.34 mmol) and dimethylamine in THF (1 mol / L, 0.7 mL, 0.7 mmol) in DCE (2 mL) was added AcOH (0.1 mL). After addition, the reaction solution was stirred for 2 hours, then NaBH(OAc)s (144 mg, 0.68 mmol) was added to the solution. The mixture was stirred at r.t for 2 hours. After completion, the reaction was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum.The residue was purified by column chromatography (DCM: MeOH = 10: 1) to give N,N- dimethyl-2-(4-nitro-2-((trifluoromethyl)sulfonyl)phenyl)ethan-l -amine (70 mg, 0.21 mmol, yield: 61.8 %) as a yellow solid.

[0265] Step B: To a stirred solution ofN,N-dimethyl-2-(4-nitro-2- ((trifluoromethyl)sulfonyl)phenyl)ethan-l -amine (70 mg, 0.21 mmol) in MeOH (2 mL) was added Pd / C (10 mg, 10% palladium on carbon). The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at r.t for 2 h. After completion, the mixture was filtered and the filtrate was concentrated to give 4-(2- (dimethylamino)ethyl)-3-((trifluoromethyl)sulfonyl)aniline (50 mg, 0.17 mmol, yield: 81.0 %) as a white solid.

[0266] Step C: To a stirred solution of 4-(2-(dimethylamino)ethyl)-3- ((trifluoromethyl)sulfonyl)aniline (50 mg, 0.17 mmol) in dichloromethane (2 mL) was added 4-isocyanatobenzonitrile (2 mg, 0.17 mmol). The mixture was stirred at r.t for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by di chloromethane. The residue was further purified by Prep-HPLC to give l-(4-cyanophenyl)- 3-(4-(2-(dimethylamino)ethyl)-3-((trifluoromethyl)sulfonyl)phenyl)urea (5 mg, 0.11 mmol, yield: 6.5 %) as a white solid. LC-MS (ESI+): m / z 441.4 (M+H)+. *H NMR (400 MHz, DMSO-ifc) d 9.56 (s, 1H), 9.50 (s, 1H), 8.44-8.42 (m, 1H), 7.85-7.80 (m, 1H), 7.76-7.73 (m, 2H), 7.68-7.62 (m, 3H), 3.10-3.07 (m, 2H), 2.54-2.51 (m, 2H), 2.21 (s, 6H).Example 52: Preparation of l-(4-cyanophenyl)-3-(4-(morpholinomethyl)-3- ((trifluoromethyl)sulfonyl)phenyl)urea (Compound 51)Step-F Compound 51

[0267] Step A: A mixture of 2-methyl-5-nitroaniline (5 g, 32.89 mmol), HBF4 (12 g, 48% wt in water, 65.78 mmol) in EtOH (150 mL) was added tert-Butyl nitrite (6.78 g, 65.75 mmol) slowly. The mixture was stirred at r.t for 4 hours. After completion, the reaction mixture was diluted with petroleum ether and filtered. The residue was washed by petroleum ether to give 2-methyl-5-nitrobenzenediazonium tetrafluoroborate (7 g, 27.89 mmol, yield: 84.8 %) as a white solid.

[0268] Step B: To a stirred mixture of NaSChCFs (13 g, 83.33 mmol) and CU2O (399 mg, 2.79 mmol) in DMSO (100 mL) was added 2-methyl-5-nitrobenzenediazonium tetrafluoroborate (7 g, 27.89 mmol) slowly. The reaction mixture was stirred at r.t for 12 h under nitrogen atmosphere. After completion, the reaction mixture was diluted with water (200 ml) and extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 1 -methyl -4-nitro-2-((trifluoromethyl)sulfonyl)benzene (2 g, 7.43 mmol, yield: 26.6 %) as yellow oil.

[0269] Step C: To a solution of l-methyl-4-nitro-2-((trifluoromethyl)sulfonyl)benzene (500 mg, 1.86 mmol) and NBS (499 mg, 2.79 mmol) in CCh (10 mL) was added AIBN (58 mg, 0.35 mmol). The mixture was heated to 70°C and stirred for 12 hours under nitrogen atmosphere. After completion, the reaction solution was diluted with water (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to give 1- (bromomethyl)-4-nitro-2-((trifluoromethyl)sulfonyl)benzene (300 mg, 0.86 mmol, yield: 46.2 %) as a yellow solid.

[0270] Step D: To a stirred solution of l-(bromomethyl)-4-nitro-2-((trifluoromethyl)sulfonyl) benzene (300 mg, 0.86 mol) in DCM (5 mL) was added morpholine (150 mg, 1.72 mol) and K2CO3 (356 mg, 2.58 mol). The reaction mixture was stirred at r.t for 2 h. After completion, the reaction mixture washed with brine twice, dried over Na2SO4 and concentrated to give 4- (4-nitro-2-((trifluoromethyl)sulfonyl)benzyl) morpholine (300 mg, 0.85 mmol, yield: 98.9 %) as a yellow solid.

[0271] Step E: To a stirred solution of 4-(4-nitro-2-((trifluoromethyl)sulfonyl)benzyl) morpholine (300 mg, 0.85 mmol) in EtOAc (5 mL) was added Pd / C (30 mg). The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at r.t for 2 h. After completion, the mixture was filtered and the filtrate was concentrated to afford 4-(morpholinomethyl)-3-((trifluoromethyl)sulfonyl)aniline (200 mg, 0.62 mmol, yield: 72.9 %) as a yellow solid.

[0272] Step F: To a stirred solution of 4-isocyanatobenzonitrile (45 mg, 0.31 mmol) in di chloromethane (3 mL) was added 4-(morpholinomethyl)-3- ((trifluoromethyl)sulfonyl)aniline (100 mg, 0.31 mmol). The mixture was stirred at r.t for 12 hours. After completion, the reaction mixture was filtered and the filter cake was washed by di chloromethane. The residue was purified by Prep-HPLC to give l-(4-cyanophenyl)-3-(4- (morpholinomethyl)-3-((trifluoromethyl)sulfonyl)phenyl)urea (20 mg, 0.043 mmol, yield: 13.9 %) as a white solid. LC-MS (ESI+): m / z 469.6 (M+H)+. *H NMR (400 MHz, DMSO-t / 6) 3 10.42 (s, 1H), 10.11 (s, 1H), 8.60 (s, 1H), 8.06-8.02 (d, J= 8.4, 1H), 7.97-7.94 (m, 1H), 7.79-7.75 (d, J= 8.8, 2H), 7.70-7.75 (d, J= 8.8, 2H), 4.60 (s, 2H), 3.97-3.94 (m, 2H), 3.75- 3.72 (m, 2H), 3.29-3.26 (m, 4H).Example 53: Preparation of l-(4-cyanophenyl)-3-(4-(2-morpholinoethyl)-3- ((trifluoromethyl)-sulfo nyl)phenyl)urea (Compound 52)

[0273] Step A: A mixture of l-bromo-4-nitro-2-((trifluoromethyl)sulfonyl)benzene (300 mg, 0.90 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (356.4 mg, 1.8 mmol), Pd2(dba)s (82.3 mg, 0.09 mmol) , tricyclohexyl phosphine (50.4 mg, 0.18 mmol) and KF (156.6 mg, 2.7 mmol) in 1,4-dioxane (15 mL) and H2O (3 mL) was degassed with nitrogen. The mixture was heated to 100°C and stirred for 4 hours under nitrogen atmosphere. After completion, the reaction was cooled to r.t and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 : 1) to give (E)-l-(2- ethoxyvinyl)-4-nitro-2-((trifluoromethyl)sulfonyl)benzene (170 mg, 0.52 mmol, yield: 58% ).

[0274] Step B: To a stirred solution of (E)-l-(2-ethoxyvinyl)-4-nitro-2-((trifluoromethyl)sulfonyl)benzene (0.17 g, 0.52 mmol) in DCM (5 mL) was added TFA (2mL). The reaction mixture was stirred at 40°C for 4 h. After completion, the mixture was cooled to r.t and concentrated in vacuo to afford 2-(4-nitro-2- ((trifluoromethyl)sulfonyl)phenyl)acetaldehyde (120 mg crude) which was used for next step directly.

[0275] Step C: To a stirred solution of 2-(4-nitro-2- ((trifluoromethyl)sulfonyl)phenyl)acetaldehyde (0.16 g, 0.5 mmol) in DCE (15 mL) was added morpholine (65.3 mg, 0.75 mmol) and AcOH (3 drops). The reaction mixture was stirred at r.t for 2 h, then NaBH(OAc)3 (212 mg, 1 mmol) was added and the mixture was stirred at r.t for 12 h. After completion, the reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM = 5% - 8%) to give 4-(4-nitro-2- ((trifluoromethyl)sulfonyl)phenethyl)morpholine (92 mg, 0.25 mmol, yield: 50 %) as a yellow oil. LC-MS (ESI+): m / z 369.1 (M+H)+.

[0276] Step D: To a stirred solution of 4-(4-nitro-2- ((trifluoromethyl)sulfonyl)phenethyl)morpholine (92 mg, 0.25 mmol) in MeOH (4 mL) was added P / C (9.2 mg, 10% palladium on carbon). The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at r.t. for 3 h. After completion, the mixture was filtered and the filtrate was concentrated in vacuo to afford 4-(2-morpholinoethyl)-3-((trifluoromethyl) sulfonyl)aniline (75 mg, 0.22 mmol, yield: 88 %) as a yellow oil. LC-MS (ESI+): m / z 339.1 (M+H)+.

[0277] Step E: To a stirred solution of 4-(2-morpholinoethyl)-3- ((trifluoromethyl)sulfonyl)aniline (75 mg, 0.22 mmol) in ACN (15 mL) was added 4- isocyanatobenzonitrile (64 mg, 0.44 mmol). The reaction mixture was stirred at 80°C under nitrogen atmosphere for 12 h. After completion, the mixture was cooled to r.t and concentrated in vacuo. The residue was purified by reverse phase column chromatography (ACN / H2O = 5% - 80%) to give l-(4-cyanophenyl)-3-(4-(2-morpholinoethyl)-3- ((trifluoromethyl)-sulfonyl)phenyl)urea (7 mg, 0.014 mmol, yield: 14%). LC-MS (ESI+): m / z 483.4 (M+H)+. ‘H NMR (400 MHz, DMSO-t / e) 8 9.58-9.57 (m, 2H), 8.42-8.40 (d, J=8.0, 1H), 7.84-7.81 (m, 1H), 7.75-7.73 (m, 2H), 7.67-7.64 (m, 3H), 4.57-4.53(m, 4H), 3.11-3.07 (m, 2H), 2.56-2.44 (m, 6H).Example 54: Preparation of l-(4-cyano-3-(2-(dimethylamino)ethyl)phenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (Compound 53)Compound 53

[0278] Step A: To a stirred solution of 4-amino-2-(2-(dimethylamino)ethyl)benzonitrile (100 mg, 0.528 mmol) in THF (3 mL) was added pyridine (0.1 ml) and phenyl carb onochlori date (100 mg, 0.634 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was concentrated in vacuo to give phenyl (4-cyano-3-(2- (dimethylamino)ethyl)phenyl)carbamate (100 mg, yield: 60 %) as a white solid. LC-MS (ESI+): m / z 310.4 (M+H)+.

[0279] Step B: To a stirred solution of phenyl (4-cyano-3-(2- (dimethylamino)ethyl)phenyl)carbamate (100 mg, 0.323 mmol) in THF (3 mL) was added 6- aminobenzo[b]thiophene 1,1-dioxide (53 mg, 0.296 mmol) and TEA (65 mg, 0.646 mmol) at room temperature. The reaction mixture was heated to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to r.t and concentrated in vacuo. The residue was purified by Prep-HPLC to give l-(4-cyano-3-(2-(dimethylamino)ethyl)phenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (5 mg, yield: 5 %) as a white solid. LC-MS (ESI+): m / z397.4 (M+H)+. ‘H NMR (400 MHz, DMSO-t / 6) d 9.96 (s, 1H), 9.82 (s, 1H), 8.07 (s, 1H), 7.71-7.69 (m, 1H), 7.63 (s, 1H), 7.59-7.47 (m, 4H), 7.25-7.23 (m, 1H), 2.95-2.91 (m, 2H), 2.67-2.63 (s, 2H), 2.32 (s, 6H).Example 55: Preparation of l-(4-cyano-3-(morpholinomethyl)phenyl)-3-(l,l- dioxidobenzo[b]thiophen -6-yl)urea (Compound 54)Compound 54

[0280] Step A: To a stirred solution of 4-amino-2-(morpholinomethyl)benzonitrile (70 mg, 0.332 mmol) in THF (4 mL) was added pyridine (0.1 ml) and phenyl carb onochlori date (60 mg, 0.386mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was concentrated in vacuo to give phenyl (4-cyano-3- (morpholinomethyl)phenyl)carbamate (100 mg, yield: 90 %) as a white solid.

[0281] Step B: To a stirred solution of phenyl (4-cyano-3- (morpholinomethyl)phenyl)carbamate (100 mg, 0.296 mmol) in THF (3 mL) was added 6- aminobenzo[b]thiophene 1,1 -di oxide (53 mg, 0.296 mmol) and TEA (60 mg, 0.592 mmol). The reaction mixture was heated to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to r.t and concentrated in vacuo. The residue was purified by Prep-HPLC to give l-(4-cyano-3-(morpholinomethyl)phenyl)-3-(l,l- dioxidobenzo[b]thiophen-6-yl)urea (10 mg, yield: 10 %) as a white solid. LC-MS (ESI+): m / z 425.4 (M+H)+. ‘H NMR (400 MHz, DMSO-t / 6) d 9.82 (s, 1H), 8.05 (s, 1H), 7.73-7.69 (m, 2H), 7.59-7.56 (m, 3H), 7.52-7.50 (m, 1H), 7.24-7.22 (m, 1H), 7.20-7.10 (m, 1H), 3.62-3.58 (m, 6H), 2.44-2.40 (m, 4H).Example 56: Preparation of l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4- cyano-3-(2-morpholinoethoxy)phenyl)urea (Compound 56)Step BCompound 56

[0282] Step A: To a stirred solution of 4-amino-2-(2-morpholinoethoxy)benzonitrile (100.0 mg, 0.404 mmol) in THF (3 mL) was added pyridine (0.05 ml) and phenyl carb onochlori date (63.0 mg, 0.404 mmol) at room temperature. The mixture was stirred for 12 hours. After completion, the reaction mixture was concentrated in vacuo to give crude phenyl (4-cyano-3- (2-morpholinoethoxy)phenyl)carbamate (100 mg, 0.27 mmol, yield: 71.0 %) as a white solid.

[0283] Step B: To a stirred solution of phenyl (4-cyano-3-(2- morpholinoethoxy)phenyl)carbamate (100.0 mg, 0.27 mmol) in THF (3 mL) was added 4- chloro-3-((trifluoromethyl)sulfonyl)aniline (70.0 mg, 0.27 mmol) and TEA (50.0 mg, 0.54 mmol). The mixture was heated to 50 °C and stirred for 12 hours. After completion, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by Prep-HPLC to give l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4-cyano- 3-(2-morpholinoethoxy)phenyl)urea (15.0 mg, yield: 11 %) as a white solid. LC-MS (ESI+): m / z 533.3 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 9.80 (s, 1H), 9.58 (s, 1H), 8.60 (s, 1H), 7.91-7.83 (m, 2H), 7.62-7.60 (m, 1H), 7.53 (s, 1H), 7.08-7.06 (m, 1H), 4.24-4.22 (m, 2H), 3.61-3.58 (m, 4H), 2.80-2.76 (m, 2H), 2.54-2.51 (m, 4H).Example 109: l-(4-cyanophenyl)-3-(4-(2-morpholinoethoxy)-3-((trifluoromethyl)sulfonyl) phenyl)urea (Compound 57)Compound 57

[0284] Step A: A mixture of l-bromo-4-nitro-2-((trifluoromethyl)sulfonyl)benzene (100 mg, 0.30 mmol), 2-morpholinoethan-l-ol (79 mg, 0.60 mmol), Pd(OAc)2 ( 13 mg, 0.06 mmol), BINAP (75 mg, 0.12 mmol) and K2CO3 (124 mg, 0.9 mmol) in DMF (2 mL) was degassed with nitrogen. The mixture was heated to 90°C and stirred for 16 hours under nitrogen atmosphere. After completion, the reaction was cooled to r.t, diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 : 1) to give 4-(2-(4-nitro-2- ((trifluoromethyl)sulfonyl)phenoxy)ethyl)morpholine (80 mg, 0.21 mmol, yield: 70.0 %) as a yellow solid.

[0285] Step B: To a stirred solution of 4-(2-(4-nitro-2- ((trifluoromethyl)sulfonyl)phenoxy)ethyl) morpholine (80 mg, 0.21 mmol) in EtOAc (2 mL) was added Pd / C (10 mg, 10% palladium on carbon). The reaction mixture was degassed and purged with hydrogen several times. Then the reaction mixture was stirred at r.t for 2 h. After completion, the mixture was filtered and the filtrate was concentrated to afford 4-(2- morpholinoethoxy)-3- ((trifluoromethyl)sulfonyl)aniline (50 mg, 0.14 mmol, yield: 66.7 %) as a white solid.

[0286] Step C: To a stirred solution of 4-(2-morpholinoethoxy)-3-((trifluoromethyl)sulfonyl) aniline (50 mg, 0.14 mmol) in dichloromethane (2 mL) was added 4-isocyanatobenzonitrile (20 mg, 0.14 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was filtered, and the filter cake was washed by dichloromethane. The residue was purified by Prep-HPLC to afford l-(4-cyanophenyl)-3-(4-(2-morpholinoethoxy)- 3-((trifluoromethyl)sulfonyl)phenyl)urea (15 mg, 0.030 mmol, yield: 21.4 %) as a white solid. LC-MS (ESI+): m / z 499.4 (M+H)+. *H NMR (400 MHz, DMSO-t / 6) d 9.43 (s, 1H), 9.31 (s, 1H), 8.25-8.23 (m, 1H), 7.87-8.84 (d, J= 7.6 , 1H), 7.76-7.73 (d, J= 8.8 , 2H), 7.67- 7.64 (d, J= 8.8, 2H), 7.48-7.45 (m, 1H), 4.30 (s, 2H), 3.58-3.54 (m, 4H), 2.72-2.68 (m, 2H), 2.49-2.46 (m, 4H).Example 57: Preparation of l-(4-cyano-3-(2-morpholinoethoxy)phenyl)-3-(l,l- dioxidobenzo[b]thiophen-6 -yl)urea (Compound 58)Compound 58

[0287] Step A: To a stirred solution of 4-amino-2-(2-morpholinoe thoxy)benzonitrile (100 mg, 0.4 mmol) in THF (20 mL) was added phenyl carb onochlori date (94.2 mg, 0.6 mmol) and pyridine (47.4 mg, 0.6 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 12 hours. After completion, the mixture was concentrated in vacuo to give the crude desired compound which was used for next step directly.

[0288] Step B: To a stirred solution of phenyl (4-cyano-3-(2- morpholinoethoxy)phenyl)carbamate (150 mg, 0.4 mmol) in THF (5 mL) was added TEA (66.7 mg, 0.66 mmol) and 6-aminobenzo[b]thiophene 1,1-dioxide (119.5 mg, 0.66 mmol).The reaction mixture was stirred at 60 °C under nitrogen atmosphere for 12 hours. After completion, the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase column chromatography (CH3CN / H2O = 5% - 80%) to give l-(4-cyano-3-(2-morpholinoethoxy)phenyl)-3-(l, l-dioxidobenzo[b]thiophen-6- yl)urea (5.0 mg, 0.01 mmol, yield: 3%). LC-MS (ESI+): m / z 455.4 (M+H)+. 'HNMR (400 MHz, DMSO-d6) 5 9.62 (s, 1H), 9.59 (s, 1H), 8.06 (s, 1H), 7.62-7.50 (m, 5H), 7.24-7.22 (m, 1H), 7.05-7.02(m, 1H), 4.25-4.22 (m, 2H), 3.60-3.58 (m, 4H), 2.82-2.78 (m, 2H), 2.56-2.51 (m, 4H).Example 58: Preparation of l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4- cyano-2-(2-(dimethylamino)ethyl)phenyl)urea (Compound 59)

[0289] Step A: To a mixture of 4-chloro-3-((trifluoromethyl)sulfonyl)aniline (100 mg, 0.38 mmol) in THF (2 mL) was added pyridine (90 mg, 1.14 mmol) and phenyl carb onochlori date (63 mg, 0.404 mmol). After addition, the reaction mixture was stirred at 50°C for 4 hours. After completion, the reaction was concentrated to give phenyl (4-chl oro-3 - ((trifluoromethyl)sulfonyl)phenyl)carbamate (200 mg crude) as a yellow solid which was used directly for next step without further purified.

[0290] Step B: To a mixture of phenyl phenyl (4-chl oro-3 - ((trifluoromethyl)sulfonyl)phenyl)carbamate (100 mg, 0.26 mmol) and 4-amino-3-(2- (dimethylamino)ethyl)benzonitrile (74 mg, 0.39 mmol) in THF (3 mL) was added TEA (79 mg, 0.78 mmol). After addition, the reaction mixture was heated to 50°C and stirred for 12hours. After completion, the reaction mixture was cooled to r.t and concentrated. The residue was further purified by reverse phase column chromatography (CH3CN / H2O = 5% - 80%) to give l-(4-chl oro-3 -((trifluoromethyl)sulfonyl)phenyl)-3 -(4-cyano-2-(2- (dimethylamino)ethyl)phenyl)urea (40 mg, 0.084 mmol, yield: 32.3 %) as a white solid. LC- MS (ESI+): m / z 475.3 (M+H)+. ‘H NMR (400 MHz, DMSO-t / 6) d 9.90 (s, 1H), 9.01 (s, 1H), 8.57-8.56 (m, 1H), 8.07-8.04 (m, 1H), 7.93-7.90 (dd, J= 8.8, 1H), 7.85-7.83 (d, J= 8.8, 1H), 7.70 (s, 1H), 7.64 (dd, J= 8.8, , 1H), 2.80 - 2.78 (m, 2H), 2.53 - 2.51 (m, 1H), 2.50 - 2.49 (m, 1H), 2.24 (s, 6H).Example 59: Preparation of l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4- cyano-2-(morpholinomethyl)phenyl)urea (Compound 59)Step A Compound 59

[0291] Step A: To a mixture of phenyl (4-chloro-3- ((trifluoromethyl)sulfonyl)phenyl)carbamate (100 mg, 0.26 mmol) and 4-amino-3- (morpholinomethyl)benzonitrile (85 mg, 0.39 mmol) in THF (3 mL) was added TEA (79 mg, 0.78 mmol). After addition, the reaction mixture was heated to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to r.t and concentrated. The residue was further purified by reverse phase column chromatography (CH3CN / H2O = 5% - 80%) to give l-(4-chl oro-3 -((trifluoromethyl)sulfonyl)phenyl)-3 -(4-cyano-2- (morpholinomethyl)phenyl)urea (45 mg, 0.089 mmol, yield: 34.2 %) as a white solid. LC-MS (ESI+): m / z 503.3 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 10.14 (s, 1H), 9.72 (s, 1H), 8.54-8.53 (m, 1H), 8.24-8.22 (d, J= 8.4, 1H), 8.03-8.01 (dd, J= 8.8, 1H), 7.87-7.85 (d, J= 8.8 Hz, 1H), 7.74-7.71 (m, 1H), 7.72 (s, 1H), 3.65 - 3.63 (m, 6H), 2.41 - 2.38 (m, 4H).Example 113: Preparation of l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4- cyano-2-(2-morpholinoethyl)phenyl)urea (Compound 61)Step A Compound 61

[0292] Step A: To a mixture of phenyl phenyl (4-chloro-3- ((trifluoromethyl)sulfonyl)phenyl)carbamate (100 mg, 0.26 mmol) and 4-amino-3-(2- morpholinoethyl)benzonitrile (90 mg, 0.39 mmol) in THF (3 mL) was added TEA (79 mg, 0.78 mmol). After addition, the reaction mixture was warmed to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to r.t and concentrated. The residue was purified by reverse phase column chromatography (CH3CN / H2O = 5% - 80%) to give 1 -(4-chl oro-3 -((tri fluoromethyl)sulfonyl)phenyl)-3-(4-cyano-2-(2- morpholinoethyl)phenyl)urea (60 mg, 0.116 mmol, yield: 44.6 %) as a white solid. LC-MS (ESI+): m / z 517.2 (M+H)+. 'HNMR (400 MHz, DMSO-t / 6) d 10.03 - 9.99 (m, 1H), 8.69 - 8.65 (m, 1H), 8.57( s, 1H), 8.12-8.10 (d, J= 8.4, 1H), 7.91-7.88 (m, 1H), 7.87-7.85 (d, J= 8.8, 1H), 7.71 (s, 1H), 7.66-7.64 (d, J= 8.4, 1H), 3.64 - 3.52 (m, 4H), 2.85 - 2.83 (m, 2H), 2.57 - 2.54 (m, 2H), 2.40 - 2.37 (m, 4H).Example 60: Preparation of l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4- cyano-2- (2-morpholinoethoxy)phenyl)urea (Compound 62)Step ACompound 62

[0293] Step A: To a mixture of phenyl (4-chloro-3- ((trifluoromethyl)sulfonyl)phenyl)carbamate (100 mg, 0.26 mmol) and 4-amino-3-(2- morpholinoethoxy)benzonitrile (96 mg, 0.39 mmol) in THF (3 mL) was added TEA (79 mg, 0.78 mmol). After addition, the reaction mixture was heated to 50°C and stirred for 12 hours. After completion, the reaction mixture was cooled to r.t and concentrated. The residue was purified by reverse phase column chromatography (CH3CN / H2O = 5% - 80%) to give l-(4-chloro-3-((trifluoromethyl)sulfonyl)phenyl)-3-(4-cyano-2-(2-morpholinoethoxy)phenyl)urea (70 mg, 0.131 mmol, yield: 50.5 %) as a white solid. LC-MS (ESI+): m / z 533.3 (M+H)+. 'H NMR (400 MHz, DMSO-t / 6) 3 10.33 (s, 1H), 8.56 - 8.53 (m, 2H), 8.32-8.30 (d, J= 8.0 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.60 (s, 1H), 7.42-7.39 (m, 1H), 4.32-4.29 (t, J= 6.0, 2H), 3.56- 3.54 (m, 4H), 2.80-2.77 (t, J= 6.0, 2H), 2.50 - 2.47 (m, 4H).Example 61: Preparation of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4- cyanocyclohexyl)urea (Compound 63)

[0294] Step A: To a stirred solution of compound 1 (1.95 g, 10 mmol) in THF (60 mL) was added phenyl carb onochlori date (1.56 g, 10 mmol) at room temperature and stirred for 12 hours. After completion, the reaction mixture was used to next step directly. LC-MS (ESI+): m / z 316.0(M+H)+.

[0295] Step B: To a stirred solution of compound 2 (189 mg, 0.6 mmol), 4- aminocyclohexane-1 -carbonitrile (74 mg, 1.2 mmol) and TEA ((184 mg, 1.8 mmol) in THF (6 mL) at room temperature, the mixture was stirred for 16 hours at room temperature. After completion, the reaction mixture was purified by silica gel column chromatography to give the desired compound. (25.0 mg, 0.72 mmol, yield: 44.0%). LC-MS (ESI+): m / z 346.2 (M+H)+. ‘H NMR (400 MHz, DMSO) 3 8.78 (d, J= 12.6 Hz, 1H), 8.09 - 8.02 (m, 1H), 7.57 - 7.47 (m, 2H), 6.52 - 6.32 (m, 1H), 3.62 - 3.42 (m, 1H), 3.04 - 2.68 (m, 1H), 2.03 - 1.98 (m, 1H), 1.92 - 1.74 (m, 3H), 1.73 - 1.54 (m, 2H), 1.52 - 1.43 (m, 1H), 1.29 - 1.23 (m, 1H).Example 62

[0296] C57BL / 6 mice were acquired from the Jackson laboratory at 6 weeks of age and allowed to acclimate in the vivarium for 2 weeks. TRAMP-C2 cells used in the syngeneic experiments passed the IMPACT III rodent pathogen test. TRAMP-C2 cells were cultured in complete growth medium to 70% confluency, detached using trypsinization as for xenograft experiments, washed twice with PBS, and resuspended in Dulbecco’s minimum essential medium-high glucose (HG) (no phenol red, Gibco 21063029) medium. The cell suspension was prechilled on ice at 4°C, mixed well with Matrigel (Coming 354234) at a 1 : 1 ratio, and maintained on ice. One hundred microliters of final cell suspension was administered subcutaneously into the right flank of each mouse using 26-G x 1.6 cm SubQ needles (BD 305115). A total of 1 x 106 cells were administered per animal.

[0297] For intraperitoneal administration of small molecules, the compound or enzalutamide was dissolved in DMSO. For compound A, polyethylene glycol (PEG) 400 was then added to DMSO in a 4: 1 volume ratio. Then, 40% Captisol (RC-0C7-100) in saline was added to the PEG 400 / DMSO mixture in a 3 : 1 volume ratio to achieve the final intraperitoneal formulation: 30% Captisol + 45% saline + 20% PEG 400 + 5% DMSO. One hundred microliters of the intraperitoneal solution was administered to animals intraperitoneally using 27-G x 1 / 2-in needles (BD 305109). For enzalutamide, PEG 400 was added to DMSO in a 4: 1 volume ratio. Then, 40% Captisol in saline was added to the PEG 400 / DMSO mixture in a 3:2 volume ratio to achieve the final intraperitoneal formulation of 24% Captisol + 36% saline + 32% PEG 400 + 8% DMSO. One hundred microliters of the enzalutamide solution was administered to animals intraperitoneally using 27-G x 1 / 2-in needles (BD 305109). Tumors were measured using a digital caliper (Thermo Fisher Scientific 06-664-16) and tumor volumes calculated using the formula V = ((WA2) x L) / 2. Animals’ general health was noted daily. Tumor and body weight measurements were collected every 2ndday.Example 62

[0298] HSF1 degradation of compound 6 was measured and compared to compound A. A nuclear HSF1 degradation reporter cell line was created from C4-2 prostate cancer cells expressing a modified HSFl-eGFP fusion protein in which -70% of the HSFl-eGFP protein is nuclear. Nuclear-specific HSFl-eGFP degradation was independently validated and fluorescence activated cell sorting (FACS) used to quantitate HSF1 degradation in response to compounds. The results are shown in FIG. 1. The data shows that Compound 6 has a superior degradation profile as compared to Compound A.

[0299] HSF1 degradation after administration of Compound 6 and HSF1 resynthesis after washout of Compound 6 was also measured, the results shown in FIG. 2. The data shows that Compound 6 has a short duration of dosing and that HSF1 degradation occurs rapidly after administration.

[0300] The expression of genes promoted or repressed by HSF1, specifically HSPA4L, DNAJB1, SPTN1, and CDH1, was measured 24 hours after administration of Compound 6. The data is shown in FIG. 3. SPTN1 and CDH1 expression increased 24 hours after administration, while HSPA4L and DNAJB1 expression decreased.Example 63

[0301] A pharamceutical formulation comprising Compound 6 was created. 84 pL of DMSO was drawn into a vial containing 0.84 mg of Compound 6. Next, 1596 pL of 15% 2- hydroxypropyl-P-cyclodextrin in water was added to the vial. The ratio of DMSO: 15% 2- hydroxypropyl-P-cyclodextrin in water was 5:95 (v / v). The vial was vortexted for 1-2 minutes, then sonicated for 2-3 minutes. The final concentration of the formulation was 0.5 mg / mL of Compound 6, as shown in Table 3 below. A similar formulation including Compound A was also prepared.Table 3: Preparation of dosing solution

[0302] The formulations were orally administered to mice and to rats. The pharmacokinetic parameters of the administration were measured and are shown below in Table 4. The serum concentration of Compound 6 in mice is also shown in FIG. 4.Table 4

[0303] The microsomal stability of the compound was also measured in mice, rats, dogs, and humans. The results are shown in Table 5.Table 5Example 64

[0304] A formulation comprising Compound 6 as described in the previous example was administered orally and intravenously to mice to compare the pharmacokinetic profiles of each method of administration. For further comparison, formulations comprising Compound A and Compound B were also administered.

[0305] Compounds were dosed to male ICR mice or SD rats, 3 animals per arm of administration. Food and water were provided ad libitum. The following formulations were used to prepare compound solutions: IV, 0.2 mg / ml in DMSO: 15%HP- P-CD in water=5:95 (V / V); PO, 0.5 mg / ml in DMSO: 15%HP- P-CD in water=5:95 (V / V).

[0306] The compounds were administered intravenously and orally and plasma was sampled at 0.083 (IV), 0.25, 0.5, 1, 2, 4, 8 and 24 hour time points. Approximately 50 pL of plasma sample (K2EDTA) were collected at the designated time point to collect plasma respectively. Bioanalytical methods were developed by LC-MS / MS method for the measurement of test article in mouse plasma. Samples were analyzed using at least one set of calibration curve (1- 2500 ng / mL) and two sets of QC.

[0307] The results of the intravenous administration are shown in Table 6, and the concentration over time is shown in FIG. 5. The results of the oral administration are shown in Table 7, and the concentration over time is shown in FIG. 6.Table 6: Intravenous DoseTable 7: Oral DoseExample 65

[0308] A formulation comprising compound 6 was prepared as in the previous examples for oral and intravenous administration to rats. Pharmacokinetic parameters of each administration were measured and are shown in Table 8, and the concentration over time is shown in FIG. 7.Table 8Example 66

[0309] The growth arrest of 22RV1 prostate tumor was measured after oral administration of Compound 6, intra peritoneal administration of compound A, and a vehicle control. Nude (nu / nu) mice were acclimated for 1 week in a vivarium. Prostate cancer cells used in xenograft experiments passed the IMPACT III rodent pathogen test at IDEXX BioAnalytics. Cells were cultured in complete growth medium to 70% confluency, detached bytrypsinization at 37°C for 2 min, and trypsin was inactivated by adding prewarmed complete growth medium to the cell suspension. Cells were washed twice with phosphate-buffered saline (PBS) at room temperature and resuspended in ice-cold RPMI 1640 (no phenol red, Gibco 2404-014) medium. Before administration to nu / nu mice, the cell suspension was prechilled on ice at 4°C, mixed well with Matrigel (Corning 354234) at a 1 : 1 ratio, and maintained on ice. One hundred microliters of final cell suspension was injected subcutaneously into the right flank of each mouse using 26-G x 1.6 cm SubQ needles (BD 305115). A total of 1 x 106 cells were administered per animal. The results are shown in FIG. 8. It is shown that Compounds 6 and A arrested the growth of the 22RV1 prostate tumor.Example 67

[0310] The killing of human acute myeloid leukemia (AML) bone marrow cells was measured by intra peritoneal administration of Compound A in a dose of 5 mg / kg and oral administration of Compound 6 indoses of 1.5 mg / kg, 5 mg / kg, and 15 mg / kg. A vehicle control was also administered for comparison. NSGS mice were used for transplantation of primary AML, human CD34+ BM cells. NSGS mice were conditioned 24 h prior to transplant with 25mg / kg busulfan via intraperitoneal (IP) injection. Primary AML cells (1 x 106cells / recipient) or human CD34+ BM cells (5 x 105 cells / recipient) in 0.2ml saline were injected into the tail vein. For delivery of HSF1 degrader, mice were treated with 5mg / kg Compound A daily via intra-peritoneal (IP) injection 5 days after transplantation for 10 days. Donor chimerisms were analyzed using BM cells by flow cytometry after staining with hCD45-APC or-FITC, mCD45.1-A700 or-APC and hCD33-BV421. The results, shown in FIGs. 9A and 9B, show the dose-depenent selective killing of malignant bone marrow in AML patient derived xenograft.

[0311] One skilled in the art will readily appreciate that the present disclosure is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The embodiments described herein, are exemplary, and are not intended as limitations on the scope of the present disclosure. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the present disclosure as defined by the scope of the claims.

[0312] No admission is made that any reference, including any non-patent or patent document cited in this specification, constitutes prior art. In particular, it will be understoodthat, unless otherwise stated, reference to any document herein does not constitute an admission that any of these documents forms part of the common general knowledge in the art in the United States or in any other country. Any discussion of the references states what their authors assert, and the applicant reserves the right to challenge the accuracy and pertinence of any of the documents cited herein. All references cited herein are fully incorporated by reference, unless explicitly indicated otherwise. The present disclosure shall control in the event there are any disparities between any definitions and / or description found in the cited references.

Claims

1. What is Claimed is:

1. A method for treating cancer in a subject in need thereof, the method comprising administering a composition comprising a compound having the formula:wherein A2 is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro; each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen.

2. The method of claim 1, wherein the compound is administered at a concentration from about 0.01 mg / kg body weight of the subject to about 5 mg / kg body weight of the subject, such as about 0.01 mg / kg to about 2.5 mg / kg, about 0.05 mg / kg to about 2 mg / kg, or about 0.08 mg / kg to about 1.6 mg / kg.

3. The method of claim 1, wherein the subject is human.

4. The method of claim 1, wherein the administration results in degradation of nuclear HSF1.

5. The method of claim 4, wherein nuclear HSF1 is degraded by greater than 50% in less than 20 hours, less than 10 hours, or less than 5 hours.

6. The method of claim 1, wherein the cancer is prostate cancer.

7. The method of claim 6, wherein the administration results in reduction of 22RV1 prostate tumor growth as compared to a vehicle control.

8. The method of claim 6, wherein the administration results in reduction of 22RV1 prostate tumor growth by at least 500%, at least 1000%, at least 1500%, at least 2000%, at least 2500%, or at least 3000%.

9. The method of claim 1, wherein the cancer is leukemia.

10. The method of claim 9, wherein administration of the composition results in a reduction in cell count of human AML bone marrow cells as compared to a vehicle control.

11. The method of claim 10, wherein the reduction is 2xl06cells or more.

12. The method of claim 3, wherein the compound has a half-life of greater than 500 minutes, greater than 750 minutes, greater than 1000 minutes, greater than 1250 minutes, or greater than 1500 minutes after administration.

13. The method of claim 1, wherein the administration comprises oral administration.

14. The method of claim 13, wherein the compound has a Tmax of 3.33 ± 0.25 hours as a result of the administration.

15. The method of claim 13, wherein the compound has a Tmax of 2.67 ± 0.25 hours as a result of the administration.

16. The method of claim 13, wherein the compound has a half life of 10.3 hours ± 15% as a result of the administration.

17. The method of claim 13, wherein the compound has a half life of 6.47 hours ± 15% as a result of the administration.

18. The method of claim 13, wherein the compound has a Cmax of 2520 ng / mL ± 15% as a result of the administration of a dose of about 0.1 to about 1 mg / kg of the compound.

19. The method of claim 13, wherein the compound has a Cmax of 1070 ng / mL ± 15% as a result of the administration of a dose of about 0.1 to about 1 mg / kg of the compound.

20. The method of claim 13, wherein the compound has a AUCo-® of 39600 ng / mL h ± 15% as a result of the administration of a dose of about 0.1 to about 1 mg / kg of the compound.

21. The method of claim 13, wherein the compound has a AUCo-® of 15900 ng / mL h ± 15% as a result of the administration of a dose of about 0.1 to about 1 mg / kg of the compound.

22. The method of claim 13, wherein the compound has a bioavailability from 60% ± 15% to 100% ± 5% as a result of the administration.

23. The method of claim 13, wherein the compound has a bioavailability from 60% ± 15% to 80% ± 15%.

24. The method of claim 13, wherein the compound has a bioavailability from 80% ± 5% to 100% ± 5%.

25. The method of claim 1, wherein the administration comprises intravenous administration.

26. The method of claim 25, wherein the compound has a half life of 8.23 hours ± 15% as a result of the administration.

27. The method of claim 25, wherein the compound has a half life of 6.62 hours ± 15% as a result of the administration.

28. The method of claim 25, wherein the compound has a Cmax of 1040 ng / mL ± 15% as a result of the administration of a dose of about 0.01 to about 0.2 mg / kg of the compound.

29. The method of claim 25, wherein the compound has a Cmax of 276 ng / mL ± 15% as a result of the administration of a dose of about 0.01 to about 0.2 mg / kg of the compound.

30. The method of claim 25, wherein the compound has a AUCo-® of 8120 ng / mL h ± 15% as a result of the administration of a dose of about 0.01 to about 0.2 mg / kg of the compound.

31. The method of claim 25, wherein the compound has a AUCo-® of 3170 ng / mL h ± 15% as a result of the administration of a dose of about 0.01 to about 0.2 mg / kg of the compound.

32. The method of claim 1, wherein 2-15% of hCD45+cells remain 5 days, 10 days, 15 days, 20 days, 25 days, or greater than 25 days after administration.

33. The method of claim 1, wherein median tumor volume decreases by at least 5 mm3to at least 100 mm3at least 5 days, 10 days, 15 days, 20 days, or at least 25 days after administration.

34. The method of claim 1, wherein median tumor volume decreases by at least 5 mm3to at least 10 mm3at least 5 days, 10 days, 15 days, 20 days, or at least 25 days after administration.

35. The method of claim 1, wherein the ring Al is selected from the group consisting of36. The method of claim 1, wherein the ring Al has the formula:3 m 1, wherein the ring Al has the formula:

38. The method of claim 1, wherein A2 is selected from the group consisting of:

40. The method of claim 1, wherien the compound has the formula:

41. The method of claim 1, wherien the compound has the formula:

42. The method of claim 1, wherien the compound has the formula:

43. The method of claim 1, wherien the compound has the formula:

44. The method of claim 1, wherien the compound has the formula:

45. The method of claim 1, wherien the compound has the formula:

46. The method of claim 1, wherien the compound has the formula:

47. The method of claim 1, wherien the compound has the formula:

48. The method of claim 1, with the further proviso that at least one of R3aor R4ais cyano.

49. The method of claim 11, wherein the compound is:

50. The method of claim 1, wherein each R3ais independently selected from the group consisting of hydrogen, unsubstituted Ci-Ce alkyl, Ci-Ce alkyl substituted with halogen, unsubstituted Ci-Ce cycloalkyl, — (unsubstituted Ci-Ce alkyl) — N(unsubstituted Ci-Ce alkyl)2, — O — (unsubstituted Ci-Ce alkyl), — O — (unsubstituted Ci-Ce alkyl) — (3- to 10- membered heterocycloalkyl), — S(O)2(Ci-Ce alkyl substituted with halogen), — S(O)2(unsubstituted Ci-Ce alkyl), halogen, cyano, and nitro.

51. The method of claim 1, wherein each R4ais independently selected from the group consisting of hydrogen, unsubstituted Ci-Ce alkyl, Ci-Ce alkyl substituted with halogen, unsubstituted Ci-Ce cycloalkyl, 3- to 10-membered heterocycloalkyl, — (unsubstituted Ci- Ce alkyl) — (3- to 10-membered heterocycloalkyl), — (unsubstituted Ci-Ce alkyl) — N(unsubstituted Ci-Ce alkyl)2, — O — (unsubstituted Ci-Ce alkyl), — O — (unsubstituted Ci- Ce alkyl) — (3- to 10-membered heterocycloalkyl), — S(O)2(Ci-Ce alkyl substituted with halogen), — S(O)2(unsubstituted Ci-Ce alkyl), — NHS(O)2(unsubstituted Ci-Ce alkyl), halogen, cyano, and nitro.

52. The method of claim 1, wherein each R3ais independently selected from the group consisting of hydrogen, cyano, and halogen.

53. The method of claim 1, wherein each R4ais independently selected from the group consisting of hydrogen, cyano, halogen, — S(O)2(Ci-Ce alkyl substituted with halogen), and — S(O)2(unsubstituted Ci-Ce alkyl).

54. The method of claim 1, wherein the compound is:

55. The method of claim 1, wherein the compound is:

56. The method of claim 1, wherein the compound is:

57. The method of claim 1, wherein the compound is:

58. The method of claim 1, wherein the compound is:

59. A method for degrading HSF1 in a subject in need thereof, the method comprising administering a composition comprising a compound having the formulawherein Al is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen.

60. The method of claim 59, wherein the percentage of HSF1 is degraded at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more within an hour after administration.

61. The method of claim 59, wherein the percentage of HSF1 is degraded at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more within five hours after administration.

62. The method of claim 59, wherein the percentage of HSF1 is degraded at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more within ten hours after administration.

63. The method of claim 59, wherein the percentage of HSF1 is degraded at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more within fifteen hours after administration.

64. The method of claim 59, wherein the percentage of HSF1 is degraded at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more within twenty hours after administration.

65. The method of claim 59, wherein the percentage of HSF1 degraded is substantially similar to the line indicated with circles, denoted as Nuclear HSF1 Degradation, in FIG. 2.

66. The method of any one of claims 59-65, wherein HSF1 resynthesis occurs from about 18 to about 32 hours, about 20 to about 30 hours, about 22 to about 26 hours, or about 23 to about 25 hours after administration.

67. The method of any one of claims 59-65, wherein HSF1 synthesis is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% of full potential by 25 hours after administration.

68. The method of any one of claims 59-65, wherein HSF1 synthesis is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% of full potential by 30 hours after administration.

69. The method of any one of claims 59-65, wherein HSF1 synthesis is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 85%, 90% or more of full potential by 40 hours after administration.

70. The method of any one of claims 59-65, wherein HSF1 synthesis is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 85%, 90% or more of full potential by 50 hours after administration.

71. The method of any one of claims 59-65, wherein HSF1 synthesis is at least 75%, 85%, 90% or more of full potential by 60 hours after administration.

72. A method of degrading HSF1 in a subject in need thereof, the method comprising administering a composition comprising a compound having the formulawherein Al is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro; each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen,and having a half-life (Ti / 2)(min) greater than 40, 50, 75, 100, 200, 300, 500, 700, 900, 1,000, or more.

73. A method for arresting tumor growth or decreasing tumor size in a subject in need thereof, the method comprising administering a composition comprising a compound having the formulawherein Al is selected from the group consisting of:wherein A2 is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro; each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen.

74. A method for treating malignant bone marrow in a subject in need thereof, the method comprising administering a composition comprising a compound having the formulawherein Al is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro; each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen.

75. A method for selective killing of malignant bone marrow in a subject in need thereof, the method comprising administering a composition comprising a compound having the formulawherein Al is selected from the group consisting of:each R3ais independently selected from the group consisting of hydrogen, Rla, — ORla, — ORlaR2a, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro; each R4ais independently selected from the group consisting of hydrogen, Rla, — ORla, — OC(O)R2a, — NR2aR2b, — S(O)i-2R2a, — SO2NR2aR2b, — NR2aSO2R2b, — C(O)R2b, — C(O)OR2a, — C(O)NR2aR2b, — NR2aC(O)R2b, — NR2aC(O)OR2b, halogen, cyano, oxo, and nitro;Rlaand Rlbare each independently selected from unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cio aryl; Ce-Cioaryl 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;R2aand R2bare each independently selected from hydrogen, hydroxy, cyano, — COOH; — C(O)(OCi-Cealkyl); unsubstituted Ci-Ce alkyl; Ci-Ce alkyl substituted with halogen, amine, cyano, oxo, or nitro; C2-Ce alkene; C2-Ce alkenyl; unsubstituted C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted with C1-C4 alkyl, halogen, amine, cyano, oxo, or nitro; unsubstituted Ce-Cioaryl; Ce-Cio aryl 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; and with the further proviso that at least one of R3aand R4ais hydrogen.

Images