Substituted pyrazole and isoxazole derivatives and methods of use thereof

Abstract

In one aspect, the present disclosure relates to compounds of Formula (I)-(IV), which inhibit palmitoyl transferases and / or palmitoylation, pharmaceutical compositions thereof, and methods of using the same. In certain embodiments, the present disclosure relates to methods of treating, preventing, and / or ameliorating cancer in a subject. In certain embodiments, the cancer is lung cancer and / or pancreatic cancer. In certain embodiments, the present disclosure relates to methods of inhibiting palmitoylation in a subject. In certain embodiments, EGFR palmitoylation is inhibited in a subject.

Description

[0001]Attorney Docket No.046483-7421WO1(03880) TITLE OF THE INVENTION Substituted Pyrazole and Isoxazole Derivatives and Methods of Use Thereof CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No.63 / 635,916, filed April 18, 2024, which is incorporated herein by reference in its entirety. SEQUENCE LISTING The XML file named “046483-7421WO1 - Sequence Listing.xml” created on April 18, 2025, comprising 21,400 Bytes, is hereby incorporated by reference in its entirety. BACKGROUND Palmitoylation comprises the covalent attachment of fatty acids, such as palmitic acid, to nucleophilic amino acid side chains (e.g., cysteine thiols) of proteins, thus allowing for the proteins' anchoring to cell membranes. The process is catalyzed by a DHHC domain (named after a conserved sequence motif of its protein sequence) of a palmitoyl transferase. Despite discovery of this process over 40 years ago, there remains a lack of specific palmitoylation inhibitors (e.g., inhibitors of palmitoyl transferases). The most widely used palmitoylation inhibitor is a palmitate analog (i.e., 2-bromo-palmitate or 2-BP), which is not specific to any one palmitoyl transferase, and also inhibits other enzymes for which palmitate is a substrate. Cyanomyracrylamide (CMA), a recently developed palmitoyl transferase inhibitor, is more specific than 2-BP, but is not specific to a single DHHC domain-containing enzyme ("DHHC enzyme"). Without a pharmacological means for inhibiting palmitoylation, any understanding of this modification (i.e., palmitoylation) and its on dynamic processes like cell signaling are incomplete. Further, palmitoyl transferases and / or DHHC enzymes represent a potential therapeutic target for RTK and Ras driven cancers. There is thus a need in the art for small molecule inhibitors of palmitoyl transferases and / or DHHC enzymes and methods of use thereof for the treatment, prevention, and / or amelioration of one or more diseases, including but not limited to cancer. The present disclosure addresses this need. BRIEF SUMMARY - 1 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) In one aspect, the disclosure provides a compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof, wherein R1, R2a, R2b, R3a, R3b, X, and a are defined elsewhere herein: . In one aspect, the disclosure of Formula (II), or a salt, solvate, stereoisomer, or isotopologue R2c, and X are defined elsewhere herein: . In one aspect, the of Formula (III), or a salt, solvate, stereoisomer, or isotopologue X are defined elsewhere herein: (III). In another aspect, the disclosure provides a pharmaceutical composition comprising at least one compound of the disclosure and a pharmaceutically acceptable carrier. In certain embodiments, the composition further comprises at least one additional agent. In certain embodiments, the at least one additional agent is an EGFR inhibitor, a KRasG12Cinhibitor, a PI3K inhibitor, a RAF inhibitor, or a cytotoxic agent. In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating cancer in a subject. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure or a pharmaceutical composition thereof. In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating cancer in a subject. In certain embodiments, the method comprises administering to the subject at least one compound of Formula (IV), or a salt, solvate, stereoisomer, or isotopologue thereof, wherein R1, R2a, R2b, R3a, R3b, X, and a are defined elsewhere herein: . In certain embodiments, the pancreas, bladder, blood, bone, - 2 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, and / or uterus. In certain embodiments, the cancer comprises RTK driven cancer and / or Ras driven cancer. In certain embodiments, the at least one compound of Formula (IV) selectively inhibits a DHHC enzyme. In certain embodiments, the DHHC enzyme is DHHC20. In certain embodiments, the DHHC enzyme is selectively inhibited over kinesin spindle protein (KSP). In certain embodiments, the subject is further subjected to trans-arterial chemoembolization (TACE). In certain embodiments, the subject is further subjected to trans-arterial embolization (TAE). In another aspect, the disclosure provides a method of inhibiting palmitoylation in a subject. In certain embodiments, the method comprises administering to the subject at least one compound of the disclosure or a pharmaceutical composition thereof. In another aspect, the disclosure provides a method of inhibiting palmitoylation in a subject. In certain embodiments, the method comprises administering to the subject at least one compound of Formula (IV), or a salt, solvate, stereoisomer, or isotopologue thereof, wherein R1, R2a, R2b, R3a, R3b, X, and a are defined elsewhere herein: . BRIEF DESCRIPTION OF THE FIGURES The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application. FIG.1A: CRISPR ablation of DHHC20 in a genetically engineered mouse model of Kras driven lung adenocarcinoma. Quantification of tumor burden 12 weeks after induction. FIG.1B: xenograft tumors grown from A549 human lung cancer cells stably transduced with inducible control shRNA or DHHC20 shRNA. shDHHC20 induction blocks tumor growth. FIG.1C: patients with alterations in ZDHHC20 or ZDHHC14 and with Kras mutations have a significant increase in overall survival compared to patients with wild type Kras (Patient data from cBioPortal, TCGA database) Logrank Test. FIG.1D: silencing DHHC20 expression by shRNA increases sensitivity to 5 μM gefitinib (gef) induced cell death in gefitinib resistant H1975 lung cancer cells. FIGs.2A-2D: Mechanism is mediated by blocking EGFR palmitoylation. FIG.2A: mutation of cysteine 1025 to alanine reduces palmitoylation measured by the ABE assay. - 3 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) FIG.2B: expression of EGFRC1025Ahas no effect on cell proliferation of NIH3T3 cells. FIG. 2C: expression of EGFRC1025Areduces cell proliferation of NIH3T3 cells expressing KrasG12Vcompared to EGFRWT. FIG.2D: expression of EGFRC1025Areduces membrane association of PI3K regulatory subunit p85 and increases MAPK adaptor Grb2 membrane association. FIG.3A: mutation of cysteine 1025 to alanine causes auto-phosphorylation on tyrosine residues 1068 and 1173 and increased Erk phosphorylation. FIG.3B: palmitoylated cysteine 1025 is encoded in exon 26 which is deleted in lung adenocarcinoma. FIG.3C: EGFRC1025Ablocks Kras driven tumorigenesis like the L858R activating kinase mutation in the KrasG12D; p53- / - lung cancer mouse model. FIGs.4A-4C: Inhibiting DHHC20 blocks the PI3K-Myc signaling axis. FIG.4A: silencing DHHC20 in H23 lung cancer cells decreases pAKT and pGSK3β as well as c-Myc protein expression. FIG.4B: expression of c-MycT58Ain H23 shDHHC20 cells rescues the growth defect from loss of DHHC20. *** P < 0.001, Student’s T test. FIG.4C: expression of palmitoylation resistant mutant EGFRC1025Ahas reduced c-Myc expression. FIGs.5A-5C: Loss of DHHC20 reduces autophagy. FIG.5A: A549 expressing DHHC20 shRNA have decreased viability when grown in HBSS (error bars = Stdev). FIG. 5B: A549 lung cancer cells expressing DHHC20 shRNA have reduced autophagy measured by LC3iii conversion grown in amino acid deprived conditions (-AA) BafilomycinA (BafA) treatment blocks lysosomal degradation of LC3. FIG.5C: A549 cells expressing shDHHC20 have a reduction in activating phosphorylation of serine 93 on Beclin1 when grown without amino acids (-AA). FIG.6A: schematic of acyl biotin exchange (ABE) assay. FIG.6B: ABE assay indicates overexpression of DHHC11 or DHHC23 increases EGFR palmitoylation compared to parental (Pa) H1975 cells. palmitoylated. FIG.6C: effect of filanesib on cell growth correlates with ZDHHC11 expression in lung cancer cells with damaged ZDHHC23 gene (red) (Spearman -0.9, P-value 0.03). FIG.6D: treatment of H1975 cells with filanesib reduces EGFR palmitoylation within 30 minutes. FIG.7A: structures of filanesib and ispinesib. FIG.7B: low energy conformers of certain compounds generated in ROCS. FIG.8A: ROCS identified compound 1 dose-dependently inhibits EGFR palmitoylation. FIG.8B: compound 1, and novel derivatives thereof, including lead compound SD-066-4, induce varying levels of palmitoylation inhibition (1 h treatment). FIG. 8C: cellular Thermal Shift Assay (CETSA) demonstrates engagement of SD-066-4 with target DHHC20. - 4 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) FIG.9A: ABE assay measuring pan Ras palmitoylation in H1975 cells treated with Compound 1 and SD-066-4 for 1 hour. FIG.9B: cell proliferation assay for SD-066-4 in H1975 cells treated with SD-066-4. FIG.10: Kinesin inhibitor Filanesib (20 nM) inhibits centrosome separation during mitosis. Centrosome separation is unimpaired in SD-066-4 (10 μM) treated cells. Acetylated tubulin antibody labels the mitotic spindles. Two representative mitotic cells are shown per treatment. FIG.11: selectivity of SD-066-4. SD-066-4 inhibits the EGFR palmitoylation in H1975 cells over-expressing DHHC11 but not DHHC23. FIGs.12A-12B: biotinylated peptides interact with DHHC20. Peptides can be used as a substrate for in vitro palmitoylation assay. FIG.13: LC-MS methods to detect EGFR peptide and palmitoylated EGFR peptide. FIGs.14A-14B: SD-066-4 (72 h) inhibits cell proliferation in lung cancer cell line H23 (FIG.14A), but not normal lung fibroblast cell line IMR-90 (FIG.14B). FIG.14C: inhibition of EGFR expression reduces growth inhibition by SD-066-4. FIG.14D: SD-066-4 (2.5 μM) increases cell death in A549 cells under amino acid deprived conditions (72 h) while IMR90 cells are resistant. (Error bars = Std. dev.). FIG.14E: SD-066-4 (10 µM) inhibits amino acid deprivation induced autophagy in A549 lung cancer cells (2 h treatment). FIG.15: SD-066-4 increases sensitivity to EGFR inhibitor 5 µM gefitinib in lung cancer cell line H1975 with the gefitinib resistance mutation T790M. FIG.16: in vivo imaging of xenograft tumors grown from A549 human lung cancer cells stably transduced with inducible control shRNA or DHHC20 shRNA. shDHHC20 blocks tumor growth. FIG.17: SD-066-4 (2.5 µM) increases EGFR signaling measured by EGFR and ERK phosphorylation. FIG.18: SD-066-4 (1 µM) increases Myc protein levels at early time points followed by a rapid and sustained decrease in Myc. FIG.19: murine pharmacokinetics of SD-066-4 per oral (PO) and intraperitoneal (IP) at 10 mg / kg. N=3 for each condition. FIGs.20A-20B: DHHC20 inhibitor blocks tumor growth. FIG.20A: MIAPACA2 pancreatic xenograft tumors from treated with SD-066-450 mg / kg or vehicle control measured by caliper 4 mice in each treatment arm. FIG.20B: A549 xenograft lung cancer tumors treated 50 mg / kg (2 mice treated 3 mice vehicle control). Dashed vertical line indicates increased dose to 75 mg / kg. - 5 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) FIG.21: SD-066-4 increases sensitivity to PI3K inhibitor 5 µM BKM120 in lung cancer cell line H1975 expressing DHHC20 shRNA. FIG.22A: genetic inhibition of DHHC20 increases paclitaxel (PTX) induced cell death compared to shControl. FIG.22B: PTX increases EGFR palmitoylation. FIG.22C: DHHC20 knockdown cells have reduced LC3 levels when treated with PTX compared to shRNA control. FIG.23: Palmitoylated EGFR and DHHC20 in xenograft tumors grown from H23 lung cancer cells. FIGs.24A-24B: images (FIG.24A) and graphs (FIG.24B) showing melanoma tissue arrays treated with the ABE-PLA. FIGs.24C-24D: images (FIG.24C) and graphs (FIG.24D) showing ABE-PLA of formalin fixed H1975 lung cancer cells treated with EGF. PLA signal is detected in cells treated with hydroxylamine (+HAM). DAPI is shown in cyan and PLA signal in magenta. Paired Student’s T-test. FIG.25 provides a mechanistic model. EGFR palmitoylation (left) promotes PI3K / AKT signaling leading to stable Myc production and cell proliferation. Loss of EGFR palmitoylation (right) promotes binding of Grb2-SOS leading to hyperactivation of KRAS / MAPK, but impedes PI3K / AKT signaling, causing Myc depletion and reduced cell proliferation. FIG.26A: Patients with deletions in ZDHHC20 or ZDHHC14 together with Kras alterations have a significant increase in overall survival compared to patients with wild type Kras (TCGA database) Logrank Test (Blue Kras altered, Red Kras wild type). FIG.26B: IngMeb inhibits EGFR S- acylation measured by ABE assay. FIG.26C: Correlation between growth effect of IngMeb and ZDHHC14 mRNA expression in Kras mutant (orange) vs Kras wild type (gray) LUAD cell lines. DepMap cancer dependency database. FIG.26D: Correlation between growth effect of filanesib and ZDHHC14 mRNA in Kras mutant (orange) vs Kras wild type (gray) LUAD cell lines. FIG.26E: Treatment of H1975 cells with filanesib inhibits EGFR S-acylation. FIG.26F: Structures of filanesib and IngMeb. FIG.26G: Treatment of NCI-H23 cells expressing V5-tagged ZDHHC20 with fillanesib increases the thermal stability of ZDHHC20-V5 by cellular thermal shift assay (CETSA). FIG.26H: Quantification of CESTA. FIG.26I: Overlay of filanesib with ROCS identified compounds 1 and 2. FIG.26J: Treatment of H1975 cells with SD-066-4 for 1 hour decreases EGFR S- acylation. FIG.27A: Modeling of potential SD-066-4 binding site on ZDHHC20. FIG.27B: Methyl group of SD-066-4 clashes with leucine (yellow) in ZDHHC14 (AlphaFold). FIG. - 6 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) 27C: Cells expressing ZDHHC14 are resistant to SD-066-4 mediated inhibition of EGFR S- acylation, but permissive to SD-128 which has no effect on parental cells. FIG.27D: Chemical structures of SD-066-4 compared to SD-128 which lacks the methyl group on SD- 066-4 that clashes with leucine on ZDHHC14. FIG.27E: Class i ZDHHC enzymes (Bold) have small amino acid side groups in position of alanine 144 (central box) in ZDHHC20 (SEQ ID NOs:1-23). Class ii enzymes have bulky amino acid side groups (SEQ ID NOs:1- 23). FIG.27F: Overexpression of ZDHHC11 or 23 increase EGFR S-acylation. FIG.27G: EGFR S-acylation is inhibited by SD-066-4 in cells overexpressing ZDHHC11 but not in cells overexpressing ZDHHC23. FIG.28A: Overexpression of KrasG12Vin NIH3T3 cells increases EGFR S-acylation which is inhibited linearly by SD-066-4 over time compared to non-linear inhibition of parental NIH3T3 cells. FIG.28B: Overexpression of KrasG12Vin NIH3T3 cells increases ZDHHC20 protein levels compared to parental cells by immunofluorescence staining. FIG. 28C: Altered PI3K signaling and Myc protein levels in Kras mutant compared to Kras wild type LUAD cell lines. FIG.28D: Inhibition of EGFR S- acylation over time in Kras mutant and Kras wild type LUAD cell lines. FIG 28E: Cell proliferation of a A549 Kras512Scell line with dosage increase in SD-066-4. FIGs.28F-28G: Treatment of Kras mutant LUAD cells decreases ZDHHC14-HA protein levels over time (FIG.28F), in contrast to Kras WT LUAD cells where ZDHHC14-HA increases (FIG.28G). FIG.29A: Change in volume of A549 LUAD xenograft tumors on Day 5 and Day 23 of vehicle vs. SD-066-4 treated tumors. Treatment was initiated when tumors were 300 mm3. Student’s T- test. FIG.29B: Average percent tumor volume change of vehicle vs. SD-066-4 treated tumors over 29 days. FIG.29C: Percent body weight change of vehicle or SD-066-4 treated animals at endpoint. FIG.29D: Kaplan Myer Plot of probability of survival of vehicle vs. SD-066-4 animals. FIG.29E: Immunofluorescence staining of frozen tumor sections probed with anti-Myc (yellow) anti-E-cadherin (magenta) and DAPI (cyan). Tile scan at 10X magnification, scale bar = 1 mm. FIG.29F: Schematic of S-acyl PLA to detect S-acylated phosphorylated EGFR. FIG.29G: Representative image of frozen tumor section treated and analyzed with S-acyl PLA from vehicle and SD-066-4 treated tumors. Scale bar = 50 μm. FIG.29H: Quantification of PLA puncta of vehicle and SD-066-4 treated tumors counted from deconvoluted z-series. P<0.0001; 2-way Anova. FIG.29I: CRISPR / Cas9 ablation of zDHHC20 blocks tumor formation in KrasG12Ddriven genetically engineered mouse model of lung adenocarcinoma. FIG.29J: Xenograft tumors treated with SD-066-4 (100 mg / kg) daily by oral gavage reduces tumor growth with no impact on body weight and significantly - 7 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) improves probability of survival of tumor bearing mice. FIG.30 depicts dose-dependent inhibition of EGFR palmitoylation by certain exemplary compounds of the disclosure. FIG.31A provides a bar graph depicting percentage tumor volume change with administration of SD-664 (50 mg / kg) as compared to vehicle. FIG.31B provides a bar graph depicting percentage tumor volume change with administration of SD-664 (100 mg / kg) as compared to vehicle. FIG.31C provides a graph depicting individual tumor volume (mm3) as a function of days elapsed post-treatment with SD-664. FIG.32A: Immunofluorescence staining of frozen tumor sections of individual mice probed with anti-Myc (yellow), anti-E-cadherin (magenta), and DAPI (cyan), and merged images thereof, 37 days post-treatment. FIG.32B: S-acyl exchange-PLA assay detects dually phosphorylated and S-acylated EGFR. S-acylated pEGFR is reduced in SD-066-4 treated tumors (scale bar = 50 µm). FIG.33: Palmitoyl proteomic analysis of NCIH1975 lung cancer cells treated with SD-066-4 (5 µM) compared to vehicle (DMSO) treatment for 1 hour. Volcano plot showing proteins that decrease with drug treatment on the left and proteins that increase on the right. FIG.34 shows that compound TM163 decreases EGFR palmitoylation at concentrations below 500 nM. FIGs.35A-35C: Catheterization (↑) in rat identifies arteries (↑) to enable TAE in hepatic artery (FIG.35A) and pulmonary arteries (FIG.35B). FIG.35C: Scatter plot of % necrosis in tumors from untreated rats and rats treated with TAE alone or TAE + Lys05. FIG.36A: A549 lung cancer cells treated with SD-066-4 have reduced autophagic flux measured by LC3i-ii conversion grown in amino acid deprived conditions (-AA). FIG. 35B: SD-066-4 (2.5 µM) increases cell death in A549 cells under amino acid deprived conditions (72 h) while IMR90 lung fibroblasts are resistant. (Error bars = Stdev). FIG.37A: Decrease in HCC tumor volume following single treatment with TAE + SD-066-4 on day 0. Each color represents a single tumor. FIG.37B: SD-066-4 inhibits autophagy in HCC cells grown in amino acid free media (-A.A). Bafilomycin A (BafA) blocks autophagic flux allowing easier detection of changes in flux. FIG.38A: Lung cancer cell line srH23 is resistant to sotorasib compared to parental H23. FIG.38B: Sotorasib resistant srH23 cells respond to SD-066-4. FIG.38C: Sotorasib resistant srH23 cells have altered Myc expression in response to SD-066-4 compared to parental cells. FIG.38D: SD-066-4 increases cell death in H23 cells treated with sotorasib (1µM). FIG.38E: Combined treatment with SD-066-4 and sotorasib suppresses Myc - 8 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) expression compared to sotorasib alone. All drug treatments were for 72 hours. DETAILED DESCRIPTION OF THE INVENTION It has been previously demonstrated that the enzyme responsible for EGFR palmitoylation (i.e., DHHC20) sensitizes cells to EGFR inhibitors, as well as exhibiting synthetic lethality with oncogenic KRas mutations. Thus, the development of small molecule inhibitors of DHHC20 has significant therapeutic potential both as an adjuvant to EGFR inhibitors and / or KRasG12Cinhibitors, and as a potential single agent therapy against cancers, such as cancers characterized and / or driven by KRas mutations. The present disclosure describes, in part, the repurposing of drugs for the inhibition of EGFR palmitoylation (e.g., PTX). Further, the present disclosure relates to the design, synthesis, and evaluation of palmitoylation inhibitors (e.g. pyrazole and / or isoxazole compounds, and derivatives thereof). In one aspect, the present disclosure relates to the identification of a first-in-class, drug-like palmitoylation inhibitor: . In certain (e.g., SD-066-4) are selective for specific DHHC enzymes (e.g., selective for DHHC11 over DHHC23). In certain embodiments, the compounds disclosed herein (e.g., SD-066-4) are selective for specific DHHC enzymes (e.g., DHHC20). In certain embodiments, the compounds disclosed herein (e.g., SD-066-4) reduce expression of c-Myc. In certain embodiments, the compounds disclosed herein (e.g., SD-066-4) reduce autophagy in lung cancer cells. In certain embodiments, the toxicity of the compounds disclosed herein (e.g., SD-066-4) is lower than the toxicity of MRT68921 (i.e., a ULK inhibitor). In certain embodiments, the compounds disclosed herein (e.g., SD-066-4) inhibit Kras mutant lung and pancreas tumor growth in xenografts. In certain embodiments, improved tumor growth suppression is observed with daily treatment with the compounds disclosed herein (e.g., SD-066-4). Definitions Reference is made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be - 9 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement "about X to Y" has the same meaning as "about X to about Y," unless indicated otherwise. Likewise, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z," unless indicated otherwise. In this document, the terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. The statement "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B." In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. The term "about" as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term "alkenyl" as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon - 10 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. The term "alkoxy" as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith. The term "alkyl" as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "alkynyl" as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – C^CH, -C^C(CH3), -C^C(CH2CH3), -CH2C^CH, -CH2C^C(CH3), and -CH2C^C(CH2CH3) among others. The term "amine" as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3wherein each group can independently be H or non-H, - 11 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein. The term "amino group" as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes a monoalkylamino, dialkylamino, and trialkylamino group. The term "aryl" as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. The term "cycloalkyl" as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term - 12 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group. The term "cytotoxic agent" as used herein refers to natural or synthetic substances which inhibit cell growth or cell division in vivo. The term is intended to include chemotherapeutic agents, antibiotics, and toxins such as enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof. Preferably, the term "cytotoxic agent" is a natural or synthetic substance which inhibits the cell growth or the cell division of a tumor in vivo. Most preferably, the cytotoxic agent is a chemotherapeutic agent. The therapeutic use of these preferred cytotoxic agents, most preferably of the chemotherapeutic agents, is based on this difference in the rate of cell division and cell growth of tumor cells compared to normal cells. Among others, tumor cells differ from normal cells in that tumor cells are no longer subject to physiological growth control and therefore have an increased rate of cell division. Since the toxic activity of cytotoxic agents is usually primarily directed against proliferating cells, such cytotoxic agents can be used for inhibiting a development or progression of a neoplasm in vivo, particularly a malignant (cancerous) lesion, such as a carcinoma, sarcoma, lymphoma, or leukemia. Inhibition of metastasis is frequently also a property of the cytotoxic agents encompassed by the present invention. Non-limiting examples of cytotoxic agents and / or chemotherapeutic agents contemplated for use herein include paclitaxel, doxorubicin, cyclophosphamide, methotrexate, fluorouracil, cisplatin, carboplatin, vinblastine, vincristine, etoposide, bleomycin, mitomycin c, gemcitabine, irinotecan, topotecan, docetaxel, camptothecin, melphalan, busulfan, chlorambucil, dacarbazine, procarbazine, temozolomide, bendamustine, oxaliplatin, ifosfamide, lomustine, streptozocin, daunorubicin, idarubicin, fludarabine, cladribine, pentostatin, mercaptopurine, azathioprine, hydroxyurea, thiotepa, mitoxantrone, teniposide, cytarabine, decitabine, clofarabine, nelarabine, azacytidine, eribulin, cabazitaxel, liposomal doxorubicin, pegylated liposomal doxorubicin, trabectedin, and ixabepilone. Any cytotoxic agent and / or chemotherapeutic agent known to those of ordinary skill in the art is further contemplated within the scope of the present disclosure. In certain embodiments, the compound of the present disclosure may be administered in combination with one or more chemotherapeutic agents and / or combinations thereof, including but not limited to: (a) FOLFOX (i.e., a combination of folinic acid (leucovorin), 5- fluorouracil (5-FU), and oxaliplatin); (b) ABVD (i.e., a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine); (c) BEACOPP (i.e., a combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone); (d) CHOP (i.e., a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone); - 13 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) (e) CMF (i.e., a combination of cyclophosphamide, methotrexate, and fluorouracil); (f) AC (i.e., a combination of doxorubicin and cyclophosphamide); (g) TAC (i.e., a combination of docetaxel, doxorubicin, and cyclophosphamide); (h) R-CHOP (i.e., a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone); (i) ICE (i.e., a combination of ifosfamide, carboplatin, and etoposide); and (j) BEP (i.e., a combination of bleomycin, etoposide, and cisplatin). A "disease" is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate. In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health. A disease or disorder is "ameliorated" if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced. As used herein, the terms "effective amount," "pharmaceutically effective amount" and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. The terms "halo," "halogen," or "halide" group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term "haloalkyl" group, as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. The term "heteroaryl" as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A - 14 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- - 15 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the The term "heterocycloalkyl" as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. A heterocycloalkyl can include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom can be optionally substituted. Representative heterocycloalkyl groups include, but are not limited, to the following exemplary groups: pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. The term heterocycloalkyl group can also be a C2 heterocycloalkyl, C2-C3 heterocycloalkyl, C2-C4 heterocycloalkyl, C2-C5heterocycloalkyl, C2-C6heterocycloalkyl, C2-C7heterocycloalkyl, C2-C8 heterocycloalkyl, C2-C9 heterocycloalkyl, C2-C10 heterocycloalkyl, C2-C11 heterocycloalkyl, and the like, up to and including a C2-145heterocycloalkyl. For example, a C2 heterocycloalkyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocycloalkyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, and the like. It is understood that a heterocycloalkyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocycloalkyl ring. The - 16 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) heterocycloalkyl group can be substituted or unsubstituted. The term "heterocyclyl" as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein. The term "hydrocarbon" or "hydrocarbyl" as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups. As used herein, the term "hydrocarbyl" refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- - 17 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group. The term "independently selected from" as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase "X1, X2, and X3are independently selected from noble gases" would include the scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations. The terms "patient," "subject," or "individual" are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human. As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the language "pharmaceutically acceptable salt" refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. - 18 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods - 19 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) or compounds described herein are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. The term "RAF inhibitor" or "RAF kinase inhibitor" as used herein refers to a compound which is capable of interacting with one or more isoform members (i.e., BRAF, C- RAF (RAF-1), and / or A-RAF) of the serine / threonine-protein kinase RAF family, including mutant forms. Some examples of BRAF mutant forms include BRAF V600E, BRAF V600D, and BRAF V600K. Non-limiting examples of RAF inhibitors include PLX4720, PLX4032, BAY 43-9006 (sorafenib), vemurafenib (zelboraf), dabrafenib (tafinlar), encorafenib (braftovi), cobimetinib (cotellic), binimetinib (mektovi), ZM 336372, RAF 265, AAL-881, LBT-613 (Novartis), and CJS352. PLX4720, PLX4032, BAY 43-9006 (sorafenib), ZM 336372, and RAF 265. Vemurafenib (zelboraf) and dabrafenib (tafinlar) are selective inhibitors of the mutated BRAF V600E protein. encorafenib (braftovi) is a selective inhibitor of BRAF with activity against both the V600E and V600K mutations. cobimetinib (cotellic) and binimetinib (mektovi) are inhibitors of MEK1 / 2, which are downstream targets of RAF kinases, and may be used in combination with BRAF inhibitors to treat melanoma and other cancers. While sorafenib (nexavar) is primarily a multi-kinase inhibitor that targets VEGFR, PDGFR, and RAF-1 (CRAF), it has also been shown to have activity against mutated forms of BRAF and ARAF. Additional RAF inhibitors known to those of ordinary skill in the art may also be used. The term "room temperature" or "rt" as used herein refers to a temperature of about 15 °C to 28 °C. The term "solvent" as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids. The term "specifically binds", or "specifically binds", or the like, means that a small molecule, an antibody, and / or antigen-binding fragment forms a complex with a target and / or an antigen that is relatively stable under physiological conditions. The specific bond can be characterized by an equilibrium dissociation constant (for example, a smaller KDdenotes a firmer bond). Methods for determining whether two molecules specifically bind to each other are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. The term "substantially" as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at - 20 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) least about 99.999% or more, or 100%. The term "substantially free of" as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term "substantially free of" can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term "substituted" as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1- C100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. A "therapeutic" treatment is a treatment administered to a subject who exhibits signs - 21 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) of pathology, for the purpose of diminishing or eliminating those signs. The term "trans-arterial chemoembolization" or "TACE" refers to a minimally invasive, image-guided interventional procedure in which a chemotherapeutic agent is delivered directly into the arterial blood supply of a tumor, followed by or concurrently with administration of embolic material to obstruct the vessel and trap the chemotherapeutic agent at the target site. TACE is commonly used to treat primary or metastatic liver tumors by maximizing local drug concentration and minimizing systemic exposure. The term "trans-arterial embolization" or "TAE" as used herein refers to a minimally invasive, catheter-based medical procedure in which embolic material is delivered via the arterial vasculature to selectively occlude one or more blood vessels supplying a targeted tissue or organ, thereby reducing or eliminating blood flow to the target site. The procedure is typically performed under image guidance and may be used for therapeutic purposes including but not limited to treatment of tumors, vascular malformations, or hemorrhages. The terms "treat," "treating" and "treatment," as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject. Compounds In one aspect, the present disclosure provides a compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: R1is selected from the group , ; - 22 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) R2ais selected from the group ; R2bis H or absent; R3aand R3bare each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2, wherein R3bcan be present or absent; and X is selected from the group consisting of N(R4) and O; L is selected from the group consisting of optionally substituted methylene and a bond; R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6alkyl and optionally substituted C6-C10 aryl; Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, optionally substituted C2-C10 heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1and Rb2, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10 heteroaryl; and bond a is a single bond or a double bond, wherein one of the following applies: (a) bond a is a single bond and each of R2a, R2b, R3a, and R3bare present; or (b) bond a is a double bond, R2aand R3aare present, and R2band R3bare - 23 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) absent. In certain embodiments, if bond a is a double bond, X is N, R4is H, and R1is , then at least one of Ra1, Ra2, Ra3, Ra4, and Ra5is optionally substituted C1-C6and at least one of Rc1, Rc2, Rc3, Rc4, and Rc5is optionally substituted C1-C6 or In certain embodiments, the compound is not (2-fluorophenyl)(5-(2-fluorophenyl)-3- (p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone. In certain embodiments, the compound is not 3-(5-phenyl-1H-pyrazol-3-yl)-1H-indole. In certain embodiments, the compound is not 1- methyl-3-(5-phenyl-1H-pyrazol-3-yl)-1H-indole. In certain embodiments, the compound is not 3-(5-(2-chlorophenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole. In certain embodiments, the compound is not 3-(5-(2-methylphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole. In certain embodiments, the compound is not 3-(5-(2-hydroxyphenyl)-1H-pyrazol-3-yl)-1-methyl-1H- indole. In certain embodiments, the compound is not 3-(5-(2-methoxyphenyl)-1H-pyrazol-3- yl)-1-methyl-1H-indole. In certain embodiments, the compound is not 3-(5-(4-chlorophenyl)- 1H-pyrazol-3-yl)-1-methyl-1H-indole. In certain embodiments, the compound is not 3-(5-(4- methoxyphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole. In certain embodiments, the compound is not 3-(5-(4-methylphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole. In certain embodiments, the compound of Formula (I) is a compound of Formula (Ia): . In certain embodiments, Ra1 Ra1is F. In certain embodiments, Ra2is H. In certain embodiments, Ra2is F. In certain embodiments, Ra3is H. In certain embodiments, Ra3is F. In certain embodiments, Ra4is H. In certain embodiments, Ra4is F. In certain embodiments, Ra5is H. In certain embodiments, Ra5is F. In certain embodiments, at least one of Ra1, Ra2, Ra3, Ra4, and Ra5is H. In certain embodiments, at least two of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least three of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least four of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, each of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least one of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is H. In certain embodiments, at least two of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, at - 24 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) least three of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, at least four of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, at least five of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, Rb1is H. In certain embodiments, Rb1is CH3. . In certain embodiments, R1. In certain embodiments, R1In certain . In certain one of Rc1, Rc2, Rc3, Rc4, and Rc5is H. In certain embodiments, at least two of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least three of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least four of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, each of Rc1, Rc2, Rc3, Rc4, and Rc5is H. In certain embodiments, Rb2is H. In certain embodiments, Rb2is CH3. In certain embodiments, L is a bond. In certain embodiments, L is -CH2-. In certain embodiments, R2a. In certain embodiments, R2a. In certain embodiments, R2a. In certain embodiments, R2a. In certain embodiments, R2a. In certain embodiments, R2a. In certain certain embodiments, R2a. In is H. In certain embodiments, R5is CH3. In certain embodiments, X is NH. In certain embodiments, X is NC(=O)CH3. In certain embodiments, X is O. In certain embodiments, the compound of Formula (I) is a compound of Formula (Ib): - 25 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) . In certain embodiments, the (Ib) is: . In certain embodiments, the (Ib) is: . In certain embodiments, the (Ib) is: . In certain embodiments, the (Ib) is: . In certain embodiments, Ra1Ra1is F. In certain embodiments, Ra2is H. In certain embodiments, Ra2is F. In certain embodiments, Ra3is H. In certain embodiments, Ra3is F. In certain embodiments, Ra4is H. In certain embodiments, Ra4is F. In certain embodiments, Ra5is H. In certain embodiments, Ra5is F. In certain embodiments, at least one of Ra1, Ra2, Ra3, Ra4, and Ra5is H. In certain embodiments, at least two of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least three of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least four of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, each of Ra1, Ra2, Ra3, Ra4, and Ra5is H. is H. In certain embb1 odiments, R is CH3. In certain embodiments, R1. In certain . In certain . - 26 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) In certain embodiments, Rc1is H. In certain embodiments, Rc1is CH3. In certain embodiments, Rc2is H. In certain embodiments, Rc2is CH3. In certain embodiments, Rc3is H. In certain embodiments, Rc3is CH3. In certain embodiments, Rc4is H. In certain embodiments, Rc4is CH3. In certain embodiments, Rc5is H. In certain embodiments, Rc5is CH3. In certain embodiments, at least one of Rc1, Rc2, Rc3, Rc4, and Rc5is H. In certain embodiments, at least two of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least three of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least four of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, each of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, Rb2is H. In certain embodiments, Rb2is CH3. In certain embodiments, L is a bond. In certain embodiments, L is -CH2-. In certain . In certain each independently H. In certain embodiments, R5is CH3. In certain embodiments, R5is phenyl substituted with a halogen. In certain embodiments, R5is 4-chlorophenyl. In certain embodiments, R4is C(=O)CH. In certain embodiments, R4is C(=O)(4- chlorophenyl). In certain embodiments, X is NH. In certain embodiments, X is NC(=O)CH3. In certain embodiments, X is NC(=O)(4-chlorophenyl). In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted methylene, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C2-C12heterocycloalkyl, C1-C6hydroxyalkyl, halogen, CN, NO2, ORI, N(RI)(RII), C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, aryl, heteroaryl, (C1-C6alkylenyl)C(=O)N(RI)(RII), (C1-C6alkylenyl)C(=O)ORI, O(C1-C3alkylenyl)C(=O)ORII, O(C1-C3 alkylenyl)C(=O)N(RI)(RII), C(=O)RI, C(=O)ORI, OC(=O)RI, OC(=O)ORI, SRI, S(=O)RI, S(=O)2RI, S(=O)2N(RI)(RII), S(=O)2NRIC(=O)NHRII, wherein RIand RIIare each of H, -C(=O)(C1-C6alkyl), C1-C6alkyl, C1- C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C12 heterocycloalkyl, C7-C12 aralkyl, - 27 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) aryl, and heteroaryl. In certain embodiments, the compound is selected from the group consisting of: 1-(3-(2-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(2-fluorophenyl)-5-(p-tolyl)-1H-pyrazole; 1-(3-(1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(5-(p-tolyl)-1H-pyrazol-3-yl)-1H-indole; 1-(3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)isoxazole; 3-(1H-indol-3-yl)-5-(p-tolyl)isoxazole; 3-(2-fluorophenyl)-5-(p-tolyl)isoxazole; (4-chlorophenyl)(3-(2-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)methanone; (3-(1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone; (3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)(phenyl)methanone; 3-(5-(m-tolyl)-1H-pyrazol-3-yl)-1H-indole; 1-methyl-3-(5-(m-tolyl)-1H-pyrazol-3-yl)-1H-indole; 3-(5-benzyl-1H-pyrazol-3-yl)-1H-indole; 3-(5-benzyl-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-fluorophenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-fluorophenyl)-1H-pyrazol-3-yl)-1H-indole; 3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)-1H-indole; 3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)-1-methyl-1H-indole; 1-(3-(2-fluorophenyl)-5-(1H-indol-3-yl)-1H-pyrazol-1-yl)ethan-1-one; 1-(3-(2-fluorophenyl)-5-(1-methyl-1H-indol-3-yl)-1H-pyrazol-1-yl)ethan-1-one; 3-(5-(p-tolyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine; 4-(3-(1H-indol-3-yl)-1H-pyrazol-5-yl)benzonitrile; and 3-(5-(p-tolyl)-1H-pyrazol-3-yl)quinoline. In another aspect, the present disclosure provides a compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: - 28 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) ; ; L is selected from the group consisting of optionally substituted methylene and a bond; R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6alkyl and optionally substituted C6-C10 aryl; Ra1, Ra2, Ra3, Ra4, and Ra5are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2- C8 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10 heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1is selected from the group consisting of H and optionally substituted C1-C6 alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10 heteroaryl. In certain embodiments, the compound of Formula (II) is a compound of Formula (IIa): . - 29 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) In certain . In certain . In certain embodiments, the compound of Formula (IIb) is (E)-N'-((1H-indol-3- yl)methylene)-4-methylbenzenesulfonohydrazide. In another aspect, the present disclosure provides a compound of Formula (III), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: ; consisting of optionally substituted methylene and a bond; R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6 alkyl and optionally substituted C6-C10aryl; Ra1, Ra2, Ra3, Ra4, and Ra5are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2- C8 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10 heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1is selected from the group consisting of H and optionally substituted C1-C6 alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting - 30 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) of H, optionally substituted C1-C6 alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10 heteroaryl. In certain embodiments, the compound of Formula (III) is a compound of Formula (IIIa): (IIIa). In certain . In certain . In certain Formula (IIb) is N-(p-tolyl)-1H-indole-3- carboxamide. Table 1. Exemplary compounds Cmpd Structure Name - - 31 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) 1-(3-(1H-indol-3-yl)-5-(p-tolyl)-4,5- 4 dihydro-1H-pyrazol-1-yl)ethan-1-one e - - 32 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) (3-(1-methyl-1H-indol-3-yl)-5-(p- tolyl)-4,5-dihydro-1H-pyrazol-1- - - 33 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) 1-(3-(2-fluorophenyl)-5-(1H-indol-3- yl)-1H-pyrazol-1-yl)ethan-1-one - The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In - 34 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and - 35 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) are not limited to2H,3H,11C,13C,14C,36Cl,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In certain embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as11C,18F,15O, and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. In certain 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. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. - 36 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable. In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react. Typically blocking / protecting groups may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), methyl, ethyl, t-butyl, t- butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), t-butyloxycarbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (trityl), acetyl, and fluorenylmethoxycarbonyl (FMOC). Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. In certain embodiments, a compound of Formula (I) and (IV) can be prepared - 37 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) according to the synthesis described in Scheme 1, wherein R1, R2a, R2b, R3a, R3b, and R4are defined elsewhere herein. ℃, 12 h ; (d) N2H2, EtOH, 85 ℃, 12 h (32-78% yield) Scheme 1. In certain embodiments, a compound of Formula (I) or (IV), including compounds comprising a partially saturated pyrazoles (e.g., compounds 1-4a, 1-5a, and 1-6a) and unsaturated pyrazoles (e.g., compounds 1-4b, 1-5b, 1-6b) can be prepared as shown in Scheme 1. In certain embodiments, the α,β-unsaturated ketone (1-3) can be prepared from the corresponding ketone (1-1) and carbonyl compound (1-2) by an aldol condensation reaction under suitable conditions, including but not limited to a suitable base (e.g., NaOH) and a suitable solvent (e.g., EtOH). In certain embodiments, acetylated dihydropyrazole (1-4a) and / or pyrazole (1-4b) can be prepared from α,β-unsaturated ketone (1-3) under suitable reaction conditions, including but not limited to diazene (i.e., N2H2) in the presence of acetic acid, at a suitable temperature (e.g., 120 ℃). In certain embodiments, acylated dihydropyrazole (1-5a) and / or pyrazole (1- 5b) can be prepared from α,β-unsaturated ketone (1-3) under suitable reaction conditions, including a suitable aryl hydrazide, a suitable acid (e.g., HCl), and a suitable solvent (e.g., EtOH), at a suitable temperature (e.g., 85 ℃). In certain embodiments, dihydropyrazole (1- 6a) and / or pyrazole (1-6b) can be prepared from α,β-unsaturated ketone (1-3) under suitable reaction conditions, including but not limited to diazene (i.e., N2H2) in the presence of a suitable solvent (e.g., EtOH), at a suitable temperature (e.g., 85 ℃). In certain embodiments, in each synthetic transformation provided in Scheme 1 starting from α,β-unsaturated ketone (1-3), one or more of the dihydropyrazole and the pyrazole may be obtained as a product. In certain embodiments, the dihydropyrazole is the - 38 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) major product. In certain embodiments, the pyrazole is the major product. In certain embodiments, the ratio of dihydropyrazole to pyrazole is approximately 1:1. It is further appreciated that compounds of Formula (I) and / or (IV) comprising alternate heterocyclic cores (e.g., isoxazoles) are contemplated within the scope of the present invention, and further, such compounds can be prepared by one of ordinary skill in the art utilizing the methods described herein in combination with reactions known to those in the art without undue experimentation. Methods In another aspect, the present disclosure provides a method of treating, preventing, and / or ameliorating cancer in a subject, the method comprising administering to the subject at least one compound of the present disclosure and / or the pharmaceutical composition of the present disclosure. In another aspect, the present disclosure provides a method of treating, preventing, and / or ameliorating cancer in a subject, the method comprising administering to the subject at least one compound of Formula (IV), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: R1is selected from the group , ; R2ais selected from the group ; - 39 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) R2bis H or absent; R3aand R3bare each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2, wherein R3bcan be present or absent; and X is selected from the group consisting of N(R4) and O; L is selected from the group consisting of optionally substituted methylene and a bond; R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6alkyl and optionally substituted C6-C10 aryl; Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10 heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1and Rb2, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10 heteroaryl; and bond a is a single bond or a double bond, wherein one of the following applies: (a) bond a is a single bond and each of R2a, R2b, R3a, and R3bare present; or (b) bond a is a double bond, R2aand R3aare present, and R2band R3bare absent. In certain embodiments, the compound of Formula (IV) is a compound of Formula (IVa): (IVa). - 40 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) In certain embodiments, Ra1is H. In certain embodiments, Ra1is F. In certain embodiments, Ra2is H. In certain embodiments, Ra2is F. In certain embodiments, Ra3is H. In certain embodiments, Ra3is F. In certain embodiments, Ra4is H. In certain embodiments, Ra4is F. In certain embodiments, Ra5is H. In certain embodiments, Ra5is F. In certain embodiments, at least one of Ra1, Ra2, Ra3, Ra4, and Ra5is H. In certain embodiments, at least two of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least three of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least four of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, each of Ra1, Ra2, Ra3, Ra4, and Ra5is H. In certain at least one of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is H. In certain Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, at least three of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, at least four of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, at least five of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, Rb1is H. In certain embodiments, Rb1is CH3. In certain embodiments, R1. In certain . In certain embodiments, R1. In certain embodiments, R1. In certain . In certain one of Rc1, Rc2 c3 c4 c5 , R , R , and R is H. In certain embodiments, at least two of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least three of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least four of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, each of Rc1, Rc2, Rc3, Rc4, and Rc5is H. In certain embodiments, Rb2is H. In certain embodiments, Rb2is CH3. In certain embodiments, L is a bond. In certain embodiments, L is -CH2-. In certain embodiments, R2a. In certain embodiments, R2a. In certain - 41 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) embodiments, R2a. In certain embodiments, R2a. In certain certain embodiments, R2a. In is H. In is CH3. In certain embodiments, X is NH. In certain embodiments, X is NC(=O)CH3. In certain embodiments, X is O. In certain embodiments, the compound of Formula (IV) is a compound of Formula (IVb): . In certain embodiments, the (IVb) is: . In certain embodiments, (IVb) is: . In certain embodiments, (IVb) is: . In certain embodiments, (IVb) is: . In certain embodiments, Ra1is F. In certain embodiments, Ra2is H. In certain embodiments, Ra2is F. In certain embodiments, Ra3is H. In certain embodiments, Ra3is F. In certain embodiments, Ra4is H. In certain embodiments, Ra4- 42 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) is F. In certain embodiments, Ra5is H. In certain embodiments, Ra5is F. In certain embodiments, at least one of Ra1, Ra2, Ra3, Ra4, and Ra5is H. In certain embodiments, at least two of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least three of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least four of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, each of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, Rb1is H. In certain embodiments, Rb1is CH3. In certain embodiments, R1. In certain . In certain . In certain In certain embodiments, Rc1is CH3. In certain embodiments, Rc2 is H. Rc2is CH3. In certain embodiments, Rc3is H. In certain embodiments, Rc3is CH3. In certain embodiments, Rc4is H. In certain embodiments, Rc4is CH3. In certain embodiments, Rc5is H. In certain embodiments, Rc5is CH3. In certain embodiments, at least one of Rc1, Rc2, Rc3, Rc4, and Rc5is H. In certain embodiments, at least two of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least three of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least four of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, each of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, Rb2is H. In certain embodiments, Rb2is CH3. In certain embodiments, L is a bond. In certain embodiments, L is -CH2-. . each independently H. In certain embodiments, R5is CH3. In certain embodiments, R5is phenyl substituted with a halogen. In certain embodiments, R5is 4-chlorophenyl. In certain embodiments, R4is C(=O)CH. In certain embodiments, R4is C(=O)(4- chlorophenyl). In certain embodiments, X is NH. In certain embodiments, X is NC(=O)CH3. In certain embodiments, X is NC(=O)(4-chlorophenyl). In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted methylene, optionally substituted alkenyl, - 43 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C2-C12heterocycloalkyl, C1-C6hydroxyalkyl, halogen, CN, NO2, ORI, N(RI)(RII), C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, aryl, heteroaryl, (C1-C6alkylenyl)C(=O)N(RI)(RII), (C1-C6alkylenyl)C(=O)ORI, O(C1-C3alkylenyl)C(=O)ORII, O(C1-C3 alkylenyl)C(=O)N(RI)(RII), C(=O)RI, C(=O)ORI, OC(=O)RI, OC(=O)ORI, SRI, S(=O)RI, S(=O)2RI, S(=O)2N(RI)(RII), S(=O)2NRIC(=O)NHRII, N(RI)S(=O)2RII, N(RI)C(=O)RII, and C(=O)NRIRII, wherein RIand RIIare each independently selected from the group consisting of H, -C(=O)(C1-C6alkyl), C1-C6alkyl, C1- C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C12 heterocycloalkyl, C7-C12 aralkyl, aryl, and heteroaryl. In certain embodiments, the compound is selected from the group consisting of: (2-fluorophenyl)(5-(2-fluorophenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)methanone; 3-(5-phenyl-1H-pyrazol-3-yl)-1H-indole; 1-(3-(2-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(2-fluorophenyl)-5-(p-tolyl)-1H-pyrazole; 1-(3-(1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(5-(p-tolyl)-1H-pyrazol-3-yl)-1H-indole; 1-(3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)isoxazole; 3-(1H-indol-3-yl)-5-(p-tolyl)isoxazole; 3-(2-fluorophenyl)-5-(p-tolyl)isoxazole; (4-chlorophenyl)(3-(2-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)methanone; (3-(1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone; (3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)(phenyl)methanone; 3-(5-(m-tolyl)-1H-pyrazol-3-yl)-1H-indole; 1-methyl-3-(5-(m-tolyl)-1H-pyrazol-3-yl)-1H-indole; 3-(5-benzyl-1H-pyrazol-3-yl)-1H-indole; 3-(5-benzyl-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-fluorophenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; - 44 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) 3-(5-(2-fluorophenyl)-1H-pyrazol-3-yl)-1H-indole; 3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)-1H-indole; 3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)-1-methyl-1H-indole; 1-(3-(2-fluorophenyl)-5-(1H-indol-3-yl)-1H-pyrazol-1-yl)ethan-1-one; 1-(3-(2-fluorophenyl)-5-(1-methyl-1H-indol-3-yl)-1H-pyrazol-1-yl)ethan-1-one; 3-(5-(p-tolyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine; 4-(3-(1H-indol-3-yl)-1H-pyrazol-5-yl)benzonitrile; and 3-(5-(p-tolyl)-1H-pyrazol-3-yl)quinoline. In certain embodiments, the cancer is of the lung. In certain embodiments, the cancer is of the pancreas. In certain embodiments, the cancer is of the bladder. In certain embodiments, the cancer is of the blood. In certain embodiments, the cancer is of the bone. In certain embodiments, the cancer is of the bone marrow. In certain embodiments, the cancer is of the brain. In certain embodiments, the cancer is of the breast. In certain embodiments, the cancer is of the colon. In certain embodiments, the cancer is of the esophagus. In certain embodiments, the cancer is of the gastrointestine. In certain embodiments, the cancer is of the gum. In certain embodiments, the cancer is of the head. In certain embodiments, the cancer is of the kidney. In certain embodiments, the cancer is of the liver. In certain embodiments, the cancer is of the nasopharynx. In certain embodiments, the cancer is of the neck. In certain embodiments, the cancer is of the ovary. In certain embodiments, the cancer is of the prostate. In certain embodiments, the cancer is of the skin. In certain embodiments, the cancer is of the stomach. In certain embodiments, the cancer is of the testis. In certain embodiments, the cancer is of the tongue. In certain embodiments, the cancer is of the uterus. In certain embodiments, the cancer comprise a receptor tyrosine kinase (RTK) driven cancer and / or Ras driven cancer. In certain embodiments, the at least one compound selectively inhibits a DHHC enzyme. In certain embodiments, the DHHC enzyme is DHHC20. In certain embodiments, the DHHC enzyme is selectively inhibited over kinesin spindle protein (KSP). In certain embodiments, EGFR palmitoylation is inhibited. In certain embodiments, the subject is administered at least one additional agent. In certain embodiments, the at least one additional agent is selected from the group consisting of an EGFR inhibitor, KRasG12Cinhibitor, a PI3K inhibitor, a RAF inhibitor, and a cytotoxic agent. In certain embodiments, the EGFR inhibitor is at least one selected from the group consisting of gefitinib, afatinib, erlotinib, osimertinib, neratinib, cetuximab, panitumumab, - 45 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) dacomitinib, lapatinib, necitumumab, mobocertinib, and vandetanib. In certain embodiments, the KRasG12Cinhibitor is at least one selected from the group consisting of adagrasib (MRTX849), sotorasib (AMG510), ARS-853, ARS-1620, JNJ- 74699157 (ARS-3248), LY3499446 / LY3537982, GDC-6036, D-1553, JDQ443, and BI1823911. In certain embodiments, the PI3K inhibitor is at least one selected from the group consisting of aliqopa, alpelisib, copanlisib, copiktra, duvelisib, idelalisib, piqray, ukoniq, umbralisib, zydelig, buparlisib, dactolisib, leniolisib, parsaclisib, paxalisib, taselisib, inavolisib, apitolisib, bimiralisib, eganelisib, fimepinostat, gedatolisib, linperlisib, nemairilisib, pictilisib, pilaralisib, samotolisib, seletalisib, serabelisib, sonolisib, tenalisib, voxtalisib, AMG 319, AZD8186, GSK2636771, and SF1126. In certain embodiments, the RAF inhibitor is at least one selected from the group consisting of PLX4720, PLX4032, BAY 43-9006 (sorafenib), vemurafenib (zelboraf), dabrafenib (tafinlar), encorafenib (braftovi), cobimetinib (cotellic), binimetinib (mektovi), ZM 336372, RAF 265, AAL-881, LBT-613 (Novartis), and CJS352. PLX4720, PLX4032, BAY 43-9006 (sorafenib), ZM 336372, and RAF 265. In certain embodiments, the cytotoxic agent is at least one selected from the group consisting of paclitaxel, doxorubicin, cyclophosphamide, methotrexate, fluorouracil, cisplatin, carboplatin, vinblastine, vincristine, etoposide, bleomycin, mitomycin c, gemcitabine, irinotecan, topotecan, docetaxel, camptothecin, melphalan, busulfan, chlorambucil, dacarbazine, procarbazine, temozolomide, bendamustine, oxaliplatin, ifosfamide, lomustine, streptozocin, daunorubicin, idarubicin, fludarabine, cladribine, pentostatin, mercaptopurine, azathioprine, hydroxyurea, thiotepa, mitoxantrone, teniposide, cytarabine, decitabine, clofarabine, nelarabine, azacytidine, eribulin, cabazitaxel, liposomal doxorubicin, pegylated liposomal doxorubicin, trabectedin, and ixabepilone. In certain embodiments, the subject is further subjected to trans-arterial chemoembolization (TACE) or trans-arterial embolization (TAE). In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. In another aspect, the disclosure provides a method for treating a tumor in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of at least one compound of the disclosure and performing transarterial embolization (TAE) or transarterial chemoembolization (TACE) on the subject. In certain embodiments, the administration of the compound of the disclosure and the embolization are - 46 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) performed in combination. In another aspect, the present disclosure provides a method of inhibiting palmitoylation in a subject, the method comprising administering to the subject at least one compound of the present disclosure and / or the pharmaceutical composition of the present disclosure. In another aspect, the present disclosure provides a method of inhibiting palmitoylation in a subject, the method comprising administering to the subject at least one compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: R1is selected from the group , ; R2ais selected from the group ; R2bis H or absent; R3aand R3bare each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2, wherein R3bcan be present or absent; and X is selected from the group consisting of N(R4) and O; L is selected from the group consisting of optionally substituted methylene and a bond; - 47 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6alkyl and optionally substituted C6-C10 aryl; Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1and Rb2, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl; and bond a is a single bond or a double bond, wherein one of the following applies: (a) bond a is a single bond and each of R2a, R2b, R3a, and R3bare present; or (b) bond a is a double bond, R2aand R3aare present, and R2band R3bare absent. In certain embodiments, the compound of Formula (IV) is a compound of Formula (IVa): (IVa). In certain embodiments, Ra1is H. In certain embodiments, Ra1is F. In certain embodiments, Ra2is H. In certain embodiments, Ra2is F. In certain embodiments, Ra3is H. In certain embodiments, Ra3is F. In certain embodiments, Ra4is H. In certain embodiments, Ra4is F. In certain embodiments, Ra5is H. In certain embodiments, Ra5is F. In certain embodiments, at least one of Ra1, Ra2, Ra3, Ra4, and Ra5is H. In certain embodiments, at least two of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least three of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least four of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, each of Ra1, Ra2, Ra3, Ra4, and Ra5is H. - 48 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) In certain embodiments, at least one of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is H. In certain embodiments, at least two of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, at least three of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, at least four of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, at least five of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H. In certain embodiments, Rb1is H. In certain embodiments, Rb1is CH3. In certain embodiments, R1. In certain . In certain embodiments, R1. In certain embodiments, R1. In certain . In certain one of Rc1, Rc2, Rc3, Rc4, and Rc5is H. In certain embodiments, at least two of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least three of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least four of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, each of Rc1, Rc2, Rc3, Rc4, and Rc5is H. In certain embodiments, Rb2is H. In certain embodiments, Rb2is CH3. In certain embodiments, L is a bond. In certain embodiments, L is -CH2-. In certain embodiments, R2a. In certain embodiments, . In certain embodiments, R2a. In certain embodiments, R2a. In certain certain embodiments, R2ais . In is H. In certain embodiments, R5is CH3. In certain embodiments, X is NH. In certain embodiments, X is NC(=O)CH3. In - 49 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) certain embodiments, X is O. In certain embodiments, the compound of Formula (IV) is a compound of Formula (IVb): . In certain embodiments, the (IVb) is: . In certain embodiments, (IVb) is: . In certain embodiments, (IVb) is: . In certain embodiments, (IIb) is: . In certain embodiments,a1 R is F. In certain embodiments, Ra2is H. In certain embodiments, Ra2is F. In certain embodiments, Ra3is H. In certain embodiments, Ra3is F. In certain embodiments, Ra4is H. In certain embodiments, Ra4is F. In certain embodiments, Ra5is H. In certain embodiments, Ra5is F. In certain embodiments, at least one of Ra1, Ra2, Ra3, Ra4, and Ra5is H. In certain embodiments, at least two of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least three of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, at least four of Ra1, Ra2, Ra3, Ra4, and Ra5are H. In certain embodiments, each of Ra1, Ra2, Ra3, Ra4, and Ra5is H. In certain embodiments, Rb1is H. In certain embodiments, Rb1is CH3. - 50 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) In certain embodiments, R1. In certain . In certain . In certain H. In certain embodiments, Rc1is CH3. In certain odiments, Rc2 emb is H. Rc2is CH3. In certain embodiments, Rc3is H. In certain embodiments, Rc3is CH3. In certain embodiments, Rc4is H. In certain embodiments, Rc4is CH3. In certain embodiments, Rc5is H. In certain embodiments, Rc5is CH3. In certain embodiments, at least one of Rc1, Rc2, Rc3, Rc4, and Rc5is H. In certain embodiments, at least two of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least three of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, at least four of Rc1, Rc2, Rc3, Rc4, and Rc5are H. In certain embodiments, each of Rc1, Rc2, Rc3, Rc4, and Rc5is H. is H. In certain embodiments, Rb2is CH3. a bond. In certain embodiments, L is -CH2-. In certain . In certain each independently H. In certain embodiments, R5is CH3. In certain embodiments, R5is phenyl substituted with a halogen. In certain embodiments, R5is 4-chlorophenyl. In certain embodiments, R4is C(=O)CH. In certain embodiments, R4is C(=O)(4- chlorophenyl). In certain embodiments, X is NH. In certain embodiments, X is NC(=O)CH3. In certain embodiments, X is NC(=O)(4-chlorophenyl). In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted methylene, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C12 heterocycloalkyl, C1-C6 hydroxyalkyl, halogen, CN, NO2, ORI, N(RI)(RII), C1-C6haloalkoxy, C3-C8halocycloalkoxy, aryl, heteroaryl, (C1-C6 alkylenyl)C(=O)N(RI)(RII), (C1-C6 alkylenyl)C(=O)ORI, O(C1-C3 - 51 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) alkylenyl)C(=O)ORII, O(C1-C3 alkylenyl)C(=O)N(RI)(RII), C(=O)RI, C(=O)ORI, OC(=O)RI, OC(=O)ORI, SRI, S(=O)RI, S(=O)2RI, S(=O)2N(RI)(RII), S(=O)2NRIC(=O)NHRII, N(RI)S(=O)2RII, N(RI)C(=O)RII, and C(=O)NRIRII, wherein RIand RIIare each independently selected from the group consisting of H, -C(=O)(C1-C6alkyl), C1-C6alkyl, C1- C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C12 heterocycloalkyl, C7-C12 aralkyl, aryl, and heteroaryl. In certain embodiments, the compound is selected from the group consisting of: (2-fluorophenyl)(5-(2-fluorophenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone; 3-(5-phenyl-1H-pyrazol-3-yl)-1H-indole; 1-(3-(2-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(2-fluorophenyl)-5-(p-tolyl)-1H-pyrazole; 1-(3-(1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(5-(p-tolyl)-1H-pyrazol-3-yl)-1H-indole; 1-(3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)isoxazole; 3-(1H-indol-3-yl)-5-(p-tolyl)isoxazole; 3-(2-fluorophenyl)-5-(p-tolyl)isoxazole; (4-chlorophenyl)(3-(2-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone; (3-(1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone; (3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone; 3-(5-(m-tolyl)-1H-pyrazol-3-yl)-1H-indole; 1-methyl-3-(5-(m-tolyl)-1H-pyrazol-3-yl)-1H-indole; 3-(5-benzyl-1H-pyrazol-3-yl)-1H-indole; 3-(5-benzyl-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-fluorophenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-fluorophenyl)-1H-pyrazol-3-yl)-1H-indole; 3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)-1H-indole; 3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)-1-methyl-1H-indole; 1-(3-(2-fluorophenyl)-5-(1H-indol-3-yl)-1H-pyrazol-1-yl)ethan-1-one; 1-(3-(2-fluorophenyl)-5-(1-methyl-1H-indol-3-yl)-1H-pyrazol-1-yl)ethan-1-one; 3-(5-(p-tolyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine; 4-(3-(1H-indol-3-yl)-1H-pyrazol-5-yl)benzonitrile; and 3-(5-(p-tolyl)-1H-pyrazol-3-yl)quinoline. In certain embodiments, palmitoylation of EGFR is inhibited. - 52 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) In certain embodiments, a palmitoyl transferase is inhibited. In certain embodiments, the palmitoyl transferase is DHHC20. In certain embodiments, the palmitoyl transferase is selectively inhibited. In certain embodiments, the palmitoyl transferase is selectively inhibited over kinesin spindle protein (KSP). In certain embodiments, the subject is administered at least one additional agent. In certain embodiments, the at least one additional agent is selected from the group consisting of an EGFR inhibitor, KRasG12Cinhibitor, a PI3K inhibitor, a RAF inhibitor, and a cytotoxic agent. In certain embodiments, the EGFR inhibitor is at least one selected from the group consisting of gefitinib, afatinib, erlotinib, osimertinib, neratinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, and vandetanib. In certain embodiments, the KRasG12Cinhibitor is at least one selected from the group consisting of adagrasib (MRTX849), sotorasib (AMG510), ARS-853, ARS-1620, JNJ- 74699157 (ARS-3248), LY3499446 / LY3537982, GDC-6036, D-1553, JDQ443, and BI1823911. In certain embodiments, the PI3K inhibitor is at least one selected from the group consisting of aliqopa, alpelisib, copanlisib, copiktra, duvelisib, idelalisib, piqray, ukoniq, umbralisib, zydelig, buparlisib, dactolisib, leniolisib, parsaclisib, paxalisib, taselisib, inavolisib, apitolisib, bimiralisib, eganelisib, fimepinostat, gedatolisib, linperlisib, nemairilisib, pictilisib, pilaralisib, samotolisib, seletalisib, serabelisib, sonolisib, tenalisib, voxtalisib, AMG 319, AZD8186, GSK2636771, and SF1126. In certain embodiments, the RAF inhibitor is at least one selected from the group consisting of PLX4720, PLX4032, BAY 43-9006 (sorafenib), vemurafenib (zelboraf), dabrafenib (tafinlar), encorafenib (braftovi), cobimetinib (cotellic), binimetinib (mektovi), ZM 336372, RAF 265, AAL-881, LBT-613 (Novartis), and CJS352. PLX4720, PLX4032, BAY 43-9006 (sorafenib), ZM 336372, and RAF 265. In certain embodiments, the cytotoxic agent is at least one selected from the group consisting of paclitaxel, doxorubicin, cyclophosphamide, methotrexate, fluorouracil, cisplatin, carboplatin, vinblastine, vincristine, etoposide, bleomycin, mitomycin c, gemcitabine, irinotecan, topotecan, docetaxel, camptothecin, melphalan, busulfan, chlorambucil, dacarbazine, procarbazine, temozolomide, bendamustine, oxaliplatin, ifosfamide, lomustine, streptozocin, daunorubicin, idarubicin, fludarabine, cladribine, pentostatin, mercaptopurine, azathioprine, hydroxyurea, thiotepa, mitoxantrone, teniposide, cytarabine, decitabine, clofarabine, nelarabine, azacytidine, eribulin, cabazitaxel, liposomal - 53 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) doxorubicin, pegylated liposomal doxorubicin, trabectedin, and ixabepilone. In certain embodiments, the subject is further subjected to trans-arterial chemoembolization (TACE) or trans-arterial embolization (TAE). In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. Pharmaceutical Compositions In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition further comprises at least one additional agent. In certain embodiments, the at least one additional agent is selected from the group consisting of an EGFR inhibitor, KRasG12Cinhibitor, a PI3K inhibitor, a RAF inhibitor, and a cytotoxic agent. In certain embodiments, the EGFR inhibitor is at least one selected from the group consisting of gefitinib, afatinib, erlotinib, osimertinib, neratinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, and vandetanib. In certain embodiments, the KRasG12Cinhibitor is at least one selected from the group consisting of adagrasib (MRTX849), sotorasib (AMG510), ARS-853, ARS-1620, JNJ- 74699157 (ARS-3248), LY3499446 / LY3537982, GDC-6036, D-1553, JDQ443, and BI1823911. In certain embodiments, the PI3K inhibitor is at least one selected from the group consisting of aliqopa, alpelisib, copanlisib, copiktra, duvelisib, idelalisib, piqray, ukoniq, umbralisib, zydelig, buparlisib, dactolisib, leniolisib, parsaclisib, paxalisib, taselisib, inavolisib, apitolisib, bimiralisib, eganelisib, fimepinostat, gedatolisib, linperlisib, nemairilisib, pictilisib, pilaralisib, samotolisib, seletalisib, serabelisib, sonolisib, tenalisib, voxtalisib, AMG 319, AZD8186, GSK2636771, and SF1126. In certain embodiments, the RAF inhibitor is at least one selected from the group consisting of PLX4720, PLX4032, BAY 43-9006 (sorafenib), vemurafenib (zelboraf), dabrafenib (tafinlar), encorafenib (braftovi), cobimetinib (cotellic), binimetinib (mektovi), ZM 336372, RAF 265, AAL-881, LBT-613 (Novartis), and CJS352. PLX4720, PLX4032, BAY 43-9006 (sorafenib), ZM 336372, and RAF 265. In certain embodiments, the cytotoxic agent is at least one selected from the group consisting of paclitaxel, doxorubicin, cyclophosphamide, methotrexate, fluorouracil, - 54 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) cisplatin, carboplatin, vinblastine, vincristine, etoposide, bleomycin, mitomycin c, gemcitabine, irinotecan, topotecan, docetaxel, camptothecin, melphalan, busulfan, chlorambucil, dacarbazine, procarbazine, temozolomide, bendamustine, oxaliplatin, ifosfamide, lomustine, streptozocin, daunorubicin, idarubicin, fludarabine, cladribine, pentostatin, mercaptopurine, azathioprine, hydroxyurea, thiotepa, mitoxantrone, teniposide, cytarabine, decitabine, clofarabine, nelarabine, azacytidine, eribulin, cabazitaxel, liposomal doxorubicin, pegylated liposomal doxorubicin, trabectedin, and ixabepilone. Administration / Dosage / Formulations The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of the disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat the disease or disorder in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat the disease or disorder in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non- limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the - 55 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound. In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent - 56 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) which delays absorption, for example, aluminum monostearate or gelatin. In certain embodiments, the compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account. The compound(s) described herein for administration may be in the range of from about 1 µg to about 10,000 mg, about 20 µg to about 9,500 mg, about 40 µg to about 9,000 mg, about 75 µg to about 8,500 mg, about 150 µg to about 7,500 mg, about 200 µg to about 7,000 mg, about 350 µg to about 6,000 mg, about 500 µg to about 5,000 mg, about 750 µg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween. In some embodiments, the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or - 57 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) partial increments thereof. In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, or reduce one or more symptoms of a disease or disorder in a patient. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. Routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain - 58 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid). Parenteral Administration For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used. Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's - 59 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol. Additional Administration Forms Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757. Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations described herein can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form. For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation. In some cases, the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl - 60 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein. Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects. Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled-release component" is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug - 61 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration. The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration. Dosing The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of the disease or disorder in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. - 62 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compound(s) described herein is optionally 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%. Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and / or infection. The compounds described herein can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, - 63 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure of the present disclosure as set forth herein. EXAMPLES Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein. Example 1: Small molecule inhibitors of EGFR palmitoylation may significantly impact treatment of cancer The certainty with which cancer cells evolve resistance to effective targeted therapies makes identifying new therapeutic strategies of paramount importance. Previous studies have indicated that the transferase that palmitoylates EGFR, DHHC20, may be an important vulnerability in lung cancer. Thus, small molecule inhibitors of DHHC20 possess therapeutic potential. Recent in vivo studies demonstrated that palmitoyl transferase DHHC20 is essential for Kras driven lung tumorigenesis in a genetically engineered mouse model (FIG.1A). Similarly, induced silencing of DHHC20 by shRNA blocks the growth of existing human lung tumors in xenograft mouse models (FIG.1B). This requirement for DHHC20 appears to be specific for cancer cells since a full body knock out of DHHC20 in mice is homozygous viable. In lung cancer patients, the deletion or mutation of either DHHC20 or DHHC14 - 64 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) corelates with improved patient survival in tumors with activating Kras mutations compared to Kras wild type tumors (FIG.1C). Lastly, inhibiting DHHC20 expression increases the sensitivity of cancer cells to the EGFR inhibitor gefitinib irrespective of EGFR mutation status (FIG.1D). These findings highlight the potential of targeting specific palmitoyl transferases in cancer. The therapeutic impact of these findings is significant and indicates that small molecule inhibitors of EGFR palmitoylation could have significant impact on patients. S-Palmitoylation is the reversible addition of the 16-carbon fatty acid palmitate to cysteine residues, which mediates the membrane localization of a variety of proteins most notably specific isoforms of Ras (e.g., Nras, Hras and Kras) to the plasma membrane. The requirement of membrane localization for Ras signaling has seeded interest in identifying small molecules that inhibit lipid modification of Ras including early attempts with farnesyl- transferase inhibitors and very recently a palmitoylation inhibitor artemisinin. A family of 23 protein acyl transferases (PATs) containing the DHHC catalytic motif mediates the addition of palmitate to protein substrates. However, the specificity between DHHC enzyme-substrate pairs and the recognition of specific amino acid sequences has not been well studied due to lack of tools. EGFR is a known driver of multiple cancer types including lung cancer and glioblastoma where it is frequently mutated or overexpressed. The ErbB family of receptor tyrosine kinases (RTKs) that include EGFR and Her2 are also some of the most successful examples of targeted therapies for cancers. Multiple generations of EGFR and Her2 inhibitors have been developed that are used clinically against many cancer types. Unfortunately, with each new drug that is developed, mutations in EGFR evolve causing resistance. Therefore, new approaches to target this important class of receptors are urgently needed. EGFR is S-palmitoylated on the C-terminal domain (CTD) by DHHC20 in cancer cells. Palmitoylation sites were mapped on the CTD of EGFR to cysteine 1025 and cysteine 1034 using mass spectrometry. When cysteine 1025 is mutated to alanine, palmitoylation is reduced (FIG.2A) and EGFR autophosphorylation on tyrosine residues 1068, 1173 and phosphorylation of downstream effector ERK are all increased (FIG.3A). Expression of EGFRC1025Ain NIH3T3 cells have no effect on cell proliferation (FIG. 2B). In contrast, in NIH3T3 cells expressing KrasG12V, cells expression of EGFRC1025Areduces cell proliferation compared to cells expressing wild type EGFR (FIG.2C), highlighting this synthetic lethality and EGFR / Kras crosstalk. Finally, palmitoylation of the CTD of EGFR increases binding of the Grb2 adaptor which increases MAPK signaling, but - 65 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) decreases PI3K (p85) association with EGFR at the membrane, resulting in decreased PI3K signaling (FIG.2D). Stimulation with EGF increases EGFR palmitoylation and reducing DHHC20 expression or mutating one of the palmitoylation sites increases EGFR signaling in response to EGF (FIG.3A). Of clinical importance cysteine residue 1025 is located within exon 26, which is deleted in lung adenocarcinoma and glioblastoma (FIG.3B). The exon deletions are activating mutations and confirm in human patients the clinical importance of the palmitoylated peptide sequence as a negative regulator of EGFR signaling. Expression of EGFRC1025Ain the KrasG12D; p53- / -genetically engineered mouse model of lung cancer decreases tumor burden. It has been hypothesized the inhibition of tumor growth is caused by synthetic lethality between active EGFRC1025and Kras since a similar effect is observed with constitutively active EGFRL858Rmutant that has been reported by other groups (FIG.3C). Inhibiting EGFR palmitoylation is therefore an enticing strategy to exploit this Kras EGFR synthetic lethality. Example 2: Mechanisms of Kras tumor inhibition by DHHC20 loss Initial characterization of DHHC20 loss in lung cancer cells revealed c-Myc protein expression is reduced (FIG.4A). Myc is required for cell growth and dysregulated in over 50% of cancers. Under normal conditions c-Myc protein is targeted for proteosomal degradation by GSK3β phosphorylation. Myc can be stabilized by deposition of an inhibitory phosphorylation on GSK3β by AKT, downstream of PI3K. It has been demonstrated that the entire PI3K-AKT-GSK3β pathway is suppressed when DHHC20 is genetically inhibited leading to decreased c-Myc levels (FIG.4A). Expression of a stabilized c-Myc mutant (T58A) is sufficient to restore cell growth in DHHC20 knockdown cells (FIG.4B). c-Myc expression is also decreased when a palmitoylation resistant EGFR mutant is expressed in Kras mutant cells confirming the mechanism is regulated by EGFR palmitoylation (FIG.4C). Additionally, DHHC20 inhibition exploits Kras mutant tumors dependency on autophagy to survive. Autophagy allows tumor cells to survive and grow under low nutrient conditions by degrading cellular material and organelles in the lysosome to provide energy and macromolecular precursors. It has been demonstrated herein that shDHHC20 lung cancer cells have decreased survival under amino acid deprivation conditions, under which autophagy is induced (FIG.5A). Amino acid deprivation also reduces autophagic flux measured by autophagy marker LC3iii levels (FIG.5B). Reducing DHHC20 expression blocks autophagy signaling at an early step by reducing the activating phosphorylation of - 66 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) Beclin1, a component of the autophagy activation complex, on serine 93 (FIG.5C). There is heightened interest in inhibiting autophagy in combination with both targeted therapeutics and conventional chemotherapy to increase the efficacy of treatment based on nutrient deprivation in the tumor microenvironment. It has been hypothesized that the inhibition of tumor growth is caused by inhibition of both PI3K signaling and autophagy in lung cancer. Inhibiting EGFR palmitoylation is therefore a unique strategy to simultaneously inhibit both Myc expression and autophagy, which are key dependencies for Kras driven tumor growth. Example 3: DHHC loss correlates with improved survival of Kras mutant NSCLC patients Considering the mechanistic requirement for ZDHHC20 demonstrated in mouse models of lung adenocarcinoma (LUAD), correlative evidence implicating ZDHHC20 loss being protective in human lung cancer was sought by examining LUAD patient data in The Cancer Genome Atlas. Deletions in ZDHHC20 were present in 2% of patients, and when patients with wild type Kras were compared to patients with Kras altered patients harboring activating mutations or amplifications where ZDHHC20 is also deleted, a significant increase in survival in the Kras altered patients was found. Upon further examination of the TCGA database it was found that ZDHHC14 is also deleted in 1.2% of LUAD, and this also conferred similar survival benefits in Kras mutant lung cancer patients (FIG.26A). Evidence of a protective function of ZDHHC20 loss in human patients, specifically those harboring activating Kras alterations, aligns with in vivo mouse studies that demonstrate ZDHHC20 loss inhibits Kras driven tumorigenesis and was further motivation to develop small molecule inhibitors to the enzyme. Considering the challenges related to the unique properties of the enzyme, it was reasoned identifying a specific inhibitor would require assays in intact cells to capture the protein in its native state. Example 4: Design and validation of small molecule inhibitors of EGFR palmitoylation As indicated elsewhere herein, the development of small molecule inhibitors of DHHC enzymes, opens the door to drug discovery efforts in this area which has significant therapeutic potential for RTK and Ras driven cancers. The present disclosure describes the repurposing of several drugs for inhibition of EGFR palmitoylation. The first candidate was Paclitaxel (PTX) that is commonly used in combination with EGFR inhibitors to treat NSCLC. Treatment of NSCLC cells with PTX for - 67 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) 15 hours reduces EGFR palmitoylation dose dependently starting at 20 nM. The DepMap database was examined for correlations between DHHC enzyme expression and effect of PTX treatment and it was found that the effect correlated with DHHC11 expression specifically in cells where DHHC23 is damaged. Protein palmitoylation is measured by the acyl-biotinyl exchange (ABE) assay (FIG.6A). It was confirmed that DHHC11 and DHHC23 increase EGFR palmitoylation when overexpressed in H1975 lung cancer cells (FIG.6B). Precomputed correlations generated by DepMap were used to identify multiple compounds with the same correlation observed with PTX. One candidate (i.e., filanesib) (FIG.6C and FIG.7A), the kinesin spindle protein (KSP) inhibitor, also reduced EGFR palmitoylation in H1975 cells (FIG.6D). The effect is not likely due to an indirect effect of blocking mitosis through KSP inhibition since inhibition occurred within 30 minutes. This repurposed drug was then used as a template to find structurally similar compounds that can be chemically modified and optimized to be specific for DHHC enzymes of interest. Using Rapid Overlay of Chemicals Shape (ROCS) computational methods, the NIH Molecular Libraries Small Molecule Repository of approx.350K compounds was searched and three small molecule compounds were identified which possess no known biological function, and which share 3D structural similarities with filanesib (FIGs.7A-7B). Crucially the pendant amine in filanesib (FIG.7A) is critical to its activity as an inhibitor of KSP. Thus, the 3-aminopropyl group was excluded from the shape searching query to provide compounds with differentiated activity, resulting in 3 compounds as hit compounds (e.g. compound 1) (FIG.7B). These compounds were tested in the acyl-biotinyl exchange (ABE) assay (FIG.6A) to measure EGFR palmitoylation in H1975 lung cancer cells. Preliminary results indicate two of these compounds inhibit EGFR palmitoylation at concentrations as low as 1 μM after treatment for 1 hour with compound 1 being the most potent (FIG.8A). Importantly, these structurally related compounds begin to outline the structure-activity relationships (SAR) for inhibition of EGFR palmitoylation (FIG.8A). Based on the SAR studies described herein, SD-042 and SD-066-4 were synthesized and found to inhibit EGFR palmitoylation (FIG.8B). A second chemotype of compounds was also identified with no structural similarity, but which also induces a similar effect on EGFR palmitoylation. Crucially, the Cellular Thermal Shift Assay (CETSA) has also been used to confirm that SD-066-4 engages DHHC20 in situ (FIG.8C). Additionally, the present compounds appear to have little to no effect on RAS palmitoylation therefore indicating they have some selectivity for different DHHC enzymes (FIG.9A). - 68 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) To further explore the SAR of this class of compounds, a synthetic route for the preparation of analogue was designed and validated. Using this synthetic route, a number of compounds have been prepared and evaluated, wherein compounds with increased potency. Several compounds have been prepared, and at least one of such compounds (i.e., SD-066-4), possess sub-micromolar antiproliferative activity in an ABE assay, and displays low micromolar antiproliferative activity against H1975 cells (FIG.9B). Crucially, it has also been demonstrated that these filanesib inspired compounds no longer inhibit kinesin spindle protein (KSP) as evidence by their inability to inhibit centrosome separation (FIG.10). Example 5: Repurposing existing drugs to inhibit EGFR S-acylation A chemo-proteomic screen of proteins that bound the drug ingenol-mebutate (IngMeb) in live cells identified ZDHHC13 as a potential protein target, but the candidate was not studied further. IngMeb is a natural product from the plant Euphorbia peplus that is used topically to treat actinic keratosis, a precancerous skin condition. It was found that 1nM IngMeb inhibited EGFR S-acylation within one hour of treatment (FIG.26B). Based on the TCGA analysis, it was reasoned that ZDHHC14 might be partially redundant with ZDHHC20 and that Kras mutant cell lines with low ZDHHC14 levels may be more sensitive to IngMeb. Using the DepMap database it was found that the sensitivity of LUAD cell lines to IngMeb correlated negatively with ZDHHC14 mRNA expression levels, and this correlation was exclusive to the Kras mutant LUAD cell lines (FIG.26C). Next, DepMap was searched for compounds with a similar correlation in Kras mutant LUAD cell lines. The search identified the inhibitor of the kinesis spindle protein (KSP), filanesib, with a similar correlation with ZDHHC14 mRNA levels as IngMeb in Kras mutant LUAD cell lines (FIG.26D). Treatment of cells with nanomolar concentrations of filanesib inhibited EGFR S- acylation (FIG.26E). For both IngMeb and filanesib there was no statistically significant correlation between drug effect and ZDHHC14 expression in Kras wild type cell lines (FIGs.26C-26D). Unlike the natural product IngMeb, filanesib is a synthetic molecule with a simpler chemical structure and synthesis pathway (FIG.26F). To determine if filanesib directly binds ZDHHC20, the cellular thermal shift assay (CeTSA) was used, reasoning that the CeTSA would ensure capture of the relevant conformation of ZDHHC20 in live cells. The CeTSA revealed treatment of ZDHHC20-V5 expressing cells with filanesib increased the Tm of ZDHHC20- V5 compared to cells treated with the vehicle control (DMSO) (FIGs.26G-26H). Filanesib treatment did not change the Tm of the negative control actin (FIGs.26G-26H). Next, - 69 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) filanesib was used as a template to find structurally similar compounds that can be chemically modified and optimized to be specific for DHHC enzymes of interest. Example 6: In vitro characterization of EGFR palmitoylation inhibitors While DHHC20 is challenging to purify and study, as it is a 4-pass transmembrane protein, Cellular Thermal Shift Assay (CTSA) can be used to assess the change in melting temperature (Tm) of the protein upon ligand binding, and thus represents a means to assess ligand binding. Preliminary results demonstrated that SD-066-4 (10 µM) significantly shifts the unfolding temperature of DHHC20, which is indicative of a direct binding interaction. In this experiment, as a control, actin was immunoblotted and a change in melting temperature was not observed with SD-066-4 treatment (FIG.8C). Based on the in cell palmitoylation studies (FIG.11) it is expected that SD-066-4 inhibits DHHC11 but not DHHC23. Further, binding of SD-066-4 to DHCC20 has been demonstrated (FIGs 12A-12B) the efficacy of SD-066-4 for the inhibition of palmitoylation by DHCC20 can be quantified by mass spectrometry (FIG.13). Preliminary data shows that the effect of SD-066-4 can be rescued by over expression of DHHC23 but not DHHC11 (FIG.11) and that SD-066-4 engages DHHC20 (FIG.8B). This degree of specificity has never before been reported for inhibitors of palmitoylation, demonstrating that SD-066-4 is advantageous over currently employed pan-DHHC tool compounds (e.g., 2-BP). In certain embodiments, the compounds described herein inhibit the growth and viability of cancer cell lines regardless of KRas-mutant isoform as previously observed with DHHC20 shRNA. Indeed, preliminary studies demonstrated that SD-066- 4 (10 μM) inhibited cell growth by 60% over 72 hours in Kras mutant lung cancer cell lines (i.e., A549 (KRasG12S) and H23 (KRasG12C)) while normal lung fibroblasts show no proliferation defect at the same concentration (FIGs 14A-14B). Confirming the importance of EGFR in the mechanism of SD-066-4 growth inhibition, reducing EGFR expression attenuates the proliferation effect (FIG.14C). Furthermore, SD-066-4 (5 μM) is more effective under nutrient deprived conditions, a hallmark of the tumor microenvironment, and kills 15% of A549 lung cancer cells in 72 hours under amino acid deprived conditions with no effect on IMR90 under identical conditions (FIG.14D), highlighting its specificity for cancer cells and providing preliminary evidence for a therapeutic window. Consistent with the role of palmitoylation in modulating EGFR activity, the use of non-specific palmitoyltransferase inhibitor 2-bromopalmitate (2BP) significantly sensitizes - 70 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) MDA-MB-231 cells to EGFR inhibitors such as gefitinib. It has been hypothesized that this is directly related to EGFR palmitoylation. Preliminary data (FIG.15) demonstrates that this is the case for the first-generation EGFR inhibitor gefitinib. Example 7: In vivo characterization of EGFR palmitoylation inhibitors In one aspect, the present disclosure describes characterization of cell fate of SD-066- 4 treated cells under normal and amino acid deprived conditions. As described elsewhere herein, both reduced cell proliferation and increased cell death were observed under nutrient deprived conditions for cells with genetic ablation of DHHC20 (FIG.9B and FIG.14D). The effect under nutrient deprived conditions occurs through inhibition of autophagy, as measured by autophagy marker LC3 (FIG.14E). Inhibition of autophagy may contribute to the inhibition of tumor group caused by genetic ablation of DHHC20 in vivo (FIG.16). As supported by the data disclosed herein (FIG.14A), under normal growth conditions SD-066-4 inhibits cell proliferation. However, it has been further hypothesized that this effect is accentuated under amino acid deprivation. Under amino acid deprived conditions, significant levels of apoptosis are anticipated, which can be measured by immunoblotting for active cleaved-caspase 3 and cleaved PARP. Regarding the effects of SD-066-4 on EGFR signaling, genetic studies revealed that inhibiting EGFR palmitoylation increased the duration of EGFR autophosphorylation and downstream signaling to ERK in response to EGF. Further, preliminary data indicates a 16- hour treatment of H23 lung cancer cells with 2.5 μM SD-066-4 results in sustained EGFR phosphorylation at tyrosine 1068, most noticeably at 1 hour after EGF stimulation, with a concurrent increase in phosphorylated ERK (FIG.17), thus again phenocopying genetic ablation. Additionally, it has been demonstrated that Myc levels are dependent on the DHHC20 / PI3K axis, and accordingly, the effects of SD-066-4 on Myc levels are of interest. Further, preliminary data indicates Myc levels decrease dramatically after 6 hours of treatment with SD-066-4 (FIG.18). This example of kinetic changes that can only be observed with the compounds of the present disclosure informs potential treatment strategies. Further, it is anticipated that SD-066-4 treatment will fully recapitulate DHHC20 knockdown. Consistent with the hypothesis that SD-066-4 is a direct DHHC20 inhibitor, significant effects on autophagy are observed with SD-066-4. For example, treating A549 lung cancer cells with SD-066-4 for 2 hours decreases autophagic flux as measured by - 71 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) immunoblotting for LC3 in both complete media and media without amino acids (FIG.14E), phenocopying shDHHC20 expression (FIGs.5A-5C). Additionally, SD-066-4 treatment increases cell death of Kras mutant A549 lung cancer cells under amino acid deprivation but has no effect on lung fibroblast cell line Kras WT IMR-90 under identical conditions (FIG. 14D). These data suggest the occurrence of a therapeutic window of efficacy, further supported by the DHHC20 knockout mouse data. Preliminary data demonstrates that SD-066-4 is orally bioavailable, has good exposure (i.e., maximum concentration of 4.6 μM from a 10 mg / kg IP administration) and an in vivo half-life of over 4 hours when formulated in 50% PEG400 and 50% (20% captisol) solution (FIG.19). SD-066-4 was formulated and administered via intraperitoneal, or oral routes at 10 mg / kg dosing (N=3 per group). Plasma samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h following dosing, and the concentration of compound determined by analytical HPLC according to a standard curve of compound response. Animals were also observed for acute adverse effects during this experiment, and none were observed. This will determine the availability and clearance of SD-066-4 in vivo and thus inform the in vivo experiments below. Based on in vitro efficacy data and this PK profile it is anticipated that 50 mg / kg IP injection once daily will be suitable for in vivo efficacy studies. Example 8: Optimization of SD-066-4 for treatment of Kras driven cancer Previous studies have demonstrated that genetic ablation or non-specific inhibition of DHHC20 resulted in enhanced sensitivity of lung cancer cells to EGFR inhibitors. It is thus hypothesized that SD-066-4, which phenocopies genetic inhibition of EGFR palmitoylation, displays synergy with EGFR and PI3K inhibitors in vitro and in vivo. A pilot study described herein indicates that intraperitoneal administration of SD-066- 4 (50 mg / kg) every 48 hours inhibits MIAPACA2 pancreas tumor growth for at least 16 days after starting treatment (FIG.20A). Similar treatment also inhibits A549 lung cancer tumor growth, which is KrasG12Smutant, for which there are no targeted therapies (FIG.20B). Continuing studies indicate that mice tolerate up to 75 mg / kg every 48 hours and 25 mg / kg daily (SD-066-4). In certain embodiments, SD-066-4 may be effective against cancer cell lines harboring any type of Kras mutation (e.g., G12C (NCI-H23), G12S (A549), and G12V (SHP- 77) mutants). - 72 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) Example 9: Use of combinations comprising first line lung cancer therapies and SD-066- 4 in vitro and in vivo Autophagy inhibitors are currently being used in the clinic in combination with chemotherapeutic agents and targeted therapies since cancer cells use autophagy as a survival mechanism. Consistent with the fact that genetic inhibition of DHHC20 sensitizes cells to PI3K inhibitors it has been found that SD-066-4 also increases sensitivity of gefitinib resistant lung cancer cells to gefitinib (FIG.21 and FIG.15), SD-066-4 may also display sensitization and potential additive of synergistic effects with other inhibitors. Chemotherapeutic agents like paclitaxel and gemcitabine are still common front-line treatments for lung cancer and are often used in combination with targeted therapies like EGFR inhibitors. Preliminary data indicates genetic inhibition of DHHC20 in lung cancer cells increases the response to paclitaxel compared to control cells (FIG.22A). One mechanism of cell survival in response to drugs like paclitaxel is through autophagy and inhibiting autophagy can suppress paclitaxel resistance in lung adenocarcinoma cells. It has been found that paclitaxel (PTX) treatment increases EGFR palmitoylation and that LC3 levels are reduced in DHHC20 knockdown cells treated with paclitaxel (FIGs.22B-22C). Preliminary in vivo studies reveal promising results with inhibition of tumor growth of both A549 lung cancer and MIAPACA2 pancreas cancer xenograft tumors (FIGs.20A-20B). Use of SD-066-4 in combination with first line treatments may induce durable tumor regression. Levels of palmitoylated proteins such as EGFR and Ras can be measured in xenograft tumors using the ABE assay in tumor lysates or on fixed tumor sections (FIG.23 and FIGs.24A-24B). Example 10: Development of an S-acyl transferase inhibitor Using Rapid Overlay of Chemicals Shape (ROCS) computational methods, a search was performed using the NIH Molecular Libraries Small Molecule Repository of approximately 350K compounds and three small molecule compounds were identified with no known biological function that share 3D structural similarities with filanesib (FIG.26I). Crucially, the pendant amine in filanesib (also present in KSP inhibitor ispinesib) is critical to its activity as an inhibitor of KSP. To differentiate these compounds from KSP inhibitors, the 3-aminopropyl group was excluded from the shape searching query, resulting in three hit compounds. These compounds were tested in an acyl-biotinyl exchange assay to measure EGFR palmitoylation in NCI-H1975 lung cancer cells. One of these compounds, Compound- - 73 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) 1, inhibits EGFR palmitoylation at concentrations as low as 1 μM after treatment for one hour, but has no effect on Ras S-acylation suggesting isoform selectivity (FIG.8A). Importantly, these structurally related compounds begin to outline the structure-activity relationships (SAR) for inhibition of EGFR palmitoylation. Building on this, multiple compounds were synthesized based on the SAR of Compound-1 producing the most potent inhibitor, SD-066-4 (FIG.26J). SD-066-4 reduces EGFR palmitoylation in NCI-H1975 lung adenocarcinoma cells at sub micromolar concentrations within one hour of treatment (FIG.26J). SD-066-4 had no observable inhibition of spindle separation compared to filanesib and no inhibition of Ras S- acylation, confirming there are no off-target effects (FIG.9A and FIG.10). Example 11: Modeling the binding site of SD-066-4 Treatment of ZDHHC20-V5 expressing cells with SD-066-4 increased the Tm of ZDHHC20-V5 compared to cells treated with the vehicle control (DMSO) indicative of direct ligand binding and did not change the Tm of the negative control actin (FIG.8C). The binding site of SD-066-4 on ZDHHC20 was next modeled. The crystal structure of ZDHHC20 (PDB ID:6BML) was prepared for docking but no constraints were enforced on the site of binding. Low energy conformers of SD-066-4 were generated using Omega2 and docked into ZDHHC20 using FRED (FIG.27A). The model predicts ZDHHC14 should be resistant to SD-066-4 because of a steric clash introduced by an alanine to leucine variation between ZDHHC20 and ZDHHC14 (FIG.27B). This is the case, as SD-066-4 was found to be unable to inhibit EGFR acylation in NCI-H1975 cells overexpressing ZDHHC14 (FIG.27C). The SAR around SD-066-4 is also explained by this binding mode, for example methylation of the indole abrogates activity since it would introduce a steric clash with the protein surface. To test this docking model, an analog of SD- 066-4 was developed that lacks methylation of the indole, SD-128 (FIG.27D). It was found that the analog induced a potent dose dependent inhibition of EGFR palmitoylation in cells overexpressing ZDHHC14-HA but had minimal effect on the parental cells without ZDHHC14-HA (FIG.27C). Analysis of the predicted structures of all twenty-three DHHC enzymes reveals only ZDHHC1, 11, 20 and 24 contain a small side chain amino acid at the spatial position of alanine 144 while the remaining 19 DHHC enzymes contain bulky residues (FIG.27E). This indicates SD-066-4 likely has specificity for only four of the twenty-three DHHC enzymes. The generality of this model for evaluating DHHC enzyme specificity was considered - 74 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) for other DHHC enzymes. DHHC11 or ZDHHC23 are sufficient to S-acylate EGFR as forced expression of either increases EGFR acylation (FIG.6B). ZDHHC11 contains a serine in the same spatial position as alanine 144 in ZDHHC20 and ZDHHC11 overexpressing cells are responsive to SD-066-4 (FIG.27F). ZDHHC23 contains an isoleucine at the alanine position and ZDHHC23 overexpressing cells are resistant to SD-066-4 at identical concentrations (FIG.27F). The observed selectivity for ZDHHC20 and ZDHHC11 supports the model that alanine 144 provides SD-066-4 specificity for ZDHHC20. Example 12: Oncogenic Kras increases EGFR S-acylation and prevents compensation by alternate acyltransferases The increase in survival observed in patients that harbor ZDHHC20 deletion concurrent with Kras alterations suggests an essential function for ZDHHC20 in cells with activated Kras. To understand the role of oncogenic Kras in greater detail, EGFR S-acylation was examined in NIH3T3 cells in the presence of absence of oncogenic KrasG12V. It was found that EGFR S-acylation was greater than ten-fold higher in the KrasG12V expressing cells than the parental NIH3T3 cells, and immunofluorescence staining of ZDHHC20 revealed increased levels of ZDHHC20 in the KrasG12V expressing cells compared to the control NIH3T3 cells (FIGs.28A-28B). This marked increase in ZDHHC20 EGFR S- acylation is consistent with EGFR S-acylation functioning to attenuate oncogenic signaling. The elevated EGFR S-acylation levels were reduced by SD-066-4 treatment over twenty hours in the KrasG12V expressing cells while the NIH3T3 cell line displayed a similar recovery in EGFR S-acylation at six hours after SD-066-4 treatment as the H1975 cell line (FIG.28A). Previous studies showed that genetic inhibition of ZDHHC20 in Kras mutant lung cancer cells reduced pAKT and decreased Myc protein levels and it was asked if SD-066-4 has a similar effect. In Kras mutant cells pAKT and Myc levels initially increased but steadily decreased by 6 hours of treatment and were lower than control cells by twenty hours (FIG. 28C). In contrast the Kras wild type cell line NCI-H1975 pAKT levels were constant over the time course while Myc also initially increased but returned to control treated levels by six hours (FIG.28C). To determine if the kinetic difference in signaling correlates with EGFR S- acylation, EGFR S-acylation was measured in SD-066-4 treated Kras mutant cells and compared to Kras wild type cells over twenty hours. In the KrasG12S mutant cell line A549 EGFR S-acylation was maximally inhibited by six hours of 1 uM SD-066-4 and remained inhibited at twenty hours (FIG.28D). In contrast, Kras wild type line NCI-H1975 was - 75 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) maximally inhibited at one hour treatment but S-acylation recovered by six hours (FIG.28D). Next, the sensitivity to ZDHHC20 inhibition by SD-066-4 of Kras mutant and Kras wild type lung cancer cells was compared. It was found that proliferation of the Kras mutant lung cancer lines NCI-H23 and A549 were inhibited with an IC50of approximately 2 µM SD- 066-4 whereas the Kras wild type EGFR mutant (L858R / T790M) lung cancer cell line required 5-10 µM SD-066-4 to achieve similar growth inhibition (FIGs.28E-28G). Inhibition of proliferation was specific to cancer cells as SD-066-4 was unable to inhibit proliferation of the lung fibroblast cell line IMR90 at identical concentrations and indicates the nonspecific toxicity is low. To test if the recovery in EGFR S-acylation in Kras wild type cells upon six hours of SD- 066-4 treatment may be mediated by an alternate transferase with overlapping function, A549 KrasG12S NCI-H23 KrasG12C and H1975 Kras wild type cell lines were established expressing HA tagged DHHC14, and DHHC14 protein levels were measured over twenty hours of SD-066-4 treatment. DHHC14-HA levels decreased modestly after twenty hours in A549 and NCI-H23 (FIG.28F). In contrast, DHHC14-HA protein levels rapidly increase by one hour of treatment in H1975 cells and reach the highest level by six hours followed by a decrease at twenty hours. Example 13: SD-066-4 inhibits lung cancer tumor growth To determine if an exemplary small molecule inhibitor of ZDHHC20 has therapeutic potential, a xenograft tumor model was used to measure the ability of SD-066-4 to inhibit tumor growth in vivo. The KrasG12S lung cancer cell line A549 was engrafted in the flanks of NOD SCID mice and when tumors reached a volume of 100 mm3mice were treated with SD-066-4 or vehicle control by oral gavage to find an optimal dosing regimen. Daily treatment with 50 mg / kg with SD-066-4 showed no effect on tumor growth but increasing the dose to 100 mg / kg daily showed growth inhibition over seven days (FIGs.31A-31B). After determining the therapeutic dose, the study was repeated, and when tumor volume reached 300 mm3mice were treated daily with 100 mg / kg by oral gavage. After 5 days of treatment the average percent change in volume was 0% compared to 29.2% for the vehicle control (FIG.29A). By day twenty-three the first animal in the vehicle cohort reached the endpoint tumor volume (1000 mm3) and the average change for vehicle treated tumors was 174.5% compared to 59.0% for SD-066-4 treated tumors (FIGs.29A-29B and FIG.31C). After day thirty-seven, there was no significant difference in percent body weight change between vehicle and SD-066-4 treated animals, indicating there is no overt general toxicity at the - 76 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) therapeutic dose (FIG.29C). Treatment with SD-066-4 as a single agent increased overall survival with seven of the eight control treated animals reaching end point tumor volume by the end of the study compared to only one of the eight SD-066-4 treated animals (FIG.29D). To molecularly characterize the effect of SD-066-4 in vivo, tumors were sectioned and analyzed by immunofluorescence staining and the tumors that showed the greatest inhibition Myc protein expression was restricted to the regions of the treated tumor that were intact and counterstained positive for the junctional marker β-catenin in contrast to the vehicle control tumor that was mostly intact with uniform expression of both Myc and β-catenin (FIG.32A). Since the most effectively inhibited tumors contained only small regions of intact healthy tumor tissue, it was reasoned the conventional ABE assay on tumor lysate would not provide accurate levels of EGFR S-acylation in the tumor cells, and instead a recently developed method to spatially resolve S-acylated EGFR in situ was used. A variation of the S-acyl exchange assay was performed on frozen tumor sections to label S-acylated cystine residues with the fluorophore Oregon Green and the dually S-acylated and phosphorylated EGFR was detected by a Duolink proximity ligation assay with antibodies to Oregon Green and pEGFR and detected as fluorescent puncta (FIGs.29F-29G and FIG.32B). The number of PLA puncta per field were quantified and it was found that the treated tumors that were harvested two hours after treatment were significantly lower than the vehicle control tumors confirming the EGFR S-acylation in the tumors was inhibited by SD-066-4. These findings demonstrate the efficacy of targeting a small subset of the twenty-three DHHC enzyme family members with a small molecule inhibitor, revealing a critical residue near the acyl-CoA binding pocket that confers specificity for ZDHHC20 and ZDHHC11. As a tool SD-066-4 revealed the dynamic changes in expression of alternate ZDHHC enzymes at early timepoints that could not be observed by genetic inhibition. The increase in ZDHHC14 protein upon ZDHHC20 inhibition is suppressed by oncogenic Kras and uncovers the complex regulation of EGFR S-acylation and the need to maintain precise levels of protein S- acylation. EGFR expressing cells appear to respond to oncogenic Kras by increasing EGFR S-acylation by as much as tenfold. This increase is consistent with a necessity of ZDHHC20 in Kras mutant lung cancer tumors evidenced by increased Kras mutant lung adenocarcinoma patient survival when ZDHHC20 or ZDHHC14 is deleted. Example 14: Promoting Efficacy of Trans-Arterial Chemoembolization (TACE) with SD-066-4 TACE involves the embolization of the bronchial artery feeding the lung cancer with - 77 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) the simultaneous intra-arterial infusion of a chemotherapeutic agent. Embolization obstructs arterial blood flow and mitigates washout of the therapeutic agent improving drug retention. TACE represents a promising strategy for exploiting cancer’s dependence on the tumor vasculature while delivering therapeutics at tissue concentrations that are an order of magnitude greater than those achievable through systemic delivery, with tumor-to-normal parenchyma ratios ranging from 3:1 to 20:1. Current TACE protocols for NSLC are based on protocols developed to treat hepatocellular carcinoma using cell cycle specific agents that target actively proliferating cells (e.g., doxorubicin, mitomycin, and cisplatin). The rationale of these protocols is that the ischemic microenvironment will enhance their cytotoxic effect by increasing intracellular retention and overcoming resistance mechanisms. However, prospective, randomized trials have shown TACE is equally effective with respect to survival as trans-arterial embolization without intra-arterial chemotherapy (TAE), and no chemotherapeutic has been found to be superior to others. Without wishing to be bound by any theory, it is hypothesized herein that cellular autophagy induced by TACE mitigates the efficacy of the chemotherapeutic agents. In one aspect, the disclosure describes a solution to this deficiency by pharmacologically targeting autophagy with SD-066-4 to maximize the embolic effects of TAE and TACE. Thus, in one aspect, it is reasoned that increasing local concentration of SD-066-4 by locoregional delivery will increase levels of tumor inhibition similar to genetic ablation. Autophagy is essential for cancer cells surviving severe ischemia. Consistent with these in vitro findings, tumors treated with transarterial embolization incorporating the autophagy inhibition (Lys05) demonstrated a significant increase in necrosis versus tumors treated with transarterial embolization (TAE) alone (FIGs.35A-35C). These findings confirmed a prior study in liver tumors demonstrating a similar increase in autophagic flux following TACE as well as a profound improvement in therapeutic efficacy for tumors treated with the autophagy inhibitor chloroquine in combination with TACE as compared to TACE alone. The palmitoyl transferase inhibitor SD-066-4 inhibits autophagy in lung cancer cells and nutrient deprivation induces cell death in A549 cells treated with SD-066-4 while normal IMR90 lung fibroblasts are unaffected (FIGs.36A-36B). This selectivity for cancer cells is unique among autophagy inhibitors. These findings suggest that the autophagy dependence generated by TACE-induced ischemia in surviving lung cancer cells may be similarly targeted by incorporating SD-066-4, while minimizing the required therapeutic dose through the local delivery of high drug concentrations. - 78 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) Preliminary studies described herein for the locoregional treatment of carcinogen induced HCC in rat by TAE indicate a single treatment with SD-066-4 at 6 mg / kg reduced the largest tumor by 71% after 10 days and was maintained after 17 days (FIG.37A). All three tumors regressed and were undetectable by day 24 and did not relapse by day 31. Similar inhibition of autophagy was observed in hepatocellular carcinoma cells treated with SD-066- 4 when cells are cultured without amino acids (FIG.37B). The robust response with a single treatment of a single agent indicates great promise for future studies with sequential treatments and in combination with conventional chemotherapeutic drugs. Recent studies also indicate inhibition of autophagy synergizes with checkpoint inhibitors which will be explored in future studies. Sequence Listing SEQ ID NO Polypeptide Sequence C G - 79 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) HYNHRYFF 16 ZDHHC17 IFCSTCLIRKPVRSKHCGVCNRCIAKFDHHCPWVGNCVG AGNHRYFM V G V S The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance: Embodiment 1 provides a compound selected from the group consisting of: a compound of Formula (I): , a compound of Formula (II): a compound of Formula (III), wherein: R1is selected from the group consisting of ; - 80 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) R2ais selected from the group consisting of ; R2bis H or absent; R2cis H; R3aand R3bare each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, halogen, CN, and NO2, wherein R3bcan be present or absent; X is selected from the group consisting of N(R4) and O; L is selected from the group consisting of optionally substituted methylene and a bond; R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6 alkyl and optionally substituted C6-C10aryl; Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1and Rb2, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10heteroaryl; bond a is a single bond or a double bond, wherein one of the following applies: (a) bond a is a single bond and each of R2a, R2b, R3a, and R3bare present; or - 81 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) (b) bond a is a double bond, R2aand R3aare present, and R2band R3bare absent; wherein if bond a is a double , then at least one of Ra1, C1-C6 alkyl or halogen, and optionally substituted C1-C6alkyl or halogen; wherein the compound of Formula (I) is not selected from the group consisting of: (2-fluorophenyl)(5-(2-fluorophenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)methanone; 3-(5-phenyl-1H-pyrazol-3-yl)-1H-indole; 1-methyl-3-(5-phenyl-1H-pyrazol-3-yl)-1H-indole; 3-(5-(2-chlorophenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-methylphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-hydroxyphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-methoxyphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(4-chlorophenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(4-methoxyphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; and 3-(5-(4-methylphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; or a salt, solvate, stereoisomer, or isotopologue thereof. Embodiment 2 provides the compound of Embodiment 1, wherein the compound of Formula (I) is a compound of Formula (Ia): . Embodiment 3 provides thea1 a2 a3 a4 2, wherein R , R , R , R , and Ra5are each independently selected from the group consisting of H and F. Embodiment 4 provides the compound of Embodiment 2 or 3, wherein at least one of the following applies: (a) at least one of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is H; (b) at least two of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H; (c) at least three of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H; - 82 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) (d) at least four of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H; (e) at least five of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H; and (f) each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is H. Embodiment 5 provides the compound of any one of Embodiments 2-4, wherein Rb1is selected from the group consisting of H and CH3. Embodiment 6 provides the compound of any one of Embodiments 2-5, wherein R1is selected from the group consisting of . wherein Rc1, Rc2, Rc3, of H, F, CN, and CH3. Embodiment 8 provides the compound of any one of Embodiments 2-7, wherein at least one of the following applies: (a) at least one of Rc1, Rc2, Rc3, Rc4, and Rc5is H; (b) at least two of Rc1, Rc2, Rc3, Rc4, and Rc5are H; (c) at least three of Rc1, Rc2, Rc3, Rc4, and Rc5are H; (d) at least four of Rc1, Rc2, Rc3, Rc4, and Rc5are H; and (e) each of Rc1, Rc2, Rc3, Rc4, and Rc5are H. Embodiment 9 provides the compound of any one of Embodiments 2-8, wherein Rb2is selected from the group consisting of H and CH3. Embodiment 10 provides the compound of any one of Embodiments 2-9, wherein L is selected from the group consisting of a bond and -CH2-. Embodiment 11 provides the compound of any one of Embodiments 2-10, wherein R2ais selected from the group consisting of R3ais H. - 83 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) Embodiment 13 provides the compound of any one of Embodiments 2-12, wherein R5is CH3. Embodiment 14 provides the compound of any one of Embodiments 2-13, wherein X is selected from the group consisting of NH, NC(=O)CH3, and O. Embodiment 15 provides the compound of Embodiment 1, wherein the compound of Formula (I) is a compound of Formula (Ib): . Embodiment 16 provides the 15, wherein the compound of Formula (Ib) is selected from the 4). Ra2, a3 R , are group Embodiment 18 provides the compound of any one of Embodiments 15-17, wherein at least one of the following applies: (a) at least one of Ra1, Ra2, Ra3, Ra4, and Ra5is H; (b) at least two of Ra1, Ra2, Ra3, Ra4, and Ra5are H; (c) at least three of Ra1, Ra2, Ra3, Ra4, and Ra5are H; (d) at least four of Ra1, Ra2, Ra3, Ra4, and Ra5are H; and (e) each of Ra1, Ra2, Ra3, Ra4, and Ra5is H. Embodiment 19 provides the compound of any one of Embodiments 15-18, wherein Rb1is selected from the group consisting of H and CH3. Embodiment 20 provides the compound of any one of Embodiments 15-19, wherein R1is selected from the group consisting of . Embodiment 21 15-20, wherein Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H and CH3. - 84 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) Embodiment 22 provides the compound of any one of Embodiments 15-21, wherein at least one of the following applies: (a) at least one of Rc1, Rc2, Rc3, Rc4, and Rc5is H; (b) at least two of Rc1, Rc2, Rc3, Rc4, and Rc5are H; (c) at least three of Rc1, Rc2, Rc3, Rc4, and Rc5are H; (d) at least four of Rc1, Rc2, Rc3, Rc4, and Rc5are H; and (e) each of Rc1, Rc2, Rc3, Rc4, and Rc5is H. Embodiment 23 provides the compound of any one of Embodiments 15-22, wherein Rb2is selected from the group consisting of H and CH3. Embodiment 24 provides the compound of any one of Embodiments 15-23, wherein L is selected from the group consisting of a bond and -CH2-. Embodiment 25 provides the compound of any one of Embodiments 15-24, wherein . 26 provides the compound of any one of Embodiments 15-25, wherein R3aand R3bare each independently H. Embodiment 27 provides the compound of any one of Embodiments 15-26, wherein R5is selected from the group consisting of CH3and phenyl substituted with a halogen. Embodiment 28 provides the compound of any one of Embodiments 15-27, wherein R4is selected from the group consisting of C(=O)CH3and C(=O)(4-chlorophenyl). Embodiment 29 provides the compound of any one of Embodiments 15-28, wherein X is selected from the group consisting of NH, NC(=O)CH3, and NC(=O)(4-chlorophenyl). Embodiment 30 provides the compound of Embodiment 1, wherein the compound of Formula (II) is a compound of Formula (IIa): . Embodiment 31 provides1 30, wherein R is . 32 provides the compound of Embodiment 30 or 31, wherein R2ais . - 85 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) Embodiment 33 provides the compound of Embodiment 1, wherein the compound of Formula (III) is a compound of Formula (IIIa): . Embodiment 34 provides the 33, wherein R1is . 35 provides the compound of Embodiment 33 or 34, wherein R2ais . 36 provides the compound of any one of Embodiments 1-35, wherein each occurrence of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted methylene, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C2-C12heterocycloalkyl, C1-C6hydroxyalkyl, halogen, CN, NO2, ORI, N(RI)(RII), C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, aryl, heteroaryl, (C1-C6 alkylenyl)C(=O)N(RI)(RII), (C1-C6alkylenyl)C(=O)ORI, O(C1-C3alkylenyl)C(=O)ORII, O(C1-C3 alkylenyl)C(=O)N(RI)(RII), C(=O)RI, C(=O)ORI, OC(=O)RI, OC(=O)ORI, SRI, S(=O)RI, S(=O) N(RI)C(=O)RII, from the group consisting of H, -C(=O)(C1-C6alkyl), C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, C3-C8 cycloalkyl, C2-C12 heterocycloalkyl, C7-C12 aralkyl, aryl, and heteroaryl. Embodiment 37 provides the compound of any one of Embodiments 1-36, which is selected from the group consisting of: 1-(3-(2-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(2-fluorophenyl)-5-(p-tolyl)-1H-pyrazole; 1-(3-(1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(5-(p-tolyl)-1H-pyrazol-3-yl)-1H-indole; 1-(3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)isoxazole; - 86 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) 3-(1H-indol-3-yl)-5-(p-tolyl)isoxazole; 3-(2-fluorophenyl)-5-(p-tolyl)isoxazole; (4-chlorophenyl)(3-(2-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)methanone; (3-(1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone; (3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)(phenyl)methanone; 3-(5-(m-tolyl)-1H-pyrazol-3-yl)-1H-indole; 1-methyl-3-(5-(m-tolyl)-1H-pyrazol-3-yl)-1H-indole; 3-(5-benzyl-1H-pyrazol-3-yl)-1H-indole; 3-(5-benzyl-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-fluorophenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-fluorophenyl)-1H-pyrazol-3-yl)-1H-indole; 3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)-1H-indole; 3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)-1-methyl-1H-indole; 1-(3-(2-fluorophenyl)-5-(1H-indol-3-yl)-1H-pyrazol-1-yl)ethan-1-one; 1-(3-(2-fluorophenyl)-5-(1-methyl-1H-indol-3-yl)-1H-pyrazol-1-yl)ethan-1-one; 3-(5-(p-tolyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine; N-(p-tolyl)-1H-indole-3-carboxamide; 4-(3-(1H-indol-3-yl)-1H-pyrazol-5-yl)benzonitrile; (E)-N'-((1H-indol-3-yl)methylene)-4-methylbenzenesulfonohydrazide; and 3-(5-(p-tolyl)-1H-pyrazol-3-yl)quinoline. Embodiment 38 provides a pharmaceutical composition comprising at least one compound of any one of Embodiments 1-37 and a pharmaceutically acceptable carrier. Embodiment 39 provides the pharmaceutical composition of Embodiment 38, further comprising at least one additional agent. Embodiment 40 provides the pharmaceutical composition of Embodiment 39, wherein the at least one additional agent is selected from the group consisting of an EGFR inhibitor, KRasG12Cinhibitor, a PI3K inhibitor, a RAF inhibitor, and a cytotoxic agent. Embodiment 41 provides the pharmaceutical composition of Embodiment 40, wherein at least one of the following applies: (a) the EGFR inhibitor is at least one selected from the group consisting of gefitinib, afatinib, erlotinib, osimertinib, neratinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, and vandetanib; - 87 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) (b) the KRasG12Cinhibitor is at least one selected from the group consisting of adagrasib (MRTX849), sotorasib (AMG510), ARS-853, ARS-1620, JNJ-74699157 (ARS- 3248), LY3499446 / LY3537982, GDC-6036, D-1553, JDQ443, and BI1823911; (c) the PI3K inhibitor is at least one selected from the group consisting of aliqopa, alpelisib, copanlisib, copiktra, duvelisib, idelalisib, piqray, ukoniq, umbralisib, zydelig, buparlisib, dactolisib, leniolisib, parsaclisib, paxalisib, taselisib, inavolisib, apitolisib, bimiralisib, eganelisib, fimepinostat, gedatolisib, linperlisib, nemairilisib, pictilisib, pilaralisib, samotolisib, seletalisib, serabelisib, sonolisib, tenalisib, voxtalisib, AMG 319, AZD8186, GSK2636771, and SF1126; (d) the RAF inhibitor is at least one selected from the group consisting of PLX4720, PLX4032, BAY 43-9006 (sorafenib), vemurafenib (zelboraf), dabrafenib (tafinlar), encorafenib (braftovi), cobimetinib (cotellic), binimetinib (mektovi), ZM 336372, RAF 265, AAL-881, LBT-613 (Novartis), and CJS352. PLX4720, PLX4032, BAY 43-9006 (sorafenib), ZM 336372, and RAF 265; and (e) the cytotoxic agent is at least one selected from the group consisting of paclitaxel, doxorubicin, cyclophosphamide, methotrexate, fluorouracil, cisplatin, carboplatin, vinblastine, vincristine, etoposide, bleomycin, mitomycin c, gemcitabine, irinotecan, topotecan, docetaxel, camptothecin, melphalan, busulfan, chlorambucil, dacarbazine, procarbazine, temozolomide, bendamustine, oxaliplatin, ifosfamide, lomustine, streptozocin, daunorubicin, idarubicin, fludarabine, cladribine, pentostatin, mercaptopurine, azathioprine, hydroxyurea, thiotepa, mitoxantrone, teniposide, cytarabine, decitabine, clofarabine, nelarabine, azacytidine, eribulin, cabazitaxel, liposomal doxorubicin, pegylated liposomal doxorubicin, trabectedin, and ixabepilone. Embodiment 42 provides a method of treating, preventing, and / or ameliorating cancer in a subject, the method comprising administering to the subject at least one compound of any one of Embodiments 1-37 and / or the pharmaceutical composition of any one of Embodiments 38-41. Embodiment 42 provides a method of treating, preventing, and / or ameliorating cancer in a subject, the method comprising administering to the subject at least one compound of Formula (IV), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: - 88 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) R1is selected from the group consisting of ; optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2, wherein R3bcan be present or absent; X is selected from the group consisting of N(R4) and O; L is selected from the group consisting of optionally substituted methylene and a bond; R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6 alkyl and optionally substituted C6-C10aryl; Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, optionally substituted C2-C10 heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1and Rb2, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally - 89 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) substituted C2-C10 heteroaryl; and bond a is a single bond or a double bond, wherein one of the following applies: (a) bond a is a single bond and each of R2a, R2b, R3a, and R3bare present; or (b) bond a is a double bond, R2aand R3aare present, and R2band R3bare absent. Embodiment 44 provides the method of Embodiment 42 or 43, wherein the cancer is of the lung, pancreas, bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, and / or uterus. Embodiment 45 provides the method of any one of Embodiments 42-44, wherein the cancer is of the lung and / or pancreas. Embodiment 46 provides the method of any one of Embodiments 42-45, wherein the cancer comprises RTK driven cancer and / or Ras driven cancer. Embodiment 47 provides the method of any one of Embodiments 42-46, wherein the at least one compound selectively inhibits a DHHC enzyme. Embodiment 48 provides the method of Embodiment 47, wherein the DHHC enzyme is DHHC20. Embodiment 49 provides the method of any one of Embodiments 46-48, wherein the DHHC enzyme is selectively inhibited over kinesin spindle protein (KSP). Embodiment 50 provides the method of any one of Embodiments 42-49, wherein EGFR palmitoylation is inhibited. Embodiment 51 provides the method of any one of Embodiments 42-50, wherein the subject is administered at least one additional agent. Embodiment 52 provides the method of Embodiment 51, wherein the at least one additional agent is selected from the group consisting of an EGFR inhibitor, KRasG12Cinhibitor, a PI3K inhibitor, a RAF inhibitor, and a cytotoxic agent. Embodiment 53 provides the method of Embodiment 52, wherein at least one of the following applies: (a) the EGFR inhibitor is at least one selected from the group consisting of gefitinib, afatinib, erlotinib, osimertinib, neratinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, and vandetanib; (b) the KRasG12Cinhibitor is at least one selected from the group consisting of adagrasib (MRTX849), sotorasib (AMG510), ARS-853, ARS-1620, JNJ-74699157 (ARS- - 90 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) 3248), LY3499446 / LY3537982, GDC-6036, D-1553, JDQ443, and BI1823911; (c) the PI3K inhibitor is at least one selected from the group consisting of aliqopa, alpelisib, copanlisib, copiktra, duvelisib, idelalisib, piqray, ukoniq, umbralisib, zydelig, buparlisib, dactolisib, leniolisib, parsaclisib, paxalisib, taselisib, inavolisib, apitolisib, bimiralisib, eganelisib, fimepinostat, gedatolisib, linperlisib, nemairilisib, pictilisib, pilaralisib, samotolisib, seletalisib, serabelisib, sonolisib, tenalisib, voxtalisib, AMG 319, AZD8186, GSK2636771, and SF1126; (d) the RAF inhibitor is at least one selected from the group consisting of PLX4720, PLX4032, BAY 43-9006 (sorafenib), vemurafenib (zelboraf), dabrafenib (tafinlar), encorafenib (braftovi), cobimetinib (cotellic), binimetinib (mektovi), ZM 336372, RAF 265, AAL-881, LBT-613 (Novartis), and CJS352. PLX4720, PLX4032, BAY 43-9006 (sorafenib), ZM 336372, and RAF 265; and (e) the cytotoxic agent is at least one selected from the group consisting of paclitaxel, doxorubicin, cyclophosphamide, methotrexate, fluorouracil, cisplatin, carboplatin, vinblastine, vincristine, etoposide, bleomycin, mitomycin c, gemcitabine, irinotecan, topotecan, docetaxel, camptothecin, melphalan, busulfan, chlorambucil, dacarbazine, procarbazine, temozolomide, bendamustine, oxaliplatin, ifosfamide, lomustine, streptozocin, daunorubicin, idarubicin, fludarabine, cladribine, pentostatin, mercaptopurine, azathioprine, hydroxyurea, thiotepa, mitoxantrone, teniposide, cytarabine, decitabine, clofarabine, nelarabine, azacytidine, eribulin, cabazitaxel, liposomal doxorubicin, pegylated liposomal doxorubicin, trabectedin, and ixabepilone. Embodiment 54 provides the method of any one of Embodiments 42-53, wherein the subject is further subjected to trans-arterial chemoembolization (TACE) or trans-arterial embolization (TAE). Embodiment 55 provides the method of any one of Embodiments 42-54, wherein the subject is a mammal. Embodiment 56 provides the method of Embodiment 55, wherein the mammal is a human. Embodiment 57 provides a method of inhibiting palmitoylation in a subject, the method comprising administering to the subject at least one compound of any one of Embodiments 1-37. Embodiment 58 provides a method of inhibiting palmitoylation in a subject, the method comprising administering to the subject at least one compound of Formula (IV), or a salt, solvate, stereoisomer, or isotopologue thereof: - 91 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) , wherein: R1is selected from the group ; R3aand are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, halogen, CN, and NO2, wherein R3bcan be present or absent; and X is selected from the group consisting of N(R4) and O; L is selected from the group consisting of optionally substituted methylene and a bond; R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6 alkyl and optionally substituted C6-C10 aryl; Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1and Rb2, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting - 92 - 55405813.2 Attorney Docket No.046483-7421WO1(03880) of H, optionally substituted C1-C6 alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10 heteroaryl; and bond a is a single bond or a double bond, wherein one of the following applies: (a) bond a is a single bond and each of R2a, R2b, R3a, and R3bare present; or (b) bond a is a double bond, R2aand R3aare present, and R2band R3bare absent. Embodiment 59 provides the method of Embodiment 57 or 58, wherein palmitoylation of EGFR is inhibited. Embodiment 60 provides the method of any one of Embodiments 57-59, wherein a palmitoyl transferase is inhibited. Embodiment 61 provides the method of Embodiment 60, wherein the palmitoyl transferase is DHHC20. Embodiment 62 provides the method of Embodiment 60 or 61, wherein the palmitoyl transferase is selectively inhibited. Embodiment 63 provides the method of Embodiment 62, wherein the palmitoyl transferase is selectively inhibited over kinesin spindle protein (KSP). The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application. - 93 - 55405813.2

Claims

Attorney Docket No.046483-7421WO1(03880) CLAIMS What is claimed is:

1. A compound selected from the group consisting of: a compound of Formula (I): , a compound of Formula (II):a compound of Formula(III), wherein: R1is selected from the group consisting of ;; R2bis H or absent;R2cis H; R3aand R3bare each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2, wherein R3bcan be present or absent; X is selected from the group consisting of N(R4) and O; L is selected from the group consisting of optionally substituted methylene and a - 94 - 55405813.2Attorney Docket No.046483-7421WO1(03880) bond; R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6 alkyl and optionally substituted C6-C10aryl; Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are each independently selected from the group of H, substituted C1-C6alkyl, optionally substituted C2-C6alkenyl,substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, optionally substituted C2-C10 heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1and Rb2, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl; bond a is a single bond or a double bond, wherein one of the following applies: (a) bond a is a single bond and each of R2a, R2b, R3a, and R3bare present; or (b) bond a is a double bond, R2aand R3aare present, and R2band R3bare absent; wherein if bond a is a double , then at least one of Ra1,C1-C6 alkyl or halogen, and at least one of Rc1, Rc2, Rc3, Rc4, and Rc5is optionally substituted C1-C6 alkyl or halogen; wherein the compound of Formula (I) is not selected from the group consisting of: (2-fluorophenyl)(5-(2-fluorophenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)methanone; 3-(5-phenyl-1H-pyrazol-3-yl)-1H-indole; 1-methyl-3-(5-phenyl-1H-pyrazol-3-yl)-1H-indole; - 95 - 55405813.2Attorney Docket No.046483-7421WO1(03880) 3-(5-(2-chlorophenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-methylphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-hydroxyphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-methoxyphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(4-chlorophenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(4-methoxyphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; and 3-(5-(4-methylphenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; or a salt, solvate, stereoisomer, or isotopologue thereof.

2. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (Ia): .

3. The compound of claim 2, Ra4, and Ra5are each independently selected from the group consisting of H and F.

4. The compound of claim 2 or 3, wherein at least one of the following applies: (a) at least one of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is H; (b) at least two of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H; (c) at least three of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H; (d) at least four of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H; (e) at least five of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are H; and (f) each of Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6is H.

5. The compound of any one of claims 2-4, wherein Rb1is selected from the group consisting of H and CH3.

6. The compound of any one of claims 2-5, wherein R1is selected from the group consisting of .- 96 - 55405813.2Attorney Docket No.046483-7421WO1(03880) 7. The compound of any one of claims 2-6, wherein Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H, F, CN, and CH3.

8. The compound of any one of claims 2-7, wherein at least one of the following applies: (a) at least one of Rc1, Rc2, Rc3, Rc4, and Rc5is H; (b) at least two of Rc1, Rc2, Rc3, Rc4, and Rc5are H; (c) at least three of Rc1, Rc2, Rc3, Rc4, and Rc5are H; (d) at least four of Rc1, Rc2, Rc3, Rc4, and Rc5are H; and (e) each of Rc1, Rc2, Rc3, Rc4, and Rc5are H.

9. The compound of any one of claims 2-8, wherein Rb2is selected from the group consisting of H and CH3.

10. The compound of any one of claims 2-9, wherein L is selected from the group consisting of a bond and -CH2-.

11. The compound of any one of claims 2-10, wherein R2ais selected from the group consisting of12. The compound of any one of claims 2-11, wherein R3ais H.

13. The compound of any one of claims 2-12, wherein R5is CH3.

14. The compound of any one of claims 2-13, wherein X is selected from the group consisting of NH, NC(=O)CH3, and O.

15. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (Ib): - 97 - 55405813.2Attorney Docket No.046483-7421WO1(03880) .

16. The compound of claim 15,of Formula (Ib) is selected from the group consisting of: 4).

17. independently selected from the group consisting of H and F.

18. The compound of any one of claims 15-17, wherein at least one of the following applies: (a) at least one of Ra1, Ra2, Ra3, Ra4, and Ra5is H; (b) at least two of Ra1, Ra2, Ra3, Ra4, and Ra5are H; (c) at least three of Ra1, Ra2, Ra3, Ra4, and Ra5are H; (d) at least four of Ra1, Ra2, Ra3, Ra4, and Ra5are H; and (e) each of Ra1, Ra2, Ra3, Ra4, and Ra5is H.

19. The compound of any one of claims 15-18, wherein Rb1is selected from the group consisting of H and CH3.

20. The compound of any one of claims 15-19, wherein R1is selected from the group consisting of .

21. The compound of any one of claims 15-20, wherein Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H and CH3. - 98 - 55405813.2Attorney Docket No.046483-7421WO1(03880) 22. The compound of any one of claims 15-21, wherein at least one of the following applies: (a) at least one of Rc1, Rc2, Rc3, Rc4, and Rc5is H; (b) at least two of Rc1, Rc2, Rc3, Rc4, and Rc5are H; (c) at least three of Rc1, Rc2, Rc3, Rc4, and Rc5are H; (d) at least four of Rc1, Rc2, Rc3, Rc4, and Rc5are H; and (e) each of Rc1, Rc2, Rc3, Rc4, and Rc5is H.

23. The compound of any one of claims 15-22, wherein Rb2is selected from the group consisting of H and CH3.

24. The compound of any one of claims 15-23, wherein L is selected from the group consisting of a bond and -CH2-.

25. The compound of any one of claims 15-24, wherein R2a.

26. The compound of any one of claims 15-25, wherein R3aand R3bare each independently H.

27. The compound of any one of claims 15-26, wherein R5is selected from the group consisting of CH3 and phenyl substituted with a halogen.

28. The compound of any one of claims 15-27, wherein R4is selected from the group consisting of C(=O)CH3and C(=O)(4-chlorophenyl).

29. The compound of any one of claims 15-28, wherein X is selected from the group consisting of NH, NC(=O)CH3, and NC(=O)(4-chlorophenyl).

30. The compound of claim 1, wherein the compound of Formula (II) is a compound of Formula (IIa): .- 99 - 55405813.2Attorney Docket No.046483-7421WO1(03880) 31. The compound of claim 30, wherein R1.

32. The of claim 30 or wherein R2ais .(III) is a compound of Formula (IIIa): .

34. The compound of claim 33, wherein .

35. The compound of claim 33 or 34, wherein R2a.

36. The compound of any one of claims 1-35, wherein each occurrence of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted methylene, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C2-C12heterocycloalkyl, C1-C6hydroxyalkyl, halogen, CN, NO2, ORI, N(RI)(RII), C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, aryl, heteroaryl, (C1-C6alkylenyl)C(=O)N(RI)(RII), (C1-C6alkylenyl)C(=O)ORI, O(C1-C3alkylenyl)C(=O)ORII, O(C1-C3 alkylenyl)C(=O)N(RI)(RII), C(=O)RI, C(=O)ORI, OC(=O)RI, OC(=O)ORI, SRI, S(=O)RI, S(=O)2RI, S(=O)2N(RI)(RII), S(=O)2NRIC(=O)NHRII, N(RI)S(=O)2RII, N(RI)C(=O)RII, and C(=O)NRIRII, wherein RIand RIIare each independently selected from the group consisting of H, -C(=O)(C1-C6alkyl), C1-C6alkyl, C1- C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C12 heterocycloalkyl, C7-C12 aralkyl, - 100 - 55405813.2Attorney Docket No.046483-7421WO1(03880) aryl, and heteroaryl.

37. The compound of any one of claims 1-36, which is selected from the group consisting of: 1-(3-(2-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(2-fluorophenyl)-5-(p-tolyl)-1H-pyrazole; 1-(3-(1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(5-(p-tolyl)-1H-pyrazol-3-yl)-1H-indole; 1-(3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethan-1-one; 3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)isoxazole; 3-(1H-indol-3-yl)-5-(p-tolyl)isoxazole; 3-(2-fluorophenyl)-5-(p-tolyl)isoxazole; (4-chlorophenyl)(3-(2-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)methanone; (3-(1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone; (3-(1-methyl-1H-indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1- yl)(phenyl)methanone; 3-(5-(m-tolyl)-1H-pyrazol-3-yl)-1H-indole; 1-methyl-3-(5-(m-tolyl)-1H-pyrazol-3-yl)-1H-indole; 3-(5-benzyl-1H-pyrazol-3-yl)-1H-indole; 3-(5-benzyl-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-fluorophenyl)-1H-pyrazol-3-yl)-1-methyl-1H-indole; 3-(5-(2-fluorophenyl)-1H-pyrazol-3-yl)-1H-indole; 3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)-1H-indole; 3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)-1-methyl-1H-indole; 1-(3-(2-fluorophenyl)-5-(1H-indol-3-yl)-1H-pyrazol-1-yl)ethan-1-one; 1-(3-(2-fluorophenyl)-5-(1-methyl-1H-indol-3-yl)-1H-pyrazol-1-yl)ethan-1-one; 3-(5-(p-tolyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine; N-(p-tolyl)-1H-indole-3-carboxamide; 4-(3-(1H-indol-3-yl)-1H-pyrazol-5-yl)benzonitrile; (E)-N'-((1H-indol-3-yl)methylene)-4-methylbenzenesulfonohydrazide; and 3-(5-(p-tolyl)-1H-pyrazol-3-yl)quinoline.

38. A pharmaceutical composition comprising at least one compound of any one of - 101 - 55405813.2Attorney Docket No.046483-7421WO1(03880) claims 1-37 and a pharmaceutically acceptable carrier.

39. The pharmaceutical composition of claim 38, further comprising at least one additional agent.

40. The pharmaceutical composition of claim 39, wherein the at least one additional agent is selected from the group consisting of an EGFR inhibitor, KRasG12Cinhibitor, a PI3K inhibitor, a RAF inhibitor, and a cytotoxic agent.

41. The pharmaceutical composition of claim 40, wherein at least one of the following applies: (a) the EGFR inhibitor is at least one selected from the group consisting of gefitinib, afatinib, erlotinib, osimertinib, neratinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, and vandetanib; (b) the KRasG12Cinhibitor is at least one selected from the group consisting of adagrasib (MRTX849), sotorasib (AMG510), ARS-853, ARS-1620, JNJ-74699157 (ARS- 3248), LY3499446 / LY3537982, GDC-6036, D-1553, JDQ443, and BI1823911; (c) the PI3K inhibitor is at least one selected from the group consisting of aliqopa, alpelisib, copanlisib, copiktra, duvelisib, idelalisib, piqray, ukoniq, umbralisib, zydelig, buparlisib, dactolisib, leniolisib, parsaclisib, paxalisib, taselisib, inavolisib, apitolisib, bimiralisib, eganelisib, fimepinostat, gedatolisib, linperlisib, nemairilisib, pictilisib, pilaralisib, samotolisib, seletalisib, serabelisib, sonolisib, tenalisib, voxtalisib, AMG 319, AZD8186, GSK2636771, and SF1126; (d) the RAF inhibitor is at least one selected from the group consisting of PLX4720, PLX4032, BAY 43-9006 (sorafenib), vemurafenib (zelboraf), dabrafenib (tafinlar), encorafenib (braftovi), cobimetinib (cotellic), binimetinib (mektovi), ZM 336372, RAF 265, AAL-881, LBT-613 (Novartis), and CJS352. PLX4720, PLX4032, BAY 43-9006 (sorafenib), ZM 336372, and RAF 265; and (e) the cytotoxic agent is at least one selected from the group consisting of paclitaxel, doxorubicin, cyclophosphamide, methotrexate, fluorouracil, cisplatin, carboplatin, vinblastine, vincristine, etoposide, bleomycin, mitomycin c, gemcitabine, irinotecan, topotecan, docetaxel, camptothecin, melphalan, busulfan, chlorambucil, dacarbazine, procarbazine, temozolomide, bendamustine, oxaliplatin, ifosfamide, lomustine, streptozocin, daunorubicin, idarubicin, fludarabine, cladribine, pentostatin, mercaptopurine, azathioprine, - 102 - 55405813.2Attorney Docket No.046483-7421WO1(03880) hydroxyurea, thiotepa, mitoxantrone, teniposide, cytarabine, decitabine, clofarabine, nelarabine, azacytidine, eribulin, cabazitaxel, liposomal doxorubicin, pegylated liposomal doxorubicin, trabectedin, and ixabepilone.

42. A method of treating, preventing, and / or ameliorating cancer in a subject, the method comprising administering to the subject at least one compound of any one of claims 1-37 and / or the pharmaceutical composition of any one of claims 38-41.

43. A method of treating, preventing, and / or ameliorating cancer in a subject, the method comprising administering to the subject at least one compound of Formula (IV), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein:R1is selected from the group ;R3aand R3bare each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, halogen, CN, and NO2, wherein R3bcan be present or absent; X is selected from the group consisting of N(R4) and O; L is selected from the group consisting of optionally substituted methylene and a bond; - 103 - 55405813.2Attorney Docket No.046483-7421WO1(03880) R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6alkyl and optionally substituted C6-C10 aryl; Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl,substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C10heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1and Rb2, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C10 heteroaryl; and bond a is a single bond or a double bond, wherein one of the following applies: (a) bond a is a single bond and each of R2a, R2b, R3a, and R3bare present; or (b) bond a is a double bond, R2aand R3aare present, and R2band R3bare absent.

44. The method of claim 42 or 43, wherein the cancer is of the lung, pancreas, bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, and / or uterus.

45. The method of any one of claims 42-44, wherein the cancer is of the lung and / or pancreas.

46. The method of any one of claims 42-45, wherein the cancer comprises RTK driven cancer and / or Ras driven cancer.

47. The method of any one of claims 42-46, wherein the at least one compound - 104 - 55405813.2Attorney Docket No.046483-7421WO1(03880) selectively inhibits a DHHC enzyme.

48. The method of claim 47, wherein the DHHC enzyme is DHHC20.

49. The method of any one of claims 46-48, wherein the DHHC enzyme is selectively inhibited over kinesin spindle protein (KSP).

50. The method of any one of claims 42-49, wherein EGFR palmitoylation is inhibited.

51. The method of any one of claims 42-50, wherein the subject is administered at least one additional agent.

52. The method of claim 51, wherein the at least one additional agent is selected from the group consisting of an EGFR inhibitor, KRasG12Cinhibitor, a PI3K inhibitor, a RAF inhibitor, and a cytotoxic agent.

53. The method of claim 52, wherein at least one of the following applies: (a) the EGFR inhibitor is at least one selected from the group consisting of gefitinib, afatinib, erlotinib, osimertinib, neratinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, and vandetanib; (b) the KRasG12Cinhibitor is at least one selected from the group consisting of adagrasib (MRTX849), sotorasib (AMG510), ARS-853, ARS-1620, JNJ-74699157 (ARS- 3248), LY3499446 / LY3537982, GDC-6036, D-1553, JDQ443, and BI1823911; (c) the PI3K inhibitor is at least one selected from the group consisting of aliqopa, alpelisib, copanlisib, copiktra, duvelisib, idelalisib, piqray, ukoniq, umbralisib, zydelig, buparlisib, dactolisib, leniolisib, parsaclisib, paxalisib, taselisib, inavolisib, apitolisib, bimiralisib, eganelisib, fimepinostat, gedatolisib, linperlisib, nemairilisib, pictilisib, pilaralisib, samotolisib, seletalisib, serabelisib, sonolisib, tenalisib, voxtalisib, AMG 319, AZD8186, GSK2636771, and SF1126; (d) the RAF inhibitor is at least one selected from the group consisting of PLX4720, PLX4032, BAY 43-9006 (sorafenib), vemurafenib (zelboraf), dabrafenib (tafinlar), encorafenib (braftovi), cobimetinib (cotellic), binimetinib (mektovi), ZM 336372, RAF 265, AAL-881, LBT-613 (Novartis), and CJS352. PLX4720, PLX4032, BAY 43-9006 - 105 - 55405813.2Attorney Docket No.046483-7421WO1(03880) (sorafenib), ZM 336372, and RAF 265; and (e) the cytotoxic agent is at least one selected from the group consisting of paclitaxel, doxorubicin, cyclophosphamide, methotrexate, fluorouracil, cisplatin, carboplatin, vinblastine, vincristine, etoposide, bleomycin, mitomycin c, gemcitabine, irinotecan, topotecan, docetaxel, camptothecin, melphalan, busulfan, chlorambucil, dacarbazine, procarbazine, temozolomide, bendamustine, oxaliplatin, ifosfamide, lomustine, streptozocin, daunorubicin, idarubicin, fludarabine, cladribine, pentostatin, mercaptopurine, azathioprine, hydroxyurea, thiotepa, mitoxantrone, teniposide, cytarabine, decitabine, clofarabine, nelarabine, azacytidine, eribulin, cabazitaxel, liposomal doxorubicin, pegylated liposomal doxorubicin, trabectedin, and ixabepilone.

54. The method of any one of claims 42-53, wherein the subject is further subjected to trans-arterial chemoembolization (TACE) or trans-arterial embolization (TAE).

55. The method of any one of claims 42-54, wherein the subject is a mammal.

56. The method of claim 55, wherein the mammal is a human.

57. A method of inhibiting palmitoylation in a subject, the method comprising administering to the subject at least one compound of any one of claims 1-37.

58. A method of inhibiting palmitoylation in a subject, the method comprising administering to the subject at least one compound of Formula (IV), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein:R1is selected from the group consisting of ;- 106 - 55405813.2Attorney Docket No.046483-7421WO1(03880) R2ais selected from the group consisting of ; R2bis H or absent; R3aand R3bare eachof H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2, wherein R3bcan be present or absent; and X is selected from the group consisting of N(R4) and O; L is selected from the group consisting of optionally substituted methylene and a bond; R4is selected from the group consisting of H and C(=O)R5; R5is selected from the group consisting of optionally substituted C1-C6alkyl and optionally substituted C6-C10 aryl; Ra1, Ra2, Ra3, Ra4, Ra5, and Ra6are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, optionally substituted C2-C10 heteroaryl, halogen, ORd1, N(Rd1)(Rd2), CN, and NO2; Rb1and Rb2, if present, are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl; Rc1, Rc2, Rc3, Rc4, and Rc5are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, halogen, CN, and NO2; Rd1and Rd2are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10 heteroaryl; and bond a is a single bond or a double bond, wherein one of the following applies: (a) bond a is a single bond and each of R2a, R2b, R3a, and R3bare present; or (b) bond a is a double bond, R2aand R3aare present, and R2band R3bare - 107 - 55405813.2Attorney Docket No.046483-7421WO1(03880) absent.

59. The method of claim 57 or 58, wherein palmitoylation of EGFR is inhibited.

60. The method of any one of claims 57-59, wherein a palmitoyl transferase is inhibited.

61. The method of claim 60, wherein the palmitoyl transferase is DHHC20.

62. The method of claim 60 or 61, wherein the palmitoyl transferase is selectively inhibited.

63. The method of claim 62, wherein the palmitoyl transferase is selectively inhibited over kinesin spindle protein (KSP). - 108 - 55405813.2

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