Methods and compositions for inhibiting metastasis of solid tumors

Abstract

Methods and pharmaceutical compositions for inhibiting metastasis of a solid tumor such as renal cell carcinoma (RCC), breast, CNS, adrenal or pancreatic cancer in a subject are provided. Compositions comprising a statin or analogue thereof are useful for such purposes.

Description

[0001] P-632882-PC METHODS AND COMPOSITIONS FOR INHIBITING METASTASIS OF SOLID TUMORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional patent application serial no. 63 / 545,424, filed October 24, 2023, which is incorporated herein by reference in its entirety. GOVERNMENT SUPPORT

[0002] This invention was made with government support under Grant Number CA016042, awarded by National Institutes of Health and under Grant Number W81XWH-20-1-0918, awarded by the U.S. Department of Defense. The government has certain rights in the invention. FIELD

[0003] Provided herein are pharmaceutical compositions and methods for treating, inhibiting and preventing metastasis of solid tumors such as renal cell carcinoma, breast, CNS, adrenal and pancreatic tumors. BACKGROUND

[0004] Renal cell carcinoma (RCC) is the most common cancer of the kidney, and it arises from the epithelial cells of renal cortex. RCC consistently ranks amongst the top ten most prevalent malignancies in the world, with over 62,000 and 250,000 newly diagnosed cases annually in US and worldwide, respectively. RCC is characterized by a wide range of histological subtypes with variable clinical behaviors. The clear cell subtype of RCC (ccRCC) makes up over 70% of RCC, and features tumor cells with abundant clear cytoplasms and acentric nuclei. Patients with localized disease are treated with nephrectomy and have a favorable 5-year survival of 73%. Unfortunately, approximately 30% of patients will develop metastatic disease, frequently spreading to distant vital organs, such as the lung. Despite the development of new targeted therapies, patients with metastatic ccRCC have a very poor outcome with a median survival of 13 months and a five-year survival rate of only 11%. P-632882-PC

[0005] Detailed studies of the von Hippel–Lindau (VHL) disease, a rare hereditary cancer syndrome manifested by renal, CNS, adrenal and pancreatic tumors, led to the identification and cloning of the VHL tumor suppressor gene. VHL plays an integral role in the pathogenesis of the sporadic, non-familial form of ccRCC, as somatic mutations of this gene are reported to be seen in as high as 90% of cancer cases, the majority being missense or nonsense loss of function mutations. Seminal research in the last two decades have unraveled the VHL protein’s intricate and important function as an E3 ubiquitin ligase that targets the degradation of the alpha subunit of hypoxia inducible transcription factors (HIF-αs) in an oxygen-dependent manner. The constitutive activation of the HIF pathway through loss of VHL function has implicated this pathway as an oncogenic driver and therapeutic target. Despite intensive investigative efforts, the precise oncogenic mechanism of VHL loss remains elusive. Numerous mouse models of renal tubule targeted deletion of VHL gene have failed to generate renal lesions beyond preneoplastic cysts, even when combined with deletion of other tumor suppressor genes such as PTEN or p53. It is clear that the loss of VHL function upregulates both HIF1α and HIF2α, however these two paralogs appear to have distinct and often contrary roles in their gene regulatory activities. Recent research suggests that HIF2α plays a dominant oncogenic role, whereas HIF1α is tumor suppressive in ccRCC. These opposing oncogenic roles of HIF1α (HIF1A) and HIF2α (HIF2A) are an active area of debate.

[0006] The potential contribution of VHL loss or its downstream effectors to metastatic progression is also poorly defined. The analysis of numerous ccRCC clinical specimen was unable to find a significant correlation between VHL mutation status and clinical outcome. It has been reported that the silencing or deletion of the VHL gene consistently resulted in epithelial to mesenchymal transition (EMT). EMT is an embryonic program used by polarized epithelial cells to break away from cell-cell contacts and basement membrane attachment, enabling cellular migration to distant sites. It is highly reminiscent of the process that carcinomas adapt during metastatic spread, although the direct role of EMT in cancer metastasis is under debate.

[0007] Accordingly, there exists a need for compositions and methods for treating metastasis of cancers, in particular metastasis of clear cell renal cell carcinoma as well as CNS, adrenal and pancreatic tumors, among others. P-632882-PC SUMMARY

[0008] In one aspect, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (IV) or a thereof, or lactone thereof, wherein R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group; R2 and R3 taken together form an optionally substituted 3-14 membered ring; and R4 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl ring.

[0009] In some embodiments, R1 is an optionally substituted alkyl group. In some embodiments, alkyl is C1-C6alkyl, an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11. In some embodiments, R1 is aryl, such as phenyl. In some embodiments, R2 and R3 taken together with the carbons to which they are bound form a phenyl group, wherein the phenyl ring is optionally substituted with one or more alkyl groups, such as 4-methylindolyl, 5-methylindolyl, 6- methylindolyl or 7-methylindolyl. In some embodiments, R4 is an optionally substituted alkyl group, such as C1-C6alkyl, 1-propyl group, 2-propyl group, propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11. In some embodiments, R4 is an aryl group, such as a phenyl group, optionally substituted with one or more independent halo, alkyl, or haloalkyl, such as p-fluorophenyl, p-tolyl, p-chlorophenyl, p- bromophenyl or p-F3C-phenyl. P-632882-PC

[0010] In some embodiments, the compound of Formula (IV) is fluvastatin or an analogue thereof.

[0011] In some embodiments, the compound of Formula (IV) is any one of: Compound D

[0002] P-632882-PC

[0012] In one aspect, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein R is H or an optionally substituted alkyl.

[0013] In some embodiments, R is a C1-C6 alkyl group such as an ethyl group, a 1-propyl group or a 2-propyl group, or an optionally substituted cycloalkyl or aryl group such as phenyl. In some P-632882-PC embodiments, R is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11 or CH2CH2C6H11.

[0014] In some embodiments, the compound of Formula (I) is fluvastatin or an analogue thereof.

[0015] In some embodiments, the compound of Formula (I) is any one of

[0016] In one aspect, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (Ia) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein each R is independently H, optionally substituted alkyl, halo, carboxyl, or -CF3.

[0017] In some embodiments, alkyl is C1-C6 alkyl, 2-CH3 and 4-F; 3,5-(CH3)2; 3-CH3 and 4-F; H; 3,5-(CH3)2, 4-F; 4-CF3; 2-CH3; 4-CH3; 5-Br, 5-Cl or 4-CO2Na. P-632882-PC

[0018] In some embodiments, the compound of Formula (Ia) is fluvastatin or an analogue thereof.

[0019] In some embodiments, the compound of Formula (1a) is among:

[0020] In one aspect, a method is provided for inhibiting metastasis of a solid tumor such in a subject comprising administering to the subject a compound of Formula (II) or a racemate, enantiomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a lactone thereof, wherein R1is H or optionally substituted alkyl, and R2 is H, optionally substituted alkyl, hydroxy or an optionally substituted aryl group. P-632882-PC

[0021] In some embodiments, R1is H, alkyl, C1-C6alkyl, methyl, ethyl, n-propyl, i-propyl or butyl. In some embodiments, R2 is H, OH, alkyl, such as methyl, ethyl, n-propyl, i-propyl or butyl, or an optionally substituted phenyl group.

[0022] In some embodiments, the compound of Formula (II) is an analogue of pravastatin.

[0023] In one aspect, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (III) or a pharmaceutically or diastereomer thereof, or a β-hydroxy acid open ring form, wherein R1 is selected from an optionally substituted alkyloyl or heterocyclyl group; and R2 is selected from an optionally substituted alkyl or heterocyclyl group.

[0024] In some embodiments, R1 is an optionally substituted alkyloyl group such as 2- methylbutanoyl. In some embodiments, R2 is an optionally substituted alkyl group such as C1-C6alkyl, methyl; or an optionally substituted heterocyclyl group.

[0025] In some embodiments, the compound of Formula (III) is lovastatin, simvastatin or mevastatin or an analogue thereof. P-632882-PC

[0026] In one aspect, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (V) or or diastereomer thereof, or lactone thereof, wherein R1 is an optionally substituted aryl, heteroaryl or heterocyclyl ring; R2 is an optionally substituted alkyl group; R3 and R4 are independently, optionally substituted alkyl.

[0027] In some embodiments, R1 is an aryl group such as phenyl group optionally substituted with one or more halo, alkyl, or haloalkyl, such as p-fluorophenyl, p-tolyl, p-chlorophenyl. p- bromophenyl, or p-F3C-phenyl. In some embodiments, R2 is C1-6alkyloxy-C1-6alkyl, such as methoxymethyl. In some embodiments, R3 and R4 are independently a C1-C6alkyl, such as an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

[0028] In some embodiments, the compound of Formula (V) is cerivastatin.

[0029] In one aspect, a pharmaceutical composition is provided for inhibiting metastasis of a solid tumor in a subject comprising a compound of Formula (IV) P-632882-PC or a thereof, or lactone thereof, wherein R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group; R2 and R3 taken together form an optionally substituted 3-14 membered ring; and R4 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl ring.

[0030] In some embodiments, R1 is an optionally substituted alkyl group. In some embodiments, alkyl is C1-C6alkyl, an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11. In some embodiments, R1 is aryl, such as phenyl. In some embodiments, R2 and R3 taken together with the carbons to which they are bound form a phenyl group, wherein the phenyl ring is optionally substituted with one or more alkyl groups, such as 4-methylindolyl, 5-methylindolyl, 6- methylindolyl or 7-methylindolyl. In some embodiments, R4 is an optionally substituted alkyl group, such as C1-C6alkyl, 1-propyl group, 2-propyl group, propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11. In some embodiments, R4 is an aryl group, such as a phenyl group, optionally substituted with one or more independent halo, alkyl, or haloalkyl, such as p-fluorophenyl, p-tolyl, p-chlorophenyl, p- bromophenyl or p-F3C-phenyl.

[0031] In some embodiments, the pharmaceutical composition comprising the compound of Formula (IV) is fluvastatin or an analogue thereof. P-632882-PC

[0032] In some embodiments, the pharmaceutical composition comprising the compound of Formula (IV) is any one of: Compound D

[0003] P-632882-PC

[0033] In one aspect, a pharmaceutical composition is provided for inhibiting metastasis of a solid tumor in a subject comprising a compound of Formula (I) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein R is H or an optionally substituted alkyl.

[0034] In some embodiments, R is a C1-C6 alkyl group such as an ethyl group, a 1-propyl group or a 2-propyl group, or an optionally substituted cycloalkyl or aryl group such as phenyl. In some P-632882-PC embodiments, R is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11 or CH2CH2C6H11.

[0035] In some embodiments, the pharmaceutical composition comprising the compound of Formula (I) is fluvastatin or an analogue thereof.

[0036] In some embodiments, the pharmaceutical composition comprising the compound of Formula (I) is any one of

[0037] In one aspect, a pharmaceutical composition is provided for inhibiting metastasis of a solid tumor in a subject comprising a compound of Formula (Ia) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein each R is independently H, optionally substituted alkyl, halo, carboxyl, or -CF3. P-632882-PC

[0038] In some embodiments, alkyl is C1-C6alkyl, 2-CH3and 4-F; 3,5-(CH3)2; 3-CH3and 4-F; H; 3,5-(CH3)2, 4-F; 4-CF3; 2-CH3; 4-CH3; 5-Br, 5-Cl or 4-CO2Na.

[0039] In some embodiments, the pharmaceutical composition comprising the compound of Formula (Ia) is fluvastatin or an analogue thereof.

[0040] In some embodiments, the pharmaceutical composition comprising the compound of Formula (1a) is among:

[0041] In one aspect, a pharmaceutical composition is provided the for inhibiting metastasis of a solid tumor such in a subject comprising a compound of Formula (II)

[0004] P-632882-PC or a racemate, enantiomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a lactone thereof, wherein R1 is H or optionally substituted alkyl, and R2 is H, optionally substituted alkyl, hydroxy or an optionally substituted aryl group.

[0042] In some embodiments, R1 is H, alkyl, C1-C6 alkyl, methyl, ethyl, n-propyl, i-propyl or butyl. In some embodiments, R2 is H, OH, alkyl, such as methyl, ethyl, n-propyl, i-propyl or butyl, or an optionally substituted phenyl group.

[0043] In some embodiments, pharmaceutical composition comprising the compound of Formula (II) is an analogue of pravastatin.

[0044] In one aspect, a pharmaceutical composition is provided for inhibiting metastasis of a solid tumor in a subject comprising a compound of Formula (III) or a pharmaceutically or or diastereomer thereof, or a β-hydroxy acid open ring form, wherein R1 is selected from an optionally substituted alkyloyl or heterocyclyl group; and R2 is selected from an optionally substituted alkyl or heterocyclyl group. P-632882-PC

[0045] In some embodiments, R1 is an optionally substituted alkyloyl group such as 2- methylbutanoyl. In some embodiments, R2 is an optionally substituted alkyl group such as C1-C6 alkyl, methyl; or an optionally substituted heterocyclyl group.

[0046] In some embodiments, pharmaceutical composition comprising the compound of Formula (III) is lovastatin, simvastatin or mevastatin or an analogue thereof.

[0047] In one aspect, a pharmaceutical composition is provided for inhibiting metastasis of a solid tumor in a subject comprising a compound of Formula (V) or or diastereomer thereof, or lactone thereof, wherein R1 is an optionally substituted aryl, heteroaryl or heterocyclyl ring; R2 is an optionally substituted alkyl group; R3 and R4 are independently, optionally substituted alkyl.

[0048] In some embodiments, R1 is an aryl group such as phenyl group optionally substituted with one or more halo, alkyl, or haloalkyl, such as p-fluorophenyl, p-tolyl, p-chlorophenyl. p- bromophenyl, or p-F3C-phenyl. In some embodiments, R2 is C1-6alkyloxy-C1-6alkyl, such as methoxymethyl. In some embodiments, R3 and R4 are independently a C1-C6 alkyl, such as an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11. P-632882-PC

[0049] In some embodiments, the pharmaceutical composition comprising the compound of Formula (V) is cerivastatin.

[0050] In one aspect, a method is provided for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of detecting a deletion or mutation of Von Hippel Lindau (VHL) tumor suppressor gene in a sample from the solid tumor; and upon detection of a deletion or mutation of the gene, treating the patient with any compound, formula or pharmaceutical composition described herein.

[0051] In some embodiments, of the foregoing, the solid tumor is a kidney tumor.

[0052] In one aspect, a method is provided for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of detecting evidence of spread of the tumor beyond the primary site and / or having a high histological score; and upon detection of spread or high histologic score, treating the patient with any compound, formula or pharmaceutical composition described herein.

[0053] In some embodiments, the solid tumor is a kidney tumor. In some embodiments, the spread comprises a high grade histologic criterion or spread of the tumor beyond Gerota fascia of the kidney.

[0054] In one aspect, a method is provided for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of detecting activation of the hypoxia program of gene expression in tumor cells in a sample from the solid tumor; and upon detection of hypoxia program activation, treating the patient with a compound, formula or pharmaceutical composition described herein. P-632882-PC

[0055] In some embodiments, the activation of the hypoxia program is due to mutation or loss of VHL expression.

[0056] In one aspect, a method is provided for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of detecting extracellular vesicles in a bodily fluid of a patient; and upon detection of extracellular vesicles, treating the patient with a compound, formula or pharmaceutical composition as described herein.

[0057] In some embodiments, the extracellular vesicles are detected in a ccRCC patient. In some embodiments, the bodily fluid is blood or urine.

[0058] In one aspect, a method is provided for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of detecting overexpression of periostin in tumor cells in a sample from the solid tumor; and upon detection of periostin overexpression, treating the patient with a compound, formula, or pharmaceutical composition as disclosed herein.

[0059] In one aspect a compound is provided of Formula (IV) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein P-632882-PC R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group; R2 and R3 taken together form an optionally substituted 3-14 membered ring; and R4 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl ring.

[0060] In some embodiments, R1 is an optionally substituted alkyl group. In some embodiments, alkyl is C1-C6 alkyl, an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11. In some embodiments, R1 is aryl, such as phenyl. In some embodiments, R2 and R3 taken together with the carbons to which they are bound form a phenyl group, wherein the phenyl ring is optionally substituted with one or more alkyl groups, such as 4-methylindolyl, 5-methylindolyl, 6- methylindolyl or 7-methylindolyl. In some embodiments, R4 is an optionally substituted alkyl group, such as C1-C6alkyl, 1-propyl group, 2-propyl group, propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11. In some embodiments, R4 is an aryl group, such as a phenyl group, optionally substituted with one or more independent halo, alkyl, or haloalkyl, such as p-fluorophenyl, p-tolyl, p-chlorophenyl, p- bromophenyl or p-F3C-phenyl.

[0061] In some embodiments, the compound of Formula (IV) is any one of:

[0005] P-632882-PC

[0062] In one aspect, a compound is provided of Formula (I) P-632882-PC or a pharmaceutically enantiomer or diastereomer thereof, or lactone thereof, wherein R is H or an optionally substituted alkyl.

[0063] In some embodiments, R is a C1-C6alkyl group such as an ethyl group, a 1-propyl group or a 2-propyl group, or an optionally substituted cycloalkyl or aryl group such as phenyl. In some embodiments, R is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11or CH2CH2C6H11.

[0064] In some embodiments, the compound of Formula (I) is any one of

[0065] In one aspect, a compound is provided of Formula (Ia) P-632882-PC or a pharmaceutically enantiomer or diastereomer thereof, or lactone thereof, wherein each R is independently H, optionally substituted alkyl, halo, carboxyl, or -CF3.

[0066] In some embodiments, alkyl is C1-C6 alkyl, 2-CH3 and 4-F; 3,5-(CH3)2; 3-CH3 and 4-F; H; 3,5-(CH3)2, 4-F; 4-CF3; 2-CH3; 4-CH3; 5-Br, 5-Cl or 4-CO2Na.

[0067] In some embodiments, the compound of Formula (1a) is among:

[0068] In one aspect, a compound is provided of Formula (II) P-632882-PC or a racemate, or a pharmaceutically acceptable salt thereof, or a lactone thereof, wherein R1is H or optionally substituted alkyl, and R2 is H, optionally substituted alkyl, hydroxy or an optionally substituted aryl group.

[0069] In some embodiments, R1is H, alkyl, C1-C6alkyl, methyl, ethyl, n-propyl, i-propyl or butyl. In some embodiments, R2is H, OH, alkyl, such as methyl, ethyl, n-propyl, i-propyl or butyl, or an optionally substituted phenyl group.

[0070] In one aspect, a compound is provided of Formula (III) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or a β-hydroxy acid open ring form, wherein P-632882-PC R1 is selected from an optionally substituted alkyloyl or heterocyclyl group; and R2 is selected from an optionally substituted alkyl or heterocyclyl group.

[0071] In some embodiments, R1 is an optionally substituted alkyloyl group such as 2- methylbutanoyl. In some embodiments, R2 is an optionally substituted alkyl group such as C1-C6alkyl, methyl; or an optionally substituted heterocyclyl group.

[0072] In one aspect, a compound is provided of Formula (V) or or diastereomer thereof, or lactone thereof, wherein R1 is an optionally substituted aryl, heteroaryl or heterocyclyl ring; R2 is an optionally substituted alkyl group; R3 and R4 are independently, optionally substituted alkyl.

[0073] In some embodiments, R1 is an aryl group such as phenyl group optionally substituted with one or more halo, alkyl, or haloalkyl, such as p-fluorophenyl, p-tolyl, p-chlorophenyl. p- bromophenyl, or p-F3C-phenyl. In some embodiments, R2 is C1-6alkyloxy-C1-6alkyl, such as methoxymethyl. In some embodiments, R3 and R4 are independently a C1-C6 alkyl, such as an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11.

[0074] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure P-632882-PC belongs. Other features and advantages of the present disclosure will become apparent from the following detailed description examples and figures. It should be understood, however, that the detailed description and the specific examples while indicating certain embodiments disclosed herein are given by way of illustration only, since various changes and modifications within the spirit and scope disclosed herein will become apparent to those skilled in the art from this detailed description. It is also contemplated that whenever appropriate, any embodiment of the present disclosure can be combined with one or more other embodiments of the present disclosure, even though the embodiments are described under different aspects of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] FIGS. 1A-1B show the VHL heterogeneity in a clinical specimen of renal cell carcinoma (RCC). Fig. 1A: Survey of 26 cases of RCC by IHC showed heterogeneous VHL expression in a great majority of RCC cases; none showed uniform VHL negative. VHL in the primary tumor (Fig. 1B) of case #22. Boxed areas are magnified. Case #22 is the most aggressive metastatic ccRCC, in which the patient succumbed in one year after diagnosis.

[0076] FIGS. 2A-2B-2C-2D show that VHL-KO cells cooperate with VHL-WT cells to induce metastasis. Fig. 2A: VHL-KO RENCA cells alone (middle) grew poorly in mice. VHL-WT cells (top) established renal tumors but were not metastatic. Equal mixture of VHL-KO and VHL-WT cells (5x10^5 cells each) induced robust renal tumors and lung metastases (bottom). Fig. 2B: Histological analysis showed greatly increased lung metastases in mixed compared to VHL-WT tumor. Fig. 2C: in vitro VHL-KO cells migrate faster than VHL-WT cells. In co-culture, the presence of VHL-KO cells induces the motility of VHL-WT cells. Fig. 2D: in the cooperative metastasis model, the VHL-KO cells drive metastasis by promoting the growth and migration of VHL-WT cells via extracellular vesicles (EVs).

[0077] FIGS.3A-3B-3C-3D show that extracellular vesicles (EVs) mediate communication from VHL-KO to VHL-WT cells. Fig. 3A: The yield of EVs is 4 times higher in VHL-KO cells. Fig. 3B: A transmission EM image of EVs isolated from VHL-KO cells, size 30-150 nm. Fig.3C: The EVs from VHL-KO cells, labeled with lipophilic dye PKH26, are taken up into the cytoplasm of P-632882-PC VHL-WT cells as visualized by confocal microscopy. Fig. 3D: The addition of EVs induces growth of VHL-WT cells.

[0078] FIGS.4A-4B-4C shows that high throughput screening (HTS) identified statins’ ability to inhibit VHL-KO cells. Fig. 4A: HTS with VHL-KO cells labeled with EGFP and VHL-WT cells labeled with strawberry RFP were used to screen 2530 FDA approved compounds. Images of cells after 48 hrs of drug treatment of three lighted groups were shown. Three statins were identified to exhibit selective toxicity to VHL-KO cells. Fig. 4B: Cell culture studies validated simvastatin’s selective inhibition of the growth of VHL-KO cells compared to VHL-WT cells. Fig. 4C: The addition of simvastatin to 1:1 mixed tumors established on duck CAM also reduced their tumor growth.

[0079] FIGS. 5A-5B show Fig. 5A, the Cre-lox reporter system used in the present studies to explore exosome-mediated crosstalk, and Fig. 5B, that certain statins inhibit VHL-KO ccRCC cells selectively.

[0080] FIGS. 6A-6B-6C-6D-6E-6F-6G-6H show, in Figs. 6A-6G, that an avian chorioallantoic membrane (CAM) model supports ccRCC of patient-derived xenograft (PDX) growth and metastasis of mammalian tumors, and H) that day 10 after implanting 1:1 VHL-KO:VHL-WT at embryonic day 7, at embryonic day 17, simvastatin inhibits metastasis. Fig. 6A: Tumor cells are implanted on upper CAM. Rich blood supply enables metastatic spread into the chick embryo. Fig. 6B: Longitudinal growth of CAM tumors (in triplicate) established from primary tumor cell line from a patient’s tumor, Case #25, Fig. 1A. Growth (Fig.6C) and vascular invasion represented by circulating tumor cells (Fig. 6D) of VHL-WT, VHL-KO and mixed RENCA tumors fully recapitulate their behaviors in mice. Fig. 6E: Intravascular injection of drugs on substrate into the chorionic vein will enable assessment of imaging and therapeutic activities in the tumor. Luciferase and bioluminescence (Fig.6F) and F18-FDG positron emission tomography (PET) / CT imaging (Fig. 6G) can be used to monitor tumor growth and therapeutic effects. FIG. 6I shows a timeline of experiment, treated 10 days with 0, 1 or 5uM simvastatin. FIG.6J shows tumor weight in the experiment.

[0081] FIGS. 7A-7B show a mouse model (Fig. 7A) to evaluate metastasis of the cooperative effect of VHL-KO and VHL-WT cells (Fig. 7B). P-632882-PC

[0082] FIG. 8 shows the IC50s of statins on growth of VHL-KO and VHL-WT cells in vitro.

[0083] FIG. 9 depicts a cooperative metastasis model for metastatic spread to the lung.

[0084] FIGS. 10A-10B-10C show the metastatic driving activities of VHL-Neg cells. The presence of VHL-Neg cells in co-culture induced EMT changes (Fig. 10A), cellular motility (Fig. 10B), and proliferation (Fig. 10C) of VHL-Pos cells. FIG. 10D shows a summary of the cell- intrinsic and extrinsic changes induced by VHL gene deletion and the upregulation of hypoxia program in VHL-Neg cells, leading to decreased growth and increased EMT and motility. Increased secretion of soluble factors mediates the paracrine instructions of metastasis.

[0085] FIGS. 11A-11B-11C-11D-11E-11F show dose response of statins in murine and human RCC cell lines. Fig. 11A: Initial therapeutic activity of 4 statins in VHL-Pos and VHL-Neg RENCA cells. Fig. 11B: Detailed dosage titration of 4 statins in VHL-Neg cells. Fig. 11C: Rank order of 8 statins’ therapeutic response in RENCA VHL-Neg cells. Therapeutic response in 3 VHL-Neg human ccRCC models: RCC-4 (Fig. 11D), 786-O (Fig. 11E), and primary cell line #2- 1006 (Fig. 11F) are shown.

[0086] FIGS. 12A-12B-12C-12D show no impact of HMG-CR silencing on the growth or statin treatment response. Fig. 12A: Shutdown of HMG-CR expression assessed by qPCR. Fig. 12B: Shutdown of HMG-CR has no impact on the growth of RENCA VHL-Neg cells. Treatment response with Simvastatin (Fig.12C) or Fluvastatin (Fig.12D) in HMG-CR shutdown cells remain the same as non-shutdown VHL-Neg cells. DETAILED DESCRIPTION

[0087] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present disclosure.

[0088] The following abbreviations are used herein. CAM- chorioallantoic membrane model; CRISPR / Cas9 – Clustered regularly interspaced short palindromic repeats (CRISPR)-associated P-632882-PC protein 9; ccRCC – Clear cell renal cell carcinoma; EVs – Extracellular vesicles; HTS- High throughput drug screen; PDXs – Patient-derived xenografts; RENCA – Renal cortical adenocarcinoma cell line; VHL – von Hippel-Lindau syndrome gene; VHL-KO – von Hippel- Lindau syndrome gene (VHL) knockout (also referred to as VHL-neg, VHL-null or VHL-) ; VHL- WT – wild-type von Hippel-Lindau syndrome gene (VHL) (also referred to as VHL-pos or VHL+).

[0089] A new mechanism of metastasis in ccRCC was described that relies on the metastatic crosstalk between two distinct tumor cell populations (PCT / US2020 / 19601, published as WO2020 / 176446; Hu J, Schokrpur S, Archang M, Hermann K, Sharrow AC, Khanna P, Novak J, Signoretti S, Bhatt RS, Knudsen BS, Xu H, Wu L. A Non-integrating Lentiviral Approach Overcomes Cas9-Induced Immune Rejection to Establish an Immunocompetent Metastatic Renal Cancer Model. Mol Ther Methods Clin Dev. 20189:203-210; Schokrpur S, Hu J, Moughon DL, Liu P, Lin LC, Hermann K, Mangul S, Guan W, Pellegrini M, Xu H, Wu L. CRISPR-Mediated VHL Knockout Generates an Improved Model for Metastatic Renal Cell Carcinoma. Sci Rep. 20166:29032. https: / / doi.org / 10.1038 / srep29032). Tumors with both VHL(-) and VHL(+) cells metastasize rampantly to lungs but tumors with either cell type alone do not. This unexpected finding indicates a cooperative metastatic mechanism is at play. Additionally, the VHL(-) cells are the metastatic drivers. They produce a high amount of extracellular vesicles (EVs) that induce the proliferation and aggression of the VHL(+) cells. Several statins (simvastatin, lovastatin and fluvastatin) were identified by a high throughput screen (HTS) to possess the ability to selectively inhibit the metastatic driver VHL(-) cells and suppress their EV-mediated signaling. A Cre-loxP EV reporter system was created facilitates the identification and study of drugs that can disrupt the EV-mediated metastatic crosstalk. An innovative avian chorioallantoic membrane (CAM) tumor model system that will enable assessment of the efficacy of the identified hit compounds to suppress metastasis in vivo in a cost- and time-efficient manner. Methods of Use

[0090] In one aspect, the disclosure provides a method for inhibiting metastasis of a solid tumor in a subject, such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, comprising administering to the subject a compound of Formula (IV) P-632882-PC or a thereof, or lactone thereof, wherein R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group; R2 and R3 taken together form an optionally substituted 3-14 membered ring; and R4 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl ring.

[0091] In certain embodiments, R1 is an optionally substituted alkyl group. In some embodiments, alkyl is C1-C6alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group, a 2-propyl group, or a propynyl group. In some embodiments, R1 is CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11.

[0092] In some embodiments, R1 is aryl. In some embodiments, R1 is phenyl.

[0093] In certain embodiments, R2 and R3 taken together with the carbons to which they are bound form a phenyl group. In some embodiments, the phenyl ring is substituted with one or more alkyl groups. In some embodiments, the alkyl group is methyl. In some embodiments, the alkyl is 4- methylindolyl, 5-methylindolyl, 6-methylindolyl or 7-methylindolyl.

[0094] In certain embodiments, R4 is an optionally substituted alkyl group. In some embodiments, alkyl is C1-C6alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group, a 2-propyl group, or a propynyl group. In some embodiments, R1 is CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11. P-632882-PC

[0095] In certain embodiments, R4 is an optionally substituted aryl group. In some embodiments, the aryl group is a phenyl group optionally substituted with one or more independent halo, alkyl, or haloalkyl. In certain embodiments, R4 is p-fluorophenyl. In certain embodiments, R4 is p-tolyl. In certain embodiments, R4 is p-chlorophenyl. In some embodiments, R4 is p-bromophenyl. In certain embodiments, R4 is p-F3C-phenyl.

[0096] In some embodiments, R1 is lower alkyl, R2 and R3 taken together is an optionally substituted phenyl, and R4 is an optionally substituted phenyl group. In some embodiments, R1 is lower alkyl, R2 and R3 taken together is an alkyl, halo or haloalkyl substituted phenyl, and R4 is an optionally substituted phenyl group.

[0097] In some embodiments, when R1 is 2-propyl and R4 is p-fluorophenyl, R2 and R3 taken together is an optionally substituted phenyl, such as alkyl, halo or haloalkyl substituted phenyl. In some embodiments, the alkyl is 4-methylindolyl, 5-methylindolyl, 6-methylindolyl or 7- methylindolyl, or any combination thereof.

[0098] In some embodiments, when R2 and R3 taken together is phenyl and R4 is p-fluorophenyl, R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group. In some embodiments, R1 is alkyl. In some embodiments, alkyl is C1-C6 alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group or a 2-propyl group. In some embodiments, R1 is phenyl. In some embodiments, R1 is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

[0099] In some embodiments, when R2 and R3 taken together is phenyl and R4 is p-fluorophenyl, R1 is a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11. In some embodiments, R1 is phenyl.

[0100] In some embodiments, when R1 is 2-propyl and R2 and R3 taken together is phenyl, R4 may be an optionally substituted phenyl, such as one or more independent alkyl, halo or haloalkyl. In some embodiments, alkyl is a lower alkyl. In some embodiments, haloalkyl is CF3. In some embodiments CF3is p-CF3. P-632882-PC

[0101] In some embodiments, a racemate is provided of a compound of Formula (IV). In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (IV). In some embodiments, the compound of Formula (IV) is 3R,5S. In some embodiments, the compound of Formula (IV) is 3S,5R. In some embodiments, the compound of Formula (IV) is 3R,5S,6E. In some embodiments, the compound of Formula (IV) is 3S,5R,6E. In some embodiments, the compound of Formula (IV) has the same stereochemistry as fluvastatin ((3R,5S,6E)-7-[3-(4- fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid). In some embodiments, the compound of Formula (IV) is ((3S,5R,6E)-7-[3-(4-fluorophenyl)-1-(propan-2- yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid).

[0102] In some embodiments, the compound of Formula (IV) is a lactone.

[0103] In certain embodiments, the compound of Formula (IV) does not have substantial HMG- CoA reductase activity.

[0104] In certain embodiments, the compound of Formula (IV) is fluvastatin or an analogue thereof. In certain embodiments, the compound of Formula (IV) is fluvastatin.

[0105] In some embodiments, the compound of Formula (IV) is

[0006] P-632882-PC

[0106] In one aspect, the disclosure provides a method for inhibiting metastasis of a solid tumor such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, the method comprising administering to the subject a compound of Formula (I). P-632882-PC or a pharmaceutically enantiomer or diastereomer thereof, or lactone thereof, wherein R is H or an optionally substituted alkyl.

[0107] In certain embodiments, R is a C1-C6 alkyl group. In certain embodiments, R is an ethyl group, a 1-propyl group or a 2-propyl group. In some embodiments, the alkyl is substituted with an optionally substituted cycloalkyl or aryl group. In some embodiments, aryl is phenyl.

[0108] In some embodiments, R is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

[0109] In some embodiments, a racemate is provided of a compound of Formula (I). In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (I). In some embodiments, the compound of Formula (I) is 3R,5S. In some embodiments, the compound of Formula (I) is 3S,5R. In some embodiments, the compound of Formula (I) is 3R,5S,6E. In some embodiments, the compound of Formula (I) is 3S,5R,6E. In some embodiments, the compound of Formula (I) has the same stereochemistry as fluvastatin ((3R,5S,6E)-7-[3-(4-fluorophenyl)-1- (propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid). In some embodiments, the compound of Formula (I) is ((3S,5R,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]- 3,5-dihydroxyhept-6-enoic acid).

[0110] In some embodiments, the compound of Formula (I) is a lactone. P-632882-PC

[0111] In certain embodiments, the compound of Formula (I) does not have substantial HMG- CoA reductase activity.

[0112] In certain embodiments, the compound of Formula (I) is fluvastatin or an analogue thereof. In some embodiments, the compound of Formula (I) is fluvastatin.

[0113] In some embodiments, the compound of Formula (I) is

[0114] In one aspect, the disclosure provides a method for inhibiting metastasis of a solid tumor such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, the method comprising administering to the subject a compound of Formula (Ia) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein each R is independently H, optionally substituted alkyl, halo, carboxyl, or -CF3. P-632882-PC

[0115] In some embodiments, alkyl is C1-C6alkyl. In some embodiments of the compound of Formula (1a), R is 2-CH3 and 4-F; 3,5-(CH3)2; 3-CH3 and 4F; H; 3,5-(CH3)2, 4-F; 4-CF3; 2-CH3; 4-CH3; 5-Br, 5-Cl or 4-CO2Na.

[0116] In certain embodiments, the compound of Formula (Ia) is fluvastatin or an analogue thereof. In some embodiments, the compound of Formula (Ia) is fluvastatin.

[0117] In some embodiments, a racemate is provided of a compound of Formula (Ia). In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (Ia). In some embodiments, the compound of Formula (Ia) is 3R,5S. In some embodiments, the compound of Formula (I) is 3S,5R. In some embodiments, the compound of Formula (Ia) is 3R,5S,6E. In some embodiments, the compound of Formula (Ia) is 3S,5R,6E. In some embodiments, the compound of Formula (Ia) has the same stereochemistry as fluvastatin ((3R,5S,6E)-7-[3-(4-fluorophenyl)-1- (propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid). In some embodiments, the compound of Formula (Ia) is ((3S,5R,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]- 3,5-dihydroxyhept-6-enoic acid).

[0118] In some embodiments, the compound of Formula (Ia) is a lactone.

[0119] In certain embodiments, the compound of Formula (Ia) does not have substantial HMG- CoA reductase activity.

[0120] In some embodiments, a compound of Formula (1a) is:

[0007] P-632882-PC

[0121] In one aspect, the disclosure provides a method for inhibiting metastasis of a solid tumor such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, the method comprising administering to the subject a compound of Formula (II) or a racemate, enantiomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a lactone thereof, wherein R1is H or optionally substituted alkyl, and R2is H, optionally substituted alkyl, hydroxy or an optionally substituted aryl group.

[0122] In some embodiments of the compound of Formula (II), R1 is H. In some embodiments R1 is alkyl. In some embodiments, alkyl is C1-C6alkyl. In some embodiments R1methyl, ethyl, n- propyl, i-propyl or butyl. In some embodiments R2is H. In some embodiments R2is OH. In some embodiments R2 is alkyl, such as methyl, ethyl, n-propyl, i-propyl or butyl. In some embodiments R2 is an optionally substituted phenyl group.

[0123] In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (II). In some embodiments, the compound of Formula (II) is 1S,3R,7S,8S,8aR and 8-[2-[(2R,4R)], and when R1=H, (2S)-2-methylbutanoate. P-632882-PC

[0124] In some embodiments, the compound of Formula (II) has the same stereochemistry as lovastatin [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl- 1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate, simvastatin, [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a- hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate, or mevastatin, [(1S,7S,8S,8aR)-8-[2- [(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate.

[0125] In some embodiments, the compound of Formula (II) is a lactone.

[0126] In certain embodiments, the compound of Formula (II) does not have substantial HMG- CoA reductase activity.

[0127] In some embodiments, the compound of Formula (II) is an analogue of pravastatin.

[0128] In one aspect, the disclosure provides a method for inhibiting metastasis of a solid tumor in a subject, such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, comprising administering to the subject a compound of Formula (III) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or a β-hydroxy acid open ring form, wherein R1 is selected from an optionally substituted alkyloyl or heterocyclyl group; and P-632882-PC R2 is selected from an optionally substituted alkyl or heterocyclyl group.

[0129] In certain embodiments, R1 is an optionally substituted alkyloyl group. In certain embodiments, the optionally substituted alkyloyl group is 2-methylbutanoyl. In certain embodiments, R2 is an optionally substituted alkyl group. In certain embodiments, alkyl is C1-C6alkyl. In certain embodiments, the optionally substituted alkyl group is methyl. In certain embodiments, R2 is an optionally substituted heterocyclyl group.

[0130] In some embodiments, the compound of Formula (III) is a β-hydroxy acid open ring.

[0131] In some embodiments, the compound of Formula (I) has the same stereochemistry as lovastatin, simvastatin or mevastatin.

[0132] In certain embodiments, the compound of Formula (III) does not have substantial HMG- CoA reductase activity.

[0133] In certain embodiments, the compound of Formula (III) is lovastatin, simvastatin or mevastatin or an analogue thereof. In certain embodiments, the compound of Formula (III) is lovastatin, simvastatin or mevastatin.

[0134] In one aspect, the disclosure provides a method for inhibiting metastasis of a solid tumor in a subject, such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, comprising administering to the subject a compound of Formula (V) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein P-632882-PC R1 is an optionally substituted aryl, heteroaryl or heterocyclyl ring; R2 is an optionally substituted alkyl group; R3 and R4 are independently, optionally substituted alkyl.

[0135] In certain embodiments, R1 is an aryl group. In some embodiments, the aryl group is a phenyl group optionally substituted with one or more halo, alkyl, or haloalkyl. In certain embodiments, R1 is p-fluorophenyl. In certain embodiments, R4 is p-tolyl. In certain embodiments, R4 is p-chlorophenyl. In some embodiments, R4 is p-bromophenyl. In certain embodiments, R4 is p-F3C-phenyl.

[0136] In certain embodiments, R2 is C1-6alkyloxy-C1-6alkyl. In some embodiments, R2 is methoxymethyl.

[0137] In certain embodiments, R3 and R4 are independently a C1-C6alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group, a 2-propyl group, or a propynyl group. In some embodiments, R1 is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5,CH2C6H11or CH2CH2C6H11.

[0138] In one embodiment, the compound is cerivastatin ((+)-(3R,5S,6E)-7-[4-(4-fluorophenyl)- 2,6-diisopropyl-5-methoxymethylpyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid monosodium salt), as shown below.

[0139] For any of the foregoing formulas and compounds, a compound of the formula or a compound may be used for inhibiting metastasis of a solid tumor such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC. In some embodiments, a patient with a solid tumor is treated with a compound of a formula disclosed herein to inhibit or prevent metastasis of the P-632882-PC tumor. In some embodiments, a patient who has undergone the resection of a solid tumor is administered a compound disclosed herein, to inhibit or prevent metastasis of any residual tumor or secondary tumor sites. In some embodiments, the solid tumor is a kidney tumor. In some embodiments, the kidney tumor is renal cell carcinoma. In some embodiments, the tumor is a CNS, breast, adrenal or pancreatic tumor. Other embodiments of the uses of the formulas and compounds disclosed herein are as described herein throughout. Pharmaceutical Compositions

[0140] In one aspect, the disclosure provides a pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, comprising a pharmaceutically acceptable carrier and a compound of Formula (IV) or a or or thereof, or lactone thereof, wherein R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group; R2 and R3 taken together form an optionally substituted 3-14 membered ring; and R4 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl ring.

[0141] In certain embodiments, R1 is an optionally substituted alkyl group. In some embodiments, alkyl is C1-C6alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group, P-632882-PC a 2-propyl group, or a propynyl group. In some embodiments, R1 is CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

[0142] In some embodiments, R1 is aryl. In some embodiments, R1 is phenyl.

[0143] In certain embodiments, R2 and R3 taken together with the carbons to which they are bound form a phenyl group. In some embodiments, the phenyl ring is substituted with one or more alkyl groups. In some embodiments, the alkyl group is methyl. In some embodiments, the alkyl is 4- methylindolyl, 5-methylindolyl, 6-methylindolyl or 7-methylindolyl.

[0144] In certain embodiments, R4 is an optionally substituted alkyl group. In some embodiments, alkyl is C1-C6 alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group, a 2-propyl group, or a propynyl group. In some embodiments, R1 is CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11.

[0145] In certain embodiments, R4 is an optionally substituted aryl group. In some embodiments, the aryl group is a phenyl group optionally substituted with one or more independent halo, alkyl, or haloalkyl. In certain embodiments, R4 is p-fluorophenyl. In certain embodiments, R4 is p-tolyl. In certain embodiments, R4 is p-chlorophenyl. In some embodiments, R4 is p-bromophenyl. In certain embodiments, R4 is p-F3C-phenyl.

[0146] In some embodiments, R1 is lower alkyl, R2 and R3 taken together is an optionally substituted phenyl, and R4 is an optionally substituted phenyl group. In some embodiments, R1 is lower alkyl, R2 and R3 taken together is an alkyl, halo or haloalkyl substituted phenyl, and R4 is an optionally substituted phenyl group.

[0147] In some embodiments, when R1 is 2-propyl and R4 is p-fluorophenyl, R2 and R3 taken together is an optionally substituted phenyl, such as alkyl, halo or haloalkyl substituted phenyl. In some embodiments, the alkyl is 4-methylindolyl, 5-methylindolyl, 6-methylindolyl or 7- methylindolyl, or any combination thereof. In some embodiments, when R1 is 2-propyl and R4 is p-fluorophenyl, R2 and R3 taken together is not an unsubstituted phenyl.

[0148] In some embodiments, when R2 and R3 taken together is phenyl and R4 is p-fluorophenyl, R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group. In some embodiments, P-632882-PC R1 is alkyl. In some embodiments, alkyl is C1-C6alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group or a 2-propyl group. In some embodiments, R1 is phenyl. In some embodiments, R1 is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11or CH2CH2C6H11. In some embodiments, when R2 and R3 taken together is unsubstituted phenyl and R4 is p-fluorophenyl, R1 is not a 2-propyl group.

[0149] In some embodiments, when R2 and R3 taken together is phenyl and R4 is p-fluorophenyl, R1 is a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11. In some embodiments, R1 is phenyl.

[0150] In some embodiments, when R1 is 2-propyl and R2 and R3 taken together is phenyl, R4 may be an optionally substituted phenyl, such as one or more independent alkyl, halo or haloalkyl. In some embodiments, alkyl is a lower alkyl. In some embodiments, haloalkyl is CF3. In some embodiments CF3 is p-CF3. In some embodiments CF3 is p-CF3. In some embodiments, when R1 is 2-propyl and R2 and R3 taken together is an unsubstituted phenyl, R4 is not p-fluorophenyl.

[0151] In some embodiments, a racemate is provided of a compound of Formula (IV). In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (IV). In some embodiments, the compound of Formula (IV) is 3R,5S. In some embodiments, the compound of Formula (IV) is 3S,5R. In some embodiments, the compound of Formula (IV) is 3R,5S,6E. In some embodiments, the compound of Formula (IV) is 3S,5R,6E. In some embodiments, the compound of Formula (IV) has the same stereochemistry as fluvastatin ((3R,5S,6E)-7-[3-(4- fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid). In some embodiments, the compound of Formula (IV) is ((3S,5R,6E)-7-[3-(4-fluorophenyl)-1-(propan-2- yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid).

[0152] In some embodiments, the compound of Formula (IV) is a lactone.

[0153] In certain embodiments, the compound of Formula (IV) does not have substantial HMG- CoA reductase activity.

[0154] In certain embodiments, the compound of Formula (IV) is fluvastatin or an analogue thereof. In certain embodiments, the compound of Formula (IV) is fluvastatin. P-632882-PC

[0155] In some embodiments, the compound of Formula (IV) is Compound D

[0008] P-632882-PC

[0156] In one aspect, the disclosure provides a pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, comprising a pharmaceutically acceptable carrier and a compound of Formula (I). or a pharmaceutically or enantiomer or diastereomer thereof, or lactone thereof, wherein R is H or an optionally substituted alkyl.

[0157] In certain embodiments, R is a C1-C6 alkyl group. In certain embodiments, R is an ethyl group, a 1-propyl group or a 2-propyl group. In some embodiments, the alkyl is substituted with an optionally substituted cycloalkyl or aryl group. In some embodiments, aryl is phenyl. In some embodiments, R is not 2-propyl.

[0158] In some embodiments, R is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5,CH2C6H11or CH2CH2C6H11. P-632882-PC

[0159] In some embodiments, a racemate is provided of a compound of Formula (I). In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (I). In some embodiments, the compound of Formula (I) is 3R,5S. In some embodiments, the compound of Formula (I) is 3S,5R. In some embodiments, the compound of Formula (I) is 3R,5S,6E. In some embodiments, the compound of Formula (I) is 3S,5R,6E. In some embodiments, the compound of Formula (I) has the same stereochemistry as fluvastatin ((3R,5S,6E)-7-[3-(4-fluorophenyl)-1- (propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid). In some embodiments, the compound of Formula (I) is ((3S,5R,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]- 3,5-dihydroxyhept-6-enoic acid).

[0160] In some embodiments, the compound of Formula (I) is a lactone.

[0161] In certain embodiments, the compound of Formula (I) does not have substantial HMG- CoA reductase activity.

[0162] In certain embodiments, the compound of Formula (I) is fluvastatin or an analogue thereof. In some embodiments, the compound of Formula (I) is fluvastatin.

[0163] In some embodiments, the compound of Formula (I) is

[0164] In one aspect, the disclosure provides a pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, comprising a pharmaceutically acceptable carrier and a compound of Formula (Ia) P-632882-PC or a pharmaceutically enantiomer or diastereomer thereof, or lactone thereof, wherein each R is independently H, optionally substituted alkyl, halo, carboxyl, or -CF3.

[0165] In some embodiments, alkyl is C1-C6 alkyl. In some embodiments of the compound of Formula (1a), R is 2-CH3 and 4-F; 3,5-(CH3)2; 3-CH3 and 4F; H; 3,5-(CH3)2, 4-F; 4-CF3; 2-CH3; 4-CH3; 5-Br, 5-Cl or 4-CO2Na. In some embodiments, R is not 4-F.

[0166] In certain embodiments, the compound of Formula (Ia) is fluvastatin or an analogue thereof. In some embodiments, the compound of Formula (Ia) is fluvastatin.

[0167] In some embodiments, a racemate is provided of a compound of Formula (Ia). In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (Ia). In some embodiments, the compound of Formula (Ia) is 3R,5S. In some embodiments, the compound of Formula (I) is 3S,5R. In some embodiments, the compound of Formula (Ia) is 3R,5S,6E. In some embodiments, the compound of Formula (Ia) is 3S,5R,6E. In some embodiments, the compound of Formula (Ia) has the same stereochemistry as fluvastatin ((3R,5S,6E)-7-[3-(4-fluorophenyl)-1- (propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid). In some embodiments, the compound of Formula (Ia) is ((3S,5R,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]- 3,5-dihydroxyhept-6-enoic acid).

[0168] In some embodiments, the compound of Formula (Ia) is a lactone.

[0169] In certain embodiments, the compound of Formula (Ia) does not have substantial HMG- CoA reductase activity. P-632882-PC

[0170] In some embodiments, a compound of Formula (1a) is:

[0171] In one aspect, the disclosure provides a pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, comprising a pharmaceutically acceptable carrier and a compound of Formula (II) or a racemate, enantiomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a lactone thereof, wherein R1 is H or optionally substituted alkyl, and R2 is H, optionally substituted alkyl, hydroxy or an optionally substituted aryl group. P-632882-PC

[0172] In some embodiments of the compound of Formula (II), R1is H. In some embodiments R1is alkyl. In some embodiments, alkyl is C1-C6 alkyl. In some embodiments R1 methyl, ethyl, n- propyl, i-propyl or butyl. In some embodiments R2 is H. In some embodiments R2 is OH. In some embodiments R2is alkyl, such as methyl, ethyl, n-propyl, i-propyl or butyl. In some embodiments R2 is an optionally substituted phenyl group. In some embodiments, when R1 is H, R2 is not OH.

[0173] In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (II). In some embodiments, the compound of Formula (II) is 1S,3R,7S,8S,8aR and 8-[2-[(2R,4R)], and when R1=H, (2S)-2-methylbutanoate.

[0174] In some embodiments, the compound of Formula (II) has the same stereochemistry as lovastatin [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl- 1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate, simvastatin, [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a- hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate, or mevastatin, [(1S,7S,8S,8aR)-8-[2- [(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate.

[0175] In some embodiments, the compound of Formula (II) is a lactone.

[0176] In certain embodiments, the compound of Formula (II) does not have substantial HMG- CoA reductase activity.

[0177] In some embodiments, the compound of Formula (II) is an analogue of pravastatin.

[0178] In one aspect, the disclosure provides a pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, comprising a pharmaceutically acceptable carrier and a compound of Formula (III) P-632882-PC or a pharmaceutically or diastereomer thereof, or a β-hydroxy acid open ring form, wherein R1 is selected from an optionally substituted alkyloyl or heterocyclyl group; and R2 is selected from an optionally substituted alkyl or heterocyclyl group.

[0179] In certain embodiments, R1 is an optionally substituted alkyloyl group. In certain embodiments, the optionally substituted alkyloyl group is 2-methylbutanoyl. In certain embodiments, R2 is an optionally substituted alkyl group. In certain embodiments, alkyl is C1-C6 alkyl. In certain embodiments, the optionally substituted alkyl group is methyl. In certain embodiments, R2 is an optionally substituted heterocyclyl group. In some embodiments, when R2 is methyl, R1 is not 2-methybutanoyl or 2,2-dimethylbutanoyl. In some embodiments, when R2 is H, R1 is not 2-methybutanoyl.

[0180] In some embodiments, the compound of Formula (III) is a β-hydroxy acid open ring.

[0181] In some embodiments, the compound of Formula (I) has the same stereochemistry as lovastatin, simvastatin or mevastatin.

[0182] In certain embodiments, the compound of Formula (III) does not have substantial HMG- CoA reductase activity. P-632882-PC

[0183] In certain embodiments, the compound of Formula (III) is lovastatin, simvastatin or mevastatin or an analogue thereof. In certain embodiments, the compound of Formula (III) is lovastatin, simvastatin or mevastatin.

[0184] In one aspect, the disclosure provides a pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC, comprising a pharmaceutically acceptable carrier and a compound of Formula (V) or a thereof, or lactone thereof, wherein R1 is an optionally substituted aryl, heteroaryl or heterocyclyl ring; R2 is an optionally substituted alkyl group; R3 and R4 are independently, optionally substituted alkyl.

[0185] In certain embodiments, R1 is an aryl group. In some embodiments, the aryl group is a phenyl group optionally substituted with one or more halo, alkyl, or haloalkyl. In certain embodiments, R1 is p-fluorophenyl. In certain embodiments, R1 is p-tolyl. In certain embodiments, R1 is p-chlorophenyl. In some embodiments, R1 is p-bromophenyl. In certain embodiments, R1 is p-F3C-phenyl.

[0186] In certain embodiments, R2 is C1-6alkyloxy-C1-6alkyl. In some embodiments, R2 is methoxymethyl. P-632882-PC

[0187] In certain embodiments, R3 and R4 are independently a C1-C6alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group, a 2-propyl group, or a propynyl group. In some embodiments, R3 or R4 is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11.

[0188] In some embodiments, when R1 is p-fluorophenyl, R2 is methoxymethyl, and R3 is 2- propyl, R4 is not 2-propyl.

[0189] In one embodiment, the compound is cerivastatin ((+)-(3R,5S,6E)-7-[4-(4-fluorophenyl)- 2,6-diisopropyl-5-methoxymethylpyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid monosodium salt), as shown below.

[0190] For any of the foregoing formulas and compounds, a pharmaceutical composition comprising a compound of the formula or a compound and a pharmaceutically acceptable carrier may be used for inhibiting metastasis of a solid tumor such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC. In some embodiments, a patient with a solid tumor is treated with a pharmaceutical composition of a compound of a formula disclosed herein to inhibit or prevent metastasis of the tumor. In some embodiments, a patient who has undergone the resection of a solid tumor is administered a pharmaceutical composition of a compound disclosed herein, to inhibit or prevent metastasis of any residual tumor or secondary tumor sites. In some embodiments, the solid tumor is a kidney tumor. In some embodiments, the kidney tumor is renal cell carcinoma. In some embodiments, the tumor is a CNS, breast, adrenal or pancreatic tumor. Other embodiments of the uses of the formulas and compounds disclosed herein are as described herein throughout. P-632882-PC

[0191] In one aspect, the disclosure provides for a pharmaceutical composition for inhibiting metastasis in a subject comprising a compound that is a fungal-derived statin or an analogue of a fungal-derived statin. In certain embodiments, the compound is lovastatin, simvastatin, mevastatin or fluvastatin, or an analogue thereof.

[0192] In one aspect, the disclosure provides for a pharmaceutical composition for inhibiting metastasis in a subject comprising a statin comprising an inactive lactone that is metabolized to an hydroxy acid. In certain embodiments, the compound is lovastatin, simvastatin, mevastatin or fluvastatin, or an analogue thereof.

[0193] In one aspect, the disclosure provides for any of the pharmaceutical compositions herein provided in a unit dose form and dosing regimen effective for inhibiting metastasis. In one embodiment, the pharmaceutical composition comprises fluvastatin. Compounds

[0194] In one aspect, the disclosure provides a compound of Formula (IV): or a or or thereof, or lactone thereof, wherein R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group; R2 and R3 taken together form an optionally substituted 3-14 membered ring; and R4 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl ring. P-632882-PC

[0195] In certain embodiments, R1 is an optionally substituted alkyl group. In some embodiments, alkyl is C1-C6 alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group, a 2-propyl group, or a propynyl group. In some embodiments, R1 is CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11.

[0196] In some embodiments, R1 is aryl. In some embodiments, R1 is phenyl.

[0197] In certain embodiments, R2 and R3 taken together with the carbons to which they are bound form a phenyl group. In some embodiments, the phenyl ring is substituted with one or more alkyl groups. In some embodiments, the alkyl group is methyl. In some embodiments, the alkyl is 4- methylindolyl, 5-methylindolyl, 6-methylindolyl or 7-methylindolyl.

[0198] In certain embodiments, R4 is an optionally substituted alkyl group. In some embodiments, alkyl is C1-C6alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group, a 2-propyl group, or a propynyl group. In some embodiments, R1 is CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

[0199] In certain embodiments, R4 is an optionally substituted aryl group. In some embodiments, the aryl group is a phenyl group optionally substituted with one or more independent halo, alkyl, or haloalkyl. In certain embodiments, R4 is p-fluorophenyl. In certain embodiments, R4 is p-tolyl. In certain embodiments, R4 is p-chlorophenyl. In some embodiments, R4 is p-bromophenyl. In certain embodiments, R4 is p-F3C-phenyl.

[0200] In some embodiments, R1 is lower alkyl, R2 and R3 taken together is an optionally substituted phenyl, and R4 is an optionally substituted phenyl group. In some embodiments, R1 is lower alkyl, R2 and R3 taken together is an alkyl, halo or haloalkyl substituted phenyl, and R4 is an optionally substituted phenyl group.

[0201] In some embodiments, when R1 is 2-propyl and R4 is p-fluorophenyl, R2 and R3 taken together is an optionally substituted phenyl, such as alkyl, halo or haloalkyl substituted phenyl. In some embodiments, the alkyl is 4-methylindolyl, 5-methylindolyl, 6-methylindolyl or 7- methylindolyl, or any combination thereof. In some embodiments, when R1 is 2-propyl and R4 is p-fluorophenyl, R2 and R3 taken together is not an unsubstituted phenyl. P-632882-PC

[0202] In some embodiments, when R2 and R3 taken together is phenyl and R4 is p-fluorophenyl, R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group. In some embodiments, R1 is alkyl. In some embodiments, alkyl is C1-C6 alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group or a 2-propyl group. In some embodiments, R1 is phenyl. In some embodiments, R1 is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11. In some embodiments, when R2 and R3 taken together is unsubstituted phenyl and R4 is p-fluorophenyl, R1 is not a 2-propyl group.

[0203] In some embodiments, when R2 and R3 taken together is phenyl and R4 is p-fluorophenyl, R1 is a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11. In some embodiments, R1 is phenyl.

[0204] In some embodiments, when R1 is 2-propyl and R2 and R3 taken together is phenyl, R4 may be an optionally substituted phenyl, such as one or more independent alkyl, halo or haloalkyl. In some embodiments, alkyl is a lower alkyl. In some embodiments, haloalkyl is CF3. In some embodiments CF3 is p-CF3. In some embodiments, when R1 is 2-propyl and R2 and R3 taken together is an unsubstituted phenyl, R4 is not p-fluorophenyl.

[0205] In some embodiments, a racemate is provided of a compound of Formula (IV). In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (IV). In some embodiments, the compound of Formula (IV) is 3R,5S. In some embodiments, the compound of Formula (IV) is 3S,5R. In some embodiments, the compound of Formula (IV) is 3R,5S,6E. In some embodiments, the compound of Formula (IV) is 3S,5R,6E. In some embodiments, the compound of Formula (IV) has the same stereochemistry as fluvastatin ((3R,5S,6E)-7-[3-(4- fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid). In some embodiments, the compound of Formula (IV) is ((3S,5R,6E)-7-[3-(4-fluorophenyl)-1-(propan-2- yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid).

[0206] In some embodiments, the compound of Formula (IV) is a lactone.

[0207] In certain embodiments, the compound of Formula (IV) does not have substantial HMG- CoA reductase activity. P-632882-PC

[0208] In certain embodiments, the compound of Formula (IV) is fluvastatin or an analogue thereof. In certain embodiments, the compound of Formula (IV) is fluvastatin.

[0209] In some embodiments, the compound of Formula (IV) is Compound D

[0009] P-632882-PC

[0210] In one aspect, the disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein R is H or an optionally substituted alkyl.

[0211] In certain embodiments, R is a C1-C6 alkyl group. In certain embodiments, R is an ethyl group or a 1-propyl group. In some embodiments, the alkyl is substituted with an optionally P-632882-PC substituted cycloalkyl or aryl group. In some embodiments, aryl is phenyl. In some embodiments, R is not 2-propyl.

[0212] In some embodiments, R is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5,CH2C6H11or CH2CH2C6H11.

[0213] In some embodiments, a racemate is provided of a compound of Formula (I). In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (I). In some embodiments, the compound of Formula (I) is 3R,5S. In some embodiments, the compound of Formula (I) is 3S,5R. In some embodiments, the compound of Formula (I) is 3R,5S,6E. In some embodiments, the compound of Formula (I) is 3S,5R,6E. In some embodiments, the compound of Formula (I) has the same stereochemistry as fluvastatin ((3R,5S,6E)-7-[3-(4-fluorophenyl)-1- (propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid). In some embodiments, the compound of Formula (I) is ((3S,5R,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]- 3,5-dihydroxyhept-6-enoic acid).

[0214] In some embodiments, the compound of Formula (I) is a lactone.

[0215] In certain embodiments, the compound of Formula (I) does not have substantial HMG- CoA reductase activity.

[0216] In some embodiments, the compound of Formula (I) is

[0217] In one aspect, the disclosure provides a compound of Formula (Ia) P-632882-PC or a pharmaceutically enantiomer or diastereomer thereof, or lactone thereof, wherein each R is independently H, optionally substituted alkyl, halo, carboxyl, or -CF3.

[0218] In some embodiments, alkyl is C1-C6 alkyl. In some embodiments of the compound of Formula (1a), R is 2-CH3 and 4-F; 3,5-(CH3)2; 3-CH3 and 4F; H; 3,5-(CH3)2, 4-CF3; 2-CH3; 4-CH3; 5-Br, 5-Cl or 4-CO2Na. In some embodiments, R is not 4-F.

[0219] In some embodiments, a racemate is provided of a compound of Formula (Ia). In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (Ia). In some embodiments, the compound of Formula (Ia) is 3R,5S. In some embodiments, the compound of Formula (I) is 3S,5R. In some embodiments, the compound of Formula (Ia) is 3R,5S,6E. In some embodiments, the compound of Formula (Ia) is 3S,5R,6E. In some embodiments, the compound of Formula (Ia) has the same stereochemistry as fluvastatin ((3R,5S,6E)-7-[3-(4-fluorophenyl)-1- (propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid). In some embodiments, the compound of Formula (Ia) is ((3S,5R,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]- 3,5-dihydroxyhept-6-enoic acid).

[0220] In some embodiments, the compound of Formula (Ia) is a lactone.

[0221] In certain embodiments, the compound of Formula (Ia) does not have substantial HMG- CoA reductase activity.

[0222] In some embodiments, a compound of Formula (1a) is: P-632882-PC

[0223] Thus, in some embodiments, the following compounds and their pharmaceutical compositions as well as methods of use as disclosed herein are provided: sodium rel-(3R,5S,E)-7- (1-ethyl-3-(4-fluorophenyl)-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium rel-(3S,5R,E)-7- (3-(4-fluorophenyl)-1-isopropyl-5-methyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate; sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-propyl-1H-indol-2-yl)-3,5-dihydroxyhept- 6-enoate; sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate; sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H- indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium rel-(3S,5R,E)-3,5-dihydroxy-7-(1-isopropyl-3- (p-tolyl)-1H-indol-2-yl)hept-6-enoate; sodium rel-(3S,5R,E)-7-(3-(4-chlorophenyl)-1-isopropyl- 1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium rel-(3S,5R,E)-7-(3-(4-bromophenyl)-1- isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium rel-(3R,5S,E)-3,5-dihydroxy-7-(1- isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)hept-6-enoate; sodium (3R,5S,E)-7-(1- ethyl-3-(4-fluorophenyl)-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium (3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-5-methyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium (3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate; sodium (3S,5R,E)-7-(3-(4-fluorophenyl)-1-propyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate; sodium (3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H-indol-2-yl)-3,5- P-632882-PC dihydroxyhept-6-enoate; sodium (3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H- indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium (3S,5R,E)-3,5-dihydroxy-7-(1-isopropyl-3-(p- tolyl)-1H-indol-2-yl)hept-6-enoate; sodium (3S,5R,E)-7-(3-(4-chlorophenyl)-1-isopropyl-1H- indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium (3S,5R,E)-7-(3-(4-bromophenyl)-1-isopropyl- 1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium (3R,5S,E)-3,5-dihydroxy-7-(1-isopropyl-3- (4-(trifluoromethyl)phenyl)-1H-indol-2-yl)hept-6-enoate; sodium rel-(3S,5R,E)-7-(1-ethyl-3-(4- fluorophenyl)-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium rel-(3R,5S,E)-7-(3-(4- fluorophenyl)-1-isopropyl-5-methyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium rel- (3R,5S,E)-7-(3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate; sodium rel-(3R,5S,E)-7-(3-(4-fluorophenyl)-1-propyl-1H-indol-2-yl)-3,5-dihydroxyhept- 6-enoate; sodium rel-(3R,5S,E)-7-(3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate; sodium rel-(3R,5S,E)-7-(3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H- indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium rel-(3R,5S,E)-3,5-dihydroxy-7-(1-isopropyl-3- (p-tolyl)-1H-indol-2-yl)hept-6-enoate; sodium rel-(3R,5S,E)-7-(3-(4-chlorophenyl)-1-isopropyl- 1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; sodium rel-(3R,5S,E)-7-(3-(4-bromophenyl)-1- isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; and sodium rel-(3S,5R,E)-3,5-dihydroxy- 7-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)hept-6-enoate.

[0224] In one aspect, the disclosure provides a compound of Formula (II) or a racemate, enantiomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a lactone thereof, wherein R1 is H or optionally substituted alkyl, and R2 is H, optionally substituted alkyl, hydroxy or an optionally substituted aryl group. P-632882-PC

[0225] In some embodiments of the compound of Formula (II), R1is H. In some embodiments R1is alkyl. In some embodiments, alkyl is C1-C6 alkyl. In some embodiments R1 methyl, ethyl, n- propyl, i-propyl or butyl. In some embodiments R2 is H. In some embodiments R2 is OH. In some embodiments R2is alkyl, such as methyl, ethyl, n-propyl, i-propyl or butyl. In some embodiments R2 is an optionally substituted phenyl group. In some embodiments, when R1 is H, R2 is not OH.

[0226] In some embodiments, a stereoisomer or enantiomer is provided of a compound of Formula (II). In some embodiments, the compound of Formula (II) is 1S,3R,7S,8S,8aR and 8-[2-[(2R,4R)], and when R1=H, (2S)-2-methylbutanoate.

[0227] In some embodiments, the compound of Formula (II) has the same stereochemistry as lovastatin [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl- 1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate, simvastatin, [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a- hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate, or mevastatin, [(1S,7S,8S,8aR)-8-[2- [(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate.

[0228] In some embodiments, the compound of Formula (II) is a lactone.

[0229] In certain embodiments, the compound of Formula (II) does not have substantial HMG- CoA reductase activity.

[0230] In some embodiments, the compound of Formula (II) is an analogue of pravastatin.

[0231] In one aspect, the disclosure provides a compound of Formula (III)

[0010] P-632882-PC or a pharmaceutically or diastereomer thereof, or a β-hydroxy acid open ring form, wherein R1 is selected from an optionally substituted alkyloyl or heterocyclyl group; and R2 is selected from an optionally substituted alkyl or heterocyclyl group.

[0232] In certain embodiments, R1 is an optionally substituted alkyloyl group. In certain embodiments, the optionally substituted alkyloyl group is 2-methylbutanoyl. In certain embodiments, R2 is an optionally substituted alkyl group. In certain embodiments, alkyl is C1-C6 alkyl. In certain embodiments, the optionally substituted alkyl group is methyl. In certain embodiments, R2 is an optionally substituted heterocyclyl group. In some embodiments, when R2 is methyl, R1 is not 2-methybutanoyl or 2,2-dimethylbutanoyl. In some embodiments, when R2 is H, R1 is not 2-methybutanoyl.

[0233] In some embodiments, the compound of Formula (III) is a β-hydroxy acid open ring.

[0234] In some embodiments, the compound of Formula (I) has the same stereochemistry as lovastatin, simvastatin or mevastatin.

[0235] In certain embodiments, the compound of Formula (III) does not have substantial HMG- CoA reductase activity.

[0236] In one aspect, the disclosure provides a compound of Formula (V) P-632882-PC or a thereof, or lactone thereof, wherein R1 is an optionally substituted aryl, heteroaryl or heterocyclyl ring; R2 is an optionally substituted alkyl group; R3 and R4 are independently, optionally substituted alkyl groups.

[0237] In certain embodiments, R1 is an aryl group. In some embodiments, the aryl group is a phenyl group optionally substituted with one or more halo, alkyl, or haloalkyl. In certain embodiments, R1 is p-fluorophenyl. In certain embodiments, R1 is p-tolyl. In certain embodiments, R1 is p-chlorophenyl. In some embodiments, R1 is p-bromophenyl. In certain embodiments, R1 is p-F3C-phenyl.

[0238] In certain embodiments, R2 is C1-6alkyloxy-C1-6alkyl. In some embodiments, R2 is methoxymethyl.

[0239] In certain embodiments, R3 and R4 are independently a C1-C6 alkyl. In certain embodiments, the alkyl group is an ethyl group, a 1-propyl group, a 2-propyl group, or a propynyl group. In some embodiments, R3 or R4 is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

[0240] In some embodiments, when R1 is p-fluorophenyl, R2 is methoxymethyl, and R3 is 2- propyl, R4 is not 2-propyl. P-632882-PC

[0241] For any of the foregoing formulas and compounds, a compound of the formula or a compound may be used for inhibiting metastasis of a solid tumor such as but not limited to a renal cell carcinoma (RCC) in a subject having RCC. In some embodiments, a patient with a solid tumor is treated with a compound of a formula disclosed herein to inhibit or prevent metastasis of the tumor. In some embodiments, a patient who has undergone the resection of a solid tumor is administered a compound disclosed herein, to inhibit or prevent metastasis of any residual tumor or secondary tumor sites. In some embodiments, the solid tumor is a kidney tumor. In some embodiments, the kidney tumor is renal cell carcinoma. In some embodiments, the tumor is a CNS, breast, adrenal or pancreatic tumor. Other embodiments of the uses of the formulas and compounds disclosed herein are as described herein throughout.

[0242] As used herein, in some embodiments, the term “alkyl” refers to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n- pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. In some embodiments, an alkyl group of from 1 to about 6 carbon atoms is referred to as lower alkyl.

[0243] In some embodiments, “aryl” refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, an aryl group has from 6 to about 20 carbon atoms. In some embodiments, “aryl” may be optionally substituted at any one or more positions.

[0244] In some embodiments, “halo” includes fluoro, chloro, bromo, and iodo.

[0245] In some embodiments, each of alkyl and aryl may be optionally substituted with one or more independently selected groups such as alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxylic acid and derivatives thereof, including esters, amides, and nitrites, hydroxy, alkyloxy, acyloxy, amino, alky and dialkylamino, acylamino, thio, and the like, and combinations thereof.

[0246] In some embodiments, the term “substituted” refers to the replacement of a hydrogen moiety with a non-hydrogen moiety in a molecule or group. It can refer to “mono-substituted” or P-632882-PC “poly-substituted.” The term “mono-substituted” or “poly-substituted” means substituted with one or more than one substituent up to the valence of the substituted group. For example, a mono- substituted group can be substituted with 1 substituent, and a poly-substituted group can be substituted with 2, 3, 4, or 5 substituents. When a list of possible substituents is provided, the substituents can be independently selected from that group.

[0247] The term “optionally substituted,” in some embodiments, refers to that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent, the substituents may be the same or different. Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, CN, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like. Illustratively, any of amino, hydroxyl, CH, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and / or sulfonic acid is optionally substituted. In some embodiments, the functional groups are the substituents described herein for any one of variables. Furthermore, when using the terms “independently,” “independently are,” and “independently selected from” mean that the groups in question may be the same or different. Certain of the herein defined terms may occur more than once in the structure, and upon such occurrence each term shall be defined independently of the other.

[0248] Alkyloyl refers to a branched or unbranched, optionally substituted alkyl group as described herein with a carboxyl group. In certain embodiments, alkyloyl groups include formyl, acetyl, n-propionyl, isopropionyl, alloyl, n-butanoyl, sec-butanoyl, isobutanoyl, tert-butanoyl, n- pentanoyl, sec-pentanoyl, isopentanoyl, tert-pentanoyl, n-hexanoyl, sec-hexanoyl, moieties and the like, which again, may bear one or more substituents. Alkenoyl groups include, but are not limited to, for example, propenoyl, butenoyl, 1-methyl-2-buten-l-oyl, and the like. Such R1 alkyloyl groups taken with the O to which they are attached are also referred to as esters. In certain embodiments, an isostere of the carboxyl group is provided.

[0249] In general, the term “aromatic” or “aromatic moiety”, as used herein, refers to a stable mono- or polycyclic, unsaturated moiety having preferably 3-14 carbon atoms, each of which may P-632882-PC be substituted or unsubstituted. In certain embodiments, the term “aromatic moiety” refers to a planar ring having p-orbitals perpendicular to the plane of the ring at each ring atom and satisfying the Huckel rule where the number of pi electrons in the ring is (4n+2) wherein n is an integer. A mono- or polycyclic, unsaturated moiety that does not satisfy one or all of these criteria for aromaticity is defined herein as “non-aromatic”, and is encompassed by the term “alicyclic”.

[0250] In general, the term “heteroaromatic” or “heteroaromatic moiety”, as used herein, refers to a stable mono- or polycyclic, unsaturated moiety having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted; and comprising at least one heteroatom selected from O, S and N within the ring (i.e., in place of a ring carbon atom). In certain embodiments, the term “heteroaromatic moiety” refers to a planar ring comprising at least one heteroatom, having p- orbitals perpendicular to the plane of the ring at each ring atom, and satisfying the Hückel’s rule where the number of pi electrons in the ring is (4n+2) wherein n is an integer.

[0251] An optionally substituted 3-14 membered ring in certain embodiments can be a 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-membered aryl, or 5-6 membered heteroaryl ring, any of which may a further fused 3-8 membered ring.

[0252] It will also be appreciated that aromatic and heteroaromatic moieties, as defined herein may be attached via an alkyl or heteroalkyl moiety and thus also include –(alkyl)aromatic, - (heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the phrases “aromatic or heteroaromatic moieties” and “aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic” are interchangeable. Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.

[0253] The term “aryl”, as used herein, does not differ significantly from the common meaning of the term in the art, and refers to an unsaturated cyclic moiety comprising at least one aromatic ring. In certain embodiments, “aryl” refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. P-632882-PC

[0254] The term “heteroaryl”, as used herein, does not differ significantly from the common meaning of the term in the art, and refers to a cyclic aromatic radical having from five to twelve ring atoms of which one ring atom is selected from S, O and N; zero, one, two, three, four, or five ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, and the like.

[0255] It will be appreciated that aryl and heteroaryl groups (including bicyclic aryl groups) can be unsubstituted or substituted, wherein substitution includes replacement of one or more of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; C1; Br; I; -OH; -NO2; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; - C(=O)Rx; -CO2(Rx); -C(=O)N(Rx)2; -OC(=O)Rx; -OCO2Rx; -OC(=O)N(Rx)2; -N(Rx)2; -ORx; -SRx; -S(O)Rx; -S(O)2Rx; -NRx(CO)Rx; -N(Rx)CO2Rx; -N(Rx)S(O)2Rx; -N(Rx)C(=O)N(Rx)2; -S(O)2N(Rx)2; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl substituents described above and herein may be substituted or unsubstituted. Additionally, it will be appreciated, that any two adjacent groups taken together may represent a 4, 5, 6, or 7-membered substituted or unsubstituted alicyclic or heterocyclic moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0256] The term “heterocycloalkyl”, “heterocycle” or “heterocyclic”, as used herein, refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include, but are not limited to, saturated, unsaturated and partially saturated mono- or polycyclic cyclic ring systems having 5-16 atoms wherein at least one ring atom is a heteroatom selected from O, S and P-632882-PC N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), wherein the ring systems are optionally substituted with one or more functional groups, as defined herein. In certain embodiments, the term “heterocycloalkyl”, “heterocycle” or “heterocyclic” refers to a non- aromatic or partially aromatic 5-12 membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to a bi- or tri-cyclic group, comprising fused rings having between one and four heteroatoms independently selected from O, S and N, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 3 double bonds and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative heterocycles include, but are not limited to, heterocycles such as furanyl, thiofuranyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, dioxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, thiatriazolyl, oxatriazolyl, thiadiazolyl, oxadiazolyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, dithiazolyl, dithiazolidinyl, tetrahydrofuryl, indolinyl, oxoindolinyl, and benzofused derivatives thereof. In certain embodiments, a “substituted heterocycle, or heterocycloalkyl or heterocyclic” group is utilized and as used herein, refers to a heterocycle, or heterocycloalkyl or heterocyclic group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; - OH; -NO2; -CN; -CF3; -CH2CF3; -CHCl2; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(=O)Rx; -CO2(Rx); -C(=O)N(Rx)2; -OC(=O)Rx; - OCO2Rx; -OC(=O)N(Rx)2; -N(Rx)2; -ORx; -SRx; -S(O)Rx; -S(O)2Rx; -NRx(CO)Rx; - N(Rx)CO2Rx; -N(Rx)S(O)2Rx; -N(Rx)C(=O)N(Rx)2; -S(O)2N(Rx)2; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or P-632882-PC unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown herein.

[0257] Additionally, it will be appreciated that any of the alicyclic or heterocyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0258] Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible optical isomers, enantiomers, diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formulas (I), (1a), (II), (III), (IV) and (V) are shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formulas (I), (1a), (II), (III), (IV) and (V) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included.

[0259] Non-limiting examples of compounds useful for the purposes disclosed herein include compounds described in Z. Casar, Recent progress in the synthesis of super-statins, Top Heterocycl Chem 2015, DOI: 10.1007 / 7081_2015_189, Springer International Publishing Switzerland, incorporated herein by reference in its entirety.

[0260] Non-limiting examples of compounds useful for the purposes disclosed herein include type I statins and analogues of type I statins.

[0261] Non-limiting examples of compounds useful for the purposes disclosed herein include fungal-derived statins and analogues of fungal-derived statins.

[0262] Non-limiting examples of compounds useful for the purposes disclosed herein include statins, and analogues thereof, in the form of inactive lactones that are metabolized to their active hydroxy acid forms. P-632882-PC

[0263] Non-limiting examples of compounds useful for the purposes disclosed herein include statin prodrugs, and analogues thereof, that are metabolized to their active forms.

[0264] Non-limiting examples of compounds useful for the purposes disclosed herein include type I statins, such as but not limited to lovastatin, simvastatin, mevastatin and fluvastatin, and analogues thereof.

[0265] In certain embodiments, a compound disclosed herein such as any in Formulas (I), (1a), (II), (III), (IV) and (V) useful for the purposes herein does not have substantive activity at inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase, HMGCoAR, or other syntactic variants thereof). Thus, a compound may be an analogue or structural relative of a “statin” (e.g., compounds with HMG CoA reductase activity) but without substantive such activity (e.g., would not be useful for reducing cholesterol at a dose regimen administered). Thus, in certain embodiments, administration of a compound disclosed herein does not have effects of or as cholesterol-lowering drugs.

[0266] Lovastatin, [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7- dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate, has the structure

[0267] Simvastatin, [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7- dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate, has the structure P-632882-PC

[0268] Mevastatin, [ - - oxooxan-2-yl]ethyl]-7-methyl- 1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2S)-2-methylbutanoate, has the structure .

[0269] Fluvastatin, (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5- dihydroxyhept-6-enoic acid, has the structure

[0270] Cerivastatin, ((+)-(3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5- methoxymethylpyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid monosodium salt, has the structure P-632882-PC .

[0271] Analogues of fluvastatin are described in, for example, Valentovic, 2007, Fluvastatin, xPharm: The Comprehensive Pharmacology Reference, incorporated by reference herein in its entirety.

[0272] Fluvastatin and other statins, and their analogues as disclosed herein, may exist as a lactone, shown below for fluvastatin, and similarly for other statins. The disclosure encompasses the open acid and lactone forms of these compounds as well as the Formulas (I), (1a), (II), (III), (IV) and (V) herein. .

[0273] Non-limiting examples of compounds useful for the purposes disclosed herein include type I statins, such as but not limited to lovastatin, simvastatin, fluvastatin and mevastatin. Methods of Treatment

[0274] In some embodiments, a patient with a solid tumor is treated with a compound disclosed herein to inhibit or prevent metastasis of the tumor. In some embodiments, a patient who has undergone the resection of a solid tumor is administered a compound disclosed herein, to inhibit or prevent metastasis of any residual tumor or secondary tumor sites. P-632882-PC

[0275] In some embodiments, the solid tumor is a kidney tumor. In some embodiments, the kidney tumor is renal cell carcinoma.

[0276] In some embodiments, the tumor is a CNS, breast, adrenal or pancreatic tumor.

[0277] In some embodiments, the solid tumor is a sarcoma, a carcinoma, a fibrosarcoma, a myxosarcoma, a liposarcoma, a chondrosarcoma, an osteogenic sarcoma, a chordoma, an angiosarcoma, an endotheliosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a synovioma, a mesothelioma, an Ewing's tumor, a leiomyosarcoma, a rhabdomyosarcoma, a colon carcinoma, a pancreatic cancer or tumor, a breast cancer or tumor, an ovarian cancer or tumor, a prostate cancer or tumor, a squamous cell carcinoma, a basal cell carcinoma, an adenocarcinoma, a sweat gland carcinoma, a sebaceous gland carcinoma, a papillary carcinoma, a papillary adenocarcinomas, a cystadenocarcinoma, a medullary carcinoma, a bronchogenic carcinoma, a renal cell carcinoma, a hepatoma, a bile duct carcinoma, a choriocarcinoma, a seminoma, an embryonal carcinoma, a Wilm's tumor, a cervical cancer or tumor, a uterine cancer or tumor, a testicular cancer or tumor, a lung carcinoma, a small cell lung carcinoma, a bladder carcinoma, an epithelial carcinoma, a glioma, an astrocytoma, a medulloblastoma, a craniopharyngioma, an ependymoma, a pinealoma, a hemangioblastoma, an acoustic neuroma, an oligodenroglioma, a schwannoma, a meningioma, a melanoma, a neuroblastoma, or a retinoblastoma.

[0278] A “cancer” is one of a group of diseases characterized by uncontrollable growth and having the ability to invade normal tissues and to metastasize to other parts of the body. Cancers have many causes, including, but not limited to, diet, alcohol consumption, tobacco use, environmental toxins, heredity, and viral infections. In most instances, multiple genetic changes are required for the development of a cancer cell. Progression from normal to cancerous cells involves a number of steps to produce typical characteristics of cancer including, e.g., cell growth and division in the absence of normal signals and / or continuous growth and division due to failure to respond to inhibitors thereof; loss of programmed cell death (apoptosis); unlimited numbers of cell divisions (in contrast to a finite number of divisions in normal cells); aberrant promotion of angiogenesis; and invasion of tissue and metastasis. Non-limiting examples of cancer include esophageal cancer, pancreatic cancer, metastatic pancreatic cancer, metastatic adenocarcinoma of the pancreas, bladder cancer, stomach cancer, breast cancer, fibrotic cancer, glioma, malignant glioma, diffuse P-632882-PC intrinsic pontine glioma, recurrent childhood brain neoplasm renal cell carcinoma, clear-cell metastatic renal cell carcinoma, kidney cancer, prostate cancer, metastatic castration resistant prostate cancer, stage IV prostate cancer, metastatic melanoma, melanoma, malignant melanoma, recurrent melanoma of the skin, melanoma brain metastases, stage IIIA skin melanoma; stage IIIB skin melanoma, stage IIIC skin melanoma; stage IV skin melanoma, malignant melanoma of head and neck, lung cancer, non-small cell lung cancer (NSCLC), squamous cell non-small cell lung cancer, breast cancer, recurrent metastatic breast cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, follicular lymphoma, non-Hodgkin’s lymphoma, advanced B-cell NHL, HL including diffuse large B-cell lymphoma (DLBCL), multiple myeloma, chronic myeloid leukemia, adult acute myeloid leukemia in remission; adult acute myeloid leukemia with Inv(16)(p13.1q22); CBFB-MYH11; adult acute myeloid leukemia with t(16;16)(p13.1;q22); CBFB-MYH11; adult acute myeloid leukemia with t(8;21)(q22;q22); RUNX1-RUNX1T1; adult acute myeloid leukemia with t(9;11)(p22;q23); MLLT3-MLL; adult acute promyelocytic leukemia with t(15;17)(q22;q12); PML-RARA; alkylating agent-related acute myeloid leukemia, chronic lymphocytic leukemia, Richter’s syndrome; Waldenstrom’s macroglobulinemia, adult glioblastoma; adult gliosarcoma, recurrent glioblastoma, recurrent childhood rhabdomyosarcoma, recurrent Ewing sarcoma / peripheral primitive neuroectodermal tumor, recurrent neuroblastoma; recurrent osteosarcoma, colorectal cancer, MSI positive colorectal cancer; MSI negative colorectal cancer, nasopharyngeal nonkeratinizing carcinoma; recurrent nasopharyngeal undifferentiated carcinoma, cervical adenocarcinoma; cervical adenosquamous carcinoma; cervical squamous cell carcinoma; recurrent cervical carcinoma; stage IVA cervical cancer; stage IVB cervical cancer, anal canal squamous cell carcinoma; metastatic anal canal carcinoma; recurrent anal canal carcinoma, recurrent head and neck cancer; carcinoma, squamous cell of head and neck, head and neck squamous cell carcinoma (HNSCC), ovarian carcinoma, colon cancer, gastric cancer, advanced GI cancer, gastric adenocarcinoma; gastroesophageal junction adenocarcinoma, bone neoplasms, soft tissue sarcoma; bone sarcoma, thymic carcinoma, urothelial carcinoma, recurrent Merkel cell carcinoma; stage III Merkel cell carcinoma; stage IV Merkel cell carcinoma, myelodysplastic syndrome and recurrent mycosis fungoides and Sezary syndrome. Any of the foregoing can be considered a solid tumor for the purposes of the present disclosure.

[0279] Treatment of a human or mammalian subject with a compound disclosed herein for any one of the aforementioned solid tumors is typically achieved by administration of the compound P-632882-PC in a pharmaceutical composition. The disclosure also encompasses a pharmaceutical composition that is comprised of any of the compound described herein, compounds of any of the formulae described herein, and analogues thereof, in combination with a pharmaceutically acceptable carrier.

[0280] Thus, in some embodiments, an intravenous formulation of any compound disclosed herein is provided.

[0281] In some embodiments, the presence of metastases in the patient is established prior to treating with a compound disclosed herein. In some embodiments, the presence of a metastatic form of the primary tumor in the absence of detectable metastases, is established prior to treating with a compound disclosed herein. In some embodiments, the patient’s tumor is removed prior to treating with a compound disclosed herein. In some embodiments, a patient’s metastases are removed prior to treating with a compound disclosed herein. Removed, in some embodiments, is surgical, radiation, chemotherapy, radioimmunotherapy, etc., or any combination thereof.

[0282] In some embodiments, the presence of a mutation the causes metastasis is identified in the tumor prior to treating with a compound disclosed herein. In some embodiments, the mutation is a mutation in the VHL gene. Thus, in one embodiment, the VHL mutation is identified in a biopsy of the tumor, or a sample of tumor tissue on resection, and treatment is started with a compound disclosed herein. A VHL mutation may be identified following guidance in the literature such as Xu et al., Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor, Cell 2012 Mar 2; 148(5):886-95; Schokrpur et al., CRISPR-Mediated VHL Knockout Generates an Improved Model for Metastatic Renal Cell Carcinoma, Sci Rep 2016 6:29032; and PCT / US2020 / 019601, published as WO20200176446; all of which are incorporated herein by reference in their entireties.

[0283] In some embodiments, the spread of a tumor beyond the primary site and / or a high grade by histological criterion is identified prior to treating with a compound disclosed herein. Thus, in one embodiment, the spread of a tumor beyond the primary site and / or a high grade by histological criterion is identified is identified in a biopsy of the tumor, or a sample of tumor tissue on resection, and treatment is started with a compound disclosed herein. In some embodiments, the solid tumor is a kidney tumor. In some embodiments, a high grade histologic criterion comprises Grade 3 or Grade 4. Thus, a method is provided for inhibiting the metastasis of a solid tumor in a subject or P-632882-PC treating a solid tumor in a subject comprising the steps of (a) detecting a high histological grade of tumor and / or evidence of spread of the tumor beyond the primary site; and (b) upon detection of the high grade and / or spread, treating the patient with a pharmaceutical composition comprising a compound as disclosed herein. In some embodiments, the compound is a statin or an analogue thereof.

[0284] In another embodiment, the extent of spread of the tumor and / or the histological grade of the tumor may be used to monitor the effectiveness of therapy using a compound as disclosed herein, to adjust the dose level or dosing regimen, to identify recurrence of the tumor, or to discontinue therapy.

[0285] In some embodiments, the presence of activation of the hypoxia program of gene expression is identified prior to treating with a compound disclosed herein. Thus, in one embodiment, activation of the hypoxia program of gene expression is identified in a biopsy of the tumor, or a sample of tumor tissue on resection, and treatment is started with a compound disclosed herein. Thus, a method is provided for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of (a) detecting activation of the hypoxia program of gene expression in tumor cells in a sample from the solid tumor; and (b) upon detection of hypoxia program activation, treating the patient with a pharmaceutical composition comprising a compound as disclosed herein. In some embodiments, the compound is a statin or an analogue thereof.

[0286] In some embodiments, the activation of the hypoxia program is due to mutation or loss of VHL expression.

[0287] In another embodiment, the presence of activation of the hypoxia program of gene expression may be used to monitor the effectiveness of therapy using a compound as disclosed herein, to adjust the dose level or dosing regimen, to identify recurrence of the tumor, or to discontinue therapy.

[0288] In some embodiments, the presence of extracellular vesicles in a bodily fluid of the subject is identified prior to treating with a compound disclosed herein. Thus, in one embodiment, presence of extracellular vesicles in a bodily fluid of the subject, and treatment is started with a P-632882-PC compound disclosed herein. Thus, a method is provided for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of (a) detecting extracellular vesicles in a bodily fluid of a patient; and (b) upon detection of extracellular vesicles, treating the patient with a pharmaceutical composition comprising a compound as disclosed herein. In some embodiments, extracellular vesicles are detected in a ccRCC patient. In some embodiments, bodily fluid is blood or urine. In some embodiments, the compound is a statin or an analogue thereof.

[0289] In another embodiment, the presence of extracellular vesicles in a bodily fluid of the subject may be used to monitor the effectiveness of therapy using a compound as disclosed herein, to adjust the dose level or dosing regimen, to identify recurrence of the tumor, or to discontinue therapy.

[0290] In some embodiments, the presence of an overexpression of periostin in the tumor is identified prior to treating with a compound disclosed herein. Thus, in one embodiment, periostin expression is identified in a biopsy of the tumor, or a sample of tumor tissue on resection, and treatment is started with a compound disclosed herein. In some embodiments, the compound is a statin or an analogue thereof. Periostin overexpression may be identified following guidance in PCT / US2020 / 019601, published as WO20200176446, and incorporated herein by reference in their entireties.

[0291] In another embodiment, the expression level of periostin of the subject may be used to monitor the effectiveness of therapy using a compound as disclosed herein, to adjust the dose level or dosing regimen, to identify recurrence of the tumor, or to discontinue therapy.

[0292] In one embodiment, the cancer in which the VHL mutation is identified as an indication to begin treatment with a compound disclosed herein is clear cell renal cell carcinoma, renal cell carcinoma, lung adenocarcinoma, colon adenocarcinoma, or bladder urothelial carcinoma. In other embodiments, the cancer is any one of those disclosed herein.

[0293] The terms "treat" or "treating," as used herein, refer to partially or completely alleviating, delaying onset of, reducing the incidence of, ameliorating and / or relieving a disorder, disease, or condition, or one or more symptoms of the disorder, disease or condition. In some embodiments, P-632882-PC treat or treating refers to preventing, reducing, inhibiting or controlling metastasis of a tumor, and preventing, reducing, inhibiting or controlling a cancer or solid tumor.

[0294] The term "patient" or “subject,” as used herein, means a mammal to which a formulation or composition comprising a formulation is administered, and includes humans.

[0295] The term "substantially free of',” as used herein, refers to containing no more than an insignificant amount. In some embodiments, a composition or preparation is "substantially free of' a recited element if it contains less than 5%, 4%, 3%, 2%, or 1%, by weight of the element. In some embodiments, the composition or preparation contains less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or less of the recited element. In some embodiments, the composition or preparation contains an undetectable amount of the recited element. Pharmaceutical Compositions

[0296] In practice, the compounds disclosed herein, for example, as disclosed herein or represented by any formula herein, or pharmaceutically acceptable salts thereof, can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non- aqueous liquid, as an oil in water emulsion, or as a water in oil liquid emulsion.

[0297] The present invention also includes “pharmaceutically acceptable salts” of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the compound of the invention include the conventional non-toxic salts of the parent compound P-632882-PC formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the compound of the invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0298] The pharmaceutically acceptable salts of the compound of the invention can be also obtained by converting derivatives which possess tertiary amino groups into the corresponding quaternary ammonium salts in a manner known per se using quaternizing agents. Examples of suitable quaternizing agents are alkyl halides, such as methyl iodide, ethyl bromide, and n-propyl chloride, and also arylalkyl halides, such as benzyl chloride or 2-phenylethyl bromide. In some embodiments, the salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of an existing salt for another ion or suitable ion-exchange resin.

[0299] Possible pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977; incorporated herein by reference.

[0300] Typically, a pharmaceutically acceptable salt form of a compound can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the free base functionality with a suitable organic or inorganic acid. Examples of typical pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.

[0301] Other pharmaceutically acceptable salts can include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, P-632882-PC cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0302] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0303] In addition to the common dosage forms set out above, the compound of formula disclosed herein, or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and / or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0304] Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminum stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); preparations which are suitable for oral administration can comprise additional flavorings and / or sweetening agents, if desired.

[0305] Liquid medicinal forms can be sterilized and / or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, P-632882-PC spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and / or viscosity regulators. Examples of such additives are tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its nontoxic salts). High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.

[0306] Oily suspensions for parenteral or topical applications can be vegetable synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic / capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia. Silicone oils of differing viscosity, or fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids, such as oleic acid, are also suitable. It is furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil.

[0307] Suitable solvents, gelatinizing agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc. P-632882-PC

[0308] Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as additional formulation aids: glycerol, paraffin of differing viscosity, triethanolamine, collagen, allantoin and novantisolic acid. Use of surfactants, emulsifiers or wetting agents, for example of sodium lauryl sulphate, fatty alcohol ether sulphates, di-Na-N-lauryl-β-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono- / dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation. Stabilizers, such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.

[0309] Preparations for parenteral administration, e.g., intravenous, can be present in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the compound or formula disclosed herein, preferably aqueous solution and, in particular, isotonic solutions and also suspensions. These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent.

[0310] Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending agent.

[0311] Inhalable preparations can present as powders, solutions or suspensions. Preferably, inhalable preparations are in the form of powders, e.g. as a mixture of the active ingredient with a suitable formulation aid such as lactose.

[0312] The preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions. P-632882-PC

[0313] Thus, the present disclosure further provides a pharmaceutical composition comprising a compound or formula as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0314] The term "carrier" refers to any chemical entity that can be incorporated into a composition containing an active agent (e.g., a compound or formula as disclosed herein) without interfering with the stability and / or activity of the agent. In some embodiments, the term "carrier" refers to a pharmaceutically acceptable carrier. An exemplary carrier herein is water.

[0315] As used herein, in some embodiments, “pharmaceutical composition” refers to therapeutically effective amounts of the compound disclosed herein together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and / or carriers.

[0316] Also comprehended by the disclosure are particulate compositions coated with polymers (e.g., poloxamers or poloxamines). Other embodiments of the compositions disclosed herein incorporate particulate forms protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral. In some embodiments, the pharmaceutical composition is administered parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intravaginally, intracranially and intratumorally.

[0317] As used herein, in some embodiments, the terms "therapeutically effective amount" and "effective amount" of an agent refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention and / or management of a disease, disorder, or condition, e.g., to delay onset of or minimize (e.g., reduce the incidence, frequency, and / or magnitude of) one or more symptoms associated with the disease, disorder or condition to be treated, such as but no limited to tumor metastasis or tumor growth. Those of ordinary skill in the art will appreciate that, a composition may be said to contain a "therapeutically effective amount" of an agent if it contains an amount that is effective when administered as a single dose within the context of a therapeutic regimen. In some embodiments, a therapeutically effective amount is an amount that, when administered as part of a dosing regimen, is statistically likely to delay onset of or minimize (reduce the incidence and / or magnitude of) one or more symptoms or side effects of a disease, disorder or condition, in one embodiment, metastasis or spread of a tumor. In some embodiments, a "therapeutically P-632882-PC effective amount" is an amount that enhances therapeutic efficacy of another agent with which the composition is administered in combination.

[0318] The duration of treatment will, in some embodiments, be determined by the effectiveness of treatment and elimination of the primary tumor. In some embodiments, treatment will continue for the rest of the patient’s life. In some embodiments treatment will continue until diagnostic tests confirm the absence of cancer in the patient. In some embodiments treatment will continue after resection of the primary tumor and any metastases until further diagnostic tests confirm the absence of tumor in the patient. These and other aspects of the dosing regimen will be guided by the health care professional based on an assessment of each patient’s needs.

[0319] In some embodiments, a therapeutically effective amount for administration to a human corresponds to a reference amount (e.g., a therapeutically effective amount in an animal model such as a mouse model) adjusted for body surface area of a human as compared with body surface area of the animal model, as is known in the art (see, for example Reagan-Shaw et al., "Dose translation from animal to human studies revisited," The FASEB Journal 22: 659-661 (2007), the entirety of which is herein incorporated by reference). In some embodiments, the reference therapeutically effective amount is an amount that is therapeutically effective in an animal model (e.g., in a mouse model such as the cooperative VHL-KO / VHL-WT model described herein). In some embodiments, the reference therapeutically effective amount is within the range of about 0.01 mg / kg to about 500 mg / kg. In some embodiments, the reference therapeutically effective amount is within the range of about 0.01 mg / kg to about 0.1 mg / kg. In some embodiments, the reference therapeutically effective amount is within the range of about 0.1 mg / kg to about 0.5 mg / kg. In some embodiments, the reference therapeutically effective amount is within the range of about 0.5 mg / kg to about 1 mg / kg. In some embodiments, the reference therapeutically effective amount is within the range of about 1 mg / kg to about 2.5 mg / kg. In some embodiments, the reference therapeutically effective amount is within the range of about 2.5 mg / kg to about 10 mg / kg. In some embodiments, the reference therapeutically effective amount is within the range of about 10 mg / kg to about 50 mg / kg. In some embodiments, the reference therapeutically effective amount is within the range of about 50 mg / kg to about 100 mg / kg. In some embodiments, the reference therapeutically effective amount is within the range of about 100 mg / kg to about 250 P-632882-PC mg / kg. In some embodiments, the reference therapeutically effective amount is within the range of about 250 mg / kg to about 500 mg / kg.

[0320] In some embodiments, the term “comprise” or grammatical forms thereof, refers to the inclusion of the indicated active agent, such as the compound of formula of this disclosure, as well as inclusion of other active agents, and pharmaceutically acceptable carriers, excipients, emollients, stabilizers, etc., as are known in the pharmaceutical industry. In some embodiments, the term “consisting essentially of” refers to a composition, whose only active ingredient is the indicated active ingredient, however, other compounds may be included which are for stabilizing, preserving, etc. the formulation, but are not involved directly in the therapeutic effect of the indicated active ingredient. In some embodiments, the term “consisting essentially of” may refer to components, which exert a therapeutic effect via a mechanism distinct from that of the indicated active ingredient. In some embodiments, the term “consisting essentially of” may refer to components, which exert a therapeutic effect and belong to a class of compounds distinct from that of the indicated active ingredient. In some embodiments, the term “consisting essentially of” may refer to components which facilitate the release of the active ingredient. In some embodiments, the term “consisting” refers to a composition, which contains the active ingredient and a pharmaceutically acceptable carrier or excipient.

[0321] In some embodiments, the pharmaceutically acceptable carriers, adjuvants, or vehicles refer to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. P-632882-PC

[0322] As used herein, the term “combination,” “combined,” and related terms refer to the simultaneous exposure of a subject to two or more therapeutic agents in accordance with this disclosure. It will be appreciated that two or more agents are considered to be administered "in combination" whenever a subject is simultaneously exposed to both (or more) of the agents. Each of the two or more agents may be administered according to a different schedule; it is not required that individual doses of different agents be administered at the same time, or in the same composition. Rather, so long as both (or more) agents remain in the subject's body, they are considered to be administered "in combination." For example, one or more doses of a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, in some embodiments, the present disclosure provides a single unit dosage form comprising a compound or formula disclosed herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0323] In some embodiments, two of more of the compounds of formulae disclosed herein may comprise the active agent for administration in accordance to the teachings herein. Non-limiting combinations may comprise lovastatin and simvastatin, or lovastatin and mevastatin, or lovastatin and fluvastatin, or simvastatin and mevastatin, or simvastatin and fluvastatin, or mevastatin and fluvastatin. Other non-limiting combinations include any of lovastatin, simvastatin, mevastatin and fluvastatin, or an analogue thereof, in combination with any compound of any formula disclosed herein, or an analogue thereof.

[0324] The term "formulation" refers to a composition that includes at least one active agent (e.g., a compound of formula (I)) in combination with one or more carriers, excipients or other pharmaceutical additives for administration to a patient. In general, particular carriers, excipients and / or other pharmaceutical additives are selected in accordance with knowledge in the art to achieve a desired stability, release, distribution and / or activity of active agent(s).

[0325] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Formulations provided herein for parenteral administration are typically water or oil-based (e.g., aqueous or oleaginous) suspensions or solutions. Such P-632882-PC formulations may be prepared according to techniques known in the art, for example using suitable dispersing, wetting agents or suspending agents. In some embodiments, such formulations are sterile injectable solutions or suspensions 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 solution and isotonic sodium chloride solution. Alternatively or additionally, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0326] As noted above, compounds and those of the formulae disclosed herein may be administered intratumorally, such as into a solid tumor. In some embodiment the tumor may be a primary tumor. In some embodiments the tumor may be a secondary tumor, such as a metastasis.

[0327] In some embodiments, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non- aqueous liquid, as an oil in water emulsion, or as a water in oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and / or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0328] Thus, the pharmaceutical compositions of this disclosure may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of a compound disclosed herein, e.g., a compound represented by any one of Formulas (I), (Ia), (II), (III), (IV) or (V). The compound disclosed herein, e.g., the compounds of Formula (I), (Ia), (II), (III), (IV) or (V), or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0329] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. P-632882-PC

[0330] For example, a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 1mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, l00 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or l000 mg.

[0331] Generally, dosage levels on the order of from about 0.0l mg / kg to about l50 mg / kg of body weight per day are useful in the treatment of the above indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, dermatological diseases and cancers may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day. It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[0332] The expression "unit dose" as used herein refers to a physically discrete unit of a formulation appropriate for a subject to be treated (e.g., for a single dose); each unit containing a predetermined quantity of an active agent selected to produce a desired therapeutic effect (it being understood that multiple doses may be required to achieve a desired or optimum effect), optionally together with a pharmaceutically acceptable carrier, which may be provided in a predetermined amount. The unit dose may be, for example, a volume of liquid (e.g., an acceptable carrier) containing a predetermined quantity of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, etc. It will be appreciated that a unit dose may contain a variety of components in addition to the therapeutic agent(s). For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc., may be included as described infra. It will be understood, however, that the total daily usage of a formulation of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism may depend upon a variety of factors including the P-632882-PC disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and / or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.

[0333] Accordingly, in another aspect of the present disclosure, pharmaceutical compositions are provided, which comprise any one or more of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise a pharmaceutically acceptable carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, a compound of this disclosure may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents. For example, additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this disclosure may be an approved agent to treat the same or related indication, or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment of any disorder related to dysproliferation. It will also be appreciated that certain of the compounds of present disclosure can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present disclosure, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro drug or other adduct or derivative of a compound of this disclosure which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0334] Generally, dosage levels on the order of from about 0.0l mg / kg to about l50 mg / kg of body weight per day are useful in the treatment of the above indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, dermatological diseases and cancers may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day. P-632882-PC

[0335] In another embodiment, compounds capable of inhibiting the metastasis of a tumor can be identified in a cooperative model comprising VHL-WT and VHL-KO cells.

[0336] It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. EXAMPLES

[0337] All publications, accession numbers, patents, and patent applications cited in this specification are herein incorporated by reference as if each was specifically and individually indicated to be incorporated by reference. Synthesis of compounds disclosed herein General Procedure 1: C3-Selective Arylation of Indoles

[0338] Based on H.-S.; Jang, Y. H.; Shin, J.-W.; Won, H.-J.; Sim, J.; Kim, N.-J. Ligand-Controlled Regiodivergent Direct Arylation of Indoles via Oxidative Boron Heck Reaction. Org. Chem. Front. 2022, 9 (21), 5906–5911), 1H- indole (1.0 eq), phenylboronic acid (2.0 eq), Pd(OAc)2(10.0 mol%), and 5-nitro-1,10- phenanthroline (20.0 mol%) were dissolved in DMF to a concentration of 0.3 M. Under air, the reaction mixture was stirred vigorously at 100 °C for 24 h. The reaction mixture was then cooled to room temperature and quenched with 1 M HCl(aq). The resulting mixture was then extracted with CH2Cl2three times, and the combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue was then further concentrated under a stream of nitrogen, to remove residual DMF. The resulting residue was then purified by P-632882-PC column chromatography (0 to 20% Et2O in petroleum ether), resulting in the desired arylated indoles. 3-(4-fluorophenyl)-4-methyl-1H-indole

[0339] 3-(4-fluorophenyl)-4-methyl-1H- according to general procedure 1, using 4-methyl-1H-indole (700 mg, 5.34 mmol, 1.0 eq), (4-fluorophenyl)boronic acid (1.49 g, 10.7 mmol, 2.0 eq), palladium diacetate (120 mg, 534 µmol, 0.1 eq) and 5-nitro[1,10]phenanthroline (240 mg, 1.07 mmol, 0.2 eq) in DMF (15 mL). The reaction yielded the product as a colorless solid (720 mg, 60%). Rf = 0.22 (10% EtOAc in petroleum ether); m.p. 80–82 °C (Et2O); ^ ̅max (thin film) / cm−12916, 2851, 1545, 1497, 1317, 1211, 845, 750;1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.79 – 7.69 (m, 1H), 7.66 – 7.58 (m, 2H), 7.33 (d, J = 2.6 Hz, 1H), 7.20 – 7.05 (m, 4H), 2.54 (s, 3H);19F NMR (376 MHz, CDCl3) δ -116.76;13C NMR (101 MHz, CDCl3) δ 162.12 (d, J = 244.9 Hz), 136.28, 133.04 (d, J = 3.6 Hz), 132.21 (d, J = 7.8 Hz), 131.24, 125.44, 123.01, 122.61, 121.82, 118.74, 114.56 (d, J = 21.2 Hz), 109.23, 20.82; HRMS m / z (ESI+) found 226.1034 [M+H]+(C15H13FN requires 226.1032 [M+H]+). 3-(4-fluorophenyl)-5-methyl-1H-indole

[0340] 3-(4-fluorophenyl)-5-methyl-1H-indole was synthesized according to general procedure 1, using 5-methyl-1H-indole (700 mg, 5.34 mmol, 1.0 eq), (4-fluorophenyl)boronic acid (1.49 g, 10.7 mmol, 2.0 eq), palladium diacetate (120 mg, 534 µmol, 0.1 eq) and 5-nitro[1,10]phenanthroline P-632882-PC (240 mg, 1.07 mmol, 0.2 eq) in DMF (15 mL). The reaction yielded the product as a colorless oil (791 mg, 66%). Rf= 0.19 (10% EtOAc in petroleum ether); ^ ̅max (thin film) / cm−13395, 1548, 1500, 1216, 1157, 837, 799;1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.68 – 7.56 (m, 2H), 7.25 (d, J = 2.5 Hz, 1H), 7.23 – 7.21 (m, 1H), 7.14 (dd, J = 8.8, 8.8 Hz, 1H), 7.04 (dd, J = 8.2, 1.5 Hz, 2H), 2.50 (s, 3H);19F NMR (376 MHz, CDCl3) δ -117.16; HRMS m / z (ESI+) found 226.1034 [M+H]+(C15H13FN requires 226.1032 [M+H]+).These data are in good agreement with the literature values (Lokhande, S. K.; Vaidya, G. N.; Satpute, D. P.; Venkatesh, A.; Kumar, S.; Kumar, D. Structure Ligation Relationship of Amino Acids for the Selective Indole C−H Arylation Reaction: L-Aspartic Acid as Sustainable Alternative of Phosphine Ligands. Adv. Synth. Catal. 2020, 362 (14), 2857–2863). 3-(4-fluorophenyl)-6-methyl-1H-indole

[0341] 3-(4-fluorophenyl)-6-methyl- was according to general procedure 1, using 6-methyl-1H-indole (700 mg, 5.34 mmol, 1.0 eq), (4-fluorophenyl)boronic acid (1.49 g, 10.7 mmol, 2.0 eq), palladium diacetate (120 mg, 534 µmol, 0.1 eq) and 5-nitro[1,10]phenanthroline (240 mg, 1.07 mmol, 0.2 eq) in DMF (15 mL). The reaction yielded the product as a colorless solid (723 mg, 60%). Rf= 0.20 (10% EtOAc in petroleum ether); m.p. 123–125 °C (Et2O); ^ ̅max (thin film) / cm−13420, 1545, 1497, 1451, 1219, 1101, 840, 802;1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.70 – 7.54 (m, 2H), 7.25 (d, J = 2.3 Hz, 1H), 7.24 – 7.20 (m, 1H), 7.14 (dd, J = 8.7, 8.7 Hz, 2H), 7.09 – 7.01 (m, 1H), 2.50 (s, 3H);19F NMR (376 MHz, CDCl3) δ - 117.2;13C NMR (101 MHz, CDCl3) δ 161.6 (d, J = 244.3 Hz), 137.2, 132.5, 131.9 (d, J = 3.5 Hz), 128.9 (d, J = 7.7 Hz), 123.7, 122.3, 121.0, 119.3, 117.4, 115.7 (d, J = 21.2 Hz), 111.5, 21.8; HRMS m / z (ESI+) found 226.1034 [M+H]+(C15H13FN requires 226.1033 [M+H]+). 3-(4-fluorophenyl)-7-methyl-1H-indole P-632882-PC

[0342] 3-(4-fluorophenyl)-7-methyl- according to general procedure 1, using 7-methyl-1H-indole (700 mg, 5.34 mmol, 1.0 eq), (4-fluorophenyl)boronic acid (1.49 g, 10.7 mmol, 2.0 eq), palladium diacetate (120 mg, 534 µmol, 0.1 eq) and 5-nitro[1,10]phenanthroline (240 mg, 1.07 mmol, 0.2 eq) in DMF (15 mL). The reaction yielded the product as a colorless solid (889 mg, 74%). Rf = 0.20 (10% EtOAc in petroleum ether); m.p. 147–150 °C (Et2O) [lit.3151– 153 °C (Et2O)]; δH(400 MHz, CDCl3) 8.12 (1 H, s), 7.74 (1 H, d, J = 7.9 Hz), 7.62 (2 H, ddd, J = 8.4, 5.3, 2.6 Hz), 7.33 (1 H, d, J = 2.6 Hz), 7.18 – 7.11 (3 H, m), 7.08 (1 H, d, J = 7.0 Hz), 2.54 (3 H, s);19F NMR (376 MHz, CDCl3) δ -117.0; HRMS m / z (ESI+) found 226.1034 [M+H]+(C15H13FN requires 226.1032 [M+H]+). These data are in good agreement with the literature values (Andersen, K.; Perregaard, J.; Arn, J.; Nielsen, J. B.; Begtrup, M. Selective, Centrally Acting Serotonin 5-HT2 Antagonists.2. Substituted 3-(4-Fluorophenyl)-1H-Indoles. J. Med. Chem.1992, 35 (26), 4823–4831). 3-(p-tolyl)-1H-indole

[0343] 3-(p-tolyl)-1H-indole was synthesized using the general procedure 1, using 1H-indole (700 mg, 5.98 mmol, 1.0 eq), p-tolylboronic acid (1.62 g, 12.0 mmol, 2.0 eq), palladium diacetate (134 mg, 598 µmol, 0.1 eq) and 5-nitro[1,10]phenanthroline (269 mg, 1.20 mmol, 0.2 eq) in DMF (20 mL). The reaction yielded the product as a yellow solid (863 mg, 70%). Rf= 0.36 (20% EtOAc in petroleum ether); m.p. 93–95 °C (CH2Cl2) [lit.190 °C ];1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.26 – 7.16 (m, 4H), 2.41 (s, 3H); HRMS m / z (ESI+) found P-632882-PC 208.1124 [M+H]+(C15H14N requires 208.1126 [M+H]+). These data are in good agreement with the literature values (Yang et al., op. cit.) 3-(4-chlorophenyl)-1H-indole

[0344] 3-(4-chlorophenyl)-1H- the general procedure 1, using 1H- indole (700 mg, 5.98 mmol, 1.0 eq), (4-chlorophenyl)boronic acid (1.87 g, 12.0 mmol, 2.0 eq), palladium diacetate (134 mg, 598 µmol, 0.1 eq) and 5-nitro[1,10]phenanthroline (269 mg, 1.20 mmol, 0.2 eq) in DMF (20 mL). The reaction yielded the product as a yellow solid (713 mg, 52%). Rf = 0.34 (20% EtOAc in petroleum ether); m.p. 130–133 °C (CH2Cl2) [lit.1135 °C];1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.89 (dd, J = 7.9, 1.4 Hz, 1H), 7.63 – 7.58 (m, 2H) – 7.39 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.26 – 7.19 (m, 2H); LRMS m / z (ESI+) found 228.0584 [M+H]+(C14H1135ClN requires 228.0584 [M+H]+). These data are in good agreement with the literature values (Yang et al., op. cit). 3-(4-bromophenyl)-1H-indole

[0345] 3-(4-bromophenyl)-1H-indole was synthesized using the general procedure 1, using 1H- indole (700 mg, 5.98 mmol, 1.0 eq), (4-bromophenyl)boronic acid (2.40 g, 12.0 mmol, 2.0 eq), palladium diacetate (134 mg, 598 µmol, 0.1 eq) and 5-nitro[1,10]phenanthroline (269 mg, 1.20 mmol, 0.2 eq) in DMF (20 mL). The reaction yielded the product as a yellow solid (596 mg, 37%). Rf= 0.34 (20% EtOAc in petroleum ether); m.p. 129–131 °C (CH2Cl2) [lit.1135 °C];1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.89 (d, J = 7.9, 1H), 7.59 – 7.52 (m, 4H), 7.44 (ddd, J = 8.1, P-632882-PC 1.0, 1.0 Hz, 1H), 7.38 – 7.19 (m, 3H); LRMS m / z (ESI+) found 272.0075 [M+H]+(C14H1179BrN requires 272.0077 [M+H]+). These data are in good agreement with the literature values (Wang, Z.-L.; Zhang, Y.-H.; Huang, J.-Y.; Zhou, J.; Yu, Y.-Q.; Feng, D.; Xu, D.-Z. Iron-Catalyzed Intramolecular C–H Amination for the Synthesis of N–H Carbazoles and Indoles. Green Chem. 2023, 25 (11), 4463–4468). General Procedure 2: N-alkylation of indoles

[0346] Indole (1.0 to 0 °C. NaH (60% in mineral oil) was then added in a single batch, and the mixture was allowed to come to rt over 30 minutes. The reaction mixture was then again cooled to 0 °C, and alkyl halide (1.5 eq) was added. The mixture was stirred for 16 h at rt, and then quenched with H2O (30 mL). The mixture was then extracted with CH2Cl2 (3 × 30 mL), the combined CH2Cl2 was then washed with brine, and then dried over Na2SO4, and concentrated in vacuo. Remaining DMF was removed under a stream of air and the resulting residue was then purified via silica gel column chromatography (0 to 10% Et2O in petroleum ether). 3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H-indole

[0347] 3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H-indole was synthesized according to general procedure 2, using 3-(4-fluorophenyl)-4-methyl-1H-indole (500 mg, 2.22 mmol, 1.0 eq), isopropyl bromide (625 µL, 6.66 mmol, 3.0 eq) and NaH (60% in mineral oil, 133 mg, 3.33 mmol, 1.5 eq) P-632882-PC in DMF (6 mL). The reaction yielded the product as a colorless solid (440 mg, 74%). Rf= 0.56 (10% Et2O in petroleum ether); m.p. 68–69 °C (Et2O); ^m̅ax (thin film) / cm−12973, 2926, 1546, 1500, 1299, 1214, 1199, 836, 744; δ H (400 MHz, CDCl3) 7.44 – 7.38 (2 H, m), 7.30 (1 H, d, J 8.2), 7.17 (1 H, dd, J = 8.4, 7.1 Hz), 7.14 (1 H, s), 7.12 – 7.04 (2 H, m), 6.92 – 6.87 (1 H, m), 4.72 (1 H, hept, J = 6.7 Hz), 2.29 (3 H, s), 1.57 (6 H, d, J = 6.7 Hz);19F NMR (376 MHz, CDCl3) δ - 117.1; δC(101 MHz, CDCl3) 162.0 (d, J = 244.3 Hz), 135.9, 133.4 (d, J = 3.1 Hz), 132.2 (d, J = 7.7 Hz), 131.4, 125.8, 122.7, 121.8, 121.4, 117.3, 114.5 (d, J = 21.2 Hz), 107.6, 47.1, 22.9, 20.9; HRMS m / z (ESI+) found 268.1509 [M+H]+(C18H19FN requires 268.1501 [M+H]+). 3-(4-fluorophenyl)-1-isopropyl-5-methyl-1H-indole

[0348] 3-(4-fluorophenyl)-1-isopropyl- was synthesized according to general procedure 2, using 3-(4-fluorophenyl)-5-methyl-1H-indole (300 mg, 1.33 mmol, 1.0 eq), isopropyl bromide (375 µL, 4.00 mmol, 3.0 eq) and NaH (60% in mineral oil, 80 mg, 2.0 mmol, 1.5 eq) in DMF (4 mL). The reaction yielded the product as a colorless oil (323 mg, 91%). Rf= 0.56 (10% Et2O in petroleum ether); ^m̅ax (thin film) / cm−11547, 1499, 1368, 1208, 1197, 1155, 838, 787;1H NMR (400 MHz, CDCl3) δ 7.68 – 7.63 (m, 1H), 7.63 – 7.56 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.19 – 7.06 (m, 3H), 4.68 (hept, J = 6.7 Hz, 1H), 2.48 (s, 3H), 1.56 (d, J = 6.7 Hz, 6H);19F NMR (376 MHz, CDCl3) δ -117.69;13C NMR (101 MHz, CDCl3) δ 161.39 (d, J = 243.9 Hz), 134.81, 132.22 (d, J = 2.9 Hz), 129.40, 128.87 (d, J = 7.6 Hz), 126.56, 123.52, 121.52, 119.42, 115.63 (d, J = 21.2 Hz), 115.59, 109.64, 47.31, 22.96, 21.68; HRMS m / z (ESI+) found 268.1508 [M+H]+(C18H19FN requires 268.1501 [M+H]+). 3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H-indole P-632882-PC

[0349] 3-(4-fluorophenyl)-1- was synthesized according to general procedure 2, using 3-(4-fluorophenyl)-6-methyl-1H-indole (500 mg, 2.22 mmol, 1.0 eq), isopropyl bromide (625 µL, 6.66 mmol, 3.0 eq) and NaH (60% in mineral oil, 133 mg, 3.33 mmol, 1.5 eq) in DMF (6 mL). The reaction yielded the product as a colorless solid (481 mg, 81%). Rf= 0.56 (10% Et2O in petroleum ether); m.p.102–103 °C (Et2O); ^m̅ax (thin film) / cm−12957, 1551, 1500, 1210, 838;1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.1 Hz, 1H), 7.65 – 7.55 (m, 2H), 7.28 (s, 1H), 7.22 , 7.18 – 7.07 (m, 2H), 7.02 (dd, J = 8.3, 1.4 Hz, 1H), 4.69 (hept, J = 6.7 Hz, 1H), 2.53 (s, 3H), 1.57 (d, J = 6.7 Hz, 6H);19F NMR (376 MHz, CDCl3) δ -117.67;13C NMR (101 MHz, CDCl3) δ 161.38 (d, J = 244.0 Hz), 136.84, 132.23 (d, J = 3.3 Hz), 131.75, 128.74 (d, J = 7.7 Hz), 124.20, 121.85, 120.74, 119.52, 115.97, 115.63 (d, J = 21.2 Hz), 109.88, 47.07, 22.97, 22.04; HRMS m / z (ESI+) found 268.1504 [M+H]+(C18H19FN requires 268.1501 [M+H]+). 3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H-indole

[0350] 3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H-indole was synthesized according to general procedure 2, using 3-(4-fluorophenyl)-7-methyl-1H-indole (500 mg, 2.22 mmol, 1.0 eq), isopropyl bromide (625 µL, 6.66 mmol, 3.0 eq) and NaH (60% in mineral oil, 133 mg, 3.33 mmol, 1.5 eq) in DMF (6 mL). The reaction yielded the product as a colorless solid (198 mg, 33%). Rf = 0.56 (10% Et2O in petroleum ether); m.p.148–150 °C (Et2O); ^m̅ax (thin film) / cm−11554, 1504, 1279, 1217, 840;1H NMR (400 MHz, CDCl3) δ 7.74 – 7.67 (m, 1H), 7.62 – 7.52 (m, 2H), 7.34 (s, 1H), 7.17 – 7.09 (m, 2H), 7.06 (dd, J = 7.5, 7.5 Hz, 1H), 7.01 – 6.95 (m, 1H), 5.22 (hept, J = 6.6 Hz, P-632882-PC 1H), 2.78 (s, 3H), 1.57 (d, J = 6.6 Hz, 6H);19F NMR (376 MHz, CDCl3) δ -117.4;13C NMR (101 MHz, CDCl3) δ 161.5 (d, J = 244.2 Hz), 135.5, 132.1 (d, J = 3.2 Hz), 129.3 (d, J = 7.7 Hz), 127.2, 125.5, 121.8, 121.1, 120.1, 117.8, 116.8, 115.6 (d, J = 21.2 Hz), 48.2, 24.4, 21.0; HRMS m / z (ESI+) found 268.1506 [M+H]+(C18H19FN requires 268.1501 [M+H]+). 3-(4-fluorophenyl)-1-ethyl-1H-indole

[0351] 3-(4-fluorophenyl)-1-ethyl-1H- according to general procedure 2, using 3-(4-fluorophenyl)-1H-indole (500 mg, 2.37 mmol, 1.0 eq), ethyl iodide (486 µL, 7.10 mmol, 3.0 eq) and NaH (60% in mineral oil, 142 mg, 3.55 mmol, 1.5 eq) in DMF (6 mL). The reaction yielded the product as a colorless solid (323 mg, 57%). Rf= 0.42 (10% Et2O in petroleum ether); m.p. 66–68 °C (Et2O); ^ ̅max (thin film) / cm−11545, 1373, 1205, 1154, 1141, 840, 810, 744;1H NMR (400 MHz, CDCl3) δ 7.89 (ddd, J = 8.0, 1.0, 1.0 Hz, 1H), 7.66 – 7.55 (m, 2H), 7.41 (ddd, J = 8.2, 1.0, 1.0 Hz, 1H), 7.32 – 7.24 (m, 2H), 7.23 – 7.10 (m, 3H), 4.23 (q, J = 7.3 Hz, 2H), 1.53 (t, J = 7.3 Hz, 3H);19F NMR (376 MHz, CDCl3) δ -117.42;13C NMR (101 MHz, CDCl3) δ 161.5 (d, J = 244.1 Hz), 136.6, 131.9 (d, J = 3.2 Hz), 128.9 (d, J = 7.7 Hz), 126.4, 124.7, 122.1, 120.1, 119.9, 116.0, 115.7 (d, J = 21.2 Hz), 109.8, 41.2, 15.6; HRMS m / z (ESI+) found 240.1191 [M+H]+(C16H15FN requires 240.1189 [M+H]+).

[0011] P-632882-PC 3-(4-fluorophenyl)-1-propyl-1H-indole

[0352] 3-(4-fluorophenyl)-1-propyl- according to general procedure 2, using 3-(4-fluorophenyl)-1H-indole (180 mg, 852 µmol, 1.0 eq), 1-bromopropane (210 mg, 1.70 mmol, 2.0 eq) and NaH (60% in mineral oil, 68 mg, 1.7 mmol, 2.0 eq) in DMF (3 mL). The reaction yielded the product as a colorless solid (190 mg, 88%). Rf= 0.52 (10% Et2O in petroleum ether); m.p. 62–64 °C (Et2O); ^ ̅max (thin film) / cm−11550, 1501, 1156, 839, 740;1H NMR (400 MHz, CDCl3) δ 7.88 (ddd, J = 8.0, 0.9, 0.9 Hz, 1H), 7.65 – 7.55 (m, 2H), 7.39 J = 8.2, 0.9, 0.9 Hz, 1H), 7.29 – 7.24 (m, 1H), 7.24 (s, 1H), 7.21 – 7.09 (m, 3H), 4.13 (t, J = 7.1 Hz, 2H), 1.92 (h, J = 7.3 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H);19F NMR (376 MHz, CDCl3) δ -117.5;13C NMR (101 MHz, CDCl3) δ 161.5 (d, J = 244.2 Hz), 136.9, 131.9 (d, J = 3.4 Hz), 128.9 (d, J = 7.7 Hz), 126.4, 125.6, 122.0, 120.0, 119.8, 115.9, 115.7 (d, J = 21.3 Hz), 109.9, 48.3, 23.7, 11.7; HRMS m / z (ESI+) found 254.1347 [M+H]+(C17H17FN requires 254.1345 [M+H]+). 3-(p-tolyl)-1-isopropyl-1H-indole

[0353] 3-(p-tolyl)-1-isopropyl-1H-indole was synthesized according to general procedure 2, using 3-(p-tolyl)-1H-indole (776 mg, 3.74 mmol, 1 eq), 2-iodopropane (1.1 mL, 11.2 mmol, 3 eq) and NaH (60% in mineral oil, 135 mg, 5.62 mmol, 1.5 eq) in DMF (12.5 mL). The reaction yielded the product as a yellow oil (438 mg, 47%). Rf= 0.25 (5% EtOAc in petroleum ether); ^ ̅max (thin film) / cm−11481, 1202, 738; δH(500 MHz, CDCl3) δ 7.93 (ddd, J = 8.0, 1.0, 1.0 Hz, 1H), 7.59 – P-632882-PC 7.54 (m, 2H), 7.42 (dd, J = 8.0, 1.0 Hz, 1H), 7.37 (s, 1H), 7.26 (q, J = 3.7 Hz, 3H), 7.17 (ddd, J = 7.9, 6.9, 1.0 Hz, 1H), 4.72 (hept, J = 6.7 Hz, 1H), 2.40 (s, 3H), 1.58 (d, J = 6.7 Hz, 6H); δ C (126 MHz, CDCl3) δ 136.4, 135.3, 133.0, 129.5, 127.3, 126.4, 121.7, 121.3, 120.1, 119.8, 116.9, 109.7, 47.1, 22.9, 21.3; HRMS m / z (ESI+) found 250.1612 [M+H]+(C18H19N requires 250.1596 [M+H]+). 3-(4-chlorophenyl)-1-isopropyl-1H-indole

[0354] 3-(4-chlorophenyl)-1- according to general procedure 2, using 3-(4-chlorophenyl)-1H-indole (498 mg, 2.19 mmol, 1.0 eq), 2-iodopropane (0.66 mL, 6.6 mmol, 3.0 eq) and NaH (60% in mineral oil, 78.7 mg, 3.28 mmol, 1.5 eq) in DMF (7.3 mL). The reaction yielded the product as a light yellow solid (354 mg, 60%). Rf= 0.27 (5% EtOAc in petroleum ether); m.p. 102–104 °C (CH2Cl2); ^m̅ax (thin film) / cm−11469, 1204, 808, 745; δH(500 MHz, CDCl3) δ 7.88 (ddd, J = 8.1, 1.0, 1.0 Hz, 1H), 7.61 – 7.57 (m, 2H), 7.44 – 7.42 (m, 1H), 7.41 – 7.37 (m, 3H), 7.27 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.19 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 4.73 (hept, J = 6.7 Hz, 1H), 1.58 (d, J = 6.7 Hz, 6H); δ C (126 MHz, CDCl3) δ 136.5, 134.5, 131.3, 128.9, 128.6, 126.1, 122.0, 121.7, 120.2, 119.9, 115.9, 110.0, 47.3, 23.0; HRMS m / z (ESI+) found 270.1067 [M+H]+(C17H16ClN requires 270.1049 [M+H]+). 3-(4-bromophenyl)-1-isopropyl-1H-indole

[0355] 3-(4-bromophenyl)-1-isopropyl-1H-indole was synthesized according to general procedure 2, using 3-(4-bromophenyl)-1H-indole (489 mg, 1.80 mmol, 1.0 eq), 2-iodopropane P-632882-PC (538 μL, 5.39 mmol, 3.0 eq) and NaH (60% in mineral oil, 64.7 mg, 2.70 mmol, 1.5 eq) in DMF (6 mL). The reaction yielded the product as a light yellow solid (336 mg, 60%). Rf = 0.30 (5% EtOAc in petroleum ether); m.p.90–92 °C (CH2Cl2); ^m̅ax (thin film) / cm−11468, 1204, 744, 540; δ H (500 MHz, CDCl3) δ 7.89 (d, J = 0.9 Hz, 1H), 7.61 – 7.57 (m, 2H), 7.43 (d, J = 8.3 Hz, 1H), 7.41 – 7.37 (m, 3H), 7.27 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.19 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 4.73 (hept, J = 6.7 Hz, 1H), 1.58 (d, J = 6.7 Hz, 6H); δC(126 MHz, CDCl3) δ 136.8, 135.3, 132.2, 129.2, 126.4, 122.3, 122.0, 120.5, 120.1, 119.6, 116.1, 110.3, 47.6, 23.2; HRMS m / z (ESI+) found 314.0547 [M+H]+(C17H16BrN requires 314.0544 [M+H]+). 3-(4-(trifluoromethyl)phenyl)-1H-indole

[0356] 3-(4-(trifluoromethyl)phenyl)- using the general procedure 1, using 1H-indole (700 mg, 5.98 mmol, 1.0 eq), (4-trifluoromethylphenyl)boronic acid (2.27 g, 12.0 mmol, 2.0 eq), palladium diacetate (134 mg, 598 µmol, 0.1 eq) and 5-nitro[1,10]phenanthroline (269 mg, 1.20 mmol, 0.2 eq) in DMF (20 mL). The reaction yielded the product as a yellow solid (329 mg, 29%). Rf= 0.27 (20% EtOAc in petroleum ether); m.p. 129–131 °C (CH2Cl2) [lit.1129– 132 °C];1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.95 – 7.91 (m, 1H), 7.81 – 7.76 (m, 2H), 7.71 – (m, 2H), 7.49 – 7.43 (m, 2H), 7.32 – 7.21 (m, 3H);19F NMR (376 MHz, CDCl3) δ - 62.2; HRMS m / z (ESI+) found 262.0842 [M+H]+(C15H11F3N requires 262.0844 [M+H]+). These data are in good agreement with the literature values. (Jardim Etchart, R.; Rambo, R. S.; Lopes Abbadi, B.; Sperotto, N.; Ev Neves, C.; Fries Silva, F.; Dornelles, M.; Duarte, L.; Souza Macchi, F.; Alberton Perelló, M.; Vescia Lourega, R.; Valim Bizarro, C.; Basso, L. A.; Machado, P. Synthesis and Antimycobacterial Activity of 3-Phenyl-1H-Indoles. Molecules 2021, 26 (17), 5148). 3-(4-(trifluoromethyl)phenyl)-1-isopropyl-1H-indole P-632882-PC

[0357] 3-(4-(trifluoromethyl)phenyl)- was synthesized according to general procedure 2, using 3-(4-(trifluoromethyl)phenyl)-1H-indole (242 mg, 1.80 mmol, 1.0 eq), 2- iodopropane (261 μL, 2.78 mmol, 3.0 eq) and NaH (60% in mineral oil, 33.3 mg, 1.39 mmol, 1.5 eq) in DMF (3 mL). The reaction yielded the product as a light yellow solid (181 mg, 64%). Rf = 0.30 (5% EtOAc in petroleum ether); m.p.76–78 °C (CH2Cl2); ^m̅ax (thin film) / cm−11204, 1117, 745;1H NMR (500 MHz, CDCl3) δ 7.94 (ddd, J = 8.0, 1.0, 1.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.29 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.22 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 4.75 (hept, J = 6.7 Hz, 1H), 1.60 (d, J = 6.7 Hz, 6H);19F NMR (376 MHz, CDCl3) δ -62.1; HRMS m / z (ESI+) found 304.1323 [M+H]+(C18H17F3N requires 304.1313 [M+H]+). General Procedure 3 for the synthesis of acrylaldehydes

[0358] For approximately a 300 mg scale of indole, POCl3 (3 eq) was dissolved in anhydrous acetonitrile (1 mL) and cooled to 0 °C. (E)-3-(methyl(phenyl)amino)acrylaldehyde (MPAA) (2.5 eq) in anhydrous acetonitrile (0.5 mL), was then added dropwise over 30 mins to 1 h. The reaction mixture was then stirred at 10 °C for 10 mins, before the indole (1 eq) in anhydrous acetonitrile (0.5 mL) was added rapidly. The reaction mixture was then heated to 100 °C for 3 h. The temperature was then reduced to 55 °C and 5 mL of water was added and stirred for 2 h. The mixture was then cooled to rt, and then extracted with toluene (3 × 10 mL). The combined toluene P-632882-PC was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was then purified via silica gel chromatography (0 to 15% EtOAc in petroleum ether) to furnish a vibrant yellow product. (E)-3-(methyl(phenyl)amino)acrylaldehyde (MPAA)

[0359] A solution of oxalyl chloride eq) in acetonitrile (10 mL) was cooled to −15 °C. N-methylformanilide (6.8 g, 50 mmol) and butyl vinyl ether (5.4 g, 54 mmol, 1.07 eq) in acetonitrile (10 mL) was then added dropwise over 30 min. The reaction mixture was gradually warmed to rt over 30 min and stirring was continued for 1 h. The reaction contents were again cooled to −15 °C and a solution of Na2CO3 (6.4 g, 60 mmol, 1.2 eq) in water (30 mL) was added dropwise over 30 min. Toluene (25 mL) was then added and the solution was stirred at RT for 15 min before being allowed to settle for 15 min. The layers were then separated, and the toluene layer was washed with water (2 x 25 mL), brine, and dried over Na2SO4. The toluene layer was then concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (0 to 20% EtOAc in petroleum ether) giving MPAA as a low melting point pale brown / red solid (4.09 g, 50%). Rf= 0.05 (10% EtOAc in petroleum ether); δH(400 MHz, CDCl3) 9.27 (1 H, d, J 8.1), 7.52 (1 H, d, J 13.1), 7.44 – 7.34 (2 H, m), 7.24 – 7.12 (3 H, m), 5.45 (1 H, dd, J 13.1, 8.1), 3.31 (3 H, s); LRMS m / z (ESI+) 160.20 ([M+H]+, 100%). These data are in good agreement with the literature values (Zacharia, J. T.; Tanaka, T.; Hayashi, M. Facile and Highly Enantioselective Synthesis of (+)- and (−)-Fluvastatin and Their Analogues. J. Org. Chem. 2010, 75 (22), 7514–7518). (E)-3-(3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H-indol-2-yl)acrylaldehyde P-632882-PC

[0360] (E)-3-(3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H-indol-2-yl)acrylaldehyde was synthesized according to general procedure 3, using 3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H- indole (400 mg, 1.50 mmol, 1.0 eq), MPAA (603 mg, 3.74 mmol, 2.5 eq) and phosphoryl trichloride (418 µL, 4.49 mmol, 3.0 eq). Following silica gel column chromatography, the desired less polar product needed to be separated from its regioisomer (E)-3-(3-(4-fluorophenyl)-1- isopropyl-4-methyl-1H-indol-5-yl)acrylaldehyde by reverse-phase isocratic preparative HPLC using an eluent of 60% MeCN in water with a 0.1% additive of formic acid. This resulted in the product as a vibrant yellow powder following lyophilization (50 mg, 10%). Rf = 0.46 (20% EtOAc in petroleum ether); ^ ̅max (thin film) / cm−11667, 1499, 1370, 1124, 840;1H NMR (400 MHz, CDCl3) δ 9.45 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 16.1 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.21 – 7.09 (m, 3H), 6.83 (ddd, J = 7.1, 1.0, 1.0 Hz, 1H), 6.05 (dd, J = 16.1, 7.5 Hz, 1H), 4.97 (hept, J = 7.0 Hz, 1H), 2.03 (s, 3H), 1.73 (d, J = 7.0 Hz, 6H);19F NMR (376 MHz, CDCl3) δ -114.31;13C NMR (101 MHz, CDCl3) δ 193.37, 162.54 (d, J = 247.4 Hz), 140.97, 137.51, 132.99, 132.53 (d, J = 8.0 Hz), 132.09 (d, J = 3.3 Hz), 130.84, 128.84, 126.95, 124.44, 123.44, 121.95, 115.30 (d, J = 21.5 Hz), 110.16, 48.09, 21.83, 20.54; HRMS m / z (ESI+) found 322.1606 [M+H]+(C21H21FNO requires 322.1607 [M+H]+). (E)-3-(3-(4-fluorophenyl)-1-isopropyl-5-methyl-1H-indol-2-yl)acrylaldehyde

[0361] (E)-3-(3-(4-fluorophenyl)-1-isopropyl-5-methyl-1H-indol-2-yl)acrylaldehyde was synthesized according to general procedure 3, using 3-(4-fluorophenyl)-1-isopropyl-5-methyl-1H- indole (500 mg, 1.87 mmol, 1.0 eq), MPAA (754 mg, 4.68 mmol, 2.5 eq) and phosphoryl trichloride (523 µL, 5.61 mmol, 3.0 eq) which resulted in the desired product as a vibrant yellow solid (410 mg, 68%). Rf= 0.27 (15% EtOAc in petroleum ether); m.p. 119–120 °C (Et2O); ^ma̅x (thin film) / cm−11659, 1602, 1541, 1495, 1293, 1211, 1128, 1108, 971, 798;1H NMR (400 MHz, P-632882-PC CDCl3) δ 9.55 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 16.2 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.31 – 7.28 (m, 1H), 7.23 – 7.12 (m, 3H), 6.29 (dd, J = 16.2, 7.6 Hz, 1H), 4.95 (hept, J = 7.0 Hz, 1H), 2.41 (s, 3H), 1.71 (d, J = 7.0 Hz, 6H);19F NMR (376 MHz, CDCl3) δ -114.67;13C NMR (101 MHz, CDCl3) δ 193.5, 162.4 (d, J = 247.0 Hz), 141.2, 136.2, 132.1 (d, J = 8.1 Hz), 130.6, 130.3, 130.2 (d, J = 3.5 Hz), 129.3, 128.8, 126.7, 122.5, 120.4, 116.0 (d, J = 21.3 Hz), 112.4, 48.4, 22.0, 21.4; HRMS m / z (ESI+) found 322.1614 [M+H]+(C21H21FNO requires 322.1607 [M+H]+). (E)-3-(3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H-indol-2-yl)acrylaldehyde

[0362] (E)-3-(3-(4-fluorophenyl)-1- 2-yl)acrylaldehyde was synthesized according to general procedure 3, using 3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H- indole (400 mg, 1.50 mmol, 1.0 eq), MPAA (603 mg, 3.74 mmol, 2.5 eq) and phosphoryl trichloride (418 µL, 4.49 mmol, 3.0 eq) which resulted in the desired product as a vibrant yellow amorphous solid (461 mg, 96%). Rf = 0.50 (20% EtOAc in petroleum ether); ^ ̅max (thin film) / cm−11664, 1609, 1543, 1334, 1119, 1089, 958, 844, 806;1H NMR (400 MHz, CDCl3) δ 9.54 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 16.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.39 – 7.34 (m, 3H), 7.21 – 7.14 (m, 2H), 7.00 – 6.93 (m, 1H), 6.29 (dd, J = 16.1, 7.6 Hz, 1H), 4.95 (hept, J = 7.0 Hz, 1H), 2.52 (s, 3H), 1.72 (d, J = 7.0 Hz, 6H);19F NMR (376 MHz, CDCl3) δ -114.6;13C NMR (101 MHz, CDCl3) δ 193.5, 162.4 (d, J = 247.0 Hz), 141.4, 138.3, 135.1, 132.0 (d, J = 8.0 Hz), 130.2 (d, J = 3.0 Hz), 130.1, 128.9, 126.5, 123.3, 122.8, 120.8, 116.0 (d, J = 21.3 Hz), 112.4, 48.3, 22.5, 21.9; HRMS m / z (ESI+) found 322.1603 [M+H]+(C21H21FNO requires 322.1607 [M+H]+). (E)-3-(3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H-indol-2-yl)acrylaldehyde P-632882-PC

[0363] (E)-3-(3-(4-fluorophenyl)-1- indol-2-yl)acrylaldehyde was synthesized according to general procedure 3, using 3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H- indole (250 mg, 935 µmol, 1.0 eq), MPAA (377 mg, 2.34 mmol, 2.5 eq) and phosphoryl trichloride (261 µL, 2.81 mmol, 3.0 eq). Following silica gel column chromatography, the desired less polar product needed to be separated from its regioisomer (E)-3-(3-(4-fluorophenyl)-1-isopropyl-7- methyl-1H-indol-5-yl)acrylaldehyde by reverse-phase isocratic preparative HPLC using an eluent of 60% MeCN in water with a 0.1% additive of formic acid. This resulted in the product as a vibrant yellow powder following lyophilization (40 mg, 14%). Rf= 0.19 (10% EtOAc in petroleum ether); ^ma̅x (thin film) / cm−11160, 1606, 1541, 1498, 1332, 1215, 1142, 1115, 747;1H NMR (500 MHz, CDCl3) δ 9.54 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 15.9 Hz, 1H), 7.35 – 7.28 , 7.22 (ddd, J = 7.9, 1.3, 0.7 Hz, 1H), 7.18 – 7.12 (m, 2H), 7.06 (ddd, J = 7.0, 1.2, 1.2 Hz, 1H), 6.98 (dd, J = 8.0, 7.1 Hz, 1H), 6.10 (dd, J = 15.9, 7.5 Hz, 1H), 5.52 (hept, J = 7.1 Hz, 1H), 2.79 (s, 3H), 1.70 (d, J = 7.1 Hz, 6H);19F NMR (376 MHz, CDCl3) δ -114.6;13C NMR (126 MHz, CDCl3) δ 193.3, 162.4 (d, J = 247.0 Hz), 142.4, 138.0, 132.0 (d, J = 8.1 Hz), 130.7, 130.6 (d, J = 3.4 Hz), 129.9, 129.2, 128.9, 123.2, 121.1, 120.9, 119.0, 116.2 (d, J = 21.3 Hz), 48.3, 24.0, 21.7; HRMS m / z (ESI+) found 322.1606 [M+H]+(C21H21FNO requires 322.1607 [M+H]+). (E)-3-(1-ethyl-3-(4-fluorophenyl)-1H-indol-2-yl)acrylaldehyde

[0364] (E)-3-(1-ethyl-3-(4-fluorophenyl)-1H-indol-2-yl)acrylaldehyde was synthesized according to general procedure 3, using 1-ethyl-3-(4-fluorophenyl)-1H-indole (400 mg, 1.67 mmol, 1 eq), MPAA (674 mg, 4.18 mmol, 2.5 eq) and phosphoryl trichloride (467 µL, 5.01 mmol, 3.0 eq) to P-632882-PC give the product as a vibrant yellow solid (351 mg, 72%). Rf= 0.40 (20% EtOAc in petroleum ether); m.p. 97–99 °C (Et2O); ^ ̅max (thin film) / cm−11672, 1602, 1524, 1371, 1339, 1225, 1113, 845, 738;1H NMR (400 MHz, CDCl3) δ 9.57 (d, J = 7.5 Hz, 1H), 7.57 (ddd, J = 8.2, 1.0, 1.0 Hz, 1H), 7.53 (d, J = 16.3 Hz, 1H), 7.45 – 7.36 (m, 4H), 7.26 – 7.13 (m, 3H), 6.49 (dd, J = 16.4, 7.5 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H);19F NMR (376 MHz, CDCl3) δ -114.34;13C NMR (101 MHz, CDCl3) δ 193.9, 162.5 (d, J = 247.3 Hz), 140.6, 138.9, 132.1 (d, J = 7.9 Hz), 129.9 (d, J = 3.2 Hz), 129.7, 127.8, 127.4, 125.8, 124.3, 121.2, 121.0, 116.1 (d, J = 21.4 Hz), 109.9, 39.4, 15.6; HRMS m / z (ESI+) found 294.1311 [M+H]+(C19H17FNO requires 294.1294 [M+H]+). (E)-3-(3-(4-fluorophenyl)-1-propyl-1H-indol-2-yl)acrylaldehyde

[0365] (E)-3-(3-(4-fluorophenyl)-1- was synthesized according to general procedure 3, using 3-(4-fluorophenyl)-1-propyl-1H-indole (150 mg, 592 µmol, 1.0 eq), MPAA (239 mg, 1.48 mmol, 2.5 eq) and phosphoryl trichloride (166 µL, 1.78 mmol, 3.0 eq) to give the product as a vibrant yellow solid (158 mg, 87%). Rf= 0.54 (20% EtOAc in petroleum ether); m.p. 88–90 °C (EtOAc); ^ ̅max (thin film) / cm−11670 (C=O), 1615, 1604, 1336, 1117, 837, 742;1H NMR (400 MHz, CDCl3) δ 9.55 (d, J = 7.5 Hz, 1H), 7.55 (ddd, J = 8.1, 1.0, 1.0 Hz, 1H), 7.53 (d, J = 16.3 Hz, 1H), 7.45 – 7.34 (m, 4H), 7.24 – 7.12 (m, 3H), 6.44 (dd, J = 16.3, 7.5 Hz, 1H), 4.33 – 4.25 (m, 2H), 1.91 (h, J = 7.5 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H);19F NMR (376 MHz, CDCl3) δ -114.4;13C NMR (101 MHz, CDCl3) δ 193.8, 162.5 (d, J = 247.1 Hz), 140.7, 139.3, 132.2 (d, J = 8.0 Hz), 130.0, 129.9, 127.8, 127.3, 125.7, 124.1, 121.1, 120.9, 116.1 (d, J = 21.5 Hz), 110.2, 46.1, 23.9, 11.6; HRMS m / z (ESI+) found 308.1452 [M+H]+(C20H19FNO requires 308.1451 [M+H]+). (E)-3-(1-isopropyl-3-(p-tolyl)-1H-indol-2-yl)acrylaldehyde P-632882-PC

[0366] (E)-3-(1-isopropyl-3-(p-tolyl)- was synthesized with general procedure 3, using 1-isopropyl-3-(p-tolyl)-1H-indole (438 mg, 1.76 mmol, 1.0 eq), MPAA (708 mg, 4.39 mmol, 2.5 eq) and phosphoryl trichloride (491 µL, 5.27 mmol, 3.0 eq) which resulted in the product as a vibrant yellow powder (439 mg, 82%). Rf= 0.44 (20% EtOAc in petroleum ether); ^ma̅x (thin film) / cm−12974, 2918, 1653, 1103;1H NMR (500 MHz, CDCl3) δ 9.56 (d, J = 7.6 Hz, 1H), 7.63 – 7.56 (m, 3H), 7.34 – 7.28 (m, 5H), 7.11 (ddd, J = 8.1, 7.0, 0.8 Hz, 1H), 6.35 (dd, J = 16.2, 7.6 Hz, 1H), 4.98 (hept, J = 7.0 Hz, 1H), 2.44 (s, 3H), 1.73 (d, J = 7.0 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 193.8, 141.8, 137.9, 137.3, 131.0, 130.5, 130.4, 130.3, 129.7, 129.2, 128.5, 124.7, 124.5, 121.5, 120.6, 112.6, 48.4, 21.9, 21.4; HRMS m / z (ESI+) found 304.1719 [M+H]+(C21H22NO requires 304.1701 [M+H]+). (E)-3-(3-(4-chlorophenyl)-1-isopropyl-1H-indol-2-yl)acrylaldehyde

[0367] (E)-3-(3-(4-chlorophenyl)-1-isopropyl-1H-indol-2-yl)acrylaldehyde was synthesized with general procedure 3, using 3-(4-chlorophenyl)-1-isopropyl-1H-indole (354 mg, 1.31 mmol, 1.0 eq), MPAA (529 mg, 3.28 mmol, 2.5 eq) and phosphoryl trichloride (367 µL, 3.94 mmol, 3.0 eq) which resulted in the product as a vibrant yellow powder (317 mg, 75%). Rf = 0.37 (20% EtOAc in petroleum ether); m.p.113–115 °C (CH2Cl2); ^m̅ax (thin film) / cm−12973, 2934, 1653, 1103, 834;1H NMR (500 MHz, CDCl3) δ 9.58 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 16.2 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.32 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.13 (m, 1H), 6.33 (dd, J = 16.1, 7.5 Hz, 1H), 4.97 (hept, J = 7.1 Hz, 1H), P-632882-PC 1.73 (d, J = 7.1 Hz, 6H);13C NMR (126 MHz, CDCl3) δ 193.4, 141.0, 137.7, 133.6, 132.6, 131.7, 130.6, 129.9, 129.3, 128.3, 124.8, 122.5, 121.0, 120.9, 112.7, 48.5, 21.9; HRMS m / z (ESI+) found 324.1167 [M+H]+(C20H19ClNO requires 324.1155 [M+H]+). (E)-3-(3-(4-bromomphenyl)-1-isopropyl-1H-indol-2-yl)acrylaldehyde

[0368] (E)-3-(3-(4-bromophenyl)-1- yl)acrylaldehyde was synthesized with general procedure 3, using 3-(4-bromophenyl)-1-isopropyl-1H-indole (386 mg, 1.23 mmol, 1.0 eq), MPAA (495 mg, 3.07 mmol, 2.5 eq) and phosphoryl trichloride (343 µL, 3.69 mmol, 3.0 eq) which resulted in the product as a vibrant yellow powder (228 mg, 51%). Rf= 0.30 (20% EtOAc in petroleum ether); m.p. 152–154 °C (CH2Cl2); ^ ̅max (thin film) / cm−12973, 2934, 1656, 1105, 647;1H NMR (500 MHz, CDCl3) δ 9.58 (d, J = 7.5 Hz, 1H), 7.65 – 7.51 (m, 5H), 7.34 – 7.28 (m, 3H), 7.13 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.33 (dd, J = 16.2, 7.5 Hz, 1H), 4.97 (hept, J = 7.0 Hz, 1H), 1.73 (d, J = 7.0 Hz, 6H);13C NMR (126 MHz, CDCl3) δ 193.4, 141.0, 137.7, 133.1, 132.2, 132.1, 130.5, 130.0, 128.2, 124.8, 122.5, 121.7, 121.0, 120.9, 112.7, 48.5, 21.9; HRMS m / z (ESI+) found 368.0712 [M+H]+ (C20H19BrNO requires 368.0712 [M+H]+). (E)-3-(3-(4-(trifluoromethyl)phenyl)-1-isopropyl-1H-indol-2-yl)acrylaldehyde

[0369] (E)-3-(3-(4-(trifluoromethyl)phenyl)-1-isopropyl-1H-indol-2-yl)acrylaldehyde was synthesized with general procedure 3, using 3-(4-(trifluoromethyl)phenyl)-1-isopropyl-1H-indole P-632882-PC (549 mg, 1.81 mmol, 1.0 eq), MPAA (729 mg, 4.52 mmol, 2.5 eq) and phosphoryl trichloride (506 µL, 5.43 mmol, 3.0 eq) which resulted in the product as a vibrant yellow powder (216 mg, 33%). Rf = 0.27 (20% EtOAc in petroleum ether); m.p. 141–143°C (CH2Cl2); ^m̅ax (thin film) / cm−12969, 2925, 1661, 1319, 1107;1H NMR (500 MHz, CDCl3) δ 9.59 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.65 – 7.53 (m, 5H), 7.33 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 7.15 (dd, J = 7.6, 7.6 Hz, 1H), 6.33 (dd, J = 16.2, 7.5 Hz, 1H), 4.98 (hept, J = 7.0 Hz, 1H), 1.74 (d, J = 7.0 Hz, 6H);19F NMR (376 MHz, CDCl3) δ -62.4; HRMS m / z (ESI+) found 304.1419 [M+H]+(C21H19F3NO requires 358.1423 [M+H]+). General procedure 4: Synthesis of tert-butyl esters

[0370] For on a mg (1.3 eq) was slowly added dropwise to a solution of NaH (1.3 eq) in anhydrous THF (344 µL). The solution was then cooled to 0 °C and n-BuLi (1.8 M in hexanes, 1.3 eq) was added dropwise, producing a vibrant yellow solution. The required acrylaldehyde (100 mg, 1 eq) was dissolved in anhydrous THF (286 µL) and added dropwise over 1 h to the yellow solution at 0 °C. The solution was stirred for a further 1 h, and then quenched by the addition of glacial acetic acid (1 mL), and then water (1 mL). The mixture was extracted with EtOAc (3 × 50 mL), and the combined EtOAc extracts were washed with H2O (150 mL), until the washes were at pH 6–7, and then finally washed with brine, dried over Na2SO4and concentrated in vacuo. A portion of the residue was subject to LCMS where only the desired aldol intermediate was observed. The sample was stored at –20 °C until required for the following step. Next, to anhydrous THF (856 µL) at –78 °C, was added NaBH4 (1.3 eq), and then diethylmethoxyborane (1.0 M in THF, 0.75 to 1 eq) dropwise, over 15 mins. The aldol intermediate was then dissolved in anhydrous THF (217 µL) and anhydrous MeOH (289 µL), and was then added slowly, dropwise over 1 h to the solution of borane, and stirred for a P-632882-PC further 1 h. The reaction mixture was then poured into a separating funnel containing EtOAc and saturated sodium bicarbonate and shaken vigorously until effervescence ceased. The EtOAc was separated, and the aqueous phase was further extracted with EtOAc three times. The combined EtOAc extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was then dissolved in MeOH and concentrated in vacuo. This process was repeated three times to remove excess borane, and the resulting residue was purified via isocratic preparative HPLC (C18, column size 5 µm, 10x250, 20 mLmin-1) to give the desired cis-diol as a colorless / pale yellow powder after lyophilization. tert-butyl rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate

[0371] Tert-butyl rel- - - 4-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 4 using tert-butyl acetoacetate (27 µL, 0.16 mmol, 1.3 eq), NaH (60% in mineral oil, 7 mg, 0.2 mmol, 1.3 eq), n- BuLi (1.8 M, 90 µL, 0.16 mmol, 1.2 eq), (E)-3-(3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H- indol-2-yl)acrylaldehyde (40 mg, 0.12 mmol, 1.0 eq), NaBH4(6 mg, 0.2 mmol, 1.3 eq) and diethylmethoxyborane (1.0 M in THF, 90 µL, 0.75 eq), resulting in a residue that was purified via an isocratic preparative HPLC, using an eluent of 70% acetonitrile in water with an additive of 0.1% formic acid to give the product (6 mg, 10%) as a fluffy colorless powder after lyophilization. ^ma̅x (thin film) / cm−12976, 2933, 1724, 1539, 1501, 1393, 1218, 1153, 838, 750;1H NMR (500 MHz, CD3CN) δ 7.44 (d, J = 8.4 Hz, 1H), 7.35 – 7.27 (m, 2H), 7.15 – 7.07 (m, 2H), 7.02 (dd, J = 8.4, 7.1 Hz, 1H), 6.73 (ddd, J = 7.1, 0.9, 0.9 Hz, 1H), 6.51 (dd, J = 16.0, 1.4 Hz, 1H), 5.51 (dd, J = 16.0, 6.1 Hz, 1H), 4.88 (hept, J = 7.0 Hz, 1H), 4.26 – 4.20 (m, 1H), 3.92 – 3.82 (m, 1H), 3.38 (dd, J = 18.8, 3.8 Hz, 2H), 2.30 – 2.24 (m, 1H), 2.25 – 2.20 (m, 1H), 2.01 (s, 3H), 1.61 (d, J = 7.0 Hz, 6H), 1.43 (s, 9H), 1.45 – 1.37 (m, 1H), 1.34 – 1.27 (m, 1H);19F NMR (376 MHz, CD3CN) δ -118.2;13C NMR (126 MHz, CD3CN) δ 172.1, 162.8 (d, J = 242.8 Hz), 140.5, 135.8, 135.4, 135.1 P-632882-PC (d, J = 3.3 Hz), 134.7 (d, J = 7.4 Hz), 134.4 (d, J = 7.4 Hz), 131.5, 127.7, 122.2, 121.8, 119.0, 115.8, 115.1 (d, J = 21.2 Hz), 110.4, 81.2, 71.6, 67.7, 48.5, 44.1, 28.2, 21.8, 21.7, 20.8; HRMS m / z (ESI+) found 482.2710 [M+H]+(C29H37FNO4 requires 482.2707 [M+H]+). tert-butyl rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-5-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate

[0372] Tert-butyl rel- 5-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 4 using tert-butyl acetoacetate (123 µL, 747 µmol, 1.2 eq), NaH (60% in mineral oil, 30 mg, 0.75 mmol, 1.2 eq), n- BuLi (1.8 M, 299 µL, 747 µmol, 1.2 eq), (E)-3-(3-(4-fluorophenyl)-1-isopropyl-5-methyl-1H- indol-2-yl)acrylaldehyde (200 mg, 622 µmol, 1.0 eq), NaBH4 (31 mg, 0.81 mmol, 1.3 eq) and diethylmethoxyborane (1.0 M in THF, 467 µL, 0.75 eq), resulting in a residue that was purified via an isocratic preparative HPLC, using an eluent of 65% acetonitrile in water with an additive of 0.1% formic acid to give the product (23 mg, 8%) as a fluffy colorless powder after lyophilization. ^ma̅x (thin film) / cm−12977, 2933, 1725, 1502, 1458, 1219, 1152, 841;1H NMR (500 MHz, CD3CN) δ 7.50 (d, J = 8.5 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.28 – 7.24 (m, 1H), 7.17 (dd, J = 8.9, 8.9 Hz, 2H), 7.00 (dd, J = 8.5, 1.7 Hz, 1H), 6.64 (dd, J = 16.1, 1.4 Hz, 1H), 5.69 (dd, J = 16.1, 6.0 Hz, 1H), 4.87 (hept, J = 7.0 Hz, 1H), 4.38 – 4.30 (m, 1H), 4.05 – 3.96 (m, 1H), 3.46 (d, J = 1.3 Hz, 1H), 3.46 (d, J = 1.8 Hz, 1H), 2.36 (s, 3H), 2.33 (dd, J = 15.5, 4.8 Hz, 1H), 2.28 (dd, J = 15.5, 7.9 Hz, 1H), 1.60 (d, J = 7.0 Hz, 3H), 1.60 (d, J = 7.0 Hz, 3H), 1.57 – 1.46 (m, 2H), 1.43 (s, 9H);19F NMR (376 MHz, CD3CN) δ -118.7;13C NMR (126 MHz, CD3CN) δ 172.1, 162.1 (d, J = 242.2 Hz), 141.1, 135.2, 134.4, 132.96 (d, J = 3.0 Hz), 132.9 (d, J = 7.8 Hz), 129.8, 129.3, 124.1, 119.3, 119.1, 116.0 (d, J = 21.2 Hz), 114.2, 112.6, 81.2, 71.7, 67.9, 48.5, 44.1, 43.9, 28.2, 21.8, 21.3; HRMS m / z (ESI+) found 482.2711 [M+H]+(C29H37FNO4requires 482.2707 [M+H]+). P-632882-PC tert-butyl rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate

[0373] Tert-butyl rel- 6-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 4 using tert-butyl acetoacetate (62 µL, 0.37 mmol, 1.2 eq), NaH (60% in mineral oil, 15 mg, 0.38 mmol, 1.2 eq), n- BuLi (1.8 M, 207 µL, 373 µmol, 1.2 eq), (E)-3-(3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H- indol-2-yl)acrylaldehyde (100 mg, 311 µmol, 1.0 eq), NaBH4 (15 mg, 0.40 mmol, 1.3 eq) and diethylmethoxyborane (1.0 M in THF, 233 µL, 0.75 eq), resulting in a residue that was purified via an isocratic preparative HPLC, using an eluent of 65% acetonitrile in water with an additive of 0.1% formic acid to give the product (30 mg, 20%) as a fluffy colorless powder after lyophilization. ^ma̅x (thin film) / cm−12974, 2933, 1725, 1548, 1500, 1368, 1219, 1154, 837, 805;1H NMR (500 MHz, CD3CN) δ 7.46 – 7.41 (m, 3H), 7.35 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 9.0, 9.0 Hz, 2H), 6.90 (ddd, J = 8.0, 1.4, 0.6 Hz, 1H), 6.64 (dd, J = 16.0, 1.4 Hz, 1H), 5.68 (dd, J = 16.1, 6.0 Hz, 1H), 4.87 (hept, J = 7.0 Hz, 1H), 4.38 – 4.29 (m, 1H), 4.05 – 3.95 (m, 1H), 3.50 – 3.41 (m, 2H), 2.46 (s, 3H), 2.33 (dd, J = 15.5, 4.8 Hz, 1H), 2.28 (dd, J = 15.5, 7.9 Hz, 1H), 1.61 (d, J = 7.0 Hz, 3H), 1.61 (d, J = 7.0 Hz, 3H), 1.56 – 1.47 (m, 2H), 1.43 (s, 9H);19F NMR (376 MHz, CD3CN) δ -118.7;13C NMR (126 MHz, CD3CN) δ 172.1, 162.1 (d, J = 242.2 Hz), 140.9, 136.5, 134.6, 133.0 (d, J = 2.9 Hz), 132.8 (d, J = 7.6 Hz), 132.4, 127.0, 122.3, 119.5, 119.2, 116.0 (d, J = 21.3 Hz), 114.5, 112.7, 81.1, 71.7, 67.9, 48.5, 44.2, 43.9, 28.2, 21.9, 21.7; HRMS m / z (ESI+) found 482.2708 [M+H]+(C29H36FNO4requires 482.2707 [M+H]+). tert-butyl rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate P-632882-PC

[0374] Tert-butyl rel- 7-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 4 using tert-butyl acetoacetate (27 µL, 0.16 mmol, 1.3 eq), NaH (60% in mineral oil, 7 mg, 0.2 mmol, 1.3 eq), n- BuLi (1.8 M, 90 µL, 0.16 mmol, 1.3 eq), (E)-3-(3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H- indol-2-yl)acrylaldehyde (40 mg, 0.12 mmol, 1.0 eq), NaBH4(6 mg, 0.16 mmol, 1.3 eq) and diethylmethoxyborane (1.0 M in THF, 90 µL, 0.75 eq), resulting in a residue that was purified via an isocratic preparative HPLC, using an eluent of 70% acetonitrile in water with an additive of 0.1% formic acid to give the product (16 mg, 28%) as a fluffy colorless powder after lyophilization. ^ma̅x (thin film) / cm−12974, 1723, 1549, 1503, 1219, 1153, 832, 744;1H NMR (500 MHz, CD3CN) δ 7.39 – 7.34 (m, 2H), 7.21 – 7.18 (m, 1H), 7.18 – 7.12 (m, 2H), 6.94 – 6.88 (m, 2H), 6.79 (dd, J = 15.9, 1.4 Hz, 1H), 5.53 (dd, J = 15.9, 5.9 Hz, 1H), 5.46 (hept, J = 7.0 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.98 – 3.90 (m, 1H), 3.48 – 3.43 (m, 2H), 2.75 (s, 3H), 2.29 (dd, J = 15.5, 4.9 Hz, 1H), 2.25 (dd, J = 15.5, 7.9 Hz, 1H), 1.59 (d, J = 7.0 Hz, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.43 (s, 9H), 1.49 – 1.35 (m, 2H);19F NMR (376 MHz, CD3CN) δ -118.5;13C NMR (126 MHz, CD3CN) δ 172.0, 162.2 (d, J = 242.7 Hz), 140.3, 136.7, 135.9, 133.4 (d, J = 8.0 Hz), 133.1 (d, J = 3.3 Hz), 129.4, 127.0, 121.8, 120.7, 120.6, 117.8, 116.8, 116.0 (d, J = 21.3 Hz), 81.1, 71.5, 68.0, 49.1, 44.1, 43.7, 28.2, 23.50, 23.47, 21.7; HRMS m / z (ESI+) found 482.2711 [M+H]+(C29H37FNO4 requires 482.2707 [M+H]+). tert-butyl rel-(3S,5R,E)-7-(1-ethyl-3-(4-fluorophenyl)-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate

[0012] P-632882-PC

[0375] Tert-butyl rel-(3S,5R,E)-7-(1-ethyl-3-(4-fluorophenyl)-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 4 using tert-butyl acetoacetate (135 µL, 818 µmol, 1.2 eq), NaH (60% in mineral oil, 33 mg, 0.82 mmol, 1.2 eq), n- BuLi (1.8 M, 455 µL, 818 µmol, 1.2 eq), (E)-3-(1-ethyl-3-(4-fluorophenyl)-1H-indol-2- yl)acrylaldehyde (200 mg, 682 µmol, 1.0 eq), NaBH4 (34 mg, 0.89 mmol, 1.3 eq) and diethylmethoxyborane (1.0 M in THF, 512 µL, 0.75 eq), resulting in a residue that was purified via an isocratic preparative HPLC, using an eluent of 65% acetonitrile in water with an additive of 0.1% formic acid to give the product (173 mg, 56%) as a fluffy colorless powder after lyophilization. ^ ̅max (thin film) / cm−12978, 2933, 1718, 1500, 1459, 1220, 1152, 838, 742;1H NMR (500 MHz, CD3CN) δ 7.51 – 7.46 (m, 3H), 7.45 (ddd, J = 8.4, 0.9, 0.9 Hz, 1H), 7.24 – 7.17 (m, 3H), 7.08 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H), 6.65 (dd, J = 16.2, 1.4 Hz, 1H), 5.88 (dd, J = 16.2, 6.0 Hz, 1H), 4.37 (m, 1H), 4.31 (q, J = 7.2 Hz, 2H), 4.08 – 4.01 (m, 1H), 3.48 (s, 2H), 2.35 (dd, J = 15.4, 4.8 Hz, 1H), 2.29 (dd, J = 15.5, 8.0 Hz, 1H), 1.62 – 1.52 (m, 2H), 1.43 (s, 9H), 1.35 (t, J = 7.2 Hz, 3H);19F NMR (376 MHz, CD3CN) δ -118.3;13C NMR (126 MHz, CD3CN) δ 172.1, 162.4 (d, J = 242.8 Hz), 139.9, 137.3, 134.2, 132.9 (d, J = 8.0 Hz), 132.7 (d, J = 3.2 Hz), 128.3, 123.2, 121.0, 119.7, 118.4*, 116.2 (d, J = 21.4 Hz), 115.0, 110.6, 81.2, 71.9, 68.0, 44.3, 44.0, 39.2, 28.3, 15.7. HRMS m / z (ESI+) found 454.2401 [M+H]+(C27H33FNO4 requires 454.2393 [M+H]+). *observed via HSQC. tert-butyl rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-propyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate

[0376] Tert-butyl rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-propyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 4 using tert-butyl acetoacetate (70 µL, 0.42 mmol, 1.3 eq), NaH (60% in mineral oil, 17 mg, 0.42 mmol, 1.3 eq), n- BuLi (1.8 M, 235 µL, 423 µmol, 1.3 eq), (E)-3-(3-(4-fluorophenyl)-1-propyl-1H-indol-2- P-632882-PC yl)acrylaldehyde (100 mg, 325 µmol, 1.0 eq), NaBH4(16 mg, 0.42 mmol, 1.3 eq) and diethylmethoxyborane (1.0 M in THF, 244 µL, 0.75 eq), resulting in a residue that was purified via an isocratic preparative HPLC, using an eluent of 70% acetonitrile in water with an additive of 0.1% formic acid to give the product (38 mg, 25%) as a fluffy colorless powder after lyophilization. ^ma̅x (thin film) / cm−12971, 2933, 1724, 1545, 1500, 1461, 1333, 1221, 1152, 837, 743;1H NMR (500 MHz, CD3CN) δ 7.51 – 7.42 (m, 4H), 7.24 – 7.16 (m, 3H), 7.07 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.65 (dd, J = 16.2, 1.5 Hz, 1H), 5.85 (dd, J = 16.2, 6.1 Hz, 1H), 4.39 – 4.32 (m, 1H), 4.24 – 4.18 (m, 2H), 4.08 – 4.00 (m, 1H), 3.47 (dd, J = 3.8, 1.3 Hz, 2H), 2.34 (dd, J = 15.4, 4.8 Hz, 1H), 2.29 (dd, J = 15.4, 7.9 Hz, 1H), 1.84 – 1.75 (m, 2H), 1.62 – 1.49 (m, 2H), 1.43 (s, 9H), 0.93 (t, J = 7.4 Hz, 3H);19F NMR (376 MHz, CD3CN) δ -118.4;13C NMR (126 MHz, CD3CN) δ 172.1, 162.3 (d, J = 243.0 Hz), 139.9, 137.7, 134.5, 132.9 (d, J = 7.9 Hz), 132.7 (d, J = 3.3 Hz), 128.2, 123.0, 120.9, 119.5, 118.5, 116.2 (d, J = 21.4 Hz), 114.8, 110.8, 81.1, 71.9, 68.0, 45.9, 44.2, 44.0, 28.2, 24.2, 11.5; HRMS m / z (ESI+) found 468.2555 [M+H]+(C28H35FNO4 requires 468.2550 [M+H]+). Tert-butyl rel-(3R,5S,E)-3,5-dihydroxy-7-(1-isopropyl-3-(p-tolyl)-1H-indol-2-yl)hept-6- enoate

[0377] Tert-butyl rel-(3R,5S,E)-3,5-dihydroxy-7-(1-isopropyl-3-(p-tolyl)-1H-indol-2-yl)hept-6- enoate was synthesized according to general procedure 4 using tert-butyl acetoacetate (71 µL, 0.33 mmol, 1.3 eq), NaH (60% in mineral oil, 16 mg, 0.39 mmol, 1.3 eq), n-BuLi (1.8 M, 0.24 mL, 0.42 mmol, 1.2 eq), (E)-3-(1-isopropyl-3-(p-tolyl)-1H-indol-2-yl)acrylaldehyde (100 mg, 0.33 mmol, 1.0 eq), NaBH4 (13 mg, 0.35 mmol, 1.3 eq) and diethylmethoxyborane (1.0 M in THF, 217 µL, 0.75 eq), resulting in a residue that was purified via an isocratic preparative HPLC, using an eluent of 70% acetonitrile in water with an additive of 0.1% formic acid to give the product (64 mg, 42%) as a fluffy pale yellow powder after lyophilization. ^ ̅max (thin film) / cm−13420, 2973, 2932, 1457, 1367, 1147, 1103;1H NMR (500 MHz, CD3CN) δ 7.61 (ddd, J = 8.4, 1.0,1.0 Hz, 1H), P-632882-PC 7.49 (ddd, J = 7.9, 1.0, 1.0 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.27 – 7.23 (m, 2H), 7.15 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 7.03 (ddd, J = 8.0, 7.0, 0.9 Hz, 1H), 6.66 (dd, J = 16.2, 1.4 Hz, 1H), 5.73 (dd, J = 16.1, 6.0 Hz, 1H), 4.92 (hept, J = 7.0 Hz, 1H), 4.41 – 4.22 (m, 1H), 4.08 – 4.02 (m,1H), 3.47 (dd, J = 5.5, 3.8 Hz, 2H), 2.38 (s, 3H), 2.39 – 2.24 (m, 2H), 1.62 (d, J = 7.0 Hz, 6H), 1.56 – 1.45 (m, 2H), 1.43 (s, 9H);13C NMR (126 MHz, CD3CN) δ 172.1, 140.9, 136.5, 136.1, 134.9, 133.5, 131.1, 130.0, 129.1, 122.4, 120.4, 120.0, 119.3, 115.7, 112.8, 81.1, 71.7, 67.9, 48.5, 44.2, 43.9, 28.3, 21.7, 21.2; HRMS m / z (ESI+) found 464.2799 [M+H]+(C29H38NO4requires 464.2801 [M+H]+). tert-butyl rel-(3R,5S,E)-7-(3-(4-chlorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate

[0378] Tert-butyl - - isopropyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate) was synthesized according to general procedure 4 using tert-butyl acetoacetate (67 µL, 0.40 mmol, 1.3 eq), NaH (60% in mineral oil, 16 mg, 0.40 mmol, 1.3 eq), n- BuLi (1.8 M, 0.22 mL, 0.40 mmol, 1.2 eq), (E)-3-(1-isopropyl-3-(p-tolyl)-1H-indol-2- yl)acrylaldehyde (100 mg, 0.31 mmol, 1.0 eq), NaBH4(15.2 mg, 0.31 mmol, 1.3 eq) and diethylmethoxyborane (1.0 M in THF, 247 µL, 0.75 eq), resulting in a residue that was purified via an isocratic preparative HPLC, using an eluent of 70% acetonitrile in water with an additive of 0.1% formic acid to give the product (19 mg, 13%) as a fluffy pale yellow powder after lyophilization. ^m̅ax (thin film) / cm−13367, 2974, 2931, 1456, 1367, 1148, 1102, 831;1H NMR (500 MHz, CD3CN) δ 7.62 (ddd, J = 8.4, 0.8, 0.8 Hz, 1H), 7.53 – 7.48 (m, 1H), 7.46 – 7.41 (m, 4H), 7.17 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 7.06 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.67 (dd, J = 16.1, 1.5 Hz, 1H), 5.73 (dd, J = 16.1, 5.9 Hz, 1H), 4.91 (hept, J = 7.0 Hz, 1H), 4.40 – 4.32 (m, 1H), 4.08 – 4.01 (m, 1H), 3.48 (s, 2H), 2.40 – 2.24 (m, 2H), 1.62 (dd, J = 7.0, 2.1 Hz, 6H), 1.58 – 1.49 (m, 2H), 1.43 (s, 9H);13C NMR (126 MHz, CD3CN) δ 172.1, 141.8, 136.0, 135.5, 132.8, 132.0, 129.4, P-632882-PC 128.8, 122.6, 120.7, 119.8, 119.0, 114.3, 112.9, 81.2, 71.6, 67.9, 48.7, 44.1, 43.8, 28.3, 21.7.; HRMS m / z (ESI+) found 530.1763 [M+H]+(C28H34ClNO4 requires 530.1733 [M+H]+). Tert-butyl rel-(3R,5S,E)-7-(3-(4-bromophenyl)-1-isopropyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate

[0379] Tert-butyl - - isopropyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate) was synthesized according to general procedure 4 using tert-butyl acetoacetate (58.5 µL, 0.35 mmol, 1.3 eq), NaH (60% in mineral oil, 14.1 mg, 0.35 mmol, 1.3 eq), n-BuLi (1.8 M, 196 µL, 0.35 mmol, 1.2 eq), (E)-3-(1-isopropyl-3-(p-tolyl)-1H-indol-2- yl)acrylaldehyde (100 mg, 0.27 mmol, 1.0 eq), NaBH4 (13.4 mg, 0.35 mmol, 1.3 eq) and diethylmethoxyborane (1.0 M in THF, 217 µL, 0.75 eq), resulting in a residue that was purified via an isocratic preparative HPLC, using an eluent of 70% acetonitrile in water with an additive of 0.1% formic acid to give the product (30 mg, 21%) as a fluffy pale yellow powder after lyophilization. ^ ̅max (thin film) / cm−13396, 2973, 2931, 1456, 1367, 1148, 1102, 740;1H NMR (500 MHz, CD3CN) δ 7.62 (dd, J = 8.4, 0.9 Hz, 1H), 7.60 – 7.56 (m, 2H), 7.51 (ddd, J = 8.0, 1.1, 1.1 Hz, 1H), 7.40 – 7.36 (m, 2H), 7.17 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 7.06 (ddd, J = 8.0, 7.0, 0.9 Hz, 1H), 6.66 (dd, J = 16.1, 1.4 Hz, 1H), 5.73 (dd, J = 16.1, 5.9 Hz, 1H), 4.91 (hept, J = 7.0 Hz, 1H), 4.39 – 4.33 (m, 1H), 4.06 – 3.97 (m, 1H), 3.51 (s, 1H), 3.48 (s, 1H), 2.37 – 2.24 (m, 2H), 1.62 (dd, J = 7.0, 2.0 Hz, 6H), 1.57 – 1.48 (m, 2H), 1.43 (s, 9H);13C NMR (126 MHz, CD3CN) δ 172.1, 141.8, 136.1, 135.9, 135.5, 133.1, 132.4,128.7, 122.6, 120.7, 120.0, 119.7, 119.0, 114.3, 112.9, 81.2, 71.6, 67.9, 48.7, 44.1, 43.8, 28.3, 21.7; HRMS m / z (ESI+) found 530.1763 [M+H]+(C28H3581BrNO4 requires 530.1733 [M+H]+). Tert-butyl rel-(3R,5S,E)-3,5-dihydroxy-7-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H- indol-2-yl)hept-6-enoate P-632882-PC

[0380] Tert-butyl rel- (4-(trifluoromethyl)phenyl)-1H- indol-2-yl)hept-6-enoate was synthesized according to general procedure 4 using tert-butyl acetoacetate (60.3 µL, 0.36 mmol, 1.2 eq), NaH (60% in mineral oil, 14.6 mg, 0.36 mmol, 1.2 eq), n-BuLi (1.8 M, 202 µL, 0.36 mmol, 1.2 eq), (E)-3-(1-isopropyl-3-(p-tolyl)-1H-indol-2- yl)acrylaldehyde (100 mg, 0.27 mmol, 1.0 eq), NaBH4 (13.6 mg, 0.36 mmol, 1.3 eq) and diethylmethoxyborane (1.0 M in THF, 222 µL, 0.75 eq), resulting in a residue that was purified via an isocratic preparative HPLC, using an eluent of 70% acetonitrile in water with an additive of 0.1% formic acid to give the product (53 mg, 37%) as a fluffy pale yellow powder after lyophilization. ^m̅ax (thin film) / cm−13449, 2979, 1457, 1368, 1102, 740;1H NMR (500 MHz, CD3CN) δ 7.73 (d, J = 8.1 Hz, 2H), 7.67 – 7.65 (m, 2H), 7.65 – 7.63 (m, 1H), 7.56 (dd, J = 8.0, 1.1 Hz, 1H), 7.19 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.08 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.70 (dd, J = 16.0, 1.5 Hz, 1H), 5.73 (dd, J = 16.0, 5.9 Hz, 1H), 4.92 (hept, J = 7.0 Hz, 1H), 4.40 – 4.33 (m, 1H), 4.06 – 3.99 (m, 1H), 3.53 (d, J = 3.5 Hz, 1H), 3.48 (d, J = 3.9 Hz, 1H), 2.35 – 2.25 (m, 2H), 1.63 (d, J = 7.0 Hz, 3H), 1.63 (d, J = 7.0 Hz, 3H), 1.58 – 1.46 (m, 2H), 1.42 (s, 9H);19F NMR (376 MHz, CD3CN) δ -62.6; HRMS m / z (ESI+) found 518.2518 [M+H]+(C29H35F3NO4 requires 518.2524 [M+H]+). General procedure 5: Synthesis of sodium salts

[0013] P-632882-PC

[0381] The tert-butyl ester (10 mg, 1.0 eq) was dissolved in MeOH (150 µL). Aqueous NaOH (0.5 M, 0.99 eq) was then added, and the reaction mixture was stirred for 3 h. The reaction was monitored by LCMS until the majority of the tert-butyl ester was consumed. The reaction mixture was then concentrated in vacuo to remove MeOH, and then diluted with water (2 mL). The solution was extracted with Et2O (2 mL) to remove residual starting material, and the remaining aqueous solution was filtered through a 0.2 µm syringe filter. The clear solution was then frozen and lyophilized to give the desired sodium salt as a colorless / pale yellow powder. Sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate (Compound E)

[0382] Sodium rel- - - 4-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 5 with tert-butyl rel- (3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-4-methyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate (4.0 mg, 8.3 µmol, 1.0 eq) giving a pale yellow powder (3.0 mg, 81%) after lyophilization. ^ma̅x (thin film) / cm−12974, 2934, 1723,1503, 1368, 1219, 1153, 832, 744;1H NMR (500 MHz, MeOD) δ 7.39 (d, J = 8.4 Hz, 1H), 7.35 – 7.25 (m, 2H), 7.12 – 7.07 (m, 2H), 6.98 (dd, J = 8.4, 7.1 Hz, 1H), 6.68 (ddd, J = 7.0, 0.9, 0.9 Hz, 1H), 6.56 (dd, J = 16.0, 1.2 Hz, 1H), 5.53 (dd, J = 16.0, 6.6 Hz, 1H), 4.96 – 4.88 (m, 1H), 4.31 – 4.23 (m, 1H), 3.82 – 3.74 (m, 1H), 2.27 (dd, J = 15.3, 4.5 Hz, 1H), 2.18 (dd, J = 15.3, 7.9 Hz, 1H), 1.99 (s, 3H), 1.64 (d, J = 7.0 Hz, 3H), 1.63 (d, J = 7.0 Hz, 3H), 1.67 – 1.54 (m, 1H), 1.30 (ddd, J = 13.6, 6.9, 3.9 Hz, 1H);19F NMR (376 MHz, MeOD) δ -118.4;13C NMR (126 MHz, MeOD) δ 180.3, 163.4 (d, J = 243.8 Hz), 139.9, 136.3, 135.6 (d, J = 3.4 Hz), 135.2, 135.0 (d, J = 7.7 Hz), 134.6 (d, J = 7.7 Hz), 131.7, 128.3, 122.4, 121.9, 120.1, 116.5, 115.5 (d, J = 21.4 Hz), 115.3 (d, J = 21.4 Hz), 110.5, 71.7, 68.0, 45.0, 44.9, 21.91, 21.85, 20.9; HRMS m / z (ESI+) found 426.2081 [M–Na+2H]+(C25H29FNO4requires 426.2081 [M– Na+2H]+); Purity (95.9%@254 nm), (95.8%@220 nm), (96.4%@310 nm). P-632882-PC Sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-5-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate (Compound B)

[0383] Sodium rel- 5-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 5 with tert-butyl rel- (3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-5-methyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate (10 mg, 21 µmol, 1.0 eq) giving a pale yellow powder (7.2 mg, 77%) after lyophilization. ^ma̅x (thin film) / cm−12974, 2935, 1573, 1501, 1218, 841, 790;1H NMR (500 MHz, MeOD) δ 7.44 (d, J = 8.5 Hz, 1H), 7.42 – 7.37 (m, 2H), 7.20 (ddd, J = 1.7, 0.9, 0.9 Hz, 1H), 7.17 – 7.11 (m, 2H), 6.97 – 6.94 (m, 1H), 6.67 (dd, J = 16.1, 1.3 Hz, 1H), 5.70 (dd, J = 16.1, 6.5 Hz, 1H), 4.90 (hept, J = 7.0 Hz, 1H), 4.42 – 4.32 (m, 1H), 4.00 – 3.92 (m, 1H), 2.36 – 2.30 (m, 4H), 2.26 (dd, J = 15.2, 7.8 Hz, 1H), 1.72 – 1.64 (m, 1H), 1.62 (d, J = 7.0 Hz, 6H), 1.56 – 1.46 (m, 1H);19F NMR (376 MHz, MeOD) δ -119.1;13C NMR (126 MHz, MeOD) δ 180.3, 162.8 (d, J = 243.5 Hz), 140.5, 135.018, 135.010, 133.4 (d, J = 3.4 Hz), 133.2 (d, J = 7.7 Hz), 130.0, 129.7, 124.2, 120.2, 119.7, 116.1 (d, J = 21.4 Hz), 115.1, 112.6, 71.7, 68.3, 45.1, 44.8, 21.90, 21.88, 21.5; HRMS m / z (ESI+) found 426.2075 [M–Na+2H]+(C25H29FNO4 requires 426.2081 [M–Na+2H]+); Purity (91.1%@254 nm), (90.0%@220 nm), (91.2%@310 nm). Sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate (Compound C)

[0014] P-632882-PC

[0384] Sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 5 with tert-butyl rel- (3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-6-methyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate (10.3 mg, 21.4 µmol, 1.0 eq) giving a pale yellow powder (8 mg, 80%) after lyophilization. ^ma̅x (thin film) / cm−12971, 2933, 1564, 1394, 1215, 1104, 837, 800;1H NMR (500 MHz, MeOD) δ 7.43 – 7.37 (m, 2H), 7.37 – 7.34 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.16 – 7.10 (m, 2H), 6.85 (ddd, J = 8.2, 1.4, 0.7 Hz, 1H), 6.67 (dd, J = 16.1, 1.3 Hz, 1H), 5.69 (dd, J = 16.0, 6.5 Hz, 1H), 4.92 (hept, J = 7.0 Hz, 1H), 4.41 – 4.33 (m, 1H), 4.01 – 3.92 (m, 1H), 2.45 (s, 3H), 2.33 (dd, J = 15.2, 4.7 Hz, 1H), 2.26 (dd, J = 15.2, 7.8 Hz, 1H), 1.68 (ddd, J = 13.7, 8.9, 7.2 Hz, 1H), 1.63 (d, J = 7.0 Hz, 6H), 1.51 (ddd, J = 13.7, 6.6, 4.1 Hz, 1H);19F NMR (376 MHz, MeOD) δ -119.1;13C NMR (126 MHz, MeOD) δ 180.3, 162.8 (d, J = 243.5 Hz), 140.2, 137.1, 134.4, 133.4 (d, J = 3.3 Hz), 133.1 (d, J = 7.7 Hz), 132.4, 127.7, 122.3, 120.3, 119.8, 116.1 (d, J = 21.4 Hz), 115.5, 112.7, 71.8, 68.3, 45.2, 44.9, 22.1, 21.87, 21.85; HRMS m / z (ESI+) found 426.2083 [M–Na+2H]+(C25H29FNO4 requires 426.2081 [M–Na+2H]+); Purity (99.6%@254 nm), (100%@220 nm), (98.7%@310 nm). Sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate (Compound F)

[0385] Sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized using general procedure 5 with tert-butyl rel-(3S,5R,E)- 7-(3-(4-fluorophenyl)-1-isopropyl-7-methyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate (9.3 mg, 19 µmol, 1.0 eq) giving a pale yellow powder (8 mg, 93%) after lyophilization. ^ ̅max (thin film) / cm−12969, 2932, 1577, 1503, 1408, 1219, 833, 783, 743;1H NMR (500 MHz, MeOD) δ 7.39 – 7.31 (m, 2H), 7.20 – 7.09 (m, 3H), 6.91 – 6.81 (m, 3H), 5.59 – 5.53 (m, 1H), 5.48 (hept, J = 7.0 Hz, 1H), 4.37 – 4.28 (m, 1H), 3.94 – 3.85 (m, 1H), 2.75 (s, 3H), 2.31 (dd, J = 15.3, 4.5 Hz, 1H), 2.23 (dd, J = 15.3, 7.9 Hz, 1H), 1.63 (d, J = 7.0 Hz, 3H), 1.67 – 1.57 (m, 1H), 1.62 (d, J = 7.0 P-632882-PC Hz, 3H), 1.45 – 1.35 (m, 1H);19F NMR (376 MHz, MeOD) δ -118.9;13C NMR (126 MHz, MeOD) δ 180.3, 162.9 (d, J = 243.7 Hz), 139.8, 137.3, 135.8, 133.64 (d, J = 7.5 Hz), 133.59 (d, J = 2.9 Hz), 130.1, 127.2, 121.5, 121.4, 120.7, 118.2, 117.7, 116.2 (d, J = 21.4 Hz), 71.5, 68.2, 44.9, 44.8, 28.4, 23.6, 21.7; HRMS m / z (ESI+) found 426.2083 [M–Na+2H]+(C25H29FNO4requires 426.2081 [M–Na+2H]+); Purity (99.2%@254 nm), (98.9%@220 nm), (98.9%@310 nm). Sodium rel-(3R,5S,E)-7-(1-ethyl-3-(4-fluorophenyl)-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate (Compound A)

[0386] Sodium rel-(3R,5S,E)-7- 2-yl)-3,5-dihydroxyhept-6- enoate was synthesized using general procedure 5 with tert-butyl rel-(3S,5R,E)-7-(1-ethyl-3-(4- fluorophenyl)-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate (15 mg, 33 µmol, 1.0 eq) giving a pale yellow powder (11 mg, 79%) after lyophilization. ^ ̅max (thin film) / cm−12972, 2934, 1570, 1499, 1400, 1218, 1154, 1096, 838, 740;1H NMR (500 MHz, MeOD) δ 7.48 – 7.38 (m, 4H), 7.21 – 7.14 (m, 3H), 7.03 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.71 (dd, J = 16.2, 1.2 Hz, 1H), 5.90 (dd, J = 16.2, 6.6 Hz, 1H), 4.43 – 4.38 (m, 1H), 4.35 (q, J = 7.2 Hz, 2H), 4.05 – 3.99 (m, 1H), 2.40 – 2.24 (m, 2H), 1.74 (ddd, J = 13.7, 8.9, 7.1 Hz, 1H), 1.58 (ddd, J = 13.7, 6.7, 4.1 Hz, 1H), 1.39 (t, J = 7.2 Hz, 3H);19F NMR (376 MHz, MeOD) δ -118.9;13C NMR (126 MHz, MeOD) δ 180.27, 162.92 (d, J = 243.6 Hz), 139.07, 137.86, 134.0, 133.2 (d, J = 3.2 Hz), 133.1 (d, J = 7.8 Hz), 128.9, 123.3, 120.9, 119.9, 119.6, 116.3 (d, J = 21.5 Hz), 115.9, 110.4, 72.0, 68.3, 45.3, 45.0, 39.3, 15.7; HRMS m / z (ESI+) found 398.1781 [M–Na+2H]+(C23H25FNO4 requires 398.1768 [M–Na+2H]+); Purity (96.4%@254 nm), (94.6%@220 nm), (95.9%@310 nm). Sodium rel-(3S,5R,E)-7-(3-(4-fluorophenyl)-1-propyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoate (Compound D) P-632882-PC

[0387] Sodium rel-(3S,5R,E)- indol-2-yl)-3,5-dihydroxyhept- 6-enoate was synthesized using general procedure 5 with tert-butyl rel-(3S,5R,E)-7-(3-(4- fluorophenyl)-1-propyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate (11.5 mg, 24.6 µmol, 1.0 eq) giving a pale yellow powder (7 mg, 70%) after lyophilization. ^m̅ax (thin film) / cm−12963, 2933, 1569, 1399, 1156, 1111, 838, 740;1H NMR (500 MHz, MeOD) δ 7.48 – 7.38 (m, 5H), 7.20 – 7.14 (m, 3H), 7.02 (ddd, J = 8.0, 7.0, , 6.70 (dd, J = 16.2, 1.3 Hz, 1H), 5.87 (dd, J = 16.2, 6.5 Hz, 1H), 4.43 – 4.35 (m, 1H), 4.28 – 4.21 (m, 2H), 4.07 – 3.96 (m, 1H), 2.35 (dd, J = 15.2, 4.8 Hz, 1H), 2.28 (dd, J = 15.2, 7.8 Hz, 1H), 1.88 – 1.80 (m, 2H), 1.72 (ddd, J = 13.7, 8.9, 7.2 Hz, 1H), 1.56 (ddd, J = 13.7, 6.6, 4.1 Hz, 1H), 0.97 (t, J = 7.4 Hz, 3H);19F NMR (376 MHz, MeOD) δ - 118.8;13C NMR (126 MHz, MeOD) δ 180.2, 162.9 (d, J = 243.6 Hz), 139.2, 138.3, 134.3, 133.2 (d, J = 3.3 Hz), 133.1 (d, J = 7.8 Hz), 128.8, 123.2, 120.9, 119.8, 119.7, 116.3 (d, J = 21.5 Hz), 115.7, 110.7, 71.9, 68.3, 46.1, 45.2, 45.0, 24.7, 11.6; HRMS m / z (ESI+) found 412.1921 [M– Na+2H]+(C24H27FNO4requires 412.1924 [M–Na+2H]+); Purity (98.9%@254 nm), (98.0%@220 nm), (98.4%@310 nm). Sodium rel-(3S,5R,E)-3,5-dihydroxy-7-(1-isopropyl-3-(p-tolyl)-1H-indol-2-yl)hept-6-enoate (Compound G)

[0388] Sodium rel-(3S,5R,E)-3,5-dihydroxy-7-(1-isopropyl-3-(p-tolyl)-1H-indol-2-yl)hept-6- enoate was synthesized according to general procedure 5 with tert-butyl rel-(3S,5R,E)-3,5- dihydroxy-7-(1-isopropyl-3-(p-tolyl)-1H-indol-2-yl)hept-6-enoate (10.0 mg, 21.6 µmol, 1.0 eq) P-632882-PC giving a pale yellow powder (8.0 mg, 90%) after lyophilization. ^m̅ax (thin film) / cm−12971, 2931, 1570, 1103;1H NMR (500 MHz, MeOD) δ 7.56 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.32 – 7.27 (m, 2H), 7.25 – 7.21 (m, 2H), 7.11 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.98 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.70 (dd, J = 16.1, 1.3 Hz, 1H), 5.74 (dd, J = 16.0, 6.4 Hz, 1H), 5.01 – 4.89 (m, 1H), 4.42 – 4.34 (m, 1H), 3.96 – 3.87 (m, 1H), 2.38 (s, 3H), 2.31 (dd, J = 3.7, 1.7 Hz, 1H), 2.24 (dd, J = 15.3, 7.9 Hz, 1H), 1.74 – 1.67 (m, 1H), 1.65 (d, J = 7.0 Hz, 6H), 1.49 (ddd, J = 13.8, 6.7, 4.0 Hz, 1H);13C NMR (126 MHz, MeOD) δ 180.4, 140.3, 136.7, 136.6, 134.8, 134.1, 131.5, 130.1, 129.9, 122.5, 120.4, 120.3, 120.2, 116.7, 112.7, 71.7, 68.2, 45.0, 44.9, 21.9, 21.3; HRMS m / z (ESI+) found 430.2007 [M+H]+(C25H29NNaO4requires 430.1994 [M+H]+); Purity (97.6%@254 nm), (97.4%@220 nm) , (96.4%@280 nm). Sodium rel-(3S,5R,E)-7-(3-(4-chlorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept- 6-enoate (Compound H)

[0389] Sodium rel-(3S,5R,E)-7-(3-(4-chlorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 5 with tert-butyl rel- (3S,5R,E)-7-(3-(4-chlorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate (10.0 mg, 20.7 µmol, 1.0 eq) giving a pale yellow powder (7.2 mg, 82%) after lyophilization. ^m̅ax (thin film) / cm−12983, 2938, 1572, 1101, 738;1H NMR (500 MHz, MeOD) δ 7.60 – 7.55 (m, 1H), 7.45 (dd, J = 7.9, 1.1 Hz, 1H), 7.41 (d, J = 1.1 Hz, 4H), 7.17 – 7.10 (m, 1H), 7.05 – 6.98 (m, 1H), 6.70 (d, J = 16.2 Hz, 1H), 5.75 (ddd, J = 16.0, 6.3, 1.1 Hz, 1H), 4.99 – 4.93 (m, 1H), 4.46 – 4.31 (m, 1H), 4.03 – 3.92 (m, 1H), 2.36 (ddd, J = 15.2, 4.7, 1.2 Hz, 1H), 2.27 (ddd, J = 15.4, 7.7, 1.1 Hz, 1H), 1.75 – 1.67 (m, 1H), 1.66 – 1.63 (m, 6H), 1.58 – 1.49 (m, 1H).;13C NMR (126 MHz, MeOD) δ 180.4, 141.2, 136.7, 136.0, 135.2, 133.0, 132.7, 129.6, 129.5, 122.7, 120.7, 120.0, 119.9, 115.2, 112.9, 71.6, 68.3, 45.2, 44.8, 21.9; HRMS m / z (ESI+) found 450.1447 [M+H]+(C24H26ClNNaO4 requires 450.1448 [M+H]+); Purity (98.3%@254 nm), (99.4%@220 nm), (98.2%@280 nm). P-632882-PC Sodium rel-(3S,5R,E)-7-(3-(4-bromophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept- 6-enoate (Compound I)

[0390] Sodium - -1-isopropyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoate was synthesized according to general procedure 5 with tert-butyl rel- (3S,5R,E)-7-(3-(4-bromophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate (10.0 mg, 18.9 µmol, 1.0 eq) giving a pale yellow powder (8.0 mg, 90%) after lyophilization. ^m̅ax (thin film) / cm−12978, 2934, 1560, 1105, 738;1H NMR (500 MHz, MeOD) δ 7.59 (d, J = 0.9 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.46 (ddd, J = 8.0, 1.0, 1.0 Hz, 1H), 7.38 – 7.34 (m, 2H), 7.14 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 7.02 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.71 (dd, J = 16.0, 1.3 Hz, 1H), 5.76 (dd, J = 16.0, 6.3 Hz, 1H), 4.95 (Hept, J = 7.0 Hz, 1H), 4.47 – 4.32 (m, 1H), 4.07 – 3.86 (m, 1H), 2.36 (dd, J = 15.2, 4.7 Hz, 1H), 2.28 (dd, J = 15.2, 7.8 Hz, 1H), 1.71 (ddd, J = 13.7, 8.8, 7.3 Hz, 1H), 1.65 (d, J = 7.0 Hz, 6H), 1.55 (ddd, J = 13.7, 6.5, 4.2 Hz, 1H);13C (126 MHz, MeOD) δ 180.3, 141.2, 136.7, 136.4, 135.2, 133.3, 132.6, 129.4, 122.7, 120.7, 120.6, 120.0, 119.9, 115.2, 112.9, 71.6, 68.3, 45.1, 44.8, 21.8; HRMS m / z (ESI+) found 494.0937 [M+H]+(C24H26BrNNaO4 requires 494.0943 [M+H]+); Purity (99.5%@254 nm), (99.5%@220 nm), (99.1%@280 nm). Sodium rel-(3S,5R,E)-3,5-dihydroxy-7-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-indol- 2-yl)hept-6-enoate (Compound J)

[0015] P-632882-PC

[0391] Sodium rel-(3S,5R,E)-3,5-dihydroxy-7-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H- indol-2-yl)hept-6-enoate was synthesized according to general procedure 5 with tert-butyl rel- (3S,5R,E)-3,5-dihydroxy-7-(1-isopropyl-3-(4-(trifluoromethyl)phenyl)-1H-indol-2-yl)hept-6- enoate (10.0 mg, 19.3 µmol, 1.0 eq) giving a pale yellow powder (8.5 mg, 91%) after lyophilization. ^ma̅x (thin film) / cm−12977, 2937, 1568, 1159, 1106;1H NMR (500 MHz, MeOD) δ 7.71 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.52 (ddd, J = 7.9, 1.0, 1.0 Hz, 1H), 7.16 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.05 (ddd, J = 8.0, 7.0, 0.9 Hz, 1H), 6.74 (dd, J = 16.0, 1.3 Hz, 1H), 5.77 (dd, J = 16.0, 6.3 Hz, 1H), 4.98 (hept, J = 7.3 Hz, 1H), 4.45 – 4.38 (m, 1H), 4.05 – 3.96 (m, 1H), 2.35 (dd, J = 15.2, 4.8 Hz, 1H), 2.28 (dd, J = 15.2, 7.7 Hz, 1H), 1.75 – 1.69 (m, 1H), 1.67 (d, J = 7.0 Hz, 3H), 1.67 (d, J = 7.0 Hz, 3H), 1.55 (ddd, J = 13.7, 6.4, 4.2 Hz, 1H);19F NMR (376 MHz, MeOD) δ -63.6; HRMS m / z (ESI+) found 484.1712 [M+H]+(C25H26F3NaNO4 requires 484.1705 [M+H]+); Purity (98.3%@254 nm), (99.4%@220 nm), (98.2%@280 nm). EXAMPLE 1. VHL heterogeneity drives metastasis.

[0392] Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer. The 5-year survival of metastatic ccRCC is only 10%. The loss of von Hippel-Lindau (VHL) gene, found in over 70% of cases, is presumed to be causative for ccRCC. The loss of VHL gene was found to not be uniform, meaning tumor cells that produce VHL protein, VHL (+), and those do not, VHL(-), coexist in the same tumor of an individual (Figure 1). To understand the functional consequence of this VHL heterogeneity, CRISPR / Cas9 technology was employed to delete the VHL gene and engineered three paired VHL-KO (-) and VHL-WT (+) ccRCC models (Schokrpur S, Hu J, Moughon DL, Liu P, Lin LC, Hermann K, Mangul S, Guan W, Pellegrini M, Xu H, Wu L. CRISPR-Mediated VHL Knockout Generates an Improved Model for Metastatic Renal Cell Carcinoma. Sci. Rep. 6, 29032; doi: 10.1038 / srep29032 (2016); Hu J, Schokrpur S, Archang M, Hermann K, Sharrow AC, Khanna P, Novak J, Signoretti S, Bhatt RS, Knudsen BS, Xu H, Wu L. A Non-integrating Lentiviral Approach Overcomes Cas9-Induced Immune Rejection to Establish an Immunocompetent Metastatic Renal Cancer Model. Mol Ther Methods Clin Dev. 20189:203-210; Hu J, et al. Tumor Heterogeneity in VHL Drives Metastasis in Clear Cell Renal Cell Carcinoma, submitted, 2021). Renal tumors with both VHL-KO and VHL-WT cells metastasize rampantly to the lungs in mice, but tumors with either cell population alone do not disseminate (Figure 2A, B). This unexpected finding indicates a new, paradigm-shifting P-632882-PC cooperative metastatic mechanism is at play. VHL deletion in ccRCC cell lines slowed proliferation and induced an epithelial to mesenchymal transition (EMT) phenotype that greatly increased the motility of VHL-KO cells (Figure 2C). Results showed that the VHL-KO cells are the metastatic drivers as they induce the growth and aggression of VHL-WT cells through intercellular communication, such as exosomes or extracellular vesicles (EVs) (Figure 2D).

[0393] Figure 9 depicts a cooperative metastasis model, showing the presence of both VHL-KO and VHL-WT cells and their cooperative interactions via soluble factors and cellular contacts are required to achieve metastatic spread to the lung. EXAMPLE 2. VHL(-) or VHL- KO cells drive metastasis via EV-mediated crosstalk.

[0394] A large volume of evidence supports that hypoxic cells produce heightened levels of EVs. As VHL-KO cells exist in a pseudo-hypoxia state due to the lack of VHL (1, 3), they indeed produced 4 times higher levels of EVs than VHL- WT cells (Figure 3A) harvested by ultracentrifugation (Barreiro K, Dwivedi OP, Leparc G, et al. Comparison of urinary extracellular vesicle isolation methods for transcriptomic biomarker research in diabetic kidney disease. J Extracell Vesicles. 2020;10:e12038). The EVs isolated from VHL-KO cells exhibit conventional disc-shaped morphology and size (30-150nm) (Figure 3B). The uptake of EVs into the cytoplasm of VHL-WT cells was demonstrated by confocal microscopy of EVs labeled with lipophilic dye PKH26 (Figure 3C). The proliferation of VHL-WT cells was increased upon the uptake of the VHL-KO EVs (Figure 3D). EXAMPLE 3. Statins selectively inhibit VHL(-) cells.

[0395] A high throughput drug screening (HTS) assay was established to screen for compounds that can selectively inhibit VHL-KO cells in the UCLA MSSR. The seeding cell number, DMSO concentration, and 2-DG (positive control) concentration were optimized via gradient testing. Total cell number of 3000 / well mix population VHL(-): VHL(+) = 2:1, DMSO concentration of 0.5% (v / v), and 2-DG concentration of 1% (v / v) were used. To prepare the screening plates, 25μL of appropriate complete media was first distributed in columns 1-22 of 11 black-lid 384-well plates (Greiner Bio-One, #781091) using a MultiFlo Fx (BioTek). Using the same machine, columns 23- P-632882-PC 24 filled 25μL of complete media with 1% (v / v) 2-DG. These plates were next pinned by BioMek FX (Beckman Coulter) with 250 nL of the MSSR Repurposing Libraries containing 2,530 FDA- approved small molecules (LOPAC 1-4, NIHII 1-3, NPW 1-4; final concentration of drug = 5μM). 25L of cell-containing complete media was added to each well using MultiFlo Fx; then, cells were incubated for 48h at the normal cell culturing condition. On the day of imaging, the stock Hoechst 33342 at 1.25μg / mL (1000x) concentration was diluted to 7.5 ng / mL (6x) and added 10μL to each well containing 50μL cells + complete media + drug. After a 45-minute incubation, an automated imaging system (ImageXpress Confocal, Molecular Devices) was used to image for three fluorescent colors: TexasRed (VHL(+)), GFP (VHL(-)), and Hoechst (nucleus). Images were imported to MetaXpress (Molecular Devices) for automated analysis to determine the cell number and area of each color. Results are imported to CDD Vault (CDD) for hit determination (“total cellnumber between 600 &1200” & “%green between 25% and 50%” ).

[0396] Screening through the library of 2530 FDA approved drugs (Figure 4A), we identified three drugs in the statin family (simvastatin, lovastatin, and fluvastatin) capable of selectively inhibiting the growth of VHL-KO over VHL-WT cells in cell culture (Figure 4B) as well as suppressing the growth of 1:1 mixed tumor in vivo on a duck chorioallantoic membrane (CAM) model (Figure 4C).

[0397] IC50 was determined at MSSR using the same settings as described above, except for each drug having triplicates instead of a single well, the cell number adjusted to 1500 / well from 3000 / well, and the absence of 2-DG as the positive control.20-step titration ranging from 95.4pM to 50μM (each step = 1:1 dilution) was prepared for each compound by BioMek FX or Echo 555 (Beckman Coulter). With Echo 555, compounds were added first, and then a 50uL cell-media mix was added. In addition to MultiFlo Fx, Multidrop384 (Thermo LabSystems) was used as a liquid handler. The nucleus staining, imaging, and image analysis by MetaXpress were conducted the same way as above. Data was exported to Prism (GraphPad) instead of CDD Vault to determine IC50. P-632882-PC

[0398] Initial dose titration of therapeutic activity of the statins in RENCA VHL-Neg cells compared to VHL-Pos cells confirmed the identified drugs’ selectivity for VHL-Neg cells, with Fluvastatin having the most potent activity (IC50 ~0.8uM), followed by simvastatin and lovastatin, while pravastatin, atorvastatin and rosuvastatin are inactive (Figure 11A). Detailed dosage titration determined the IC50 of fluvastatin is 0.73µM, while simvastatin, lovastatin and rosuvastatin is 0.84, 1.6 and 23µM, respectively (Figure 11B). The IC50 of cerivastatin was found to be less than 0.1 µM. Assessment in human VHL-Neg ccRCC models of RCC4 and 786-O and a new primary ccRCC cell line we generated, #2-1006 again confirmed the therapeutic activity of the statins with the same rank order observed in the RENCA line. This result is reassuring as it supports the drug selection scheme in RENCA VHL-Neg cells is relevant to VHL-Neg human ccRCC tumor models (Figures 11C-11F). Next, the ability of simvastatin to inhibit lung metastasis was assessed in a chicken chorioallantoic membrane (CAM) tumor model. This model saves time, efforts and cost compared to mouse model. Figure 6 illustrates the therapeutic experiment in the CAM model. The administration of 5µM simvastatin to 1:1 mixed RENCA tumor resulted in significant reduction of tumor growth as well as micrometastases to the lungs of the chicken embryo (Figures 6H, 6J). Fluvastatin is effective in suppressing lung metastases of a human ccRCC PDX in mice (data not shown). Collectively, these results support that statins hold promise in preventing metastasis in mRCC.

[0399] Compounds A through J had IC50s less than about 7 µM. Compounds A, B, C, E, G, H and I had IC50 less than about 5 µM. Compounds C and E had IC50s less than about 2 µM. Cerivastatin had an IC50 less than 0.1 µM

[0400] It has been recently reported that statin selectively inhibit VHL-Neg human ccRCC tumor cells by targeting cholesterol metabolism. The known target of statins in lowering cholesterol is HMG-CoA Reductase (HMG-CR). It is intriguing that the most advanced statins, namely atorvastatin and rosuvastatin with the greatest affinity for HMG-CR, are inactive in RCC tumor cells. Thus, whether HMG-CR is the target of the RCC cell inhibitory activity was directly assessed. A tetracycline-inducible shRNA system was introduced into the RENCA VHL-Neg cell by transfection to silence the HMGCR gene. The addition of 100 ng / ml of doxycycline activated the expression of HMG-CR targeted shRNA and resulted in significantly reduction of HMG-CR expression (Figure 12A). The shutdown of HMG-CR did not have an impact on the cell growth of P-632882-PC VHL-Neg cells (Figure 12B). Furthermore, therapeutic activity of simvastatin and Fluvastatin in HMG-CR-silenced VHL-Neg cells were identical to the HMG-CR intact counterparts (Figures 12C-12D). These results directly support that HMG-CR is not the target of statins’ inhibitory action in VHL-Neg RCC cells. This finding is a clear distinction from published reports of potential cancer therapeutic action of statins. EXAMPLE 4. Use of an EV reporter system to study new inhibitors of the EV-mediated metastatic crosstalk.

[0401] An innovative Cre-lox reporter system has been used to study EV-mediated metastatic signaling (Zomer A, Maynard A, Verweij FJ, Kamermans A, Schäfer R, et al. In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior, Cell, 161:5, 1046- 1057 (2015), Figure 5A, left panel). This system was adapted to the ccRCC models described herein by engineering the VHL-KO cells to express the Cre recombinase and the VHL-WT cells expressing the floxed GFP. Upon the uptake of Cre containing EVs from VHL-KO cells, the VHL- WT cells will convert from red to green fluorescence. The functionality of the reporter system is demonstrated in our RENCA metastatic RCC model (Figure 5A, right panel). Figure 5B shows that certain statins inhibit VHL-KO ccRCC cells selectively. EXAMPLE 5. Use of an innovative avian chorioallantoic membrane (CAM) tumor model to assess the efficacy of potential therapeutic agents to block metastasis.

[0402] An avian chorioallantoic membrane (CAM) system has been established to efficiently engraft pre- existing ccRCC cell line-based and new patient-derived xenografts from surgical specimens (Hu J, Ishihara M, Chin AI, Wu L. Establishment of Xenografts of Urological Cancers on Chicken Chorioallantoic Membrane (CAM) to Study Metastasis. Precision Clinical Medicine, 2019 Oct 1; 2(3): 140–151; Ishihara M, Hu J, Wong A, Cano-Ruiz C, and Wu L. Mouse- and Patient-Derived CAM Xenografts for Studying Metastatic Renal Cell Carcinoma. In: Tamanoi F, ed. The Enzymes: Chick Chorioallantoic Membrane Model and Precision Cancer Therapy. Cambridge, MA: Academic Press; 2019;46:59-80; Ishihara M, Hu J, Zhang X, Choi Y, Wong A, Cano-Ruiz C, Zhao R, Tan P, Tso JL, Wu L. Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane. Journal of Visual Experiment. 2020 Feb 8;(156), Figure 6A), The CAM model has been widely P-632882-PC used in cancer research (Ribatti D. The chick embryo chorioallantoic membrane as a model for tumor biology. Exp Cell Res. Nov 1;328(2):314-24) and offers numerous advantages. (i) The time frame for CAM tumor growth is only a maximum of 12 days, as the CAM is destroyed upon embryo hatching. (ii) The CAM’s rich blood supply and immunodeficient status enable efficient engraftment of ccRCC cell lines, primary tumor cells (Figure 6B), or undisrupted tumor pieces from patient samples. The success rate for establishing new CAM PDXs is ~80%. (iii) CAM tumors can retain the tumor growth and metastatic behavior seen in mice (Figure 6C, D). (iv) The cost of each SCID mouse is over $100. In contrast, each fertilized egg is only ~$1. This low cost enables expanded cohort sizes for experiments, improving the accuracy and sensitivity of findings. Furthermore, we recently showed that converting to duck eggs will extend the tumor growth period to a maximum of 25 days, increasing the time in chicken eggs by 13 days (Figure 4C). This longer incubation period will allow more thorough analyses of the therapeutic effects of new drugs. For these reasons, the CAM model will be a valuable model to assess the efficacy of newly identified EV- and metastasis-blocking drugs with substantial savings in time, labor, and cost compared to mouse models. Figure 6H shows that day 10 after implanting 1:1 VHL-KO:VHL-WT at embryonic day 7, at embryonic day 17, simvastatin inhibits metastasis. EXAMPLE 6. Cooperative metastasis model VHL-WT and VHL-KO

[0403] Fig. 7 shows the design of a model that uses VHL-deleted (VHL-KO) cells from three VHL+ RCC models: RENCA, ACHN and a new mRCC primary cell line #22. The model uses marked VHL+ (VHL-WT) cells with RFP and VHL- KO cells with GFP and luciferase to track cells in vitro and in vivo. Tumor cells are implanted in the left kidney. As shown in the figure, imaging after 4 weeks shows that animals implanted with VHL-WT have only localized growth of the tumor, and mice implanted with VHL-KO little to no growth. However, the combination of VHL-KO and VHL-WT implantation results in extensive metastasis of the tumor. Abundant lung metastases are found in the latter animals. Such model may also be used to evaluate compounds disclosed herein.

[0404] To understand the cooperative metastatic behavior, cellular crosstalk between the RENCA VHL-Pos and VHL-Neg cell lines were studied. In transwell co-culture setting, the presence of VHL-Neg cells induced the EMT changes in VHL-Pos cells as assessed by the expression of EMT P-632882-PC markers (Figure 10A). The VHL-Pos and VHL-Neg cells were then marked respectively with red fluorescent protein (RFP) and enhanced green fluorescent protein (EGFP). The motility of these two cell lines in closing a gap were quantified by time-lapse microscopy. The VHL-Neg cells migrated three times farther in 20hrs than VHL-Pos cells, and the presence of VHL-Neg cells markedly increased the motility of VHL-Pos cells in coculture (Figure 10B). Furthermore, VHL- Neg cells were poorly proliferative but they induced the proliferation of VHL-Pos cells in co- culture (Figure 10C). This proliferative crosstalk phenomenon was also observed in VHL-deleted Caki-1 and case #6-0127 primary cell line model (data not shown).

[0405] Figure 10D highlights the crux of this novel metastatic cross communication scheme. The loss of VHL upregulates HIF and activates the hypoxia program intrinsically within the VHL-Neg cells, which induced EMT and cellular motility but slowed proliferation significantly. Concurrently, these pseudohypoxic VHL-Neg cells also produce a high level of soluble factors and exosomes to transmit their paracrine metastatic instructions on VHL-pos cells. This new model uncovered that metastatic dissemination requires a cooperation between the VHL-Neg and the epithelial VHL-Pos cells in which the VHL-Neg cells are the driver of metastasis. EXAMPLE 7. Certain statins inhibit VHL-KO cells

[0406] Fig. 8 shows a dose response and IC50s of the inhibition of the growth of VHL-KO cells in vitro after 24 hours. EXAMPLE 8. TREATMENT SUPPRESSES TUMOR METASTASIS

[0407] Mice are injected into the kidney with detectable VHL-KO and VHL-WT cells as described above. Simvastatin or fluvastatin, 10 mg / kg, are administered orally, daily, and the mice monitored for metastasis of the tumor. Suppression of metastasis by statin administration is found.

[0408] While certain features disclosed herein have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the guidance herein.

Claims

P-632882-PC WHAT IS CLAIMED IS:

1. A method for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (IV) or athereof, or lactone thereof, wherein R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group; R2 and R3 taken together form an optionally substituted 3-14 membered ring; and R4 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl ring.

2. The method of claim 1, wherein R1 is an optionally substituted alkyl group.

3. The method of claim 1 wherein alkyl is C1-C6alkyl, an ethyl group, a 1-propyl group, a 2- propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

4. The method of claim 1, wherein R1 is aryl, such as phenyl.

5. The method of claim 1, wherein R2 and R3 taken together with the carbons to which they are bound form a phenyl group, wherein the phenyl ring is optionally substituted with one or more alkyl groups, such as 4-methylindolyl, 5-methylindolyl, 6-methylindolyl or 7-methylindolyl.P-632882-PC 6. The method of claim 1, wherein R4 is an optionally substituted alkyl group, such as C1-C6alkyl, 1-propyl group, 2-propyl group, propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo- C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

7. The method of claim 1, wherein R4 is an aryl group, such as a phenyl group, optionally substituted with one or more independent halo, alkyl, or haloalkyl, such as p-fluorophenyl, p-tolyl, p-chlorophenyl, p-bromophenyl or p-F3C-phenyl.

8. The method of claim 1, wherein the compound of Formula (IV) is fluvastatin or an analogue thereof.

9. The method of claim 1, wherein the compound of Formula (IV) is any one of:Compound DP-632882-PC10. A method for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (I)P-632882-PC (I) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein R is H or an optionally substituted alkyl.

11. The method of claim 10, wherein R is a C1-C6alkyl group such as an ethyl group, a 1- propyl group or a 2-propyl group, or an optionally substituted cycloalkyl or aryl group such as phenyl.

12. The method of claim 10, wherein R is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

13. The method of claim 10, wherein the compound of Formula (I) is fluvastatin or an analogue thereof.

14. The method of claim 10, wherein the compound of Formula (I) is any one of15. A method for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (Ia)P-632882-PC or a pharmaceuticallyenantiomer or diastereomer thereof, or lactone thereof, wherein each R is independently H, optionally substituted alkyl, halo, carboxyl, or -CF3.

16. The method of claim 15, wherein alkyl is C1-C6 alkyl, 2-CH3 and 4-F; 3,5-(CH3)2; 3-CH3 and 4-F; H; 3,5-(CH3)2, 4-F; 4-CF3; 2-CH3; 4-CH3; 5-Br, 5-Cl or 4-CO2Na.

17. The method of claim 15, wherein the compound of Formula (Ia) is fluvastatin or an analogue thereof.

18. The method of claim 15, wherein the compound of Formula (1a) is among:P-632882-PC19. A method for inhibiting metastasis of a solid tumor such in a subject comprising administering to the subject a compound of Formula (II) or a racemate, enantiomeror a pharmaceutically acceptable salt thereof, or a lactone thereof, wherein R1 is H or optionally substituted alkyl, and R2 is H, optionally substituted alkyl, hydroxy or an optionally substituted aryl group.

20. The method of claim 19, wherein R1is H, alkyl, C1-C6alkyl, methyl, ethyl, n-propyl, i- propyl or butyl.

21. The method of claim 19, wherein R2is H, OH, alkyl, such as methyl, ethyl, n-propyl, i- propyl or butyl, or an optionally substituted phenyl group.

22. The method of claim 19, wherein the compound of Formula (II) is an analogue of pravastatin.

23. A method for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (III)P-632882-PC or a pharmaceuticallyor diastereomer thereof, or a β-hydroxy acid open ring form, wherein R1 is selected from an optionally substituted alkyloyl or heterocyclyl group; and R2 is selected from an optionally substituted alkyl or heterocyclyl group.

24. The method of claim 23, wherein R1 is an optionally substituted alkyloyl group such as 2- methylbutanoyl.

25. The method of claim 23, wherein R2 is an optionally substituted alkyl group such as C1-C6 alkyl, methyl; or an optionally substituted heterocyclyl group.

26. The method of claim 23, wherein the compound of Formula (III) is lovastatin, simvastatin or mevastatin or an analogue thereof.

27. A method for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (V)P-632882-PC (V) or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein R1 is an optionally substituted aryl, heteroaryl or heterocyclyl ring; R2 is an optionally substituted alkyl group; R3 and R4 are independently, optionally substituted alkyl.

28. The method of claim 27, wherein R1 is an aryl group such as phenyl group optionally substituted with one or more halo, alkyl, or haloalkyl, such as p-fluorophenyl, p-tolyl, p- chlorophenyl. p-bromophenyl, or p-F3C-phenyl.

29. The method of claim 27, wherein R2 is C1-6alkyloxy-C1-6alkyl, such as methoxymethyl.

30. The method of claim 27, wherein R3 and R4 are independently a C1-C6alkyl, such as an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

31. The method of claim 27, wherein the compound of Formula (V) is cerivastatin.

32. A pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject comprising a pharmaceutically acceptable carrier and a compound of Formula (IV)or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, whereinP-632882-PC R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group; R2 and R3 taken together form an optionally substituted 3-14 membered ring; and R4 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl ring.

33. The pharmaceutical composition of claim 32, wherein R1 is an optionally substituted alkyl group.

34. The pharmaceutical composition of claim 32 wherein alkyl is C1-C6 alkyl, an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo- C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

35. The pharmaceutical composition of claim 32, wherein R1 is aryl, such as phenyl.

36. The pharmaceutical composition of claim 32, wherein R2 and R3 taken together with the carbons to which they are bound form a phenyl group, wherein the phenyl ring is optionally substituted with one or more alkyl groups, such as 4-methylindolyl, 5-methylindolyl, 6- methylindolyl or 7-methylindolyl.

37. The pharmaceutical composition of claim 32, wherein R4 is an optionally substituted alkyl group, such as C1-C6 alkyl, 1-propyl group, 2-propyl group, propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

38. The pharmaceutical composition of claim 32, wherein R4 is an aryl group, such as a phenyl group, optionally substituted with one or more independent halo, alkyl, or haloalkyl, such as p- fluorophenyl, p-tolyl, p-chlorophenyl, p-bromophenyl or p-F3C-phenyl.

39. The pharmaceutical composition of claim 32, wherein the compound of Formula (IV) is fluvastatin or an analogue thereof.

40. The pharmaceutical composition of claim 32, wherein the compound of Formula (IV) is any one of:P-632882-PCP-632882-PC41. A pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject comprising a pharmaceutically acceptable carrier and a compound of Formula (I)or a pharmaceutically enantiomer or diastereomer thereof, or lactone thereof, wherein R is H or an optionally substituted alkyl.

42. The pharmaceutical composition of claim 41, wherein R is a C1-C6alkyl group such as an ethyl group, a 1-propyl group or a 2-propyl group, or an optionally substituted cycloalkyl or aryl group such as phenyl.

43. The pharmaceutical composition of claim 41, wherein R is CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11.

44. The pharmaceutical composition of claim 41, wherein the compound of Formula (I) is fluvastatin or an analogue thereof.P-632882-PC 45. The pharmaceutical composition of claim 41, wherein the compound of Formula (I) is any one of46. A pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject comprising a pharmaceutically acceptable carrier and a compound of Formula (Ia)or a pharmaceutically or enantiomer or diastereomer thereof, or lactone thereof, wherein each R is independently H, optionally substituted alkyl, halo, carboxyl, or -CF3.

47. The pharmaceutical composition of claim 46, wherein alkyl is C1-C6alkyl, 2-CH3and 4-F; 3,5-(CH3)2; 3-CH3 and 4-F; H; 3,5-(CH3)2, 4-F; 4-CF3; 2-CH3; 4-CH3; 5-Br, 5-Cl or 4-CO2Na.

48. The pharmaceutical composition of claim 46, wherein the compound of Formula (Ia) is fluvastatin or an analogue thereof.P-632882-PC 49. The pharmaceutical composition of claim 46, wherein the compound of Formula (1a) is among:

50. A pharmaceutical composition for inhibiting metastasis of a solid tumor such in a subject comprising a pharmaceutically acceptable carrier and a compound of Formula (II)or a racemate, enantiomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a lactone thereof, wherein R1is H or optionally substituted alkyl, and R2is H, optionally substituted alkyl, hydroxy or an optionally substituted aryl group.P-632882-PC 51. The pharmaceutical composition of claim 50, wherein R1is H, alkyl, C1-C6alkyl, methyl, ethyl, n-propyl, i-propyl or butyl.

52. The pharmaceutical composition of claim 50, wherein R2 is H, OH, alkyl, such as methyl, ethyl, n-propyl, i-propyl or butyl, or an optionally substituted phenyl group.

53. The pharmaceutical composition of claim 50, wherein the compound of Formula (II) is an analogue of pravastatin.

54. A pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject comprising a pharmaceutically acceptable carrier and a compound of Formula (III)or a pharmaceutically or or diastereomer thereof, or a β-hydroxy acid open ring form, wherein R1 is selected from an optionally substituted alkyloyl or heterocyclyl group; and R2 is selected from an optionally substituted alkyl or heterocyclyl group.

55. The pharmaceutical composition of claim 54, wherein R1 is an optionally substituted alkyloyl group such as 2-methylbutanoyl.

56. The pharmaceutical composition of claim 54, wherein R2 is an optionally substituted alkyl group such as C1-C6alkyl, methyl; or an optionally substituted heterocyclyl group.P-632882-PC 57. The pharmaceutical composition of claim 54, wherein the compound of Formula (III) is lovastatin, simvastatin or mevastatin or an analogue thereof.

58. A pharmaceutical composition for inhibiting metastasis of a solid tumor in a subject comprising a pharmaceutically acceptable carrier and a compound of Formula (V) or athereof, or lactone thereof, wherein R1 is an optionally substituted aryl, heteroaryl or heterocyclyl ring; R2 is an optionally substituted alkyl group; R3 and R4 are independently, optionally substituted alkyl.

59. The pharmaceutical composition of claim 58, wherein R1 is an aryl group such as phenyl group optionally substituted with one or more halo, alkyl, or haloalkyl, such as p-fluorophenyl, p- tolyl, p-chlorophenyl. p-bromophenyl, or p-F3C-phenyl.

60. The pharmaceutical composition of claim 58, wherein R2 is C1-6alkyloxy-C1-6alkyl, such as methoxymethyl.

61. The pharmaceutical composition of claim 58, wherein R3 and R4 are independently a C1- C6 alkyl, such as an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11.

62. The pharmaceutical composition of claim 58, wherein the compound of Formula (V) is cerivastatin.P-632882-PC 63. The pharmaceutical composition of any one of claims 32-62 for inhibiting metastasis of a solid tumor such as a renal cell carcinoma (RCC) in a subject having RCC, or for preventing metastasis of the tumor; or where the solid tumor is a kidney tumor; or wherein the kidney tumor is renal cell carcinoma; or wherein the tumor is a CNS, breast, adrenal or pancreatic tumor.

64. A compound of Formula (IV) or aor diastereomer thereof, or lactone thereof, wherein R1 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl group; R2 and R3 taken together form an optionally substituted 3-14 membered ring; and R4 is an optionally substituted alkyl, aryl, heteroaryl or heterocyclyl ring.

65. The compound of claim 64, wherein R1 is an optionally substituted alkyl group.

66. The compound of claim 64 wherein alkyl is C1-C6 alkyl, an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5,CH2CH2C6H5,CH2C6H11or CH2CH2C6H11.

67. The compound of claim 64, wherein R1 is aryl, such as phenyl.

68. The compound of claim 64, wherein R2 and R3 taken together with the carbons to which they are bound form a phenyl group, wherein the phenyl ring is optionally substituted with one or more alkyl groups, such as 4-methylindolyl, 5-methylindolyl, 6-methylindolyl or 7-methylindolyl.P-632882-PC 69. The compound of claim 64, wherein R4 is an optionally substituted alkyl group, such as C1-C6 alkyl, 1-propyl group, 2-propyl group, propynyl group, CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

70. The compound of claim 64, wherein R4 is an aryl group, such as a phenyl group, optionally substituted with one or more independent halo, alkyl, or haloalkyl, such as p-fluorophenyl, p-tolyl, p-chlorophenyl, p-bromophenyl or p-F3C-phenyl.

71. The compound of claim 64, wherein the compound is any one of:Compound DP-632882-PC72. A compound of Formula (I)or a pharmaceutically acceptable salt, or racemate, enantiomer or diastereomer thereof, or lactone thereof, wherein R is H or an optionally substituted alkyl.

73. The compound of claim 72, wherein R is a C1-C6 alkyl group such as an ethyl group, a 1- propyl group or a 2-propyl group, or an optionally substituted cycloalkyl or aryl group such as phenyl.P-632882-PC 74. The compound of claim 72, wherein R is CH3, CH2CH(CH3)2, cyclo-C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

75. The compound of claim 72, wherein the compound of Formula (I) is any one of76. A compound of Formula (Ia)or a pharmaceutically or enantiomer or diastereomer thereof, or lactone thereof, wherein each R is independently H, optionally substituted alkyl, halo, carboxyl, or -CF3.

77. The compound of claim 76, wherein alkyl is C1-C6alkyl, 2-CH3and 4-F; 3,5-(CH3)2; 3- CH3 and 4-F; H; 3,5-(CH3)2, 4-F; 4-CF3; 2-CH3; 4-CH3; 5-Br, 5-Cl or 4-CO2Na.

78. The compound of claim 76, wherein the compound of Formula (1a) is among:P-632882-PC79. A compound of Formula (II)or a racemate, or or a pharmaceutically acceptable salt thereof, or a lactone thereof, wherein R1is H or optionally substituted alkyl, and R2 is H, optionally substituted alkyl, hydroxy or an optionally substituted aryl group.

80. The compound of claim 79, wherein R1is H, alkyl, C1-C6alkyl, methyl, ethyl, n-propyl, i- propyl or butyl.P-632882-PC 81. The compound of claim 79, wherein R2is H, OH, alkyl, such as methyl, ethyl, n-propyl, i- propyl or butyl, or an optionally substituted phenyl group.

82. A compound of Formula (III) or a pharmaceuticallyor diastereomer thereof, or a β-hydroxy acid open ring form, wherein R1 is selected from an optionally substituted alkyloyl or heterocyclyl group; and R2 is selected from an optionally substituted alkyl or heterocyclyl group.

83. The compound of claim 82, wherein R1 is an optionally substituted alkyloyl group such as 2-methylbutanoyl.

84. The compound of claim 82, wherein R2 is an optionally substituted alkyl group such as C1- C6 alkyl, methyl; or an optionally substituted heterocyclyl group.

85. A compound for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (V)P-632882-PC oror diastereomer thereof, or lactone thereof, wherein R1 is an optionally substituted aryl, heteroaryl or heterocyclyl ring; R2 is an optionally substituted alkyl group; R3 and R4 are independently, optionally substituted alkyl.

86. The compound of claim 85, wherein R1 is an aryl group such as phenyl group optionally substituted with one or more halo, alkyl, or haloalkyl, such as p-fluorophenyl, p-tolyl, p- chlorophenyl. p-bromophenyl, or p-F3C-phenyl.

87. The compound of claim 85, wherein R2 is C1-6alkyloxy-C1-6alkyl, such as methoxymethyl.

88. The compound of claim 85, wherein R3 and R4 are independently a C1-C6 alkyl, such as an ethyl group, a 1-propyl group, a 2-propyl group, a propynyl group, CH3, CH2CH(CH3)2, cyclo- C3H5, cyclo-C6H11, CH2C6H5, CH2CH2C6H5, CH2C6H11 or CH2CH2C6H11.

89. A method for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of a. detecting a deletion or mutation of Von Hippel Lindau (VHL) tumor suppressor gene in a sample from the solid tumor; and b. upon detection of a deletion or mutation of the gene, treating the patient with a pharmaceutical composition of any one of claims 32-63.P-632882-PC 90. A method for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of a. detecting evidence of spread of the tumor beyond the primary site and / or having a high histological score; and b. upon detection of spread or high histologic score, treating the patient with a pharmaceutical composition of any one of claims 32-63.

91. The method of claim 89 or 90 wherein the solid tumor is a kidney tumor.

92. The method of claim 90 wherein the spread comprises a high grade histologic criterion or spread of the tumor beyond Gerota fascia of the kidney.

93. A method for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of a. detecting activation of the hypoxia program of gene expression in tumor cells in a sample from the solid tumor; and b. upon detection of hypoxia program activation, treating the patient with a pharmaceutical composition of any one of claims 32-63.

94. The method of claim 94 wherein the activation of the hypoxia program is due to mutation or loss of VHL expression.

95. A method for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of a. detecting extracellular vesicles in a bodily fluid of a patient; and b. upon detection of extracellular vesicles, treating the patient with a pharmaceutical composition of any one of claims 32-63.

96. The method of claim 95 wherein extracellular vesicles are detected in a ccRCC patient.

97. The method of claim 95 wherein the bodily fluid is blood or urine.P-632882-PC 98. A method for inhibiting the metastasis of a solid tumor in a subject or treating a solid tumor in a subject comprising the steps of a. detecting overexpression of periostin in tumor cells in a sample from the solid tumor; and b. upon detection of periostin overexpression, treating the patient with a pharmaceutical composition of any one of claims 32-63.

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