Compounds and methods for inhibiting metastasis of solid tumors

Abstract

Compounds, pharmaceutical compositions and methods for inhibiting solid tumors and metastasis of solid tumors such as renal cell carcinoma (RCC), breast, CNS, adrenal or pancreatic cancer in a subject are provided.

Description

[0001] P-633720-PC COMPOUNDS AND METHODS 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 / 605,311, filed December 1, 2023, which is incorporated herein by reference in its entirety. GOVERNMENT SUPPORT

[0002] This invention was made with government support under W81XWH-20-1-0918, and HT9425-23-1-0858 awarded by the Defense Health Agency, Medical Research and Development Branch. The government has certain rights in the invention. FIELD

[0003] Provided herein are compounds, 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%.

[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 P-633720-PC 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. SUMMARY

[0008] In one aspect, a method for inhibiting metastasis of a solid tumor in a subject is provided comprising administering to the subject a compound of Formula (I) or a pharmaceutical composition thereof: P-633720-PC or a acceptable salt thereof, wherein R1and R2are each independently hydrogen, hydroxy, SOR3, or a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety; or wherein R1and R2taken together with the N to which they are bound form a 4, 5, 6, 7, 8 or 9 membered substituted or unsubstituted, saturated or unsaturated alicyclic or a substituted or unsubstituted heterocyclic moiety; R3for each occurrence is independently hydrogen, -N(R4)2, aliphatic, aryl or heteroaryl moiety; and R4for each occurrence is independently hydrogen or a substituted or unsubstituted aliphatic moiety, substituted or unsubstituted phenyl, or a substituted or unsubstituted heterocyclic ring.

[0009] In some embodiments, at least one of R1and R2is not hydrogen. In some embodiments, R1and R2are independently selected from H or an optionally substituted, saturated or unsaturated C1-C6 alkyl. In some embodiments, R1is H and R2is a saturated or unsaturated C1- C6alkyl, such as methyl, ethyl or 2-propargyl. In some embodiments, R1is H and R2is C0-C6- adamantanyl. P-633720-PC

[0010] In some embodiments, R1and R2taken together is an optionally substituted C1-C8aliphatic such as n-propyl, n-butyl, n-pentyl, n-hexyl or n-heptyl. In some embodiments, R1and R2together with the N to which they are bound form an optionally substituted 4, 5, 6, 7, 8 or 9 membered ring with 1-3 additional heteroatoms selected from N, O or S, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or azepinyl. In some embodiments, R1and R2taken together is a piperazinyl N-substituted with an alkoxycarbonyl moiety such as tert- butoxycarbonyl.

[0011] In some embodiments, R1or R2independently is an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL-161, EEDi-5273 and MAK683 or any other optimal linker substituted with an E3 ligase recruiting moiety. In some embodiments, the linker is a C1-C8alkyl or polyethylene glycol.

[0012] In some embodiments, the compound of Formula (I) is:

[0002] P-633720-PC I-F or an analogue thereof.

[0013] In some embodiments, the compounds of Formula (I) are capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.

[0014] In one aspect, a method for inhibiting metastasis of a solid tumor in a subject is provided comprising administering to the subject a compound of Formula (IA) or a pharmaceutical composition thereof: or a racemate, enantiomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, P-633720-PC wherein X is O, NR2or CR3R4, R2is an unsubstituted or substituted aliphatic, alkoxycarbonyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted heteroaryl moiety; R3and R4are independently H or a substituted or unsubstituted C1-C8alkyl.

[0015] In some embodiments, R2is tert-butoxycarbonyl. In some embodiments, is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl or

[0016] In some embodiments, R2, R3or R4may be an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL- 161, EEDi-5273 and MAK683 or any other optimal linkers substituted with an E3 ligase recruiting moiety. In some embodiments, the linker is a C1-C8alkyl or polyethylene glycol.

[0017] In some embodiments, compounds of Formula (IA) are capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.

[0018] In some embodiments, the compound of Formula (IA) is:

[0003] P-633720-PC I-B to I-J does not have substantial HMG-CoA reductase activity.

[0020] In one aspect, a method for inhibiting metastasis of a solid tumor in a subject is provided comprising administering to the subject a compound of Formula II-A below or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof: or an analogue

[0021] In some embodiments, Compound II-A is capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis. P-633720-PC

[0022] In one aspect, a method for inhibiting metastasis of a solid tumor in a subject is provided comprising administering to the subject a compound of Formula (III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof: wherein R5is selected from an amino acid residue, a fibric acid residue, guanidine, tetrazolyl, agmatine, an amino-containing compound; a lower alkyl terminating in ΟΝΟ, (ONO2)p, guanidine; a resveratrol residue; an imidazoline receptor agonist residue, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl or a substituted or unsubstituted heterocycle; and p is 1, 2 or 3.

[0023] In some embodiments, the amino acid residue is alanine, asparagine, N-β-trityl- asparagine, aspartic acid, aspartic acid-β-t-butyl ester, arginine, Ng-Mtr-arginine, cysteine, S- trityl-cysteine, glutamic acid, glutamic acid-γ-t-butyl ester, glutamine, N-γ-trityl- glutamine, glycine, histidine, Nim-trityl-histidine, isoleucine, leucine, lysine, Nε-Boc-lysine, methionine, phenylalanine, proline, serine, O-t-butyl-serine, threonine, tryptophan, Nin-Boc-tryptophan, tyrosine, valine, sarcosine, L-alanine, chloro-L-alanine, 2-aminoisobutyric acid, 2- (methylamino)isobutyric acid, D,L-3-aminoisobutyric acid, (R)- (-)-2 amino isobutyric acid, (S)-(+)-2-aminoisobutyric acid, D-leucine, L-leucine, D- norvaline, L-norvaline, L-2-amino-4- P-633720-PC pentenoic acid, D-isoleucine, L-isoleucine, D- norleucine, 2,3-diaminopropionic acid, L- norleucine, D,L-2-aminocaprylic acid, β- alanine, D,L-3-aminobutyric acid, 4-aminobutyric acid, 4-(methylamino)butyric acid, 5- aminovaleric acid, 5-aminocaproic acid, 7- aminoheptanoic acid, 8-aminocaprylic acid, 11-aminodecanoic acid, 12-aminododecanoic acid, carboxymethoxylamine, D-serine, D-homoserine, L-homoserine, D-allothreonine, L- allothreonine, D-threonine, L-threonine, D,L-4-amino-3-hydroxybutyric acid, D-,L-3- hydroxynorvaline, (3S,4S)-(-)-statine, 5-hydroxy-D,L-lysine, 1-amino-1- cyclopropanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid, 1-amino-1- cyclohexanecarboxylic acid, 5-amino-l,3- cyclohexadiene-1-carboxylic acid, 2-amino-2- norbornanecarboxylic acid, (S)-(-)-2- azetidinecarboxylic acid, cis-4-hydroxy-D-proline, cis- 4-hydroxy-L-proline, trans-4- hydroxy-L-proline, 3,4-dehydro-D,L-proline, 3 ,4-dehydro-L- proline, D-pipecolinic acid, L-pipecolinic acid, nipecotic acid, isonipecotic acid, mimosine, 2,3- diaminopropionic acid, D,L-2,4-diaminobutyric acid, (S)-(+)-diaminobutyric acid, D- ornithine, L-ornithine, 2-methylornithine, N-ε-methyl-L-lysine, N-methyl-D-aspartic acid, D,L-2-methylglutamic acid, D,L-2-aminoadipic acid, D-2-aminoadipic acid, L-2- aminoadipic acid, (+ / -)-3-aminoadipic acid, D-cysteine, D-penicillamine, L- penicillamine, D,L- homocysteine, S-methyl-L-cysteine, L-methionine, D-ethionine, L-ethionine, S- carboxymethyl-L-cysteine, (S)-(+)-2-phenylglycine, (R)-(-)-2-phenylglycine, N- phenylglycine, N-(4-hydroxyphenyl)glycine, D-phenylalanine, thienylalanine, (S)- (- )indoline-2-carboxylic acid, α-methyl,D,L-phenylalanine, β-methyl-D,L-phenylalanine, D- homophenylalanine, L-homophenylalanine, D,L-2-fluorophenylglycine, D,L-2- fluorophenylalanine, D,L-3-fluorophenylalanine, D,L-4-fluorophenylalanine, D,L-4- chlorophenylalanine, L-4-chlorophenylalanine, 4-bromo-D,L-phenylalanine, 4-iodo-D- phenylalanine, 3,3’,5-triiodo-L-thyronine, (+)-3,3’,5-triiodo-L-thyronine, D-thyronine, L- thyronine, D,L-m-tyrosine, D-4-hydroxyphenylglycine, D-tyrosine, L-tyrosine, O- methyl-L- tyrosine, 3-fluoro-D,L-tyrosine, 3-iodo-L-tyrosine, 3-nitro-L-tyrosine, 3,5- diiodo-L-tyrosine, D,L-dopa, L-dopa, 2,4,5-trihydroxyphenyl-D,L-alanine, 3-amino-L- tyrosine, 4-amino-D- phenylalanine, 4-amino-L-phenylalanine, 4-amino-D,L- phenylalanine, 4-nitro-L- phenylalanine, 4-nitro-D,L-phenylalanine, 3,5-dinitro-L-tyrosine, D,L-α-methyltyrosine, L-α- methyltyrosine, (-)-3-(3,4-dihydroxyphenyl)-2- methyl-L-alanine, D,L-threo-3-phenylserine, trans-4-(aminomethyl)cyclohexane carboxylic acid, 4-(aminomethyl)benzoic acid, D,L-3- aminobutyric acid, 3- aminocyclohexane carboxylic acid, cis-2-amino-l-cyclohexane carboxylic acid, γ-amino- β-(p-chlorophenyl) butyric acid (baclofen), D,L-3- P-633720-PC aminophenylpropionic acid, 3-amino- 3-(4-chlorophenyl) propionic acid, 3-amino-3-(2- nitrophenyl)propionic acid, and 3- amino-4,4,4-trifluorobutyric acid.

[0024] In some embodiments, the fibric acid residue is fenofibrate, beclofibrate, benzafibrate, bezafibrate, binifibrate, ciprofibrate, clinofϊbrate, clofibrate, ethyl 2-(p-chlorophenoxy)-2- methyl-propionate, etofϊbrate, fenofibrate, ((2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl- propanoic acid, 1-methylethyl ester), gemcabene, gemfibrozil, 5-(2,5-dimethylphenoxy)-2,2- dimethylpentanoic acid, lifϊbrol, GW 7647, BM 170744 or LY518674.

[0025] In some embodiments, the amino-containing compound is agmatine, aminoguanidine, guanidine, tetrazole, amino-tetrazole, or an amino acid residue as described above.

[0026] In some embodiments, the resveratrol residue is ((E)-5-(4- hydroxystyryl)benzene-l,3- diol).

[0027] In some embodiments, the imidazoline receptor agonist residue is LNP509, S-21663, S-22068 or S-23515.

[0028] In some embodiments, the compound of Formula (III) is (3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-N-(4-guanidinobutyl)-3,5-dihydroxyhept-6- enamide, (3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5- dihydroxy-N-(2H- tetrazol-5-yl)hept-6-enamide, (3S, 5R,E)-7-(3-(4-fluoro phenyl )-1-isopropyl-1 H-indol-2-yl) - 3,5-dihydroxy-N-((E)-N’-methylcarbamimidoyl)hept-6-en amide; (3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1 H-indol-2-yl)-N-((S)-1-(4-guanidinobutylamino)-1 -oxopropan- 2-yl)-3,5-dihydroxyhept-6-enamide, 2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl- 1H- indol-2-yl)-3,5-dihydroxyhept-6-enoyl)h yd razinecarboximidamide; (S)-2-((3S,5R,E)-7-(3- (4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)propanoic acid; (R)-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enamido)propanoic acid; (R,S)-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2- yl)-3,5-dihydroxyhept-6-enamido)propanoic acid; (S)-6-amino-2-((3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)hexanoic acid; (R)- 6-amino-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1-iso propyl-1H-indol-2-yl)-3,5-dihydroxyhept- 6-enamido)hexanoic acid; (R, S)-6-amino-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl- 1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)hexanoic acid; S)-2-((3S,5R,E)-7-(3-(4- fluorophenyl)-1 -isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)-5- guanidinopentanoic acid; (R)-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2- P-633720-PC yl)-3,5-dihydroxyhept-6-enamido)-5-guanidinopentanoic acid; (RS)-2-((3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)-5- guanidinopentanoic acid; (3S,5R,E)-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoyloxy) methyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; (3S, 5R ,E)- 3-hydroxy-5-(4-hydroxystyryl)phenyl-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2- yl)-3,5-dihydroxyhept-6-enoate; (3S,5R,E)-N-(5-((2-bromophenoxy)methyl)-4,5- dihydrooxazol-2-yl)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enamide; (3S,5R,E)-Λ / -(dicyclopropylmethyl)-Λ / -(2,3-dimethyl-3,4-dihydro-2H-pyrrol-5- yl)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamide; (3S,5R,E)-1-(2-(1-(2,4-dichlorobenzyl)-4-methylpiperazin-2-yl) -4,5-dihydro-1H-imidazol-1- yl)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl) -3,5-dihydroxyhept-6-en-1-one; or (3S,5R,E)-1-(2-(1,4-diisopropylpiperazin-2-yl)-4,5-dihydro-1H-imidazol-1-yl)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-en-1-one.

[0029] In any of the foregoing aspects and embodiments, the solid tumor comprises a VHL mutation. In some embodiments, the solid tumor comprises a VHL mutation and wild type VHL. In some embodiments, the solid tumor is a kidney tumor. In some embodiments, the kidney tumor is renal cell carcinoma or clear cell renal cell carcinoma (ccRCC). In some embodiments, the solid tumor is breast cancer. In some embodiments, the breast tumor is triple negative breast cancer (TNBC). In some embodiments, the tumor is prostate cancer. In some embodiments, the prostate cancer is neuroendocrine prostate cancer (NEPC).

[0030] 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 a compound of Formula (I), Formula (I-A) or Formula (III), or Compound I-B to I-J or II-A, an analogue thereof, or a racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0031] 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 P-633720-PC 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 a compound of Formula (I), Formula (I-A) or Formula (III), or Compound I-B to I-J or II-A, an analogue thereof, or a racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0032] In one embodiment, the solid tumor is a kidney tumor. In one embodiment, the spread comprises a high grade histologic criterion or spread of the tumor beyond Gerota fascia of the kidney.

[0033] 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 of Formula (I), Formula (I-A) or Formula (III), or Compound I-B to I-J or II-A, an analogue thereof, or a racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0034] In one embodiment, the activation of the hypoxia program is due to mutation or loss of VHL expression.

[0035] 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 of Formula (I), Formula (I-A) or Formula (III), or Compound I-B to I-J or II-A, an analogue thereof, or a racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0036] In one embodiment, extracellular vesicles are detected in a ccRCC patient. In one embodiment, the bodily fluid is blood or urine. P-633720-PC

[0037] 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 of Formula (I), Formula (I-A) or Formula (III), or Compound I-B to I-J or II-A, an analogue thereof, or a racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0038] In one aspect, a compound is described of Formula (I): or a or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently hydrogen, hydroxy, SOR3, or a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety; or wherein R1and R2taken together with the N to which they are bound form a 4, 5, 6, 7, 8 or 9 membered substituted or unsubstituted, saturated or unsaturated alicyclic or a saturated or unsaturated heterocyclic moiety; P-633720-PC R3for each occurrence is independently hydrogen, -N(R4)2, aliphatic, aryl or heteroaryl moiety; and R4for each occurrence is independently hydrogen or a substituted or unsubstituted aliphatic moiety, substituted or unsubstituted phenyl, or a substituted or unsubstituted heterocyclic ring.

[0039] In some embodiments, at least one of R1and R2is not hydrogen. In some embodiments, R1and R2are independently selected from H or an optionally substituted, saturated or unsaturated C1-C6 alkyl. In some embodiments, R1is H and R2is a saturated or unsaturated C1- C6alkyl, such as methyl, ethyl or 2-propargyl. In some embodiments, R1is H and R2is C0-C6- adamantanyl.

[0040] In some embodiments, R1and R2taken together is an optionally substituted C1-C8 aliphatic such as n-propyl, n-butyl, n-pentyl, n-hexyl or n-heptyl. In some embodiments, R1and R2together with the N to which they are bound form an optionally substituted 4, 5, 6, 7, 8 or 9 membered ring with 1-3 additional heteroatoms selected from N, O or S, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or azepinyl. In some embodiments, R1and R2taken together is a piperazinyl N-substituted with an alkoxycarbonyl moiety such as tert- butoxycarbonyl.

[0041] In some embodiments, R1or R2independently is an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL-161, EEDi-5273 and MAK683 or any other optimal linker substituted with an E3 ligase recruiting moiety. In some embodiments, the linker is a C1-C8 alkyl or polyethylene glycol.

[0042] In some embodiments, the compound of Formula (I) is:

[0004] P-633720-PC or an analogue thereof.

[0005] P-633720-PC

[0043] In one aspect, a compound is described of Formula (IA): or a pharmaceutically acceptable salt thereof, wherein X is O, NR2or CR3R4, R2is an unsubstituted or substituted aliphatic, alkoxycarbonyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted heteroaryl moiety; R3and R4are independently H or a substituted or unsubstituted C1-C8alkyl.

[0006] P-633720-PC

[0044] In some embodiments, R2is tert-butoxycarbonyl. In some embodiments, is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl or

[0045] In some embodiments, R2, R3or R4may be an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL- 161, EEDi-5273 and MAK683 or any other optimal linkers substituted with an E3 ligase recruiting moiety. In some embodiments, the linker is a C1-C8alkyl or polyethylene glycol.

[0046] In some embodiments, the compound of Formula (IA) is:

[0007] P-633720-PC

[0047] In one aspect, a pharmaceutical composition comprising a compound of any one of Formula (I) or Formula (IA), and a pharmaceutically acceptable buffer, excipient, diluent, vehicle or carrier.

[0048] In certain embodiments, any of the foregoing pharmaceutical compositions are provided in a unit dose form and dosing regimen effective for inhibiting metastasis.

[0049] 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 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. DETAILED DESCRIPTION

[0050] 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.

[0051] 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 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 P-633720-PC 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.

[0052] The following abbreviations are used herein. CRISPR / Cas9 – Clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9; ccRCC – Clear cell renal cell carcinoma; EVs – Extracellular vesicles; VHL – von Hippel-Lindau syndrome gene; VHL- KO – von Hippel-Lindau syndrome gene (VHL) knockout; VHL-WT – wild-type von Hippel- Lindau syndrome gene (VHL).

[0053] 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. 2018 9:203-210; 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; Hu, J.; Tan, P.; Ishihara, M.; Bayley, N.A.; Schokrpur, S.; Reynoso, J.G.; Zhang, Y.; Lim, R.J.; Dumitras, C.; Yang, L.; et al. Tumor Heterogeneity in VHL Drives Metastasis in Clear Cell Renal Cell Carcinoma. Signal Transduct. Target. Ther. 2023, 8, 155). Tumors with both VHL(-) and VHL(+) cells metastasize rampantly to lungs but tumors with either type of cell 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.

[0054] Disclosed herein are compounds of Formula (I): P-633720-PC or a racemate, acceptable salt thereof, wherein R1and R2are each independently hydrogen, hydroxy, SOR3, or a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety; or wherein R1and R2taken together with the N to which they are bound form a 4, 5, 6, 7, 8 or 9 membered substituted or unsubstituted, saturated or unsaturated alicyclic or a saturated or unsaturated heterocyclic moiety; R3for each occurrence is independently hydrogen, -N(R4)2, aliphatic, aryl or heteroaryl moiety; and R4for each occurrence is independently hydrogen or a substituted or unsubstituted aliphatic moiety, substituted or unsubstituted phenyl, or a substituted or unsubstituted heterocyclic ring.

[0055] In some embodiments, at least one of R1and R2is not hydrogen.

[0056] In some embodiments, R1and R2are independently selected from H or an optionally substituted, saturated or unsaturated C1-C6alkyl. In some embodiments, R1is H and R2is a saturated or unsaturated C1-C6 alkyl. In some embodiments, R2is methyl, ethyl or 2-propargyl.

[0057] In some embodiments, R1is H and R2is C0-C6-adamantanyl. P-633720-PC

[0058] In some embodiments, R1and R2taken together is an optionally substituted C1-C8aliphatic such as n-propyl, n-butyl, n-pentyl, n-hexyl or n-heptyl. In some embodiments, R1and R2together with the N to which they are bound form an optionally substituted 4, 5, 6, 7, 8 or 9 membered ring with 1-3 additional heteroatoms selected from N, O or S, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or azepinyl.

[0059] In some embodiments, R1and R2taken together is an optionally substituted piperidinyl. In some embodiments, the piperazinyl is N- substituted with an alkoxycarbonyl moiety. In some embodiments, the alkoxycarbonyl is tert-butoxycarbonyl.

[0060] In some embodiments, R1or R2independently is an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL-161, EEDi-5273 and MAK683 or any other optimal linker substituted with an E3 ligase recruiting moiety. In some embodiments, the linker is a C1-C8alkyl or polyethylene glycol.

[0061] Such compounds of Formula (I) are capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.

[0062] Disclosed herein are compounds of Formula (IA):

[0008] P-633720-PC or a racemate, enantiomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is O, NR2or CR3R4, R2is an unsubstituted or substituted aliphatic, alkoxycarbonyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted heteroaryl moiety; R3and R4are independently H or a substituted or unsubstituted C1-C8alkyl.

[0063] In some embodiments, R2is tert-butoxycarbonyl.

[0064] In some embodiments, is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,

[0065] In some embodiments, R2, R3or R4may be an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL- 161, EEDi-5273 and MAK683 or any other optimal linkers substituted with an E3 ligase recruiting moiety. In some embodiments, the linker is a C1-C8 alkyl or polyethylene glycol.

[0066] Such compounds of Formula (IA) are capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.

[0067] 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 or tert-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. In some embodiments, an alkyl group of from 1 to about 8 carbon atoms is referred to as lower alkyl. In some embodiments, an alkyl group of from 1 to about 10 carbon atoms is referred to as lower alkyl. P-633720-PC

[0068] 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.

[0069] In some embodiments, “halo” includes fluoro, chloro, bromo, and iodo.

[0070] 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.

[0071] 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 “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.

[0072] 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. P-633720-PC

[0073] 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.

[0074] 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 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”.

[0075] 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.

[0076] 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.

[0077] 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, - P-633720-PC (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.

[0078] 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.

[0079] 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.

[0080] 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 - P-633720-PC (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, 7, 8, or 9-membered substituted or unsubstituted saturated or unsaturated alicyclic or saturated or unsaturated heterocyclic moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0081] 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 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, azepinyl, azetidinyl, 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; P-633720-PC 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 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.

[0082] 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.

[0083] 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 present invention includes all stereoisomers of Formulas (I), (IA) and (III), and Compounds I-B to I-J, and II-A, and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included.

[0084] Non-limiting examples of compounds of Formula (I) include any one of Compounds I- B to I-J below, or an analogue thereof.

[0009] P-633720-PC I-B

[0085] As used herein, “I-B to I-J” refers to I-B, I-C, I-D, I-E, I-F, I-G, I-H and I-J.

[0086] Embraced within the present disclosure are stereoisomers or enantiomers of a compound of any one of Compounds I-B to I-J. In some embodiments, the compound is 3R,5S. In some embodiments, the compound is 3S, 5R. In some embodiments, the compound is a racemate.

[0087] 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 present invention includes all stereoisomers of Compounds I-B to I-J and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. P-633720-PC

[0088] In certain embodiments, a formula or compound disclosed herein such as any compound of Formula (I), any of Compounds I-B to I-J, or Compound II-A 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).

[0089] Non-limiting examples of compounds of Formula (IA) include:

[0090] Embraced within the present disclosure are stereoisomers or enantiomers of any one of Compounds I-B, I-C, I-F, I-G or I-J. In some embodiments, the compound is 3R,5S. In some embodiments, the compound is 3S,5R. In some embodiments, the compound is a racemate.

[0091] 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 P-633720-PC 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 present invention includes all stereoisomers of Compounds I-B, I-C, I-F, I-G or I-J and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included.

[0092] In certain embodiments, a formula or compound disclosed herein such as any compound of Formula (IA) or any of Compounds I-B, I-C, I-F, I-G or I-J that is 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). Pharmaceutical Compositions

[0093] In one aspect, a pharmaceutical composition is providing comprising a compound of Formula (I), Formula (IA), any of Compounds I-B to I-J, or an analogue, racemate or stereoisomer thereof, and a pharmaceutically-acceptable buffer, excipient, diluent, vehicle or carrier. Also embraced are pharmaceutically acceptable salts of any of the formulas or compounds.

[0094] In one aspect, a pharmaceutical composition is providing comprising a compound of Compound II-A below, or an analogue, racemate or stereoisomer thereof, and a pharmaceutically-acceptable buffer, excipient, diluent, vehicle or carrier. Also embraced are other pharmaceutically acceptable salts. . (II-A)

[0095] Compound II-A is also called fenpiverinium, CAS Reg. No.258329-46-3.

[0096] Pharmaceutical compositions comprising the formulas and compounds disclosed herein, for example, as disclosed herein or represented by any compound or formula herein, analogue P-633720-PC thereof 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, intratumoral and intrarenal). 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.

[0097] The present invention also includes “pharmaceutically acceptable salts” of the formulas and compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed formulas and 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 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.

[0098] The pharmaceutically acceptable salts of the formulas and compound of the invention can also be 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 P-633720-PC 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.

[0099] 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.

[0100] Typically, a pharmaceutically acceptable salt form of a formula or 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.

[0101] Other pharmaceutically acceptable salts can include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, 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.

[0102] 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.

[0103] In addition to the common dosage forms set out above, the compound or 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 P-633720-PC 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.

[0104] 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.

[0105] Liquid medicinal forms can be sterilized and / or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, 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.

[0106] 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, P-633720-PC 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.

[0107] 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.

[0108] 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.

[0109] Preparations for parenteral administration 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 P-633720-PC 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.

[0110] 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.

[0111] 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.

[0112] The preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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, P-633720-PC subcutaneously, intraperitoneally, intraventricularly, intravaginally, intracranially and intratumorally.

[0117] As described herein, a compound disclosed herein or that of a formula disclosed herein may be used to reduce or prevent metastasis from a primary or secondary tumor, and may thus be administered in proximity to the tumor. Embraced herein are formulations and means for delivery of a compound intratumorally or paracancerally, such as into or in the proximity of a tissue or organ comprising the tumor, such as but not limited to the kidney, CNS, breast, adrenal or pancreas.

[0118] As used herein, in some embodiments, the terms "therapeutically effective amount" and "effective amount" of an agent or compound 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 not 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 effective amount" is an amount that enhances therapeutic efficacy of another agent with which the composition is administered in combination.

[0119] The duration of treatment will, in some embodiments, be determined by the effectiveness of treatment and elimination of the primary tumor or to prevent or suppress metastatic growth. 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. P-633720-PC

[0120] 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). 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 mg / kg. In some embodiments, the reference therapeutically effective amount is within the range of about 250 mg / kg to about 500 mg / kg. As noted herein, the dose level, in combination with the frequency of administration, duration of administration, periods of dosing and dosing holidays, will be guided by the health care professional, and may include one or more methods for monitoring the progression and / or status of the disease.

[0010] P-633720-PC Methods of Use

[0121] As described herein, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof: or a racemate, acceptable salt thereof, wherein R1and R2are each independently hydrogen, hydroxy, SOR3, or a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety; or wherein R1and R2taken together with the N to which they are bound form a 4, 5, 6, 7, 8 or 9 membered substituted or unsubstituted, saturated or unsaturated alicyclic or a saturated or unsaturated heterocyclic moiety; R3for each occurrence is independently hydrogen, -N(R4)2, aliphatic, aryl or heteroaryl moiety; and R4for each occurrence is independently hydrogen or a substituted or unsubstituted aliphatic moiety, substituted or unsubstituted phenyl, or a substituted or unsubstituted heterocyclic ring.

[0122] In some embodiments, at least one of R1and R2is not hydrogen. P-633720-PC

[0123] In some embodiments, R1and R2are independently selected from H or an optionally substituted, saturated or unsaturated C1-C6alkyl. In some embodiments, R1is H and R2is a saturated or unsaturated C1-C6 alkyl. In some embodiments, R2is methyl, ethyl or 2-propargyl.

[0124] In some embodiments, R1is H and R2is C0-C6-adamantanyl.

[0125] In some embodiments, R1and R2taken together is an optionally substituted C1-C8aliphatic such as n-propyl, n-butyl, n-pentyl, n-hexyl or n-heptyl. In some embodiments, R1and R2together with the N to which they are bound form an optionally substituted 4, 5, 6, 7, 8 or 9 membered ring with 1-3 additional heteroatoms selected from N, O or S, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or azepinyl.

[0126] In some embodiments, R1and R2taken together is an optionally substituted piperidinyl. In some embodiments, the piperazinyl is N- substituted with an alkoxycarbonyl moiety. In some embodiments, the alkoxycarbonyl is tert-butoxycarbonyl.

[0127] In some embodiments, R1or R2independently is an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL-161, EEDi-5273 and MAK683 or any other optimal linker substituted with an E3 ligase recruiting moiety. In some embodiments, the linker is a C1-C8 alkyl or polyethylene glycol.

[0128] Such compounds of Formula (I) are capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.

[0011] P-633720-PC

[0129] As described herein, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (IA), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof: or a acceptable salt thereof, wherein X is O, NR2or CR3R4, R2is an unsubstituted or substituted aliphatic, alkoxycarbonyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted heteroaryl moiety; R3and R4are independently H or a substituted or unsubstituted C1-C8alkyl.

[0130] In some embodiments, R2is tert-butoxycarbonyl.

[0131] In some embodiments, is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,

[0132] In some embodiments, R2, R3or R4may be an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, P-633720-PC dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL- 161, EEDi-5273 and MAK683 or any other optimal linkers substituted with an E3 ligase recruiting moiety. In some embodiments, the linker is a C1-C8alkyl or polyethylene glycol.

[0133] Such compounds of Formula (IA) are capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.

[0134] As described herein, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject any one of Compound I-B to I-J below, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof:

[0012] P-633720-PC I-H or an analogue thereof.

[0135] As described herein, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject any one of Compounds of Formula (IA) below, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof: compound of any one of Compounds I-B to I-J. In some embodiments, the compound is 3R,5S. In some embodiments, the compound is 3S, 5R. In some embodiments, a racemate is administered. P-633720-PC

[0137] In certain embodiments of the method, the compound of any one of formulas I-B to I-J does not have substantial HMG-CoA reductase activity.

[0138] As described herein, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula II-A below or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof: . or an analogue

[0139] Compound II-A is also called fenpiverinium, CAS Reg. No.258329-46-3.

[0140] Compound II-A is capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.

[0141] As described herein, a method is provided for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof:

[0013] P-633720-PC wherein X is a R5is selected from an amino acid residue, a fibric acid residue, guanidine, tetrazolyl, agmatine, an amino-containing compound; a lower alkyl terminating in ΟΝΟ, (ONO2)p, guanidine; a resveratrol residue; an imidazoline receptor agonist residue, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl or a substituted or unsubstituted heterocycle; and p is 1, 2 or 3.

[0142] In some embodiments, the amino acid residue is alanine, asparagine, N-β-trityl- asparagine, aspartic acid, aspartic acid-β-t-butyl ester, arginine, Ng-Mtr-arginine, cysteine, S- trityl-cysteine, glutamic acid, glutamic acid-γ-t-butyl ester, glutamine, N-γ-trityl- glutamine, glycine, histidine, Nim-trityl-histidine, isoleucine, leucine, lysine, Nε-Boc-lysine, methionine, phenylalanine, proline, serine, O-t-butyl-serine, threonine, tryptophan, Nin-Boc-tryptophan, tyrosine, valine, sarcosine, L-alanine, chloro-L-alanine, 2-aminoisobutyric acid, 2- (methylamino)isobutyric acid, D,L-3-aminoisobutyric acid, (R)- (-)-2 amino isobutyric acid, (S)-(+)-2-aminoisobutyric acid, D-leucine, L-leucine, D- norvaline, L-norvaline, L-2-amino-4- pentenoic acid, D-isoleucine, L-isoleucine, D- norleucine, 2,3-diaminopropionic acid, L- norleucine, D,L-2-aminocaprylic acid, β- alanine, D,L-3-aminobutyric acid, 4-aminobutyric acid, 4-(methylamino)butyric acid, 5- aminovaleric acid, 5-aminocaproic acid, 7- aminoheptanoic acid, 8-aminocaprylic acid, 11-aminodecanoic acid, 12-aminododecanoic acid, P-633720-PC carboxymethoxylamine, D-serine, D-homoserine, L-homoserine, D-allothreonine, L- allothreonine, D-threonine, L-threonine, D,L-4-amino-3-hydroxybutyric acid, D-,L-3- hydroxynorvaline, (3S,4S)-(-)-statine, 5-hydroxy-D,L-lysine, 1-amino-1- cyclopropanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid, 1-amino-1- cyclohexanecarboxylic acid, 5-amino-l,3- cyclohexadiene-1-carboxylic acid, 2-amino-2- norbornanecarboxylic acid, (S)-(-)-2- azetidinecarboxylic acid, cis-4-hydroxy-D-proline, cis- 4-hydroxy-L-proline, trans-4- hydroxy-L-proline, 3,4-dehydro-D,L-proline, 3 ,4-dehydro-L- proline, D-pipecolinic acid, L-pipecolinic acid, nipecotic acid, isonipecotic acid, mimosine, 2,3- diaminopropionic acid, D,L-2,4-diaminobutyric acid, (S)-(+)-diaminobutyric acid, D- ornithine, L-ornithine, 2-methylornithine, N-ε-methyl-L-lysine, N-methyl-D-aspartic acid, D,L-2-methylglutamic acid, D,L-2-aminoadipic acid, D-2-aminoadipic acid, L-2- aminoadipic acid, (+ / -)-3-aminoadipic acid, D-cysteine, D-penicillamine, L- penicillamine, D,L- homocysteine, S-methyl-L-cysteine, L-methionine, D-ethionine, L-ethionine, S- carboxymethyl-L-cysteine, (S)-(+)-2-phenylglycine, (R)-(-)-2-phenylglycine, N- phenylglycine, N-(4-hydroxyphenyl)glycine, D-phenylalanine, thienylalanine, (S)- (- )indoline-2-carboxylic acid, α-methyl,D,L-phenylalanine, β-methyl-D,L-phenylalanine, D- homophenylalanine, L-homophenylalanine, D,L-2-fluorophenylglycine, D,L-2- fluorophenylalanine, D,L-3-fluorophenylalanine, D,L-4-fluorophenylalanine, D,L-4- chlorophenylalanine, L-4-chlorophenylalanine, 4-bromo-D,L-phenylalanine, 4-iodo-D- phenylalanine, 3,3’,5-triiodo-L-thyronine, (+)-3,3’,5-triiodo-L-thyronine, D-thyronine, L- thyronine, D,L-m-tyrosine, D-4-hydroxyphenylglycine, D-tyrosine, L-tyrosine, O- methyl-L- tyrosine, 3-fluoro-D,L-tyrosine, 3-iodo-L-tyrosine, 3-nitro-L-tyrosine, 3,5- diiodo-L-tyrosine, D,L-dopa, L-dopa, 2,4,5-trihydroxyphenyl-D,L-alanine, 3-amino-L- tyrosine, 4-amino-D- phenylalanine, 4-amino-L-phenylalanine, 4-amino-D,L- phenylalanine, 4-nitro-L- phenylalanine, 4-nitro-D,L-phenylalanine, 3,5-dinitro-L-tyrosine, D,L-α-methyltyrosine, L-α- methyltyrosine, (-)-3-(3,4-dihydroxyphenyl)-2- methyl-L-alanine, D,L-threo-3-phenylserine, trans-4-(aminomethyl)cyclohexane carboxylic acid, 4-(aminomethyl)benzoic acid, D,L-3- aminobutyric acid, 3- aminocyclohexane carboxylic acid, cis-2-amino-l-cyclohexane carboxylic acid, γ-amino- β-(p-chlorophenyl) butyric acid (baclofen), D,L-3- aminophenylpropionic acid, 3-amino- 3-(4-chlorophenyl) propionic acid, 3-amino-3-(2- nitrophenyl)propionic acid, and 3- amino-4,4,4-trifluorobutyric acid.

[0143] In some embodiments, the fibric acid residue is fenofibrate, beclofibrate, benzafibrate, bezafibrate (C.A.S. Registry No. 41859-67-0, see US3781328), binifibrate (C.A.S. Registry P-633720-PC No. 69047-39-8, see BE884722), ciprofibrate (C.A.S. Registry No. 52214-84-3, see US3948973), clinofϊbrate (C.A.S. Registry No.30299-08-2, see US3716583), clofibrate (such as ethyl 2-(p-chlorophenoxy)-2-methyl-propionate, etofϊbrate, fenofibrate, ((2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester), gemcabene, gemfibrozil (such as 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, lifϊbrol, GW 7647, BM 170744, LY518674 and those fibrate and fibrate acid derivatives disclosed in WO03 / 033456, WO03 / 033481, WO03 / 043997, WO03 / 048116, WO03 / 053974, WO03 / 059864, and WO03 / 05875.

[0144] In some embodiments, the amino-containing compound is agmatine, aminoguanidine, guanidine, tetrazole, amino-tetrazole, or an amino acid residue as described above.

[0145] In some embodiments, the resveratrol residue is ((E)-5-(4- hydroxystyryl)benzene-l,3- diol).

[0146] In some embodiment, the imidazoline receptor agonist residue is LNP509, S-21663, S- 22068 or S-23515.

[0147] Non-limiting examples of compounds of Formula (III) and their syntheses are described in WO2008157537, incorporated herein by reference. Examples include (3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-N-(4-guanidinobutyl)-3,5-dihydroxyhept-6- enamide, (3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5- dihydroxy-N-(2H- tetrazol-5-yl)hept-6-enamide, (3S, 5R,E)-7-(3-(4-fluoro phenyl )-1-isopropyl-1 H-indol-2-yl) - 3,5-dihydroxy-N-((E)-N’-methylcarbamimidoyl)hept-6-en amide; (3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1 H-indol-2-yl)-N-((S)-1-(4-guanidinobutylamino)-1 -oxopropan- 2-yl)-3,5-dihydroxyhept-6-enamide, 2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl- 1H- indol-2-yl)-3,5-dihydroxyhept-6-enoyl)hydrazinecarboximidamide; (S)-2-((3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)propanoic acid; (R)- 2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enamido)propanoic acid; (R,S)-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2- yl)-3,5-dihydroxyhept-6-enamido)propanoic acid; (S)-6-amino-2-((3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)hexanoic acid; (R)- 6-amino-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1-iso propyl-1H-indol-2-yl)-3,5-dihydroxyhept- 6-enamido)hexanoic acid; (R, S)-6-amino-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl- 1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)hexanoic acid; S)-2-((3S,5R,E)-7-(3-(4- P-633720-PC fluorophenyl)-1 -isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)-5- guanidinopentanoic acid; (R)-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2- yl)-3,5-dihydroxyhept-6-enamido)-5-guanidinopentanoic acid; (RS)-2-((3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)-5- guanidinopentanoic acid; (3S,5R,E)-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoyloxy) methyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; (3S, 5R ,E)- 3-hydroxy-5-(4-hydroxystyryl)phenyl-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2- yl)-3,5-dihydroxyhept-6-enoate; (3S,5R,E)-N-(5-((2-bromophenoxy)methyl)-4,5- dihydrooxazol-2-yl)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enamide; (3S,5R,E)-N-(dicyclopropylmethyl)-Λ / -(2,3-dimethyl-3,4-dihydro-2H-pyrrol-5-yl)- 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamide; (3S,5R,E)- 1-(2-(1-(2,4-dichlorobenzyl)-4-methylpiperazin-2-yl) -4,5-dihydro-1H-imidazol-1-yl)-7-(3- (4-fluorophenyl)-1-isopropyl-1H-indol-2-yl) -3,5-dihydroxyhept-6-en-1-one; and (3S,5R,E)- 1-(2-(1,4-diisopropylpiperazin-2-yl)-4,5-dihydro-1H-imidazol-1-yl)-7-(3-(4-fluorophenyl)-1- isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-en-1-one.

[0148] The foregoing compounds and compounds of Formula (III) are capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.

[0149] In any of the foregoing aspects regarding Formulas (I), (IA) and (III), or Compounds I- B to I-J and II-A, as well as any of the compounds embraced herein, the solid tumor comprises a VHL mutation. In any of the foregoing aspects, the solid tumor comprises a VHL mutation and wild type VHL. In any of the foregoing aspects, the solid tumor is a kidney tumor. In any of the foregoing aspects, the kidney tumor is renal cell carcinoma. In any of the foregoing embodiments, the kidney tumor is clear cell renal cell carcinoma (ccRCC). In any of the foregoing embodiments, the solid tumor is breast cancer. In any of the foregoing embodiments, the breast tumor is triple negative breast cancer (TNBC), In any of the foregoing embodiments, the tumor is prostate cancer. In any of the foregoing embodiments, the tumor is neuroendocrine prostate cancer (NEPC).

[0150] In certain embodiments, any of the foregoing pharmaceutical compositions are provided in a unit dose form and dosing regimen effective for inhibiting metastasis. P-633720-PC

[0151] In addition to the formulas, compounds, pharmaceutical compositions and methods of use described herein, in some aspects, various related methods are provided. In one embodiment, 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 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 comprising any formula or compound as disclosed herein.

[0152] In one embodiment, 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 evidence of spread of the tumor beyond the primary site; and b. upon detection of spread, treating the patient with a pharmaceutical composition comprising any formula or compound as disclosed herein.

[0153] In some embodiments, the solid tumor is a kidney tumor. In some embodiments, spread comprises a high grade histologic criterion or spread of the tumor beyond the Gerota fascia of the kidney.

[0154] In one embodiment, 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 any formula or compound as disclosed herein.

[0155] In some embodiments, the activation of the hypoxia program is due to mutation or loss of VHL expression. P-633720-PC

[0156] In one embodiment, 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 any formula or compound disclosed herein.

[0157] In some embodiments, extracellular vesicles are detected in a ccRCC patient. In some embodiments, bodily fluid is blood or urine.

[0158] In one embodiment, 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 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 comprising any formula or compound disclosed herein.

[0159] With regard to any of the foregoing aspects or 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 formula or compound disclosed herein, to inhibit or prevent metastasis of any residual tumor or secondary tumor sites.

[0160] In some embodiments, the solid tumor is a kidney tumor. In some embodiments, the kidney tumor is renal cell carcinoma. In some embodiments, the kidney tumor is renal cell carcinoma. In any of the foregoing embodiments, the kidney tumor is clear cell renal cell carcinoma (ccRCC). In some embodiments, the solid tumor is breast cancer. In some embodiments, the breast tumor is triple negative breast cancer (TNBC). In some embodiments, the tumor is prostate cancer. In some embodiments, the tumor is neuroendocrine prostate cancer (NEPC).

[0161] In some embodiments, the tumor is a CNS, breast, adrenal or pancreatic tumor. P-633720-PC

[0162] 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.

[0163] 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 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 P-633720-PC 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.

[0164] 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 in a pharmaceutical composition. The disclosure also encompasses a pharmaceutical composition that is comprised of any of the formulas or compounds described herein, compounds of any of the formulas or compounds described herein, and analogues thereof, in combination with a pharmaceutically acceptable carrier. P-633720-PC

[0165] In some embodiments, the presence of metastases in the patient is established prior to treating with a formula or 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 formula or compound disclosed herein. In some embodiments, the patient’s tumor is removed prior to treating with a formula or compound disclosed herein. In some embodiments, a patient’s metastases are removed prior to treating with a formula or compound disclosed herein. Removed, in some embodiments, is surgical, radiation, chemotherapy, radioimmunotherapy, etc., or any combination thereof.

[0166] In some embodiments, the presence of a mutation the causes metastasis is identified in the tumor prior to treating with a formula or 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 formula or 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 20166:29032; and PCT / US2020 / 019601, published as WO20200176446; all of which are incorporated herein by reference in their entireties.

[0167] 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 formula or 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 formula or 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 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 formula or compound as disclosed herein.

[0168] 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 formula or compound P-633720-PC as disclosed herein, to adjust the dose level or dosing regimen, to identify recurrence of the tumor, or to discontinue therapy.

[0169] In some embodiments, the presence of activation of the hypoxia program of gene expression is identified prior to treating with a formula or 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 formula or 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 formula or compound as disclosed herein. In some embodiments, the compound is a statin or an analogue thereof.

[0170] In some embodiments, the activation of the hypoxia program is due to mutation or loss of VHL expression.

[0171] 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 formula or compound as disclosed herein, to adjust the dose level or dosing regimen, to identify recurrence of the tumor, or to discontinue therapy.

[0172] In some embodiments, the presence of extracellular vesicles in a bodily fluid of the subject is identified prior to treating with a formula or compound disclosed herein. Thus, in one embodiment, presence of extracellular vesicles in a bodily fluid of the subject, 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 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 formula or 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.

[0173] 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 formula or compound as P-633720-PC disclosed herein, to adjust the dose level or dosing regimen, to identify recurrence of the tumor, or to discontinue therapy.

[0174] In some embodiments, the presence of an overexpression of periostin in the tumor is identified prior to treating with a formula or 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. Periostin overexpression may be identified following guidance in PCT / US2020 / 019601, published as WO20200176446, and incorporated herein by reference in their entireties.

[0175] In another embodiment, the expression level of periostin of the subject may be used to monitor the effectiveness of therapy using a formula or compound as disclosed herein, to adjust the dose level or dosing regimen, to identify recurrence of the tumor, or to discontinue therapy.

[0176] In one embodiment, the cancer in which the VHL mutation is identified as an indication to begin treatment with a formula or 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.

[0177] 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, 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.

[0178] 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.

[0179] 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. P-633720-PC

[0180] 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

[0181] 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. EXAMPLE 1. Synthesis of Compounds.

[0182] General procedure A for synthesis of exemplary compounds within Formulas (I) and (IA). Fluvastatin sodium (20 mg, 0.046 mmol, 1.0 eq) was dissolved in anhydrous DMF (262 µL). The required amine (0.184 mmol, 4.0 eq) and DIPEA (32 µL, 0.184 mmol, 4.0 eq) were then added, followed by PyBOP (33 mg, 0.064 mmol, 1.4 eq). The reaction mixture was stirred until LCMS confirmed the reaction was complete. The reaction mixture was then injected directly onto a semi-preparative HPLC column using a gradient of 95% water, 5% acetonitrile to 5% water, 95% acetonitrile with a 0.1% formic acid additive over 15 minutes. The fractions containing the desired compound were then lyophilized to give the desired product as a colorless to pale yellow powder. (3S,5R,E)-rel-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxy-N,N- dimethylhept-6-enamide (Compound I-D)

[0183] (3S,5R,E)-rel-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxy-N,N- dimethylhept-6-enamide was synthesized according to general procedure A using dimethyl amine (2 M in THF, 92 µL, 0.18 mmol, 4.0 eq) resulting in the product as a pale-yellow powder P-633720-PC (11.4 mg, 57%) after lyophilization. ^m̅ax (thin film) / cm−13404, 2936, 1624, 1501, 1219, 1155, 839, 743;1H NMR (600 MHz, CD3CN) δ 7.61 (ddd, J = 8.4, 0.8, 0.8 Hz, 1H), 7.47 (ddd, J = 8.0, 1.0, 1.0 Hz, 1H), 7.46 – 7.43 (m, 2H), 7.20 – 7.13 (m, 3H), 7.05 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.67 (dd, J = 16.1, 1.5 Hz, 1H), 5.74 (dd, J = 16.0, 5.7 Hz, 1H), 4.91 (hept, J = 7.0 Hz, 1H), 4.60 (s, 1H), 4.41 – 4.36 (m, 1H), 4.03 – 3.95 (m, 1H), 3.71 (s, 1H), 2.95 (s, 3H), 2.88 (s, 3H), 2.47 (dd, J = 16.3, 3.3 Hz, 1H), 2.32 (dd, J = 16.3, 8.9 Hz, 1H), 1.63 (d, J = 3.4 Hz, 3H), 1.61 (d, J = 3.4 Hz, 3H), 1.57 (ddd, J = 13.8, 9.3, 7.9 Hz, 1H), 1.49 (ddd, J = 13.9, 5.2, 3.7 Hz, 1H);19F NMR (471 MHz, CD3CN) δ -118.7;13C NMR (151 MHz, CD3CN) δ 173.4, 162.3 (d, J = 242.5 Hz), 141.8, 136.0, 135.5, 133.04 (d, J = 7.8 Hz), 132.95 (d, J = 3.2 Hz), 129.2, 122.5, 120.6, 119.8, 118.9, 116.1 (d, J = 21.3 Hz), 114.6, 112.8, 71.5, 68.3, 48.7, 44.0, 40.1, 37.5, 35.2, 21.80, 21.79; HRMS m / z (ESI+) found 439.2393 [M+H]+(C26H32FN2O3requires 439.2392 [M+H]+); Purity (98.6%@254 nm), (98.7%@220 nm), (90.2%@365 nm). (3S,5R,E)-rel-1-(azetidin-1-yl)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-en-1-one (Compound I-F)

[0184] (3S,5R,E)-rel-1- - - isopropyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-en-1-one was synthesized according to general procedure A using azetidine (13 µL, 0.18 mmol, 4.0 eq) resulting in the product as a pale-yellow powder (10 mg, 50%) after lyophilization. ^m̅ax (thin film) / cm−13389, 1618, 1458, 1341, 1219, 840, 743;1H NMR (600 MHz, MeOD) δ 7.58 (ddd, J = 8.4, 0.9, 0.9 Hz, 1H), 7.46 – 7.39 (m, 3H), 7.19 – 7.11 (m, 3H), 7.01 (ddd, J = 8.0, 7.0, 0.9 Hz, 1H), 6.71 (dd, J = 16.0, 1.3 Hz, 1H), 5.73 (dd, J = 16.0, 6.4 Hz, 1H), 4.95 (hept, J = 7.0 Hz, 1H), 4.41 – 4.34 (m, 1H), 4.30 – 4.19 (m, 2H), 4.06 – 4.03 (m, 1H), 4.03 – 3.99 (m, 2H), 2.32 – 2.24 (m, 3H), 2.20 (dd, J = 14.6, 4.4 Hz, 1H), 1.70 (ddd, J = 13.8, 8.8, 7.1 Hz, 1H), 1.66 (d, J = 2.5 Hz, 3H), 1.65 (d, J = 2.5 Hz, 3H), 1.54 (ddd, J = 13.8, 6.7, 4.2 Hz, 1H);19F NMR (471 MHz, MeOD) δ -119.1;13C NMR (151 MHz, MeOD) δ 173.5, 162.8 (d, J = 243.3 Hz), 140.7, 136.6, 134.9, 133.4 (d, J = 3.3 Hz), 133.3 (d, J = 7.9 Hz), 129.8, 122.7, 120.6, 120.3, 120.1, 116.2 (d, J = 21.3 Hz), 115.6, 112.8, 71.4, 67.7, 51.7, 48.9, 44.9, P-633720-PC 39.6, 21.90, 21.86, 15.7; HRMS m / z (ESI+) found 451.2408 [M+H]+(C27H32FN2O3requires 451.2392 [M+H]+); Purity (97.7%@254 nm), (96.1%@220 nm), (92.9%@365 nm). (3S,5R,E)-rel-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxy-1- (pyrrolidin-1-yl)hept-6-en-1-one (Compound I-G)

[0185] (3S,5R,E)-rel-7-(3- 2-yl)-3,5-dihydroxy-1- (pyrrolidin-1-yl)hept-6-en-1-one was synthesized according to general procedure A using pyrrolidine (15 µL, 0.18 mmol, 4.0 eq) resulting in the product as a pale-yellow powder (3.7mg, 17%) after lyophilization. ^ ̅max (thin film) / cm−13444, 2975, 2878, 1613, 1458, 1221, 849,744;1H NMR (600 MHz, MeOD) δ 7.58 (d, J = 8.4 Hz, 1H), 7.46 – 7.39 (m, 3H), 7.18 – 7.11 (m, 3H), 7.01 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.71 (dd, J = 16.0, 1.3 Hz, 1H), 5.74 (dd, J = 16.0, 6.4 Hz, 1H), 4.95 (hept, J = 7.0 Hz, 1H), 4.43 – 4.37 (m, 1H), 4.11 – 4.04 (m, 1H), 3.58 – 3.47 (m, 2H), 3.43 (t, J = 6.9 Hz, 2H), 2.50 (dd, J = 15.3, 8.2 Hz, 1H), 2.43 (dd, J = 15.3, 4.3 Hz, 1H), 2.01 – 1.93 (m, 2H), 1.93 – 1.86 (m, 2H), 1.72 (ddd, J = 13.7, 8.9, 6.9 Hz, 1H), 1.66 (d, J = 7.0 Hz, 3H), 1.66 (d, J = 7.0 Hz, 3H), 1.56 (ddd, J = 13.7, 6.7, 4.1 Hz, 1H);19F NMR (471 MHz, MeOD) δ -119.1;13C NMR (151 MHz, MeOD) δ 172.4, 162.8 (d, J = 243.4 Hz), 140.7, 136.6, 135.0, 133.4 (d, J = 3.3 Hz), 133.3 (d, J = 7.8 Hz), 129.8, 122.7, 120.6, 120.3, 120.1, 116.2 (d, J = 21.3 Hz), 115.6, 112.8, 71.4, 67.7, 48.9, 48.2, 46.8, 44.8, 42.8, 26.9, 25.4, 21.9, 21.9; HRMS m / z (ESI+) found 465.2550 [M+H]+(C28H34FN2O3 requires 465.2548 [M+H]+); Purity (99.0%@254 nm), (100%@220 nm), (83.7%@365 nm). (3S,5R,E)-rel-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxy-1- (piperidin-1-yl)hept-6-en-1-one (Compound I-B) P-633720-PC

[0186] (3S,5R,E)-rel-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxy-1- (piperidin-1-yl)hept-6-en-1-one was synthesized according to general procedure A using piperidine (18 µL, 0.18 mmol, 4.0 eq) resulting in the product as a pale-yellow powder (9.0 mg, 41%) after lyophilization. ^m̅ax (thin film) / cm−13421, 2939, 1616, 1458, 1220, 839, 743;1H NMR (600 MHz, CD3CN) δ 7.61 (ddd, J = 8.4, 0.9, 0.9 Hz, 1H), 7.47 (ddd, J = 8.0, 0.9, 0.9 Hz, 1H), 7.46 – 7.43 (m, 2H), 7.20 – 7.13 (m, 3H), 7.05 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.67 (dd, J = 16.1, 1.5 Hz, 1H), 5.74 (dd, J = 16.0, 5.7 Hz, 1H), 4.91 (hept, J = 7.0 Hz, 1H), 4.56 (s, 1H), 4.42 – 4.35 (m, 1H), 4.04 – 3.97 (m, 1H), 3.77 – 3.66 (m, 1H), 3.52 – 3.47 (m, 2H), 3.41 – 3.36 (m, 2H), 2.48 (dd, J = 16.2, 3.4 Hz, 1H), 2.33 (dd, J = 16.2, 8.8 Hz, 1H), 1.63 (d, J = 3.5 Hz, 3H), 1.61 (d, J = 3.5 Hz, 3H), 1.66 – 1.46 (m, 8H);19F NMR (471 MHz, CD3CN) δ - 118.6;13C NMR (151 MHz, CD3CN) δ 171.4, 162.3 (d, J = 242.7 Hz), 141.8, 136.1, 135.5, 133.0 (d, J = 7.7 Hz), 132.9 (d, J = 3.2 Hz), 129.2, 122.6, 120.6, 119.8, 118.9, 116.1 (d, J = 21.3 Hz), 114.6, 112.8, 71.6, 68.3, 48.7, 47.2, 44.0, 43.0, 40.0, 27.1, 26.4, 25.2, 21.8; HRMS m / z (ESI+) found 479.2718 [M+H]+(C29H36FN2O3 requires 479.2705 [M+H]+); Purity (100%@254 nm), (100%@220 nm), (100%@365 nm). (3S,5R,E)-rel-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxy-1- morpholinohept-6-en-1-one (Compound I-C)

[0187] (3S,5R,E)-rel-7-(3- - 2-yl)-3,5-dihydroxy-1- morpholinohept-6-en-1-one was synthesized according to general procedure A using morpholine (16 µL, 0.18 mmol, 4.0 eq) resulting in the product as a pale-yellow powder (13.6 mg, 62%) after lyophilization. ^m̅ax (thin film) / cm−13388, 2975, 1621, 1458, 1220, 1115, 841, 718;1H NMR (600 MHz, CD3CN) δ 7.61 (ddd, J = 8.3, 0.9, 0.9 Hz, 1H), 7.49 – 7.41 (m, 3H), 7.22 – 7.13 (m, 3H), 7.05 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.67 (dd, J = 16.1, 1.5 Hz, 1H), 5.74 (dd, J = 16.1, 5.7 Hz, 1H), 4.91 (hept, J = 7.0 Hz, 1H), 4.42 – 4.35 (m, 1H), 4.31 (dd, J = 2.9, 1.0 Hz, 1H), 4.05 – 3.99 (m, 1H), 3.65 (d, J = 3.2 Hz, 1H), 3.62 – 3.57 (m, 4H), 3.57 – 3.48 (m, 2H), 3.43 (dd, J = 5.8, 3.8 Hz, 2H), 2.46 (dd, J = 16.2, 3.5 Hz, 1H), 2.36 (dd, J = 16.3, 8.7 Hz, 1H), 1.62 (dd, J = 7.0, 3.3 Hz, 6H), 1.60 – 1.54 (m, 1H), 1.53 – 1.48 (m, 1H);19F NMR P-633720-PC (471 MHz, CD3CN) δ -118.6;13C NMR (151 MHz, CD3CN) δ 171.9, 162.3 (d, J = 242.5 Hz), 141.7, 136.1, 135.5, 133.0 (d, J = 7.7 Hz), 132.9 (d, J = 3.2 Hz), 129.1, 122.6, 120.6, 119.8, 118.9, 116.1 (d, J = 21.5 Hz), 114.6, 112.8, 71.5, 68.2, 67.3, 67.2, 48.7, 46.6, 44.0, 42.5, 40.0, 21.81, 21.79; HRMS m / z (ESI+) found 481.2506 [M+H]+(C28H34FN2O4requires 481.2497 [M+H]+); Purity (99.8%@254 nm), (98.4%@220 nm), (100%@365 nm). tert-butyl 4-((3S,5R,E)-rel-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5- dihydroxyhept-6-enoyl)piperazine-1-carboxylate (Compound I-J)

[0188] tert-butyl 1H-indol-2-yl)-3,5- dihydroxyhept-6-enoyl)piperazine-1-carboxylate was synthesized according to general procedure A using tert-butyl piperazine-1-carboxylate (34 mg, 0.18 mmol, 4.0 eq) resulting inthe product as a pale-yellow powder (13.0 mg, 59%) after lyophilization. ^ ̅max (thin film) / cm−13384, 2981, 1734, 1458, 1420, 1167, 840, 743;1H NMR (600 MHz, CD3CN) δ 7.61 (ddd, J = 8.4, 0.8, 0.8 Hz, 1H), 7.47 (dt, J = 8.0, 1.0 Hz, 1H), 7.46 – 7.43 (m, 2H), 7.19 – 7.14 (m, 3H), 7.05 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.67 (dd, J = 16.1, 1.5 Hz, 1H), 5.74 (dd, J = 16.0, 5.7 Hz, 1H), 4.91 (hept, J = 7.0 Hz, 1H), 4.41 – 4.35 (m, 1H), 4.28 (s, 1H), 4.05 – 3.98 (m, 1H), 3.66 (s, 1H), 3.53 – 3.48 (m, 2H), 3.43 – 3.37 (m, 4H), 3.37 – 3.33 (m, 2H), 2.48 (dd, J = 16.2, 3.5 Hz, 1H), 2.38 (dd, J = 16.2, 8.7 Hz, 1H), 1.62 (d, J = 7.0 Hz, 3H), 1.62 (d, J = 7.0 Hz, 3H), 1.58 (ddd, J = 13.9, 9.2, 7.9 Hz, 1H), 1.50 (ddd, J = 13.9, 5.3, 3.7 Hz, 1H), 1.44 (s, 9H);19F NMR (471 MHz, CD3CN) δ -118.6;13C NMR (151 MHz, CD3CN) δ 171.9, 162.3 (d, J = 242.6 Hz), 155.4, 141.7, 136.1, 135.5, 133.0 (d, J = 7.8 Hz), 132.9 (d, J = 3.3 Hz), 129.1, 122.6, 120.6, 119.8, 118.9, 116.1 (d, J = 21.5 Hz), 114.6, 112.8, 80.4, 71.5, 68.2, 48.7, 46.0, 44.0, 41.9, 40.3, 28.5, 21.81, 21.79; HRMS m / z (ESI+) found 580.3190 [M+H]+(C33H43FN3O5requires 580.3181 [M+H]+); Purity (100%@254 nm), (100%@220 nm), (100%@365 nm). (3S,5R,E)-rel-N-((3R,5R,7R)-adamantan-1-yl)-7-(3-(4-fluorophenyl)-1-isopropyl-1H- indol-2-yl)-3,5-dihydroxyhept-6-enamide (Compound I-H) P-633720-PC

[0189] (3S,5R,E)-rel-N-( -1-isopropyl-1H- indol-2-yl)-3,5-dihydroxyhept-6-enamide was synthesized according to general procedure A using 1-adamantylamine (28 mg, 0.18 mmol, 4.0 eq) resulting in the product as a pale-yellow powder (8.0 mg, 32%) after lyophilization. ^ma̅x (thin film) / cm−13384, 1648, 1542, 1458, 1267, 1104, 837, 743;1H NMR (600 MHz, CD3CN) δ 7.61 (ddd, J = 8.4, 0.9, 0.9 Hz, 1H), 7.47 (ddd, J = 7.9, 1.0, 1.0 Hz, 1H), 7.46 – 7.43 (m, 2H), 7.21 – 7.13 (m, 3H), 7.05 (ddd, J = 7.9, 6.9, 0.9 Hz, 1H), 6.66 (dd, J = 16.0, 1.5 Hz, 1H), 6.18 (s, 1H), 5.72 (dd, J = 16.1, 5.8 Hz, 1H), 4.91 (hept, J = 7.0 Hz, 1H), 4.39 – 4.34 (m, 2H), 3.98 – 3.90 (m, 1H), 3.66 (d, J = 3.3 Hz, 1H), 2.21 (dd, J = 14.9, 4.1 Hz, 1H), 2.16 – 2.16 (m, 1H), 2.05 – 2.02 (m, 3H), 1.98 (m, 6H), 1.70 – 1.66 (m, 6H), 1.62 (d, J = 7.0 Hz, 3H), 1.62 (d, J = 7.0, 3H), 1.53 (ddd, J = 13.9, 9.0, 8.0 Hz, 1H), 1.47 (ddd, J = 13.9, 5.1, 3.8 Hz, 1H);19F NMR (471 MHz, CD3CN) δ -118.5;13C NMR (151 MHz, CD3CN) δ 172.4, 162.3 (d, J = 242.7 Hz), 141.7, 136.1, 135.4, 133.0 (d, J = 8.0 Hz), 132.9 (d, J = 3.3 Hz), 129.1, 122.6, 120.6, 119.8, 118.9, 116.1 (d, J = 21.3 Hz), 114.6, 112.8, 71.6, 68.7, 52.6, 48.7, 43.9, 43.8, 42.2, 37.1, 30.4, 21.8; HRMS m / z (ESI+) found 545.3186 [M+H]+(C34H42FN2O3requires 545.3174 [M+H]+); Purity (99.3%@254 nm), (100%@220 nm), (100%@365 nm). (3S,5R,E)-rel-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxy-N-(prop- 2-yn-1-yl)hept-6-enamide (Compound I-E)

[0190] (3S,5R,E)-rel-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxy-N- (prop-2-yn-1-yl)hept-6-enamide was synthesized according to general procedure A using propargylamine (12 µL, 0.18 mmol, 4.0 eq) resulting in the product as a pale-yellow powder (12.2 mg, 59%) after lyophilization. ^m̅ax (thin film) / cm−13351, 1653, 1541, 1458, 1345, 1220, P-633720-PC 839, 743;1H NMR (600 MHz, CD3CN) δ 7.61 (ddd, J = 8.4, 0.9 Hz, 1H), 7.47 (ddd, J = 8.0, 1.0, 1.0 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.21 – 7.14 (m, 3H), 7.05 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.85 (s, 1H), 6.66 (dd, J = 16.0, 1.5 Hz, 1H), 5.72 (dd, J = 16.1, 5.9 Hz, 1H), 4.91 (hept, J = 7.0 Hz, 1H), 4.40 – 4.33 (m, 1H), 4.03 (d, J = 3.3 Hz, 1H), 4.02 – 3.98 (m, 1H), 3.94 (ddd, J = 5.6, 2.6, 1.2 Hz, 2H), 3.58 (d, J = 3.5 Hz, 1H), 2.43 (t, J = 2.5 Hz, 1H), 2.30 (dd, J = 15.0, 3.9 Hz, 1H), 2.23 (dd, J = 15.0, 7.9 Hz, 1H), 1.62 (d, J = 7.0 Hz, 3H), 1.62 (d, J = 7.0 Hz, 3H), 1.58 – 1.47 (m, 2H);19F NMR (471 MHz, CD3CN) δ -118.6;13C NMR (151 MHz, CD3CN) δ 172.4, 162.3 (d, J = 242.7 Hz), 141.5, 136.1, 135.4, 133.0 (d, J = 7.8 Hz), 132.9 (d, J = 3.3 Hz), 129.1, 122.6, 120.6, 119.8, 119.1, 116.1 (d, J = 21.4 Hz), 114.7, 112.8, 81.3, 71.8, 71.7, 68.4, 48.7, 43.9, 43.5, 29.0, 21.8; HRMS m / z (ESI+) found 449.2237 [M+H]+(C27H30FN2O3requires 449.2235 [M+H]+); Purity (97.2%@254 nm), (98.5%@220 nm), (77.5%@365 nm) EXAMPLE 2. Compounds selectively inhibit VHL(-) cells.

[0191] A plate-based assay was established to measure IC50s for compounds disclosed herein. Each drug concentration was tested in triplicate over a 20 step range from 95.4 pM to 50 µM (each step a 1:1 dilution) prepared by BioMek FX or Echo 555 (Beckman Coulter). The total cell number was 1500 / well mix population VHL(-): VHL(+) = 2:1; DMSO concentration of 0.5% (v / v). To prepare the 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). These plates were next pinned by BioMek FX (Beckman Coulter) with 250 nL of the compound.50 µL 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. Data was exported to Prism (GraphPad) instead of CDD Vault to determine IC50.

[0192] Compounds I-A through I-J demonstrated IC50s less than 50 µM against VHL(-) cells. Compounds I-E, I-F, I-H and I-J showed IC50s less than 15 µM. Compounds I-E, I-H and I-J showed IC50s less than 10 µM. Compound I-E had an IC50 less than 5 µM. P-633720-PC

[0193] Compound II-A showed specific toxicity against VHL(-) cells. Example 4. Methods for Evaluating In vivo Activity.

[0194] A 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)). This system can be adapted to the ccRCC models described herein by engineering the VHL-KO cells to express the Cre recombinase and the VHL-WT cells to express 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 can be demonstrated in the RENCA metastatic RCC model to show that compounds disclosed herein inhibit VHL-KO ccRCC cells selectively.

[0195] 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). The CAM model has been widely 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). The model can be used to show that ten days after implanting 1:1 VHL-KO:VHL-WT at embryonic day 7, at embryonic day 17, compounds disclosed herein inhibit metastasis.

[0196] In a model that uses VHL-deleted (VHL-KO) cells from three VHL+ RCC models: RENCA, ACHN and mRCC primary cell line #22, VHL+ (VHL-WT) cells marked with RFP and VHL-KO cells marked with GFP and luciferase are used to track cells in vitro and in vivo. Tumor cells are implanted in the left kidney. Imaging after 4 weeks will show 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. This model can be used to evaluate the compounds disclosed herein as inhibitors of metastasis.

[0197] Mice are injected into the kidney with detectable VHL-KO and VHL-WT cells as described above. A compound disclosed herein at 10 mg / kg is administered orally, daily, and P-633720-PC the mice monitored for metastasis of the tumor. Suppression of metastasis by statin administration is found.

[0198] 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-633720-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 (I) or a pharmaceutical composition thereof: or a racemate,acceptable salt thereof, wherein R1and R2are each independently hydrogen, hydroxy, SOR3, or a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety; or wherein R1and R2taken together with the N to which they are bound form a 4, 5, 6, 7, 8 or 9 membered substituted or unsubstituted, saturated or unsaturated alicyclic or a saturated or unsaturated heterocyclic moiety; R3for each occurrence is independently hydrogen, -N(R4)2, aliphatic, aryl or heteroaryl moiety; and R4for each occurrence is independently hydrogen or a substituted or unsubstituted aliphatic moiety, substituted or unsubstituted phenyl, or a substituted or unsubstituted heterocyclic ring.

2. The method of claim 1, wherein at least one of R1and R2is not hydrogen.P-633720-PC 3. The method of claim 1, wherein R1and R2are independently selected from H or an optionally substituted, saturated or unsaturated C1-C6 alkyl.

4. The method of claim 1,wherein R1is H and R2is a saturated or unsaturated C1-C6alkyl, such as methyl, ethyl or 2-propargyl.

5. The method of claim 1, wherein R1is H and R2is C0-C6-adamantanyl.

6. The method of claim 1, wherein R1and R2taken together is an optionally substituted C1-C8 aliphatic such as n-propyl, n-butyl, n-pentyl, n-hexyl or n-heptyl.

7. The method of claim 1, wherein R1and R2together with the N to which they are bound form an optionally substituted 4, 5, 6, 7, 8 or 9 membered ring with 1-3 additional heteroatoms selected from N, O or S, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or azepinyl.

8. The method of claim 1,wherein R1and R2taken together is a piperazinyl N-substituted with an alkoxycarbonyl moiety such as tert-butoxycarbonyl.

9. The method of claim 1, wherein R1or R2independently is an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL-161, EEDi-5273 and MAK683 or any other optimal linker substituted with an E3 ligase recruiting moiety.

10. The method of claim 9, wherein the linker is a C1-C8alkyl or polyethylene glycol.

11. The method of claim 1, wherein the compound of Formula (I) is:P-633720-PCor an analogue thereof.

12. The method of claim 1, wherein the compounds of Formula (I) are capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.P-633720-PC 13. A method for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (IA) or a pharmaceutical composition thereof: or aor a pharmaceutically acceptable salt thereof, wherein X is O, NR2or CR3R4, R2is an unsubstituted or substituted aliphatic, alkoxycarbonyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted heteroaryl moiety; R3and R4are independently H or a substituted or unsubstituted C1-C8alkyl.

14. The method of claim 13, wherein R2is tert-butoxycarbonyl.

15. The method of claim 13, wherein is azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, azepinyl 16. The method of claim 13, wherein R2, R3or R4may be an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methylP-633720-PC bestatin, ATRA, LCL-161, EEDi-5273 and MAK683 or any other optimal linkers substituted with an E3 ligase recruiting moiety.

17. The method of claim 16, wherein the linker is a C1-C8alkyl or polyethylene glycol.

18. The method of claim 13, wherein compounds of Formula (IA) are capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.

19. The method of claim 13, wherein the compound of Formula (IA) is:P-633720-PC 20. The method of any one of claims 1-19, wherein the compound of any one of Formulas (I) or (IA), or compounds I-B to I-J does not have substantial HMG-CoA reductase activity.

21. A method for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula II-A below or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof: . or an analogue22. The method of claim 21, wherein Compound II-A is capable of inhibiting the metastatic driver VHL(-) cells and suppressing their EV-mediated signaling, inhibiting or preventing metastasis.

23. A method for inhibiting metastasis of a solid tumor in a subject comprising administering to the subject a compound of Formula (III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof:P-633720-PC (III) wherein X is a bond, O, NH or an amino acid residue; R5is selected from an amino acid residue, a fibric acid residue, guanidine, tetrazolyl, agmatine, an amino-containing compound; a lower alkyl terminating in ΟΝΟ, (ONO2)p, guanidine; a resveratrol residue; an imidazoline receptor agonist residue, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl or a substituted or unsubstituted heterocycle; and p is 1, 2 or 3.

24. The method of claim 23, wherein the amino acid residue is alanine, asparagine, N-β- trityl- asparagine, aspartic acid, aspartic acid-β-t-butyl ester, arginine, Ng-Mtr-arginine, cysteine, S-trityl-cysteine, glutamic acid, glutamic acid-γ-t-butyl ester, glutamine, N-γ-trityl- glutamine, glycine, histidine, Nim-trityl-histidine, isoleucine, leucine, lysine, Nε-Boc-lysine, methionine, phenylalanine, proline, serine, O-t-butyl-serine, threonine, tryptophan, Nin-Boc- tryptophan, tyrosine, valine, sarcosine, L-alanine, chloro-L-alanine, 2-aminoisobutyric acid, 2- (methylamino)isobutyric acid, D,L-3-aminoisobutyric acid, (R)- (-)-2 amino isobutyric acid, (S)-(+)-2-aminoisobutyric acid, D-leucine, L-leucine, D- norvaline, L-norvaline, L-2-amino-4- pentenoic acid, D-isoleucine, L-isoleucine, D- norleucine, 2,3-diaminopropionic acid, L- norleucine, D,L-2-aminocaprylic acid, β- alanine, D,L-3-aminobutyric acid, 4-aminobutyric acid, 4-(methylamino)butyric acid, 5- aminovaleric acid, 5-aminocaproic acid, 7- aminoheptanoic acid, 8-aminocaprylic acid, 11-aminodecanoic acid, 12-aminododecanoic acid, carboxymethoxylamine, D-serine, D-homoserine, L-homoserine, D-allothreonine, L- allothreonine, D-threonine, L-threonine, D,L-4-amino-3-hydroxybutyric acid, D-,L-3- hydroxynorvaline, (3S,4S)-(-)-statine, 5-hydroxy-D,L-lysine, 1-amino-1- cyclopropanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid, 1-amino-1- cyclohexanecarboxylic acid, 5-amino-l,3- cyclohexadiene-1-carboxylic acid, 2-amino-2- norbornanecarboxylic acid, (S)-(-)-2- azetidinecarboxylic acid, cis-4-hydroxy-D-proline, cis- 4-hydroxy-L-proline, trans-4- hydroxy-L-proline, 3,4-dehydro-D,L-proline, 3 ,4-dehydro-L- proline, D-pipecolinic acid, L-pipecolinic acid, nipecotic acid, isonipecotic acid, mimosine, 2,3- diaminopropionic acid, D,L-2,4-diaminobutyric acid, (S)-(+)-diaminobutyric acid, D- ornithine, L-ornithine, 2-methylornithine, N-ε-methyl-L-lysine, N-methyl-D-aspartic acid,P-633720-PC D,L-2-methylglutamic acid, D,L-2-aminoadipic acid, D-2-aminoadipic acid, L-2- aminoadipic acid, (+ / -)-3-aminoadipic acid, D-cysteine, D-penicillamine, L- penicillamine, D,L- homocysteine, S-methyl-L-cysteine, L-methionine, D-ethionine, L-ethionine, S- carboxymethyl-L-cysteine, (S)-(+)-2-phenylglycine, (R)-(-)-2-phenylglycine, N- phenylglycine, N-(4-hydroxyphenyl)glycine, D-phenylalanine, thienylalanine, (S)- (- )indoline-2-carboxylic acid, α-methyl,D,L-phenylalanine, β-methyl-D,L-phenylalanine, D- homophenylalanine, L-homophenylalanine, D,L-2-fluorophenylglycine, D,L-2- fluorophenylalanine, D,L-3-fluorophenylalanine, D,L-4-fluorophenylalanine, D,L-4- chlorophenylalanine, L-4-chlorophenylalanine, 4-bromo-D,L-phenylalanine, 4-iodo-D- phenylalanine, 3,3’,5-triiodo-L-thyronine, (+)-3,3’,5-triiodo-L-thyronine, D-thyronine, L- thyronine, D,L-m-tyrosine, D-4-hydroxyphenylglycine, D-tyrosine, L-tyrosine, O- methyl-L- tyrosine, 3-fluoro-D,L-tyrosine, 3-iodo-L-tyrosine, 3-nitro-L-tyrosine, 3,5- diiodo-L-tyrosine, D,L-dopa, L-dopa, 2,4,5-trihydroxyphenyl-D,L-alanine, 3-amino-L- tyrosine, 4-amino-D- phenylalanine, 4-amino-L-phenylalanine, 4-amino-D,L- phenylalanine, 4-nitro-L- phenylalanine, 4-nitro-D,L-phenylalanine, 3,5-dinitro-L-tyrosine, D,L-α-methyltyrosine, L-α- methyltyrosine, (-)-3-(3,4-dihydroxyphenyl)-2- methyl-L-alanine, D,L-threo-3-phenylserine, trans-4-(aminomethyl)cyclohexane carboxylic acid, 4-(aminomethyl)benzoic acid, D,L-3- aminobutyric acid, 3- aminocyclohexane carboxylic acid, cis-2-amino-l-cyclohexane carboxylic acid, γ-amino- β-(p-chlorophenyl) butyric acid (baclofen), D,L-3- aminophenylpropionic acid, 3-amino- 3-(4-chlorophenyl) propionic acid, 3-amino-3-(2- nitrophenyl)propionic acid, and 3- amino-4,4,4-trifluorobutyric acid.

25. The method of claim 23, wherein the fibric acid residue is fenofibrate, beclofibrate, benzafibrate, bezafibrate, binifibrate, ciprofibrate, clinofϊbrate, clofibrate, ethyl 2-(p- chlorophenoxy)-2-methyl-propionate, etofϊbrate, fenofibrate, ((2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester), gemcabene, gemfibrozil, 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, lifϊbrol, GW 7647, BM 170744 or LY518674.

26. The method of claim 23, wherein the amino-containing compound is agmatine, aminoguanidine, guanidine, tetrazole, amino-tetrazole, or an amino acid residue as described above.

27. The method of claim 23, wherein the resveratrol residue is ((E)-5-(4- hydroxystyryl)benzene-l,3-diol).P-633720-PC 28. The method of claim 23, wherein the imidazoline receptor agonist residue is LNP509, S-21663, S-22068 or S-23515.

29. The method of claim 23, wherein the compound of Formula (III) is (3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-N-(4-guanidinobutyl)-3,5-dihydroxyhept-6- enamide, (3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5- dihydroxy-N-(2H- tetrazol-5-yl)hept-6-enamide, (3S, 5R,E)-7-(3-(4-fluoro phenyl )-1-isopropyl-1 H-indol-2-yl) - 3,5-dihydroxy-N-((E)-N’-methylcarbamimidoyl)hept-6-en amide; (3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1 H-indol-2-yl)-N-((S)-1-(4-guanidinobutylamino)-1 -oxopropan- 2-yl)-3,5-dihydroxyhept-6-enamide, 2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl- 1H- indol-2-yl)-3,5-dihydroxyhept-6-enoyl)h yd razinecarboximidamide; (S)-2-((3S,5R,E)-7-(3- (4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)propanoic acid; (R)-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enamido)propanoic acid; (R,S)-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2- yl)-3,5-dihydroxyhept-6-enamido)propanoic acid; (S)-6-amino-2-((3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)hexanoic acid; (R)- 6-amino-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1-iso propyl-1H-indol-2-yl)-3,5-dihydroxyhept- 6-enamido)hexanoic acid; (R, S)-6-amino-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl- 1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)hexanoic acid; S)-2-((3S,5R,E)-7-(3-(4- fluorophenyl)-1 -isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)-5- guanidinopentanoic acid; (R)-2-((3S,5R,E)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2- yl)-3,5-dihydroxyhept-6-enamido)-5-guanidinopentanoic acid; (RS)-2-((3S,5R,E)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamido)-5- guanidinopentanoic acid; (3S,5R,E)-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoyloxy) methyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate; (3S, 5R ,E)- 3-hydroxy-5-(4-hydroxystyryl)phenyl-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2- yl)-3,5-dihydroxyhept-6-enoate; (3S,5R,E)-N-(5-((2-bromophenoxy)methyl)-4,5- dihydrooxazol-2-yl)-7-(3-(4-fluorophenyl)-1 -isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enamide; (3S,5R,E)-Λ / -(dicyclopropylmethyl)-Λ / -(2,3-dimethyl-3,4-dihydro-2H-pyrrol-5- yl)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enamide; (3S,5R,E)-1-(2-(1-(2,4-dichlorobenzyl)-4-methylpiperazin-2-yl) -4,5-dihydro-1H-imidazol-1- yl)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl) -3,5-dihydroxyhept-6-en-1-one; or (3S,5R,E)-1-(2-(1,4-diisopropylpiperazin-2-yl)-4,5-dihydro-1H-imidazol-1-yl)-7-(3-(4- fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-en-1-one.P-633720-PC 30. The method of any one of claims 1-29, wherein the solid tumor comprises a VHL mutation.

31. The method of any one of claims 1-29, wherein the solid tumor comprises a VHL mutation and wild type VHL.

32. The method of any one of claims 1-29, wherein the solid tumor is a kidney tumor.

33. The method of claim 32, wherein the kidney tumor is renal cell carcinoma or clear cell renal cell carcinoma (ccRCC).

34. The method of any one of claims 1-29, wherein the solid tumor is breast cancer.

35. The method of any one of claims 1-29, wherein the breast tumor is triple negative breast cancer (TNBC).

36. The method of any one of claims 1-29, wherein the tumor is prostate cancer.

37. The method of claim 36, wherein the prostate cancer is neuroendocrine prostate cancer (NEPC).

38. 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 compound of Formula (I), Formula (I-A) or Formula (III), or Compound I-B to I-J or II-A, an analogue thereof, or a racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

39. 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; andP-633720-PC b. upon detection of spread or high histologic score, treating the patient with a compound of Formula (I), Formula (I-A) or Formula (III), or Compound I-B to I-J or II-A, an analogue thereof, or a racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

40. The method of claim 38 or 39, wherein the solid tumor is a kidney tumor.

41. The method of claim 40 wherein the spread comprises a high grade histologic criterion or spread of the tumor beyond Gerota fascia of the kidney.

42. 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 compound of Formula (I), Formula (I-A) or Formula (III), or Compound I-B to I-J or II-A, an analogue thereof, or a racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

43. The method of claim 42 wherein the activation of the hypoxia program is due to mutation or loss of VHL expression.

44. 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 compound of Formula (I), Formula (I-A) or Formula (III), or Compound I-B to I-J or II-A, an analogue thereof, or a racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

45. The method of claim 44 wherein extracellular vesicles are detected in a ccRCC patient.P-633720-PC 46. The method of claim 44 wherein the bodily fluid is blood or urine.

47. 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 compound of Formula (I), Formula (I-A) or Formula (III), or Compound I-B to I-J or II-A, an analogue thereof, or a racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

48. A compound of Formula (I):or a or or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently hydrogen, hydroxy, SOR3, or a substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl moiety;P-633720-PC or wherein R1and R2taken together with the N to which they are bound form a 4, 5, 6, 7, 8 or 9 membered substituted or unsubstituted, saturated or unsaturated alicyclic or a saturated or unsaturated heterocyclic moiety; R3for each occurrence is independently hydrogen, -N(R4)2, aliphatic, aryl or heteroaryl moiety; and R4for each occurrence is independently hydrogen or a substituted or unsubstituted aliphatic moiety, substituted or unsubstituted phenyl, or a substituted or unsubstituted heterocyclic ring.

49. The compound of claim 48, wherein at least one of R1and R2is not hydrogen.

50. The compound of claim 48, wherein R1and R2are independently selected from H or an optionally substituted, saturated or unsaturated C1-C6 alkyl.

51. The compound of claim 48, wherein R1is H and R2is a saturated or unsaturated C1-C6 alkyl, such as methyl, ethyl or 2-propargyl.

52. The compound of claim 48, wherein R1is H and R2is C0-C6-adamantanyl.

53. The compound of claim 48, wherein R1and R2taken together is an optionally substituted C1-C8 aliphatic such as n-propyl, n-butyl, n-pentyl, n-hexyl or n-heptyl.

54. The compound of claim 48, wherein R1and R2together with the N to which they are bound form an optionally substituted 4, 5, 6, 7, 8 or 9 membered ring with 1-3 additional heteroatoms selected from N, O or S, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or azepinyl.

55. The compound of claim 48, wherein R1and R2taken together is a piperazinyl N- substituted with an alkoxycarbonyl moiety such as tert-butoxycarbonyl.

56. The compound of claim 48, wherein R1or R2independently is an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL-161, EEDi-5273 and MAK683 or any other optimal linker substituted with an E3 ligase recruiting moiety.P-633720-PC 57. The compound of claim 48, wherein the linker is a C1-C8alkyl or polyethylene glycol.

58. The compound of claim 48, wherein the compound of Formula (I) is:P-633720-PC 59. A compound of Formula (IA): or aor a pharmaceutically acceptable salt thereof, wherein X is O, NR2or CR3R4, R2is an unsubstituted or substituted aliphatic, alkoxycarbonyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted heteroaryl moiety; R3and R4are independently H or a substituted or unsubstituted C1-C8alkyl.

60. The compound of claim 59, wherein R2is tert-butoxycarbonyl.

61. The compound of claim 59, wherein is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl62. The compound of claim 59, wherein R2, R3or R4may be an E3 ligase ligand, such as VH032, VH101, VH298, MZ1, PROTAC_RIPK2, PROTAC_ERRα, ARD-266, VZ185, ACBI1, thalidomide, dBET1, dFKBP12, QCA570, PROTAC6, ZNL-02-096, d9A-2, methyl bestatin, ATRA, LCL-161, EEDi-5273 and MAK683 or any other optimal linkers substituted with an E3 ligase recruiting moiety.P-633720-PC 63. The compound of claim 59, wherein the linker is a C1-C8alkyl or polyethylene glycol.

64. The compound of claim 59, wherein the compound of Formula (IA) is:

65. A pharmaceutical composition comprising a compound of any one of claims 48-64, and a pharmaceutically acceptable buffer, excipient, diluent, vehicle or carrier.

Images