WO2019222134A1 - Coup-tfii receptor inhibitors and methods using same - Google Patents

Abstract

The invention relates in one aspect to the identification of compounds that inhibit COUP-TFII activity. In certain embodiments, the compounds of the invention have submicromolar activity against COUP-TFII. In other embodiments, the compounds of the invention have no measurable effect on COUP-TFII-negative cells. In yet other embodiments, the compounds of the invention inhibiting prostate tumor growth in a subject without significant effect on the subject's body weight.

Description

TITLE OF THE INVENTION

COUP-TFII Receptor Inhibitors and Methods Using Same

CROSS REFERENCE TO RELATED APPLICATION

The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/671,095, filed May 14, 2018, which is hereby incorporated by reference herein in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR

DEVELOPMENT

This invention was made with government support under grant number DK45641 and grant number DK071662 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

The chicken ovalbumin upstream promoter transcriptional factors (COUP-TFs) belong to the steroid/thyroid hormone receptor superfamily. At this point in time, the natural ligands of the COUP-TFs have not yet been identified, and thus COUP-TFs are referred to as orphan nuclear receptors.

In vertebrates, two COUP-TF homologues have been identified: COUP-TFI (EAR3) and COUP-TFII (ARP-l), which are also known as nuclear receptor 2 family 1 and 2 (NR2F1 and 2). The COUP-TF family has a highly conserved modular structure that is composed of an N- terminal DNA binding domain (DBD) and a putative C-terminal ligand-binding domain (LBD). The COUP-TF DBD and LBD share 98% and 96% amino acid homology, respectively. Both receptors were highly conserved during evolution - human COUP-TFs share almost 95% homology with other vertebrate and invertebrate homologous proteins, suggesting that COUP- TFs could be primordial members of the NR family.

COUP-TFs play important roles in various developmental processes. Both COUP-TFs are expressed during early embryonic development in mice, and their expression is reduced shortly after birth. COUP-TFI is mainly expressed in the developing peripheral and central nervous systems, while COUP-TFII is detected in the mesenchyme of various organs and the developing vasculature. COUP-TFI deletion in mice results in perinatal lethality, mainly due to defects in central nervous system. In contrast, COUP-TFII null mice exhibit vascular

abnormalities in the head, spine and heart, and die around embryonic day 10 (E10). Consistent with these results, studies using exome sequencing in human patients revealed that COUP-TFI mutations are associated with cerebral visual impairment (CVI), while variants of COUP-TFII cause congenital heart defect (CHD). These results highlight the crucial role of COUP-TFI in neuronal development and COUP-TFII in organogenesis.

Because COUP-TFs are expressed at very low basal levels in adult mice, deletion of COUP-TFs in adults yielded no discernible phenotypes, except in reproduction with respect to the loss of COUP-TFII. In contrast, emerging evidence suggests that ectopic expression of COUP-TFs, specifically COUP-TFII, plays a critical role in the development of diseases, such as cancer and heart disease.

COUP-TFII plays important roles in angiogenesis and lymphangiogenesis, both of which are required for tumor progression, invasion, and metastasis. The blood and lymphatic vessels deliver nutrients and oxygen essential for tumor growth and provide access for metastases to distant sites. Without persistent vessel formation, tumor cells undergo apoptosis or become necrotic.

COUP-TFII is highly expressed in the tumor vasculature of different types of cancers. In the tumor microenvironment, COUP-TFII is essential for angiogenesis by regulating at least three independent signaling pathways: 1) COUP-TFII shuts down the expression of VEGFR1, a decoy receptor, to enhance VEGF-induced VEGFR2 signaling for angiogenesis; 2) it activates E2F1 expression and various cell cycle regulators in the endothelial cells to enhance the proliferation of endothelial cells; and 3) it regulates the expression of the paracrine signal, Angl, in smooth muscle cells to enhance endothelial cell proliferation and differentiation. Consistently, tumors are much smaller, with lower blood vessel density, and have less metastasis in the COUP-TFII null background as compared to its wild type counterpart. Thus, COUP-TFII is a central regulator for both tumor angiogenesis and lymphangiogenesis by regulating

VEGF/VEGFR, Ang-l/Tie2 and other pathways involved in manipulating the tumor

microenvironment. This suggests that COUP-TFII is a viable target for anticancer interventions.

COUP-TFII also promotes prostate cancer progression by directly regulating tumor growth. Expression levels of COUP-TFII in prostate cancer cells correlate well with clinical stages, lymph node status and histological grades in prostate cancer patients, indicating the dysregulation of COUP-TFII expression in human prostate cancer progression. Consistent with this notion, the expression of a large number of genes used as diagnostic markers for prostate cancer metastasis are among the downstream target genes of COUP-TFII, as identified in a microarray analyses. Their expression correlates with the expression of COUP-TFII, where high expression indicates poor prognosis and low expression correlates with good outcomes.

Conditional knockout of COUP-TFII in prostate cancer cells attenuated prostate tumorigenesis, while ectopic expression of COUP-TFII in prostate epithelial cells accelerated tumor progression in a PTEN heterozygous knockout model. Importantly, overexpression of COUP-TFII in the prostate epithelial cells rendered the well confined non-aggressive prostate tumors of the PTEN model very aggressive and locally and distally invasive.

In addition, increased COUP-TFII expression has been observed in different types of human tumors, including bladder carcinomas, brain tumors, diffuse large B-cell lymphoma, acute myeloid leukemia, and esophageal adenocarcinomas. COUP-TFII is a member of the nuclear receptor superfamily, and its activity can in principle be inhibited using a small molecule inhibitor. In fact, development of COUP-TFII inhibitors should potentially benefit the cancer patients in both tumor growth and metastasis.

Furthermore, there is a need in the art for novel compounds that can bind to and inhibit the activity of COUP-TFII. Such COUP-TFII inhibitors of can be used to treat or prevent certain types of cancer, such as prostate cancer. The present invention addresses this unmet need.

BRIEF SUMMARY OF THE INVENTION

The invention provides certain compounds, or a salt, solvate, enantiomer, and/or tautomer thereof, as well as pharmaceutical compositions comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier.

The invention further provides a method of treating, ameliorating, and/or preventing prostate cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the invention.

The invention further provides a method of inhibiting, preventing, or reducing the rate of angiogenesis in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the invention. The invention further provides a method of inhibiting, preventing, or reducing the rate of lymphangiogenesis in a subject, the method comprising administering to the subject a

therapeutically effective amount of at least one compound of the invention.

The invention further provides a method of inhibiting, preventing, or reducing the rate of prostate tumor metastasis in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating the invention, there are depicted in the drawings certain embodiments of the invention. However, the invention is not limited to the precise arrangements and instrumentalities of the embodiments depicted in the drawings.

FIGs. 1 A-1D illustrate the finding that prostate cancer growth is inhibited by an exemplary COEIP-TFII receptor inhibitor of the invention (VCT-100). Tumors (PC cells) were grown in mice for 12 days (to a diameter of about 0.5 mm) before the animals were treated with compound (either 5 mg/kg (low dose, or L) or 15 mg/kg (high dose, or H)) or vehicle (DMSO). FIG. 1 A comprises images of ex vivo induced prostate tumors by PC3 cells in mice. The results indicated that VCT-100 treatment inhibited prostate tumor growth in mice. FIG. 1B comprises a graph progression of tumor growth by measuring tumor volume during 5 weeks of treatment with vehicle or VCT-100. FIG. 1C comprises a graph illustrating tumor weight of dissected tumors from mice after 5 weeks of treatment with vehicle or VCT-100. FIG. 1D comprises a graph illustrating body weight as a function of weeks of treatment with vehicle or VCT-100. Taken together, the results present in FIGs. 1 A-1D indicate that exemplary COEIP-TFII inhibitor, VCT-100, is effective in inhibiting prostate cancer progression without adverse effect on mice’s general health as indicated by their body weight.

FIGs. 2A-2C illustrate the finding that an exemplary compound of the invention (VCT- 100) inhibits angiogenesis and COEIP-TFII activity. FIG. 2A comprises a graph illustrating that treatment of mice with VCT-100 inhibited COEIP-TFII activity as measured by the expression of its negative target gene, SERPINEE FIG. 2B comprises a series of images illustrating that exemplary COEIP-TFII inhibitor, VCT-100, inhibited the tumor angiogenesis as measured by vessel density in prostate tumor. FIG. 2C comprises a graph illustrating quantitative measurement of vessel number in prostate tumor. Taken together, results in FIGs. 2A-2C indicate that VCT-100 indeed inhibited activity and function of COUP-TFII in angiogenesis.

FIGs. 3A-3D illustrate effectiveness of VCT-100 derivatives ,VCT-l to VCT-10, in inhibiting COUP-TFII activity. FIG. 3 A comprises a bar graph illustrating EC50 values of VCT- 100 derivatives, VCT-l to VCT-10, in inhibiting COUP-TFII activity in a transfection assay. FIG. 3B comprises a bar graph illustrating ability of VCT-100 derivatives, VCT-l to VCT-10, in inhibiting COUP-TFII activity in its negative target gene, SERPINE1 expression. FIG. 3C comprises a bar graph illustrating ability of VCT-100 derivatives, VCT-l to VCT-10, in inhibiting COUP-TFII activity on its positive target gene, FOXM1 expression. FIG. 3D comprises a bar graph illustrating ability of VCT-100 derivatives, VCT-l to VCT-10, in inhibiting COUP-TFII activity on another positive target gene, SLC39A6 expression. These results in FIGs. 3A-3D illustrate that certain derivatives of VCT-100 have better inhibitory ability, with EC50 less than 0.5mM, as compared to the parent compound, and can be used for treatment of prostate cancer.

FIGs. 4A-4B illustrate a correlation of inhibitors contemplated in the present invention (exemplified ina non-limiting manner with VCT-8) and COUP-TFII regulated genes. NES represents Normalized Enrichment Score. These data show a strong correlation between VCT-8 inhibited genes and COUP-TFII target genes, suggesting in a non-limiting manner that VCT-8 works through COUP-TFII to modulate gene expression. Data are analyzed from RNAseq data opf VCT8 and COUP-TFII knockdown.

FIG. 5 illustrates DMPK results for the COUP-TFII inhibitor VCT-8. which was administered p.o. (orally) in the mouse. The drug metabolism pharmacokinetics data indicates that VCT-8 is stable in the blood stream of mice for more than 24 hour.

FIG. 6 illustrates that inhibitors of the invention interact with COUP-TFII. Compounds of the invention were found to bind to Flag labeled COUP-TFII. Biotin labeled VCT compound was incubated with COUP-TFII expressed in 293T cells (top left) or PC3 cells (top right).

Binding was then measured by pull down with streptavidin beads and analyzed by western blot analysis probed with antibody to Flag (bottom). Results indicate that all active compounds bind to COUP-TFII.

FIG. 7 illustrates a western blot for an experiment wherein binding of a non-limiting compound of the invention (VCT-8) with various proteins having structure similar to COUP- TFII was interrogated. Results indicate that VCT-8 binds specifically to COUP-TFII and less to COUP-TFI, but not to the remaining proteins tested.

FIG. 8 illustrates the finding that compounds of the invention interact directly with the COUP-TFII ligand binding domain (LBD, top). Compounds of the invention (as exemplified by VCT-8) bind to the COUP-TFII ligand binding domain and to a purified COUP-TFII ligand binding domain preparation, suggesting that VCT-8 binds directly to the ligand binding domain of COUP-TFII.

FIG. 9 illustrates that certain amino acids on COUP-TFII ligand binding pocket surface are important for compound interaction. Amino acids of importance were identified in certain embodiments using an alanine scan of Flag-CII (bottom left) and are shown in bold in the schematic of the protein (bold). The graph (bottom right) shows that mutation of these pocket amino acids reduce the ability of illustrative VCT-8 to inhibit COUP-TFII activity as measured by luciferase assays. These results indicate that VCT-8 bind around the ligand pocket area.

FIG. 10 illustrates the finding that compounds of the invention inhibit prostate cancer cell growth. Illustrative VCT-8 inhibits cell growth of various prostate cancer cells, including AR positive (LNCaP), AR negative (PC3 and DU145), castration resistant (C4-2 and abl). and ARv7 dependent (22Rvl) cells.

FIG. 11 illustrates the finding that compounds of the invention inhibit growth of prostate cancer PDX Cells in an organoid model. Two VCT-8 related compounds, VCT-32 and VCT-35, have little activity in inhibiting COUP-TFII activity, serving as negative controls in these organoid assay.

FIG. 12 illustrates inhibition of prostate cancer growth by COUP-TFII inhibitor VCT-8, as demonstrated by a LNCaP cell induced xenograft model. Body weight was not altered after VCT-8 treatment (bottom right), indicating that VCT-8 has no major toxicity to animals.

FIG. 13 illustrates that the compounds of the invention (as exemplified in a non-limiting manner by VCT-8) inhibit tumor proliferation and angiogenesis in an animal model, as indicated by reduction of the expression of endothelial cell marker CD31 (top two panels). VCT-8 also inhibits cell growth as indicated by Ki67 expression, a marker of cell growth (lower two panels).

FIG. 14 illustrates that the compounds of the invention (as exemplified in a non-limiting manner by VCT-8) inhibit prostate cancer growth, as demonstrated in xenograft mouse models derived from either castration resistant LNCaP-abl or ARv7 dependent 22Rvl cells. FIG. 15 illustrates that the compounds of the invention (as exemplified in a non-limiting manner by VCT-8) inhibit prostate cancer growth, as demonstrated in a xenograft mouse model derived from AR negative PC3 cells.

FIG. 16 illustrates that the compounds of the invention (as exemplified in a non-limiting manner by VCT-8) inhibit prostate cancer metastasis. Using a tail vein injection metastasis model, VCT-8 inhibits tumor metastasis to bone and lung.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates in one aspect to the identification of compounds that inhibit COUP- TFII activity. In certain embodiments, the compounds of the invention have submicromolar activity against COUP-TFII. In other embodiments, the compounds of the invention inhibit target gene expression, cell growth, and endothelial cell sprouting (as determined using an angiogenesis assay). In yet other embodiments, the compounds of the invention have no measurable effect on COUP-TFII-negative cells. In yet other embodiments, the compounds of the invention inhibiting tumor growth in a subject without significant effect on the subject’s body weight.

In certain embodiments, the compounds of the invention treat, ameliorate, and/or prevent prostate cancer in a subject. In other embodiments, the compounds of the invention inhibit, prevent, or reduce the rate of angiogenesis in a subject. In yet other embodiments, the compounds of the invention inhibit, prevent, or reduce the rate of lymphangiogenesis in a subject. In yet other embodiments, the compounds of the invention inhibit, prevent, or reduce the rate of tumor metastasis in a subject. In yet other embodiments, the tumor comprises prostate cancer.

Definitions

As used herein, each of the following terms has the meaning associated with it in this section.

Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in animal pharmacology, pharmaceutical science, separation science, and organic chemistry are those well-known and commonly employed in the art.

As used herein, the articles“a” and“an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example,“an element” means one element or more than one element.

As used herein, the term“about” is understood by persons of ordinary skill in the art and varies to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term“about” is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

In one aspect, the terms“co-administered” and“co-administration” as relating to a subject refer to administering to the subject a compound of the invention or salt thereof along with a compound that may also treat any disease or disorder contemplated herein and/or with a compound that is useful in treating other medical conditions but which in themselves may cause or facilitate any disease or disorder contemplated herein. In certain embodiments, the co- administered compounds are administered separately, or in any kind of combination as part of a single therapeutic approach. The co-administered compound may be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution.

As used herein, a“disease” is a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject’s health continues to deteriorate.

As used herein, a“disorder” in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject’s state of health.

As used herein, the term“ED₅₀” refers to the effective dose of a formulation that produces 50% of the maximal effect in subjects that are administered that formulation. As used herein, an“effective amount,”“therapeutically effective amount” or “pharmaceutically effective amount” of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered.

“Instructional material,” as that term is used herein, includes a publication, a recording, a diagram, or any other medium of expression that can be used to communicate the usefulness of the composition and/or compound of the invention in a kit. The instructional material of the kit may, for example, be affixed to a container that contains the compound and/or composition of the invention or be shipped together with a container that contains the compound and/or composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the compound cooperatively. Delivery of the instructional material may be, for example, by physical delivery of the publication or other medium of expression communicating the usefulness of the kit, or may alternatively be achieved by electronic transmission, for example by means of a computer, such as by electronic mail, or download from a website.

As used herein, the term“pharmaceutical composition” or“composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

As used herein, the term“pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the invention, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the term“pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.

Each carrier must be“acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the subject. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein,“pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are

physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions. The“pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

As used herein, the language“pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and clathrates thereof.

The term“prevent,”“preventing” or“prevention,” as used herein, means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences. Disease, condition and disorder are used interchangeably herein.

By the term“specifically bind” or“specifically binds,” as used herein, is meant that a first molecule preferentially binds to a second molecule ( e.g ., a particular receptor or enzyme), but does not necessarily bind only to that second molecule. As used herein, a“subject” may be a human or non-human mammal or a bird. Non human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In certain embodiments, the subject is human.

The term“treat,”“treating” or“treatment,” as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject.

As used herein, the term“alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated {i.e., Ci-Cio means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, /er/-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Most preferred is (Ci-C₆)alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, «-pentyl, «-hexyl and

cyclopropylmethyl.

As used herein, the term“alkylene” by itself or as part of another substituent means, unless otherwise stated, a straight or branched hydrocarbon group having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups, wherein the group has two open valencies. Examples include methylene, 1, 2-ethylene, l,l-ethylene, 1,1 -propylene, 1, 2-propylene and 1,3 -propylene.

As used herein, the term“cycloalkyl,” by itself or as part of another substituent means, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e., C₃-C₆ means a cyclic group comprising a ring group consisting of three to six carbon atoms) and includes straight, branched chain or cyclic substituent groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Most preferred is (C3-C₆)cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term“alkenyl,” employed alone or in combination with other terms, means, unless otherwise stated, a stable mono-unsaturated or di-unsaturated straight chain or branched chain hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, l,3-pentadienyl, l,4-pentadienyl, and the higher homologs and isomers. A functional group representing an alkene is exemplified by - CH₂-CH=CH_2. As used herein, the term“alkynyl,” employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched chain hydrocarbon group with a triple carbon-carbon bond, having the stated number of carbon atoms. Non-limiting examples include ethynyl and propynyl, and the higher homologs and isomers. The term“propargylic” refers to a group exemplified by -CH₂-CºCH. The term“homopropargylic” refers to a group exemplified by -CH₂CH₂-CºCH. The term“substituted propargylic” refers to a group exemplified by -CR₂-CºCR, wherein each occurrence of R is independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, with the proviso that at least one R group is not hydrogen. The term“substituted homopropargylic” refers to a group exemplified by -CR₂CR₂-CºCR, wherein each occurrence of R is independently H, alkyl, substituted alkyl, alkenyl or substituted alkenyl, with the proviso that at least one R group is not hydrogen.

As used herein, the term“substituted alkyl,”“substituted cycloalkyl,”“substituted alkenyl” or“substituted alkynyl” means alkyl, cycloalkyl, alkenyl or alkynyl, as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, alkoxy, tetrahydro-2-H-pyranyl, -NH₂, -N(CH₃)₂, (l-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=0)0H, trifluoromethyl, -CºN, -C(=0)0(Ci-C₄)alkyl, - C(=0)NH₂, -C(=0)NH(Ci-C₄)alkyl, -C(=0)N((Ci-C₄)alkyl)₂ -S0₂NH₂, -C(=NH)NH₂, and - N0₂, preferably containing one or two substituents selected from halogen, -OH, alkoxy, -NH₂, trifluoromethyl, -N(CH₃)₂, and -C(=0)0H, more preferably selected from halogen, alkoxy and - OH. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2- carboxycyclopentyl and 3-chloropropyl. In certain embodiments, the substituted alkyl is not substituted with a hydroxy group.

As used herein, the term“alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, l-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred are (Ci-C₃)alkoxy, such as, but not limited to, ethoxy and methoxy.

As used herein, the term“halo” or“halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. As used herein, the term“heteroalkyl” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quatemized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -O-CH₂-CH₂-CH₃, -CH₂-CH₂-CH₂-OH, -CH₂-CH₂-NH- CH₃, -CH₂-S-CH₂-CH₃, and -CH₂CH₂-S(=0)-CH₃. Up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃, or -CH₂-CH₂-S-S-CH₃.

As used herein, the term“heteroalkenyl” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH- 0-CH₃, -CH=CH-CH₂-OH, -CH₂-CH=N-OCH₃, -CH=CH-N(CH₃)-CH₃, and -CH₂-CH=CH- CH₂-SH.

As used herein, the term“aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n+2) delocalized p (pi) electrons, where n is an integer.

As used herein, the term“aryl,” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. Preferred are phenyl and naphthyl, most preferred is phenyl.

As used herein, the term“aryl-(Ci-C₃)alkyl” means a functional group wherein a one to three carbon alkylene chain is attached to an aryl group, e.g ., -CH₂CH₂-phenyl or -CH₂-phenyl (benzyl). Preferred is aryl-CH₂- and aryl-CH(CH₃)-. The term“substituted aryl-(Ci-C₃)alkyl” means an aryl-(Ci-C₃)alkyl functional group in which the aryl group is substituted. Preferred is substituted aryl(CH₂)-. Similarly, the term“heteroaryl-(Ci-C₃)alkyl” means a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g, -CH2CH2- pyridyl. Preferred is heteroaryl-(CH₂)-. The term“substituted heteroaryl-(Ci-C3)alkyl” means a heteroaryl-(Ci-C3)alkyl functional group in which the heteroaryl group is substituted. Preferred is substituted heteroaryl-(CH₂)-.

As used herein, the term“heterocycle” or“heterocyclyl” or“heterocyclic” by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multi-cyclic heterocyclic ring system that consists of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. A heterocycle may be aromatic or non-aromatic in nature. In certain embodiments, the heterocycle is a heteroaryl.

As used herein, the term“heteroaryl” or“heteroaromatic” refers to a heterocycle having aromatic character. A polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, l,2,3,6-tetrahydropyridine, l,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran,

2.3-dihydropyran, tetrahydropyran, l,4-dioxane, l,3-dioxane, homopiperazine, homopiperidine,

1.3-dioxepane, 4,7-dihydro-l,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, l,2,3-triazolyl, l,2,4-triazolyl, l,3,4-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, l,2,3-oxadiazolyl, l,3,4-thiadiazolyl and l,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5- , 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), l,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5 -quinoxalinyl), quinazolinyl, phthalazinyl, l,8-naphthyridinyl, 1,4- benzodioxanyl, coumarin, dihydrocoumarin, l,5-naphthyridinyl, benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, l,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

The aforementioned listing of heterocyclyl and heteroaryl moieties is intended to be representative and not limiting.

As used herein, the term“substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

For aryl, aryl-(Ci-C₃)alkyl and heterocyclyl groups, the term“substituted” as applied to the rings of these groups refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the substituents vary in number between one and four. In other embodiments, the substituents vary in number between one and three. In yet other embodiments, the substituents vary in number between one and two. In yet other embodiments, the substituents are independently selected from the group consisting of Ci_-6 alkyl, -OH, Ci_-6 alkoxy, halo, amino, acetamido and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic, with straight being preferred.

Abbreviations used: Ang-l, Angiopoietin-l; COUP-TF, chicken ovalbumin upstream promoter transcription factor; CVI, cerebral visual impairment; DBD, DNA-binding domain; E10, embryonic day 10; LBD, ligand-binding domain; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

Compounds and Compositions

The invention includes a compound of formula (I), or a composition containing the same, or a salt, solvate, racemate (if applicable), enantiomer (if applicable), and/or tautomer (if applicable) thereof:

wherein:

X¹ is selected from the group consisting of phenylenyl and heteroaryl enyl, wherein the phenylenyl or heteroaylenyl is substituted with‘n’ independently selected R⁵ groups;

X² is selected from the group consisting of C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, halogen, aryl, and heteroaryl, wherein the cycloalkyl, cycloalkenyl, aryl or heteroaryl is independently substituted with‘p’ independently selected R⁶ groups;

R¹ is selected from the group consisting of H and Ci-C₆ alkyl;

R² is selected from the group consisting of Ci-C₆ alkyl and Ci-C₆ haloalkyl;

each occurrence of R³ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, -N(R^a)(R^a), -OR^a, - COOH, -COO(Ci-C₆ alkyl), and carboxamide, wherein each occurrence of R^a is independently H or Ci-C₆ alkyl;

R⁴ is selected from the group consisting of H and Ci-C₆ alkyl;

each occurrence of R⁵ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, -N(R^b)(R^b), -OR^b, - COOH, -COO(Ci-C₆ alkyl), and carboxamide, wherein each occurrence of R^b is independently H or Ci-C₆ alkyl;

each occurrence of R⁶ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, -N(R^C)(R^C), -OR^c, - COOH, -COO(Ci-C₆ alkyl), and carboxamide, wherein each occurrence of R^c is independently H or Ci-C₆ alkyl,

or two R⁶ bound to adjacent ring carbons optionally combine to form -0(CH₂)_I.20-; m is 0, 1, or 2;

n is 0, 1, or 2; and

p is 0, 1, 2, 3, or 4.

In certain embodiments, X¹ is phenylenyl (such as, for example, l,2-phenylenyl, 1,3- phenylenyl, or l,4-phenylenyl). In other embodiments, X¹ is thiophenylenyl or pyridylenyl.

In certain embodiments, X² is Cl, Br, or I. In other embodiments, X² is C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl. In yet other embodiments, X² is phenyl, naphthyl, thiophenyl, or pyridinyl.

In certain embodiments, R¹ is H, methyl, ethyl, n-propyl, or isopropyl. In other embodiments, R¹ is H. In yet other embodiments, R¹ is methyl.

In certain embodiments, R² is methyl, ethyl, n-propyl, isopropyl, or trifluorom ethyl. In other embodiments, R² is methyl. In yet other embodiments, R² is ethyl. In yet other embodiments, R² is trifluoromethyl.

In certain embodiments, each occurrence of R³ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, -N(R^a)(R^a), and -OR^a, wherein each occurrence of R^a is independently H or Ci-C₆ alkyl.

In other embodiments, each occurrence of R³ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, and cyano. In yet other embodiments, each occurrence of R³ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, fluoro, chloro, and bromo. In yet other embodiments, each occurrence of R³ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, and fluoro.

In certain embodiments, R⁴ is H, methyl, ethyl, n-propyl, or isopropyl. In other embodiments, R⁴ is H. In yet other embodiments, R⁴ is methyl.

In certain embodiments, each occurrence of R⁵ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, -N(R^b)(R^b), and -OR^b, wherein each occurrence of R^b is independently H or Ci-C₆ alkyl. In other embodiments, each occurrence of R⁵ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, and cyano. In yet other embodiments, each occurrence of R⁵ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, fluoro, chloro, and bromo. In yet other embodiments, each occurrence of R⁵ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, cyano, and fluoro.

In certain embodiments, each occurrence of R⁶ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, -N(R^C)(R^C), and -OR^c, wherein each occurrence of R^c is independently H or Ci-C₆ alkyl.

In other embodiments, each occurrence of R⁶ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, and cyano. In yet other embodiments, each occurrence of R⁶ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, fluoro, chloro, and bromo. In yet other embodiments, each occurrence of R⁶ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, cyano, and fluoro. In yet other embodiments, two R⁶ bound to adjacent ring carbons optionally combine to form -0(CH₂)_I.20-.

In certain embodiments, m is 0. In other embodiments, m is 1. In yet other

embodiments, m is 2.

In certain embodiments, n is 0. In other embodiments, n is 1. In yet other embodiments, n is 2.

In certain embodiments, p is 0. In other embodiments, p is 1. In yet other embodiments, p is 2. In yet other embodiments, p is 3. In yet other embodiments, p is 4.

In certain embodiments, the compound of formula (I) is a compound of formula (la):

In certain embodiments, the compound of formula (I) is selected from the group consisting of:

-bromo-N-(4-(4-(N-methylmethylsulfonamido) pheny l)thi azol -2-y l)b enzami de (VCT-l);

-difluoro-N-(4-(4-(N-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l, 1’-biphenyl]-4-carboxamide (VCT-2);

trifluoro-N-(4-(4-(N-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l, -biphenyl]-4-carboxamide (VCT-3);

fluoro-N-(4-(4-(N-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l, 1’-biphenyl]-4-carboxamide (VCT-4);

'-fluoro-N-(4-(4-(N- methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4-carboxamide (VCT-5);

difluoro-N-(4-(4-(N-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l, 1’-biphenyl]-4-carboxamide (VCT-6);

trifluoromethyl-N-(4-(4-(N-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l, 1’-biphenyl]-4-carboxamide (VCT-7);

trifluorom ethyl -N -(4-(4 -(N -methyl methylsulfonamido)phenyl)thiazol-2-yl)-[l, l’-biphenyl]-4-carboxamide (VCT-8);

methylsulfonamido)phenyl)thiazol-2-yl)-[l, 1’-biphenyl]-4-carboxamide (VCT-9);

methylsulfonamido)phenyl)thiazol-2-yl)-[l, -biphenyl]-4-carboxamide) (VCT-10);

N-(4-(4-(N-methylmethylsulfonamido)phenyl) thiazol- 2-yl)-4-(thiophen-3-yl)benzamide (VCT-l 1);

-methylmethylsulfonamido) phenyl) thiazol-2-yl)-4-(naphthalen-l-yl)benzamide (VCT-12);

-cyclohexenyl-N-(4-(4-(N- methylmethylsulfonamido)phenyl)thiazol-2-yl)benzamide (VCT-13);

2-yl)-4-(pyri din-3 -yl)benzamide (VCT-15);

'-cyano-N-(4-(4-(N- methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4-carboxamide (VCT-16);

-(benzo[d][l,3]dioxol-5-yl)-N-(4-(4-(N- methylmethylsulfonamido)phenyl)thiazol-2-yl)benzamide (VCT-17);

-trifluoro-N- methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4-carboxamide (VCT-18);

-trifluoro-N-methyl

methylsulfonamido)phenyl)thiazol-2-yl)-4'-(trifluoromethyl)biphenyl-4-carboxamide (VCT-19);

'-cyano-N-(4-(4-( 1, 1,1 -trifluoro-N- methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4-carboxamide (VCT-20);

'-chloro-N-(4-(4-(N-methyl

methylsulfonamido)phenyl)thiazol-2-yl)-4'-(trifluoromethyl)biphenyl-4-carboxamide (VCT-21);

'-fluoro-N-(4-(4-(N-methyl

methylsulfonamido)phenyl)thiazol-2-yl)-4'-(trifluoromethyl)biphenyl-4-carboxamide (VCT-22);

-ethylmethylsulfonamido)phenyl) thiazol-2- yl)biphenyl-4-carboxamide (VCT-23);

-ethylmethylsulfonamido)phenyl)thiazol- 2-yl)-2'-fluoro-4'-(trifluoromethyl)biphenyl-4-carboxamide (VCT-24);

-ethylmethylsulfonamido)phenyl) thiazol-2- yl)-4'-(trifluoromethyl)biphenyl-4-carboxamide (VCT-25); and

-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l, -biphenyl]-4-carboxamide (VCT-100).

In certain embodiments, the compound is VCT-l. In other embodiments, the compound is VCT-2. In yet other embodiments, the compound is VCT-3. In yet other embodiments, the compound is VCT-4. In yet other embodiments, the compound is VCT-5. In yet other embodiments, the compound is VCT-6. In yet other embodiments, the compound is VCT-7. In yet other embodiments, the compound is VCT-8. In yet other embodiments, the compound is VCT-9. In yet other embodiments, the compound is VCT-10. In yet other embodiments, the compound is VCT-l 1. In yet other embodiments, the compound is VCT-12. In yet other embodiments, the compound is VCT-13. In yet other embodiments, the compound is VCT-14. In yet other embodiments, the compound is VCT-15. In yet other embodiments, the compound is VCT-16. In yet other embodiments, the compound is VCT-17. In yet other embodiments, the compound is VCT-18. In yet other embodiments, the compound is VCT-19. In yet other embodiments, the compound is VCT-20. In yet other embodiments, the compound is VCT-21. In yet other embodiments, the compound is VCT-22. In yet other embodiments, the compound is VCT-23. In yet other embodiments, the compound is VCT-24. In yet other embodiments, the compound is VCT-25. In yet other embodiments, the compound is VCT-100.

In certain embodiments, the compound is not VCT-l. In other embodiments, the compound is not VCT-2. In yet other embodiments, the compound is not VCT-3. In yet other embodiments, the compound is not VCT-4. In yet other embodiments, the compound is not VCT-5. In yet other embodiments, the compound is not VCT-6. In yet other embodiments, the compound is not VCT-7. In yet other embodiments, the compound is not VCT-8. In yet other embodiments, the compound is not VCT-9. In yet other embodiments, the compound is not VCT-10. In yet other embodiments, the compound is not VCT-l 1. In yet other embodiments, the compound is not VCT-12. In yet other embodiments, the compound is not VCT-13. In yet other embodiments, the compound is not VCT-14. In yet other embodiments, the compound is not VCT-15. In yet other embodiments, the compound is not VCT-16. In yet other

embodiments, the compound is not VCT-17. In yet other embodiments, the compound is not VCT-18. In yet other embodiments, the compound is not VCT-19. In yet other embodiments, the compound is not VCT-20. In yet other embodiments, the compound is not VCT-21. In yet other embodiments, the compound is not VCT-22. In yet other embodiments, the compound is not VCT-23. In yet other embodiments, the compound is not VCT-24. In yet other

embodiments, the compound is not VCT-25. In yet other embodiments, the compound is not VCT-l 00. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis,

enantioselective synthesis and/or separation of a mixture of enantiomers and / or

diastereoisomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. All possible stereochemical configurations of a given compound containing chiral center(s) are contemplated. All possible mixtures enriched with a particular enantiomer or diastereoisomer(s) are contemplated. All pure individual enantiomers or diastereoisomers are contemplated.

The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound of the invention, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g, tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g, ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form.

In certain embodiments, the compounds of the invention may exist as tautomers.

“Tautomerization” is a form of isomerization involving the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible, (e.g, in solution), a chemical equilibrium of tautomers can be reached. One well known example of tautomerization is between a ketone and its corresponding enol. Heterocycles may form tautomers such as the interconversion of pyrrolidinone and hydroxypyrrole. All tautomers are included within the scope of the compounds presented herein.

In certain embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. In certain

embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

In certain embodiments, sites on, for example, the aromatic ring portion of compounds of the invention is susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.

Compounds described herein also include isotopically labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to ²H, ³H, ^UC, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³²P, and ³⁵S. In certain embodiments, isotopically labeled compounds are useful in drug and/or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as C, F, O and N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non- labeled reagent otherwise employed.

In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Compounds of the invention can in certain embodiments form acids or bases. In certain embodiments, the invention contemplates acid addition salts. In other embodiments, the invention contemplates base addition salts. In yet other embodiments, the invention

contemplates pharmaceutically acceptable acid addition salts. In yet other embodiments, the invention contemplates pharmaceutically acceptable base addition salts. Pharmaceutically acceptable salts refer to salts of those bases or acids that are not toxic or otherwise biologically undesirable.

Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, b-hydroxybutyric, salicylic, galactaric and

galacturonic acid.

Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, lithium and copper, iron and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (L-m ethylgl ucam i ne) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4^th Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure).

Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. Protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

Combination Therapies

In certain embodiments, the compounds of the invention are useful in the methods of the invention in combination with at least one additional agent useful for treating or preventing a disease or disorder contemplated herein. This additional agent can comprise compounds identified herein or compounds, e.g ., commercially available compounds, known to treat, prevent or reduce the symptoms of the disease or disorder contemplated herein.

In certain embodiments, the at least one additional agent is selected from the group consisting of an androgen receptor antagonist (such as, but not limited to, enzalutamide and bicalutamide), an androgen production inhibitor (such as, but not limited to, a GnRH analog (Abiratone), an 5a-reductase inhibitor (such as, but not limited to, finasteride and dutasteride), chemotherapeutic agent (such as, but not limited to, docetaxel and cabazitaxel), and/or radiation therapy.

A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigrnoid-E_max equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6: 429- 453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol

Pharmacol. 114: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

Methods

The invention provides a method of treating, ameliorating, and/or preventing prostate cancer in a subject. The invention further provides a method of inhibiting, preventing, or reducing the rate of angiogenesis in a subject. The invention further provides a method of inhibiting, preventing, or reducing the rate of lymphangiogenesis in a subject. The invention further provides a method of inhibiting, preventing, or reducing the rate of prostate tumor metastasis in a subject.

In certain embodiments, the method comprises administering to the subject a

therapeutically effective amount of at least one compound of the invention. In other

embodiments, the at least one compound of the invention is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier. In other embodiments, the at least one compound of the invention is the only therapeutically effective agent

administered to the subject. In yet other embodiments, the at least one compound of the invention is the only therapeutically effective agent administered to the subject in an amount that performs the method as recited herein.

In certain embodiments, the subject is a mammal. In other embodiments, the mammal is human. In yet other embodiments, the at least one compound is administered by an

administration route selected from the group consisting of inhalational, oral, rectal, vaginal, parenteral, intracranial, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, and intravenous. In certain embodiments, the subject is further administered at least one additional agent that treats the disease and/or disorder. In other embodiments, the compound and the at least one additional agent are co-administered. In yet other embodiments, the compound and the at least one additional agent are co-formulated.

Administration/Dosage/Formulations

The invention also encompasses pharmaceutical compositions and methods of their use. These pharmaceutical compositions may comprise an active ingredient (which can be one or more compounds of the invention, or pharmaceutically acceptable salts thereof) optionally in combination with one or more pharmaceutically acceptable agents. The compositions set forth herein can be used alone or in combination with additional compounds to produce additive, complementary, or synergistic effects.

The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of a disease or disorder contemplated herein. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

Administration of the compositions of the present invention to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated herein. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease or disorder contemplated herein. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 and 5,000 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

A medical doctor, e.g ., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique

characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of a disease or disorder contemplated herein.

In certain embodiments, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of

microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable

compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

In certain embodiments, the compositions of the invention are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions of the invention are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of

administration of the various combination compositions of the invention varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physical taking all other factors about the patient into account.

Compounds of the invention for administration may be in the range of from about 1 pg to about 10,000 mg, about 20 pg to about 9,500 mg, about 40 pg to about 9,000 mg, about 75 pg to about 8,500 mg, about 150 pg to about 7,500 mg, about 200 pg to about 7,000 mg, about 350 pg to about 6,000 mg, about 500 pg to about 5,000 mg, about 750 pg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments there between. In certain embodiments, the dose of a compound of the invention is from about 1 mg and about 2,500 mg. In other embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in other embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

In certain embodiments, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder contemplated herein.

Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g ., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for

influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g. , other analgesic agents.

Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g, sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g, trans- and perivaginally), (intra)nasal and (trans)rectal),

intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

Oral Administration

For oral application, particularly suitable are tablets, dragees, liquids, drops,

suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

For oral administration, the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents ( e.g ., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g, magnesium stearate, talc, or silica); disintegrates (e.g, sodium starch gly collate); or wetting agents (e.g, sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OP ADR Y™ film coating systems available from Colorcon, West Point, Pa. (e.g, OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents ( e.g ., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g, almond oil, oily esters or ethyl alcohol); and preservatives (e.g, methyl or propyl p-hydroxy benzoates or sorbic acid).

Parenteral Administration

For parenteral administration, the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.

Additional Administration Forms

Additional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. Patent

Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos. WO 03/35041; WO 03/35040; WO 03/35029; WO

03/35177; WO 03/35039; WO 02/96404; WO 02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO 98/11879; WO 97/47285; WO 93/18755; and WO 90/11757.

Controlled Release Formulations and Drug Delivery Systems

In certain embodiments, the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release that is longer that the same amount of agent administered in bolus form.

For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compounds. As such, the compounds for use the method of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

In certain embodiments, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release

formulation.

The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

The term immediate release is used in its conventional sense to refer to a drug

formulation that provides for release of the drug immediately after drug administration.

As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

Dosing

The therapeutically effective amount or dose of a compound of the present invention depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of a disease or disorder contemplated herein in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.

A suitable dose of a compound of the present invention may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a l2-hour interval between doses.

It is understood that the amount of compound dosed per day may be administered, in non limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.

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

Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the viral load, to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection.

The compounds for use in the method of the invention may be formulated in unit dosage form. The term“unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses ( e.g ., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD₅₀ and ED_50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g ., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

The following examples further illustrate aspects of the present invention. However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth herein.

EXPERIMENTAL EXAMPLES

The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, point out specific embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

Materials and Methods

Preparation of compounds:

Compound, VCT-100 was dissolved in DMSO to 50mg/ml as stock. The stock was further dissolved in 10% 2-hydroxypropyl-beta-cyclodextrin (HPBCD) for injection into animals.

Induction of cancer by PC3 cells:

2xl0⁶ PC3 cells were subcutaneously injected into the flank of 5-week-old male nude mice. Tumors were formed for about 12 days before treatment. The test compound was injected daily at different doses as indicated (FIG. 1 A). Tumor size was measured weekly by caliper during the entire experimental process. Tumor volume was calculated by the formula: v=0.5xa><b²

(wherein: v, tumor volume; a, major diameter of the tumor; b, minor diameter) (FIG. 1B). Mice were also weighted weekly (Figure 1D). At the last time of tumor size measurement, mice were euthanized, and tumor tissues were removed for weighting and further experiments (FIG. 1C).

Histology of tumor:

Tumor tissue was fixed with 4% paraformaldehyde, and stained for blood vessel marker CD31. Where CD31 signal formed a circle, it signified an intact blood vessel. Vessel numbers per field were quantified (FIGs. 2B-2C).

Expression of COUP-TFII target genes:

mRNA was extracted from tumor tissue. SERPINE1 expression was measured by QPCR and normalized to actin mRNA (FIG. 2A). For gene expression in culture cells, PC3 cells were treated with VCT-100 compounds at O.luM for 48 hours, and mRNA levels of COUP-TFII target genes SERPINE1, FOXM1 and SLC39A6 were measured (FIGs. 3B-3D).

Luciferase assay:

COUP-TFII and NGFIA-Luc vectors were co-transfected into 293T cells. Next day, cells were trypsinized and seeded into 96 well plate at 4xl0⁴ cells/well. 4 hours after seeding, the test compound was added into medium. About 20 hours after compound treatment, cells were harvested for luciferase assay (FIG. 3 A).

Example 1: Synthetic Examples

Synthesis of Compound VCT-1:

Step 1: To a 0°C solution of aniline (1 equiv) and pyridine (1.1 equiv) in CH2CI2 (0.35

M) was added methanesulfonyl chloride (1 equiv). The reaction mixture was allowed to warm to ambient temperature and was stirred at ambient temperature for 16 hours. The reaction was quenched with 3N NaOH, and the aqueous layer was extracted with CH₂Cl_2. The aqueous layer was acidified with cone. HC1 and filtered through a fritted funnel. The recovered white precipitate was dried under vacuum. (2.1 g, 98%). 1H NMR (400 MHz, CDCI3) d 8.09-7.87 (m, 2H), 7.32-7.26 (m, 2H), 7.07 (s, 1H), 3.12 (s, 3H), 2.61 (s, 3H). LCMS found 214.0 [M+H]⁺. Step 2: To a 0°C solution of Compound 1-2 (10.0 mmol) and K₂C0₃ (20mmol) in DMF

(20 mL), was added Mel (12.0 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred at ambient temperature for 12 hours. 100 mL water were added, and the resulting solid was filtered and dried to give 1-3 (2. lg, 93%). 1H NMR (400 MHz, CDCI3) d 8.00 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 3.39 (s, 3H), 2.89 (s, 3H), 2.62 (s, 3H). LCMS found 227.1 [M+H]⁺.

Step 3: To a solution of 1-3 (9.0 mmol) in MeOH (90 mL) was added

tetrabutylammonium bromide (10.8 mmol). The reaction mixture was then stirred for 12 h at room temperature, extracted by ethyl acetate, washed with saturated brine solution, and dried over anhydrous Na₂S0_4. The resultant solution was concentrated under reduced pressure to give 1-4 (2.7g, 99%). 1H NMR (400 MHz, CDCI₃) d 8.04 (d, J= 8.8 Hz, 2H), 7.53 (d, J= 8.8 Hz, 3H), 4.44 (s, 2H), 3.41 (s, 3H), 2.91 (s, 3H). LCMS found 306.0 [M+H]⁺.

Step 4: Compound 1-4 (9.0 mmol) and thiourea (9.0 mmoL) were dissolved in isopropanol (45 mL) and reacted at 90 ^°C for 3 h. Isopropanol was concentrated under reduced pressure, extracted by DCM, washed with saturated NaHCO, solution, and dried over anhydrous Na₂S0_4. The resultant solution was concentrated under reduced pressure to give 1-5 (2.0 g, 78%). 1H NMR (400 MHz, DMSO-d₆) d 7.77 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.25 (s, 1H), 3.27 (s, 3H), 2.99 (s, 3H). LCMS found 284.0 [M+H]⁺.

Step 5 : To a 0°C solution of Compound 1-5 (2.0 mmol)) and Et₃N (3 mmol) in DCM (10 mL) was added 4-bromobenzoyl chloride (2 mmol). The reaction mixture was then stirred for 24 h at room temperature, extracted by dichloromethane, washed with saturated brine solution and dried over anhydrous Na₂S0 _. The resultant solution was concentrated under reduced pressure and purified by column chromatography on silica gel (200-300 mesh size) to give VCT-1 as a white solid (yield, 79%). 1H NMR (400 MHz, CDCl₃) d 10.05 (s, 1H), 7.80 (m, 4H), 7.63 (d, 2H), 7.41 (d, 2H), 7.21 (s, 1H), 3.35 (s, 3H), 2.86 (s ,3H). LCMS found 466.0 [M+H]⁺.

Synthesis of Compound VCT-2:

A solution of VCT-1 (233 mg, 0.5 mmol) and 3,5-difluorophenylboronic acid (95 mg, 0.6 mmol) in DMF (5 mL) was degassed followed by the addition of PdCl2dppf (35 mg, 0.04 mmol) and 2M aqueous Na₂C0₃ (1.3 mL, 2.6 mmol). The reaction mixture was stirred at 90 °C overnight and then diluted with water (20 mL x 2) and extracted with EtOAc (20 mL). The organic extracts were washed with brine (20 mL), dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give VCT-2 as a white solid (Yield 88%). 1H NMR (400 MHz, CDCl₃) d: 10.47 (s, 1H), 7.99 (d, 2H), 7.79 (d, 2H), 7.62 (d, 2H), 7.38 (d, 2H), 7.21 (s, 1H), 7.12 (m, 2H), 6.86 (tt, 2H), 3.32 (s, 3H), 2.84 (s, 3H); LCMS found 500.1 [M+H]⁺.

Synthesis of Compound VCT-3:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-3 as a white solid (Yield 78%). 1H NMR (400 MHz, CDCl₃) d: 9.86 (s, 1H), 8.06 (d, 2H), 7.85 (d, 2H), 7.66 (d, 2H), 7.44 (d, 2H), 7.28-7.23 (m, 2H), 7.23 (s, 1H), 3.36 (s, 3H), 2.86 (s, 3H); LCMS found 518.1 [M+H]⁺.

Synthesis of Compound VCT-4:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-4 as a white solid (Yield 84 %). 1H NMR (400 MHz, CDC13) d: 10.08 (s, 1H), 8.03 (d, 2H), 7.85 (d, 2H), 7.71 (dd 2H), 7.48-7.38 (m, 4H), 7.32 (m, 1H), 7.22 (s, 1H), 7.12 (m, 1H), 3.34 (s, 3H), 2.85 (s, 3H); LCMS found 482.1 [M+H]⁺.

Synthesis of Compound VCT-5:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-5 as a white solid (Yield 81 %). 1H NMR (400 MHz, CDCI₃) d: 9.95 (s, 1H), 8.02 (d, 2H), 7.83 (d, 2H), 7.70 (d, 2H), 7.51-7.38 (m, 4H), 7.27-7.16 (m, 3H), 3.35 (s, 3H), 2.85 (s, 3H); LCMS found 482.1 [M+H]⁺.

Synthesis of Compound VCT-6:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-6 as a white solid (Yield 86 %). 1H NMR (400 MHz, CDCI₃) d: 10.06 (s, 1H), 8.02 (d, 2H), 7.83 (d, 2H), 7.65 (d, 2H), 7.47-7.22 (m, 5H), 7.22 (s, 1H), 3.34 (s, 3H), 2.85 (s, 3H); LCMS found 500.1 [M+H]⁺.

Synthesis of Compound VCT-7:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-7 as a white solid (Yield 77 %). 1H NMR (400 MHz, CDCI₃) d: 10.02 (s, 1H), 8.06 (d, 2H), 7.86 (d, 2H), 7.82 (d, 2H), 7.74 (d, 2H), 7.69 (d, 1H), 7.62(t, 1H), 7.42(d, 2H),7.22 (s, 1H), 3.35 (s, 3H), 2.85 (s, 3H); LCMS found 532.1 [M+H]⁺.

Synthesis of Compound VCT-8:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-8 as a white solid (Yield 79 %). 1H NMR (400 MHz, CDCl₃) d: 9.96 (s, 1H), 8.06 (d, 2H), 7.84 (d, 2H), 7.74 (m, 6H), 7.43 (d, 2H), 7.22 (s, 1H), 3.35 (s, 3H), 2.86 (s, 3H); LCMS found 532.1 [M+H]⁺.

Synthesis of Compound VCT-9:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-9 as a white solid (Yield 81 %). 1H NMR (400 MHz, CDCI₃) d: 9.77 (s, 1H), 8.02 (d, 2H), 7.86 (d, 2H), 7.74 (d, 2H), 7.54 (d, 2H), 7.43 (d, 2H), 7.30(d, 2H), 7.21 (s, 1H), 3.36 (s, 3H), 2.86 (s, 3H), 2.42 (s, 3H); LCMS found 478.1 [M+H]⁺.

Synthesis of Compound VCT-10:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-10 as a white solid (Yield 80 %). 1H NMR (400 MHz,

CDCI₃) d: 9.83(s, 1H), 8.03 (d, 2H), 7.85 (d, 2H), 7.74 (d, 2H), 7.47-7.35 (m, 5H), 7.23(d, 1H), 7.21 (s, 1H), 3.36 (s, 3H), 2.86 (s, 3H), 2.45 (s, 3H); LCMS found 478.1 [M+H]⁺.

Synthesis of Compound VCT-100:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-100 as a white solid (Yield 70%). 1H NMR (400 MHz, CDCI₃) d 9.85 (s, 1H), 8.05 (d, J= 8.5 Hz, 2H), 7.90 - 7.84 (m, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.70 - 7.64 (m, 2H), 7.52 (t, J= 7.4 Hz, 2H), 7.45 (dt, J= 4.3, 3.0 Hz, 3H), 7.24 (s, 1H), 3.37 (s, 3H), 2.88 (s, 3H); LCMS found 464.1 [M+H]⁺.

Synthesis of Compound VCT-11:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-11 as a white solid (Yield 67%). 1H NMR (400 MHz, CDCI₃) d 1 l .08(s, 1H), 8.08 (d, 2H), 7.84 (d, 2H), 7.70 (d, 2H), 7.56 (s, 1H), 7.37(m, 4H), 7.21 (s, 1H), 3.32 (s, 3H), 2.83 (s, 3H); LCMS found 470.1 [M+H]⁺.

Synthesis of Compound VCT-12;

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-12 as a white solid (Yield 63%). 1H NMR (400 MHz, CDCl₃) d 9.84(s, 1H), 8.10 (d, 2H), 7.97-7.81 (m, 5H), 7.68 (d, 2H), 7.59-7.42 (m, 6H), 7.23 (s, 1H),

3.36 (s, 3H), 2.87 (s, 3H); LCMS found 414.1 [M+H]⁺.

Synthesis of Compound VCT-13:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-13 as a white solid (Yield 73%). 1H NMR (400 MHz, CDCI3) d 9.69(s, 1H), 7.88 (dd, 4H), 7.53 (d, 2H), 7.41 (d, 2H), 7.19 (s, 1H), 6.30 (s, 1H), 3.36 (s, 3H), 2.85 (s, 3H), 2.43 (m, 2H), 2.26 (m, 2H), 1.82 (m, 2H), 1.70 (m, 2H); LCMS found 468.1

[M+H]⁺.

Synthesis of Compound VCT-14:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-14 as a white solid (Yield 55%). 1H NMR (400 MHz, DMSO-de) d 8.70 (d, 2H), 8.28 (d, 2H), 8.00 (dd, 4H), 7.83 (d, 2H), 7.76 (s, 1H), 7.49 (d, 2H), 3.27 (s, 3H), 2.98 (s, 3H); LCMS found 465.1 [M+H]⁺.

Synthesis of Compound VCT-15:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-15 as a white solid (Yield 38%). 1H NMR (400 MHz, DMSO-de) d 11.66 (s, 1H), 8.83 (s, 1H), 8.57 (d, 1H), 8.18 (d, 2H), 7.87 (d, 1H), 7.83 (d, 2H), 7.66 (d, 2H), 7.33 (m, 3H), 7.14 (s, 1H), 3.28 (s, 3H), 2.80 (s, 3H); LCMS found 465.1 [M+H]⁺.

Synthesis of Compound VCT-16:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-16 as a white solid (Yield 66%). 1H NMR (400 MHz, DMSO-de) 5:8.29 (d, 2H), 7.99 (m, 8H), 7.77 (s, 1H), 7.48 (d, 2H), 3.27 (s, 3H), 2.98 (s, 3H); LCMS found 489.1 [M+H]⁺.

Synthesis of Compound VCT-17:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-17 as a white solid (Yield 71%). 1H NMR (400 MHz, CDCl₃) 5 l0.04(s, 1H), 8.00 (d, 2H), 7.86 (d, 2H), 7.66 (d, 2H), 7.44 (d, 2H), 7.23 (s, 1H), 7.14 (m, 2H), 6.95 (d, 1H), 6.06 (s, 2H), 3.37 (s, 3H), 2.87 (s, 3H); LCMS found 508.1 [M+H]⁺. Synthesis of Compound VCT-18:

Step 1: To a 0°C solution of aniline (1 equiv) and pyridine (1.1 equiv) in CH2CI2 (0.35

M) was added trifluoromethanesulfonic anhydride (1 equiv). The reaction mixture was allowed to warm to ambient temperature and was stirred at ambient temperature for 16 hours. The reaction was quenched with 3 N NaOH and the aqueous layer was extracted with CH₂Cl_2. The aqueous layer was acidified with cone. HC1 and filtered through a fritted funnel. The recovered white precipitate 2-2 was dried under vacuum. (Yield 88 %). LCMS found 268.0 [M+H]⁺;

Step 2: Using the procedure consistent with the procedure described for the preparation of compound 1-3 provided compound 2-3 as a white solid (Yield 81%). 1H NMR (400 MHz, CDCI3) 5 8.03 (d, 2H), 7.50 (d, 2H), 3.53 (s, 3H), 2.64 (s, 3H); LCMS found 282.0 [M+H]⁺; Step 3: Using the procedure consistent with the procedure described for the preparation of compound 1-4 provided compound 2-4 as a white solid (Yield 74%). LCMS found 360.0

[M+H]⁺;

Step 4: Using the procedure consistent with the procedure described for the preparation of compound 1-5 provided compound 2-5 as a white solid (Yield 73%). LCMS found 338.0

[M+H]⁺;

Step 5: Using the procedure consistent with the procedure described for the preparation of compound VCT-1 provided compound 2-6 as a white solid (Yield 79%). 'H NMR (400 MHz, CDC13) d 10.59 (s, 1H), 7.83 (m, 4H), 7.64 (d, 2H), 7.41 (d, 2H), 7.27 (s, 1H), 3.51 (s, 3H);

Step 6: Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-18 as a white solid (Yield 79%). 1H NMR (400 MHz, CDC13) d 9.88(s, 1H), 8.04 (d, 2H), 7.90 (d, 2H), 7.75 (d, 2H), 7.66 (d, 2H), 7.54-7.39 (m, 5H), 7.27 (s, 1H), 3.51 (s, 3H); LCMS found 517.1 [M+H]⁺.

Synthesis of Compound VCT-19:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-19 as a white solid (Yield 65%). 1H NMR (400 MHz, CDCl₃) d 9.94(s, 1H), 8.08 (d, 2H), 7.87 (d, 2H), 7.76 (m, 5H), 7.41 (d, 2H), 7.26 (d, 2H), 3.49 (s, 3H); LCMS found 486.1 [M+H]⁺.

Synthesis of Compound VCT-20:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-20 as a white solid (Yield 53%). 1H NMR (400 MHz, CDCI₃) d 9.97(s, 1H), 8.07 (d, 2H), 7.87 (d, 2H), 7.82-7.70 (m, 5H), 7.40 (d, 2H), 7.26 (d, 2H), 3.49 (s, 3H); LCMS found 543.1 [M+H]⁺.

Synthesis of Compound VCT-21:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-21 as a white solid (Yield 68%). 1H NMR (400 MHz, CDCI3) d 10.11 (s, 1H), 8.07 (d, 2H), 7.87-7.68 (m, 6H), 7.61 (d, 1H), 7.42 (d, 2H), 7.23 (s, 1H), 3.35 (s, 3H), 2.86 (s, 3H); LCMS found 566.1 [M+H]⁺. Synthesis of Compound VCT-22:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-22 as a white solid (Yield 65%). 1H NMR (400 MHz, CDCl₃) d l0.09(s, 1H), 8.08 (d, 2H), 7.86 (d, 2H), 7.73 (d, 2H), 7.63 (t, 1H), 7.57 (d, 1H), 7.51 (d, lH),7.44 (d, 2H), 7.25 (s, 1H), 3.37 (s, 3H), 2.88 (s, 3H); LCMS found 550.1 [M+H]⁺.

Synthesis of Compound VCT-23:

Step 1: Using the procedure consistent with the procedure described for the preparation of compound 1-3 provided compound 3-3 as a white solid (Yield 84%). LCMS found 242.0

[M+H]⁺;

Step 2: Using the procedure consistent with the procedure described for the preparation of compound 1-4 provided compound 3-4 as a white solid (Yield 74%). LCMS found 319.0

[M+H]⁺;

Step 3: Using the procedure consistent with the procedure described for the preparation of compound 1-5 provided compound 3-5 as a white solid (Yield 77%). LCMS found 298.0

[M+H]⁺; Step 4: Using the procedure consistent with the procedure described for the preparation of compound VCT-1 provided compound 3-6 as a white solid (Yield 92%). 'H NMR (400 MHz, CDCI3) d 10.89 (s, 1H), 7.80 (d, 4H), 7.60 (d, 2H), 7.37 (d, 2H), 7.25 (s, 1H), 3.77 (q, 2H), 2.93 (s, 3H), 1.17 (t, 3H); LCMS found 479.0 [M+H]⁺;

Step 5: Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-23 as a white solid (Yield 74%). 1H NMR (400 MHz, CDC13) d 10.15(s, 1H), 8.03 (d, 2H), 7.87 (d, 2H), 7.73 (d, 2H), 7.65 (d, 2H), 7.52 (t, 2H), 7.48-7.36 (m, 3H), 7.25 (s, 1H), 3.78 (q, 2H); 2.91 (s, 3H), 1.17 (t, 3H); LCMS found 478.1 [M+H]⁺;

Synthesis of Compound VCT-24:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-24 as a white solid (Yield 71%). 1H NMR (400 MHz, CDCI3) d l0.03(s, 1H), 8.09 (d, 2H), 7.89 (d, 2H), 7.73 (d, 2H), 7.64 (d, 1H), 7.57 (t, 1H), 7.51 (d, 1H), 7.41 (d, 2H), 7.27 (s, 1H), 3.79 (q, 2H); 2.93 (s, 3H), 1.19 (t, 3H); LCMS found 564.1 [M+H]⁺;

Synthesis of Compound VCT-25:

Using the procedure consistent with the procedure described for the preparation of compound VCT-2 provided compound VCT-25 as a white solid (Yield 62%). 1H NMR (400 MHz, CDC13) d 9.98(s, 1H), 8.09 (d, 2H), 7.89 (d, 2H), 7.77 (m, 6H), 7.41 (d, 2H), 7.26 (s, 1H), 3.78 (q, 2H); 2.93 (s, 3H), 1.19 (t, 3H); LCMS found 546.1 [M+H]⁺.

Example 2:

As demonstrated herein, prostate cancer growth is inhibited by an exemplary COUP-TFII receptor inhibitor of the invention (VCT-100) without adverse effect on mice’s general health as indicated by their body weight. Tumors (PC cells) were grown in mice for 12 days (to a diameter of about 0.5 mm) before the animals were treated with compound (either 5 mg/kg (low dose, or L) or 15 mg/kg (high dose, or H)) or vehicle (DMSO). FIG. 1 A comprises images of ex vivo induced prostate tumors by PC3 cells in mice. The results indicated that VCT-100 treatment inhibited prostate tumor growth in mice. FIG. 1B comprises a graph progression of tumor growth by measuring tumor volume during 5 weeks of treatment with vehicle or VCT-100. FIG. 1C comprises a graph illustrating tumor weight of dissected tumors from mice after 5 weeks of treatment with vehicle or VCT-100. FIG. 1D comprises a graph illustrating body weight as a function of weeks of treatment with vehicle or VCT-100.

Example 3:

As demonstrated herein, VCT-100 indeed inhibited activity and function of COUP-TFII in angiogenesis. FIG. 2A comprises a graph illustrating that treatment of mice with VCT-100 inhibited COUP-TFII activity as measured by the expression of its negative target gene,

SERPINE1. FIG. 2B comprises a series of images illustrating that exemplary COUP-TFII inhibitor, VCT-100, inhibited the tumor angiogenesis as measured by vessel density in prostate tumor. FIG. 2C comprises a graph illustrating quantitative measurement of vessel number in prostate tumor.

Example 4:

As demonstrated herein, certain derivatives of VCT-100 have better inhibitory ability, with EC50 less than 0.5mM, as compared to the parent compound, and can be used for treatment of prostate cancer. FIGs. 3A-3D illustrate effectiveness of VCT-100 derivatives ,VCT-l to VCT-10, in inhibiting COUP-TFII activity. FIG. 3 A comprises a bar graph illustrating EC₅₀ values of VCT-100 derivatives, VCT-l to VCT-10, in inhibiting COUP-TFII activity in a transfection assay. FIG. 3B comprises a bar graph illustrating ability of VCT-100 derivatives, VCT-l to VCT-l 0, in inhibiting COUP-TFII activity in its negative target gene, SERPINE1 expression. FIG. 3C comprises a bar graph illustrating ability of VCT-100 derivatives, VCT-l to VCT-10, in inhibiting COUP-TFII activity on its positive target gene, FOXM1 expression. FIG. 3D comprises a bar graph illustrating ability of VCT-100 derivatives, VCT-l to VCT-10, in inhibiting COUP-TFII activity on another positive target gene, SLC39A6 expression.

Example 5: Oral DMPK Studies in the Mouse

200-220 g Sprague Dawley rats were used in this study. Animals were fasted for 12 hours before drug administration and refed 4 hours after drug administration. Briefly, animals were administered a single dose of VCT-8 in 10% HR-b-CD though intravenous injection (5 mg/kg) or per oral administration (20 mg/kg). Venous blood was taken from the posterior plexus of the eye over a 24-hour period. Blood samples were collected in EDTA tubes, centrifuged at 1 lOOOrmp for 5 minutes to collect blood plasma. VCT8 was determined using tandem mass spectrometry methods. Results are illustrated in FIG. 5.

Example 6: Evaluation of Interaction with COUP-TFII

Cells were lysed in IP buffer (20 mM Tris pH7.5, 150 mM NaCl, 0.5% NP-40, 1 mM EDTA, protease inhibitor). Cell lysate were incubated for 1 hour at 4 °C with streptavidin beads (65601, ThermoFisher) that were preloaded with biotinylated inhibitor. For the competition assay, cell lysate was preincubated with 20 mM competitor inhibitor for 3 hours. Beads were washed three times by IP buffer and resuspended in loading buffer. Samples were boiled at 95 °C for 5 min for separation of the protein and beads, then analyzed by western blot. Results are illustrated in FIG. 6.

Example 7: Evaluation of Specificity of Binding to COUP-TFII

293T cells were transfected with certain protein expression plasmids (see FIG. 7). 48 hours after transfection, cells were lysed in IP buffer (20 mM Tris pH7.5, 150 mM NaCl, 0.5% NP-40, 1 mM EDTA, protease inhibitor). Cell lysate were incubated for 1 hour at 4 °C with streptavidin beads (65601, ThermoFisher) that was preloaded with biotinylated inhibitor. For the competition assay, cell lysate was preincubated with 20 pM competitor inhibitor for 3 hours. Beads were washed three times by IP buffer and resuspended in loading buffer. Samples were boiled at 95 °C for 5 min for separation of the protein and beads, then analyzed by western blot. Results are illustrated in FIG. 7.

Example 8: Evaluation of Interaction with COUP-TFII

pcDNA3 vector was used to generate plasmids that express COUP-TFII full length N/C terminal proteins. 48 hours after transfection, cells were lysed in IP buffer (20 mM Tris pH7.5, 150 mM NaCl, 0.5% NP-40, 1 mM EDTA, protease inhibitor). Glutathione S-transferase tagged COUP-TFII ligand binding domain (GST-LBD) was expressed in E.coli and purified through affinity beads. Cell lysate or purified protein were incubated for 1 hour at 4 °C with streptavidin beads (65601, ThermoFisher) that was preloaded with biotinylated inhibitor. Beads were washed three times by IP buffer and resuspended in loading buffer. Samples were boiled at 95 °C for 5 min for separation of the protein and beads, then analyzed by western blot. Results are illustrated in FIG. 8.

Example 9: Evaluation of Binding to COUP-TFII

293T cells were transfected with each plasmid in which COUP-TFII has different mutation as indicated (FIG. 9). 48 hours after transfection, cells were lysed in IP buffer (20 mM Tris pH7.5, 150 mM NaCl, 0.5% NP-40, 1 mM EDTA, protease inhibitor). Cell lysate samples were boiled at 95 °C for 5 min for separation of the protein and beads, then analyzed by western blot to measure protein levels of each mutated COUP-TFII. According to western blot result, cell lysate samples were adjusted to ensure each sample has the even concentration of mutated COUP-TFII protein. Each cell lysate was incubated for 1 hour at 4 °C with streptavidin beads (65601, ThermoFisher) that were preloaded with biotinylated inhibitor. Beads were washed three times by IP buffer and resuspended in loading buffer. Results are illustrated in FIG. 9.

Example 10: Inhibition of Prostate Cancer Cell Growth

Cells were seeded in 96-well plate at 1,000-3,000 cells per well. Inhibitor with concentrations as indicated in FIG. 10 was added the following day. After 96 hours incubation, cell viability was assessed by CellTiter-Glo assay (Promega) according to the manufactory’s manual. Results are illustrated in FIG. 10.

Example 11: Inhibition of Prostate Cancer Cell Growth

Patient derived xenografts (PDX) cells were cultured in an organoid assay. 0.5 mM compounds were added to the culture medium. 16 days after culture, a photograph was taken, and organoid number and size were calculated. Results are illustrated in FIG. 11. VCT-32 corresponds to N-(4-(2-([l, r-biphenyl]-4-ylamino)thiazol-4-yl)phenyl)-N-methyl- methanesulfonamide, and VCT-35 corresponds to N-methyl-N-(4-(2-((4'-(trifluoromethyl)-[l,r- biphenyl]-4-yl)amino)thiazol-4-yl)phenyl)methanesulfonamide.

VCT-32:

VCT-35:

Example 12: Inhibition of Prostate Cancer Growth

6-week-old male nude mice (Nu/J homozygous for Foxnl^nu, stock number 002019) were purchased from The Jackson Laboratory. 10^c 10⁶ LNCaP cells, mixed with matrigel, were subcutaneously injected into the flank of mice. Daily administration of the inhibitor was started to at 15 mg/kg by intraperitoneal injection when tumor diameter reached to about 0.5 cm. The tumor size was measured by caliper during the entire experimental process, and mice weight was also measured per week. Tumor volume was calculated by the formula: v=0.5xaxb² (v, the tumor volume; a, the major diameter of the tumor; b, the minor diameter). At the end of the experiment, mice were euthanized, and tumor tissue was removed for further examination.

Results are illustrated in FIG. 12.

Example 13: Evaluation of Inhibition of Tumor Proliferation and Angiogenesis

LNCaP xenograft tumor samples were fixed with 5% PFA, and immunohistochemistry was further performed using kits form VECTOR laboratories following the manufactory manual. Primary Ki67 antibody (550609, BD Pharmingen, 1 :2,000 dilution) and CD31 antibody (AF3628-SP, R&D Systems, 1 : 1,000 dilution) was incubated overnight at 4 °C, and secondary antibodies were incubated for 1 h at room temperature. Photographs were taken and staining signal was calculated. Results are illustrated in FIG. 13.

Example 14: Inhibition of Prostate Cancer Growth

6-week-old male nude mice (Nu/J homozygous for Foxnlnu, stock number 002019) were purchased from The Jackson Laboratory. 4x 10⁶ 22Rvl cells mixed with matrigel were subcutaneously injected into the flank of mice. For LNCaP-abl xenograft, mice were castrated then injected with 10^c 10⁶ LNCaP-abl cells. Daily administration of the inhibitor was started at 15 mg/kg by intraperitoneal injection when tumor diameter reached about 0.5 cm. The tumor size was measured by caliper during the entire experimental process, and mice weight was also measured per week. Tumor volume was calculated by the formula: v=0.5xaxb² (v, the tumor volume; a, the major diameter of the tumor; b, the minor diameter). At the end of the experiment, mice were euthanized, tumor tissues were removed, and photographs were taken. Results are illustrated in FIG. 14. Example 15: Inhibition of Prostate Cancer Growth

6-week-old male nude mice (Nu/J homozygous for Foxnlnu, stock number 002019) were purchased from The Jackson Laboratory. 2x 10⁶ PC3 cells mixed with matrigel were

subcutaneously injected into the flank of mice. Daily administration of the inhibitor was started at 15 mg/kg by intraperitoneal injection when tumor diameter reached about 0.5 cm. The tumor size was measured by caliper during the entire experimental process, and mice weight was also measured per week. Tumor volume was calculated by the formula: v=0.5xa><b² (v, the tumor volume; a, the major diameter of the tumor; b, the minor diameter). At the end of the

experiment, mice were euthanized, tumor tissues were removed, and photographs were taken. Results are illustrated in FIG. 15.

Example 16: Inhibition of Prostate Cancer Metastasis

8-week-old male SCID mice (NOD-CB17 Prkdc^SCID/J, stock number 001303) were purchased from The Jackson Laboratory. 2x 10⁶ PC3-luciferase cells were injected through the tail vein. At the following day, mice were treated daily with 15 mg/kg VCT8 by intraperitoneal injection for 2 weeks. After 7 weeks, bioluminescence was measured using IVIS system by intraperitoneal injection of luciferin (Gold Biotechnology). Tissues with luciferase signal were collected and immunohistochemistry was performed to measure luciferase signal using luciferase antibody (NB100-1677SS, NOVUS Biologicals, 1 :500 dilution). Results are illustrated in FIG. 16.

Enumerated Embodiments

The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance. Embodiment 1 provides a compound of formula (I), or a salt, solvate, enantiomer, and/or

tautomer thereof:

wherein:

X¹ is selected from the group consisting of phenylenyl and heteroaryl enyl, wherein the phenylenyl or heteroaylenyl is substituted with‘n’ independently selected R⁵ groups;

X² is selected from the group consisting of C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, halogen, aryl, and heteroaryl, wherein the cycloalkyl, cycloalkenyl, aryl or heteroaryl is independently substituted with‘p’ independently selected R⁶ groups;

R¹ is selected from the group consisting of H and Ci-C₆ alkyl;

R² is selected from the group consisting of Ci-C₆ alkyl and Ci-C₆ haloalkyl;

each occurrence of R³ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, -N(R^a)(R^a), -OR^a, - COOH, -COO(Ci-C₆ alkyl), and carboxamide, wherein each occurrence of R^a is independently H or Ci-C₆ alkyl;

R⁴ is selected from the group consisting of H and Ci-C₆ alkyl;

each occurrence of R⁵ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, -N(R^b)(R^b), -OR^b, - COOH, -COO(Ci-C₆ alkyl), and carboxamide, wherein each occurrence of R^b is independently H or Ci-C₆ alkyl;

each occurrence of R⁶ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, -N(R^C)(R^C), -OR^c, - COOH, -COO(Ci-C₆ alkyl), and carboxamide, wherein each occurrence of R^c is independently H or Ci-C₆ alkyl,

or two R⁶ bound to adjacent ring carbons optionally combine to form -0(CH₂)_I.20-; m is 0, 1, or 2;

n is 0, 1, or 2; and

p is 0, 1, 2, 3, or 4.

Embodiment 2 provides the compound of Embodiment 1, wherein R¹ is H, methyl, ethyl, n-propyl, or isopropyl. Embodiment 3 provides the compound of any of Embodiments 1-2, wherein R² is methyl, ethyl, n-propyl, isopropyl, or trifluorom ethyl.

Embodiment 4 provides the compound of any of Embodiments 1-3, wherein each occurrence of R³ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, and fluoro.

Embodiment 5 provides the compound of any of Embodiments 1-4, wherein R⁴ is H, methyl, ethyl, n-propyl, or isopropyl.

Embodiment 6 provides the compound of any of Embodiments 1-5, wherein each occurrence of R⁵ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, cyano, and fluoro.

Embodiment 7 provides the compound of any of Embodiments 1-6, wherein each occurrence of R⁶ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, cyano, and fluoro, or two R⁶ bound to adjacent ring carbons optionally combine to form -0(CH₂)_I-20.

Embodiment 8 provides the compound of any of Embodiments 1-7, wherein m is 0.

Embodiment 9 provides the compound of any of Embodiments 1-8, wherein n is 0.

Embodiment 10 provides the compound of any of Embodiments 1-9, wherein p is 0, 1, 2, or 3.

Embodiment 11 provides the compound of any of Embodiments 1-10, which is a

compound of formula

Embodiment 12 provides the compound of any of Embodiments 1-11, which is selected from the group consisting of:

4-bromo-N-(4-(4-(N-methylmethylsulfonamido) phenyl)thiazol-2-yl)benzamide (VCT-l);

3’,5’-difluoro-N-(4-(4-(N-methyl-methylsulfonamido)phenyl)thiazol-2-yl)-[l,l^,-biphenyl]-4- carboxamide (VCT-2); 3^..4^..5’-trifluoro-N-(4-(4-(N-methyl-methylsulfonamido)phenyl)thiazol-2-yl)-[l, -biphenyl]-4- carboxamide (VCT-3);

3^,-fluoro-N-(4-(4-(N-methyl-methylsulfonamido)phenyl)thiazol-2-yl)-[l, -biphenyl]-4- carboxamide (VCT-4);

2'-fluoro-N-(4-(4-(N-methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4-carboxamide

(VCT-5);

3^..4^,-difluoro-N-(4-(4-(N-methyl-methylsulfonamido)phenyl)thiazol-2-yl)-[l, -biphenyl]-4- carboxamide (VCT-6);

3^,-trifluoromethyl-N-(4-(4-(N-methyl-methylsulfonamido)phenyl)thiazol-2-yl)-[l, -biphenyl]-

4-carboxamide (VCT-7);

4^,-trifluoromethyl-N-(4-(4-(N-methyl-methylsulfonamido)phenyl)thiazol-2-yl)-[l, -biphenyl]-

4-carboxamide (VCT-8);

4^,-methyl-N-(4-(4-(N-methyl-methylsulfonamido)phenyl)thiazol-2-yl)-[l, -biphenyl]-4- carboxamide (VCT-9);

3’ -methyl -N-(4-(4-(N-methyl-methylsulfonamido)phenyl)thiazol-2-yl)-[l,r-biphenyl]-4- carboxamide) (VCT-10);

N-(4-(4-(N-methylmethylsulfonamido)phenyl) thiazol-2-yl)-4-(thiophen-3-yl)benzamide (VCT- i i);

N-(4-(4-(N-methylmethylsulfonamido) phenyl) thiazol-2-yl)-4-(naphthalen-l-yl)benzamide (VCT-12);

4-cyclohexenyl-N-(4-(4-(N-methylmethylsulfonamido)phenyl)thiazol-2-yl)benzamide (VCT-

13);

N-(4-(4-(N-methylmethylsulfonamido) phenyl)thiazol-2-yl)-4-(pyridin-4-yl)benzamide (VCT-

14);

N-(4-(4-(N-methylmethylsulfonamido)phenyl) thiazol-2-yl)-4-(pyridin-3-yl)benzamide (VCT-

15);

4'-cyano-N-(4-(4-(N-methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4-carboxamide

(VCT-16);

4-(benzo[d][l,3]dioxol-5-yl)-N-(4-(4-(N-methylmethylsulfonamido)phenyl)thiazol-2- yl)benzamide (VCT-17); N-(4-(4-(l,l,l-trifluoro-N-methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4- carboxamide (VCT-18);

N-(4-(4-(l,l,l-trifluoro-N-methylmethylsulfonamido)phenyl)thiazol-2-yl)-4'- (trifluoromethyl)biphenyl-4-carboxamide (VCT-19);

4'-cyano-N-(4-(4-(l,l,l-trifluoro-N-methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4- carboxamide (VCT-20);

3'-chloro-N-(4-(4-(N-methylmethylsulfonamido)phenyl)thiazol-2-yl)-4'- (trifluoromethyl)biphenyl-4-carboxamide (VCT-21);

2'-fluoro-N-(4-(4-(N-methylmethylsulfonamido)phenyl)thiazol-2-yl)-4'- (trifluoromethyl)biphenyl-4-carboxamide (VCT-22);

N-(4-(4-(N-ethylmethylsulfonamido)phenyl) thiazol-2-yl)biphenyl-4-carboxamide (VCT-23); N-(4-(4-(N-ethylmethylsulfonamido)phenyl)thiazol-2-yl)-2'-fluoro-4'-(trifluoromethyl)biphenyl- 4-carboxamide (VCT-24);

N-(4-(4-(N-ethylmethylsulfonamido)phenyl) thiazol-2-yl)-4'-(trifluoromethyl)biphenyl-4- carboxamide (VCT-25); and

N-(4-(4-(N-methyl-methylsulfonamido)phenyl)thiazol-2-yl)-[l, -biphenyl]-4-carboxamide

(VCT-100).

Embodiment 13 provides a pharmaceutical composition comprising the compound of any of Embodiments 1-12 and at least one pharmaceutically acceptable carrier.

Embodiment 14 provides the pharmaceutical composition of Embodiment 13, further comprising at least one additional agent that treats, ameliorates, or prevents a cancer.

Embodiment 15 provides a method of treating, ameliorating, and/or preventing prostate cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any of Embodiments 1-12.

Embodiment 16 provides a method of inhibiting, preventing, or reducing the rate of angiogenesis in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any of Embodiments 1-12.

Embodiment 17 provides a method of inhibiting, preventing, or reducing the rate of lymphangiogenesis in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any of Embodiments 1-12. Embodiment 18 provides a method of inhibiting, preventing, or reducing the rate of prostate tumor metastasis in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any of Embodiments 1-12.

Embodiment 19 provides the method of any of Embodiments 15-18, wherein the compound is administered as a pharmaceutical composition comprising at least one

pharmaceutically acceptable carrier.

Embodiment 20 provides the method of any of Embodiments 15-19, wherein the compound is the only therapeutically effective agent administered to the subject.

Embodiment 21 provides the method of any of Embodiments 15-20, wherein the compound is the only therapeutically effective agent administered to the subject in a

therapeutically effective amount.

Embodiment 22 provides the method of any of Embodiments 15-21, wherein the compound is administered by an administration route selected from the group consisting of inhalational, oral, rectal, vaginal, parenteral, intracranial, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, and intravenous.

Embodiment 23 provides the method of any of Embodiments 15-22, wherein the subject is further administered at least one additional agent that treats a cancer.

Embodiment 24 provides the method of any of Embodiments 15-23, wherein the compound and the at least one additional agent are co-administered.

Embodiment 25 provides the method of any of Embodiments 15-24, wherein the compound and the at least one additional agent are co-formulated.

Embodiment 26 provides the method of any of Embodiments 15-25, wherein the subject is a mammal.

Embodiment 27 provides the method of any of Embodiments 15-26, wherein the mammal is human.

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMS What is claimed is:

1. A compound of formula (I), or a salt, solvate, enantiomer, and/or tautomer thereof:

wherein:

X¹ is selected from the group consisting of phenylenyl and heteroaryl enyl, wherein the phenylenyl or heteroaylenyl is substituted with‘n’ independently selected R⁵ groups;

X² is selected from the group consisting of C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, halogen, aryl, and heteroaryl, wherein the cycloalkyl, cycloalkenyl, aryl or heteroaryl is independently substituted with‘p’ independently selected R⁶ groups;

R¹ is selected from the group consisting of H and Ci-C₆ alkyl;

R² is selected from the group consisting of Ci-C₆ alkyl and Ci-C₆ haloalkyl;

each occurrence of R³ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, -N(R^a)(R^a), -OR^a, - COOH, -COO(Ci-C₆ alkyl), and carboxamide, wherein each occurrence of R^a is independently H or Ci-C₆ alkyl;

R⁴ is selected from the group consisting of H and Ci-C₆ alkyl;

each occurrence of R⁵ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, -N(R^b)(R^b), -OR^b, - COOH, -COO(Ci-C₆ alkyl), and carboxamide, wherein each occurrence of R^b is independently H or Ci-C₆ alkyl;

each occurrence of R⁶ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, -N(R^C)(R^C), -OR^c, - COOH, -COO(Ci-C₆ alkyl), and carboxamide, wherein each occurrence of R^c is independently H or Ci-C₆ alkyl,

or two R⁶ bound to adjacent ring carbons optionally combine to form -0(CH₂)_I.20-; m is 0, 1, or 2; n is 0, 1, or 2; and

p is 0, 1, 2, 3, or 4.

2. The compound of claim 1, wherein R¹ is H, methyl, ethyl, n-propyl, or isopropyl.

3. The compound of claim 1, wherein R² is methyl, ethyl, n-propyl, isopropyl, or trifluoromethyl.

4. The compound of claim 1, wherein each occurrence of R³ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, and fluoro.

5. The compound of claim 1, wherein R⁴ is H, methyl, ethyl, n-propyl, or isopropyl.

6. The compound of claim 1, wherein each occurrence of R⁵ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, cyano, and fluoro.

7. The compound of claim 1, wherein each occurrence of R⁶ is independently selected from the group consisting of H, Ci-C₆ alkyl, Ci-C₆ haloalkyl, cyano, and fluoro, or two R⁶ bound to adjacent ring carbons optionally combine to form -0(CH₂)_I-20.

8. The compound of claim 1, wherein m is 0.

9. The compound of claim 1, wherein n is 0.

10. The compound of claim 1, wherein p is 0, 1, 2, or 3.

11. The compound of claim 1, which is a compound of formula (la):

12. The compound of claim 1, which is selected from the group consisting of:

-bromo-N-(4-(4-(N-methylmethylsulfonamido) pheny l)thi azol -2-y l)b enzami de (VCT-l);

-difluoro-N-(4-(4-(N-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l, 1’-biphenyl]-4-carboxamide (VCT-2);

trifluoro-N-(4-(4-(N-methyl methylsulfonamido)phenyl)thiazol-2-yl)-[l, 1’-biphenyl]-4-carboxamide (VCT-3);

fluoro-N-(4-(4-(N-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l, 1’-biphenyl]-4-carboxamide (VCT-4);

'-fluoro-N-(4-(4-(N- methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4-carboxamide (VCT-5);

difluoro-N-(4-(4-(N-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l, 1’-biphenyl]-4-carboxamide (VCT-6);

trifluoromethyl-N-(4-(4-(N-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l, l’-biphenyl]-4-carboxamide (VCT-7);

trifluorom ethyl -N -(4-(4 -(N -methyl methylsulfonamido)phenyl)thiazol-2-yl)-[l, l’-biphenyl]-4-carboxamide (VCT-8);

methylsulfonamido)phenyl)thiazol-2-yl)-[l, 1’-biphenyl]-4-carboxamide (VCT-9);

methylsulfonamido)phenyl)thiazol-2-yl)-[l, l’-biphenyl]-4-carboxamide) (VCT-10);

thiazol-2-yl)-4-(naphthalen-l-yl)benzamide (VCT-12);

-cyclohexenyl-N-(4-(4-(N- methylmethylsulfonamido)phenyl)thiazol-2-yl)benzamide (VCT-13);

2-yl)-4-(pyri din-3 -yl)benzamide (VCT-l 5);

'-cyano-N-(4-(4-(N- methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4-carboxamide (VCT-16);

-(benzo[d][l,3]dioxol-5-yl)-N-(4-(4-(N- methylmethylsulfonamido)phenyl)thiazol-2-yl)benzamide (VCT-17);

-trifluoro-N- methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4-carboxamide (VCT-18);

-trifluoro-N- methylmethylsulfonamido)phenyl)thiazol-2-yl)-4'-(trifluoromethyl)biphenyl-4-carboxamide (VCT-19);

'-cyano-N-(4-(4-( 1, 1,1 -trifluoro-N- methylmethylsulfonamido)phenyl)thiazol-2-yl)biphenyl-4-carboxamide (VCT-20);

'-chloro-N-(4-(4-(N- methylmethylsulfonamido)phenyl)thiazol-2-yl)-4'-(trifluoromethyl)biphenyl-4-carboxamide

(VCT-21);

'-fluoro-N-(4-(4-(N- methylmethylsulfonamido)phenyl)thiazol-2-yl)-4'-(trifluoromethyl)biphenyl-4-carboxamide

-ethylmethylsulfonamido)phenyl) thiazol-2- yl)biphenyl-4-carboxamide (VCT-23);

-ethylmethylsulfonamido)phenyl)thiazol- 2-yl)-2'-fluoro-4'-(trifluoromethyl)biphenyl-4-carboxamide (VCT-24);

-ethylmethylsulfonamido)phenyl) thiazol-2- yl)-4'-(trifluoromethyl)biphenyl-4-carboxamide (VCT-25); and

-methyl- methylsulfonamido)phenyl)thiazol-2-yl)-[l,r-biphenyl]-4-carboxamide (VCT-100).

13. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable carrier.

14. The composition of claim 13, further comprising at least one additional agent that treats, ameliorates, or prevents a cancer.

15. A method of treating, ameliorating, and/or preventing prostate cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

16. A method of inhibiting, preventing, or reducing the rate of angiogenesis in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

17. A method of inhibiting, preventing, or reducing the rate of lymphangiogenesis in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any claim 1.

18. A method of inhibiting, preventing, or reducing the rate of prostate tumor metastasis in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

19. The method of any of claims 15-18, wherein the compound is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier.

20. The method of any of claims 15-18, wherein the compound is the only therapeutically effective agent administered to the subject.

21. The method of any of claims 15-18, wherein the compound is the only therapeutically effective agent administered to the subject in a therapeutically effective amount.

22. The method of any of claims 15-18, wherein the compound is administered by an administration route selected from the group consisting of inhalational, oral, rectal, vaginal, parenteral, intracranial, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, and intravenous.

23. The method of any of claims 15-18, wherein the subject is further administered at least one additional agent that treats a cancer.

24. The method of claim 23, wherein the compound and the at least one additional agent are co-administered.

25. The method of claim 24, wherein the compound and the at least one additional agent are co-formulated.

26. The method of any one of claims 15-18, wherein the subject is a mammal.

27. The method of claim 26, wherein the mammal is human.