Small molecules for treating cancer, inhibiting chemokine activity and / or inducing cell death

Abstract

To provide compounds capable of, or usable in, inducing death of cancer cells and / or modulating a biological activity of a chemokine e.g., cell migration, and / or treating diseases and disorders associated with a biological activity of a chemokine and / or cell migration, and / or in treating cancer.SOLUTION: Specific examples of the compound are represented by the following formulae.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims priority under 35 USC§119(e) to U.S. Provisional Patent Application No. 62 / 848,008, filed on May 15, 2019, the entire contents of which are hereby incorporated by reference into this application.

[0002] In some embodiments, the present invention relates to therapies, and more particularly, to the regulation of chemokine bioactivity, the killing of cancer cells, the inhibition of chemokine-dependent cell migration, and / or the treatment of diseases and disorders associated with chemokine bioactivity and / or cell migration (e.g., cancer), as well as methods of using these compounds.

Background Art

[0003] Chemokines are one of a number of biological factors involved in the inflammatory disease process. Chemokines belong to a group of small heparin-binding proteins, mostly basic, of about 8 - 14 kDa, related by both their primary structure and the presence of four conserved cysteine residues.

[0004] Chemokines are selective chemoattractants for leukocyte subpopulations in vitro and are chemotactic cytokines known to induce the accumulation of inflammatory cells in vivo. In addition to chemotaxis, chemokines mediate leukocyte degranulation [Baggiolini and Dahinden, Immunol Today 1994, 15:127 - 133], upregulation of adhesion receptors [Vaddi and Newton, J Immunol 1994, 153:4721 - 4732], and suppression of human immunodeficiency virus replication [Cocchi et al., Science 1995, 270:1811 - 1815].

[0005] Chemokines play an essential role in the recruitment and activation of cells derived from the immune system. They also have extensive effects in a number of different cell types beyond the immune system, such as various cells of the central nervous system [Ma et al., PNAS 1998, 95:9448-9453] and endothelial cells in which either angiogenesis or anti-angiogenic effects occur [Strieter et al., J Biol Chem 1995, 270:27348-27357]. Certain chemokines can have multiple effects on tumors, including promoting angiogenesis, growth and metastasis and suppressing the immune response to cancer, while other chemokines inhibit tumor-mediated angiogenesis and promote the anti-tumor immune response.

[0006] Chemokine receptors have increasingly attracted attention due to their important role in inflammation and in the progression of related conditions such as asthma, atherosclerosis, graft rejection, AIDS and autoimmune conditions (e.g., multiple sclerosis, arthritis, myasthenia gravis, lupus).

[0007] SDF-1 (stromal cell-derived factor 1), also known as CXCL12 (C-X-C motif chemokine 12), is a chemokine with potent chemotactic activity for lymphocytes. SDF-1 plays an important role in angiogenesis, and its role is related to angiogenesis associated with tumor progression by replenishment of endothelial progenitor cells from the bone marrow, an effect mediated by CXCR4, the receptor for SDF-1 [Zheng et al., Cardiovasc Pharmacol 2007, 50:274-280, Kryczek et al., Am J Physiol Cell Physiol 2007, 292:C987-C995]. Furthermore, cancer cells expressing CXCR4 are attracted to metastatic target tissues that secrete SDF-1.

[0008] Plerixafor, an antagonist of CXCR4, is used in combination with G-CSF (granulocyte colony-stimulating factor) to mobilize hematopoietic stem cells in cancer patients, particularly in patients with lymphoma and multiple myeloma. The stem cells are then returned to the patient by transplantation after chemotherapy or radiotherapy.

[0009] In animal studies, plerixafor has also been reported to reduce metastasis [Smith et al., Cancer Res 2004, 64:8604-8612], reduce recurrence of glioblastoma associated with angiogenesis [Kioi et al., J Clin Investigation 2010, 120:694-705], and counteract opioid-induced hyperalgesia [Wilson et al., Brain Behav Immun 2011, 25:565-573].

[0010] International Publication No. WO 2017 / 103931, an application of the assignee of the present application (the content of which is incorporated herein by reference as if fully set forth herein), discloses data obtained by screening and further examining a natural compound library of compounds capable of regulating chemokine activity. According to the study described in International Publication No. WO 2017 / 103931, compounds characterized by certain structural features were identified as being capable of regulating the effects of individual chemokines on cells and of affecting cancer cells and other pathogenic cells. International Publication No. WO 2017 / 103931 describes therein a compound designated as BKT300 (shown below) as, for example, inducing cancer cell death and inhibiting cancer cell migration.

[0011]

Chemical formula

[0012] International Publication No. 2017 / 103932, which is an application of the assignee of the present application (the content of which is incorporated herein by reference as if fully set forth herein), discloses a newly designed structural analog of BKT300, and it has been shown that the analog induces cancer cell death, inhibits cancer cell migration, selectively arrests cancer cell proliferation in the G2M phase, and induces apoptotic cancer cell death via the caspase 3 pathway. One of the compounds described in International Publication No. 2017 / 103932 is designated BKT300-3-C5 and is the compound shown below in its keto and enol forms.

[0013] [Chemical formula] Summary of the Invention

[0014] According to one aspect of some embodiments of the present invention, there is provided a compound represented by formula Ia and / or Ib.

[0015] [Chemical formula]

[0016] [wherein, A is an alkyl having a length of at least 4 carbon atoms, B is selected from hydroxy and alkoxy, D and G are each independently selected from hydrogen, hydroxy, alkoxy and alkyl, provided that at least one of D and G is hydrogen, E is hydroxy, R1 is selected from hydrogen and alkyl, R2 to R5 are each independently selected from hydrogen, hydroxy, halo, alkoxy, thioalkoxy, thiol, thioalkoxy and amine).

[0017] According to some of the embodiments described herein, B is alkoxy.

[0018] According to some of the embodiments described in this specification, one of D and G is an alkoxy group.

[0019] According to some of the embodiments described in the specification, one of D and G is an alkyl group, and the alkyl group has at least 4 carbon atoms in length.

[0020] According to some of the embodiments described in this specification, R1 is hydrogen.

[0021] According to some of the embodiments described in this specification, each of R2 to R5 is hydrogen.

[0022] According to some of the embodiments described in this specification, the compound is a compound represented by the following formula IIa or IIb.

[0023] [Chemical formula] [In the formula, A is an alkyl group having at least 4 carbon atoms in length, B is selected from hydroxy and alkoxy, D and G are each independently selected from hydrogen, hydroxy, alkoxy and alkyl, provided that at least one of D and G is hydrogen, E is hydroxy, R1 is selected from hydrogen and alkyl, R2 to R5 are each independently selected from hydrogen, hydroxy, halo, alkoxy, thioalkoxy, thiol, thioalkoxy and amine.]

[0024] According to some of the embodiments described in this specification, each of R2 to R5 is hydrogen.

[0025] According to some of the embodiments described in this specification, R1 is hydrogen.

[0026] According to some of the embodiments described in this specification, at least one of D and G is an alkoxy group.

[0027] According to some of the embodiments described in this specification, B is an alkoxy group.

[0028] According to some of the embodiments described in this specification, the compound is a compound of the following formula.

[0029]

Chemical formula

[0030] The above-exemplified compound is referred to as BKT300-N1 in this specification.

[0031] According to some of the embodiments described in this specification, the compound may induce cell death.

[0032] According to some of the embodiments described in this specification, the compound may induce apoptosis of cells.

[0033] According to some of the embodiments described in this specification, apoptosis is associated with the cleavage of caspase-3.

[0034] According to some of the embodiments described in this specification, the compound may induce the arrest of cancer cell growth in the G2M phase of cancer cells.

[0035] According to some of the embodiments described in this specification, the compound may inhibit chemokine-induced cell migration.

[0036] According to one aspect of some embodiments of the present invention, the compounds represented by formula Ia and / or Ib or formula IIa and / or IIb in any of the corresponding embodiments of the present invention, and any combination thereof, are for the treatment of cancer in a patient.

[0037] According to some of the embodiments described herein, the cancer is leukemia.

[0038] According to some of the embodiments described herein, the cancer is selected from leukemia, melanoma, lung cancer, lymphoma, myeloma, ovarian cancer, liver cancer, brain cancer, colorectal cancer, and prostate cancer.

[0039] According to some of the embodiments described herein, the cancer is drug-resistant cancer.

[0040] According to some of the embodiments described herein, the cancer treatment further comprises administering an additional anti-cancer agent to the patient.

[0041] According to one aspect of some embodiments of the present invention, the compounds represented by formula Ia and / or Ib or formula IIa and / or IIb in any of the corresponding embodiments of the present invention, and any combination thereof, are for modulating the biological activity of chemokines in a patient.

[0042] According to one aspect of some embodiments of the present invention, the compounds represented by formula Ia and / or Ib or formula IIa and / or IIb in any of the corresponding embodiments of the present invention, and any combination thereof, are for treating a condition treatable by modulating the biological activity of chemokines.

[0043] According to some of the embodiments described herein, the chemokine is SDF-1.

[0044] According to some of the embodiments described herein, the chemokine is MCP-1.

[0045] According to some of the embodiments described herein, the condition is age-related macular degeneration.

[0046] According to some of the embodiments described herein, the disease or disorder is cancer.

[0047] According to one aspect of some embodiments of the present invention, the compounds represented by formula Ia and / or Ib in any of the corresponding embodiments of the present invention, and any combination thereof, are for the treatment of inflammation.

[0048] According to one aspect of some embodiments of the present invention, the compounds represented by formula Ia and / or Ib or formula IIa and / or IIb in any of the corresponding embodiments of the present invention, and any combination thereof, are for the treatment of non-cancerous hyperproliferative diseases.

[0049] According to one aspect of some embodiments of the present invention, the compounds represented by formula Ia and / or Ib or formula IIa and / or IIb described herein are for inducing cell death in any of the respective embodiments or any combination thereof.

[0050] According to one aspect of some embodiments of the present invention, the compounds represented by formula Ia and / or Ib or formula IIa and / or IIb in any of the corresponding embodiments of the present invention, and any combination thereof, are for inducing apoptosis in cells.

[0051] According to some of the embodiments described herein, apoptosis is associated with the cleavage of caspase-3.

[0052] According to some of the embodiments described herein, the cells are cancer cells.

[0053] According to some of the embodiments described herein, the cells are drug-resistant cells (e.g., drug-resistant cancer cells).

[0054] According to one aspect of some embodiments of the present invention, the compounds represented by formula Ia and / or Ib or formula IIa and / or IIb in any of the corresponding embodiments of the present invention, and any combination thereof, are for inducing the arrest of cancer cell growth in the G2M phase of cancer cells.

[0055] Unless otherwise specified, all technical and / or scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, exemplary methods and / or materials are described below. In case of conflict, this patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting necessarily.

[0056] Some embodiments of the present invention will be described herein with reference to the accompanying drawings for purposes of illustration only. It is emphasized that the matters particularly shown and described below with reference to the drawings are for purposes of illustration and for the detailed description of embodiments of the present invention. Similarly, the description presented with the drawings will make it clear to those skilled in the art how embodiments of the present invention can be practiced.

Brief Description of the Drawings

[0057]

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Mode for Carrying Out the Invention

[0058] In some embodiments thereof, the present invention relates to therapy, and more particularly, but not exclusively, to the regulation of chemokine bioactivity, the killing of cancer cells, the inhibition of chemokine - dependent cell migration, and / or the treatment of diseases and disorders (e.g., cancer) associated with chemokine bioactivity and / or cell migration, as well as small - molecule compounds useful therefor and methods of using these compounds.

[0059] Before explaining in detail at least one embodiment of the present invention, it should be understood that the present invention is not necessarily limited in detail to the specific examples shown by the description or examples provided by the following description of its use. The present invention is capable of other embodiments and can be practiced or carried out in various ways.

[0060] As described in the above background art, the assignee of the present application has previously elucidated that small molecules having specific structural features can modulate the effects of individual chemokines on cells and affect cancer cells and other pathogenic cells using a screening assay for heavy labor. Furthermore, several structural analogs of these small molecules were designed, and it was found that they exhibit an even improved effect on chemokine activity and induction of cancer cell death. See International Publication No. 2017 / 103931 and International Publication No. 2017 / 103932.

[0061] In searching for further compounds capable of modulating chemokine activity and / or inducing cell death of cancer cells and other pathogenic cells, the inventors have clarified that modifying the structures of the compounds taught in International Publication No. 2017 / 103932 leads to a substantial improvement in the desired activity of these compounds.

[0062] Although not bound by a specific logic, the inventors have clarified that compounds having one or more hydroxy substituents, such as those obtained by substituting one or more alkoxy groups of the compounds described in International Publication No. 2017 / 103932, exhibit an improved effect.

[0063] An exemplary synthetic route for preparing such an exemplary compound, referred to herein as BKT300-N1, is shown in FIG. 1.

[0064] The inventors have shown that an exemplary such compound, referred to herein as BKT300-N1, which has a modification to the structure of the compound referred to as BKT300-3-C5 in International Publication No. 2017 / 103932, exhibits a superior effect on modulating the biological activity of chemokines (see, for example, FIGS. 2 to 5), and also induces cancer cell death and / or affects cancer cell migration and / or proliferation, interacts with other anti-cancer agents, and acts as an anti-cancer agent by inducing cancer cell death and inhibiting cancer cell proliferation in taxol-resistant cancer cells. See, for example, FIGS. 6 to 18.

[0065] The modified compounds described herein are useful in modulating the biological activity of chemokines. Accordingly, they are useful in the treatment of diseases or disorders associated with the biological activity of chemokines described herein. The modified compounds described herein are particularly useful as anti-cancer agents by inducing cancer cell death and / or arresting cell proliferation and / or affecting the migration of cancer cells (by inhibiting angiogenesis and / or metastasis), as described hereinafter herein.

[0066] The general effects of the compounds according to some embodiments of the present invention have been shown against various biological phenomena including chemokine-induced cell migration and apoptosis. These findings make the compounds described herein a potent medicine that can be used in the treatment of various medical conditions including inflammation (e.g., autoimmune diseases), cancer, and non-cancerous hyperproliferative diseases.

[0067] Accordingly, embodiments of the present invention generally relate to newly designed small molecules and their use.

[0068] Compound (Small Molecule) : According to one aspect of some embodiments of the present invention, there is provided a newly designed small molecule (compound) that can be collectively represented by Formula Ia.

[0069]

Chemical formula

[0070] [Wherein, A is an alkyl having at least 4 carbon atoms in length, B is selected from hydroxy, alkoxy, and aryloxy, or is selected from hydroxyl and alkoxy, D, E, and G are each independently selected from hydrogen, hydroxy, alkoxy, aryloxy, and alkyl, provided that one of D, E, and G is hydroxy, R1 is selected from hydrogen, alkyl, and cycloalkyl, or is selected from hydrogen and alkyl, R2 to R5 are each independently hydrogen, hydroxy, halo, alkoxy, thioalkoxy, thiol, thioalkoxy, amine, and optionally alkyne, aryloxy, thioaryloxy, carboxylate, carbonyl, sulfonyl, sulfonate, sulfinyl, cyano, nitro, and other substituents described herein.]

[0071] The compound of formula Ia is characterized by a ketone group (carbonyl) and can undergo keto-enol tautomerism to the "enol" form. Therefore, it can also be represented by formula Ib.

[0072]

Chemical formula

[0073] Keto-enol tautomerism is known in the art as showing a rapid equilibrium between a carbonyl group (C=O) and its enol tautomer.

[0074] Keto-enol tautomerism is most often thermodynamically driven, and at room temperature, the equilibrium usually favors the formation of the keto form. However, depending on environmental conditions such as the pH or ionic strength of the solution, the concentration of the compound, the temperature, the presence of agents that stabilize the enol form, etc., the equilibrium may shift in a direction where the enol form is equally present or dominant.

[0075] In some embodiments, depending on environmental conditions, the compound according to this embodiment can be in either the keto tautomer (formula Ia) form, the enol form (formula Ib), or can take an equilibrium between the keto form and the enol form, and thus can exist in both forms of formula Ia and Ib.

[0076] In any of the embodiments described herein, at least one of B, D, E, and G is alkoxy or aryloxy, preferably alkoxy. In some embodiments, at least two of B, D, E, and G are alkoxy and / or aryloxy, preferably each is alkoxy.

[0077] In any of the embodiments described herein, the alkoxy has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. By way of example, but not limited to these, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy are mentioned.

[0078] In any of the embodiments described herein, the alkoxy is methoxy.

[0079] In any of the embodiments described herein, B is alkoxy (for example, methoxy).

[0080] In any of the embodiments described herein, one or less of D, E, and G is alkyl.

[0081] In any of the embodiments described herein, two or less of D, E, and G, or one or less of D, E, and G is alkoxy or aryloxy.

[0082] In any of the embodiments described herein, when two of D, E, and G are alkoxy and / or aryloxy, none of D, E, and G is alkyl.

[0083] In any of the embodiments described herein, at least one of D, E, and G is hydroxy, and at least one of D, E, and G is hydrogen. In some of these embodiments, one or more of the other of D, E, and G can be alkoxy, aryloxy, and / or alkyl, preferably alkoxy and / or alkyl, more preferably alkoxy.

[0084] In any of the embodiments described herein, E is hydroxy, D is hydrogen, and G is alkyl.

[0085] In any of the embodiments described herein, D is hydrogen, E is hydroxy, and G is alkoxy, for example, methoxy.

[0086] In any of the embodiments described herein, D is alkoxy, for example, methoxy, E is hydroxy, and G is hydrogen.

[0087] In any of the embodiments described herein, one of D and G is alkoxy, for example, methoxy, the other of D and G is hydroxy, and E is hydrogen.

[0088] In any of the embodiments described herein, one of D and G is hydrogen, the other of D and G is alkyl, and E is hydrogen.

[0089] In any of the embodiments described herein, E is hydrogen, D is alkyl, and G is hydroxy.

[0090] In any of the embodiments described herein, G is hydrogen, E is alkyl, and D is hydroxy.

[0091] In any of the embodiments described herein, D is hydrogen, G is alkyl, and E is hydroxy.

[0092] In any of the embodiments described herein, E is hydrogen, G is alkyl, and D is hydroxy.

[0093] In any of the embodiments described herein, G is hydrogen, D is alkyl, and E is hydroxy.

[0094] In any of the embodiments described herein, E is hydrogen, D is an alkoxy, for example, methoxy, and G is hydroxy.

[0095] In any of the embodiments described herein, G is hydrogen, E is an alkoxy, for example, methoxy, and D is hydroxy.

[0096] In any of the embodiments described herein, D is hydrogen, G is hydroxy, and E is an alkoxy, for example, methoxy.

[0097] In any of the embodiments described herein, E is hydrogen, G is an alkoxy, for example, methoxy, and D is hydroxy.

[0098] In any of the embodiments described herein, E is hydroxy.

[0099] In any of the embodiments described herein, B is an alkoxy (for example, methoxy).

[0100] In any of the embodiments described herein, D is an alkoxy (for example, methoxy).

[0101] In any of the embodiments described herein, G is hydrogen.

[0102] In any of the embodiments described herein, E is hydroxy, D is an alkoxy (for example, methoxy), and G is hydrogen. In some of such embodiments, B is an alkoxy (for example, methoxy).

[0103] In any of the embodiments described herein, E is hydroxy, G is an alkoxy (for example, methoxy), and D is hydrogen. In some of such embodiments, B is an alkoxy (for example, methoxy).

[0104] In any of the embodiments described herein, E is hydroxy, and both D and G are hydrogen. In some of such embodiments, B is alkoxy (for example, methoxy).

[0105] In any of the embodiments described herein, D is hydroxy, and both E and G are hydrogen. In some of such embodiments, B is alkoxy (for example, methoxy).

[0106] In any of the embodiments described herein, G is hydroxy, and both D and E are hydrogen. In some of such embodiments, B is alkoxy (for example, methoxy).

[0107] In any of the embodiments described herein, D is the alkyl.

[0108] In some of these embodiments, one of G and E is hydrogen. In some of these embodiments, G is hydrogen and E is hydroxy.

[0109] In any of the embodiments described herein, E is hydroxy, D is alkyl, and G is hydrogen. In some of such embodiments, B is alkoxy (for example, methoxy).

[0110] In any of the embodiments described herein, when one of D, E, and G is alkyl, the alkyl always has a length of at least 4 carbon atoms.

[0111] In any of the embodiments described herein, an alkyl having a length of at least 4 carbon atoms can have, for example, a length of 1 to 20, or 1 to 10, or 1 to 8 carbon atoms. Exemplary alkyls having a length of at least 4 carbon atoms include substituted or unsubstituted butyl, substituted or unsubstituted pentyl, substituted or unsubstituted hexyl, substituted or unsubstituted heptyl, substituted or unsubstituted octyl, substituted or unsubstituted nonyl, substituted or unsubstituted decyl, substituted or unsubstituted undecyl, substituted or unsubstituted dodecyl, and the like.

[0112] In any of the embodiments described herein, an alkyl having a length of 4 carbon atoms is an unsubstituted alkyl. In some embodiments, it is hexyl, and in some embodiments, it is unsubstituted hexyl.

[0113] In any of the embodiments described herein, A is an alkyl having a length of at least 4 carbon atoms, and optionally, one of D, E, and G is an alkyl having a length of at least 4 carbon atoms.

[0114] When A and one of D, E, and G are alkyls having a length of 4 carbon atoms, these alkyls may be the same or different.

[0115] In some of these embodiments, A and one of D, E, and G are unsubstituted alkyls, and in some embodiments, both are unsubstituted hexyls.

[0116] In any of the embodiments described herein, R1 is hydrogen.

[0117] In any of the embodiments described herein, each of R2 to R5 is independently selected from hydrogen, hydroxy, halo, alkoxy, thioalkoxy, thiol, thioalkoxy, and amine.

[0118] In any of the embodiments described herein, each of R2 to R5 is hydrogen.

[0119] In any of the embodiments described herein, each of R1 to R5 is hydrogen.

[0120] Alternatively, one or more of R1 to R5 are other than hydrogen, and the nature of each substituent (singly or plurally) is such that it does not interfere with the interaction (e.g., chemokine binding) between the small molecule and its biological target(s).

[0121] In some optional embodiments of the present invention, the compounds of this embodiment can be comprehensively represented by Formula IIa or IIb.

[0122] [Chemical formula] [Wherein, A is an alkyl having at least 4 carbon atoms in length, B is selected from hydroxy and alkoxy, D and G are each independently selected from hydrogen, hydroxy, alkoxy and alkyl, provided that at least one of D and G is hydrogen, R1 is selected from hydrogen and alkyl, R2 to R5 are each independently selected from hydrogen, hydroxy, halo, alkoxy, thioalkoxy, thiol, thioalkoxy and amine.]

[0123] In any of the embodiments described herein, R2 to R5 are each hydrogen.

[0124] In any of the embodiments described herein, R1 is hydrogen.

[0125] In any of the embodiments described herein, at least one of D and G is alkoxy. Alternatively, or in addition, at least one of D and G is the alkyl described in the corresponding embodiments herein. As a further alternative, or in addition, at least one of D and G is hydroxy.

[0126] In any of the embodiments described herein, D and G are each hydrogen.

[0127] In some such embodiments, B is alkoxy. Optionally, B is hydroxy.

[0128] In any of the embodiments described herein, the compounds described herein have the following chemical structures represented by their keto and enol tautomers.

[0129]

Chemical formula

[0130] This compound is named BKT300-N1 herein.

[0131] In any of the embodiments described herein, the compounds described herein have the following chemical structures which are their keto and enol tautomers.

[0132]

Chemical formula

[0133] In any of the embodiments described herein, the compounds described herein have the following chemical structures which are their keto and enol tautomers.

[0134]

Chemical formula

[0135] In any of the embodiments described herein, the compounds described herein have the following chemical structures which are their keto and enol tautomers.

[0136]

Chemical formula

[0137] Therapeutic Application : The compounds described herein are shown herein to act as inhibitors of chemokine-dependent cell migration and as inhibitors of cancer cells (e.g., inhibitors of cancer cell growth and / or inducers of apoptosis and / or inhibitors of cancer cell migration) in any one of the respective embodiments and any combination thereof.

[0138] Thus, each of the compounds described herein is capable of, or useful in, inhibiting cancer cells and / or inducing cancer cell death and / or inducing apoptosis and / or inducing growth arrest and / or inhibiting chemokine-dependent cell migration and / or modulating the biological activity of chemokines (e.g., cell migration), and / or treating diseases and disorders associated with cell migration (e.g., cancer and inflammatory diseases and disorders), and / or treating proliferative diseases or disorders (where induction of apoptosis and / or growth arrest is desirable).

[0139] Inflammation and cancer are typically dominated by cell migration (e.g., invasion, metastasis), which is often associated with cell proliferation, and are thus contemplated for treatment with the compounds of the present embodiment.

[0140] The proliferative diseases and disorders described herein, including medical conditions other than cancer (also referred to herein as "non-cancerous proliferative diseases"), are also contemplated for treatment with the compounds of some embodiments of the present invention due to their apoptosis-inducing effects.

[0141] Although not bound by any particular theory, the compounds described herein are, as described in detail hereinafter herein, particularly useful as anticancer agents because of their induction of cancer cell death, chemokine-dependent cancer cell migration (e.g., inhibition of metastasis) and / or effects on angiogenesis, induction of apoptosis in cancer cells, induction of cancer cell growth arrest, and particularly useful as anti-inflammatory agents because of chemokine-dependent immune cell migration (e.g., immune cell infiltration).

[0142] In any of the embodiments described herein, the small molecule compounds of formula Ia and / or Ib or formula IIa and / or IIb described herein can be induced or used for the death of pathogenic cells (e.g., cancer cells or immune cells or hyperproliferative cells) in any of the respective embodiments.

[0143] In any of the embodiments described herein, the small molecule compounds of formula Ia and / or Ib or formula IIa and / or IIb described herein can be induced or used for the cell death of pathogenic cells in any of the respective embodiments.

[0144] As used herein, the term "apoptosis" refers to the endogenous self-destruction or suicide program of cells. In response to an inducing stimulus, cells undergo a cascade of events including cell shrinkage, blebbing of the cell membrane, and chromatin condensation and fragmentation. These events ultimately convert the cell into a cluster of membrane-bound particles (apoptotic bodies), which are then phagocytosed by macrophages.

[0145] Methods for monitoring cell changes induced by compounds are known in the art and include, for example, the following methods described hereinabove. The ability of live cells to reduce the yellow salt MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) (manufactured by Sigma, Aldrich, St. Louis, Missouri, USA) to selectively generate purple to blue insoluble formazan precipitates forms the basis of the MTT assay, the BrDu assay [Cell Proliferation ELISA BrdU Colorimetric Assay Kit (manufactured by Roche, Mannheim, Germany)]; the TUNEL assay [manufactured by Roche, Mannheim, Germany]; the annexin V assay [ApoAlert® Annexin V Apoptosis Kit (manufactured by Clontech Laboratories, Inc., California, USA)]; the senescence-associated β-galactosidase assay (Dimri GP, Lee X, et al. 1995. A biomarker that identifies senescent human cell in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363-9367), 7-ADD viability staining (available from MD systems), the caspase-3 assay (available from MDsystems) as well as various RNA and protein detection methods (detecting levels of expression and / or activity).

[0146] In any of the embodiments described herein, for the small molecule compounds of formula Ia and / or Ib or formula IIa and / or IIb described herein, in any of the respective embodiments, the cell change is apoptosis, such as by cleavage of caspase-3.

[0147] In any of the embodiments described herein, for the small molecule compounds of formula Ia and / or Ib or formula IIa and / or IIb described herein, in any of the respective embodiments, the small molecule compound is capable of inducing apoptosis by cleavage of caspase-3 or can be used to induce it.

[0148] In any of the embodiments described herein, for the small molecule compounds of formula Ia and / or Ib or formula IIa and / or IIb described herein, in any of the respective embodiments, the small molecule compounds are capable of inducing or can be used to induce cell growth arrest. In some embodiments, the arrest occurs in the G2M phase of the cell cycle. In some of these embodiments, the cells are cancer cells.

[0149] Chemokine Regulation : According to aspects of some embodiments of the present invention, the small molecule compounds of formula Ia and / or Ib or formula IIa and / or IIb described herein are capable of modulating or can be used to modulate the chemokine bioactivity described herein in any of the respective embodiments or any combination thereof.

[0150] According to one aspect of some embodiments of the present invention, there is provided a method of modulating chemokine bioactivity, the method comprising contacting a chemokine with a compound according to any of the embodiments described herein.

[0151] According to one aspect of some embodiments of the present invention, there is provided the use of a compound according to any of the embodiments described herein in the manufacture of a medicament for modulating the bioactivity of a chemokine.

[0152] According to one aspect of some embodiments of the present invention, there is provided the use of a compound according to any of the embodiments described herein in the modulation of the bioactivity of a chemokine.

[0153] In some embodiments, the use and / or method for modulating chemokine activity is achieved in vivo, for example, by administering a therapeutically effective amount of the compound to a patient in need of modulation of chemokine activity.

[0154] In some embodiments, the use and / or method for modulating chemokine activity is achieved, for example, in research, ex vivo (e.g., in vitro).

[0155] In some embodiments related to any one of the embodiments described herein regarding a method, use or medicament for modulating the biological activity of a chemokine, the method, use or medicament is, for example, for treating a disease or disorder associated with the biological activity of a chemokine in a patient in need of treatment thereof by administering to the patient a therapeutically effective amount of a compound according to any of the embodiments described herein.

[0156] In any of the embodiments described herein, modulation of chemokine biological activity includes inhibition of chemokine biological activity. This can be demonstrated by the ability of the small molecules described herein to inhibit chemokine-induced cell migration, as exemplified herein in multiple cell types of different kinds.

[0157] In some embodiments related to any one of the embodiments described herein regarding a method, use or medicament for modulating the biological activity of a chemokine, the method, use or medicament is, for example, for treating a disease or disorder in a patient in need thereof in which modulating (e.g., inhibiting) the biological activity of a chemokine is beneficial by administering to the patient a therapeutically effective amount of a compound according to any of the embodiments described herein.

[0158] In some embodiments related to any one of the embodiments described herein regarding a method, use or medicament for modulating the biological activity of a chemokine, the method, use or medicament is, for example, for treating a disease or disorder treatable by modulation (e.g., inhibition) of chemokine biological activity by administering to a patient suffering from a disease or disorder treatable by modulation (e.g., inhibition) of chemokine biological activity a therapeutically effective amount of a compound according to any of the embodiments described herein.

[0159] In some embodiments related to any one of the embodiments described herein for a method, use or medicament for modulating the biological activity of a chemokine, the compounds described herein (relating to any of the respective embodiments) are effective in modulating chemokine-dependent cell migration. In some of these embodiments, chemokine-dependent cell migration is associated with the cancers and / or inflammation described herein.

[0160] In some embodiments related to any one of the embodiments described herein for a method or use for modulating the biological activity of a chemokine, the chemokine is MCP-1 and / or SDF-1. In some such embodiments, the chemokine is MCP-1. In some such embodiments, the chemokine is SDF-1.

[0161] In some embodiments related to any one of the embodiments described herein for modulating chemokine activity, the compounds, methods and / or medicaments (relating to any of the respective embodiments described herein) are those that inhibit the biological activity of the chemokine. In some such embodiments, the chemokine is MCP-1 and / or SDF-1. In some such embodiments, the chemokine is MCP-1. In some such embodiments, the chemokine is SDF-1.

[0162] In any of the embodiments described herein, the chemokine is MIP3a.

[0163] Examples of diseases and disorders associated with the activity of MIP3a (e.g., inhibition of MIP3a activity is beneficial) include, but are not limited to, autoimmune diseases and disorders such as psoriasis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis (MS), atopic dermatitis, dry eye disease, and age-related macular degeneration (AMD).

[0164] In some embodiments related to any one of the embodiments described herein for the treatment of a disease or disorder, the disease or disorder is not a bacterial infection.

[0165] SDF-1 and / or CXCR4 Inhibition : According to some embodiments, the small molecule compounds of Formula Ia and / or Ib described herein are capable of modulating, or can be used for modulating, the biological activities of SDF-1 and / or CXCR4 described herein in any one of the respective embodiments or any combination thereof.

[0166] According to one aspect of some embodiments of the present invention, there is provided a method for inhibiting the biological activities of SDF-1 and / or CXCR4, the method comprising contacting SDF-1 and / or CXCR4 with a compound according to any of the embodiments described herein.

[0167] According to one aspect of some embodiments of the present invention, there is provided the use of a compound according to any of the embodiments described herein in the manufacture of a medicament for inhibiting the biological activities of SDF-1 and / or CXCR4.

[0168] According to one aspect of some embodiments of the present invention, there is provided the use of a compound according to any of the embodiments described herein in the inhibition of the biological activities of SDF-1 and / or CXCR4.

[0169] In some embodiments of any of the embodiments related to the use and / or method for inhibiting the biological activities of SDF-1 and / or CXCR4, the use and / or method is achieved in vivo, for example, by administering a therapeutically effective amount of the compound to a patient in need of inhibition of the biological activities of SDF-1 and / or CXCR4.

[0170] In some embodiments, the use and / or method for inhibiting the biological activity of SDF-1 and / or CXCR4 is achieved ex vivo (e.g., in vitro), for example, in research.

[0171] In some embodiments related to any one of the embodiments described herein regarding a method, use or medicament for inhibiting the biological activity of SDF-1 and / or CXCR4, the method, use or medicament is, for example, for treating a disease or disorder associated with the biological activity of SDF-1 and / or CXCR4 in a subject in need of treatment thereof, by administering to the subject a therapeutically effective amount of a compound according to any of the embodiments described herein.

[0172] In some embodiments related to any one of the embodiments described herein regarding a method, use or medicament for inhibiting the biological activity of SDF-1 and / or CXCR4, the method, use or medicament is, for example, for treating a disease or disorder in which it is beneficial to inhibit the biological activity of SDF-1 and / or CXCR4 in a subject in need of treatment thereof, by administering to the subject a therapeutically effective amount of a compound according to any of the embodiments described herein.

[0173] In some embodiments related to any one of the embodiments described herein regarding a method, use or medicament for inhibiting the biological activity of SDF-1 and / or CXCR4, the method, use or medicament is, for example, for treating a disease or disorder treatable by inhibiting the biological activity of SDF-1 and / or CXCR4 in a subject in need of treatment thereof, by administering to the subject a therapeutically effective amount of a compound according to any of the embodiments described herein.

[0174] One of ordinary skill in the art will understand that CXCR4 is a receptor that mediates the activity of SDF-1 and that the activities of SDF-1 and CXCR4 typically overlap.

[0175] Examples of diseases and disorders associated with the activity of SDF-1 and / or CXCR4 (e.g., where inhibition of SDF-1 and / or CXCR4 activity is beneficial) include, but are not limited to, Wiskott-Aldrich syndrome, cervical adenocarcinoma, breast cancer, synovitis, tuberculosis, intraocular lymphoma, cytomegalovirus retinitis, chronic inflammatory demyelinating polyneuropathy, ocular hypertension, polyneuropathy, dendritic cell tumor, retinal hemangioblastoma, malaria, endocarditis, leukemia, rheumatoid arthritis, arthritis, prostatitis, prostate cancer, colorectal cancer, chronic lymphocytic leukemia, pancreatitis, neuritis, lung cancer, osteoarthritis, hypoxia, adenocarcinoma, pancreatic cancer, multiple myeloma, neuroblastoma, myeloid leukemia, astrocytoma, periodontitis, glioblastoma, preeclampsia, melanoma, hepatitis, esophagitis, myeloma, eclampsia, endocervicitis, periodontal disease, central nervous system lymphoma, primary breast cancer, hepatocellular carcinoma, systemic lupus erythematosus, asthma, renal cell carcinoma, myocardial infarction, medulloblastoma, endometrial cancer, lupus erythematosus, esophageal cancer, premature ovarian insufficiency, peritonitis, vascular disease, alcoholic hepatitis, kidney disease, cutaneous leishmaniasis, encephalitis, alopecia areata, lymphocytic leukemia, adenoma, mantle cell lymphoma, oligodendroglioma, marginal zone lymphoma, pertussis, ischemia, uveal melanoma, gingivitis, pituitary adenoma, bronchiolitis, neuromyelitis optica, mesothelioma, alopecia, cervical cancer, somatic, glioblastoma multiforme, bronchiolitis obliterans, brain injury, colorectal adenoma, squamous cell carcinoma of the tongue, B-cell lymphoma, traumatic brain injury, intravascular large B-cell lymphoma, allergic asthma, tick-borne encephalitis, blastoid plasmacytoid dendritic cell, oligodendroblastoma, childhood dermatomyositis, renal oncocytoma, endometrial adenocarcinoma, optic neuritis, seminoma, Sjogren's syndrome, pleurisy, neuritis, inflammatory bowel disease, cytomegalovirus infection, malignant pleural mesothelioma, squamous cell carcinoma of the oral cavity, skeletal muscle regeneration, Emery-Dreifuss muscular dystrophy, dominant type.

[0176] In some embodiments, exemplary diseases and disorders associated with the activity of SDF-1 and / or CXCR4 (e.g., inhibition of SDF-1 and / or CXCR4 activity is beneficial) include, but are not limited to, harmful angiogenesis, tumor metastasis, WHIM syndrome, Waldenström macroglobulinemia (WM), and opioid-induced hyperalgesia.

[0177] As used herein, the term "harmful angiogenesis" refers to angiogenesis associated with clinically and / or aesthetically undesirable outcomes.

[0178] Angiogenesis associated with tumors is a non-limiting example of harmful angiogenesis.

[0179] As used herein, the phrase "tumor metastasis" refers to a malignant tumor that spreads from its primary location to other parts of the body, e.g., breast cancer that metastasizes to the lung. Tumor metastasis often involves tumor cell migration.

[0180] In some embodiments related to any one of the embodiments described herein regarding a method or use for modulating the biological activity of a chemokine, the modulation comprises inhibiting the biological activity of SDF-1 and / or CXCR4 according to any of the respective embodiments described herein.

[0181] In some embodiments related to any one of the embodiments described herein regarding inhibiting the biological activity of SDF-1 and / or CXCR4, the inhibition of the biological activity of SDF-1 and / or CXCR4 is for providing immune stimulation.

[0182] In some embodiments, the immune stimulation is provided as part of cancer treatment, e.g., to stimulate the immune activity against cancer cells.

[0183] In some embodiments, the immune stimulation comprises increasing the level of hematopoietic stem cells in the peripheral blood of a subject.

[0184] In some embodiments, increasing the level of hematopoietic stem cells in a subject's peripheral blood is performed as a preparatory part of a hematopoietic stem cell transplantation (e.g., to generate hematopoietic stem cells for collection and subsequent return to the patient by transplantation). Examples of conditions that can be treated by hematopoietic stem cell transplantation include, but are not limited to, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia), lymphoma (e.g., Hodgkin's disease, non-Hodgkin lymphoma), myeloma (e.g., multiple myeloma), neuroblastoma, desmoplastic small round cell tumor, Ewing's sarcoma, choriocarcinoma, myelodysplastic syndrome, anemia (e.g., paroxysmal nocturnal hemoglobinuria, aplastic anemia, Diamond-Blackfan anemia, Fanconi anemia, acquired pure red cell aplasia), abnormal hemoglobinopathy, sickle cell disease, severe beta-thalassemia, myeloproliferative disorders (e.g., polycythemia vera, essential thrombocythemia, myelofibrosis), amyloid light chain amyloidosis, radiation poisoning, viral diseases (e.g., HTLV and / or HIV infection), neuronal ceroid lipofuscinosis, Niemann-Pick disease, Gaucher disease, leukodystrophy (adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease), mucopolysaccharidosis, glycoproteinoses (e.g., mucolipidosis II, fucosidosis, aspartylglucosaminuria, alpha-mannosidosis), Wolman disease, immunodeficiency (e.g., ataxia telangiectasia, DiGeorge syndrome, severe combined immunodeficiency, Wiskott-Aldrich syndrome, Kostmann syndrome, Schwachman-Diamond syndrome, glycerol kinase deficiency, NF-κB essential modulator deficiency), amegakaryocytic thrombocytopenia, and hemophagocytic lymphohistiocytosis.

[0185] In some embodiments, the hematopoietic stem cell transplantation is for treating a proliferative disorder, such as cancer (e.g., cancer as described herein according to any of the respective embodiments).

[0186] In some embodiments related to any one of the embodiments described herein regarding hematopoietic stem cells, the treatment includes increasing the level of hematopoietic stem cells in the peripheral blood of a subject, obtaining hematopoietic stem cells from the peripheral blood of the subject, administering a cytotoxic therapy to the subject (e.g., anti-proliferative chemotherapy and / or radiotherapy), and transplanting back at least a portion of the stem cells to the patient following the cytotoxic therapy.

[0187] MCP-1 Inhibition : According to some embodiments, the small molecule compounds of Formula Ia and / or Ib described herein are capable of modulating the biological activity of MCP-1, or can be used to modulate it, as described herein, in any of the respective embodiments or any combination thereof.

[0188] According to one aspect of some embodiments of the present invention, there is provided a method of inhibiting the biological activity of MCP-1, the method comprising contacting MCP-1 with a compound according to any of the embodiments described herein.

[0189] According to one aspect of some embodiments of the present invention, there is provided the use of a compound according to any of the embodiments described herein in the manufacture of a medicament for inhibiting the biological activity of MCP-1.

[0190] According to one aspect of some embodiments of the present invention, there is provided the use of a compound according to any of the embodiments described herein in the inhibition of the biological activity of MCP-1.

[0191] In some embodiments of any of the embodiments regarding the use and / or method for inhibiting MCP-1 biological activity, the use and / or method is achieved in vivo, for example, by administering to a patient in need of inhibition of MCP-1 biological activity a therapeutically effective amount of the compound.

[0192] In some embodiments, the use and / or method for inhibiting MCP-1 bioactivity is achieved ex vivo (e.g., in vitro), for example, in research.

[0193] In some embodiments related to any one of the embodiments described herein regarding a method, use or medicament for inhibiting MCP-1 bioactivity, the method, use or medicament is for treating an MCP-1 bioactivity-related disease or disorder in a patient in need thereof, for example, by administering to the patient a therapeutically effective amount of a compound according to any of the embodiments described herein.

[0194] In some embodiments related to any one of the embodiments described herein regarding a method, use or medicament for inhibiting MCP-1 bioactivity, the method, use or medicament is for treating a disease or disorder in which inhibition of MCP-1 bioactivity is beneficial in a patient in need thereof, for example, by administering to the patient a therapeutically effective amount of a compound according to any of the embodiments described herein.

[0195] In some embodiments related to any one of the embodiments described herein regarding a method, use or medicament for inhibiting the bioactivity of MCP-1, the method, use or medicament is, for example, for a patient, administration of a therapeutically effective amount of a compound according to any of the embodiments described herein is for treating a disease or disorder in which inhibition of the bioactivity of MCP-1 is beneficial in a patient in need thereof.

[0196] Examples of diseases and disorders associated with MCP-1 activity (e.g., in which inhibition of MCP-1 activity is beneficial), include, but are not limited to, diseases and disorders characterized by monocytic infiltrates.

[0197] According to some embodiments, examples of diseases and disorders associated with MCP-1 activity (e.g., inhibition of MCP-1 activity is beneficial) include, but are not limited to, tuberculosis, HIV-1, proliferative glomerulonephritis, neural tube defects, xanthogranulomatous pyelonephritis, scleritis, rapidly progressive glomerulonephritis, pneumoconiosis, encephalitis, peritonitis, atherosclerosis, psoriasis, dengue shock syndrome, temporal arteritis, relapsing polychondritis, diabetic angiopathy, mesangial proliferative glomerulonephritis, sympathetic ophthalmia, ureteral diseases, lupus nephritis, pneumonia, periapical granuloma, Erdheim-Chester disease, glomerulonephritis, arterial diseases, viral encephalitis, primary cutaneous amyloidosis, arteriosclerosis, nonspecific interstitial pneumonia, acute post-streptococcal glomerulonephritis, coronary artery disease, Venezuelan equine encephalitis, diabetic macular edema, extrapulmonary tuberculosis, nephritis, rheumatoid arthritis, Kawasaki disease, arthritis, malaria, obesity, mental disorders, cancer (e.g., as described herein), inflammation (e.g., inflammatory diseases and disorders as described herein), neurodegenerative disorders, and age-related macular degeneration (AMD, e.g., dry or wet type) described herein.

[0198] According to certain embodiments, diseases include, but are not limited to, psoriasis, rheumatoid arthritis, multiple sclerosis, atherosclerosis, glomerulonephritis, epilepsy, Alzheimer's disease, cerebral ischemia, traumatic brain injury, type II diabetes, and AMD.

[0199] According to certain embodiments, the compound according to this embodiment is for the treatment of age-related macular degeneration (AMD).

[0200] According to certain embodiments, age-related macular degeneration (AMD) is atrophic with neovascularization (aAMD).

[0201] According to certain embodiments, age-related macular degeneration (AMD) is with neovascularization.

[0202] Cancer Treatment : According to some embodiments, the small molecule compounds of formula Ia and / or Ib or formula IIa and / or IIb described herein are capable of treating cancer, or can be used for treatment, in any one of the respective embodiments or in any combination thereof.

[0203] According to some embodiments, the small molecule compounds of formula Ia and / or Ib or formula IIa and / or IIb described herein are capable of inducing cancer cell death (killing cancer cells), or can be used for induction, in any one of the respective embodiments or in any combination thereof.

[0204] According to some embodiments, the small molecule compounds of formula Ia and / or Ib or formula IIa and / or IIb described herein are capable of inducing apoptosis of cancer cells, or can be used for induction, in any one of the respective embodiments or in any combination thereof.

[0205] According to some embodiments, the small molecule compounds of formula Ia and / or Ib or formula IIa and / or IIb described herein are capable of inducing growth arrest of cancer cells, or can be used for induction, and in some embodiments, the arrest occurs in the G2M phase of the cell cycle.

[0206] According to one aspect of some embodiments of the present invention, provided is a method for treating cancer in a patient in need of cancer treatment, the method comprising administering to the patient a therapeutically effective amount of a small molecule compound according to any one of the embodiments described herein, thereby treating the cancer.

[0207] According to one aspect of some embodiments of the present invention, provided is the use of a small molecule compound according to any one of the embodiments described herein in the manufacture of a medicament for treating cancer.

[0208] According to one aspect of some embodiments of the present invention, there is provided the use of a small molecule compound according to any of the embodiments described herein in cancer treatment.

[0209] As used herein, the terms “cancer” and “tumor” are used synonymously and refer to malignant growths and / or tumors caused by abnormal, uncontrolled cell proliferation (cell division). The term “cancer” includes tumor metastasis.

[0210] The term “cancer cell” refers to a cell that forms a malignant growth or tumor.

[0211] Some embodiments according to any of the embodiments described herein related to cancer (including any of the aspects described herein) and / or cancer and / or tumor metastases that can be treated according to non-limiting examples of cancer and / or tumor metastases include, but are not limited to, gastrointestinal tumors (e.g., colon carcinoma, rectal carcinoma, colorectal carcinoma, colorectal cancer, colorectal adenoma, hereditary non-polyposis type 1, hereditary non-polyposis type 2, hereditary non-polyposis type 3, hereditary non-polyposis type 6, colorectal cancer, hereditary non-polyposis type 7, small intestine and / or large intestine carcinoma, esophageal carcinoma, esophageal carcinoma with tylosis, gastric carcinoma, pancreatic carcinoma, pancreatic endocrine tumor), endometrial cancer, dermatofibrosarcoma protuberans, gallbladder cancer, biliary tract tumor, prostate cancer, prostatic adenocarcinoma, kidney cancer (e.g., Wilms tumor type 2 or type 1), liver cancer (e.g., hepatoblastoma, hepatocellular carcinoma, hepatocellular cancer), bladder cancer, embryonal rhabdomyosarcoma, germ cell tumor, choriocarcinoma, testicular germ cell tumor, immature teratoma of the ovary, uterine, ovarian epithelial, sacrococcygeal tumor, choriocarcinoma, placental site trophoblastic tumor, adult epithelial tumor, ovarian carcinoma, serous ovarian cancer, ovarian sex cord tumor, cervical cancer, cervical carcinoma, small cell and non-small cell lung cancer, nasopharynx, breast carcinoma (e.g., ductal carcinoma, invasive ductal carcinoma, lobular carcinoma, susceptibility to breast cancer, type 4 breast cancer, breast cancer-1, breast cancer-3, breast-ovarian cancer), squamous cell carcinoma (e.g., in the head and neck), neurogenic tumor, astrocytoma, ganglioneuroma, neuroblastoma, lymphoma (e.g., Hodgkin disease, non-Hodgkin lymphoma, B cell lymphoma, diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma, cutaneous T cell lymphoma, histiocytic lymphoma, lymphoblastic lymphoma, T cell lymphoma, thymic lymphoma), glioma, adenocarcinoma, adrenal tumor, hereditary adrenocortical carcinoma, brain malignancy (tumor), various other carcinomas (e.g., bronchiogenic large cell, Ehrlich-Lettre ascites, epidermoid, large cell, Lewis lung, myeloid, mucoepidermoid, oat cell, small cell, spindle cell, spinous cell, transitional cell, undifferentiated, carcinosarcoma, choriocarcinoma, cystadenocarcinoma), epithelioblastoma, epithelioma, erythroleukemia (e.g., Friend, lymphoblastic), fibrosarcoma, giant cell tumor, glioma tumor, glioblastoma (e.g., polymorphic, astrocytoma), glioma hepatocellular tumor, heterohybridoma, heteromyeloma, histiocytoma,Hybridomas (e.g., B cells), Grawitz tumors, insulinomas, pancreatic tumors, keratomas, smooth muscleblasts, leiomyosarcomas, leukemias (e.g., acute lymphocytic leukemia, acute lymphoblastic leukemia, acute lymphoblastic pre-B cell leukemia, acute lymphoblastic T cell leukemia, acute megakaryoblastic leukemia, monocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, acute myeloid leukemia with eosinophilia, B cell leukemia, basophilic leukemia, chronic myeloid leukemia, chronic B cell leukemia, eosinophilic leukemia, Friend leukemia, granulocytic or myeloblastic leukemia, hairy cell leukemia, lymphocytic leukemia, megakaryoblastic leukemia, monocytic leukemia, monocytic macrophage leukemia, myeloblastic leukemia, myelogenous leukemia, myelomonocytic leukemia, plasma cell leukemia, pre-B cell leukemia, promyelocytic leukemia, subacute leukemia, T cell leukemia, lymphoid neoplasms, predisposition to myeloid malignancies, acute non-lymphocytic leukemia), lymphosarcomas, melanomas, breast tumors, mast cell tumors, medulloblasts, mesotheliomas, metastatic tumors, monocytic tumors, multiple myelomas, myelodysplastic syndromes, myelomas, nephroblastomas, neuroglial tumors of nervous tissue, neuron tumors of nervous tissue, neurilemmomas, neuroblastomas, astrocytomas, osteochondromas, osteomyelomas, osteosarcomas (e.g., Ewing), papillomas, transitional cells, pheochromocytomas, pituitary tumors (invasive), plasmacytomas, retinoblasts, rhabdomyosarcomas, sarcomas (e.g., Ewing, histiocytic, Jensen, osteogenic, retinal cell), schwannomas, subcutaneous tumors, teratocarcinomas (e.g., pluripotent), teratomas, testicular tumors, thymomas and follicular epithelial tumors, gastric cancers, fibrosarcomas, glioblastomas multiforme, multiple glomus tumors, Li-Fraumeni syndrome, liposarcomas, Lynch cancer family syndrome II, male germ cell tumors, mast cell leukemia, medullary thyroid, multiple meningiomas, endocrine neoplasms myxosarcomas, paragangliomas, familial non-chromaffin, trichoblastomas, papillary, familial and sporadic, rabdoid predisposition syndrome, familial, rabdoid tumors, soft tissue sarcomas and Turcot syndrome with glioblastoma, any solid or non-solid cancers and / or tumor metastases including,

[0212] In some embodiments related to any one of the embodiments described herein regarding cancer, the cancer is leukemia, lymphoma, ovarian cancer, brain cancer (e.g., neuroblastoma), pancreatic cancer, prostate cancer, liver cancer (e.g., hepatocellular carcinoma), colorectal cancer and / or lung cancer (small cell lung cancer). Examples of leukemia that can be treated in connection with some embodiments of the present invention include, but are not limited to, acute leukemia such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and acute lymphoblastic leukemia.

[0213] Examples of lymphoma that can be treated in connection with some embodiments of the present invention include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), multiple myeloma and non-Hodgkin lymphoma. Burkitt lymphoma is a non-limiting example of non-Hodgkin lymphoma.

[0214] Examples of lung cancer that can be treated in connection with some embodiments of the present invention include, but are not limited to, large cell lung cancer and small cell lung cancer.

[0215] In some embodiments related to any one of the embodiments described herein regarding cancer, the cancer is leukemia, and in some embodiments it is AML.

[0216] In some embodiments related to any one of the embodiments described herein regarding cancer, the cancer is pancreatic cancer.

[0217] In some embodiments related to any one of the embodiments described herein regarding cancer, the cancer is characterized by cells that express CXCR4. In some such embodiments, the compound for use in cancer treatment is any one of the compounds described herein for use in inhibiting SDF-1 and / or CXCR4 activity.

[0218] Although not limited to any particular theory, in cancers characterized by the expression of CXCR4, the activities of SDF-1 and CXCR4 are generally associated with metastasis. Therefore, it is considered that treatment with an inhibitor of SDF-1 and / or CXCR4 activity would be particularly advantageous.

[0219] In some embodiments related to any one of the embodiments described herein regarding cancer, the cancer is a drug-resistant cancer. In some of these embodiments, the cancer is resistant to an angiogenesis-inhibiting chemotherapeutic agent, such as a taxane (e.g., paclitaxel). In some of these embodiments, the cancer is a multi-drug resistant cancer. The drug resistance of cancer cells is acquired resistance (e.g., resistance formed by treatment or repeated treatment) or intrinsic resistance. In some embodiments related to any one of the embodiments described herein regarding cancer, the cancer cells are resistant to paclitaxel. In some of these embodiments, the resistance is intrinsic. In some embodiments related to any one of the embodiments described herein regarding cancer, the cancer cells are resistant to irinotecan or any other chemotherapeutic agent belonging to the camptothecin family. In some of these embodiments, the resistance is acquired.

[0220] In some embodiments related to any one of the embodiments described herein regarding cancer treatment, the cancer treatment further comprises administration of at least one additional anti-cancer agent (i.e., in addition to the compounds described above herein).

[0221] Additional anti-cancer agents may be any agents used in medicine for treating cancer. Examples of anti-cancer agents include, but are not limited to, ashibicin, aclarubicin, acodazole hydrochloride, acronine, adriamycin, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, broxuridine, busulfan, calicheamicin, carsterone, caracemide, carbetimer, carboplatin, carmustine, carboquone, carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, cladribine, combrestatin A-4 phosphate, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, desaguanine, desaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, drostanolone propionate, duazomycin, edatrexate, efloxatin hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gemcitabine,Gemcitabine Hydrochloride, Hydroxyurea, Idarubicin Hydrochloride, Ifosfamide, Ilmofosine, Interferon Alfa-2a, Interferon Alfa-2b, Interferon Alfa-n1, Interferon Alfa-n3, Interferon Beta-Ia, Interferon Gamma-Ib, Iproplatin, Irinotecan Hydrochloride, Lanreotide Acetate, Letrozole, Leuprolide Acetate, Rialoxazole Hydrochloride, Lometrexol Sodium, Lomustine, Losoxantrone Hydrochloride, Masoprocol, Mitansine, Mechlorethamine Hydrochloride, Megestrol Acetate, Melenegestrol Acetate, Melphalan, Menogaril, Mercaptopurine, Methotrexate, Methotrexate Sodium, Metoprine, Metsredepa, Mitindomide, Mitocarcin, Mitochromin, Mitogillin, Mitomalcin, Mitomycin, Mitosper, Mitotane, Mitoxantrone Hydrochloride, Mycophenolic Acid, Nocodazole, Nogalamycin, Ombramycin, Ormaplatin, Oxisuran, Paclitaxel, Pegaspargase, Periomycin, Pentostatin, Pepromycin Sulfate, Perfosfamide, Pipobroman, Piposulfan, Pirroxantrone Hydrochloride, Plicamycin, Promestane, Porfimer Sodium, Porfiromycin, Prednimustine, Procarbazine Hydrochloride, Puromycin, Puromycin Hydrochloride, Pyrazofurin, Riboprine, Logretimide, Safingol, Safingol Hydrochloride, Semustine, Simtrazene, Sparfosate Sodium, Sparsomycin, Spirogermanium Hydrochloride, Spiro-mustine, Spiroplatin, Streptozocin, Streptozotocin, Sulofenur, Talisomycin, Tecogalan Sodium, Tegafur, Teloxantrone Hydrochloride, Temoporfin, Teniposide, Teloxiron, Testolactone, Thiamiprine,Thioguanine, thiotepa, tiazofuirin, tirapazamine, topotecan hydrochloride, tamoxifen citrate, trestolone acetate, triciribine phosphate, trimethoprim, trimethoprim glucuronate, tritriptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vincblastine, vincristine sulfate, vindesine, vindesine sulfate, vinepidinee, vinglycinate, vinleurosine, vinorelbine tartrate, vinrosidine, vinzolidine, borozole, zeniplatin, dinostatin and zorubicin hydrochloride are mentioned. Further anticancer agents include those disclosed in Chapter 52, Antineoplastic Agents (Paul Calabresi and Bruce A. Chabner) and its introduction, Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Eighth Edition, 1990, McGraw-Hill, Inc. (Health Professions Division), pages 1202-1263, the disclosure of which is incorporated herein by reference.,

[0222] In some of the embodiments described herein, the further anticancer agent is characterized in that the resistance of cancer cells to the agent is associated with the activity of SDF-1 and / or CXCR4. In some such embodiments, the compound for use in combination with the further anticancer agent is any one of the compounds described herein.

[0223] In some of the embodiments described herein, at least one additional anti-cancer agent comprises combrestatin A-4 phosphate, ombrabulin, and / or any other derivative of combrestatin.

[0224] Without being bound to any particular theory, the anti-therapeutic effects of combrestatin derivatives such as combrestatin A-4 phosphate and ombrabulin are thought to be reduced by SDF-1 / CXCR4 activity.

[0225] In some of the embodiments described herein, the small molecule compound of the present embodiment interacts with at least one additional anti-cancer agent.

[0226] "Interacts" means that the therapeutic activity when the agents are in contact with cancer cells together is higher than the sum of the activities of each agent alone. In some embodiments, the therapeutic activity is a decrease in the number of living cells, and in some embodiments, as described herein, the therapeutic activity is an inhibition of cell proliferation.

[0227] The interaction can be determined by methods known in the art. In some embodiments, the interaction is determined by the isobologram, which is widely known in the art.

[0228] When two agents interact, combination therapy using these agents allows for the use of a lower amount of at least one of these agents. This is particularly effective when it is known that treatment with anti-cancer agents induces acquired resistance.

[0229] From the perspective of cancer treatment, in some of the embodiments described herein, a combination therapy is provided that includes administering to a subject in need thereof the small molecule compound according to the present embodiment and at least one additional anti-cancer agent.

[0230] In some embodiments, at least one additional anti-cancer agent is administered at a sub-therapeutic dose, i.e., a dose less than its therapeutically effective dose (e.g., as determined by the methods described herein and / or for the anti-cancer agent).

[0231] The two agents can be administered sequentially, in any order, or simultaneously, and optionally formulated in the same pharmaceutical composition.

[0232] In some of the embodiments described herein, the additional anti-cancer agent is irinotecan.

[0233] Non-Cancerous Hyperproliferative Diseases : In some of the embodiments described herein, the small molecule compound of this embodiment is for use in the treatment of non-cancerous proliferative diseases.

[0234] In some of the embodiments described herein, provided is a method for treating a non-cancerous proliferative disease, the method comprising administering to a subject in need thereof (a subject suffering from the disease, a subject suffering from a symptom associated with the disease, a subject diagnosed as having the disease or a subject suspected of having the disease) a therapeutically effective amount of the small molecule compound described herein.

[0235] In some of the embodiments described herein, the small molecule compound of this embodiment is for use in the manufacture of a medicament for treating non-cancerous proliferative diseases.

[0236] Non-cancerous hyperproliferative diseases, also referred to as "non-neoplastic proliferative diseases" and "non-cancerous proliferative diseases", refer to diseases or disorders in which their occurrence or progression is associated with non-malignant cell proliferation. Examples of such medical conditions include, but are not limited to, atherosclerosis, rheumatoid arthritis, psoriasis, fibrosis, idiopathic pulmonary fibrosis, scleroderma, stricture, restenosis, in-stent stenosis and cirrhosis.

[0237] Inflammatory Diseases and Disorders : In some of the embodiments described herein, the small molecule compounds of the present embodiment are used for the treatment of inflammatory diseases or disorders in a subject in need of treatment.

[0238] In some of the embodiments described herein, provided is a method for treating an inflammatory disease or disorder, the method comprising administering to a subject in need thereof (a subject suffering from the disease, a subject suffering from a symptom associated with the disease, a subject diagnosed as having the disease or a subject suspected of having the disease) a therapeutically effective amount of the small molecule compounds described herein.

[0239] In some of the embodiments described herein, the small molecule compounds of the present embodiment are for use in the manufacture of a medicament for the treatment of inflammatory diseases or disorders.

[0240] Inflammatory diseases and disorders generally include diseases and disorders associated with inflammation.

[0241] As used herein, the term "inflammation" is a general term representing the local accumulation of body fluids, plasma proteins and white blood cells initiated by physical injury, infection or local immune response. Inflammation can be accompanied by several symptoms such as redness, pain, heat, swelling and / or loss of function. Inflammation is an aspect of a number of diseases and disorders including, but not limited to, diseases associated with immune disorders, viral and bacterial infections, arthritis, autoimmune diseases, collagen diseases, allergies, asthma, hay fever and atopy (as described in more detail below).

[0242] Thus, inflammation can be caused by an injury, such as an injury to the skin, muscle, tendon or nerve. Inflammation can be caused as part of an immune response, such as a pathological autoimmune response. Inflammation can also be caused by an infection where pathogen recognition and tissue damage can initiate an inflammatory response at the site of infection.

[0243] The inflammation according to the present teachings can be associated with chronic (long-term) inflammatory diseases or disorders, or acute (short-term) inflammatory diseases or disorders.

[0244] According to certain embodiments, the inflammation is associated with a disease selected from the group consisting of infectious diseases, autoimmune diseases, allergy-related inflammation, graft rejection, and injury.

[0245] According to certain embodiments, the inflammation includes skin inflammation.

[0246] According to certain embodiments, the skin inflammation is psoriasis.

[0247] Diseases characterized by skin inflammation include, but are not limited to, dermatitis, atopic dermatitis (eczema, atopy), contact dermatitis, herpes-like dermatitis, exfoliative dermatitis, seborrheic dermatitis, drug eruption, erythema multiforme, erythema nodosum, granuloma annulare, poison ivy, urushiol, toxic epidermal necrolysis, rosacea, psoriasis, and acne. Inflammation can also be caused by physical injury to the skin.

[0248] Inflammation can be caused by various types of injury to muscles, tendons, or nerves. Thus, for example, inflammation can be caused by repetitive movement of a part of the body, i.e., repetitive strain injury (RSI). Diseases characterized by inflammation caused by RSI include, but are not limited to, bursitis, carpal tunnel syndrome, Dupuytren's contracture, epicondylitis (e.g., tennis elbow), ganglion (i.e., inflammation in a cyst usually occurring at the wrist formed in the tendon sheath), rotator cuff syndrome, tendinitis (e.g., inflammation of the Achilles tendon), tenosynovitis, and trigger finger (inflammation of the tendon sheath of a finger or thumb with tendon swelling).

[0249] Among the numerous diseases associated with infectious diseases, there is an inflammatory response, which is usually part of the innate immune system triggered by invading pathogens. Inflammation can also be caused by physical (mechanical) damage to cells and tissues resulting from infection. Examples of infectious diseases include, but are not limited to, chronic infectious diseases, subacute infectious diseases, acute infectious diseases, viral diseases, bacterial diseases, protozoal diseases, parasitic diseases, fungal diseases, mycoplasma diseases, and prion diseases. According to one specific example, examples of infectious diseases characterized by inflammation include, but are not limited to, encephalitis, meningitis, encephalomyelitis, viral gastroenteritis, and viral hepatitis.

[0250] Furthermore, among the numerous immune disorders, acute or chronic inflammation is included. For example, arthritis is considered an immune disorder characterized by inflammation of the joints, but arthritis is also considered an inflammatory disorder characterized by an immune attack in joint tissue.

[0251] The inflammation according to the present teachings can be associated with a defective immune response (e.g., HIV, AIDS), or an overactive immune response (e.g., allergies, autoimmune disorders). Thus, the inflammation according to the present teachings can be associated with any of the following.

[0252] Inflammatory Diseases with Allergies : Examples of allergies include, but are not limited to, type I allergy, type II allergy, type III allergy, type IV allergy, immediate-type allergy, antibody-mediated allergy, immune complex-mediated allergy, T lymphocyte-mediated allergy, and DTH.

[0253] Type I or Immediate Hypersensitivity Such as Asthma As type II hypersensitivity, although not limited to these, rheumatoid diseases, rheumatoid autoimmune diseases, rheumatoid arthritis (Krenn V. et al., Histol Histopathol 2000 Jul;15 (3):791), spondylitis, ankylosing spondylitis (Jan Voswinkel et al., Arthritis Res 2001, 3 (3): 189), systemic diseases, systemic autoimmune diseases, systemic lupus erythematosus (Erikson J. et al., Immunol Res 1998;17 (1-2):49), sclerosis, systemic sclerosis (Renaudineau Y. et al., Clin Diagn Lab Immunol. 1999 Mar;6 (2):156), Chan OT. et al., Immunol Rev 1999 Jun;169:107), glandular diseases, glandular autoimmune diseases, pancreatic autoimmune diseases, diabetes, type I diabetes (Zimmet P. Diabetes Res Clin Pract 1996 Oct;34 Suppl:S125), thyroid diseases, autoimmune thyroid diseases, Graves' disease (Orgiazzi J. Endocrinol Metab Clin North Am 2000 Jun;29 (2):339), thyroiditis, idiopathic autoimmune thyroiditis (Braley-Mullen H. and Yu S, J Immunol 2000 Dec 15;165 (12):7262), Hashimoto's thyroiditis (Toyoda N. et al., Nippon Rinsho 1999 Aug;57 (8):1810), myxedema, idiopathic myxedema (Mitsuma T. Nippon Rinsho. 1999 Aug;57 (8):1759), autoimmune reproductive system diseases, ovarian diseases, ovarian autoimmunity (Garza KM. et al., J Reprod Immunol 1998 Feb;37 (2):87), autoimmune antisperm infertility (Diekman AB. et al., Am J Reprod Immunol. 2000 Mar;43 (3):134), recurrent fetal loss (Tincani A. et al., Lupus 1998;7 Suppl 2:S107-9), neurodegenerative diseases, neurological diseases, neurological autoimmune diseases, multiple sclerosis (Cross AH. et al., J Neuroimmunol 2001 Jan 1;112 (1-2):1), Alzheimer's disease (Oron L. et al., J Neural Transm Suppl. 1997;49:77), myasthenia gravis (Infante AJ. And Kraig E, Int Rev Immunol 1999;18 (1-2):83), motor neuropathy (Kornberg AJ. J Clin Neurosci. 2000 May;7 (3):191), Guillain-Barré syndrome, neuropathy and autoimmune neuropathy (Kusunoki S. Am J Med Sci. 2000 Apr;319 (4):234), myasthenia diseases, Lambert-Eaton myasthenic syndrome (Takamori M. Am J Med Sci. 2000 Apr;319 (4):204), paraneoplastic neurological diseases, cerebellar atrophy, paraneoplastic cerebellar atrophy, non-paraneoplastic stiff-man syndrome, cerebellar atrophy, progressive cerebellar atrophy, encephalitis, Rasmussen encephalitis, amyotrophic lateral sclerosis, Sydenham chorea, Gilles de la Tourette syndrome, polyendocrine disorders, autoimmune polyendocrine disorders (Antoine JC. and Honnorat J. Rev Neurol (Paris) 2000 Jan;156 (1):23), neuropathy, abnormal immune neuropathy (Nobile-Orazio E. et al., Electroencephalogr Clin Neurophysiol Suppl 1999;50:419), neuromyotonia, acquired neuromyotonia, congenital multiple arthrogryposis (Vincent A. et al., Ann N Y Acad Sci. 1998 May 13;841:482), cardiovascular diseases, cardiovascular autoimmune diseases, atherosclerosis (Matsuura E. et al., Lupus. 1998;7 Suppl 2:S135), myocardial infarction (Vaarala O. Lupus. 1998;7 Suppl 2:S132), thrombosis (Tincani A. et al., Lupus 1998;7 Suppl 2:S107-9), granulomatosis, granulomatosis with edema, arteritis, Takayasu's arteritis, and Kawasaki syndrome (Praprotnik S. et al., Wien Klin Wochenschr 2000 Aug 25;112 (15-16):660), anti-factor VIII autoimmune disease (Lacroix-Desmazes S. et al., Semin Thromb Hemost.2000;26 (2):157), vasculitis, microvasculitis with small vessels, microscopic polyangiitis, Chag-Strauss syndrome, glomerulonephritis, microimmune nephritis with glomerulonephritis, crescentic glomerulonephritis (Noel LH. Ann Med Interne (Paris). 2000 May;151 (3):178), anti-lipid syndrome (Flamholz R. et al., J Clin Apheresis 1999;14 (4):171), cardiomyopathy, β-adrenalin receptor antibodies in patients with cardiomyopathy (Wallukat G. et al., Am J Cardiol. 1999 Jun 17;83 (12A):75H), thrombocytopenic purpura (Moccia F. Ann Ital Med Int. 1999 Apr-Jun;14 (2):114), hemolytic anemia, autoimmune hemolytic anemia (Efremov DG. et al., Leuk Lymphoma 1998 Jan;28 (3-4):285), gastrointestinal diseases, autoimmune diseases of the gastrointestinal tract, intestinal diseases, chronic inflammatory bowel disease (Garcia Herola A. et al., Gastroenterol Hepatol. 2000 Jan;23 (1):16), cerebral ischemia (Landau YE. and Shoenfeld Y. Harefuah 2000 Jan 16;138 (2):122), autoimmune diseases of the musculoskeletal system, myofasciitis, autoimmune myofasciitis, schlepten syndrome (Feist E. et al., Int Arch Allergy Immunol 2000 Sep;123 (1):92), smooth muscle autoimmune diseases (Zauli D. et al., Biomed Pharmacother 1999 Jun;53 (5-6):234), liver diseases, hepatic autoimmune diseases, autoimmune hepatitis (Manns MP.J Hepatol 2000 Aug;33 (2):326) and primary biliary cirrhosis (Strassburg CP. et al., Eur J Gastroenterol Hepatol. 1999 Jun;11 (6):595) are mentioned.

[0254] As type IV or T cell-mediated hypersensitivity, but not limited to these, rheumatoid diseases, rheumatoid arthritis (Tisch R, McDevitt HO. Proc Natl Acad Sci U S A 1994 Jan 18;91 (2):437), systemic diseases, systemic autoimmune diseases, systemic lupus erythematosus (Datta SK., Lupus 1998;7 (9):591), glandular diseases, glandular autoimmune diseases, pancreatic diseases, pancreatic autoimmune diseases, type 1 diabetes (Castano L. and Eisenbarth GS. Ann. Rev. Immunol. 8:647), thyroid diseases, autoimmune thyroid diseases, Graves' disease (Sakata S. et al., Mol Cell Endocrinol 1993 Mar;92 (1):77), ovarian diseases (Garza KM. et al., J Reprod Immunol 1998 Feb;37 (2):87), prostatitis, autoimmune prostatitis (Alexander RB. et al., Urology 1997 Dec;50 (6):893), polyglandular syndromes, autoimmune polyglandular syndromes, type I autoimmune polyglandular syndrome (Hara T. et al., Blood. 1991 Mar 1;77 (5):1127), neurological diseases, autoimmune neurological diseases, multiple sclerosis, neuritis, optic neuritis (Soderstrom M. et al., J Neurol Neurosurg Psychiatry 1994 May;57 (5):544), myasthenia gravis (Oshima M. et al., Eur J Immunol 1990 Dec;20 (12):2563), stiff-man syndrome (Hiemstra HS. et al., Proc Natl Acad Sci U S A 2001 Mar 27;98 (7):3988), cardiovascular diseases, cardiac autoimmunity in Chagas disease (Cunha-Neto E. et al., J Clin Invest 1996 Oct 15;98 (8):1709), autoimmune thrombocytopenic purpura (Semple JW. et al., Blood 1996 May 15;87 (10):4245), anti-helper T lymphocyte autoimmunity (Caporossi AP. et al., Viral Immunol 1998;11 (1):9), hemolytic anemia (Sallah S. et al., Ann Hematol 1997 Mar;74 (3):139), liver diseases, liver autoimmune diseases, hepatitis, chronic active hepatitis (Franco A. et al., Clin Immunol Immunopathol 1990 Mar;54 (3):382), biliary cirrhosis, primary biliary cirrhosis (Jones DE. Clin Sci (Colch) 1996 Nov, 91 (5):551), kidney diseases, kidney autoimmune diseases, nephritis, interstitial nephritis (Kelly CJ. J Am Soc Nephrol 1990 Aug;1 (2):140), connective tissue diseases, ear diseases, autoimmune connective tissue diseases, autoimmune ear diseases (Yoo TJ. et al., Cell Immunol 1994 Aug;157 (1):249), inner ear diseases (Gloddek B. et al., Ann N Y Acad Sci 1997 Dec 29;830:266), skin diseases, cutaneous diseases, dermal diseases, blistering skin diseases, pemphigus vulgaris, bullous pemphigoid and pemphigus foliaceus are included.

[0255] Examples of delayed hypersensitivity include, but are not limited to, contact dermatitis and drug eruptions.

[0256] Examples of types of T lymphocyte-mediated hypersensitivity include, but are not limited to, helper T lymphocytes and cytotoxic T lymphocytes.

[0257] Examples of helper T lymphocyte-mediated hypersensitivity include, but are not limited to, T h 1 lymphocyte-mediated hypersensitivity and T h 2 lymphocyte-mediated hypersensitivity are included.

[0258] According to a particular embodiment, the eye disease is age-related macular degeneration (AMD).

[0259] According to certain embodiments, age-related macular degeneration (AMD) is atrophic, non-neovascular (aAMD).

[0260] According to certain embodiments, age-related macular degeneration (AMD) is neovascular.

[0261] Autoimmune Diseases : Autoimmune diseases include, but are not limited to, cardiovascular diseases, rheumatoid diseases, glandular diseases, gastrointestinal diseases, skin diseases, liver diseases, nerve diseases, muscle diseases, kidney diseases, diseases related to reproduction, connective tissue diseases, and systemic diseases.

[0262] Examples of autoimmune cardiovascular diseases include, but are not limited to, atherosclerosis (Matsuura E. et al., Lupus. 1998;7 Suppl 2:S135), myocardial infarction (Vaarala O. Lupus. 1998;7 Suppl 2:S132), thrombosis (Tincani A. et al., Lupus 1998;7 Suppl 2:S107-9), Wegener's granulomatosis, Takayasu arteritis, Kawasaki syndrome (Praprotnik S. et al., Wien Klin Wochenschr 2000 Aug 25;112 (15-16):660), anti-factor VIII autoimmune disease (Lacroix-Desmazes S. et al., Semin Thromb Hemost.2000;26 (2):157), necrotizing small vessel vasculitis, microscopic polyangiitis, Churg-Strauss syndrome, pauci-immune focal necrotizing and crescentic glomerulonephritis (Noel LH. Ann Med Interne (Paris). 2000 May;151 (3):178), antiphospholipid syndrome (Flamholz R. et al., J Clin Apheresis 1999;14 (4):171), antibody-induced heart failure (Wallukat G. et al., Am J Cardiol. 1999 Jun 17;83 (12A):75H), thrombocytopenic purpura (Moccia F. Ann Ital Med Int. 1999 Apr-Jun;14 (2):114, Semple JW. et al., Blood 1996 May 15;87 (10):4245), autoimmune hemolytic anemia (Efremov DG. et al., Leuk Lymphoma 1998 Jan;28 (3-4):285, Sallah S. et al., Ann Hematol 1997 Mar;74 (3):139), cardiac autoimmunity in Chagas disease (Cunha-Neto E. et al., J Clin Invest 1996 Oct 15;98 (8):1709) and anti-helper T lymphocyte autoimmunity (Caporossi AP. et al., Viral Immunol 1998;11 (1):9).

[0263] Examples of autoimmune rheumatic diseases include, but are not limited to, rheumatoid arthritis (Krenn V. et al., Histol Histopathol 2000 Jul;15 (3):791, Tisch R, McDevitt HO. Proc Natl Acad Sci units S A 1994 Jan 18;91 (2):437) and ankylosing spondylitis (Jan Voswinkel et al., Arthritis Res 2001; 3 (3): 189).

[0264] Examples of autoimmune glandular diseases include, but are not limited to, pancreatic diseases, type I diabetes, thyroid diseases, Graves' disease, thyroiditis, idiopathic autoimmune thyroiditis, Hashimoto's thyroiditis, sporadic myxedema, ovarian autoimmunity, autoimmune antisperm infertility, autoimmune prostatitis, and type I autoimmune polyendocrine syndrome. Diseases include, but are not limited to, autoimmune pancreatic diseases, type 1 diabetes (Castano L. and Eisenbarth GS. Ann. Rev. Immunol. 8:647, Zimmet P. Diabetes Res Clin Pract 1996 Oct;34 Suppl:S125), autoimmune thyroid diseases, Graves' disease (Orgiazzi J. Endocrinol Metab Clin North Am 2000 Jun;29 (2):339, Sakata S. et al., Mol Cell Endocrinol 1993 Mar;92 (1):77), idiopathic autoimmune thyroiditis (Braley-Mullen H. and Yu S, J Immunol 2000 Dec 15;165 (12):7262), Hashimoto's thyroiditis (Toyoda N. et al., Nippon Rinsho 1999 Aug;57 (8):1810), sporadic myxedema (Mitsuma T. Nippon Rinsho. 1999 Aug;57 (8):1759), ovarian autoimmunity (Garza KM. et al., J Reprod Immunol 1998 Feb;37 (2):87), autoimmune antisperm infertility (Diekman AB. et al., Am J Reprod Immunol. 2000 Mar;43 (3):134), autoimmune prostatitis (Alexander RB. et al., Urology 1997 Dec;50 (6):893), and type I autoimmune polyendocrine syndrome (Hara T. et al., Blood. 1991 Mar 1;77 (5):1127).

[0265] Examples of autoimmune gastrointestinal diseases include, but are not limited to, chronic inflammatory bowel disease (Garcia Herola A. et al., Gastroenterol Hepatol. 2000 Jan;23 (1):16), celiac disease (Landau YE. and Shoenfeld Y. Harefuah 2000 Jan 16;138 (2):122), colitis, ileitis, and Crohn's disease.

[0266] Examples of autoimmune skin diseases include, but are not limited to, autoimmune blistering skin diseases such as pemphigus vulgaris, bullous pemphigoid, and pemphigus foliaceus.

[0267] Examples of autoimmune liver diseases include, but are not limited to, hepatitis, autoimmune chronic active hepatitis (Franco A. et al., Clin Immunol Immunopathol 1990 Mar;54 (3):382), primary biliary cirrhosis (Jones DE. Clin Sci (Colch) 1996 Nov;91 (5):551, Strassburg CP. et al., Eur J Gastroenterol Hepatol. 1999 Jun;ll (6):595), and autoimmune hepatitis (Manns MP. J Hepatol 2000 Aug;33 (2):326).

[0268] Examples of autoimmune neurological diseases, although not limited thereto, include multiple sclerosis (Cross AH. et al., J Neuroimmunol 2001 Jan 1;112 (1-2):1), Alzheimer's disease (Oron L. et al., J Neural Transm Suppl. 1997;49:77), myasthenia gravis (Infante AJ. And Kraig E, Int Rev Immunol 1999;18 (1-2):83, Oshima M. et al., Eur J Immunol 1990 Dec;20 (12):2563), neuropathy, motor neuropathy (Kornberg AJ. J Clin Neurosci. 2000 May;7 (3):191), Guillain-Barré syndrome and autoimmune neuropathy (Kusunoki S. Am J Med Sci. 2000 Apr;319 (4):234), myopathy, Lambert-Eaton myasthenic syndrome (Takamori M. Am J Med Sci. 2000 Apr;319 (4):204), paraneoplastic neurological diseases, cerebellar atrophy, paraneoplastic cerebellar atrophy and stiff-man syndrome (Hiemstra HS. et al., Proc Natl Acad Sci units S A 2001 Mar 27;98 (7):3988), non-paraneoplastic stiff-man syndrome, progressive cerebellar atrophy, encephalitis, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydenham chorea, Gilles de la Tourette syndrome and autoimmune polyendocrine disorder (Antoine JC. and Honnorat J. Rev Neurol (Paris) 2000 Jan;156 (1):23), abnormal immune neuropathy (Nobile-Orazio E. et al., Electroencephalogr Clin Neurophysiol Suppl 1999;50:419), acquired neuromyotonia, congenital multiple arthrogryposis (Vincent A. et al., Ann N Y Acad Sci. 1998 May 13;841:482), neuritis, optic neuritis (Soderstrom M. et al., J Neurol Neurosurg Psychiatry 1994 May;57 (5):544), and neurodegenerative diseases are included.

[0269] Examples of autoimmune muscle diseases include, but are not limited to, myositis, autoimmune myositis, and primary Sjögren's syndrome (Feist E. et al., Int Arch Allergy Immunol 2000 Sep;123 (1):92), and autoimmune diseases of smooth muscle (Zauli D. et al., Biomed Pharmacother 1999 Jun;53 (5-6):234).

[0270] Examples of autoimmune kidney diseases include, but are not limited to, nephritis and autoimmune interstitial nephritis (Kelly CJ. J Am Soc Nephrol 1990 Aug;1 (2):140).

[0271] Examples of autoimmune diseases related to reproduction include, but are not limited to, recurrent fetal loss (Tincani A. et al., Lupus 1998;7 Suppl 2:S107-9).

[0272] Examples of autoimmune connective tissue diseases include, but are not limited to, ear diseases, autoimmune ear diseases (Yoo TJ. et al., Cell Immunol 1994 Aug;157 (1):249), and autoimmune diseases of the inner ear (Gloddek B. et al., Ann N Y Acad Sci 1997 Dec 29;830:266).

[0273] Examples of immune system diseases include, but are not limited to, systemic lupus erythematosus (Erikson J. et al., Immunol Res 1998;17 (1-2):49) and systemic sclerosis (Renaudineau Y. et al., Clin Diagn Lab Immunol. 1999 Mar;6 (2):156); Chan OT. et al., Immunol Rev 1999 Jun;169:107).

[0274] According to one embodiment, the autoimmune disease is Crohn's disease, psoriasis, scleroderma or rheumatoid arthritis.

[0275] Graft Rejection Diseases : Examples of diseases associated with transplantation of grafts include, but are not limited to, graft rejection, chronic graft rejection, subacute graft rejection, hyperacute graft rejection, acute graft rejection and graft-versus-host disease.

[0276] Allergic Diseases : Examples of allergic diseases include, but are not limited to, asthma, hives, urticaria, pollen allergy, dust mite allergy, venom allergy, cosmetic allergy, latex allergy, chemical allergy, drug allergy, insect sting allergy, animal dander allergy, thistle allergy, ivy allergy and food allergy.

[0277] Additional Uses The compounds described herein in any aspect of the embodiments of the invention described herein can be used for coating medical devices including implantable medical devices, particularly medical devices for which inhibition of cell migration and / or proliferation is desirable.

[0278] Examples of such medical devices include stents, catheters, endotracheal tubes, tubes, prostheses, medical implants, artificial joints, artificial valves, needles, intravenous access devices, cannulas, biliary stents, nephrostomy tubes, artificial blood vessels, infusion pumps, adhesive patches, sutures, meshes, surgical instruments or devices, intubation instruments, cardiovascular stents, cardiac surgical instruments, orthopedic surgical instruments, dental orthodontic or periodontal therapy instruments, dental surgical instruments, veterinary surgical instruments, bone scaffolds, hemodialysis tubes or instruments, blood exchange devices, transplant proteases, heart valves, ophthalmic devices, and breast implants.

[0279] According to some embodiments of the present invention, the medical device is an implantable device, such as a stent, an indwelling catheter, or a tracheal tube.

[0280] Catheters include, for example, urethral catheters, central venous catheters, biliary vascular catheters, pulmonary artery catheters, peripheral venous catheters, arterial line central venous catheters, peritoneal catheters, epidural catheters, and central nervous system catheters.

[0281] The implantable device may be an implantable device that is permanent or temporary.

[0282] Any commercially available or custom-made medical device, such as the implantable devices described herein, is contemplated.

[0283] According to some embodiments of the present invention, there is provided a medical device as described herein, wherein a compound described in any corresponding embodiment herein is associated with at least a part thereof. In some embodiments, the compound is deposited (e.g., coated) on at least a part of the outer surface of the medical device.

[0284] The compound may be directly associated with the device, for example, by being included in or absorbed by the materials constituting the device (e.g., being mixed with or absorbed by the polymeric material from which the device is made). Alternatively, or in addition, the compound may be deposited on the outer surface of the device by a polymeric film or other covering material containing or absorbing the compound.

[0285] Pharmaceutical Composition : The compounds described in connection with any aspect of the embodiments herein can be utilized (e.g., administered to a patient) by themselves or as a pharmaceutical composition mixed with a carrier or excipient suitable for the compound.

[0286] As used herein, "pharmaceutical composition" refers to a formulation of a compound according to any of the embodiments described herein or a compound with other chemical components such as physiologically suitable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to a living being.

[0287] As used interchangeably herein, the phrases "physiologically acceptable carrier" and "pharmaceutically acceptable carrier" refer to a carrier or diluent that does not cause significant irritation to a living being and does not inhibit the biological activity and properties of the administered compound. Adjuvants are included under these phrases.

[0288] As used herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of the active ingredient. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0289] When utilized by itself or as a pharmaceutically acceptable composition, the compound itself (i.e., without including the weight of carriers or excipients co-formulated with the compound as described herein) is optionally at least 80% pure (dry weight), optionally at least 90% pure (dry weight), at least 95% pure (dry weight), at least 98% pure (dry weight), and optionally at least 99% pure (dry weight). The purity can be enhanced, for example, by any suitable technique known in the art, such as by synthesizing the compound from natural sources or removing impurities associated with the isolation of the compound. Techniques for pharmaceutical formulation and administration can be found in the latest edition of "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, which is hereby incorporated by reference herein.

[0290] Suitable routes of administration include, for example, oral, rectal, transmucosal, particularly nasal, enteral or intramuscular, subcutaneous and intramedullary injections, as well as subarachnoid, direct intraventricular, intracardiac, for example, into the right or left ventricular cavity, into the common carotid artery, intravenous, intraperitoneal, intranasal or intraocular injections.

[0291] Alternatively, the pharmaceutical composition may be administered locally rather than systemically, for example, by injection of the pharmaceutical composition into a tissue region of the patient.

[0292] The term "tissue" refers to a part of an organism consisting of cells designed to perform a function (singular or plural). Examples include, but are not limited to, brain tissue, retina, skin tissue, liver tissue, pancreatic tissue, breast tissue, bone, cartilage, connective tissue, blood tissue, muscle tissue, heart tissue, brain tissue, vascular tissue, kidney tissue, lung tissue, gonadal tissue, hematopoietic tissue.

[0293] The pharmaceutical compositions of some embodiments of the present invention can be manufactured by processes well known in the art, such as by conventional mixing, dissolving, granulating, tablet coating, comminuting, emulsifying, encapsulating, entrapping or lyophilization processes.

[0294] Thus, pharmaceutical compositions for use in accordance with some embodiments of the present invention can be formulated in conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries. Such carriers facilitate the processing of the active ingredient into a pharmaceutically acceptable formulation. Suitable formulations vary depending on the chosen route of administration.

[0295] For injection, the active ingredient of the pharmaceutical composition can be formulated in an aqueous solution, preferably in a physiologically compatible buffer such as Hank's solution, Ringer's solution or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0296] For oral administration, the pharmaceutical composition can be readily formulated by combining the active compound with pharmaceutically acceptable carriers well known in the art. Such carriers enable the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by a patient. Pharmacological formulations for oral use can be prepared by using solid excipients, optionally grinding the obtained mixture and processing the mixture into granules, after adding suitable auxiliaries if necessary to obtain tablets or dragee cores. Examples of suitable excipients include bulking agents such as saccharides including lactose, sucrose, mannitol or sorbitol, celluloses such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts such as sodium alginate can be added if necessary.

[0297] Provide a coating suitable for the core of a sugar-coated tablet. For this purpose, optionally, a concentrated sugar solution that may contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture can be used. For identification, dyes or pigments can be added to the tablets or sugar-coated tablet coatings to characterize different combinations of the active compound dosages.

[0298] As a pharmaceutical composition that can be used orally, there may be mentioned push-fit capsule preparations made from gelatin and soft-sealed capsule preparations made from gelatin and plasticizers such as glycerol or sorbitol. The push-fit capsule preparations may contain the active ingredient in a mixture with a bulking agent such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate and optionally a stabilizer. In the soft capsule preparations, the active ingredient can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. Further, a stabilizer can be added. All formulations for oral administration should be in a dosage suitable for the selected route of administration.

[0299] For buccal administration, the composition can take the form of tablets or troches formulated in the conventional manner.

[0300] For administration by nasal inhalation, according to some embodiments of the present invention, the active ingredient for use is advantageously delivered in the form of an aerosol spray formulation from a pressurized pack or nebulizer using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for delivering a metered amount. Capsule preparations and cartridge preparations made of, for example, gelatin, containing a powder mixture of the active compound and a suitable powder base such as lactose or starch for use in a dispenser can be formulated.

[0301] The pharmaceutical compositions described herein can be formulated, for example, for parenteral administration by bolus injection or continuous infusion. Injectable formulations can be provided in unit dosage forms, for example, in ampoules or multi-dose containers, optionally with the addition of preservatives. The compositions can be suspensions, solutions or emulsions in oily or aqueous media and can contain formulating agents such as suspending agents, stabilizers and / or dispersing agents.

[0302] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of the active ingredient can be prepared as appropriate oily or water-based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions can contain agents that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the active ingredient to enable the formulation of highly concentrated solutions.

[0303] Alternatively, the active ingredient can be in powder form for constitution, prior to use, with a suitable vehicle, such as a sterile pyrogen-free water-based solution.

[0304] The pharmaceutical compositions of some embodiments of the present invention can also be formulated into rectal compositions, such as suppositories or retention enemas, using conventional suppository bases such as cocoa butter or other glycerides.

[0305] Suitable pharmaceutical compositions for use in connection with some embodiments of the present invention include compositions in which the active ingredient is contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of the active ingredient(s) effective to prevent, alleviate or palliate the symptoms of the disorder (e.g., cancer or metastatic cancer) being treated or to extend the survival of the subject being treated.

[0306] The determination of a therapeutically effective amount is well within the ability of one of ordinary skill in the art, particularly in view of the detailed disclosure provided herein.

[0307] For any formulation used in the methods of the present invention, a therapeutically effective amount or dose can first be estimated from in vitro and cell culture assays. For example, a dose can be formulated in an animal model to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans.

[0308] The toxicity and therapeutic efficacy of the active ingredients described herein can be determined in vitro, in cell cultures, or in experimental animals, according to standard pharmaceutical procedures. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage amounts for use in humans. The dosage will vary depending upon the dosage form employed and the route of administration utilized. Precise formulation, route of administration and dosage can be selected by the individual physician in view of the patient's condition (see, e.g., Fingl et al. (1975), in “The Pharmacological Basis of Therapeutics”, Ch. 1 p.1).

[0309] Dosage and dosing intervals can be adjusted individually so that the protein (e.g., SDF-1 and / or CXCR4) inhibitory level of the active ingredient is sufficient to induce or suppress a biological effect (minimum effective concentration, MEC). The MEC varies with each formulation, but can be estimated based on in vitro data, such as the results of the chemokine-induced (e.g., SDF-1-induced) migration inhibition assays described herein. The dosage required to achieve the MEC will vary according to the individual characteristics and the route of administration. Detection assays can be used to monitor plasma concentrations.

[0310] In some of the embodiments described herein, the effective amount of the compound is less than 100 μM. In some embodiments, the effective amount is less than 10 μM. In some embodiments, the effective amount is less than 5 μM. In some embodiments, the effective amount is less than 1 μM. In some embodiments, the effective amount is less than 0.5 μM. In some embodiments, the effective amount is less than 0.1 μM.

[0311] In some of the embodiments described herein, the effective amount is at least 100% of the IC50 of the compound for the chemokine (e.g., SDF-1) intended to be inhibited. In some embodiments, the effective amount is at least 200% of the IC50 of the compound for the chemokine. In some embodiments, the effective amount is at least 300% of the IC50 of the compound for the chemokine. In some embodiments, the effective amount is at least 500% of the IC50 of the compound for the chemokine. In some embodiments, the effective amount is at least 1000% of the IC50 of the compound for the chemokine.

[0312] In some of the embodiments described herein, the effective amount is at least 100% of the IC50 of the compound for the induction of cell death of the cancer cells to be inhibited. In some embodiments, the effective amount is at least 200% of the IC50 of the compound for the cancer cells. In some embodiments, the effective amount is at least 300% of the IC50 of the compound for the cancer cells.

[0313] Depending on the severity and responsiveness of the condition to be treated, the dosage can be administered in a single or multiple doses over a course of treatment lasting from several days to several weeks, or until a cure is achieved or the disappearance of the disease state is achieved.

[0314] The amount of the composition to be administered will, of course, depend on the subject to be treated, the severity of the affliction, the mode of administration, the judgment of the attending physician, and the like.

[0315] The compositions of some embodiments of the present invention may, if desired, be provided in a pack or dispenser device such as a kit approved by the FDA (U.S. Food and Drug Administration), and such a pack or device may contain one or more unit dosage forms containing the active ingredient. The pack may be, for example, a blister pack including a metal foil or a plastic foil. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice attached to the container in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, and this notice reflects that the form of the composition has been approved by the agency for administration to humans or animals. Such a notice may be, for example, in the form of a label approved by the U.S. Food and Drug Administration for prescription drugs, or in the form of an insert for an approved product. Also, a composition formulated in a pharmaceutically acceptable carrier and containing the formulation of the present invention may be prepared, placed in a suitable container, and labeled as being for the treatment or diagnosis of the indicated condition as detailed above.

[0316] It should be understood that the compounds described herein can be provided alone or in combination with other active ingredients well known in the art for reducing a medical condition.

[0317] Thus, for example, the compounds can be administered together with an immunomodulatory agent, either in a co-formulation or in separate formulations.

[0318] According to certain embodiments, the treatment of cancer (and other hyperproliferative disorders) is achieved in combination with an anti-cancer immunomodulatory agent.

[0319] As used herein, the term "anti-cancer immunomodulatory agent" refers to an agent capable of inducing an immune response (e.g., T cells, NK cells) against cancerous cells.

[0320] According to certain embodiments, the agent is selected from the group consisting of a cancer antigen, a cancer vaccine, an anti-cancer antibody, a cytokine capable of inducing activation and / or proliferation of T cells, and an immune checkpoint regulator.

[0321] Alternatively, or in addition to the above, such a regulatory substance can be an immune stimulatory substance such as an immune checkpoint regulator that has a particular value in the treatment of cancer.

[0322] As used herein, the term "immune checkpoint regulator" refers to a molecule that regulates the activity of one or more immune checkpoint proteins in an agonist-like or antagonist-like manner to result in activation of immune cells.

[0323] As used herein, the term "immune checkpoint protein" refers to a protein that activates or regulates the function of immune cells. The immune checkpoint protein can be either a co-stimulatory protein (i.e., one in which transmission of a stimulatory signal results in activation of immune cells) or an inhibitory protein (i.e., one in which transmission of an inhibitory signal results in suppression of activation of immune cells). According to certain embodiments, the immune checkpoint protein regulates the activation or function of T cells. A number of checkpoint proteins are known in the art and include, but are not limited to, PD1, PDL-1, B7H2, B7H4, CTLA-4, CD80, CD86, LAG-3, TIM-3, KIR, IDO, CD19, OX40, 4-1BB (CD137), CD27, CD70, CD40, GITR, CD28, and ICOS (CD278).

[0324] According to certain embodiments, the immune checkpoint regulator is selected from the group consisting of anti-CTLA4, anti-PD-1, and CD40 agonists.

[0325] According to certain embodiments, the immune checkpoint control substance is selected from the group consisting of anti-CTLA4, anti-PD-1, anti-PDL-1, CD40 agonist, 4-1BB agonist, GITR agonist and OX40 agonist.

[0326] CTLA4 is a member of the immunoglobulin superfamily that is expressed on the surface of helper T cells and transmits inhibitory signals to T cells upon ligand binding. As used herein, the term "anti-CTLA4" refers to an antagonist molecule that binds to CTLA4 (CD152) and inhibits its inhibitory activity. Thus, anti-CTLA4 prevents the transmission of inhibitory signals and thereby acts as a costimulatory molecule. According to certain embodiments, the anti-CDLA4 molecule is an antibody.

[0327] PD-1 (Programmed Death 1) is a member of the extended CD28 / CTLA-4 family of T cell regulators that is expressed on the surface of activated T cells, B cells and macrophages and transmits inhibitory signals upon ligand binding. As used herein, the term "anti-PD1" refers to an antagonist molecule that binds to PD-1 and inhibits its inhibitory activity. Thus, anti-PD-1 prevents the transmission of inhibitory signals and thereby acts as a costimulatory molecule. According to certain embodiments, the anti-PD1 molecule is an antibody. A number of anti-PD-1 antibodies are known in the art. See, for example, Topalian, et al. NEJM 2012.

[0328] PDL-1 is a ligand of PD-1. The binding of PDL-1 to its receptor PD-1 transmits an inhibitory signal to cells expressing PD-1. As used herein, the term "anti-PDL-1" refers to an antagonist molecule that inhibits PD-1 signaling by binding to PD-1 or inhibiting the binding of PD-Ll to PD-1 and / or the activation of PD-1. Thus, anti-PD-1 prevents the transmission of inhibitory signals and thereby acts as a costimulatory molecule. According to certain embodiments, anti-PD-Ll is an anti-PD-Ll antibody. A number of anti-PDL-1 antibodies are known in the art. See, e.g., Brahmer, et al. NEJM 2012.

[0329] CD40 (CD154) is a costimulatory receptor found on antigen-presenting cells that transmits an activating signal upon ligand binding. As used herein, the term "CD40 agonist" refers to an agonist molecule that binds to CD40 (CD154) and thereby induces the activation of antigen-presenting cells.

[0330] OX40 belongs to the TNF receptor superfamily and results in the amplification of CD4+ and CD8+ T cells. As used herein, the term "OX40 agonist" refers to an agonist molecule that binds to and activates OX40.

[0331] GITR (glucocorticoid-induced TNF receptor) is a surface receptor molecule that has been found to be involved in the inhibition of the suppressive activity of regulatory T cells and the prolongation of the survival of T-effector cells. As used herein, the term "GITR agonist" refers to an agonist molecule that binds to and activates GITR. According to certain embodiments, the GITR agonist is an antibody.

[0332] The compound can be administered in co-formulation (e.g., the same pharmaceutical composition) or in separate formulations with an additional anti-cancer agent described in any of the corresponding embodiments herein.

[0333] According to certain embodiments, the treatment of cancer (and other hyperproliferative disorders) is effected by combination with an additional anti-cancer agent as described in any of the corresponding embodiments herein.

[0334] The pharmaceutical compositions described herein may further comprise an additional agent as described herein, or alternatively may be identified for use in combination with an additional agent as described herein.

[0335] According to another aspect described herein, there is provided a kit for the treatment of a condition described herein (e.g., treatment of cancer or prevention of tumor metastasis or treatment of non-cancerous proliferative diseases or disorders or treatment of inflammation), the kit comprising packaging material for packaging a compound described herein.

[0336] In some embodiments, the kit further comprises an additional agent as described in any of the corresponding embodiments herein, and the two agents are individually packaged within the kit.

[0337] In some embodiments, the kit further comprises instructions for using the compound in combination with an additional agent (e.g., an additional anti-cancer agent) as described in any of the corresponding embodiments herein.

[0338] In some embodiments, the compound is identified as an inhibitor of SDF-1 and / or CXCR4 activity associated with the development or progression of a condition described herein.

[0339] In some embodiments, the compound is identified as inducing apoptosis and / or cell growth arrest of cells associated with a condition described herein.

[0340] In one aspect of some embodiments of the present invention, there is provided a pharmaceutical composition comprising a small molecule compound as described in any of the corresponding embodiments herein, optionally together with a pharmaceutically acceptable carrier, and further optionally together with an additional active ingredient as described in the corresponding embodiments herein.

[0341] In one aspect of some embodiments of the present invention, there is provided a small molecule compound described in any of the corresponding embodiments herein for use as a medicament or for use in the manufacture of a medicament.

[0342] The medicament may be a pharmaceutical composition described in any of the corresponding embodiments herein.

[0343] The medicament may be for the treatment of any of the conditions, diseases and / or disorders described herein.

[0344] Definition : As used herein, "treating" includes inhibiting, substantially inhibiting, delaying or reversing the progression of a condition, substantially alleviating the clinical or aesthetic symptoms of a condition, or substantially preventing the worsening of the clinical or aesthetic symptoms of a condition. For example, from the perspective of preventing metastasis and / or angiogenesis, "preventing" refers to blocking, stopping or inhibiting the process of metastasis and / or angiogenesis, or their progression and subsequent metastasis and / or angiogenesis.

[0345] As used herein, the term "subject" refers to a mammal (such as a human), for example, one diagnosed with a condition (such as cancer) described herein. The terms "comprise", "comprising", "include", "including", "having" and their conjugations mean "including but not limited to".

[0346] The term "consisting of" means "including and limited to".

[0347] The term "consisting essentially of" means that a composition, method or structure may include additional components, steps and / or parts. However, the additional components, steps and / or parts are limited to those that do not substantially change the basic and novel characteristics of the claimed composition, method or structure.

[0348] As used herein, the singular forms "a", "an" and "the" include the plural unless the context clearly dictates otherwise. For example, "a compound" or "at least one compound" can include a plurality of compounds and can also include mixtures thereof.

[0349] Throughout this application, various embodiments 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 is not to be construed as a limitation on the flexibility of the scope of the invention. Thus, a range description should be considered to specifically disclose all the sub-ranges possible and the individual numerical values within that range. For example, a range description such as 1 to 6 should be considered to specifically disclose not only the sub-ranges 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., but also the individual numerical values within that range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the size of the range.

[0350] When a numerical range is recited herein, it is intended to include any recited number (fractional or integral) within the indicated range. The phrases "range between" a first recited number and a second recited number, and "range from" a first recited number "to" a second recited number are used interchangeably herein and are intended to include the first and second recited numbers and all the fractional and integral numbers therebetween.

[0351] As used herein, the term "method" means a manner, means, technique and procedure for achieving a given task and includes, but is not limited to, those known to, or readily developed by, persons skilled in the art of chemistry, pharmacology, biology, biochemistry and medicine.

[0352] Throughout this specification, the term "linking group" refers to a group (substituent) that is bonded to another part of a compound through two or more of its atoms. To distinguish a linking group from a substituent that is bonded to another part of a compound through one atom, the latter is referred to throughout this specification as a "terminal group".

[0353] As used herein, the term "amine" refers to both -NR'R" groups and -NR'- groups, where R' and R" are each independently hydrogen, alkyl, cycloalkyl, or aryl, as defined below.

[0354] Thus, an amine group can be a primary amine where both R' and R" are hydrogen, a secondary amine where R' is hydrogen and R" is alkyl, cycloalkyl, or aryl, or a tertiary amine where each of R' and R is independently alkyl, cycloalkyl, or aryl.

[0355] Alternatively, R' and R" can each independently be hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiolhydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, carbonyl, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, N-carbamate, O-carbamate, C-amide, N-amide, guanyl, guanidine, and hydrazine.

[0356] The term "amine" is used herein to refer to an -NR'R" group when the amine is a terminal group or part of a terminal group, and to an -NR'- group when the amine is a linking group.

[0357] The term "alkyl" refers to saturated aliphatic hydrocarbons including straight-chain and branched-chain groups. The alkyl group preferably has 1 to 20 carbon atoms. When a numerical range, for example, "1 to 20" is described herein, this range means that the substituent, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms. In some embodiments, the alkyl is a medium-sized alkyl having 1 to 10 carbon atoms. Unless otherwise indicated, the alkyl is a lower alkyl having 1 to 4 carbon atoms. In some embodiments, the alkyl has at least 4 carbon atoms, for example, the alkyl has 4 to 12 or 4 to 10 or 4 to 8 carbon atoms. The alkyl group may be substituted or unsubstituted. The substituted alkyl has one or more substituents, where each substituent is independently, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloaliphatic group, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, oxo, carbonyl, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, N-carbamate, O-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine.

[0358] The alkyl group may be a terminal group, in which case it is bonded to one adjacent atom as defined above, or it may be a linking group, in which case it is bonded to two or more moieties via at least two carbons in the chain as defined above. When the alkyl is a linking group, the term "alkylene" is also used herein, for example, methylene, ethylene, propylene, etc.

[0359] The term "alkenyl" refers to an alkyl in which at least one pair of carbon atoms is linked to each other by a double bond, as defined herein.

[0360] As defined herein, the term "alkynyl" or "alkyne" refers to an alkyl in which at least one pair of carbon atoms are linked to each other by a triple bond.

[0361] The term "cycloalkyl" refers to a monocyclic or fused ring group (i.e., a ring sharing adjacent pairs of carbon atoms) consisting only of carbon, in which one or more of the rings do not have a fully conjugated π - electron system. The cycloalkyl group may be substituted or unsubstituted. A substituted cycloalkyl has one or more substituents, where each substituent is independently, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloaliphatic group, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiolhydroxy, thioalkoxy, thioaryloxy, oxo, carbonyl, cyano, nitro, azo, sulfonamide, C - carboxylate, O - carboxylate, N - thiocarbamate, O - thiocarbamate, urea, thiourea, N - carbamate, O - carbamate, C - amide, N - amide, guanyl, guanidine and hydrazine. The cycloalkyl group may be a terminal group, in which case it is bonded to one adjacent atom as defined above, or a linking group, in which case it is bonded to two or more moieties at two or more positions as defined above.

[0362] The term "heterocyclic alicyclic group" refers to a monocyclic group or a condensed ring group having one or more atoms, such as nitrogen, oxygen, sulfur, etc., in the ring. The ring may also have one or more double bonds. However, the ring does not have a completely conjugated π electron system. The heterocyclic alicyclic group may be substituted or unsubstituted. The substituted heterocyclic alicyclic group has one or more substituents, where each substituent is independently, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic alicyclic group, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiolhydroxy, thioalkoxy, thioaryloxy, oxo, carbonyl, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, O-carbamate, N-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine. The heterocyclic alicyclic group may be a terminal group, in which case it is bonded to one adjacent atom as defined above, or it may be a linking group, in which case it is bonded to two or more moieties at two or more positions as defined above. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino, etc.

[0363] The term "aryl" refers to a monocyclic or fused polycyclic group consisting only of carbon (i.e., rings sharing adjacent carbon atom pairs) having a fully conjugated electron system. The aryl group may be substituted or unsubstituted. A substituted aryl has one or more substituents, where each substituent is independently, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloaliphatic, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiol, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, N-carbamate, O-carbamate, C-amide, N-amide, guanyl, guanidine, and hydrazine. The aryl group may be a terminal group, in which case it is bonded to one adjacent atom as defined above, or a linking group, in which case it is bonded to two or more moieties at two or more positions as defined above. Preferably, aryl is phenyl. Optionally, aryl is naphthalenyl.

[0364] The term "heteroaryl" refers to a monocyclic or fused-ring group (i.e., rings sharing adjacent pairs of carbon atoms) that has one or more atoms, such as nitrogen, oxygen, sulfur, etc., within the ring(s) and a fully conjugated π electron system. Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, triazine, tetrazine, quinoline, isoquinoline, and purine. The heteroaryl group may be substituted or unsubstituted. Substituted heteroaryl has one or more substituents, where each substituent is independently, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloaliphatic, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiol, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, O-carbamate, N-carbamate, C-amide, N-amide, guanyl, guanidine, and hydrazine. The heteroaryl group may be a terminal group, in which case it is bonded to one adjacent atom as defined above, or a linking group, in which case it is bonded to two or more moieties at two or more positions as defined above.

[0365] The term "alkaryl" refers to an alkyl as defined herein substituted by one or more aryl or heteroaryl groups. An example of alkaryl is benzyl.

[0366] The terms "halide" and "halo" refer to fluorine, chlorine, bromine, or iodine.

[0367] The term "haloalkyl" refers to an alkyl group as defined above substituted by one or more halides.

[0368] The term "sulfate" refers to an -O-S(=O)2-OR' end group as defined above, or an -O-S(=O)2-O- linking group as defined above, where R' is as defined above.

[0369] "Thiosulfate" refers to an -O-S(=S)(=O)-OR' end group or an -O-S(=S)(=O)-O- linking group as defined above, where R' is as defined above.

[0370] The term "sulfite" refers to an -O-S(=O)-O-R' end group or an -O-S(=O)-O-group linking group as defined above, where R' is as defined above.

[0371] The term "thiosulfite" refers to an -O-S(=S)-O-R' end group or an -O-S(=S)-O-group linking group as defined above, where R' is as defined above.

[0372] The term "sulfinate" or "sulfinyl" refers to a -S(=O)-OR' end group or a -S(=O)-O-group linking group as defined above, where R' is as defined above.

[0373] The term "sulfoxide" refers to a -S(=O)R' end group or a -S(=O)- linking group as defined above, where R' is as defined above.

[0374] The term "sulfonate" or "sulfonyl" refers to a -S(=O)2-OR' end group (also referred to herein as -SO3R' or -SO3H) or an -OS(=O)2- linking group as defined above, where R' is as defined herein.

[0375] The term "S-sulfonamide" refers to a -S(=O)2-NR'R" end group or a -S(=O)2-NR'- linking group as defined above, where R' and R" are as defined herein.

[0376] The term "N-sulfonamide" refers to an R'S(=O)2-NR"-terminal group or an -S(=O)2-NR'-linking group as defined above, where R' and R" are as defined herein.

[0377] The term "disulfide" refers to an -S-SR'-terminal group or an -S-S-linking group as defined above, where R' is as defined herein.

[0378] The term "phosphonate" refers to a -P(=O)(OR')(OR'')-terminal group or a -P(=O)(OR')(O)-linking group as defined above, where R' and R'' are as defined herein.

[0379] The term "thiophosphonate" refers to a -P(=S)(OR')(OR'')-terminal group or a -P(=S)(OR')(O)-linking group as defined above, where R' and R'' are as defined herein.

[0380] The term "carbonyl" or "carbonate" or "ketone", when used herein, refers to a -C(=O)-R'-terminal group or a -C(=O)-linking group as defined above, where R' is as defined herein.

[0381] The term "thiocarbonyl", when used herein, refers to a -C(=S)-R'-terminal group or a -C(=S)-linking group as defined above, where R' is as defined herein.

[0382] The term "oxo" is taken herein to refer to an =O-terminal group.

[0383] The term "thioxo" is taken herein to refer to an =S-terminal group.

[0384] The term "oxime" refers to an =N-OH-terminal group or an =N-O-linking group as defined above.

[0385] The term "hydroxyl" or "hydroxy" refers to the -OH group.

[0386] The term "alkoxy" refers to both -O-alkyl and -O-cycloalkyl groups as defined herein.

[0387] The term "aryloxy" refers to both -O-aryl and -O-heteroaryl groups as defined herein.

[0388] The term "thiol" or "thio" refers to the -SH group.

[0389] The term "thioalkoxy" refers to both -S-alkyl and -S-cycloalkyl groups as defined herein.

[0390] The term "thioaryloxy" refers to both -S-aryl and -S-heteroaryl groups as defined herein.

[0391] The term "cyano" or "nitrile" refers to the -C≡N group.

[0392] The term "isocyanate" refers to the -N=C=O group. <I

[0393] The term "nitro" refers to the -NO2 group.

[0394] The term "carboxylate" includes C-carboxylate and O-carboxylate herein.

[0395] The term "C-carboxylate" refers to the -C(=O)-OR' terminal group or -C(=O)-O- linking group as defined above, and R' is as defined herein.

[0396] The term "O-carboxylate" refers to the -OC(=O)R' terminal group or -OC(=O)- linking group as defined above, and R' is as defined herein. [[ID=I45]]

[0397] The term "thiocarboxylate" as used herein includes "C-thiocarboxylate and O-thiocarboxylate.

[0398] The term "C-thiocarboxylate" refers to the -C(=S)-OR' end group or -C(=S)-O- bond group defined above, where R is as defined herein.

[0399] The term "O-thiocarboxylate" refers to the -OC(=S)R' end group or -OC(=S)- bond group defined above, where R' is as defined herein.

[0400] The term "carbamate" as used herein includes N-carbamate and O-carbamate.

[0401] The term "N-carbamate" refers to the R”OC(=O)-NR’- end group or -OC(=O)-NR’- bond group defined above, where R' and R” are as defined herein.

[0402] The term "O-carbamate" refers to the -OC(=O)-NR’R” end group or -OC(=O)-NR’- bond group defined above, where R' and R” are as defined herein.

[0403] The term "thiocarbamate" as used herein includes N-thiocarbamate and O-thiocarbamate.

[0404] The term "O-thiocarbamate" refers to the -OC(=S)-NR’R” end group or -OC(=S)-NR’- bond group defined above, where R' and R” are as defined herein.

[0405] The term "N-thiocarbamate" refers to the R”OC(=S)NR’- end group or -OC(=S)NR’- bond group defined above, where R' and R” are as defined herein.

[0406] The term "dithiocarbamate" as used herein includes N-dithiocarbamate and S-dithiocarbamate.

[0407] The term "S-dithiocarbamate" refers to the -SC(=S)-NR’R” end group or -SC(=S)NR’- linking group as defined above, where R’ and R” are as defined herein.

[0408] The term "N-dithiocarbamate" refers to the R”SC(=S)NR’- end group or -SC(=S)NR’- linking group as defined above, where R’ and R” are as defined herein.

[0409] The term "urea", also referred to herein as "ureido", refers to the NR’C(=O)-NR”R”’ end group or -NR’C(=O)-NR”- linking group as defined above, where R’ and R” are as defined herein, and R”’ is as defined herein with respect to R’ and R”.

[0410] The term "thiourea", also referred to herein as "thioureido", refers to the -NR’-C(=S)-NR”R”’ end group or -NR’-C(=S)-NR”- linking group, where R’, R” and R”’ are as defined herein.

[0411] The term "amide" as used herein includes C-amide and N-amide.

[0412] The term "C-amide" refers to the C(=O)-NR’R” end group or -C(=O)-NR’- linking group as defined above, where R’ and R” are as defined herein.

[0413] The term "N-amide" refers to the R’C(=O)-NR”- end group or R’C(=O)-N- linking group as defined above, where R’ and R” are as defined herein.

[0414] The term "guanidyl" refers to an R’R”NC(=N)-terminal group or -R’NC(=N)-bonding group as defined above, where R’ and R” are as defined herein.

[0415] The term "guanidine" refers to an R’NC(=N)-NR”R”’ terminal group or -R’NC(=N)-NR”-bonding group as defined above, where R’, R” and R”’ are as defined herein.

[0416] The term "hydrazine" refers to an -NR’-NR”R”’ terminal group or -NR’-NR”-bonding group as defined above, where R’, R” and R”’ are as defined herein.

[0417] As used herein, the term "hydrazide" represents a -C(=O)-NR’-NR”R”’ terminal group or -C(=O)-NR’-NR”-bonding group as defined above, where R’, R” and R’” are as defined herein.

[0418] As used herein, the term "thiohydrazide" represents a -C(=S)-NR’-NR”R”’ terminal group or -C(=S)-NR’-NR”-bonding group as defined above, where R’, R” and R’” are as defined herein.

[0419] For any of the embodiments described herein, the compounds described herein may be in the form of their salts, e.g., in the form of their pharmaceutically acceptable salts and / or in the form of their prodrugs.

[0420] As used herein, the phrase "pharmaceutically acceptable salt" refers to the charged species of the parent compound and its counterion and is typically used to alter the solubility properties of the parent compound and / or to reduce the significant irritation caused by the parent compound in an organism, without suppressing the biological activity and properties of the administered compound.

[0421] In some aspects of embodiments of the present invention, the pharmaceutically acceptable salts of the compounds described herein may optionally be base addition salts, and the base addition salts are at least one acidic group of the present compound in a negatively charged form (for example, a form in which an acidic group is deprotonated) (for example, a phenolic group and / or a carboxylic acid group), and a combination with at least one counterion derived from the selected acidic group that forms a pharmaceutically acceptable salt.

[0422] Therefore, the acid addition salts of the compounds described herein can be a complex formed by one or more acidic groups of the drug and one or more bases equivalent thereto.

[0423] Examples of base addition salts include, but are not limited to, various organic and inorganic counterions and bases such as sodium salts (for example, NaOH addition), potassium salts (for example, KOH addition), calcium salts (for example, Ca(OH)2 addition), magnesium salts (for example, Mg(OH)2 addition), aluminum salts (for example, Al(OH)3 addition), and ammonium salts (for example, ammonia addition). Each of these base addition salts may be either a mono-addition salt or a poly-addition salt as defined herein.

[0424] In some aspects of embodiments of the present invention, the pharmaceutically acceptable salts of the compounds described herein may optionally be acid addition salts, and the acid addition salts are at least one basic group of the present compound in a positively charged form (for example, a form in which the -NH- group is protonated) (for example, an amine or amide group), and a combination with at least one counterion derived from the selected acid that forms a pharmaceutically acceptable salt.

[0425] Therefore, the acid addition salts of the compounds described herein can be a complex formed by one or more basic groups of the drug and one or more acids equivalent thereto.

[0426] Examples of acid addition salts include, but are not limited to, hydrochloric acid which provides a hydrochloride salt, hydrobromic acid which provides a hydrobromide salt, acetic acid which provides an acetate salt, ascorbic acid which provides an ascorbate salt, benzenesulfonic acid which provides a besylate salt, camphorsulfonic acid which provides a camphorsulfonate salt, citric acid which provides a citrate salt, maleic acid which provides a maleate salt, malic acid which provides a malate salt, methanesulfonic acid (mesylate) which provides a methanesulfonate salt, naphthalenesulfonic acid which provides a naphthalenesulfonate salt, oxalic acid which provides an oxalate salt, phosphoric acid which provides a phosphate salt, toluenesulfonic acid which provides a p-toluenesulfonate salt, succinic acid which provides a succinate salt, sulfuric acid which provides a sulfate salt, tartaric acid which provides a tartrate salt, and trifluoroacetic acid which provides a trifluoroacetate salt, and may include various organic and inorganic acids. Each of these acid addition salts may be either a mono-addition salt or a poly-addition salt as defined herein.

[0427] Depending on the stoichiometric ratio between the charged group in the compound and the counterion in the salt, the acid or base addition salt can be either a mono-addition salt or a poly-addition salt.

[0428] As used herein, the term "mono-addition salt" refers to a salt in which the stoichiometric ratio between the counterion and the compound in its charged form is 1:1, and which contains 1 molar equivalent of counterion per 1 molar equivalent of the compound.

[0429] As used herein, the term "poly-addition salt" refers to a salt in which the stoichiometric ratio between the counterion and the compound in its charged form is greater than 1:1, such as 2:1, 3:1, 4:1, etc., and which contains 2 or more molar equivalents of counterion per 1 molar equivalent of the compound.

[0430] As used herein, the term "prodrug" refers to a compound that is converted in vivo to an active compound (e.g., a compound represented by the above-described formula). Prodrugs are typically designed to facilitate administration, for example, by enhancing absorption. A prodrug may include, for example, an active compound modified with an ester group (e.g., any one or more hydroxyl groups of the compound are modified with an acyl group, optionally a (C 1~4 ) acyl (e.g., acetyl) group and / or any one or more carboxylic acid groups of the compound are modified with an alkoxy group or an aryloxy group, optionally a (C 1~4 ) alkoxy (e.g., methyl, ethyl) group to form an ester group).

[0431] Furthermore, each of the compounds described herein also includes its salts and may be in the form of its solvates or hydrates.

[0432] The term "solvate" refers to a complex having a variable stoichiometry (e.g., di, tri, tetra, penta, hexa, etc.) formed by a solute (a heterocyclic compound described herein) and a solvent, where the solvent does not interfere with the biological activity of the solute.

[0433] The term "hydrate" refers to the above solvate where the solvent is water.

[0434] The compounds described herein may be used as polymorphs, and this embodiment further includes any polymorphs of the compounds and any combinations thereof.

[0435] This embodiment further includes any enantiomers and diastereomers of the compounds described herein.

[0436] As used herein, the term "enantiomer" refers to stereoisomers of a compound that can be superimposed on their corresponding structures only by complete inversion / mirroring (mirror image) of each other. Enantiomers are said to have "chirality" because they are described as being like right and left hands to each other. Enantiomers have the same chemical and physical properties, except when they are present in an environment that itself has chirality (e.g., any biological system). In embodiments of the present invention, a compound may have one or more chiral centers, each of which may be in the R configuration or the S configuration, and any combination thereof may be possible. Compounds according to some embodiments of the present invention may have any chiral center that exhibits the R configuration or the S configuration.

[0437] As used herein, the term "diastereomer" refers to stereoisomers that are not enantiomers of each other. Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more, but not all, of the equivalent (related) stereocenters and are not mirror images of each other. When two diastereoisomers differ from each other at only one stereocenter, they are epimers. Each stereocenter (chiral center) gives rise to two different configurations and thus two different stereoisomers. In the context of the present invention, embodiments of the present invention include compounds having multiple chiral centers in any combination of stereoconfigurations, i.e., any diastereomers that occur.

[0438] As used herein, the term "about" represents ±10% or ±5%.

[0439] It should be understood that the features of the present invention, which have been described as individual embodiments for clarity, can also be provided in combination as one embodiment. Conversely, the various features of the present invention described as one embodiment for brevity can also be provided individually, or in any suitable sub-combination, or in a suitable combination with other embodiments described in the present invention. The features described in connection with the various embodiments are not considered essential requirements of those embodiments unless the embodiments would be inoperable without that feature.

[0440] As described above, the various embodiments and aspects of the present invention described herein and claimed by the following claims are experimentally supported by the following examples.

Example

[0441] Refer to the following examples, which, together with the above description, illustrate without limiting some embodiments of the present invention.

[0442] Example 1 Chemical synthesis An exemplary compound in this embodiment, designated BKT300-N1, is shown in FIG. 1 and was prepared as described below.

[0443] The chemical structure of BKT300-Ni can be represented by two tautomers.

Chem.

[0444] The chemical name of the keto tautomer is 8-(4-hydroxy-2-methoxyphenoxy)-6-methoxy-3-pentylquinoline-2,4(1H,3H)-dione.

[0445] The chemical name of the enol tautomer is 4-hydroxy-8-(4-hydroxy-2-methoxyphenoxy)-6-methoxy-3-pentylquinolin-2(1H)-one.

[0446] For simplicity, only the enol tautomer is referred to below. However, two tautomers may exist, and depending on environmental conditions, they may exist in an equilibrium state or as one tautomer.

[0447] Preparation of 4-(benzyloxy)-2-methoxybenzaldehyde (S2):

Chemical formula

[0448] To a solution of 4-hydroxy-2-methoxybenzaldehyde (S1) (150.0 g, 985 mmol) in DMF (1.0 L) was added K2CO3 (272 g, 1970 mmol, 1.5 equiv) at 0 °C, and the resulting mixture was stirred for 30 minutes. BnBr (270 g, 1576 mmol, 1.6 equiv) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to come to room temperature and stirred overnight. TLC indicated that the reaction was complete. The reaction of the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (EA) (800 mL × 3). The organic phase was washed with water (1000 mL × 2) and brine (800 mL), dried over Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography to obtain the product 4-(benzyloxy)-2-methoxybenzaldehyde (S2) as a colorless oil (215.0 g, 90% yield).

[0449] Preparation of 4-methoxy-3-(trifluoromethoxy)phenol (S3):

Chemical formula

[0450] A suspension of 4-(benzyloxy)-2-methoxybenzaldehyde (S2) (200.0 g, 825 mmol) and H2O2 (150 mL, 4412 mmol, 5 equiv) in MeOH (1250 mL) was added with H2SO4 (15.0 mL, 248 mmol). The reaction mixture was stirred at room temperature overnight. TLC indicated that the reaction was complete. The reaction mixture was diluted with water (1000 mL) and extracted with EA (500 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column to obtain the product 4-methoxy-3-(trifluoromethoxy)phenol (S3) as a colorless oil (136.8 g, 72% yield).

[0451] Preparation of 4-(benzyloxy)-2-methoxy-1-(5-methoxy-2-nitrophenoxy)benzene (2):

Chemical formula

[0452] NaH (60%) (23.8 g, 594 mmol) was added portionwise to a solution of 4-(benzyloxy)-2-methoxyphenol (S3) (125 g, 540 mmol) in THF (2.0 L). The reaction mixture was stirred at 0 °C for 30 minutes. Then 2-fluoro-4-methoxy-1-nitrobenzene (1) (93.0 g, 540 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature overnight. TLC indicated that the reaction was complete (using 10:1 petrol ether (PE):ethyl acetate as the eluent). The reaction mixture was poured into ice water and extracted with EA (800 mL×3). The organic phase was washed with brine (500 mL×2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 10:1 PE:EA to obtain product 2 as a brown oil (155.0 g, 72% yield). LC-MS: m / z=382.1 (M + +H)

[0453] Preparation of 2-(4-(benzyloxy)-2-methoxyphenoxy)-4-methoxyaniline (3):

Chemical formula

[0454] HCl (850 mL, 6 N) was added to a mixture of 4-(benzyloxy)-2-methoxy-1-(5-methoxy-2-nitrophenoxy)benzene (2) (155 g, 275 mmol) and SnCl2·2H2O (372 g, 1655 mmol, 6.0 equivalents) in EtOH (900 mL). The reaction mixture was heated to reflux and stirred overnight under a stream of nitrogen. LC-MS indicated that the reaction was complete (using 2:1 PE:EA as the eluent). The reaction mixture was diluted with water (1000 mL), washed with saturated Na2CO3, filtered, and the filtrate was extracted with EA (600 mL × 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography eluting with 4:1 PE:EA to give the product 3 as a black oil (100.0 g, 83% yield). LC-MS: m / z352.4 (M + +H)

[0455] Preparation of ethyl 2-((2-(4-(benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoate (4):

Chemical formula

[0456] A mixture of 2-(4-(benzyloxy)-2-methoxyphenoxy)-4-methoxyaniline (3) (100 g, 285 mmol), diethyl 2-pentylmalonate (SM-1) (39 g, 855 mmol, 3.0 equiv), and pyridine (45.0 mL, 575 mmol, 2.0 equiv) in toluene (300 mL) was stirred under reflux for 72 h. LC-MS indicated completion of the reaction. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 7:1 PE:EA to afford the product 4 as a brown oil (100 g, 67% yield). LC-MS: m / z536.3(M + +H)

[0457] Preparation of 2-((2-(4-(benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoic acid (5):

Chem.

[0458] To a solution of ethyl 2-((2-(4-(benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoate (4) (100 g, 187 mmol) in a mixed solution of THF (500 mL) and H2O (300 mL) was added LiOH (22 g, 920 mmol, 5.0 equiv). The reaction was stirred at room temperature overnight. TLC indicated completion of the reaction. The reaction mixture was concentrated in vacuo. The residue was dissolved in H2O (300 mL) and acidified to pH 2 - 3 using concentrated HCL. The reaction mixture was extracted with EA (500 mL×3). The organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to afford the product 5 as a brown oil (90 g, 96% yield).

[0459] Preparation of 8-(4-(benzyloxy)-2-methoxyphenoxy)-4-hydroxy-6-methoxy-3-pentylquinolin-2(1H)-one (6):

Chem.

[0460] 2-((2-(4-(Benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoic acid (5) (30 g, 59.1 mmol) was added to a solution of Eaton's reagent (42 g, 177.3 mmol, 3.0 equiv) in DCM (300 mL). The reaction mixture was stirred at 40 °C for 2 h. LC-MS indicated complete consumption of compound 5. The reaction mixture was poured into H2O (50 mL), washed with saturated NaHCO3, and extracted with EA (100 mL × 3). The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford product 6 as a pale yellow solid (10.1 g, 35.1% yield).

[0461] Preparation of 4-hydroxy-8-(4-hydroxy-2-methoxyphenoxy)-6-methoxy-3-pentylquinolin-2(1H)-one (BKT300-N1):

Chemical Structure

[0462] 2-((2-(4-(Benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoic acid (6) (30 g, 59.1 mmol) was added to a solution of trifluoroacetic acid (150 mL) and stirred at room temperature for 12 h. LC-MS indicated complete consumption of compound 6. The TFA solution was removed under vacuum at 30 °C. The residue was diluted with H2O (250 mL) and extracted with EA (300 mL × 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford the final product BKT300-N1 as a white solid (10.5 g, 44.7% yield). 1HNMR (400 MHz, DMSO): δ (ppm) = 10.26 (s, 1H), 9.97 (s, 1H), 9.53 (s, 1H), 7.02 (s, 1H), 6.96 (m, 1H), 6.57 (s, 1H), 6.38 (m, 1H), 6.12 (s, 1H), 3.69 (s, 3H), 3.68 (s, 3H), 2.56 (m, 2H), 1.45 (m, 2H), 1.28 (s, 4H), 0.87 (t, 3H) HPLC purity: 97.8% (254 nm), 97.7% (214 nm) MS m / z (ESI): m / z = 400.1 (M + + H).

[0463] Using the outline of the above method, by selecting the respective compounds corresponding to compounds S3, 1 and SM-1 shown in this specification and in Figure 1, other compounds of formula Ia and / or Ib or IIa and / or IIb can be synthesized.

[0464] Example 2 In Vitro Migration and Invasion Assays Migration Assay: 600 μl of RPMI medium containing 1% fetal calf serum (FCS) was added to the lower chamber of a Transwell® migration plate supplemented with 100 ng / ml of SDF-1. Except for the control samples, BKT300-N1 was added to the lower chamber at the specified concentrations. Before starting the migration assay, SDF-1 was incubated with BKT300-N1 at room temperature for 30 minutes. Following the 30-minute incubation, a total volume of 100 μl of 2 × 10 5 Jurkat cells were added to the upper chamber of the migration plate. The number of cells that migrated to the lower chamber of the Transwell® plate within 3 hours was counted using a FACScalibur™ flow cytometer.

[0465] The results are shown in Figure 2, which indicates that BKT300-N1 at concentrations of 0.5 μM, 1 μM or 5 μM significantly inhibited the migration of lymphoid Jurkat cells towards SDF-1.

[0466] These results indicate that BKT300-N1 is an effective inhibitor against SDF-1 function, suggesting that the compound is effective in treating pathological conditions associated with the activities of SDF-1 and CXCR4 (the receptor of SDF-1).

[0467] Scratch assay: To determine the effect of BKT300-N1 on cell invasion and migration compared to BKT300-3-C5, a scratch assay was performed. This system measures in real time the closure of the scratch (scrape wound) and automatically calculates the relative wound density and wound width within the area that was originally space at each time point. The relative wound density is represented as the ratio of the occupied area to the total area of the region where the scratch was initially made.

[0468] Cells were plated in 96-well image lock plates (Essen Bioscience) and grown overnight to form a spatially uniform monolayer.

[0469] To form a uniform and reproducible scratch in all wells of the 96-well plate, a scratch was made using a 96-pin tool WoundMaker™ (Essen BioScience). After the scratch was formed, the medium was aspirated, and the wells were washed twice with fresh medium to remove all cells from the scratched area. Fresh medium containing test compounds at various concentrations was added to the wells after washing. Once the fresh medium was added, the plate was placed in an IncuCyte ZOOM™ device, and images of the collective cell spreading were recorded every 4 hours over a total period of 60 hours.

[0470] Data processing and analysis were performed using the IncuCyte S3 live cell analysis system.

[0471] The scratch assay was performed using HCC SNU449 cells. The cells were scratched and incubated with 0.05, 0.1, 0.5, 1, and 10 μM of BKT300-N1 or BKT300-3-C5.

[0472] Figure 3 represents the relative wound area at 24 hours and shows the improved effect of BKT300-N1 already exerted at a concentration of 0.1 μM.

[0473] Figures 4A to 4E represent comparison plots of the effects on the relative wound width values (microns) analyzed by IncuCyte when incubated with each of 0.05, 0.1, 0.5, 1, and 10 μM of BKT300-N1 (designated as N1 for simplicity) and 0.05, 0.1, 0.5, 1, and 10 μM of BKT300-3-C5 (designated as BKT300 for simplicity) compared to the control, further showing the improved effect of BKT300-N1 compared to BKT300-3-C5, especially at low concentrations.

[0474] In other scratch assays, MSTO cells were wounded and incubated with 0.5 μM, 0.1 μM, 0.05 μM, 10 nM, 5 nM, 1 nM, and 0.5 nM of BKT300-N1.

[0475] Figure 5A represents a comparison plot of the relative wound width values (microns) analyzed by IncuCyte.

[0476] Figure 5B shows images of the wound width obtained using the IncuCyte live cell imaging system for the control and cells incubated with 0.1 μM and 0.5 μM of BKT300-N1 after 48 hours.

[0477] Example 3 In Vitro Cell Viability Assay Annexin-V Apoptosis Assay: Apoptosis was determined by flow cytometry analysis using an Annexin-V kit.

[0478] U937 cancer cells were incubated in RPMI cell medium containing 1% fetal calf serum (FCS) at a concentration of 1×10 6 cells / well with a final volume of 1 ml in a 24-well plate. The test compounds (BKT300-N1 or BKT300-3-C5) were added to the cells at the specified concentrations. After 24 hours of incubation, the medium and cells were collected and centrifuged, and stained with an Annexin-V and propidium iodide (PI) kit according to the manufacturer's instructions. The numbers of live cells (Annexin-V negative / PI negative), early apoptotic cells (Annexin-V positive / PI negative), late apoptotic cells (Annexin-V positive / PI positive), and necrotic cells (Annexin-V negative / PI positive) were then evaluated by flow cytometry (FACS).

[0479] Figures 6A to 6B show the data obtained in this assay. Figure 6A is a bar graph representing the effect of BKT300-N1 and BKT300-3-C5 (25 - 1000 nM) on the viability of U937 cells as the number of Annexin-V- / PI- live cells, showing the improved effect of BKT300-N1 at all test concentrations. Figure 6B is a bar graph representing the effect of BKT300-N1 and BKT300-3-C5 (25 - 1000 nM) on the apoptosis of U937 cells as the percentage of Annexin-V+ cells.

[0480] The data obtained clearly show that BKT300-N1 has a substantially higher effect on the reduction in the percentage of live cells due to apoptosis.

[0481] Western blot of cleaved caspase-3: The CASP-3 (caspase-3) protein is a member of the cysteine-aspartic acid protease (caspase) family. The sequential activation of caspases plays a central role in the execution phase of cell apoptosis. Caspases exist as inactive proenzymes and, through the processing of conserved asparagine residues, produce two subunits, namely, a large one and a small one, which dimerize to form an active enzyme. The active enzyme cleaves and activates caspases 6 and 7 and is processed and activated by caspases 8, 9, and 10.

[0482] The role of caspase-3 (CASP3) in BKT300-N1-induced apoptosis of the U937 AML cell line was investigated. Cells were incubated with BKT300-N1 (0.1, 0.5, and 1 μM) for 24 hours, and then the presence of cleaved caspase 3 was examined by Western blot assay using an mAb against human cleaved caspase 3.

[0483] Figure 7A represents a Western blot showing the effect of BKT300-N1 (0.1, 0.5, and 1 μM) on the presence of cleaved caspase-3 in U937 cells after 24-hour incubation.

[0484] Figure 7B represents a bar graph showing the effect of BKT300-N1 (0.1, 0.5, and 1 μM) on the presence of cleaved caspase-3 in U937 cells after 24-hour incubation, expressed as optical density (OD) and normalized to actin.

[0485] The data obtained clearly showed that BKT300-N1-induced apoptosis occurs via the activation of caspase-3.

[0486] Analysis of the cell cycle by 7-AAD staining: To evaluate the effect of BKT300-N1 on the cell cycle distribution, a 7-aminoactinomycin D (7-AAD) protocol was used. Cells were seeded at 1 × 10 in 24 wells of a microplate 6Cells / wells were seeded at a density and exposed to test compounds at various concentrations, namely BKT300-N1 or BKT300-3-C5, in a CO2 incubator at 37 °C for 24 or 48 hours. After the incubation period, the cells were harvested and washed with cold PBS. The cells were fixed at 4 °C for 20 minutes and processed according to the 7-AAD labeling protocol. The dye intensity of the stained cells was measured by flow cytometry. Cell cycle analysis was performed by calculating the G0 / G1 phase, G2 / M phase, and sub-G0 phase from the histogram of the 7-AAD region.

[0487] Using the above protocol, U937 cells were treated with various concentrations of BKT300-N1 or BKT300-3-C5 (0.05, 0.1, 0.5, and 1 μM) for 24 hours and then the cell cycle was analyzed by flow cytometry using 7-AAD.

[0488] Figures 8A - 8B show the effects of BKT300-N1 (Figure 8A) and BKT300-3-C5 (Figure 8B) on the cell cycle of U937 cells, supporting the more improved effect exerted by BKT300-N1 compared to BKT300-3-C5, with the lower concentrations tested being more significant. As shown in Figure 8A, treatment with BKT300-N1 resulted in cell cycle arrest and induced cell death at all test concentrations. On the other hand, as shown in Figure 8B, treatment with BKT300-3-C5 did not induce cell death at concentrations below 0.5 μM.

[0489] Using the above protocol, H69 cells were treated with various concentrations of BKT300-N1 for 48 hours and the periods during the cell cycle were analyzed by flow cytometry using 7-AAD. Based on the cell cycle, the cells were gated: P1 was the G0 / G1 phase, P2 - apoptotic cells were within the sub-G0 phase, and P3 was the G2 / M phase. The data obtained are shown in Figure 9.

[0490] The data obtained indicate that BKT300-N1 blocks the growth of the G2M phase of the cell cycle and induces apoptotic cell death.

[0491] The data shown in FIGS. 8A-8B and 9 further demonstrate the improved activity of BKT300-N1 in cell cycle arrest of various cancer cells.

[0492] Example 4 In Vivo Study The effects of BKT300-N1 on in vivo cancer cell proliferation and survival were tested in NOD Scid gamma (NSG) mice or C57BL / 6 mice.

[0493] For C57BL / 6 mice, 5×10 6 cells / mouse of the mouse pancreatic cell line Panc02 were subcutaneously implanted.

[0494] For NSG mice, 5×10 6 cells / mouse of the human hepatocellular carcinoma cell line SNU449 or the human AML cell line U937 were subcutaneously implanted.

[0495] When the tumors reached a certain size and became clearly visible, BKT300-N1 was injected into the treatment groups. BKT300-N1 (formulated at 30 mg / ml in 49.7% (V / V) Cremophor EL in dehydrated alcohol and further diluted 1:6 with 0.9% NaCl to 5 mg / ml) was subcutaneously injected at a dose of 2.5 mg / mouse per injection, and this was carried out continuously for 3-4 days. Some mice were injected with BKT300-N1 (formulated at 30 mg / ml in 49.7% (V / V) Cremophor EL in dehydrated alcohol) into the tumor at a dose of 0.6 mg / mouse per injection, and this was carried out continuously for 2-4 days. The mice were sacrificed 24 hours after the last treatment, and the tumor size was evaluated and the weight was measured.

[0496] For C57BL6 mice bearing Panc02 subcutaneous tumors, BKT300-N1 (formulated at 30 mg / ml in 49.7% (V / V) Cremophor EL in dehydrated alcohol and further diluted 1:6 with 0.9% NaCl to 5 mg / ml) was subcutaneously injected at a dose of 2.5 mg / mouse per day, or injected into the tumor at a dose of 0.6 mg / mouse per day. BKT300-N1 was injected daily for a total of 4 times.

[0497] Figure 10 is a bar graph showing the in vivo effect of BKT300-N1 on pancreatic cancer in mice by showing the tumor weight (mg) after treatment (*p<0.05).

[0498] NSG mice bearing U937 subcutaneous tumors were treated with BKT300-N1 (formulated as 30 mg / ml in 49.7% (V / V) Cremophor EL of dehydrated alcohol and further diluted 1:6 with 0.9% NaCl to 5 mg / ml). BKT300-N1 was injected subcutaneously at a dose of 2.5 mg / mouse per day for 4 days, or injected intratumorally at a dose of 0.6 mg / mouse per day for 2 days.

[0499] Figure 11 is a bar graph showing the in vivo effect of BKT300-N1 on AML in mice by showing the tumor weight (mg) after treatment (*p<0.05).

[0500] NSG mice bearing SNU449 subcutaneous tumors were treated with BKT300-N1 (formulated as 30 mg / ml in 49.7% (V / V) Cremophor EL of dehydrated alcohol and further diluted 1:6 with 0.9% NaCl to 5 mg / ml). BKT300-N1 was injected subcutaneously at a dose of 2.5 mg / mouse per day for 3 days.

[0501] Figure 12 is a bar graph showing the in vivo effect of BKT300-N1 on hepatocellular carcinoma in mice by showing the tumor weight (mg) after treatment (*p<0.05).

[0502] In additional experiments, the in vivo efficiency of BKT300-N1 on the growth of subcutaneous, low passage Champions’ TumourGraft® patient-derived xenograft (PDX) models of human non-small cell lung cancer (CTG-0198), colorectal cancer (CTG-0923) and ovarian cancer (CTG-1086) in immunodeficient female mice was tested.

[0503] A 1 - 1.5 cm harvested tumor was transplanted unilaterally into the left flank of 6 - 8 - week - old thymus - deficient nude - Foxn1nu (immunodeficient) female mice. 3 Once the average volume of the tumor reached 200 cubic millimeters, the control group was treated daily with vehicle, and the treatment group was injected with 2.5 mg / mouse (low dose) or 5 mg / mouse (high dose) of BKT300 - N1. The control group was subcutaneously (SC) injected with vehicle (50% / 50% volume / volume of Cremophor EL and ethanol) diluted 1:6 with 0.9% sodium chloride.

[0504] For the low - dose treatment group, a stock solution of BKN300 - N1 at 30 mg / mL was prepared with vehicle and further diluted 1:6 with 0.9% sodium chloride to a final concentration of 5 mg / mL. The animals received 0.5 mL subcutaneous injections every 12 hours (2.5 mg / injection = 5 mg daily dose).

[0505] For the high - dose treatment group, a stock solution of BKN300 - N1 at 30 mg / mL was prepared with vehicle and further diluted 1:3 with 0.9% sodium chloride to a final concentration of 10 mg / mL. The animals received 0.5 mL subcutaneous injections every 12 hours (5 mg / injection = 10 mg daily dose).

[0506] The data obtained are shown in Figures 13A - 13C, which clearly show a substantial reduction and even arrest of tumor growth in the treatment groups compared to the controls in all tumors tested.

[0507] These results further showed that BKT300 - N1 is effective in inhibiting tumor growth against various types of cancer.

[0508] Example 5 Combination Therapy of BKT300 - N1 and Irinotecan H460 cells (1x10 6Cells / ml) were cultured in a 12-well plate with 10% FCS (fetal calf serum). After 24 hours, the medium was replaced with 1% FCS, and BKT300-N1 (125 nM), irinotecan (25 or 100 μM), or a combination of BKT300-N1 (125 nM) and irinotecan (25 or 100 μM) was added respectively.

[0509] After 24 or 48 hours of incubation, the medium and cells were collected and centrifuged, and stained with a propidium iodide (PI, 1:100) kit according to the manufacturer's instructions. The number of live cells (PI negative) and dead cells (PI positive) was evaluated by flow cytometry (FACS) after 24 or 48 hours of incubation.

[0510] The data obtained were shown in Figures 14A - 14D. Figures 14A - 14B represent the data obtained by 24-hour incubation, and Figures 14C - 14D represent the data obtained by 48-hour incubation. The results were expressed as mean ± SD. Statistical significance was determined by analysis using a two-sided Student's t-test. A value of p < 0.05 was considered statistically significant. The data are the mean ± SD of the cell numbers of two replicates for each group. *p < 0.05 vs control, **p < 0.05 vs irinotecan alone.

[0511] As seen in Figures 14A - 14D, the combination therapy of BKT300-N1 and irinotecan showed a beneficial effect on the survival rate of the tested lung cancer cells. The combination therapy induced more cell death than each treatment alone, suggesting an interaction. Such an interaction may enable the use of a lower amount of irinotecan and reduce the acquired resistance to irinotecan treatment.

[0512] Example 6 Taxol-resistant cancer cells Paclitaxel is a chemotherapy drug that directly acts on microtubules and causes mitotic arrest and cell death by stabilizing them against depolymerization. However, its clinical efficacy is hampered by the development of drug resistance. Paclitaxel resistance is a major problem in the treatment of various types of cancer.

[0513] Therefore, the effect of BKT300-N1 on paclitaxel-resistant cells was tested using the following protocol.

[0514] Cells (1x10 6 cells / ml) were cultured in 10% FCS in a 12-well plate. After 24 hours, the medium was replaced with 1% FCS, and BKT300-N1 or paclitaxel (250 - 3.75 nM) was added.

[0515] After 24-hour incubation, the cells were harvested and washed with PBS. The pellet was fixed by adding 200 μl of Fix / Perm buffer and vortexed. The fixed cells were incubated at 4°C for 20 minutes, and 1 ml of Perm / Wash buffer was added. Following centrifugation, the supernatant was removed, and the cells were resuspended in 100 μl of Perm / Wash containing 4 μl of 7-AAD and vortexed. The cells were further incubated in the dark at 4°C for 20 minutes, and then 300 μl of PBS was added. Flow cytometry analysis was performed by collecting 20,000 events per sample. Analysis was performed based on the distribution of cells in the three major phases of the cell cycle: G0 / G1 (blue), S (purple), G2 / M (green), and apoptotic cells (red) as shown in Figures 15 - 18.

[0516] All results were expressed as mean ± SD. Statistical significance was determined by analysis using a two-sided Student's T-test. A p value < 0.05 was considered statistically significant.

[0517] In the first set of experiments, the sensitivity of two ovarian cancer cell lines, OVCAR8 and HEY-T30, to paclitaxel was tested.

[0518] Cells were incubated with various doses of taxol (30, 15, 7.5, 3.75 nM) for 24 hours and then analyzed as described above.

[0519] Data obtained from Hey-T30 cells are shown in Figure 15. As can be seen, there was no effect on the cell cycle of HEY-T30 cells after treatment with taxol, indicating that these cells are resistant to taxol at concentrations up to 30 nM.

[0520] Data obtained from OVCAR8 cells are shown in Figure 16. As can be seen, at the lowest taxol concentration of 3.75 nM, there was a clear effect on the cell cycle, indicating that OVCAR8 cells are sensitive to taxol.

[0521] Figures 17A-17C are graphical representations comparing the effects of taxol on cell viability, percentage of G0 / G1, and cell levels in G2 / M of the two cell lines tested, and also show the resistance of HEY-T30 cells to taxol compared to the sensitivity of OVCAR8 cells to taxol.

[0522] Next, we tested the effect of BKT300-N1 on taxol-resistant cells. Both ovarian cancer cell lines were incubated with BKT300-N1 (250, 125, 62.5, 31.25, and 15.6 nM). For comparison, the effect of the same amount of taxol was also tested.

[0523] The data obtained are shown in Figures 18A to 18C. BKT300-N1 significantly affected taxol-resistant HEY-T30 cells, increasing the level of dead cells at a concentration of 62.5 nM (Figure 18A, red line), decreasing the percentage of cells in the G0 / G1 phase at a concentration of 125 nM (Figure 18B, red line), and increasing the level of cells in the G2 / M phase at a concentration of 125 nM (Figure 18C, red line).

[0524] On the other hand, no significant effect of taxol on HEY-T30 resistant cells was observed at any concentration tested (Figures 18A-18C, green line).

[0525] These data represent the possibility in the treatment of BKT300-N1 that affects (halts) the growth and survival rate of taxol-resistant cancer cells.

[0526] Although the present invention has been described in connection with its particular embodiments, numerous changes, modifications and variations will be apparent to those skilled in the art. Accordingly, all such changes, modifications and variations are intended to be included within the spirit and broad scope of the appended claims.

[0527] All publications, patents and patent applications mentioned in this specification are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent and patent application were specifically and individually incorporated by reference herein. In addition, the citation or identification of any reference in this specification should not be construed as an admission that such reference can be used as prior art for the present invention. Also, to the extent that section headings are used, they should not necessarily be construed as limiting.

[0528] Furthermore, the documents related to the basic application of this application are hereby incorporated herein by reference in their entirety.

Claims

【Claim 1】 A compound represented by the following formula Ia and / or formula Ib. 【Chemical 1】 [In the formula, A is an alkyl having a length of at least 4 carbon atoms, B is selected from hydroxy and alkoxy, D and G are each independently selected from hydrogen, hydroxy, alkoxy and alkyl, provided that at least one of D and G is hydrogen, E is hydroxy, R １ is selected from hydrogen and alkyl, R ２ to R ５ are each independently selected from hydrogen, hydroxy, halo, alkoxy, thioalkoxy, thiol, thioalkoxy and amine.]

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