Small molecules for the treatment of cancer, inhibition of chemokine activity and / or induction of cell death - Patent Application 20070122997

Abstract

Compounds are provided that are capable of or can be used in inducing cancer cell death and / or modulating chemokine biological activity (e.g., cell migration), and / or treating diseases and disorders associated with chemokine biological activity and / or cell migration, and / or treating cancer, and are collectively represented by Formula Ia or Ib: [Formula 1] TIFF2022532258000026.tif83145 [wherein A, B, D, E, G, and R1 to R5 are as defined herein, and one or more of D, E, and G, preferably E, is hydroxy.]

Description

[Technical Field]

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

[0002] The present invention, in some embodiments thereof, relates to therapy, and more particularly, but not exclusively, to small molecule compounds useful for modulating chemokine biological activity, killing cancer cells, inhibiting chemokine-dependent cell migration, and / or treating diseases and disorders associated with chemokine biological activity and / or cell migration (e.g., cancer), and methods utilizing these compounds. [Background technology]

[0003] Chemokines are among the many biological factors involved in inflammatory disease processes. They belong to a group of small, mostly basic, heparin-binding proteins of approximately 8-14 kDa that are related both by their primary structure and by the presence of four conserved cysteine ​​residues.

[0004] Chemokines are chemotactic cytokines that have been shown to be selective chemoattractants for leukocyte subpopulations in vitro and 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 from the immune system. They also have a wide range of effects on many different cell types beyond the immune system, including various cells of the central nervous system [Ma et al., PNAS 1998, 95:9448-9453] and endothelial cells, where either angiogenic 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 immune responses against cancer, while other chemokines inhibit tumor-mediated angiogenesis and promote anti-tumor immune responses.

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

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

[0008] Plerixafor, a CXCR4 antagonist, is used in combination with G-CSF (granulocyte colony-stimulating factor) to mobilize hematopoietic stem cells in cancer patients, particularly those with lymphoma and multiple myeloma. The stem cells are then transplanted back into the patient after chemotherapy or radiation therapy.

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

[0010] The assignee of the present application, WO 2017 / 103931 (the contents of which are incorporated herein by reference as if fully set forth herein), discloses data obtained from screening and further characterization of natural compound libraries for compounds capable of modulating chemokine activity. The studies described in WO 2017 / 103931 identified compounds characterized by specific structural features that can modulate the effects of individual chemokines on cells and affect cancer cells and other pathogenic cells. WO 2017 / 103931 describes a compound therein designated BKT300 (shown below) as, for example, inducing cancer cell death and inhibiting cancer cell migration.

[0011] [ka]

[0012] Co-owned WO 2017 / 103932, the contents of which are incorporated herein by reference as if fully set forth herein, discloses newly designed structural analogs of BKT300 that have been shown to induce cancer cell death, inhibit cancer cell migration, selectively arrest cancer cell proliferation in the G2M phase, and induce apoptotic cancer cell death via the caspase 3 pathway. One of the compounds described in WO 2017 / 103932 is designated BKT300-3-C5, shown below in its keto and enol forms.

[0013] [ka] Summary of the Invention

[0014] According to an aspect of some embodiments of the present invention, there are provided compounds represented by formula Ia and / or Ib.

[0015] [ka]

[0016] [In the formula, A is an alkyl of 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.

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

[0018] According to some of the embodiments described herein, one of D and G is alkoxy.

[0019] According to some of the embodiments described herein, one of D and G is alkyl, said alkyl being at least 4 carbon atoms in length.

[0020] According to some of the embodiments described herein, R1 is hydrogen.

[0021] According to some of the embodiments described herein, each of R2-R5 is hydrogen.

[0022] According to some of the embodiments described herein, the compound is a compound of formula IIa or IIb:

[0023] [ka] [In the formula, A is an alkyl of 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 herein, each of R2-R5 is hydrogen.

[0025] According to some of the embodiments described herein, R1 is hydrogen.

[0026] According to some of the embodiments described herein, at least one of D and G is alkoxy.

[0027] According to some of the embodiments described herein, B is alkoxy.

[0028] According to some of the embodiments described herein, the compound is of the formula:

[0029] [ka]

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

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

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

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

[0034] According to some of the embodiments described herein, the compounds may induce arrest of cancer cell growth at the G2M phase of the cancer cells.

[0035] According to some of the embodiments described herein, the compounds may inhibit chemokine-induced cell migration.

[0036] According to an aspect of some embodiments of the present invention, the compound 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, is for treating 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 a drug-resistant cancer.

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

[0041] According to an aspect of some embodiments of the present invention, the compound 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, is for modulating the biological activity of a chemokine in a patient.

[0042] According to an 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 a condition treatable by modulation of the biological activity of a chemokine.

[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 an aspect of some embodiments of the present invention, the compound represented by Formula Ia and / or Ib in any of the corresponding embodiments of the present invention, and any combination thereof, is for the treatment of inflammation.

[0048] According to an aspect of some embodiments of the present invention, the compound 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, is for the treatment of a non-cancerous hyperproliferative disease.

[0049] According to an 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, in any of the respective embodiments or any combination thereof, are for inducing cell death.

[0050] According to an aspect of some embodiments of the present invention, the compound 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, is for inducing apoptosis in cells.

[0051] According to some of the embodiments described herein, apoptosis is associated with 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 cell is a drug-resistant cell (eg, a drug-resistant cancer cell).

[0054] According to an aspect of some embodiments of the present invention, the compound 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, is for inducing arrest of cancer cell growth at the G2M phase of the cancer cells.

[0055] Unless otherwise specified, all technical and / or scientific terms used herein 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 also 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, the present patent specification, including definitions, will control. Additionally, the materials, methods, and examples are merely illustrative and are not necessarily intended to be limiting.

[0056] Certain embodiments of the present invention are described herein, by way of example only, with reference to the accompanying drawings. It is emphasized that the matter set forth hereinafter, with particular reference to the drawings, is for purposes of illustration and for purposes of detailed description of embodiments of the present invention. Similarly, the description provided in conjunction with the drawings will make apparent to those skilled in the art how embodiments of the present invention may be practiced. [Brief explanation of the drawings]

[0057] [Figure 1] FIG. 1 is a scheme showing the synthesis of BKT300-N1 in some embodiments of the present invention. [Figure 2] FIG. 2 is a bar graph showing the effect of various concentrations of BKT300-N1 on migration of Jurkat AML cells toward SDF-1 (* indicates p<0.05 vs. zero concentration). [Figure 3] Figure 3 shows the effects of various concentrations of BKT300-N1 and BKT300-3-C5 on HCC SNU449 cell migration compared to the control. SNU449 cells were scratch-wounded and incubated with 0.05, 0.1, 0.5, 1, and 10 μM BKT300-N1 or BKT300-3-C5. The relative wound area after 24 hours of incubation is shown. [Figure 4A]Figures 4A-E are comparative plots showing the effect of BKT300-N1 (referred to as N1 for simplicity) and BKT300-3-C5 (referred to as BKT300 for simplicity) at concentrations of 0.05 μM (Figure 4A), 0.1 μM (Figure 4B), 0.5 μM (Figure 4C), 1 μM (Figure 4D), and 10 μM (Figure 4E) on relative wound width values ​​(microns, μm) analyzed by IncuCyte. [Figure 4B] Figures 4A-E are comparative plots showing the effect of BKT300-N1 (referred to as N1 for simplicity) and BKT300-3-C5 (referred to as BKT300 for simplicity) at concentrations of 0.05 μM (Figure 4A), 0.1 μM (Figure 4B), 0.5 μM (Figure 4C), 1 μM (Figure 4D), and 10 μM (Figure 4E) on relative wound width values ​​(microns, μm) analyzed by IncuCyte. [Figure 4C] Figures 4A-E are comparative plots showing the effect of BKT300-N1 (referred to as N1 for simplicity) and BKT300-3-C5 (referred to as BKT300 for simplicity) at concentrations of 0.05 μM (Figure 4A), 0.1 μM (Figure 4B), 0.5 μM (Figure 4C), 1 μM (Figure 4D), and 10 μM (Figure 4E) on relative wound width values ​​(microns, μm) analyzed by IncuCyte. [Figure 4D] Figures 4A-E are comparative plots showing the effect of BKT300-N1 (referred to as N1 for simplicity) and BKT300-3-C5 (referred to as BKT300 for simplicity) at concentrations of 0.05 μM (Figure 4A), 0.1 μM (Figure 4B), 0.5 μM (Figure 4C), 1 μM (Figure 4D), and 10 μM (Figure 4E) on relative wound width values ​​(microns, μm) analyzed by IncuCyte. [Figure 4E]Figures 4A-E are comparative plots showing the effect of BKT300-N1 (referred to as N1 for simplicity) and BKT300-3-C5 (referred to as BKT300 for simplicity) at concentrations of 0.05 μM (Figure 4A), 0.1 μM (Figure 4B), 0.5 μM (Figure 4C), 1 μM (Figure 4D), and 10 μM (Figure 4E) on relative wound width values ​​(microns, μm) analyzed by IncuCyte. [Figure 5A] Figure 5A-B shows a comparative plot of the effect of various concentrations of BKT300-N1 on MSTO cell migration using a scratch assay, as measured by relative wound width values ​​(in microns) analyzed by IncuCyte (Figure 5A), and wound width images obtained with an IncuCyte live-cell imaging system after 48 hours for control and 0.1 μM (microM) and 0.5 μM (microM) BKT300-N1 (Figure 5B). [Figure 5B] Figure 5A-B shows a comparative plot of the effect of various concentrations of BKT300-N1 on MSTO cell migration using a scratch assay, as measured by relative wound width values ​​(in microns) analyzed by IncuCyte (Figure 5A), and wound width images obtained with an IncuCyte live-cell imaging system after 48 hours for control and 0.1 μM (microM) and 0.5 μM (microM) BKT300-N1 (Figure 5B). [Figure 6A] Figures 6A-B are bar graphs showing the effects of BKT300-N1 and BKT300-3-C5 (25-1000 nM) on the viability of U937 cells, expressed as the number of annexin-V / PI- cells (Figure 6A), and on apoptosis of U937 cells (Figure 6B). [Figure 6B] Figures 6A-B are bar graphs showing the effects of BKT300-N1 and BKT300-3-C5 (25-1000 nM) on the viability of U937 cells, expressed as the number of annexin-V / PI- cells (Figure 6A), and on apoptosis of U937 cells (Figure 6B). [Figure 7A]Figures 7A-B are a Western blot (Figure 7A) showing the effect of 24-hour incubation with BKT300-N1 (0.1, 0.5, and 1 μM) on the presence of cleaved caspase-3 in U937 cells, and a bar graph (Figure 7B) showing the effect of 24-hour incubation with BKT300-N1 (0.1, 0.5, and 1 μM) on the presence of cleaved caspase-3 in U937 cells, expressed as optical density (OD) and normalized to actin. [Figure 7B] Figures 7A-B are a Western blot (Figure 7A) showing the effect of 24-hour incubation with BKT300-N1 (0.1, 0.5, and 1 μM) on the presence of cleaved caspase-3 in U937 cells, and a bar graph (Figure 7B) showing the effect of 24-hour incubation with BKT300-N1 (0.1, 0.5, and 1 μM) on the presence of cleaved caspase-3 in U937 cells, expressed as optical density (OD) and normalized to actin. [Figure 8A] Figures 8A-B show the effects of various concentrations of BKT300-N1 (N1) (Figure 8A) and BKT300-3-C5 (Figure 8B) on the cell cycle of U937 cells after 24 hours of incubation. Each phase of the cell cycle was analyzed by flow cytometry using 7-AAD. [Figure 8B] Figures 8A-B show the effects of various concentrations of BKT300-N1 (N1) (Figure 8A) and BKT300-3-C5 (Figure 8B) on the cell cycle of U937 cells after 24 hours of incubation. Each phase of the cell cycle was analyzed by flow cytometry using 7-AAD. [Figure 9-1] Figure 9 shows the effect of various concentrations of BKT300-N1 on the cell cycle of H69 cells after 48 hours of incubation. Cell cycle phases were analyzed by flow cytometry using 7-AAD. Cells were gated according to cell cycle stage as follows: P1, G0 / G1 phase; P2, apoptotic cells in sub-G0 phase; and P3, G2 / M phase. [Figure 9-2]Figure 9 shows the effect of various concentrations of BKT300-N1 on the cell cycle of H69 cells after 48 hours of incubation. Cell cycle phases were analyzed by flow cytometry using 7-AAD. Cells were gated according to cell cycle stage as follows: P1, G0 / G1 phase; P2, apoptotic cells in sub-G0 phase; and P3, G2 / M phase. [Figure 10] 10 is a bar graph showing the in vivo effect of BKT300-N1 on pancreatic cancer in mice. Bars represent tumor weight (mg) (*p<0.05). [Figure 11] 11 is a bar graph showing the in vivo efficacy of BKT300-N1 against AML in mice. Bars represent tumor weight (mg) (*p<0.05). [Figure 12] 12 is a bar graph showing the in vivo effect of BKT300-N1 on hepatocellular carcinoma in mice. Bars represent tumor weight (mg) (*p<0.05). [Figure 13A] Figures 13A-C are comparative plots of the in vivo effects of 5 mg (low dose) or 10 mg (high dose) per day of BKT300-N1 compared to vehicle alone on the growth of human-derived ovarian cancer (Figure 13A), small lung cancer cells (SCLS, Figure 13B), and colorectal cancer (Figure 13C) in xenografts (PDX). [Figure 13B] Figures 13A-C are comparative plots of the in vivo effects of 5 mg (low dose) or 10 mg (high dose) per day of BKT300-N1 compared to vehicle alone on the growth of human-derived ovarian cancer (Figure 13A), small lung cancer cells (SCLS, Figure 13B), and colorectal cancer (Figure 13C) in xenografts (PDX). [Figure 13C] Figures 13A-C are comparative plots of the in vivo effects of 5 mg (low dose) or 10 mg (high dose) per day of BKT300-N1 compared to vehicle alone on the growth of human-derived ovarian cancer (Figure 13A), small lung cancer cells (SCLS, Figure 13B), and colorectal cancer (Figure 13C) in xenografts (PDX). [Figure 14A] Figures 14A-D are bar graphs showing the effect on H460 cell viability, as determined by PI-staining, following treatment with BKT300-N1 (125 nM) and irinotecan (25 μM) for 24 hours (Figure 14A), BKT300-N1 (125 nM) and irinotecan (100 μM) for 24 hours (Figure 14B), BKT300-N1 (125 nM) and irinotecan (25 μM) for 48 hours (Figure 14C), and BKT300-N1 (125 nM) and irinotecan (100 μM) for 48 hours (Figure 14D). [Figure 14B] Figures 14A-D are bar graphs showing the effect on H460 cell viability, as determined by PI-staining, following treatment with BKT300-N1 (125 nM) and irinotecan (25 μM) for 24 hours (Figure 14A), BKT300-N1 (125 nM) and irinotecan (100 μM) for 24 hours (Figure 14B), BKT300-N1 (125 nM) and irinotecan (25 μM) for 48 hours (Figure 14C), and BKT300-N1 (125 nM) and irinotecan (100 μM) for 48 hours (Figure 14D). [Figure 14C] Figures 14A-D are bar graphs showing the effect on H460 cell viability, as determined by PI-staining, following treatment with BKT300-N1 (125 nM) and irinotecan (25 μM) for 24 hours (Figure 14A), BKT300-N1 (125 nM) and irinotecan (100 μM) for 24 hours (Figure 14B), BKT300-N1 (125 nM) and irinotecan (25 μM) for 48 hours (Figure 14C), and BKT300-N1 (125 nM) and irinotecan (100 μM) for 48 hours (Figure 14D). [Figure 14D] Figures 14A-D are bar graphs showing the effect on H460 cell viability, as determined by PI-staining, following treatment with BKT300-N1 (125 nM) and irinotecan (25 μM) for 24 hours (Figure 14A), BKT300-N1 (125 nM) and irinotecan (100 μM) for 24 hours (Figure 14B), BKT300-N1 (125 nM) and irinotecan (25 μM) for 48 hours (Figure 14C), and BKT300-N1 (125 nM) and irinotecan (100 μM) for 48 hours (Figure 14D). [Figure 15] Figure 15 shows FACS analysis of HEY-T30 cells following treatment with taxol. Red represents cells in the G0 / G1 phase (P1), green represents cells in the G2 / M phase (P3), and blue represents apoptotic cells (P2). [Figure 16] Figure 16 shows FACS analysis of OVCAR8 cells following treatment with taxol. Red represents cells in the G0 / G1 phase (P1), green represents cells in the G2 / M phase (P3), and blue represents apoptotic cells (P2). [Figure 17A] Figures 17A-C are comparative plots showing cell cycle analysis of HEY-T30 cells (blue line) and OVCAR8 cells (orange line) after treatment with taxol (30, 15, 7.5, and 3.75 nM). Figure 17A shows the % of dead cells after treatment, Figure 17B shows the % of cells in G0 / G1 phase after treatment, and Figure 17C shows the % of cells in G2 / M phase after treatment. *p<0.05. [Figure 17B] Figures 17A-C are comparative plots showing cell cycle analysis of HEY-T30 cells (blue line) and OVCAR8 cells (orange line) after treatment with taxol (30, 15, 7.5, and 3.75 nM). Figure 17A shows the % of dead cells after treatment, Figure 17B shows the % of cells in G0 / G1 phase after treatment, and Figure 17C shows the % of cells in G2 / M phase after treatment. *p<0.05. [Figure 17C] Figures 17A-C are comparative plots showing cell cycle analysis of HEY-T30 cells (blue line) and OVCAR8 cells (orange line) after treatment with taxol (30, 15, 7.5, and 3.75 nM). Figure 17A shows the % of dead cells after treatment, Figure 17B shows the % of cells in G0 / G1 phase after treatment, and Figure 17C shows the % of cells in G2 / M phase after treatment. *p<0.05. [Figure 18A] Figures 18A-C are comparative plots showing cell cycle analysis of HEY-T30 cells (blue line) or BKT300-N cells (red line) after treatment with 250, 125, 62.5, 31.25, and 15.6 nm taxol. Figure 18A shows the % of dead cells after treatment, Figure 18B shows the % of cells in G0 / G1 phase after treatment, and Figure 18C shows the % of cells in G2 / M phase after treatment. *p<0.05. [Figure 18B] Figures 18A-C are comparative plots showing cell cycle analysis of HEY-T30 cells (blue line) or BKT300-N cells (red line) after treatment with 250, 125, 62.5, 31.25, and 15.6 nm taxol. Figure 18A shows the % of dead cells after treatment, Figure 18B shows the % of cells in G0 / G1 phase after treatment, and Figure 18C shows the % of cells in G2 / M phase after treatment. *p<0.05. [Figure 18C] Figures 18A-C are comparative plots showing cell cycle analysis of HEY-T30 cells (blue line) or BKT300-N cells (red line) after treatment with 250, 125, 62.5, 31.25, and 15.6 nm taxol. Figure 18A shows the % of dead cells after treatment, Figure 18B shows the % of cells in G0 / G1 phase after treatment, and Figure 18C shows the % of cells in G2 / M phase after treatment. *p<0.05. DETAILED DESCRIPTION OF THE INVENTION

[0058] The present invention, in some embodiments thereof, relates to therapy, and more particularly, but not exclusively, to small molecule compounds useful for modulating chemokine biological activity, killing cancer cells, inhibiting chemokine-dependent cell migration, and / or treating diseases and disorders associated with chemokine biological activity and / or cell migration (e.g., cancer), and methods utilizing these compounds.

[0059] Before describing at least one embodiment of the present invention in detail, it should be understood that the invention is not necessarily limited in its application to the details set forth in the description that follows or by the specific examples set forth in the examples. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0060] As explained in the Background section above, the assignee of the present application previously demonstrated, using extensive screening assays, that small molecules with specific structural features can modulate the effects of individual chemokines on cells and affect cancer cells and other pathogenic cells. Furthermore, the assignee designed structural analogs of some of these small molecules and found that they exert even improved effects on chemokine activity and induction of cancer cell death. See WO 2017 / 103931 and WO 2017 / 103932.

[0061] In searching for additional compounds capable of modulating chemokine activity and / or inducing cell death in cancer cells and other pathogenic cells, the present inventors have determined that modifications to the structure of the compounds taught in WO 2017 / 103932 lead to substantial improvements in the desired activity of these compounds.

[0062] Without being bound by any particular theory, the inventors have determined that compounds having one or more hydroxy substituents, such as those obtained by substituting one or more alkoxy groups in compounds described in WO 2017 / 103932, exhibit improved efficacy.

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

[0064] The inventors have shown that an exemplary such compound, designated herein as BKT300-N1, having modifications to the structure of the compound referenced in WO 2017 / 103932 as BKT300-3-C5, exhibits superior efficacy in modulating chemokine biological activity (see, e.g., Figures 2-5), and also acts as an anticancer agent by inducing cancer cell death and / or affecting cancer cell migration and / or proliferation, interacting with other anticancer drugs, and inducing cancer cell death and inhibiting cancer cell proliferation in taxol-resistant cancer cells (see, e.g., Figures 6-18).

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

[0066] The general effects of compounds according to some embodiments of the present invention have been demonstrated on various biological phenomena, including chemokine-induced cell migration and apoptosis. These findings make the compounds described herein potential pharmaceutical agents that can be used to treat a variety of medical conditions, including inflammation (e.g., autoimmune diseases), cancer, and non-cancer hyperproliferative diseases.

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

[0068] Compound (small molecule) : According to one aspect of some embodiments of the present invention, there are provided newly designed small molecules (compounds) that can be collectively represented by Formula Ia:

[0069] [ka]

[0070] [In the formula, A is an alkyl of at least 4 carbon atoms in length; B is selected from hydroxy, alkoxy and aryloxy, or 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 selected from hydrogen and alkyl; R2-R5 are each independently selected from 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] Compounds of formula Ia feature a ketone group (carbonyl) and can undergo keto-enol tautomerization to the "enol" form, and therefore may also be represented by formula Ib.

[0072] [ka]

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

[0074] Keto-enol tautomerization is most often thermodynamically driven, and at room temperature the equilibrium usually favors the formation of the keto form. However, environmental conditions, such as the pH or ionic strength of the solution, the concentration of the compound, temperature, or the presence of agents that stabilize the enol form, can shift the equilibrium toward the enol form being equally present or even prevalent.

[0075] In some embodiments, depending on environmental conditions, the compounds of this embodiment may be in either the keto tautomer (Formula Ia) form, or the enol form (Formula Ib) form, or may be in equilibrium between the keto and enol forms, and thus may be in both the Formula Ia and Ib forms.

[0076] In any of the embodiments described herein, at least one of B, D, E, and G is alkoxy or aryloxy, preferably alkoxy, and 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, alkoxy has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy.

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

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

[0080] In any of the embodiments described herein, not more than one of D, E and G is alkyl.

[0081] In any of the embodiments described herein, no more than two of D, E and G, or no more than one 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, then no one 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 others 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, eg, methoxy.

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

[0087] In any of the embodiments described herein, one of D and G is alkoxy, eg, 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 alkoxy, eg, methoxy, and G is hydroxy.

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

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

[0097] In any of the embodiments described herein, E is hydrogen, G is alkoxy, eg, 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 alkoxy (eg, methoxy).

[0100] In any of the embodiments described herein, D is alkoxy (eg, 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 alkoxy (e.g., methoxy), and G is hydrogen. In some of such embodiments, B is alkoxy (e.g., methoxy).

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

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

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

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

[0107] In any of the embodiments described herein, D is said 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 these embodiments, B is alkoxy (e.g., methoxy).

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

[0111] In any of the embodiments described herein, an alkyl at least 4 carbon atoms in length can be, for example, 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms in length. Exemplary alkyls at least 4 carbon atoms in length 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, the alkyl 4 carbon atoms in length is an unsubstituted alkyl. In some embodiments, it is hexyl, and in some embodiments, it is an unsubstituted hexyl.

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

[0114] When A and one of D, E and G are alkyl groups 4 carbon atoms in length, they can be the same or different.

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

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

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

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

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

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

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

[0122] [ka] [In the formula, A is an alkyl of 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, with the proviso 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-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 alkyl as described in the corresponding embodiment herein. Further alternatively, 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 of 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] [ka]

[0130] This compound is designated herein as BKT300-N1.

[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] [ka]

[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] [ka]

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

[0136] [ka]

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

[0138] Thus, each of the compounds described herein is capable of or useful in inhibiting cancer cells, and / or killing cancer cells, 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 desired).

[0139] Inflammation and cancer are generally governed by cell migration (eg, invasion, metastasis) which is often associated with cell proliferation, and are therefore considered targets for treatment with the compounds of this embodiment.

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

[0141] Without being bound by any particular theory, the compounds described herein are believed to be particularly useful as anti-cancer agents due to their ability to induce cancer cell death, chemokine-dependent cancer cell migration (e.g., inhibiting metastasis) and / or affect angiogenesis, induce apoptosis in cancer cells, induce cancer cell growth arrest, as described in detail herein below, and as anti-inflammatory agents due to their ability to induce 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 are capable of inducing or being used to kill pathogenic cells (e.g., cancer cells or immune cells or hyperproliferative cells) in any of their 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 are capable of inducing or being used to induce cell death of pathogenic cells in any of their respective embodiments.

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

[0145] Methods for monitoring cellular changes induced by compounds are known in the art and include, for example, those described herein above. These assays include the MTT test, which is based on the ability of viable cells to reduce the yellow salt MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) (Sigma-Aldrich, St. Louis, MO, USA) to selectively generate an insoluble purple-blue formazan precipitate; the BrDu assay [Cell Proliferation ELISA BrdU Colorimetric Assay Kit (Roche, Mannheim, Germany)]; the TUNEL assay [Roche, Mannheim, Germany]; the Annexin V assay [ApoAlert® Annexin V Apoptosis Kit (Clontech Laboratories, Inc., California, USA)]; and the senescence-associated β-galactosidase assay (Dimri GP, Lee X, et al. 1995. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA). 92:9363-9367), 7-ADD viability staining (available from MD systems), caspase-3 assays (available from MD systems) and various RNA and protein detection methods (to detect 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, the cellular change in any of the respective embodiments is apoptosis, such as by cleavage of caspase-3.

[0147] In any of the embodiments described herein, for 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 or can be used to induce apoptosis by cleavage of caspase-3.

[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 usable to induce growth arrest in cells, which in some embodiments 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, in any of their respective embodiments or in any combination thereof, may modulate or can be used to modulate the chemokine biological activity described herein.

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

[0151] According to an 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 biological activity of a chemokine.

[0152] According to an aspect of some embodiments of the present invention there is provided a use of a compound according to any of the embodiments described herein in modulating the biological activity of a chemokine.

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

[0154] In some embodiments, the uses and / or methods for modulating chemokine activity are accomplished ex vivo (eg, in vitro), for example, in research.

[0155] In some embodiments related to any one of the embodiments described herein relating to a method, use, or medicament for modulating the biological activity of a chemokine, the method, use, or medicament is for treating a disease or disorder associated with the biological activity of a chemokine in a patient in need of such treatment, e.g., 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, modulating chemokine biological activity includes inhibiting chemokine biological activity, which can be demonstrated by the ability of the small molecules described herein to inhibit chemokine-induced cell migration, as exemplified herein in several different cell types.

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

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

[0160] In some embodiments related to any one of the methods or uses described herein 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 relating to modulating chemokine activity, the compound, method, and / or medicament (according to any of the respective embodiments described herein) inhibits the biological activity of a 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 MIP3a activity (e.g., in which inhibition of MIP3a activity would be 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 relating to any one of the embodiments described herein relating to treating 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, in any of their respective embodiments or any combination thereof, are capable of or can be used to modulate the biological activity of SDF-1 and / or CXCR4, as described herein.

[0166] According to one aspect of some embodiments of the present invention, there is provided a method for inhibiting the biological activity 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 an 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 SDF-1 and / or CXCR4.

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

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

[0170] In some embodiments, the uses and / or methods for inhibiting the biological activity of SDF-1 and / or CXCR4 are accomplished ex vivo (eg, in vitro), eg, in research.

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

[0174] Those skilled in the art will appreciate that CXCR4 is the receptor that mediates the activity of SDF-1 and that the activities of SDF-1 and CXCR4 usually overlap.

[0175] Examples of diseases and disorders associated with SDF-1 and / or CXCR4 activity (e.g., in which inhibition of SDF-1 and / or CXCR4 activity would be beneficial) include, but are not limited to, Whim's syndrome, cervical adenocarcinoma, breast cancer, bursitis, tuberculosis, intraocular lymphoma, cytomegalovirus retinitis, chronic inflammatory demyelinating polyradiculoneuropathy, ocular hypertension, polyradiculoneuropathy, dendritic cell tumors, retinal hemangioblastoma, malaria, endotheliitis, leukemia, and the like. Disease, rheumatoid arthritis, arthritis, prostatitis, prostate cancer, colorectal cancer, chronic lymphocytic leukemia, pancreatitis, neuronitis, lung cancer, osteoarthritis, hypoxia, adenocarcinoma, pancreatic cancer, multiple myeloma, neuroblastoma, myeloid leukemia, astrocytoma, periodontitis, glioblastoma, preeclampsia, melanoma, hepatitis, esophagitis, myeloma, eclampsia, cervicitis, periodontal disease, central nervous system lymphoma, sporadic 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, Maltodipsa lymphoma, whooping cough, ischemia, uveal melanoma, gingivitis, pituitary adenoma, bronchiolitis, neuromyelitis optica, mesothelioma, alopecia, cervical cancer, somatic, glioblastoma multiforme, bronchiolitis obliterans, brain damage, colorectal adenoma, tongue squamous epithelial cell carcinoma Cancer, B-cell lymphoma, traumatic brain injury, intravascular large B-cell lymphoma, allergic asthma, tick-borne encephalitis, blastic plasmacytoid dendritic cells, oligoastrocytoma, childhood dermatomyositis, renal oncocytoma, endometrial adenocarcinoma, optic neuritis, seminoma, Sjögren's syndrome, pleurisy, neuritis, inflammatory bowel disease, cytomegalovirus infection, malignant pleural mesothelioma, oral squamous cell carcinoma, skeletal muscle regeneration, Emery-Dreifuss muscular dystrophy, dominant type.

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

[0177] As used herein, the term "detrimental angiogenesis" refers to angiogenesis that is associated with undesirable clinical and / or cosmetic consequences.

[0178] Tumor-associated angiogenesis 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 metastasizing to the lungs. Tumor metastasis often involves tumor cell migration.

[0180] In some embodiments related to any one of the embodiments described herein relating to a method or use for modulating the biological activity of a chemokine, the modulation comprises inhibition of 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 relating to inhibiting the biological activity of SDF-1 and / or CXCR4, the inhibition of the biological activity of SDF-1 and / or CXCR4 is for the purpose of providing immune stimulation.

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

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

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

[0185] In some embodiments, the hematopoietic stem cell transplant is for treating a proliferative disease, eg, cancer (eg, a cancer described herein according to any of the respective embodiments).

[0186] In some embodiments related to any one of the embodiments described herein relating to hematopoietic stem cells, the treatment includes increasing the level of hematopoietic stem cells in the subject's peripheral blood, obtaining hematopoietic stem cells from the subject's peripheral blood, administering a cytotoxic therapy to the subject (e.g., antiproliferative chemotherapy and / or radiation therapy), and transplanting at least a portion of the stem cells back into 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, in any of their respective embodiments or in any combination thereof, are capable of modulating or can be used to modulate the biological activity of MCP-1, as described herein.

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

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

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

[0192] In some embodiments, the uses and / or methods for inhibiting MCP-1 biological activity are accomplished ex vivo (eg, in vitro), eg, in research.

[0193] In some embodiments related to any one of the embodiments described herein relating to a method, use, or medicament for inhibiting MCP-1 biological activity, the method, use, or medicament is for treating a disease or disorder associated with MCP-1 biological activity in a patient in need of such treatment, e.g., 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 relating to a method, use, or medicament for inhibiting MCP-1 biological activity, the method, use, or medicament is for treating a disease or disorder in which inhibition of MCP-1 biological activity is beneficial in a patient in need of such treatment, e.g., 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 relating to a method, use, or medicament for inhibiting the biological activity of MCP-1, the method, use, or medicament is for treating a disease or disorder in a patient in need thereof in which inhibition of the biological activity of MCP-1 is beneficial, e.g., by administering to the patient a therapeutically effective amount of a compound according to any of the embodiments described herein.

[0196] Examples of diseases and disorders associated with MCP-1 activity (e.g., in which inhibition of MCP-1 activity would be 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., in which inhibition of MCP-1 activity would be 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 vasculopathy, mesangial proliferative glomerulonephritis, sympathetic ophthalmia, urinary tract disease, lupus nephritis, and pneumonia, as described herein. , periodontal granuloma, Erdheim-Chester disease, glomerulonephritis, 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, psychiatric disorders, cancer (e.g., as described herein), inflammation (e.g., the inflammatory diseases and disorders described herein), neurodegenerative disorders, and age-related macular degeneration (AMD, e.g., dry or wet).

[0198] According to certain embodiments, the disease includes, but is 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 a particular embodiment, the compounds according to the present invention are for the treatment of age-related macular degeneration (AMD).

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

[0201] According to certain embodiments, the age-related macular degeneration (AMD) is associated 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, in any of their respective embodiments or in any combination thereof, can treat or can be used to treat cancer.

[0203] According to some embodiments, the small molecule compounds of Formula Ia and / or Ib or Formula IIa and / or IIb described herein, in any of their respective embodiments or any combination thereof, can be or can be used to induce cancer cell death (kill cancer cells).

[0204] According to some embodiments, the small molecule compounds of Formula Ia and / or Ib or Formula IIa and / or IIb described herein, in any of their respective embodiments or in any combination thereof, can induce or can be used to induce apoptosis in cancer cells.

[0205] According to some embodiments, the small molecule compounds of Formula Ia and / or Ib or Formula IIa and / or IIb described herein, in any of their respective embodiments or any combination thereof, can induce or be used to induce growth arrest in cancer cells, and in some embodiments, the arrest occurs in the G2M phase of the cell cycle.

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

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

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

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

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

[0211] Non-limiting examples of cancers and / or tumor metastases that may be treated according to some of the embodiments (including any of the aspects described herein) relating to any of the embodiments described herein relating to cancer include, but are not limited to, tumors of the gastrointestinal tract (e.g., colon carcinoma, rectal carcinoma, colorectal carcinoma, colorectal cancer, colorectal adenoma, hereditary nonpolyposis type 1, hereditary nonpolyposis type 2, hereditary nonpolyposis type 3, hereditary nonpolyposis type 6, colorectal cancer, hereditary nonpolyposis type 7, small intestine and / or large intestine carcinoma, esophageal carcinoma, calluses associated with esophageal cancer, gastric carcinoma, pancreatic carcinoma, pancreatic endocrine tumors), endometrial cancer, dermatofibrosarcoma protuberans, gallbladder cancer, biliary tract tumors, prostate cancer, prostate adenocarcinoma, kidney cancer (e.g., Wilms' tumor type 2 or type 1), liver cancer (e.g., cholangioblastoma, hepatocellular carcinoma, leukemia ... carcinoma, hepatocellular carcinoma, bladder cancer, embryonal rhabdomyosarcoma, germ cell tumor, trophoblastic tumor, testicular germ cell tumor, ovarian immature teratoma, uterine, ovarian epithelial, sacrococcygeal tumor, choriocarcinoma, placental trophoblastic tumor, adult epithelial adult) tumors, ovarian carcinoma, serous ovarian cancer, ovarian sex cord tumor, cervical cancer, cervical carcinoma, small cell and non-small cell lung cancer, nasopharyngeal, breast carcinoma (e.g., ductal carcinoma, invasive intraductal carcinoma, sporadic breast cancer, 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, ganglioneuroblastoma, neuroblastoma, lymphoma (e.g., Hodgkin's disease, non-Hodgkin's lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, cutaneous T-cell lymphoma, histiocytic lymphoma, lymphoblastic lymphoma, T-cell lymphoma, lymphoma, thymic lymphoma), glioma, adenocarcinoma, adrenal tumor, hereditary adrenocortical carcinoma, brain malignant tumor (tumor), various other carcinomas (e.g., bronchogenic large cell, tubular Ehrlich-Lettre ascites, epidermoid, large cell, Lewis lung, medullary, mucoepidermoid, oat cell, small cell, spindle cell, squamous cell, transitional cell, undifferentiated, carcinosarcoma, choriocarcinoma, cystadenocarcinoma), ependymoblastoma, ependymoma, erythroleukemia (e.g., Friend, lymphoblastic), fibrosarcoma, giant cell tumor, glial tumor, glioblastoma (e.g., pleomorphic, astrocytoma), glioma hepatoma, heterohybridoma, heteromyeloma, histoblastoma,Hybridoma (e.g., B-cell), Grawitz tumor, insulinoma, pancreatic islet tumor, keratoma, leiomyoblast, leiomyosarcoma, leukemia (e.g., acute lymphocytic leukemia, acute lymphoblastic pre-B-cell leukemia, acute lymphoblastic T-cell leukemia, acute megakaryoblastic leukemia, monocytic leukemia, acute myeloid leukemia, acute myeloid leukemia with eosinophilia, B-cell leukemia, basophilic leukemia, chronic myeloid leukemia, chronic B-cell leukemia, eosinophilic leukemia, Friend's leukemia) Hematologic malignancies, granulocytic or myelocytic 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), lymphosarcoma, melanoma, breast tumor, mast cell tumor, medulloblastoma, mesothelioma, metastatic tumor, monocytic tumor, multiple myeloma, myelodysplastic syndrome group, myeloma, nephroblastoma, neural tissue glial tumor, neural tissue neuronal tumor, schwannoma, neuroblastoma, oligodendroglioma, osteochondroma, osteomyeloma, osteosarcoma (e.g., Ewing), papilloma, transitional cell, pheochromocytoma, pituitary tumor (invasive), plasmacytoma, retinoblastoma, rhabdomyosarcoma, sarcoma (e.g., Ewing, histiocytic, Jensen, osteogenic, retinal cell), schwannoma, subcutaneous tumor, teratocarcinoma (e.g., pluripotent), teratoma, testicular tumor, thymoma, and suprapocutaneous tumor Any solid or non-solid cancer and / or tumor metastasis, including: hemangioblastoma, gastric cancer, fibrosarcoma, glioblastoma multiforme, multiple glomus tumors, Li-Fraumeni syndrome, liposarcoma, Lynch cancer family syndrome II, male germ cell tumors, mast cell leukemia, medullary thyroid, multiple meningiomas, endocrine neoplasms myxosarcoma, paraganglioma, familial nonchromaffin, pilomatricoma, papillary, familial and sporadic, rhabdoid predisposition syndrome, familial, rhabdoid tumor, soft tissue sarcoma, and Turcot's syndrome with glioblastoma,

[0212] In some embodiments related to any one of the embodiments described herein relating to 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 leukemias that may be treated in connection with some embodiments of the present invention include, but are not limited to, acute leukemias, such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphocytic leukemia.

[0213] Examples of lymphomas that may 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's lymphoma. Burkitt's lymphoma is a non-limiting example of non-Hodgkin's lymphoma.

[0214] Examples of lung cancers that may be treated in accordance 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 relating to cancer, the cancer is leukemia, and in some embodiments, AML.

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

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

[0218] Without being limited to any particular theory, it is believed that in cancers characterized by expression of CXCR4, SDF-1 and CXCR4 activity are commonly associated with metastasis, and therefore treatment with inhibitors of SDF-1 and / or CXCR4 activity would be particularly advantageous.

[0219] In some embodiments related to any one of the embodiments described herein relating to cancer, the cancer is a drug-resistant cancer. In some of these embodiments, the cancer is resistant to an anti-angiogenic chemotherapeutic agent, such as a taxane (e.g., taxol). In some of these embodiments, the cancer is a multidrug-resistant cancer. The drug resistance of the cancer cells is acquired resistance (e.g., resistance developed through treatment or repeated treatment) or inherent resistance. In some embodiments related to any one of the embodiments described herein relating to cancer, the cancer cells are resistant to taxol. In some of these embodiments, the resistance is inherent. In some embodiments related to any one of the embodiments described herein relating to cancer, the cancer cells are resistant to irinotecan or any other chemotherapeutic agent in 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 relating to cancer treatment, the cancer treatment further comprises administration of at least one additional anti-cancer agent (i.e., in addition to the compounds described herein above).

[0221] The additional anti-cancer agent may be any agent used in medicine to treat cancer. Examples of anti-cancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adriamycin, adozelesin, aldesleukin, altretamine, ambomycin, amethanthrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bleomycin ... Lopirimine, busulfan, cactinomycin, calsterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, ciloremycin, cisplatin, cladribine, combrestatin A-4 phosphate, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, Dow hydrochloride Norubicin, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, zuazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, ethoxycodone hydrochloride Pirubicin, 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 alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-Ia, interferon gamma-Ib, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaprin, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocarcin, mitochromine, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ombrabulin, ormaplatin, oxisuran, paclitaxel, pegaspargase, periomycin, pentamstine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, tallysomycin, tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxilon, testolactone, thiamiprine,These include thioguanine, thiotepa, tiazofuriin, tirapazamine, topotecan hydrochloride, toremifene citrate, trestolone acetate, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine, vincristine sulfate, vindesine, vindesine sulfate, vinepidinee, vinglycinate, vinleurosine, vinorelbine tartrate, vinrosidine, vinzolidine, vorozole, zeniplatin, zinostatin, and zorubicin hydrochloride. Additional anti-cancer agents include those disclosed in Chapter 52, Antineoplastic Agents (Paul Calabresi and Bruce A. Chabner) and its introduction, pp. 1202-1263, of Goodman and Gilman's "The Pharmacological Basis of Therapeutics," Eighth Edition, 1990, McGraw-Hill, Inc. (Health Professions Division), the disclosures of which are incorporated herein by reference.

[0222] In some embodiments described herein, the additional anticancer agent is characterized in that the resistance of the 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 additional anticancer agent is any one of the compounds described herein.

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

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

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

[0226] By "interact," it is meant that the therapeutic activity of the agents when contacted together with cancer cells is greater than the sum of the activities of each agent individually. In some embodiments, the therapeutic activity is a reduction in viable cell count, 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, hi some embodiments, the interaction is determined by isobolograms, which are well known in the art.

[0228] When two drugs interact, combination therapy with these drugs allows for the use of lower doses of at least one of the drugs, which is particularly useful when anti-cancer drug treatment is known to induce acquired resistance.

[0229] In some embodiments described herein with respect to cancer treatment, combination therapy is provided that includes administering to a subject in need thereof a small molecule compound according to the present invention 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., at a dose less than its therapeutically effective amount (e.g., as determined by methods described herein and / or for that anti-cancer agent).

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

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

[0233] Noncancerous hyperproliferative disorders : In some of the embodiments described herein, the small molecule compounds of the embodiments are for use in the treatment of non-cancerous hyperproliferative diseases.

[0234] Some embodiments described herein provide methods for treating a non-cancerous hyperproliferative disease, comprising administering to a subject in need thereof (a subject afflicted with the disease, a subject suffering from symptoms associated with the disease, a subject diagnosed with the disease, or a subject suspected of having the disease) a therapeutically effective amount of a small molecule compound described herein.

[0235] In some of the embodiments described herein, the small molecule compounds of the embodiments are for use in the manufacture of a medicament for the treatment of a non-cancerous hyperproliferative disease.

[0236] Non-cancerous hyperproliferative diseases, also referred to as "non-neoplastic proliferative diseases" and "non-cancerous proliferative diseases," refer to diseases or disorders whose development 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, stenosis, restenosis, in-stent stenosis, and liver cirrhosis.

[0237] Inflammatory Diseases and Disorders : In some of the embodiments described herein, the small molecule compounds of the embodiments are for use in treating an inflammatory disease or disorder in a subject in need thereof.

[0238] Some embodiments described herein provide methods for treating an inflammatory disease or disorder, comprising administering to a subject in need thereof (a subject suffering from the disease, a subject suffering from symptoms associated with the disease, a subject diagnosed with the disease, or a subject suspected of having the disease) a therapeutically effective amount of a small molecule compound described herein.

[0239] In some of the embodiments described herein, the small molecule compounds of the embodiments are for use in the manufacture of a medicament for the treatment of an inflammatory disease or disorder.

[0240] Inflammatory diseases and disorders generally include diseases and disorders that involve inflammation.

[0241] The term "inflammation" as used herein is a general term that refers to the local accumulation of fluid, plasma proteins, and white blood cells initiated by physical injury, infection, or a 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 many diseases and disorders (as described in more detail below), 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.

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

[0243] Inflammation in accordance with the present teachings can involve a chronic (long-term) inflammatory disease or disorder or an acute (short-term) inflammatory disease or disorder.

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

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

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

[0247] Diseases characterized by inflammation of the skin include, but are not limited to, dermatitis, atopic dermatitis (eczema, atopy), contact dermatitis, dermatitis herpetiformis, generalized exfoliative dermatitis, seborrheic dermatitis, drug eruption, erythema multiforme, erythema nodosum, granuloma annulare, poison ivy, poison sumac, 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 kinds of injury to muscle, tendon or nerve.Therefore, for example, inflammation can be caused by the repeated movement of body parts, that is, repetitive strain injury (RSI).The diseases characterized by the inflammation caused by RSI include but are not limited to bursitis, carpal tunnel syndrome, Dupuytren's contracture, epicondylitis (for example, tennis elbow), ganglion (that is, inflammation in the cyst that forms in the tendon sheath, usually occurring in the wrist), rotator cuff syndrome, tendonitis (for example, inflammation of the Achilles tendon), tenosynovitis and trigger finger (inflammation of the tendon sheath of the finger or thumb, accompanied by tendon swelling).

[0249] Many diseases associated with infectious diseases include an inflammatory response, which is usually part of the innate immune system triggered by invading pathogens. Inflammation can also be caused by physical (mechanical) injury 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, mycoplasmal diseases, and prion diseases. In 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] Additionally, many immune disorders include acute or chronic inflammation. For example, arthritis is considered an immune disorder characterized by inflammation of the joints, while arthritis is also considered an inflammatory disorder characterized by an immune attack in the joint tissues.

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

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

[0253] Type I or immediate hypersensitivity disorders such as asthma Type II allergyトイド disease, リウマトイド autoimmune disease, joint リウマチ(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 エリテマトーデス (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 1 diabetes (Zimmet P. Diabetes Res Clin Pract 1996 Oct;34 Suppl:S125), thyroid diseases, autoimmune thyroid diseases, gleeves' 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, episodic myxedema (Mitsuma T. Nippon Rinsho. 1999 Aug;57 (8):1759), autoimmune reproductive system diseases, oocyte diseases, oocyte 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 disorders, 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), myasthenic disease, Lambert-Eaton myasthenic syndrome (Takamori M. Am J Med Sci. 2000 Apr;319 (4):204), paraneoplastic neurological disease, cerebellar atrophy, paraneoplastic cerebellar atrophy, non-paraneoplastic stiff-man syndrome, cerebellar atrophy, progressive cerebellar atrophy, encephalitis, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydenham's chorea, Gilles de la Tourette's syndrome, polyendocrinopathy, autoimmune polyendocrinopathy (Antoine JC. and Honnorat J. Rev Neurol (Paris) 2000 Jan;156 (1):23), neurological disorders, immunological neurological disorders (Nobile-Orazio E. et al., Electroencephalogr Clin Neurophysiol Suppl 1999;50:419), neuromyotonia, acquired neuromyotonia, arthrogryposis multiplex congenita (Vincent A. et al., Ann NY Acad Sci. 1998 May 13;841:482), cardiovascular disease, cardiovascular autoimmune disease, 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), serotonin (Landau YE. and Shoenfeld Y. Harefuah 2000 Jan 16;138 (2):122), autoimmune diseases of the tendon system, myofasciitis, autoimmune myofasciitis, schigran syndrome (Feist E. et al., Int Arch Allergy Immunol 2000 Sep;123 (1):92), autoimmune diseases of smooth tendons (Zauli D. et al., Biomed Pharmacother 1999 Jun;53 (5-6):234), liver disease, hepatic autoimmune disease, 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).

[0254] Type IV または T-cell mediated allergy として, これらにlimited されるものではないが, リウマトイド disease, joint リウマチ (Tisch R, McDevitt HO. Proc Natl Acad Sci USA 1994 Jan 18;91 (2):437), systemic disease, systemic autoimmune disease, systemic disease (Datta SK., Lupus 1998;7 (9):591), glandular diseases, glandular autoimmune diseases, genital diseases, genital 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 syndrome, autoimmune polyglandular syndrome, autoimmune polyglandular syndrome type I (Hara T. et al., Blood. 1991 Mar 1;77 (5):1127), neurological diseases, autoimmune neurological diseases, multiple sclerosis, neuritis, opthalmitis (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), Stefman syndrome (Hiemstra HS. et al., Proc Natl Acad Sci USA 2001 Mar 27;98 (7):3988), cardiovascular disease, autoimmunity of the heart (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-Helupa Tlinpa 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 disease, liver autoimmune disease, 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 disease, autoimmune disease of the kidney, nephritis, interstitial nephritis (Kelly CJ. J Am Soc Nephrol 1990 Aug;1 (2):140), connective tissue disease, ear disease, autoimmune connective tissue disease, autoimmune ear disease (Yoo TJ. et al., Cell Immunol 1994 Aug;157 (1):249), diseases of the inner ear (Gloddek B. et al., Ann NY Acad Sci 1997 Dec 29;830:266), skin diseases, cutaneous diseases, dermal diseases, bullous skin diseases, pemphigus vulgaris, bullous pemphigoid, and pemphigus foliaceus.

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

[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.

[0258] According to certain embodiments, the eye disease is age-related macular degeneration (AMD).

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

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

[0261] autoimmune disease : Autoimmune diseases include, but are not limited to, cardiovascular diseases, rheumatoid diseases, glandular diseases, gastrointestinal diseases, skin diseases, liver diseases, neurological 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's arteritis, Kawasaki syndrome (Praprotnik S. et al., Wien Klin Wochenschr 2000 Aug 25;112 (15-16):660), and 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, microimmune 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 rheumatoid 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 SA 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 disease, type I diabetes, thyroid disease, Graves' disease, thyroiditis, idiopathic autoimmune thyroiditis, Hashimoto's thyroiditis, idiopathic myxedema, ovarian autoimmunity, autoimmune antisperm infertility, autoimmune prostatitis, and type I autoimmune polyglandular syndrome. Diseases that may be affected include, but are not limited to, autoimmune diseases of the pancreas, 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 disease, 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), idiopathic 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 autoimmune polyglandular syndrome type I (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 bullous 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;11 (6):595) and autoimmune hepatitis (Manns MP. J Hepatol 2000 Aug;33 (2):326).

[0268] Examples of autoimmune neurological diseases include, but are not limited to, 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-Barre syndrome, and autoimmune neuropathy (Kusunoki S. Am J Med Sci. 2000 Apr;319 (4):234), myasthenia, Lambert-Eaton myasthenic syndrome (Takamori M. Am J Med Sci. 2000 Apr;319 (4):204), paraneoplastic neurological disorders, cerebellar atrophy, paraneoplastic cerebellar atrophy and stiff-man syndrome (Hiemstra HS. et al., Proc Natl Acad Sci units SA 2001 Mar 27;98 (7):3988), non-paraneoplastic stiff-man syndrome, progressive cerebellar atrophy, encephalitis, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydenham's chorea, Gilles de la Tourette's syndrome and autoimmune polyendocrinopathy (Antoine JC. and Honnorat J. Rev Neurol (Paris) 2000 Jan;156 (1):23), dysimmune neurological disorders (Nobile-Orazio E. et al., Electroencephalography Clin Neurophysiol Suppl 1999;50:419), acquired neuromyotonia, arthrogryposis multiplex congenita (Vincent A. et al., Ann NY 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.

[0269] Examples of autoimmune muscle diseases include, but are not limited to, myositis, autoimmune myositis, and primary Sjogren'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 associated with 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 NY 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 O T. 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] Transplant rejection disorders : Examples of diseases associated with transplantation of a graft 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 allergies, dust mite allergies, venom allergies, cosmetic allergies, latex allergies, chemical allergies, drug allergies, insect sting allergies, animal dander allergies, thorny plant allergies, poison ivy allergies, and food allergies.

[0277] Additional uses The compounds described herein in any aspect of the embodiments of the invention described herein can be used to coat medical devices, including implantable medical devices, particularly medical devices where inhibition of cell migration and / or proliferation is desired.

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

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

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

[0281] The implantable device may be a permanently or temporarily implantable device.

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

[0283] According to some embodiments of the present invention, there is provided a medical device as described herein, having associated therewith at least a portion thereof a compound as described in any corresponding embodiment herein, hi some embodiments, the compound is deposited on (e.g., coated on) at least a portion of the exterior surface of the medical device.

[0284] The compound may be directly associated with the device, for example, by being contained in or absorbed into the material that makes up the device (e.g., by being mixed into or absorbed into the polymeric material from which the device is made). Alternatively, or in addition, the compound may be deposited on the exterior surface of the device by means of a polymeric film or other coating material in which the compound is contained or absorbed.

[0285] Pharmaceutical Composition : The compounds described in connection with any aspect of the embodiments described herein can be utilized (e.g., administered to a patient) by themselves or as pharmaceutical compositions in which the compounds are mixed with suitable carriers or excipients.

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

[0287] Hereinafter, the terms "physiologically acceptable carrier" and "pharmaceutically acceptable carrier", which may be used interchangeably herein, refer to a carrier or diluent that does not cause significant irritation to an organism and does not suppress the biological activity and properties of the administered compound. Adjuvants are included under these terms.

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

[0289] When utilized by itself or as a pharmaceutically acceptable composition, the compound itself (i.e., not 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). Purity can be enhanced, for example, by removing impurities associated with the synthesis of the compound or the isolation of the compound from natural sources, by any suitable technique known in the art. Techniques for drug formulation and administration can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

[0290] Suitable routes of administration can include, for example, oral, rectal, transmucosal, especially intranasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injection, as well as intrathecal, direct intraventricular, intracardiac, e.g., into the right or left ventricular cavity, into the common carotid artery, intravenous, intraperitoneal, intranasal or intraocular injection.

[0291] Alternatively, the pharmaceutical composition may be administered in a local rather than systemic manner, 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 that is composed of cells designed to perform a function or functions. 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, vascular tissue, kidney tissue, lung tissue, gonadal tissue, and hematopoietic tissue.

[0293] Pharmaceutical compositions of some embodiments of the present invention may be manufactured by processes well known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0294] Thus, pharmaceutical compositions for use in accordance with some embodiments of the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants, which facilitate processing of the active ingredient into a pharmaceutically acceptable preparation. The appropriate formulation will depend on the selected route of administration.

[0295] For injection, the active ingredients of the pharmaceutical composition can be formulated in aqueous solution, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological salt 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, pharmaceutical compositions can be easily formulated by combining active compounds with pharmaceutically acceptable carriers well known in the art.Such carriers allow pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by patients.Pharmacological preparations for oral use can be prepared by using solid excipients, optionally grinding the resulting mixture, and processing the mixture into granules, after adding suitable excipients as needed to obtain tablets or dragee cores.Suitable excipients include, in particular, sugars including lactose, sucrose, mannitol or sorbitol, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, cellulose preparations such as methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or fillers such as physiologically acceptable polymers, such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0297] Provide suitable coating for sugar-coated tablet core.For this purpose, can optionally use concentrated sugar solution, which can contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.For identification, can add dyes or pigments to tablet or sugar-coated tablet coating to characterize different combinations of active compound dosage.

[0298] Orally usable pharmaceutical compositions include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol.Push-fit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and optionally a stabilizer.In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol.In addition, stabilizers can be added.All formulations for oral administration should be in a dosage suitable for the selected administration route.

[0299] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

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

[0301] The pharmaceutical compositions described herein can be formulated for parenteral administration, for example, by bolus injection or continuous infusion.The injection formulations can be provided in unit dosage form, 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 formulation agents such as suspending agents, stabilizers and / or dispersing agents.

[0302] Pharmaceutical compositions for parenteral administration include aqueous solutions of water-soluble active ingredients.In addition, suspensions of active ingredients can be prepared as suitable 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 carboxymethylcellulose, sorbitol or dextran.Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the active ingredient to allow the preparation of highly concentrated solutions.

[0303] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water-based solution, before use.

[0304] Pharmaceutical compositions of some embodiments of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, eg, conventional suppository bases such as cocoa butter or other glycerides.

[0305] Pharmaceutical compositions suitable for use in connection with some embodiments of the present invention include compositions containing the active ingredient in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of the active ingredient(s) effective to prevent, alleviate or ameliorate symptoms of, or prolong the survival of, the disorder (e.g., cancer or metastatic cancer) being treated.

[0306] Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0307] For any preparation used in the method of the present invention, the therapeutically effective amount or dose can be estimated initially from in vitro and cell culture assays.For example, the dose can be formulated in animal models to achieve a desired concentration or titer.This information can be used to more accurately determine the useful dose 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 by standard pharmaceutical procedures. The data obtained from these in vitro and cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. Dosages can vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage can be selected by an individual physician taking into account the patient's condition (see, for example, Fingl et al. (1975), in "The Pharmacological Basis of Therapeutics", Ch. 1 p.1).

[0309] The dosage and administration interval can be individually adjusted to ensure that the protein (e.g., SDF-1 and / or CXCR4) inhibitory level of the active ingredient is sufficient to induce or suppress the biological effect (minimum effective concentration, MEC). The MEC varies depending on each formulation, but can be estimated based on in vitro data, for example, the results of the chemokine-induced (e.g., SDF-1-induced) migration inhibition assay described herein. The dosage required to achieve the MEC varies depending on individual characteristics and the route of administration. Detection assays can be used to determine plasma concentration.

[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 embodiments described herein, an effective amount is at least 100% of the compound's IC50 for the chemokine (e.g., SDF-1) that it is intended to inhibit. In some embodiments, an effective amount is at least 200% of the compound's IC50 for the chemokine. In some embodiments, an effective amount is at least 300% of the compound's IC50 for the chemokine. In some embodiments, an effective amount is at least 500% of the compound's IC50 for the chemokine. In some embodiments, an effective amount is at least 1000% of the compound's IC50 for the chemokine.

[0312] In some embodiments described herein, the effective amount is at least 100% of the IC50 of the compound for inducing 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, dosage may be single or multiple administrations over the course of treatment lasting from several days to several weeks, or until a cure is achieved or the disease state is eliminated.

[0314] The amount of composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

[0315] 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), which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, be a blister pack comprising metal or plastic foil. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also have a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting that the composition form has been approved by that agency for administration to humans or animals. Such notice may, for example, be in the form of labeling approved by the U.S. Food and Drug Administration for prescription drugs or in the form of an approved product insert. Compositions comprising the formulations of the present invention, formulated in a compatible pharmaceutical carrier, may also be prepared, placed in an appropriate container, and labeled for the treatment or diagnosis of an indicated condition, as detailed above.

[0316] It is to be understood that the compounds described herein may be provided alone or in combination with other active ingredients known in the art to alleviate disease conditions.

[0317] Thus, for example, the compound may be administered together with an immunomodulator, either in a simultaneous formulation or in a separate formulation.

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

[0319] As used herein, the term "anti-cancer immunomodulatory agent" refers to an agent that is capable of eliciting an immune response (eg, 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 T cell activation and / or proliferation, and an immune checkpoint regulator.

[0321] Alternatively or additionally, such modulators may be immune stimulators, such as immune checkpoint regulators, which have particular value in the treatment of cancer.

[0322] As used herein, the term "immune checkpoint regulator" refers to a molecule that modulates the activity of one or more immune checkpoint proteins in an agonistic or antagonistic manner, resulting in immune cell activation.

[0323] As used herein, the term "immune checkpoint protein" refers to a protein that activates or regulates the function of immune cells. Immune checkpoint proteins can be either costimulatory proteins (i.e., those that transmit stimulatory signals, resulting in the activation of immune cells) or inhibitory proteins (i.e., those that transmit inhibitory signals, resulting in the suppression of immune cell activation). According to certain embodiments, immune checkpoint proteins regulate the activation or function of T cells. Numerous checkpoint proteins are known in the art, including, but 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 regulator 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 suppresses its inhibitory activity. Thus, anti-CTLA4 prevents the transmission of inhibitory signals, thereby acting as a costimulatory molecule. According to certain embodiments, the anti-CTLA4 molecule is an antibody.

[0327] PD-1 (Programmed Death 1) is a member of the extended CD28 / CTLA-4 family of T cell regulators 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 suppresses its inhibitory activity. Thus, anti-PD-1 prevents the transmission of inhibitory signals, thereby acting as a costimulatory molecule. According to certain embodiments, the anti-PD-1 molecule is an antibody. Numerous anti-PD-1 antibodies are known in the art. See, for example, Topalian, et al. NEJM 2012.

[0328] PDL-1 is a ligand for PD-1. 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 signal transduction by binding to PD-1 or by inhibiting PD-L1 from binding to PD-1 and / or activating PD-1. Thus, anti-PD-1 prevents the transmission of inhibitory signals, thereby acting as a costimulatory molecule. According to certain embodiments, the anti-PD-L1 is an anti-PD-L1 antibody. Many anti-PDL-1 antibodies are known in the art. See, for example, Brahmer, et al. NEJM 2012.

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

[0330] OX40 belongs to the TNF receptor superfamily and mediates the expansion 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 tumor necrosis factor receptor) is a surface receptor molecule that has been found to be involved in inhibiting the suppressive activity of regulatory T cells and prolonging 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 may be administered with an additional anti-cancer agent as described in any of the corresponding embodiments herein, either in a co-formulation (eg, in the same pharmaceutical composition) or in a separate formulation.

[0333] According to certain embodiments, the treatment of cancer (and other hyperproliferative disorders) is carried out in 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, or alternatively may be identified for use in combination with, additional agents described herein.

[0335] According to another aspect described herein, there is provided a kit for treating a condition described herein (e.g., treating cancer or preventing tumor metastasis or treating a non-cancerous proliferative disease or disorder or treating 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, wherein the two agents are each packaged separately 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 pathology described herein.

[0339] In some embodiments, the compounds are identified as inducing apoptosis and / or cell growth arrest in cells associated with the pathologies 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 optionally further comprising an additional active ingredient as described in the corresponding embodiment herein.

[0341] In one aspect of some embodiments of the present invention, there is provided a small molecule compound as 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 as 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 arresting, substantially inhibiting, slowing, or reversing the progression of a condition, substantially ameliorating the clinical or cosmetic symptoms of a condition, or substantially preventing the worsening of the clinical or cosmetic symptoms of a condition. For example, in the context of preventing metastasis and / or angiogenesis, "preventing" refers to arresting, halting, or inhibiting the processes 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 ingredients, steps, and / or moieties, but only if the additional ingredients, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0348] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, "a compound" or "at least one compound" can include multiple compounds, including 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 an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to specifically disclose all of the possible subranges and individual numerical values ​​within that range. For example, description of a range such as 1 to 6 specifically discloses subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numerical values ​​within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the magnitude of the range.

[0350] Whenever a range of numerical values ​​is given herein, it is intended to include any recited number (fractional or integer) within the range given. The phrases "range between" a first designated number and a second designated number and "range from" a first designated number to a second designated number are used interchangeably herein and are intended to include the first designated number and the second designated number, and all fractional and integer numbers therebetween.

[0351] As used herein, the term "method" means manner, means, techniques, and procedures for accomplishing a given task, including, but not limited to, those known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry, and medicine, or those that can be readily developed by practitioners from known manners, means, techniques, and procedures.

[0352] Throughout this specification, the phrase "linking group" refers to a group (substituent) that is bonded to another moiety in a compound through two or more atoms. To distinguish between a linking group and a substituent that is bonded to another moiety in a compound through a single atom, the latter is referred to as a "terminal group" throughout this specification.

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

[0354] Thus, the amine group can be a primary amine where R' and R" are both 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, heteroalicyclic amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, 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 the group --NR'R" when the amine is a terminal group or forms part of a terminal group, and to refer to the group --NR'-- when the amine is a linking group.

[0357] The term "alkyl" refers to a saturated aliphatic hydrocarbon, including straight-chain and branched-chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms. When a numerical range, e.g., "1 to 20," is mentioned herein, the range means that the substituent, in this case the alkyl group, can 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 specified, the alkyl is a lower-sized alkyl having 1 to 4 carbon atoms. In some embodiments, the alkyl has at least 4 carbon atoms, e.g., the alkyl has 4 to 12, 4 to 10, or 4 to 8 carbon atoms. The alkyl group can be substituted or unsubstituted. A substituted alkyl has one or more substituents, where each substituent can independently be, for example, a hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, 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] An alkyl group can be a terminal group, in which case it is attached to one adjacent atom, as defined above, or it can be a linking group, in which case it is attached to two or more moieties through at least two carbons in the chain, as defined above. When alkyl is a linking group, it is also referred to herein as the term "alkylene," e.g., methylene, ethylene, propylene, etc.

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

[0360] The term "alkynyl" or "alkyne" refers to an alkyl, as defined herein, in which at least one pair of carbon atoms is joined together by a triple bond.

[0361] The term "cycloalkyl" refers to an all-carbon monocyclic or fused-ring group (i.e., rings which share adjacent pairs of carbon atoms) in which one or more of the rings does not have a completely conjugated pi-electron system. Cycloalkyl groups can be substituted or unsubstituted. Substituted cycloalkyls have one or more substituents, each of which may independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, 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-amido, N-amido, guanyl, guanidine, and hydrazine. The cycloalkyl group may be a terminal group, in which case it is bonded to an 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 "heteroalicyclic group" refers to a monocyclic or fused ring group having one or more atoms, such as nitrogen, oxygen, and sulfur, in the ring(s). The ring may also have one or more double bonds. However, the ring does not have a completely conjugated pi-electron system. Heteroalicyclic groups can be substituted or unsubstituted. Substituted heteroalicyclic groups have one or more substituents, each of which may independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic 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, O-carbamate, N-carbamate, C-amide, N-amide, guanyl, guanidine, and hydrazine. Heteroalicyclic groups may be terminal groups, in which case they are bonded to adjacent atoms as defined above, or they may be linking groups, in which case they are bonded to two or more moieties at two or more positions as defined above. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino, and the like.

[0363] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a completely conjugated electron system. Aryl groups can be substituted or unsubstituted. Substituted aryls have one or more substituents, each of which can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, 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 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. Preferably, the aryl is phenyl. Optionally, the aryl is naphthalenyl.

[0364] The term "heteroaryl" refers to a monocyclic or fused ring group (i.e., rings that share adjacent pairs of carbon atoms) containing one or more atoms in the ring(s) and further having a completely 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. Heteroaryl groups can be substituted or unsubstituted. Substituted heteroaryls have one or more substituents, each of which may independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, 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 an 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 with one or more aryl or heteroaryl groups. An example of an 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 with one or more halide groups.

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

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

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

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

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

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

[0374] The terms "sulfonate" or "sulfonyl" refer to an -S(=O)2-OR' terminal group (also referred to herein as -SO3R' or -SO3H) or an -OS(=O)2- linked group, as defined above, where R' is as defined herein.

[0375] The term "S-sulfonamido" refers to the -S(=O)2-NR'R" terminal group or the -S(=O)2-NR'- linked group as defined above, where R' and R" are as defined herein.

[0376] The term "N-sulfonamido" refers to an R'S(=O)2-NR"- terminal group or an -S(=O)2-NR'- linked 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 --SS-- linked 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" as used herein refers to a -C(=O)-R' terminal or -C(=O)- linked group as defined above, where R' is as defined herein.

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

[0382] The term "oxo" is intended herein to denote the =O terminal group.

[0383] The term "thiooxo" is intended herein to denote the =S terminal group.

[0384] The term "oxime" refers to the =N-OH terminal group or the =NO- linking group as defined above.

[0385] The terms "hydroxyl" or "hydroxy" refer to an --OH group.

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

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

[0388] The term "thiohydroxy" or "thio" refers to an --SH group.

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

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

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

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

[0393] The term "nitro" refers to the group --NO.sub.2.

[0394] The term "carboxylate" as used herein encompasses C-carboxylates and O-carboxylates.

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

[0396] The term "O-carboxylate" refers to an -OC(=O)R' terminal or -OC(=O)- linked group as defined above, where R' is as defined herein.

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

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

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

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

[0401] The term "N-carbamate" refers to an R"OC(=O)-NR'- terminal group or an -OC(=O)-NR'- linked group as defined above, where R' and R" are as defined herein.

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

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

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

[0405] The term "N-thiocarbamate" refers to an R"OC(=S)NR'- terminal group or an -OC(=S)NR'- linked group as defined above, where R' and R" are as defined herein.

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

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

[0408] The term "N-dithiocarbamate" refers to an R"SC(=S)NR'- terminal group or an -SC(=S)NR'- linked 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"' terminal group or the -NR'C(=O)-NR"- linked group, as defined above, where R' and R" are as defined herein and R"' is as defined herein for R' and R".

[0410] The term "thiourea," also referred to herein as "thioureido," refers to an -NR'-C(=S)-NR"R"' terminal group or an -NR'-C(=S)-NR"- linked 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-amido" refers to a C(=O)-NR'R" terminal group or a -C(=O)-NR'- linked group as defined above, where R' and R" are as defined herein.

[0413] The term "N-amido" refers to the R'C(=O)-NR"-terminated or R'C(=O)-N-linked group as defined above, where R' and R" are as defined herein.

[0414] The term "guanyl" refers to the R'R"NC(=N)-terminated or -R'NC(=N)- linked group as defined above, where R' and R" are as defined herein.

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

[0416] The term "hydrazine" refers to the -NR'-NR"R"' terminal group or the -NR'-NR"- linked group as defined above, where R', R", and R"' are as defined herein.

[0417] As used herein, the term "hydrazide" refers to the -C(=O)-NR'-NR"R"' terminal group or the -C(=O)-NR'-NR"- linked group, as defined above, where R', R" and R'" are as defined herein.

[0418] As used herein, the term "thiohydrazide" refers to the -C(=S)-NR'-NR"R"' terminal group or the -C(=S)-NR'-NR"- linked 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 a salt thereof, for example, a pharmaceutically acceptable salt thereof, and / or a prodrug thereof.

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

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

[0422] Thus, the acid addition salts of the compounds described herein may be complexes formed with one or more acidic groups of the drug and an equivalent amount of one or more bases.

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

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

[0425] Thus, the acid addition salts of the compounds described herein may be complexes formed with one or more basic groups of the drug and an equivalent amount of one or more acids.

[0426] Acid addition salts may include, but are not limited to, various organic and inorganic acids such as hydrochloric acid to provide hydrochloric acid addition salts, hydrobromic acid to provide hydrobromide acid addition salts, acetic acid to provide acetic acid addition salts, ascorbic acid to provide ascorbic acid addition salts, benzenesulfonic acid to provide besylate addition salts, camphorsulfonic acid to provide camphorsulfonic acid addition salts, citric acid to provide citrate addition salts, maleic acid to provide maleic acid addition salts, malic acid to provide malic acid addition salts, methanesulfonic acid to provide methanesulfonic acid (mesylate) addition salts, naphthalenesulfonic acid to provide naphthalenesulfonic acid addition salts, oxalic acid to provide oxalic acid addition salts, phosphoric acid to provide phosphoric acid addition salts, toluenesulfonic acid to provide p-toluenesulfonic acid addition salts, succinic acid to provide succinic acid addition salts, sulfuric acid to provide sulfuric acid addition salts, tartaric acid to provide tartaric acid addition salts, and trifluoroacetic acid to provide trifluoroacetic acid addition salts. Each of these acid addition salts may be either a mono- or poly-addition salt, as defined herein.

[0427] Depending on the stoichiometric ratio of charged groups in the compound and counterions in the salt, acid or base addition salts can be either mono- or poly-addition salts.

[0428] The term "mono-addition salt," as used herein, refers to a salt having a 1:1 stoichiometric ratio of counterion to the charged form of the compound, containing one molar equivalent of counterion per one molar equivalent of the compound.

[0429] The term "polyaddition salt," as used herein, refers to salts in which the stoichiometric ratio of counterion to the charged form of the present compound is greater than 1:1, e.g., 2:1, 3:1, 4:1, etc., and which include two or more molar equivalents of counterion per molar equivalent of the present compound.

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

[0431] Additionally, each of the compounds described herein may be in the form of its solvates or hydrates, including its salts.

[0432] The term "solvate" refers to a complex of 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 a solvate as described above wherein the solvent is water.

[0434] The compounds described herein may be used in polymorphic forms, and the present embodiments further encompass any isomorphic form of the compound and any combination thereof.

[0435] The present embodiments further encompass any enantiomers and diastereomers of the compounds described herein.

[0436] The term "enantiomer," as used herein, refers to a stereoisomer of a compound that can be superimposed on its corresponding structure only by complete inversion / reflection (mirror image) of each other. Enantiomers are said to be "chiral" because they are described as being like right and left hands. Enantiomers have the same chemical and physical properties except when present in an environment that is chiral to itself (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 or S configuration, or any combination. Compounds according to some embodiments of the present invention may have any chiral center that exhibits the R or S configuration.

[0437] The term "diastereomers," as used herein, refers to stereoisomers that are not enantiomers of each other. Two or more stereoisomers of a compound exhibit diastereomeric properties when they have different configurations at one or more, but not all, of their 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) results in two different configurations, and therefore two different stereoisomers. In the context of the present invention, embodiments of the present invention encompass compounds with multiple chiral centers, occurring in any combination of configurations, i.e., any diastereomers.

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

[0439] It is to be understood that features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or combination with other embodiments described herein. Features described in connection with various embodiments are not deemed essential to those embodiments, unless the embodiment is inoperable without the feature.

[0440] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples. [Example]

[0441] Reference is now made to the following examples, which together with the above descriptions illustrate, in a non-limiting manner, 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-N1 can be represented by two tautomers. [ka]

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

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

[0446] For simplicity, only the enol tautomer will be referred to below, however, two tautomers may exist and may exist in equilibrium or as a single tautomer depending on environmental conditions.

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

[0448] To a solution of 4-hydroxy-2-methoxybenzaldehyde (S1) (150.0 grams, 985 mmol) in DMF (1.0 L) was added K2CO3 (272 grams, 1970 mmol, 1.5 equivalents) at 0 °C, and the resulting mixture was stirred for 30 minutes. BnBr (270 grams, 1576 mmol, 1.6 equivalents) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC showed the reaction was complete. 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 a residue. The residue was purified by column chromatography to give the product 4-(benzyloxy)-2-methoxybenzaldehyde (S2) as a colorless oil (215.0 grams, 90% yield).

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

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

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

[0452] To a solution of 4-(benzyloxy)-2-methoxyphenol (S3) (125 grams, 540 mmol) in THF (2.0 L) was added NaH (60%) (23.8 grams, 594 mmol) in portions. The reaction mixture was stirred at 0°C for 30 minutes. Then, 2-fluoro-4-methoxy-1-nitrobenzene (1) (93.0 grams, 540 mmol) was added at 0°C. The reaction mixture was stirred at room temperature overnight. TLC showed 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 x 3). The organic phase was washed with brine (500 mL x 2), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 10:1 PE:EA to give the product 2 as a brown oil (155.0 grams, 72% yield). LC-MS: m / z=382.1(M + +H)

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

[0454] To a mixture of 4-(benzyloxy)-2-methoxy-1-(5-methoxy-2-nitrophenoxy)benzene (2) (155 grams, 275 mmol) and SnCl₂·2H₂O (372 grams, 1655 mmol, 6.0 equiv.) in EtOH (900 mL) was added HCl (850 mL, 6N). The reaction mixture was heated to reflux and stirred under reflux overnight. LC-MS indicated 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 phase was 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 grams, 83% yield). LC-MS: m / z 352.4(M + +H)

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

[0456] A mixture of 2-(4-(benzyloxy)-2-methoxyphenoxy)-4-methoxyaniline (3) (100 grams, 285 mmol), diethyl 2-pentylmalonate (SM-1) (39 grams, 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 hours. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 7:1 PE:EA to give the product 4 as a brown oil (100 grams, 67% yield). LC-MS: m / z 536.3(M + +H)

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

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

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

[0460] 2-((2-(4-(benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoic acid (5) (30 grams, 59.1 mmol) was added to a solution of Eaton's reagent (42 grams, 177.3 mmol, 3.0 equivalents) in DCM (300 mL). The reaction mixture was stirred at 40° C. for 2 hours. LC-MS showed that compound 5 was completely consumed. The reaction mixture was poured into HO (50 mL), washed with saturated NaHCO, and extracted with EA (100 mL × 3). The organic phase was washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to give product 6 as a pale yellow solid (10.1 grams, 35.1% yield).

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

[0462] 2-((2-(4-(benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoic acid (6) (30 grams, 59.1 mmol) was added to a solution of trifluoroacetic acid (150 mL) and stirred at room temperature for 12 hours. LC-MS showed that compound 6 was completely consumed. The TFA solution was removed under vacuum at 30 °C. The residue was diluted with HO (250 mL) and extracted with EA (300 mL × 3). The combined organic phase was washed with brine (500 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to give the final product BKT300-N1 as a white solid (10.5 grams, 44.7% yield). 1HNMR(400MHz,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,1 H),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%(254nm), 97.7%(214nm) MS m / z(ESI): m / z=400.1(M + +H).

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

[0464] Example 2 In Vitro Migration and Invasion Assays Migration assay: Six hundred microliters of RPMI medium containing 1% fetal calf serum (FCS) was added to the lower chamber of a Transwell® transmigration plate containing 100 ng / ml of SDF-1. Except for the control sample, BKT300-N1 was added to the lower chamber at the indicated concentrations. SDF-1 was incubated with BKT300-N1 for 30 minutes at room temperature before the start of the migration assay. Following the 30-minute incubation, 2 x 10 cells were added to a total volume of 100 μl. 5 Jurkat cells were added to the upper chamber of the transmigration 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 demonstrates that BKT300-N1 at concentrations of 0.5 μM, 1 μM, or 5 μM significantly inhibited the migration of lymphoid Jurkat cells toward SDF-1.

[0466] These results demonstrate that BKT300-N1 is an effective inhibitor of SDF-1 function and suggest that the compound may be effective in treating pathologies associated with the activity of SDF-1 and CXCR4 (the receptor for SDF-1).

[0467] Scratch assay: A scratch assay was performed to determine the effect of BKT300-N1 on cell invasion and migration compared to BKT300-3-C5. The system measures scratch closure in real time and automatically calculates the relative wound density and wound width within the original open space at each time point. Relative wound density is expressed as the ratio of the occupied area to the total area of ​​the initial scratch.

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

[0469] To create uniform and reproducible scratches in all wells of a 96-well plate, scratches were created using a 96-pin tool, WoundMaker™ (Essen BioScience). After scratch creation, the medium was aspirated and the wells were washed twice with fresh medium to remove all cells from the scratched area. After washing, fresh medium containing various concentrations of test compound was added to the wells. After adding fresh medium, the plate was placed in an IncuCyte ZOOM™ instrument, and images of the collective cell spread were recorded every 4 hours for a total period of 60 hours.

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

[0471] Scratch assays were performed using HCC SNU449 cells. Cells were scratched and incubated with 0.05, 0.1, 0.5, 1, and 10 μM BKT300-N1 or BKT300-3-C5.

[0472] FIG. 3 shows the relative wound area at 24 hours, demonstrating the improved effect of BKT300-N1 already at a concentration of 0.1 μM.

[0473] Figures 4A-4E show comparative plots of the effect on relative wound width values ​​(microns) analyzed by IncuCyte when incubated with 0.05, 0.1, 0.5, 1, and 10 μM BKT300-N1 (referred to as N1 for simplicity) and 0.05, 0.1, 0.5, 1, and 10 μM BKT300-3-C5 (referred to as BKT300 for simplicity) compared to the control, further demonstrating the improved effect of BKT300-N1 compared to BKT300-3-C5, especially at lower concentrations.

[0474] In another scratch assay, 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] FIG. 5A shows a comparative plot of relative wound width values ​​(microns) analyzed by IncuCyte.

[0476] FIG. 5B shows images of wound width obtained using an IncuCyte live cell imaging system for control and cells incubated with 0.1 μM and 0.5 μM 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 cultured at 1 × 10 in RPMI cell culture medium containing 1% fetal calf serum (FCS). 6 Cells were incubated in a 24-well plate at a concentration of 1000 cells / well in a final volume of 1 ml. Test compounds (BKT300-N1 or BKT300-3-C5) were added to the cells at the indicated concentrations. After 24 hours of incubation, the medium and cells were collected, centrifuged, and stained with annexin-V and propidium iodide (PI) kits according to the manufacturer's instructions. The numbers of viable 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 assessed by flow cytometry (FACS).

[0479] Figures 6A and 6B show data from this assay. Figure 6A is a bar graph showing the effect of BKT300-N1 and BKT300-3-C5 (25-1000 nM) on U937 cell viability, expressed as the number of viable Annexin-V / PI cells, demonstrating the improved effect of BKT300-N1 at all concentrations tested. Figure 6B is a bar graph showing the effect of BKT300-N1 and BKT300-3-C5 (25-1000 nM) on apoptosis of U937 cells, expressed as the percentage of Annexin-V cells.

[0480] The data obtained clearly demonstrate that BKT300-N1 is substantially more effective in reducing the percentage of viable cells due to apoptosis.

[0481] Western blot of cleaved caspase-3: The CASP-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 cellular apoptosis. Caspases exist as inactive proenzymes, which undergo processing of a conserved asparagine residue to generate two subunits, a large and a small one, that dimerize to form the active enzyme. The active enzyme cleaves and activates caspases 6 and 7, which are then processed and activated by caspases 8, 9, and 10.

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

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

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

[0485] The data obtained clearly demonstrated that BKT300-N1-induced apoptosis was mediated by activation of caspase-3.

[0486] Cell cycle analysis by 7-AAD staining: To evaluate the effect of BKT300-N1 on cell cycle distribution, a 7-aminoactinomycin D (7-AAD) protocol was used. Cells were plated at 1 × 10 cells per 24-well microplate. 6Cells were seeded at a density of 1000 cells / well and exposed to various concentrations of the test compound, BKT300-N1 or BKT300-3-C5, for 24 or 48 hours at 37°C in a CO2 incubator. After the incubation period, cells were harvested and washed with cold PBS. Cells were fixed for 20 minutes at 4°C and processed according to the 7-AAD labeling protocol. The dye intensity of stained cells was measured by flow cytometry. Cell cycle analysis was performed by calculating G0 / G1, G2 / M, and sub-G0 phases from a 7-AAD region histogram.

[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, demonstrating the improved effect of BKT300-N1 over BKT300-3-C5, which was more pronounced at the lower concentrations tested. As shown in Figure 8A, treatment with BKT300-N1 resulted in cell cycle arrest and induced cell death at all concentrations tested. In contrast, 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 their cell cycle stage was analyzed by flow cytometry using 7-AAD. Cells were gated based on cell cycle stage: P1, G0 / G1 phase; P2, apoptotic cells in sub-G0 phase; and P3, G2 / M phase. The resulting data are shown in Figure 9.

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

[0491] The data presented in Figures 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 research The effects of BKT300-N1 on cancer cell growth and survival in vivo were tested in NOD Scid gamma (NSG) mice or C57BL / 6 mice.

[0493] 5 × 10 for C57BL / 6 mice 6 Cells / mouse of the murine pancreatic cell line Panc02 were implanted subcutaneously.

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

[0495] Once tumors reached a certain size and were clearly visible, the treatment group was injected with BKT300-N1. BKT300-N1 (30 mg / ml formulated in 49.7% (v / v) Cremophor EL dehydrated alcohol, further diluted 1:6 with 0.9% NaCl to 5 mg / ml) was injected subcutaneously at a dose of 2.5 mg / mouse for 3–4 consecutive days. Some mice were injected intratumorally with BKT300-N1 (30 mg / ml formulated in 49.7% (v / v) Cremophor EL dehydrated alcohol) at a dose of 0.6 mg / mouse for 2–4 consecutive days. 24 h after the last treatment, mice were sacrificed, and tumor size was assessed and weight was measured.

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

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

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

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

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

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

[0502] Additional experiments tested the in vivo efficacy of BKT300-N1 against the growth of subcutaneous, low-passage Champions' TumorGraft® 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.

[0503] A 1-1.5 cm incision was placed in the left flank of 6- to 8-week-old athymic nude-Foxn1nu (immunodeficient) female mice. 3 The harvested tumors were implanted unilaterally. When the tumors reached an average volume of 200 cubic millimeters, the control group was treated daily with vehicle, while the treatment groups were injected with 2.5 mg / mouse (low dose) or 5 mg / mouse (high dose) of BKT300-N1 per injection. The control group received a subcutaneous (SC) injection of vehicle (50% / 50% v / v Cremophor EL and ethanol) diluted 1:6 with 0.9% sodium chloride.

[0504] For the low-dose treatment group, a 30 mg / mL BKN300-N1 stock solution was made in vehicle and further diluted 1:6 with 0.9% sodium chloride to a final concentration of 5 mg / mL. 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 30 mg / mL BKN300-N1 stock solution was made in vehicle and further diluted 1:3 with 0.9% sodium chloride to a final concentration of 10 mg / mL. Animals received 0.5 mL subcutaneous injections every 12 hours (5 mg / injection = 10 mg daily dose).

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

[0507] These results further demonstrated that BKT300-N1 was 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 12-well plates with 10% fetal calf serum (FCS). 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.

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

[0510] The data obtained are shown in Figures 14A-14D. Figures 14A-14B represent data obtained after 24 hours of incubation, and Figures 14C-14D represent data obtained after 48 hours of incubation. Results are expressed as mean ± SD. Statistical significance was determined by analysis using a two-tailed Student's T-test. A value of p<0.05 was considered statistically significant. Data are the mean ± SD of duplicate cell counts for each group. *p<0.05 vs. control, **p<0.05 vs. irinotecan alone.

[0511] As seen in Figures 14A-14D, the combination of BKT300-N1 and irinotecan demonstrated beneficial effects on the viability of the lung cancer cells tested. The combination induced more cell death than either treatment alone, suggesting an interaction. Such an interaction may allow for the use of lower doses of irinotecan and reduce acquired resistance to irinotecan treatment.

[0512] Example 6 Taxol-resistant cancer cells Taxol is a chemotherapeutic drug that directly binds to microtubules and stabilizes them against depolymerization, resulting in mitotic arrest and cell death. However, its clinical efficacy has been hindered by the development of drug resistance. Taxol resistance is a major challenge in the treatment of various types of cancer.

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

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

[0515] After 24 hours of incubation, cells were harvested and washed with PBS. The pellet was fixed by adding 200 μl of Fix / Perm buffer and vortexing. 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 cells were resuspended in 100 μl of Perm / Wash plus 4 μl of 7-AAD and vortexed. Cells were further incubated at 4°C in the dark for 20 minutes, after which 300 μl of PBS was added. Flow cytometry analysis was performed by collecting 20,000 events per sample. Analysis was based on the distribution of cells into 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-tailed Student's T-test. A value of p<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 taxol was examined.

[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 was observed on HEY-T30 resistant cells at any of the concentrations tested (Figs. 18A to 18C, green lines).

[0525] These data demonstrate the therapeutic potential of BKT300-N1 to affect (arrest) the growth and viability of cancer cells resistant to taxol.

[0526] While the present invention has been described in conjunction with specific embodiments thereof, many alterations, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alterations, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0527] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference herein should not be construed as an admission that such reference is available as prior art to the present invention. Nor should the extent that section headings are used be construed as necessarily limiting.

[0528] Additionally, the documents relating to the prior application of this application are also incorporated herein by reference in their entirety.

Claims

1. A compound represented by the following formula: 【Chemical 1】

2. 10. The compound of claim 1 for use in treating cancer in a patient.

3. 3. The compound of claim 2 for use in treating cancer characterized by expression of CXCR4 and / or drug-resistant cancer.

4. 3. The compound of claim 2 for use in treating cancer selected from leukemia, melanoma, lung cancer, breast cancer, lymphoma, myeloma, pancreatic cancer, ovarian cancer, liver cancer, brain cancer, colorectal cancer, kidney cancer, bladder cancer, prostate cancer, uterine cancer, testicular cancer, head and neck cancer, colon cancer, and sarcoma.

5. 10. The compound of claim 2 for use in therapy, for administration with an additional anti-cancer agent.

6. 10. The compound of claim 1 for modulating the biological activity of a chemokine in a patient and / or for treating a condition treatable by modulating the biological activity of a chemokine.

7. The compound of claim 6, wherein the chemokine is SDF-1.

8. 10. The compound of claim 1 for use in inducing cell death.

9. The compound of claim 1 for use in inducing apoptosis in cells.

10. The pathology is selected from the group consisting of 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 vascular disease, mesangial proliferative glomerulonephritis, sympathetic ophthalmia, ureteral disease, lupus nephritis, pneumonia, radicular granuloma, Erdheim-Chester disease, glomerulonephritis, arterial disease, viral encephalitis, primary cutaneous amyloidosis, arteriosclerosis, nonspecific interstitial pneumonia, acute poststreptococcal glomerulonephritis, coronary artery disease, Venezuelan Encephalitis, diabetic macular edema, extrapulmonary tuberculosis, nephritis, rheumatoid arthritis, Kawasaki disease, arthritis, malaria, obesity, psychiatric disorders, cancer, neurodegenerative disorders, age-related macular degeneration, Whim's syndrome, cervical adenocarcinoma, breast cancer, bursitis, tuberculosis, intraocular lymphoma, cytomegalovirus retinitis, chronic inflammatory demyelinating polyradiculoneuropathy, ocular hypertension, polyradiculoneuropathy, dendritic cell tumor, retinal hemangioblastoma, malaria, endotheliitis, leukemia, prostatitis, prostate cancer, colorectal cancer, chronic lymphocytic leukemia, pancreatitis, neuronitis, lung cancer, osteoarthritis, hypoxia, adenocarcinoma, pancreatic cancer, multiple myeloma, neuroblastoma, myeloid leukemia Disease, astrocytoma, periodontitis, glioblastoma, preeclampsia, melanoma, hepatitis, esophagitis, myeloma, eclampsia, cervicitis, periodontal disease, central nervous system lymphoma, sporadic breast cancer, hepatocellular carcinoma, systemic lupus erythematosus, asthma, renal cell carcinoma, myocardial infarction, medulloblastoma, endometrial cancer, lupus erythematosus, esophageal cancer, premature ovarian failure, peritonitis, vascular disease, alcoholic hepatitis, kidney disease, cutaneous leishmaniasis, encephalitis, alopecia areata, lymphocytic leukemia, adenoma, mantle cell lymphoma, oligodendroglioma, Maltodextrin lymphoma, whooping cough, ischemia, uveal melanoma, gingivitis, pituitary adenoma, bronchiolitis, neuromyelitis optica, mesothelioma, alopecia , cervical cancer, somatic, glioblastoma multiforme, bronchiolitis obliterans, brain injury, colorectal adenoma, tongue squamous cell carcinoma, B-cell lymphoma, traumatic brain injury, intravascular large B-cell lymphoma, allergic asthma, tick-borne encephalitis, blastic plasmacytoid dendritic cells, oligoastrocytoma, childhood dermatomyositis, renal oncocytoma, endometrial adenocarcinoma, optic neuritis, seminoma, Sjögren's syndrome, pleurisy, neuritis, inflammatory bowel disease, cytomegalovirus infection, malignant pleural mesothelioma, oral squamous cell carcinoma, skeletal muscle regeneration, Emery-Dreifuss muscular dystrophy, dominant type, fibrosis, idiopathic pulmonary fibrosis, scleroderma, liver cirrhosis,7. The compound according to claim 6, for use in the treatment of an infectious disease, an autoimmune disease, hypersensitivity-related inflammation, transplant rejection and skin inflammation.

11. 10. The compound of claim 1 for the treatment of a disease or disorder selected from psoriasis, rheumatoid arthritis, multiple sclerosis, atherosclerosis, glomerulonephritis, epilepsy, Alzheimer's disease, cerebral ischemia, traumatic brain injury, type II diabetes, age-related macular degeneration (AMD), adverse angiogenesis, tumor metastasis, WHIM syndrome, Waldenstrom's hypergammaglobulinemia, and opioid-induced hyperalgesia.

12. 10. The compound of claim 1 for the treatment of a disease or disorder selected from dermatitis, atopic dermatitis, contact dermatitis, dermatitis herpetiformis, generalized exfoliative dermatitis, seborrheic dermatitis, drug eruption, erythema multiforme, erythema nodosum, granuloma annulare, poison ivy, poison oak, toxic epidermal necrolysis, rosacea, psoriasis, and acne.

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