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

Abstract

The present application relates to small molecules for treating cancer, inhibiting chemokine activity and / or inducing cell death. The present disclosure provides compounds that can or may be used to induce death of cancer cells and / or modulate a biological activity of a chemokine, such as cell migration, and / or to treat diseases and conditions associated with a biological activity of a chemokine and / or cell migration, and / or to treat cancer. The various compounds are collectively represented by the following Structural Formula Ia or Ib: # imgabs0 # wherein A, B, D, E, G and R1 to R5 are as defined in the specification wherein one or more of D, E and G, preferably E, are hydroxyl groups.

Description

[0001] This application is a divisional application of application number CN 202080050533.4 (PCT application number is PCT / IL2020 / 050535), application date May 15, 2020, and invention name “Small molecules for treating cancer, inhibiting chemokine activity and / or inducing cell death”.

[0002] Related Applications

[0003] This application claims the benefit of priority under 35 USC §119(e) to U.S. Provisional Patent Application No. 62 / 848,008, filed on May 15, 2019, the contents of which are incorporated herein by reference in their entirety.

[0004] Technical Field and Background Art

[0005] The present invention, in some embodiments thereof, relates to treatment, and more specifically but not limited to, to a plurality of small molecule compounds and methods of using these compounds, wherein the small molecule compounds can be used to modulate a biological activity of a chemokine, kill a plurality of cancer cells, inhibit chemokine-dependent cell migration and / or treat diseases and conditions associated with a plurality of biological activities of a plurality of chemokines and / or a plurality of cell migration, such as cancer.

[0006] Chemokines are one of many biological factors involved in the progression of inflammatory diseases. Chemokines belong to a group of small, approximately 8 to 14 kilodaltons (kDa), mostly basic, heparin-binding proteins that are related to each other by their primary structure and the presence of four conserved cysteine ​​residues.

[0007] The chemokines are chemotactic cytokines that have been shown to be selective chemoattractants for leukocyte subsets in vitro and to trigger 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, Immunol J., 1994, 153: 4721-4732], and methods of inhibiting human immunodeficiency virus replication [Cocchi et al., Science, 1995, 270: 1811-1815].

[0008] Many chemokines play an important role in the recruitment and activation of many cells of the immune system, and they also have a wide range of effects in many different cell types outside the immune system, including, for example, in various cells of the central nervous system [Ma et al., Proceedings of the National Academy of Sciences of the United States of America (PNAS), 1998, 95: 9448-9453] and endothelial cells. They cause various angiogenic or angiogenic inhibitory effects [Strieter et al., J Biol Chem, 1995, 270: 27348-27357]. Many specific chemokines may have multiple effects on many tumors, including angiogenesis, promotion of growth and metastasis, and suppression of immune responses to cancer, while other chemokines inhibit tumor-mediated angiogenesis and promote various anti-tumor immune responses.

[0009] Several chemokine receptors have received increasing attention due to their key roles in the progression of inflammation and related disorders such as asthma, atherosclerosis, transplant rejection, AIDS, and autoimmune disorders (eg, multiple sclerosis, arthritis, myasthenia gravis, lupus).

[0010] SDF-1 (stromal cell derived factor 1), also known as CXCL12 (CXC motif chemokine 12), is a chemokine with strong chemotacticity for multiple lymphocytes. SDF-1 plays an important role in angiogenesis, including angiogenesis associated with tumor progression, by recruiting multiple endothelial progenitor cells from the bone marrow through an action 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]. In addition, multiple cancer cells expressing CXCR4 are attracted to multiple metastatic target tissues that release SDF-1.

[0011] Plerixafor is a CXCR4 antagonist that, when used in combination with G-CSF (granulocyte colony-stimulating factor), can mobilize multiple hematopoietic stem cells from multiple cancer patients, particularly lymphoma and multiple myeloma patients, which are then transplanted back into the patient after chemotherapy or radiotherapy.

[0012] In multiple animal studies, plerixafor has been reported to reduce metastasis [Smith et al., Cancer Res, 2004, 64:8604-8612], reduce recurrence of glioblastoma associated with angiogenesis [Kioi et al., Clin Investigation, 2010, 120:694-705], and protect against opioid-induced hyperalgesia [Wilson et al., Brain Behav Immun, 2011, 25:565-573].

[0013] WO 2017 / 103931 of the present patentee describes data obtained when screening and further studying a natural compound library of multiple compounds capable of modulating chemokine activity, which is incorporated herein by reference. In the studies described in WO 2017 / 103931, compounds with certain structural features were identified as being capable of modulating the effects of multiple individual chemokines on cells and being capable of affecting cancer and other pathogenic cells. WO 2017 / 103931 describes the compound, referred to therein as BKT300 (shown below), as, for example, inducing cancer cell death and inhibiting cancer cell migration.

[0014]

[0015] WO 2017 / 103932 of the present patentee describes newly designed structural analogs of BKT300, which are incorporated herein by reference, and which have been shown to induce death of multiple cancer cells, inhibit cancer cell migration, selectively block cancer cell proliferation at G2M, and induce apoptotic cell death via the caspase-3 pathway. One of the compounds described in WO 2017 / 103932 is called BKT300-3-C5, and its keto and enol forms are shown below.

[0016] Summary of the invention

[0017] According to one aspect of some embodiments of the present invention, there is provided a compound represented by the following structural formula Ia and / or Ib:

[0018]

[0019] in:

[0020] A is an alkyl group having a length of at least 4 carbon atoms;

[0021] B is selected from hydroxy and alkoxy;

[0022] D and G are each independently selected from hydrogen, hydroxy, alkoxy and alkyl, provided that at least one of D and G is hydrogen;

[0023] E is hydroxyl group;

[0024] R1 is selected from hydrogen and alkyl; and

[0025] Each of R2 to R5 is independently selected from hydrogen, hydroxy, halo, alkoxy, thioalkoxy, thiol, thioalkoxy and amine.

[0026] According to some embodiments of any of the embodiments described in this specification, B is alkoxy.

[0027] According to some embodiments of any of the embodiments described in this specification, one of D and G is alkoxy.

[0028] According to some embodiments of any of the embodiments described in this specification, when one of D and G is an alkyl group, the alkyl group is at least 4 carbon atoms in length.

[0029] According to some embodiments of any of the embodiments described in this specification, R1 is hydrogen.

[0030] According to some embodiments of any of the embodiments described in this specification, each of R2 to R5 is hydrogen.

[0031] According to some embodiments of any of the embodiments described in this specification, the compound is represented by the following structural formula IIa or IIb:

[0032]

[0033] in:

[0034] A is a monoalkyl group having a length of at least 4 carbon atoms;

[0035] B is selected from hydroxyl and alkoxy;

[0036] D and G are each independently selected from hydrogen, hydroxy, alkoxy and alkyl, provided that at least one of D and G is hydrogen;

[0037] R1 is selected from hydrogen and alkyl; and

[0038] Each of R2 to R5 is independently selected from hydrogen, hydroxy, halo, alkoxy, thioalkoxy, thiol, thioalkoxy and amine.

[0039] According to some embodiments of any of the embodiments described in this specification, each of R2 to R5 is hydrogen.

[0040] According to some embodiments of any of the embodiments described in this specification, R1 is hydrogen.

[0041] According to some embodiments of any of the embodiments described in this specification, at least one of D and G is alkoxy.

[0042] According to some embodiments of any of the embodiments described in this specification, B is alkoxy.

[0043] According to some embodiments of any of the embodiments described in this specification, the compound is:

[0044]

[0045] This exemplary compound is referred to in this specification as BKT300-N1.

[0046] According to some embodiments of any of the embodiments described in this specification, the compound is capable of inducing multiple cell death.

[0047] According to some embodiments of any of the embodiments described in this specification, the compound is capable of inducing apoptosis in a plurality of cells.

[0048] According to some embodiments of any of the embodiments described herein, the apoptosis is associated with cleavage of caspase-3.

[0049] According to some embodiments of any of the embodiments described in this specification, the compound is capable of inducing cancer cell growth arrest in the G2M phase of a plurality of cancer cells.

[0050] According to some embodiments of any of the embodiments described in this specification, the compound is capable of inhibiting chemokine-induced cell migration.

[0051] According to one aspect of some embodiments of the present invention, a compound represented by structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment and any combination thereof in the present specification is used to treat cancer in an individual in need thereof.

[0052] According to some embodiments of any of the embodiments described in this specification, the cancer is leukemia.

[0053] According to some embodiments of any of the embodiments described in this specification, the cancer is selected from leukemia, melanoma, lung cancer, lymphoma, myeloma, ovarian cancer, liver cancer, brain cancer, colorectal cancer and prostate cancer.

[0054] According to some embodiments of any of the embodiments described in this specification, the cancer is a drug-resistant cancer.

[0055] According to some embodiments of any of the embodiments described in this specification, treating the cancer further comprises: administering an additional anti-cancer agent to the individual.

[0056] According to one aspect of some embodiments of the present invention, a compound represented by structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment and any combination thereof in the present specification is used to regulate a biological activity of a chemokine in an individual in need thereof.

[0057] According to one aspect of some embodiments of the present invention, a compound represented by structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment and any combination thereof in the present specification is used to treat a condition that can be treated by regulating a biological activity of a chemokine.

[0058] According to some embodiments of any of the embodiments described in this specification, the chemokine is SDF-1.

[0059] According to some embodiments of any of the embodiments described in this specification, the chemokine is MCP-1.

[0060] According to some embodiments of any of the embodiments described in this specification, the condition is age-related maculopathy.

[0061] According to some embodiments of any of the embodiments described in this specification, the disease or disorder is cancer.

[0062] According to one aspect of some embodiments of the present invention, a compound represented by structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment and any combination thereof in the present specification is used to treat inflammation.

[0063] According to one aspect of some embodiments of the present invention, a compound represented by structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment and any combination thereof in the present specification is used to treat a non-cancerous hyperproliferative disease.

[0064] According to one aspect of some embodiments of the present invention, a compound represented by structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment and any combination thereof in the present specification is used to induce cell death.

[0065] According to one aspect of some embodiments of the present invention, a compound represented by structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment and any combination thereof in the present specification is used to induce apoptosis in multiple cells.

[0066] According to some embodiments of any of the embodiments described in this specification, the apoptosis is associated with cleavage of caspase-3.

[0067] According to some embodiments of any of the embodiments described in this specification, the plurality of cells is a plurality of cancer cells.

[0068] According to some embodiments of any of the embodiments described in this specification, the plurality of cells is a plurality of drug-resistant cells (eg, a plurality of drug-resistant cancer cells).

[0069] According to one aspect of some embodiments of the present invention, a compound represented by structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment and any combination thereof in the present specification is used to induce cancer cell growth arrest in the G2M phase of multiple cancer cells.

[0070] Unless otherwise specified, all technical terms and / or scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. Although embodiments of the invention may be implemented or tested by any method and material similar or equivalent to those described in embodiments of the invention, embodiments of the invention, the methods and / or materials listed are described below. In the event of a conflict, the definitions included in this patent specification will control. In addition, materials, methods and embodiments are exemplary only and are not necessarily intended to be limiting. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Some embodiments of the present invention are described herein by way of example only and with reference to a number of drawings. By describing in detail the specific references to the drawings, it should be emphasized that the details shown are only examples for the purpose of illustrating the embodiments of the present invention. Based on this, the drawings and description together enable those skilled in the art to clearly implement the embodiments of the present invention.

[0072] In the attached picture:

[0073] Figure 1 A scheme depicting a synthesis of BKT300-N1 according to some embodiments of the present invention is presented.

[0074] Figure 2 is a bar graph showing the effect of different concentrations of BKT300-N1 on the migration of various Jurkat AML cells toward SDF-1 (* indicates p<0.05 relative to zero concentration).

[0075] Figure 3 Images demonstrating the effects of different concentrations of BKT300-N1 and BKT300-3-C5 on the migration of multiple HCC SNU449 cells using a scratch assay compared to a control are presented. Multiple SNU449 cells were scratched and cultured with 0.05, 0.1, 0.5, 1, and 10 μM (parts per million; microM) of BKT300-N1 or BKT300-3-C5. Relative wound area after 24 hours of culture is shown.

[0076] Figure 4A -E presents a comparative graph showing the effects of BKT300-N1 (denoted as N1 for simplicity) and BKT300-3-C5 (denoted as BKT300 for simplicity) at a concentration of 0.05 μM (microM) ( Figure 4A )、0.1μM(microM)( Figure 4B )、0.5μM(microM)( Figure 4C )、1μM(microM)( Figure 4D ) and 10μM (microM) ( Figure 4E ), relative wound width values ​​(micrometers; μm) for IncuCyte analysis.

[0077] Figure 5A -B presents a comparative diagram, which shows that IncuCyte ( Figure 5A ) analysis and the control at 48 hours with the IncuCyte live cell imaging system to obtain the wound width image (for 0.1μM (microM) and 0.5μM (microM) BKT300-N1 ( Figure 5B)), demonstrated the effect of different concentrations of BKT300-N1 on the migration of MSTO cells using a scratch assay.

[0078] Fig. 6A -B is a bar graph showing the effects of BKT300-N1 and BKT300-3-C5 (25-1000 nM) on the viability of various U937 cells by showing the number of Annexin-V- / PI- cells and showing the effects on apoptosis of various U937 cells ( Figure 6B ).

[0079] Fig. 7A -B presents a Western blot 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 various U937 cells ( Figure 7B ), and presents a bar graph showing the effect of 24 h of incubation with BKT300-N1 (0.1, 0.5 and 1 μM) on the presence of cleaved caspase-3 in various U937 cells (expressed by optical density (OD) and normalized to actin) ( Figure 7B ).

[0080] Fig. 8A -B presents different concentrations of BKT300-N1(N1)( Fig. 8A ) and BKT300-3-C5( Figure 8B ) Effects on the cell cycle of multiple U937 cells after 24 hours of culture. Cell cycle phases were analyzed by flow cytometry using 7-AAD.

[0081] Fig. 9 The effects of different concentrations of BKT300-N1 on the cell cycle of multiple H69 cells after 48 hours of culture are presented. The cell cycle stage was analyzed by flow cytometry using 7-AAD. Cells were gated according to the cell cycle stage: P1 for G0 / G1 phase; P2-apoptotic cells in sub-G0 phase; and P3 for G2 / M phase.

[0082] Fig.10 is a bar graph showing the effect of BKT300-N1 on pancreatic cancer in mice in vivo. The bar graph shows tumor weight (mg) (*p<0.05).

[0083] Fig.11 is a bar graph showing the in vivo effect of BKT300-N1 on mouse AML. The bar graph shows tumor weight (mg) (*p<0.05).

[0084] Fig.12is a bar graph showing the in vivo effect of BKT300-N1 on mouse hepatocellular carcinoma. The bar graph shows tumor weight (mg) (*p<0.05).

[0085] Fig.13A -C presents a comparative graph showing the effects of daily doses of 5 mg (low dose) or 10 mg (high dose) of BKT300-N1 on human ovarian cancer ( Fig.13A ), small lung cancer cells (SCL; Fig. 13B ) and colorectal cancer ( Fig. 13C In vivo effects of growth in xenografts (PDXs) compared to vehicle only.

[0086] Fig.14A -D is a bar graph showing the effect of BKT300-N1 (125 nM) and irinotecan (25 μM) treatment for 24 hours ( Fig.14A ), BKT300-N1 (125 nM) and irinotecan (100 μM) for 24 h ( Fig. 14B ), BKT300-N1 (125 nM) and irinotecan (25 μM) for 48 h ( Fig. 14C ), and BKT300-N1 (125 nM) and irinotecan (100 μM) treatment for 48 h ( Fig.14D ) on the viability of multiple H460 cells, as determined by PI staining.

[0087] Fig.15 FACS analysis of multiple HEY-T30 cells after treatment with paclitaxel is presented. The red area represents multiple cells in the G0 / G1 phase (P1), the green area represents multiple cells in the G2 / M phase (P3), and the blue area represents apoptotic cells (P2).

[0088] Fig.16 FACS analysis of multiple OVCAR8 cells after treatment with paclitaxel is presented. The red area represents cells in the G0 / G1 phase (P1), the green area represents cells in the G2 / M phase (P3), and the blue area represents apoptotic cells (P2).

[0089] Fig.17A -C presents a comparison of cell cycle analysis of multiple HEY-T30 cells (blue line) and multiple OVCAR8 cells (orange line) after treatment with paclitaxel (30, 15, 7.5 and 3.75 nM). Fig.17A The percentages of multiple dead cells after treatment are presented; Fig. 17B The percentages of various cells in the G0 / G1 phase after treatment are presented; Fig. 17C The percentage of cells in G2 / M phase after treatment is presented. *p<0.05.

[0090] Fig.18A -C presents a comparative graph showing cell cycle analysis of multiple HEY-T30 cells after treatment with 250, 125, 62.5, 31.25 and 15.6 nM of paclitaxel (green line) or BKT300-N1 (red line). Fig.18A The percentage of dead cells after treatment is presented; Fig.18B The percentages of various cells in the G0 / G1 phase after treatment are presented; Fig. 18C The percentage of cells in G2 / M phase after treatment is presented. *p<0.05. DETAILED DESCRIPTION

[0091] In some embodiments of the present invention, the present invention relates to treatment, and more specifically, but not limited to, multiple small molecule compounds and methods of using these compounds, wherein the multiple small molecule compounds can be used to modulate a biological activity of a chemokine, kill multiple cancer cells, inhibit chemokine-dependent cell migration and / or treat diseases and conditions associated with multiple biological activities of multiple chemokines and / or multiple cell migration, such as: cancer.

[0092] Before explaining at least one embodiment of the present invention in detail, it should be understood that the present invention is not necessarily limited to the details of the construction of the present invention, and the arrangement of components and / or methods described in the following description and / or the accompanying drawings and / or the embodiments. The present invention can be implemented or applied in other embodiments or in various methods.

[0093] As discussed in the background section above, the patentee previously used laborious screening analysis to find that small molecules with certain structural features can modulate the effects of multiple individual chemokines on cells and affect cancer and other pathogenic cells, and has further designed structural analogs of some of these small molecules and found that they even have improved effects on chemokine activity and inducing cancer cell death. See WO 2017 / 103931 and WO 2017 / 103932.

[0094] In the search for other compounds that modulate the activity of a chemokine and / or are capable of inducing cell death in cancer and other pathogenic cells, the present inventors have discovered that modifications to the structures of the compounds taught in WO 2017 / 103932 lead to significant improvements in the desired activity of these compounds.

[0095] Without being bound by any particular theory, the present inventors have discovered that compounds featuring one or more hydroxy substituents may exhibit improved effects by replacing one or more alkoxy groups in the compound, such as described in WO 2017 / 103932.

[0096] An exemplary synthetic route for preparing an exemplary such compound, referred to herein as BKT300-N1, is shown in Figure 1 middle.

[0097] The inventors have shown that an exemplary compound of this class, referred to herein as BKT300-N1, characterized by a modification of the structure of the compound referred to as BKT300-3-C5 in WO 2017 / 103932, exhibits improved effects in modulating a biological activity of multiple chemokines (see, e.g., Figure 2 -5) and as an anticancer agent by inducing multiple cancer cell death and / or affecting abrogation of cell migration and / or growth, by acting synergistically with another anticancer agent, and by inducing multiple cancer cell death and preventing cancer cell growth in paclitaxel-resistant cancer cells. For example, please refer to Figures 6 to 18.

[0098] The modified compounds described herein can be used to modulate a biological activity of multiple chemokines, and thus can be used to treat diseases or conditions associated with a biological activity of a chemokine, as described in further detail below. The modified compounds described herein are particularly useful as anticancer agents by inducing cell death and / or preventing cell growth and / or affecting cancer cell migration (by inhibiting angiogenesis and / or metastasis), as described in further detail below.

[0099] The general effects of the various compounds of some embodiments of the present invention have been shown on various biological phenotypes, including chemokine-induced cell migration and cell apoptosis, and these findings make the various compounds described in this specification as multiple potent drugs that can be used to treat various medical conditions, including: multiple inflammatory diseases (e.g., autoimmune diseases), multiple cancers, and multiple non-cancerous hyperproliferative diseases.

[0100] Therefore, various embodiments of the present invention generally relate to various newly designed small molecules and their uses. Various compounds (small molecules):

[0101] According to one aspect of some embodiments of the present invention, a plurality of newly designed small molecules (compounds) are provided, and the plurality of small molecules can be collectively represented by structural formula Ia:

[0102]

[0103] in:

[0104] A is a monoalkyl group having a length of at least 4 carbon atoms;

[0105] B is selected from hydroxy, alkoxy and aryloxy, or from hydroxy 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;

[0106] R1 is selected from hydrogen, alkyl and cycloalkyl, or selected from hydrogen and alkyl; and

[0107] R2 to R5 are each independently selected from hydrogen, hydroxy, halide, alkoxy, thioalkoxy, thiol, thioalkoxy, amine and optional alkyne, aryloxy, thioaryloxy, carboxylate, carbonyl, sulfonyl, sulfonate, sulfinyl, cyano, nitro and other substituents as described in this specification.

[0108] The compound of formula Ia has a keto group (carbonyl group) and can undergo a tautomerism reaction between a keto group and an enol group to form an "enol" form, and thus can be represented by formula Ib:

[0109]

[0110]

[0111] Ketone and enol tautomerism reactions are known in the art to describe the rapid equilibrium between a carbonyl group (C=O) and its enol tautomer.

[0112] In most cases, the keto-enol tautomerism reaction is thermodynamically driven, and at room temperature, the equilibrium usually favors the formation of the keto form. However, under environmental conditions such as the pH or ionic strength of the solution, the concentration of the compound, temperature, the presence of a reagent that stabilizes the enol form, the equilibrium may be tilted toward the enol form, making the enol form equally present or predominant.

[0113] In some embodiments, and depending on the environmental conditions, the compounds according to embodiments of the present invention may be in the form of the keto tautomer (Formula Ia), or in the form of the enol form (Formula Ib), or may be balanced between the keto form and the enol form. Therefore, both the Formula Ia form and the Formula Ib form are employed.

[0114] In some embodiments of any of the embodiments described in this specification, at least one of B, D, E and G is an alkoxy group or an aryloxy group, preferably an alkoxy group, and in some embodiments, at least two of B, D, E and G are alkoxy groups and / or aryloxy groups, preferably each is an alkoxy group.

[0115] In some embodiments of any of the embodiments described in this specification, the alkoxy group has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and multiple examples include but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy.

[0116] In some embodiments of any of the embodiments described in this specification, the alkoxy group is methoxy.

[0117] In some embodiments of any of the embodiments described in this specification, B is alkoxy (eg, methoxy).

[0118] In some embodiments of any of the embodiments described in this specification, no more than one of D, E, and G is alkyl.

[0119] In some embodiments of any of the embodiments described in this specification, no more than two or no more than one of D, E, and G is alkoxy or aryloxy.

[0120] In some embodiments of any of the embodiments described in this specification, when two of D, E, and G are alkoxy and / or aryloxy, none of D, E, and G is alkyl.

[0121] In some embodiments of any of the embodiments described herein, at least one of D, E and G is hydroxyl, and at least one of D, E and G is hydrogen. In some embodiments of these embodiments, another one or more of D, E and G can be alkoxy, aryloxy and / or alkyl, preferably alkoxy and / or alkyl, more preferably alkoxy.

[0122] In some embodiments of any of the embodiments described in this specification, E is hydroxy, D is hydrogen, and G is alkyl.

[0123] In some embodiments of any of the embodiments described in this specification, D is hydrogen, E is hydroxy, and G is an alkoxy group, such as methoxy.

[0124] In some embodiments of any of the embodiments described in this specification, D is an alkoxy group, such as methoxy, E is hydroxy, and G is hydrogen.

[0125] In some embodiments of any of the embodiments described in this specification, one of D and G is an alkoxy group, such as methoxy, the other of D and G is hydroxy, and E is hydrogen.

[0126] In some embodiments of any of the embodiments described in this specification, one of D and G is hydrogen, the other of D and G is alkyl, and E is hydroxy.

[0127] In some embodiments of any of the embodiments described in this specification, E is hydrogen, D is alkyl, and G is hydroxy.

[0128] In some embodiments of any of the embodiments described in this specification, G is hydrogen, E is alkyl, and D is hydroxy.

[0129] In some embodiments of any of the embodiments described in this specification, D is hydrogen, G is alkyl, and E is hydroxy.

[0130] In some embodiments of any of the embodiments described in this specification, E is hydrogen, G is alkyl, and D is hydroxy.

[0131] In some embodiments of any of the embodiments described in this specification, G is hydrogen, D is alkyl, and E is hydroxy.

[0132] In some embodiments of any of the embodiments described in this specification, E is hydrogen, D is alkoxy, eg, methoxy, and G is hydroxy.

[0133] In some embodiments of any of the embodiments described in this specification, G is hydrogen, E is alkoxy, eg, methoxy, and D is hydroxy.

[0134] In some embodiments of any of the embodiments described in this specification, D is hydrogen, G is hydroxy, and E is alkoxy, eg, methoxy.

[0135] In some embodiments of any of the embodiments described in this specification, E is hydrogen, G is alkoxy, eg, methoxy, and D is hydroxy.

[0136] In some embodiments of any of the embodiments described in this specification, E is hydroxy.

[0137] In some embodiments of any of the embodiments described in this specification, B is alkoxy (eg, methoxy).

[0138] In some embodiments of any of the embodiments described in this specification, D is alkoxy (eg, methoxy).

[0139] In some embodiments of any of the embodiments described in this specification, G is hydrogen.

[0140] In some embodiments of any of the embodiments described in this specification, E is hydroxy, D is alkoxy (eg, methoxy), and G is hydrogen. In some embodiments of these embodiments, B is alkoxy (eg, methoxy).

[0141] In some embodiments of any of the embodiments described in this specification, E is hydroxy, G is alkoxy (eg, methoxy), and D is hydrogen. In some embodiments of these embodiments, B is alkoxy (eg, methoxy).

[0142] In some embodiments of any of the embodiments described in this specification, E is hydroxy, and D and G are both hydrogen. In some embodiments of these embodiments, B is alkoxy (eg, methoxy).

[0143] In some embodiments of any of the embodiments described in this specification, D is hydroxy, and E and G are both hydrogen. In some embodiments of these embodiments, B is alkoxy (eg, methoxy).

[0144] In some embodiments of any of the embodiments described in this specification, G is hydroxy, and D and E are both hydrogen. In some embodiments of these embodiments, B is alkoxy (eg, methoxy).

[0145] In some embodiments of any of the embodiments described in this specification, D is said alkyl.

[0146] In some of these embodiments, one of G and E is hydrogen. In some of these embodiments, G is hydrogen and E is hydroxy.

[0147] In some embodiments of any of the embodiments described in this specification, E is hydroxy, D is alkyl, and G is hydrogen. In some embodiments of these embodiments, B is alkoxy (eg, methoxy).

[0148] In some embodiments of any of the embodiments described in this specification, whenever one of D, E, and G is an alkyl group, the alkyl group is at least 4 carbon atoms in length.

[0149] In some embodiments of any of the embodiments described herein, the alkyl group having a length of at least 4 carbon atoms can be, for example, 1 to 20, or 1 to 10, or 1 to 8 carbon atoms in length. A number of exemplary alkyl groups having a length of at least 4 carbon atoms include substituted or unsubstituted butyl, substituted or unsubstituted pentyl, substituted or unsubstituted hexyl, substituted or unsubstituted heptyl, substituted or unsubstituted octyl, substituted or unsubstituted nonyl, substituted or unsubstituted decyl, substituted or unsubstituted undecyl, substituted or unsubstituted dodecyl, and the like.

[0150] In some embodiments of any of the embodiments described in this specification, the alkyl group is an alkyl group of 4 carbon atoms in length and is an unsubstituted alkyl group. In some embodiments, the alkyl group is a hexyl group, and in some embodiments, is an unsubstituted hexyl group.

[0151] In some embodiments of any of the embodiments described in this specification, A is an alkyl group of at least 4 carbon atoms in length, and optionally, one of D, E, and G is an alkyl group of at least 4 carbon atoms in length.

[0152] When A and one of D, E and G are alkyl groups having a length of 4 carbon atoms, these alkyl groups may be the same or different.

[0153] In some of these embodiments, A and one of D, E and G is an unsubstituted alkyl, and in some embodiments, both are unsubstituted hexyl.

[0154] In some embodiments of any of the embodiments described in this specification, R1 is hydrogen.

[0155] In some embodiments of any of the embodiments described in this specification, each of R2 to R5 is independently selected from hydrogen, hydroxy, halo, alkoxy, thioalkoxy, thiol, thioalkoxy, and amine.

[0156] In some embodiments of any of the embodiments described in this specification, each of R2 to R5 is hydrogen.

[0157] In some embodiments of any of the embodiments described in this specification, each of R1 to R5 is hydrogen.

[0158] Alternatively, one or more of R1 to R5 is not hydrogen, and the nature of the corresponding substituent(s) does not interfere with the interactions of the small molecule with its biological target(s) (eg, binding of a chemokine).

[0159] According to some embodiments of any embodiment of the present invention, the compound of this embodiment can be collectively represented by the following structural formula IIa or IIb:

[0160]

[0161] in:

[0162] A is a monoalkyl group having a length of at least 4 carbon atoms;

[0163] B is selected from hydroxyl and alkoxy;

[0164] D and G are each independently selected from hydrogen, hydroxy, alkoxy and alkyl, provided that at least one of D and G is hydrogen;

[0165] R1 is selected from hydrogen and alkyl; and

[0166] Each of R2 to R5 is independently selected from hydrogen, hydroxy, halo, alkoxy, thioalkoxy, thiol, thioalkoxy and amine.

[0167] According to some embodiments of any of the embodiments, each of R2 to R5 is hydrogen.

[0168] According to some embodiments of any of the embodiments, R1 is hydrogen.

[0169] According to some embodiments of any of the embodiments, at least one of D and G is an alkoxy group. Alternatively, or additionally, at least one of D and G is an alkyl group, as described in any corresponding embodiment of the specification. Further alternatively, or additionally, at least one of D and G is a hydroxyl group.

[0170] According to some embodiments of any of the embodiments, D and G are both hydrogen.

[0171] In some embodiments of any of the embodiments, B is alkoxy. Alternatively, B is hydroxy.

[0172] In some embodiments of any of the embodiments described in this specification, a compound as described in this specification has the following chemical structure, which is represented by its keto and enol tautomers:

[0173]

[0174] This compound is indicated as BKT300-N1 in this specification.

[0175] In some embodiments of any of the embodiments described in this specification, a compound as described in this specification has the following chemical structure, which is represented by its keto and enol tautomers:

[0176]

[0177] In some embodiments of any of the embodiments described in this specification, a compound as described in this specification has the following chemical structure, which is represented by its keto and enol tautomers:

[0178]

[0179] In some embodiments of any of the embodiments described in this specification, a compound as described in this specification has the following chemical structure, which is represented by its keto and enol tautomers:

[0180]

[0181] Multiple therapeutic applications:

[0182] The compounds described herein, in any one of the various embodiments and in any combination thereof, are shown herein as inhibitors of chemokine-dependent cell migration and inhibitors of cancer cells (e.g., inhibitors of cancer cell growth and / or as inhibitors of inducing apoptosis and / or as inhibitors of cancer cell migration).

[0183] Therefore, each of the multiple compounds described in the present specification can or can be used to inhibit cancer cells, and / or kill cancer cells, and / or induce cell apoptosis, and / or induce growth arrest, and / or inhibit chemokine-dependent cell migration, and / or regulate a biological activity of a chemokine, such as: cell migration and / or treat diseases and disorders related to cell migration, such as: cancer and inflammatory diseases and disorders; and / or treat multiple proliferative diseases or disorders (the proliferative diseases or disorders require the induction of cell apoptosis and / or growth arrest).

[0184] Since inflammation and cancer are often governed by cell migration (eg, invasion, metastasis) which is often associated with cell proliferation, the compounds according to the present examples are contemplated for use in treating these conditions.

[0185] The various proliferative diseases and conditions described herein, including various medical conditions other than cancer (also referred to herein as various "non-cancerous hyperproliferative diseases"), are also considered to be treated using the compounds of some embodiments of the present invention due to the apoptosis-inducing effects of the various compounds.

[0186] Without being bound by any particular theory, it is believed that the compounds described herein are particularly useful as multiple anticancer agents by affecting chemokine-dependent cancer cell migration (e.g., by inhibiting metastasis) and / or angiogenesis and by inducing cancer cell death and / or by inducing apoptosis of cancer cells and / or by inducing growth arrest of cancer cells; and / or as anti-inflammatory agents by affecting chemokine-dependent immune cell migration (e.g., immune cell infiltration), as described in further detail below.

[0187] In some embodiments of any of the embodiments described in this specification, a small molecule compound of structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment of this specification can or can be used to induce the death of pathogenic cells (for example: multiple cancer cells or multiple immune cells or multiple overproliferative cells).

[0188] In some embodiments of any of the embodiments described in this specification, a small molecule compound of structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment of this specification can or can be used to induce cell death of multiple pathogenic cells.

[0189] As used in this specification, the term "apoptosis" refers to a self-destruction or suicide program in cells. In response to triggering stimuli, multiple cells undergo a series of events, including: cell shrinkage, cell membrane blebbing, pigment concentration and fragmentation, which ultimately lead to the transformation of cells into membrane-bound particle clusters (apoptotic bodies), which are then engulfed by multiple macrophages.

[0190] Methods for monitoring cellular changes induced by the compounds are known in the art and include, for example, the MTT assay, which is based on the selective reduction of the yellow salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (Sigma, Aldrich St. Louis, MO, USA) by living cells to a purple to blue insoluble formazan precipitate; BrDu assay [Cell Proliferation ELISA Bromodeoxyuridine (BrdU) Colorimetric Kit (Roche, Mannheim, Germany); TUNEL assay [Roche, Mannheim, Germany]; Annexin V assay [Annexin V Apoptosis Kit (Clontech Laboratories, Inc., California, USA)]; Senescence-associated β-galactosidase assay (Dimri GP, Lee et al., 2003; X et al., 1995). A biomarker that can identify senescent human cells in culture and in vivo aging skin. Proc. Natl. Acad. Sci. USA, 92:9363-9367); 7-ADD viability stain (available from MD Systems), caspase-3 assay (available from MD Systems) and various RNA and protein detection methods (the methods detect expression levels and / or activity), which are further described above.

[0191] In some embodiments of any of the embodiments described in this specification, for a small molecule compound of structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment of this specification, the cellular change is apoptosis, for example: by cleavage of caspase-3.

[0192] In some embodiments of any of the embodiments described herein, a small molecule compound of formula Ia and / or Ib or formula IIa and / or IIb as described in any corresponding embodiment of this specification can or can be used to induce apoptosis by cleaving caspase-3.

[0193] In some embodiments of any of the embodiments described in this specification, a small molecule compound of formula Ia and / or Ib or formula IIa and / or IIb as described in any corresponding embodiment of this specification can or can be used to induce growth arrest of multiple cells, and in some embodiments, the arrest is in the G2M phase of the cell cycle. In some embodiments of these embodiments, the multiple cells are multiple cancer cells.

[0194] Chemokine Regulation:

[0195] According to one aspect of some embodiments of the present invention, a small molecule compound of structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment and any combination thereof in the present specification can or can be used to regulate a biological activity of a chemokine as described in the present specification.

[0196] According to an aspect of some embodiments of the present invention, there is provided a method for modulating a biological activity of a chemokine, the method comprising contacting the chemokine with a compound according to any embodiment described in this specification.

[0197] According to one aspect of some embodiments of the present invention, there is provided a use of a compound according to any embodiment described in this specification in the preparation of a medicament for regulating a biological activity of a chemokine.

[0198] According to one aspect of some embodiments of the present invention, provided is a use of a compound according to any embodiment described in this specification in a biological activity of a chemokine.

[0199] In some embodiments, the use and / or the method for modulating the activity of a chemokine is performed in vivo, for example, by administering a therapeutically effective amount of the compound to a subject in need thereof.

[0200] In some embodiments, the uses and / or the methods for modulating chemokine activity are performed in vitro (eg, in a test tube), eg, in research.

[0201] In some embodiments of any one of the embodiments described in this specification, it relates to a method, use or medicine for regulating a biological activity of a chemokine, wherein the method, use or medicine is used to treat a disease or condition associated with a biological activity of a chemokine in an individual in need thereof, for example: by administering a therapeutically effective amount of a compound according to any embodiment described in this specification to the individual.

[0202] In some embodiments of any of the embodiments described in this specification, modulating a biological activity of a chemokine comprises inhibiting a biological activity of a chemokine, which can be demonstrated by the ability of a small molecule described in this specification to inhibit chemokine-induced cell migration in a variety of different types of cell types as exemplified in this specification.

[0203] In some embodiments of any one of the embodiments described in this specification, it relates to a method, use or medicine for modulating a biological activity of a chemokine, wherein the method, use or medicine is used to treat a disease or condition in an individual in need thereof, wherein modulating (e.g., inhibiting) a biological activity of a chemokine is beneficial for the disease or condition, for example, by administering to the individual a therapeutically effective amount of a compound according to any embodiment described in this specification.

[0204] In some embodiments of any one of the embodiments described in this specification, it relates to a method, use or drug for regulating a biological activity of a chemokine, wherein the method, use or drug is used for a disease or condition that can be treated by regulating (e.g., inhibiting) a biological activity of a chemokine in an individual in need thereof, for example, by administering a therapeutically effective amount of a compound according to any embodiment described in this specification to the individual.

[0205] In some embodiments of any one of the embodiments described in this specification, it is related to a method, use or medicine for regulating a biological activity of a chemokine, and the compound described in this specification (according to any corresponding embodiment) effectively regulates chemokine-dependent cell migration. In some embodiments of these embodiments, as described in this specification, the chemokine-dependent cell migration is related to cancer and / or inflammation.

[0206] In some embodiments of any of the embodiments described in this specification, it is related to a method or use of regulating a biological activity of a chemokine, and 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.

[0207] In some embodiments of any one of the embodiments described in this specification, it is related to a compound, method and / or drug (according to any corresponding embodiment described in this specification) that regulates the activity of a chemokine, and the compound, method and / or drug are used to inhibit a 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.

[0208] In some embodiments of any of the embodiments described herein, the chemokine is MIP3a.

[0209] Examples of various diseases and conditions associated with the activity of MIP3a (e.g., where inhibition of MIP3a activity is beneficial) include, but are not limited to, various autoimmune diseases and conditions, such as psoriasis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis (MS), atopic dermatitis, dry eye, and age-related macular degeneration (AMD).

[0210] In some embodiments of any of the embodiments described herein, a disease or condition is treated that is not a bacterial infection.

[0211] SDF-1 and / or CXCR4 inhibition:

[0212] According to some embodiments, a small molecule compound of structural formula Ia and / or Ib as described in any corresponding embodiment of the present specification and any combination thereof can or can be used to modulate a biological activity of SDF-1 and / or CXCR4 as described in the present specification.

[0213] According to one aspect of some embodiments of the present invention, there is provided a method of inhibiting a biological activity of SDF-1 and / or CXCR4, the method comprising contacting SDF-1 and / or CXCR4 with a compound according to any embodiment described in this specification.

[0214] According to one aspect of some embodiments of the present invention, there is provided a use of a compound according to any embodiment described in this specification in the preparation of a medicament for inhibiting a biological activity of SDF-1 and / or CXCR4.

[0215] According to one aspect of some embodiments of the present invention, there is provided a use of a compound according to any embodiment described in this specification in inhibiting a biological activity of SDF-1 and / or CXCR4.

[0216] In some embodiments of any of the embodiments, it relates to a use and / or method of inhibiting a biological activity of SDF-1 and / or CXCR4, wherein the use and / or method is performed in vivo, for example, by administering a therapeutically effective amount of a compound to a subject in need thereof.

[0217] In some embodiments, the use and / or method for inhibiting a biological activity of SDF-1 and / or CXCR4 is achieved in vitro (eg, in a test tube), for example, in research.

[0218] In some embodiments of any one of the embodiments described in this specification, it relates to a method, use or drug for inhibiting a biological activity of SDF-1 and / or CXCR4, wherein the method, use or drug is used to treat a disease or condition associated with a biological activity of SDF-1 and / or CXCR4 in an individual in need thereof, for example: by administering a therapeutically effective amount of a compound according to any embodiment described in this specification to the individual.

[0219] In some embodiments of any one of the embodiments described in this specification, it relates to a method, use or drug for inhibiting a biological activity of SDF-1 and / or CXCR4, wherein the method, use or drug is used to treat a disease or condition in an individual in need thereof, wherein inhibiting the biological activity of SDF-1 and / or CXCR4 is beneficial for the disease or condition, for example: by administering to the individual a therapeutically effective amount of a compound according to any embodiment described in this specification.

[0220] In some embodiments of any one of the embodiments described in this specification, it relates to a method, use or drug for inhibiting a biological activity of SDF-1 and / or CXCR4, which is useful for treating a disease or condition that can be treated by inhibiting a biological activity of SDF-1 and / or CXCR4 in an individual in need thereof. For example, by administering to the individual a therapeutically effective amount of a compound according to any embodiment described in this specification.

[0221] The skilled artisan will appreciate that CXCR4 is a receptor that mediates SDF-1 activity and that the activities of SDF-1 and CXCR4 generally overlap.

[0222] Examples of diseases and conditions associated with an activity of SDF-1 and / or CXCR4 (e.g., in which inhibition of SDF-1 and / or CXCR4 activity is beneficial) include, but are not limited to, Whim syndrome; cervical adenocarcinoma; breast cancer; bursitis; tuberculosis; intraocular lymphoma; cytomegalovirus retinitis; chronic inflammatory demyelinating polyneuropathy; ocular hypertension; polyradiculoneuropathy; dendritic cell tumors; retinal hemangioblastoma; malaria; endotheliitis; leukemia; rheumatoid arthritis; arthritis; prostatitis; prostate cancer; colorectal cancer; chronic lymphocytic leukemia; pancreatitis; neuronitis; lung cancer; osteoarthritis; hypoxia; adenocarcinoma; pancreatic cancer 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 failure; peritonitis; vascular disease; alcoholic hepatitis; kidney disease; cutaneous leishmaniasis; encephalitis; alopecia areata; lymphocytic leukemia; adenoma; mantle cell lymphoma; oligodendroglioma; maltoid lymphoma; whooping cough; ischemia; uveal melanoma adenomas; 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; plasmacytoid dendritic cells; oligoastrocytoma; dermatomyositis, childhood; 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; dominant Ehrlich-Derrickson muscular dystrophy.

[0223] In some embodiments, a plurality of exemplary diseases and conditions associated with an activity of SDF-1 and / or CXCR4 (e.g., diseases and conditions in which inhibition of SDF-1 and / or CXCR4 activity is beneficial) include, but are not limited to, unwanted angiogenesis, tumor metastasis, WHIM syndrome, Waldenstrom macroglobulinemia (WM), and opioid-induced hyperalgesia.

[0224] As used herein, the term "undesirable angiogenesis" refers to angiogenesis that is associated with clinically and / or cosmetically undesirable consequences.

[0225] Tumor-associated angiogenesis is a non-limiting example of deleterious angiogenesis.

[0226] As used herein, the phrase "tumor metastasis" refers to the spread of a malignancy from the primary location of the malignancy to other parts of the body, for example: breast cancer metastasizing to the lungs. Tumor metastasis generally involves the migration of tumor cells.

[0227] In some embodiments of any one of the embodiments described in this specification, it relates to a method or use of regulating a biological activity of a chemokine, wherein the regulation comprises inhibiting a biological activity of SDF-1 and / or CXCR4 according to any corresponding embodiment described.

[0228] In some embodiments of any one of the embodiments described herein, it relates to an inhibition of a biological activity of SDF-1 and / or CXCR4, wherein the inhibition of a biological activity of SDF-1 and / or CXCR4 is used to achieve immune stimulation.

[0229] In some embodiments, immune stimulation is implemented as part of a cancer treatment, for example, to stimulate immune activity against multiple cancer cells.

[0230] In some embodiments, immune stimulation comprises increasing a level of hematopoietic stem cells in the peripheral blood of a subject.

[0231] In some embodiments, increasing the level of a plurality of hematopoietic stem cells in the peripheral blood of an individual is accomplished as a preliminary part of a hematopoietic stem cell transplant (eg, in order to generate a plurality of hematopoietic stem cells that can be collected and subsequently transplanted back into the individual). Examples of multiple conditions that can be treated by hematopoietic stem cell transplantation include, but are not limited to, leukemias (e.g., acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia), lymphomas (e.g., Hodgkin's disease, non-Hodgkin's lymphoma), myelomas (e.g., multiple myeloma), neuroblastoma, hyperplastic small round cell tumor, Ewing's sarcoma, choriocarcinoma, myelodysplasia, anemias (e.g., paroxysmal nocturnal hemoglobinuria, aplastic anemia, Budd-Diesel anemia, Fanconi anemia, acquired pure red cell aplasia), hemoglobinopathies, sickle cell disease, major beta-thalassemia, multiple myeloproliferative diseases (e.g., polycythemia vera, essential thrombocythemia, myelofibrosis), amyloid light chain amyloidosis, radiation poisoning, viral diseases diseases (e.g., human T-lymphotropic virus (HTLV) and / or human immunodeficiency virus (HIV) infection), neuronal ceroid lipofuscinosis, Niemann-Pick disease, Gaucher disease, leukodystrophies (e.g., adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe's disease), mucopolysaccharidoses, glycoproteinopathies (e.g., hyperlipidemia type II, fucosidosis, aspartylglucosuria, α-mannosidosis), Wolman's disease, immunodeficiency disorders (e.g., ataxia-telangiectasia, DiGeorge syndrome, severe combined immunodeficiency, Wiskott-Aldrich syndrome, Cockswain syndrome, Schuyler-Dieter syndrome, Griseley syndrome, NF-κB essential regulator deficiency), amegakaryocytic thrombocytopenia, and hemophagocytic lymphohistiocytosis.

[0232] In some embodiments, the hematopoietic stem cell transplantation is used to treat a proliferative disease, such as cancer (eg, a cancer described herein according to any corresponding embodiment).

[0233] In some embodiments of any one of the embodiments described in this specification involving multiple hematopoietic stem cells, the treatment includes increasing a level of multiple hematopoietic stem cells in the individual's peripheral blood, obtaining multiple hematopoietic stem cells from the individual's peripheral blood, administering a cytotoxic therapy (e.g., antiproliferative chemotherapy and / or radiotherapy) to the individual, and transplanting at least a portion of the stem cells back into the patient after the cytotoxic therapy.

[0234] MCP-1 Inhibition:

[0235] According to some embodiments, a small molecule compound of structural formula Ia and / or Ib as described in any corresponding embodiment of the present specification and any combination thereof can or can be used to modulate a biological activity of MCP-1 as described in the present specification.

[0236] According to one aspect of some embodiments of the present invention, there is provided a method of inhibiting a biological activity of MCP-1, the method comprising contacting MCP-1 with a compound according to any embodiment described in this specification.

[0237] According to one aspect of some embodiments of the present invention, there is provided a use of a compound according to any embodiment described in this specification in preparing a medicament for inhibiting a biological activity of MCP-1.

[0238] According to one aspect of some embodiments of the present invention, there is provided a use of a compound according to any embodiment described in this specification in inhibiting a biological activity of MCP-1.

[0239] In some embodiments of any of the embodiments, a use and / or method of inhibiting a biological activity of MCP-1 is provided, wherein the use and / or method is performed in vivo, for example, by administering a therapeutically effective amount of a compound to a subject in need thereof.

[0240] In some embodiments, the use and / or method for inhibiting a biological activity of MCP-1 is performed in vitro (eg, in a test tube), eg, in research.

[0241] In some embodiments of any one of the embodiments described in this specification, it relates to a method, use or drug for inhibiting a biological activity of MCP-1, wherein the method, use or drug is used to treat a disease or condition associated with a biological activity of MCP-1 in an individual in need thereof, for example: by administering a therapeutically effective amount of a compound according to any embodiment described in this specification to the individual.

[0242] In some embodiments of any one of the embodiments described in this specification, it relates to a method, use or drug for inhibiting a biological activity of MCP-1, wherein the method, use or drug is used to treat a disease or condition in an individual in need, wherein inhibiting the biological activity of MCP-1 is beneficial for the disease or condition, for example: by administering to the individual a therapeutically effective amount of a compound according to any embodiment described in this specification.

[0243] In some embodiments of any one of the embodiments described in this specification, it relates to a method, use or drug for inhibiting a biological activity of MCP-1, which is useful for treating a disease or condition that can be treated by inhibiting a biological activity of MCP-1 in an individual in need thereof. For example, by administering to the individual a therapeutically effective amount of a compound according to any embodiment described in this specification.

[0244] Examples of diseases and disorders associated with an activity of MCP-1 (eg, where inhibition of MCP-1 activity is beneficial) include, but are not limited to, diseases and disorders characterized by mononuclear cell infiltration.

[0245] According to some embodiments, examples of multiple diseases and conditions associated with an activity of MCP-1 (e.g., in which inhibition of MCP-1 activity is beneficial) include, but are not limited to: tuberculosis; human immunodeficiency virus type 1 (HIV-1); proliferative glomerulonephritis; neural tube defects; xanthogranulomatous pyelonephritis; scleritis; rapidly progressive glomerulonephritis; pneumoconiosis; encephalitis; peritonitis; atherosclerosis; psoriasis; dengue shock syndrome; temporal arteritis; relapsing polychondritis; diabetic angiopathy; mesangial proliferative glomerulonephritis; sympathetic ophthalmia; ureteral disease; lupus nephritis; Pneumonia; periapical granuloma; Edheim-Chester disease; glomerulonephritis; arterial disease; viral encephalitis; primary cutaneous amyloidosis; arteriosclerosis; nonspecific interstitial pneumonia; acute post-streptococcal glomerulonephritis; coronary artery disease; Venezuelan equine encephalitis; diabetic macular edema; extrapulmonary tuberculosis; nephritis; rheumatoid arthritis; Kawasaki disease; arthritis; malaria; obesity; mental illness; cancer (e.g., as described in this specification); inflammation (e.g., inflammatory diseases and disorders as described in this specification); neurodegenerative disease; age-related macular degeneration (AMD, e.g., dry or wet) as described in this specification.

[0246] According to a specific embodiment, 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 age-related macular degeneration.

[0247] According to one embodiment, a compound according to this embodiment is used to treat age-related macular degeneration (AMD).

[0248] According to a specific embodiment, the age-related macular degeneration (AMD) is atrophic, non-neovascular (aAMD).

[0249] According to a specific embodiment, the age-related macular degeneration (AMD) is neovascular.

[0250] Cancer treatment:

[0251] According to some embodiments, a small molecule compound of structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment of this specification and any combination thereof can or can be used to treat cancer.

[0252] According to some embodiments, a small molecule compound of structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment of the present specification and any combination thereof can or can be used to induce the death of multiple cancer cells (kill multiple cancer cells).

[0253] According to some embodiments, a small molecule compound of structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment of this specification and any combination thereof can or can be used to induce apoptosis in multiple cancer cells.

[0254] According to some embodiments, a small molecule compound of structural formula Ia and / or Ib or structural formula IIa and / or IIb as described in any corresponding embodiment of the present specification and any combination thereof can or can be used to induce growth arrest in multiple cancer cells, and in some embodiments, the arrest is in the G2M phase of the cell cycle.

[0255] According to one aspect of some embodiments of the present invention, there is provided a method of treating a cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a small molecule compound according to any embodiment, thereby treating the cancer.

[0256] According to one aspect of some embodiments of the present invention, there is provided a use of a small molecule compound according to any embodiment described in this specification in the preparation of a drug for treating cancer.

[0257] According to one aspect of some embodiments of the present invention, there is provided a use of a small molecule compound according to any embodiment described in this specification in treating a cancer.

[0258] As used in this specification, the terms "cancer" and "tumor" are used interchangeably and refer to malignant growths and / or tumors caused by abnormal and uncontrolled cell proliferation (cell division). The term "cancer" includes tumor metastasis.

[0259] The term "cancer cell" describes the plurality of cells that form the malignant growth or tumor.

[0260] Non-limiting examples of cancers and / or tumor metastases that can be treated according to some embodiments of any embodiment of this specification related to cancer (including any aspects described in this specification) include: any solid or non-solid cancer and / or tumor metastasis, including but not limited to: gastrointestinal tumors (e.g., colon cancer, rectal cancer, colorectal cancer, colorectal cancer, colorectal adenoma, hereditary non-polyposis type 1, hereditary non-polyposis type 2, hereditary non-polyposis type 3, hereditary non-polyposis type 6; colorectal cancer, hereditary non-polyposis type 7, small intestine cancer and / or large intestine cancer, esophageal cancer, esophageal cancer with thyroid hypertrophy, gastric cancer, pancreatic cancer, pancreatic endocrine tumors), endometrial cancer, cutaneous fibrosarcoma, gallbladder cancer, biliary tumors, Prostate cancer, prostate adenocarcinoma, kidney cancer (e.g., Wilm's tumor type 2 or type 1), liver cancer (e.g., hepatoblastoma, hepatocellular carcinoma, hepatocellular carcinoma), bladder cancer, embryonal rhabdomyosarcoma, germ cell tumor, trophoblastic tumor, testicular germ cell tumor, ovarian immature teratoma, uterine cancer, epithelial ovarian cancer, sacrococcygeal tumor, choriocarcinoma, placental site trophoblastic tumor, epithelial adult tumor, ovarian cancer, serous ovarian cancer, ovarian sex cord tumor, cervical cancer, cervical cancer, small cell and non-small cell lung cancer, nasopharyngeal cancer, breast cancer (e.g., ductal breast cancer, invasive intraductal breast cancer), sporadic breast cancer, breast cancer predisposition, stage 4 breast cancer, breast cancer type 1, breast cancer type 3, breast cancer - ovarian cancer, squamous cell carcinoma cell carcinoma (e.g., head and neck), neurogenic tumors, astrocytomas, ganglioneuromas, neuroblastomas, lymphomas (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, thymic lymphoma), gliomas, adenocarcinomas, adrenal tumors, hereditary adrenocortical carcinomas, brain malignancies (tumors), various other cancers (e.g., bronchial large cell, ductal, Ehrlich-Ritter ascites carcinoma), epidermoid, large cell, Lewis lung, medullary, mucoepidermoid, oat cell, small cell, spindle cell, prickle cell, transitional cell, undifferentiated, carcinosarcoma , choriocarcinoma, cystadenocarcinoma), endolymphoblastoma, epithelioma, erythroleukemia (e.g., Freund's, lymphoblastic), fibrosarcoma, giant cell tumor, glioma, glioblastoma (e.g., pleomorphic, astrocytoma), glioma hepatocellular carcinoma, heterohybridoma, allomyeloma, histiocytoma, hybridoma (e.g., B cell), renal pelvic tumor, insulinoma, insulinoma, keratoma, leiomyoblastoma, leiomyosarcoma, leukemia (e.g., acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute lymphoblastic pre-B cell leukemia, acute lymphoblastic T-cell leukemia, acute megakaryocytic leukemia, monocytic leukemia, acute myeloid leukemia, acute myeloid leukemia, acute myeloid leukemia with eosinophilia,B-cell leukemia, basophilic leukemia, chronic myeloid leukemia, chronic B-cell leukemia, eosinophilic leukemia, Freund's leukemia, granulocytic or myeloid leukemia, hairy cell leukemia, lymphocytic leukemia, megakaryocyte leukemia, monocytic leukemia, monocytic-macrophage leukemia, myeloblastic leukemia, myeloid leukemia, granulomonocytic leukemia, plasma cell leukemia, pre-B-cell leukemia, promyelocytic leukemia, subtype Acute leukemia, T-cell leukemia, lymphoid neoplasms, susceptibility to myeloid malignancies, acute non-lymphocytic leukemia, lymphosarcoma, melanoma, breast tumors, mastocytoma, medulloblastoma, mesothelioma, metastatic tumors, monocytic tumors, multiple myeloma, myelodysplastic syndrome, myeloma, Wilms tumor, neural tissue glioma, neural tissue neuron tumor, neuroma, neuroblastoma, oligodendroglioma, osteochondroma, myeloma, osteosarcoma (e.g. Ewing's), papilloma, transitional cell, pheochromocytoma, pituitary tumor (invasive), plasmacytoma, retinoblastoma, rhabdomyosarcoma, sarcoma (e.g. Ewing's, histiocytic, Jensen's, osteoblastic, reticular cell), schwannoma, subcutaneous tumors, teratocarcinoma (e.g. pluripotent), teratoma, testicular tumors, thymoma and trichoepithelioma, gastric cancer, fibrosarcoma, glioblastoma multiforme tumors, multiple glomus tumors, Li-Fraumeni syndrome, liposarcoma, Lynch cancer family syndrome type II, male germ cell tumors, mast cell leukemia, medullary thyroid, multiple meningiomas, endocrine tumors myxoma, paraganglioma, familial non-pheochromocytoma, capillary hemangioma, papillary, familial and sporadic, rhabdoid-prone syndrome, familial, rhabdoid tumors, soft tissue sarcomas, and Turcot syndrome with glioblastoma.

[0261] In some embodiments of any of the embodiments in this specification 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 (e.g., small cell lung cancer).

[0262] Examples of leukemias that may be treated in the context of 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 lymphoblastic leukemia.

[0263] Examples of lymphomas that may be treated in the context of some embodiments of the invention include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), multiple myeloma, and non-Hodgkin lymphoma. Burkitt's lymphoma is a non-limiting example of a non-Hodgkin lymphoma.

[0264] Various examples of lung cancers that may be treated in the context of some embodiments of the invention include, but are not limited to, large cell lung cancer and small cell lung cancer.

[0265] In some embodiments of any of the embodiments in this specification relating to cancer, the cancer is leukemia, and in some embodiments, it is AML.

[0266] In some embodiments of any of the embodiments herein relating to cancer, the cancer is pancreatic cancer.

[0267] In some embodiments of any of the embodiments in this specification relating to cancer, the cancer is characterized by cells expressing CXCR4. In some such embodiments, one of the compounds described in this specification for treating cancer is used to inhibit SDF-1 and / or CXCR4 activity.

[0268] Without being bound by any particular theory, it is believed that in cancers characterized by expression of CXCR4, SDF-1 and CXCR4 activity are often associated with metastasis and therefore, treatment with an inhibitor of SDF-1 and / or CXCR4 activity is particularly beneficial.

[0269] In some embodiments of any of the embodiments in this specification relating to cancer, the cancer is a resistant cancer. In some embodiments of these embodiments, the cancer is resistant to an anti-angiogenic chemotherapeutic agent (e.g., a taxane (e.g., paclitaxel)). In some embodiments of these embodiments, the cancer is a multi-drug resistant cancer. The drug resistance of the plurality of cancer cells may be acquired resistance (e.g., resistance arising after treatment or repeated treatment) or inherent resistance. In some embodiments of any of the embodiments in this specification relating to cancer, the plurality of cancer cells is resistant to paclitaxel. In some embodiments of these embodiments, the drug resistance is inherent.

[0270] In some embodiments of any of the embodiments in this specification relating to cancer, the plurality of cancer cells are resistant to irinotecan or any other chemotherapeutic agent of the camptothecin family. In some embodiments of these embodiments, the resistance is acquired.

[0271] In some embodiments of any of the embodiments in this specification relating to treatment of cancer, the treatment further comprises administering at least one additional anti-cancer agent (ie, in addition to the compounds described above).

[0272] The additional anticancer agent can be any agent used in the medical field to treat a cancer, and examples of the anticancer agents include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; aclonine; adriamycin; adolesin; aldesleukin; hexamethylmelamine; dimethicone; amitinib acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; aspirin; azacitidine; azatepa; azomycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; binefad dimesylate; bisezole; bleomycin sulfate; buquina sodium; bropiridamine; busulfan; actinomycin; carrusterone; caracetamide; carbetim; carboplatin; carmustine; carrubicin hydrochloride; carzeresin; cedifingol; phenylbutamol Acid mustard; Cilomycin; Cisplatin; Cladribine; Combretastatin A-4 phosphate; Clinatoyl mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Actinomycin D; Daunorubicin hydrochloride; Docetaxel; Dexomaplatin; Dezaguanine; Dezaguanine mesylate; Diazocone; Docetaxel; Doxorubicin; Doxorubicin hydrochloride; Droloxifene; Droloxifene citrate; Methandrostanolone propionate; Dazomycin; Edatrexa; Eflornithine hydrochloride; Elsamirucin; Enloplatin; Enprabamate; Epipiperidine; Epirubicin hydrochloride; Erbulazole; Esorubicin hydrochloride; Estramustine; Estramustine sodium phosphate; Etanidazole; Etoposide; Etoposide phosphate; Chlorpheniramine; Fadrozole hydrochloride; Fazarabine; Retinoic acid phenamide; Floxuridine; Fludarabine phosphate; Fluorouracil; Flucytosine; Fosquinol; Fostrexone sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Imofosine; Interferon 2a; Interferon α-2b; Interferon α-n1; Interferon α-n3; Interferon β-1a; Interferon γ-1b; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprorelin acetate; Lirazo; Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Maprocol; Maytansine; Megestrol acetate hydrochloride; Megestrol acetate; Melengestrol acetate; Phenylalanine mustard; Melogrit; Mercaptopurine; Methotrexate; Methotrexate sodium; Tetramethylurethaneimide; Metodepa; Mitochondramide; Mitokacin; Mitochondrone; Mitomycin; Mitomycin; Mitomycin; Mitomycin mitopamectin; mitotane; mitoxantrone hydrochloride; mycophenolic acid; locodazole; nogaramycin; ormaplatin; sulfenylpyridine; paclitaxel; asparaginase; pelimycin; pentamidine nitrogen mustard; peliomycin sulfate; pipefosfamide; piperobroman; pipebosufan; bisantron hydrochloride; plicamycin; plomestane; porfimer sodium; porfimicin; phenyl mustard; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazolomycin; lipoadenosine; lotramide; safenol; safenol hydrochloride; methyl nitrosourea; bisoprolol; sodium phosphoacetyl aspartate; sparse mycin; spirogermanium hydrochloride; spirochlorine mustard; cis-spiroplatin; streptozotocin; streptozotocin; sulfenyl urea; talismycin; tecogalan sodium; fluridine; tiloxantrone hydrochloride; temoporfin; teniposide; tarosirone;Testolactone; Thiamiprine; Thioguanine; Temozolomide; Temozolomide; Thiotepa; Thiazofurine; Tirapazamine; Toremifene citrate; Methylnandrolone; Triciribine phosphate; Trimethoate; Trimetrexate glucuronate; Triptorelin; Tobradazole hydrochloride; Uracil mustard; Uredepa; Vapreotide; Verteporfin; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vinblastine amide; Vindesine; Vindesine sulfate; Vinpitidine sulfate; Vincoside sulfate; Vinblastine sulfate epoxy; Vinorelbine tartrate; Isovinblastine sulfate; Vinmustine sulfate; Vorozole; Ziniratine; Neocarcinomatine; Zorubicin hydrochloride. Additional anticancer agents include those disclosed in Chapter 52, Antineoplastic Agents (Paul Calabresi and Bruce A. Chabner) with its introduction, 1202 to 1263, and Goodman and Gilman, "The Pharmacological Basis of Therapeutics", 8th edition, 1990 McGraw-Hill Companies (Health Professions Division), the contents of which are incorporated herein by reference.;

[0273] In some embodiments of any of the embodiments described herein, the additional anticancer agent is characterized in that resistance of multiple cancer cells to the agent is associated with the activity of SDF-1 and / or CXCR4. In some such embodiments, the compound used in combination with the additional anticancer agent is any one of the compounds described herein.

[0274] In some embodiments of any of the embodiments described in the specification, the at least one additional anticancer agent comprises combretastatin A-4 phosphate, orabulin, and / or any other derivative of combretastatin.

[0275] Without being bound by any particular theory, it is believed that SDF-1 / CXCR4 activity reduces the anti-therapeutic effects of combretastatin derivatives such as combretastatin A-4 phosphate and orabulin.

[0276] In some embodiments of any of the embodiments described in this specification, the small molecule compound of this embodiment and the at least one additional anticancer agent act synergistically.

[0277] "Synergism" means that when two agents are contacted with cancer cells together, the therapeutic activity is greater than the additive activity of each agent alone. In some embodiments, the therapeutic activity is a reduction in the number of viable cells, and in some embodiments, the therapeutic activity is an inhibition of cell growth, as described herein.

[0278] Synergy can be determined by methods known in the art. In some embodiments, synergy is determined by contour plots, as widely described in the art.

[0279] When two agents act synergistically, combination therapy with these agents allows the use of lower amounts of at least one of the agents. This is particularly useful when treatment with anticancer agents is known to induce acquired drug resistance.

[0280] According to any of the embodiments described in the context of cancer treatment in this specification, a combination therapy is provided, which comprises administering a small molecule compound according to the embodiments of the present invention and at least one additional anti-cancer agent to an individual in need thereof.

[0281] In some of these embodiments, at least one additional anti-cancer agent is administered at a subtherapeutic dose, ie, at a dose less than its therapeutically effective amount (eg, as described herein and / or in the art relating to the anti-cancer agent).

[0282] The two agents may be administered sequentially, in any order, or simultaneously, and may optionally be formulated in the same pharmaceutical composition.

[0283] In some embodiments of any of the embodiments described in the specification, the additional anticancer agent is irinotecan.

[0284] Various noncancerous hyperproliferative disorders:

[0285] In some embodiments of any of the embodiments described herein, a small molecule compound according to this embodiment is used to treat a non-cancerous hyperproliferative disease.

[0286] In some embodiments of any of the embodiments described herein, a method for treating a non-cancerous hyperproliferative disease is provided, the method comprising administering a therapeutically effective amount of a small molecule compound as described herein to an individual in need thereof (an individual suffering from the disease, an individual suffering from symptoms associated with the disease, an individual diagnosed with the disease, or an individual suspected of having the disease).

[0287] In some embodiments of the embodiments described in this specification, the small molecule compound according to this embodiment is used to manufacture a drug for treating a non-cancerous hyperproliferative disease.

[0288] Non-cancerous hyperproliferative diseases, also known as "non-neoplastic proliferative diseases" and "non-cancerous proliferative diseases," refer to the onset or progression of a disease or condition associated with the proliferation of non-malignant cells. Various 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 cirrhosis. Various inflammatory diseases and conditions:

[0289] In some embodiments of any of the embodiments described herein, a small molecule compound according to this embodiment is used to treat an inflammatory disease or disorder in a subject in need thereof.

[0290] In some embodiments of any of the embodiments described in this specification, a method for treating an inflammatory disease and condition is provided, the method comprising administering a therapeutically effective amount of a small molecule compound as described herein to an individual in need thereof (an individual suffering from the disease, an individual suffering from symptoms associated with the disease, an individual diagnosed with the disease, or an individual suspected of suffering from the disease).

[0291] In some embodiments of the embodiments described in this specification, the small molecule compound according to this embodiment is used to manufacture a drug for treating inflammatory diseases or disorders.

[0292] Multiple inflammatory diseases and conditions generally include multiple diseases and conditions associated with inflammation.

[0293] As used herein, the term "inflammation" is a general term that refers to the local accumulation of fluids, plasma proteins, and leukocytes caused by physical injury, infection, or a local immune response. Inflammation may be associated with a number of signs, such as redness, pain, fever, swelling, and / or loss of function. Inflammation is an aspect of many diseases and conditions, including, but not limited to, diseases associated with immune disorders, viral and bacterial infections, arthritis, autoimmune diseases, collagen diseases, allergies, asthma, hay fever, and atopic allergies (e.g., described in further detail below).

[0294] Thus, inflammation can be triggered by injury, such as damage to the skin, muscles, tendons, or nerves. Inflammation can be triggered as part of an immune response, such as a pathological autoimmune response. Inflammation can also be triggered by infection, where pathogen recognition and tissue damage can trigger an inflammatory response at the site of infection.

[0295] Inflammation according to the present teachings can be associated with a number of chronic (long-term) inflammatory diseases or conditions or a number of acute (short-term) inflammatory diseases or conditions.

[0296] According to a specific embodiment, the inflammation is associated with a disease selected from the group consisting of infectious diseases, autoimmune diseases, allergy-related inflammation, transplant rejection and injury.

[0297] According to a specific embodiment, the inflammation comprises skin inflammation.

[0298] According to a specific embodiment, the skin inflammation is psoriasis.

[0299] Diseases characterized by inflammation of the skin include, but are not limited to, dermatitis, atopic dermatitis (eczema, atopy), contact dermatitis, dermatitis herpetiformis, systemic exfoliative dermatitis, seborrheic dermatitis, drug eruptions, erythema multiforme, erythema nodosum, granuloma annulare, poison ivy, poison oak, toxic epidermal necrolysis, rosacea, psoriasis, and acne. Inflammation may also be caused by physical trauma to the skin.

[0300] Inflammation may be caused by various injuries to multiple muscles, tendons, or nerves. Thus, for example, inflammation may be caused by repetitive movement of a part of the body, i.e., repetitive strain injury (RSI). Diseases characterized by inflammation caused by repetitive strain injury include, but are not limited to, bursitis, carpal tunnel syndrome, Dupultrehn's contracture, epicondylitis (e.g., tennis elbow), ganglion (i.e., inflammation in a cyst that forms in a tendon sheath, which usually occurs in the wrist), rotator cuff syndrome, tendinitis (e.g., Achilles tendinitis), tenosynovitis, and trigger finger (multiple tenosynovitis of multiple fingers or thumbs with tendon swelling).

[0301] Many diseases associated with multiple infectious diseases include multiple inflammatory responses, which are usually part of the innate immune system triggered by invading pathogens. Inflammation can also be triggered by infection caused by physical (mechanical) damage to cells and tissues. Multiple examples of multiple infectious diseases include, but are not limited to: chronic infectious diseases, subacute infectious diseases, acute infectious diseases, viral diseases, bacterial diseases, protozoan diseases, parasitic diseases, fungal diseases, mycoplasmosis and prion diseases. According to one embodiment, multiple examples of infections characterized by inflammation include, but are not limited to: encephalitis, meningitis, encephalomyelitis, viral gastroenteritis and viral hepatitis.

[0302] In addition, many immune diseases involve acute or chronic inflammation. For example, arthritis is considered an immune disorder characterized by arthritis, but arthritis is also considered an inflammatory disorder characterized by an immune attack on joint tissue.

[0303] Inflammation according to the present teachings may be associated with a deficient immune response (e.g., human immunodeficiency virus, acquired immunodeficiency syndrome (AIDS)) or an overactive immune response (e.g., allergies, autoimmune diseases). Thus, inflammation according to the present teachings may be associated with any of the following:

[0304] Several inflammatory diseases associated with allergies:

[0305] Examples of hypersensitivity reactions 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 delayed-type hypersensitivity (DTH).

[0306] Type I or immediate hypersensitivity reactions, such as asthma.

[0307] Type II hypersensitivity reactions include, but are not limited to, rheumatoid diseases, rheumatoid autoimmune diseases, rheumatoid arthritis (Krenn V. et al., Histol Histopathol 2000 July; 15(3): 791), spondylitis, ankylosing spondylitis (Jan Voswinkel et al., Arthritis Res 2001; 3(3): 189), systemic diseases, systemic autoimmune diseases, systemic lupus erythematosus (Erikson J. et al., Immunol Res 1998; 17(1-2): 49), sclerosis, systemic sclerosis (Renaudineau Y et al., Clin Diagn Lab Immunol 1999 March; 6(2): 156); Chan OT et al., Immunol Reviews 1999; 6(3): 157; 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, Graves' disease (Orgiazzi J. Endocrinol Metab Clin North Am 2000 Jun;29(2):339), thyroiditis, spontaneous autoimmune thyroiditis (Braley-Mullen H. and Yu S. J Immunol 2000 Dec 15;165(12):7262), Hashimoto's thyroiditis (Toyoda N. et al. Nippon Clin 2000 Jun;29(2):134-135), Rinsho 1999 Aug;57(8):1810), myxedema, idiopathic myxedema (Mitsuma T. Nippon Rinsho 1999 Aug;57(8):1759); autoimmune reproductive diseases, ovarian diseases, ovarian autoimmunity (Garza KM. et al. J Reprod Immunol 1998 Feb;37(2):87), autoimmune antisperm infertility (Diekman AB. et al. Am J Reprod Immunol 2000 Mar;43(3):134), recurrent fetal loss (Tincani A. et al.et al., Lupus 1998;7 Suppl 2:S107-9), neurodegenerative diseases, neurological diseases, neurological autoimmune diseases, multiple sclerosis (Cross AH et al., J Neuroimmunol 2001 Jan 1;112(1-2):1), Alzheimer's disease (Oron L. et al., J Neural Transm Suppl: 1997;49:77), myasthenia gravis (Infante AJ. and Kraig E, Int Rev Immunol 1999;18(1-2):83), motor neuron disease (Kornberg AJ. J Clin Neurosci. 2000 May;7(3):191), Guillain-Barré syndrome, neurological diseases and autoimmune neuropathies (Kusunoki S. Am J Med 1998;11(1-2):191), J Med Sci. 2000 Apr;319(4):234), myasthenic diseases, Lambert syndrome (Takamori M. Am J Med Sci. 2000 Apr;319(4):204), paraneoplastic nervous system diseases, cerebellar atrophy, paraneoplastic cerebellar atrophy, non-paraneoplastic rigid syndrome, cerebellar atrophy, progressive cerebellar atrophy, encephalitis, Rasmussen encephalitis, amyotrophic lateral sclerosis, Sindenn's chorea, Gilles-Doura-Tourette syndrome, polyendocrinopathy, autoimmune polyendocrinopathy (Antoine JC. and Honnorat J. Rev Neurol (Paris) 2000 Jan;156(1):23); neuropathy, neuropathy neuropathy (Nobile-Orazio E. et al. Electroencephalogr Clin Neurophysiol Suppl 1999;50:419); neuromyotonia, acquired neuromyotonia, multiple congenital arthropathy (Vincent A. et al., Annals of the New York Academy of Sciences (Ann N Y 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, Wegener's granulomatosis, arteritis, Takayasu's arteritis, and Kawasaki syndrome (Praprotnik S.et al., Wien Klin Wochenschr. 2000 Aug 25;112(15-16):660); autoimmune diseases due to anticoagulation factor VIII (Lacroix-Desmazes S. et al., Semin Thromb Hemost. 2000;26(2):157); vasculitis, necrotizing small vessel vasculitis, microscopic polyangiitis, Churg-Strauss syndrome, glomerulonephritis, Paxil immune focal necrotizing glomerulonephritis, crescentic glomerulonephritis (Noel LH. Ann Med Interne (Paris) 2000 May;151(3):178); antiphospholipid syndrome (Flamholz R. et al., J Clin Isolates. 2000;26(2):157); =Apheresis 1999;14(4):171); heart failure, agonist-like beta-adrenergic receptor antibodies in 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); hemolytic anemia, autoimmune hemolytic anemia (Efremov DG. et al., Leuk Lymphoma 1998 Jan;28(3-4):285), gastrointestinal diseases, gastrointestinal autoimmune diseases, intestinal diseases, chronic inflammatory bowel disease (Garcia Herola A. et al., Gastroenterol Hepatol. 1998 Jun;28(3-4):285); Hepatol. 2000 Jun;23(1):16), celiac disease (Landau YE. and Shoenfeld Y. Harefuah 2000 Jan 16;138(2):122), autoimmune diseases of muscle tissue, myositis, autoimmune myositis, Sjögren's syndrome (Feist E. et al., Int Arch Allergy Immunol 2000 Sep;123(1):92), smooth muscle autoimmune diseases (Zauli D. et al., Biomed Pharmacother 1999 Jun;53(5-6):234), liver diseases, autoimmune liver diseases, autoimmune hepatitis (Manns MP. J Hepatol 2000 Aug;33(2):326) and primary biliary cirrhosis (Strassburg CP.et al., Eur J Gastroenterol Hepatol. 1999 Jun;ll(6):595).

[0308] Type IV hypersensitivity reactions or T cell-mediated hypersensitivity reactions include, but are not limited to: rheumatoid diseases, rheumatoid arthritis (Tisch R, McDevitt HO. Proc Natl Acad Sci USA 1994 Jan 18;91(2):437), systemic diseases, systemic autoimmune diseases, systemic lupus erythematosus (Datta SK., Lupus 1998;7(9):591), glandular diseases, glandular autoimmune diseases, pancreatic diseases, pancreatic autoimmune diseases, type I 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 et al., Mol Cell Endocrinol 1993 Mar;92(1):77); 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), nervous system diseases, autoimmune nervous system diseases, multiple sclerosis, neuritis, optic neuritis (Soderstrom M. et al., J Neurol Neurosurg Psychiatry 1994 May;57(5):544), myasthenia gravis (Oshima M. et al., Eur J Immunol 1994 Mar;57(5):544), Immunol 1990 Dec;20(12):2563), stiffness syndrome (Hiemstra HS. et al., Proc Natl Acad Sci USA 2001 Mar 27;98(7):3988), cardiovascular disease, cardiac autoimmunity in Chagas disease (Cunha-Neto E. et al., J Clin Invest 1996 Oct 15;98(8):1709), autoimmune thrombocytopenic purpura (Semple JW. et al., Blood 1996 May 15;87(10):4245), anti-helper T lymphocyte autoimmunity (Caporossi AP.et al., Viral Immunol 1998; 11(1): 9), hemolytic anemia (Sallah S. et al., Ann Hematol 1997 March; 74(3): 139), liver disease, autoimmune liver disease, hepatitis, chronic active hepatitis (Franco A. et al., Clin Immunol Immunopathol 1990 March; 54(3): 382), biliary cirrhosis, primary biliary cirrhosis clinical science (Jones DE. Clin Sci (Colchester) 1996 November; 91(5): 551), kidney disease, renal autoimmune disease, nephritis, interstitial nephritis (Kelly CJ. Journal of the American Society of Nephrology (JNS) 1996 November; 91(5): 551), Am Soc Nephrol 1990 Aug; 1(2): 140), connective tissue diseases, ear diseases, autoimmune connective tissue diseases, autoimmune ear diseases (Yoo TJ. et al., Cell Immunol 1994 Aug; 157(1): 249), inner ear diseases (Gloddek B. et al., Ann NY Acad Sci 1997 Dec 29; 830: 266), skin diseases, cutaneous diseases, dermal diseases, bullous skin diseases, pemphigus vulgaris, bullous pemphigoid, and pemphigus. .

[0309] Examples of delayed hypersensitivity reactions include, but are not limited to, contact dermatitis and drug eruptions.

[0310] Examples of types of T lymphocyte-mediated hypersensitivity reactions include, but are not limited to, helper T lymphocytes and cytotoxic T lymphocytes.

[0311] Examples of hypersensitivity reactions mediated by helper T lymphocytes include, but are not limited to, type 1 helper T cells (T h 1) Lymphocyte-mediated hypersensitivity reactions and type 2 helper T cells (T h 2) Lymphocyte-mediated hypersensitivity reaction.

[0312] According to a specific embodiment, the eye disease is age-related macular degeneration (AMD).

[0313] According to a specific embodiment, the age-related macular degeneration (AMD) is atrophic, non-neovascular (aAMD).

[0314] According to a specific embodiment, the age-related macular degeneration (AMD) is neovascular.

[0315] Multiple autoimmune diseases:

[0316] Multiple 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.

[0317] Examples of multiple 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, anti-factor VIII autoimmune disease (Lacroix-Desmazes S. et al., Semin Thrombosis et Hemostasis) Hemost. 2000;26(2):157, necrotizing vasculitis, microscopic polyangiitis, Churg-Strauss syndrome, immune focal necrotizing and crescentic glomerulonephritis (Noel LH. Ann Med Interne (Paris) 2000 May;151(3):178, antiphospholipid syndrome (Flamholz R. et al. J Clin Apheresis 1999;14(4):171, antibody-induced heart failure (Wallukat G. et al. Am J Cardiol. 1999 Jun 17;83(12A):75H, thrombocytopenic purpura (Moccia F. Ann Ital Med Int. 1999 Apr-Jun;14(2):114; Semple JW. et al., Blood 1996 May 15;87(10):4245, autoimmune hemolytic anemia (Efremov DG. et al., Leuk Lymphoma 1998 Jan;28(3-4):285; Sallah S. et al., Ann Hematol 1997 Mar;74(3):139, cardiac autoimmunity in Chagas disease (Cunha-Neto E. et al., J Clin Invest 1996 Oct 15;98(8):1709), and anti-helper T lymphocyte autoimmunity (Caporossi AP. et al., Viral Immunol 1998;11(1):9).

[0318] Examples of multiple 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 USA 1994 Jan 18;91(2):437) and ankylosing spondylitis (Jan Voswinkel et al. Arthritis Res 2001;3(3):189).

[0319] Examples of multiple autoimmune glandular diseases include, but are not limited to, pancreatic disease, type 1 diabetes, thyroid disease, Graves' disease, thyroiditis, spontaneous autoimmune thyroiditis, Hashimoto's thyroiditis, idiopathic myxedema, ovarian autoimmunity, autoimmune antisperm infertility, autoimmune prostatitis, and type 1 autoimmune polyglandular syndrome, diseases 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. Endocrinol 1993 Mar;92(1):77), spontaneous autoimmune thyroiditis (Braley-Mullen H. and Yu S, Eur J Immunol 2000 Dec 15;165(12):72-62), 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 1998 Feb;37(2):87), 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).

[0320] 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.

[0321] Examples of autoimmune skin diseases include, but are not limited to, autoimmune bullous skin diseases such as, but not limited to, pemphigus vulgaris, bullous pemphigoid, and pemphigus foliaceus.

[0322] 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 (Colchester) 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).

[0323] 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. J Clin Neurosci. 2000 May; 7(3): 191); Guillain-Barré syndrome and autoimmune neuropathies (Kusunoki S. Am J Med 1997; 35(4): 194). J Med Sci. 2000 Apr;319(4):234), myasthenic diseases, Lambert syndrome (Takamori M. Am J Med Sci. 2000 Apr;319(4):204); paraneoplastic neurological diseases, cerebellar atrophy, paraneoplastic cerebellar atrophy, and rigid syndrome (Hiemstra HS et al. Proc Natl Acad Sci USA 2001 Mar 27;98(7):3988); non-paraneoplastic rigid syndrome, progressive cerebellar atrophy, encephalitis, Rasmussen encephalitis, amyotrophic lateral sclerosis, Sindenn's chorea, Gilles-Dora-Tourette syndrome, and autoimmune polyendocrinopathy (Antoine JC and Honnorat J. Rev Neurology 2001 Mar;27;98(7):3988). Neurol (Paris) January 2000; 156(1): 23); immune neuropathies (Nobile-Orazio E. et al., Electroencephalogr Clin Neurophysiol Suppl. 1999; 50: 419); acquired neuromyotonia, arthropathy congenital (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.

[0324] Examples of autoimmune muscle diseases include, but are not limited to, myositis, autoimmune myositis, and primary Sjögren's syndrome (Feist E. et al., Int Arch Allergy Immunol 2000 Sep;123(1):92) and smooth muscle autoimmune diseases (Zauli D. et al., Biomed Pharmacother 1999 Jun;53(5-6):234).

[0325] Examples of various autoimmune renal diseases include, but are not limited to, nephritis and autoimmune interstitial nephritis (Kelly CJ. J Am Soc Nephrol 1990 Aug;1(2):140).

[0326] Examples of various autoimmune diseases associated with reproduction include, but are not limited to, repetitive fetal loss (Tincani A. et al., Lupus 1998;7 Suppl 2:S107-9).

[0327] Several 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).

[0328] Examples of autoimmune systemic diseases include, but are not limited to, systemic lupus erythematosus (Erikson J. et al., Immunol Res 1998; 17(1-2): 49) and systemic sclerosis (Renaudineau Y. et al., Clin Diagn Lab Immunol 1999 Mar; 6(2): 156); Chan OT. et al., Immunol Rev 1999 Jun; 169: 107).

[0329] According to one embodiment, the autoimmune disease is Crohn's disease, psoriasis, scleroderma or rheumatoid arthritis.

[0330] Multiple transplant rejection disorders:

[0331] Examples of various diseases associated with graft transplantation 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.

[0332] Multiple allergic diseases:

[0333] Examples of allergic diseases include, but are not limited to, asthma, hives, urticarial, pollen allergy, dust mite allergy, venom allergy, cosmetic allergy, latex allergy, chemical allergy, drug allergy, insect bite allergy, animal dander allergy, stinging plant allergy, poison ivy allergy, and food allergies.

[0334] Other applications:

[0335] According to any aspect of the embodiments of the invention described herein, the compounds 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.

[0336] Exemplary such medical devices include stents, catheters, endotracheal tubes, tubing, prostheses, medical implants, artificial joints, artificial valves, needles, venous access devices, cannulas, biliary stents, nephrostomy tubes, vascular grafts, infusion pumps, adhesive patches, sutures, meshes, surgical tools or instruments, intubation devices, cardiovascular stents, cardiac surgical devices, orthopedic surgical devices, orthodontic or periodontal devices, dental surgical devices, veterinary surgical devices, bone scaffolds, hemodialysis tubing or equipment, blood exchange devices, implantable prostheses, heart valves, ophthalmic devices, and breast implants.

[0337] According to some embodiments of the present invention, the medical device is an implantable device, such as a stent, an indwelling catheter, or an endotracheal tube.

[0338] Catheters include, for example, urinary catheters, central venous catheters, biliary catheters, pulmonary artery catheters, peripheral venous catheters, arterial catheters, central venous catheters, peritoneal catheters, epidural catheters, and central nervous system catheters.

[0339] The implantable device may be a permanent or temporary implantable device.

[0340] Any commercially available or custom medical decision, such as the implantable devices described herein, is contemplated.

[0341] According to some embodiments of the present invention, there is provided a medical device as described herein, the medical device having a compound as described herein in any corresponding embodiment associated with at least a portion of the medical device. In some embodiments, the compound is deposited on at least a portion of the outer surface of the medical device (e.g., coated).

[0342] The compound may be directly associated with the device, for example, by being included within or absorbed into a material forming the device (e.g., being mixed or absorbed into a polymeric material from the device). Alternatively, or in addition, the compound may be deposited on the outer surface of the device via a polymeric film or any other coating material that contains or absorbs the compound.

[0343] Multiple pharmaceutical compositions:

[0344] The compounds described in this specification according to any aspect of the embodiments of the invention may be used (eg, administered to a subject) by themselves or in a pharmaceutical composition, wherein the compounds are mixed with suitable carriers or excipients.

[0345] As used in this specification, a "pharmaceutical composition" refers to a preparation of one or more compounds according to any embodiment described in this specification including other chemical components (e.g., a plurality of physiologically suitable carriers and excipients), the purpose of which is to facilitate the administration of a compound to an organism.

[0346] Hereinafter, the phrases "physiologically acceptable carrier" and "pharmaceutically acceptable carrier" are used interchangeably to refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. These phrases include an adjuvant.

[0347] The term "excipient" as used herein refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of an active ingredient. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0348] When the compound is used by itself or in a pharmaceutically acceptable composition, the compound by itself (i.e., excluding the weight of multiple carriers or multiple excipients formulated with the compound as described in the specification) is optionally at least 80% pure (by dry weight), optionally at least 90% pure (by dry weight), optionally at least 95% pure (by dry weight), optionally at least 98% pure (by dry weight), and optionally at least 99% pure (by dry weight). Purity can be increased by any suitable technique known in the art, such as by removing multiple impurities associated with the synthesis of the compound or isolating the compound from a natural source. A variety of techniques for formulating and administering various drugs can be found in "Remington's Pharmaceutical Sciences", the latest edition of Mack Publishing Company, Easton, Pennsylvania, which is incorporated into the specification by reference.

[0349] A variety of suitable routes of administration may include, for example, oral, rectal, transmucosal, particularly nasal, enteral or parenteral administration, including intramuscular, subcutaneous and intramedullary injections, as well as intrathecal, directly intraventricular, intracardial, for example into the right or left ventricular cavity, into the coronary arteries, intravenous, intraperitoneal, intranasal or intraocular injections.

[0350] Alternatively, the pharmaceutical composition may be administered in a local rather than systemic manner, for example, by injecting the pharmaceutical composition directly into a tissue area of ​​a patient.

[0351] The term "tissue" refers to a part of an organism composed of multiple cells designed to perform one or more 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, hematopoietic tissue.

[0352] The pharmaceutical compositions of some embodiments of the present invention can be prepared by various methods well known in the art, for example, by conventional mixing, dissolving, granulating, sugar-coating, grinding, emulsifying, encapsulating, embedding or lyophilizing methods.

[0353] Thus, the multiple pharmaceutical compositions used according to some embodiments of the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, which include multiple excipients and multiple auxiliaries, which facilitate processing of the multiple active ingredients into multiple preparations that can be used pharmaceutically, the appropriate formulation depending on the selected route of administration.

[0354] For injection, the active ingredients of the pharmaceutical composition can be formulated in aqueous solutions, preferably in physiologically compatible buffers, such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation, such penetrants being generally known in the art.

[0355] For oral administration, the pharmaceutical composition can be easily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art, such carriers enabling the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a patient. Pharmaceutical preparations for oral use can be prepared using a solid excipient, optionally grinding the resulting mixture, and, if necessary, processing the granular mixture after adding suitable auxiliaries to obtain tablets or dragee cores. Suitable excipients are in particular fillers such as sugars, including: lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as: corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; and / or physiologically acceptable polymers, such as: polyvinylpyrrolidone (PVP). If desired, multiple disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0356] Dragee cores are provided with suitable coatings, for which purpose concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0357] A plurality of pharmaceutical compositions for oral use include push-fit capsules made of gelatin and a plurality of soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the plurality of active ingredients blended with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and optionally a plurality of stabilizers. In a plurality of soft capsules, the plurality of active ingredients may be dissolved or suspended in a plurality of suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycol. In addition, a plurality of stabilizers may be added. All formulations for oral administration should be a plurality of doses suitable for the selected route of administration.

[0358] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0359] For administration by nasal inhalation, the active ingredients used in accordance with some embodiments of the present invention can be conveniently delivered in the form of an aerosol spray from a pressurized pack or a nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, a dosage unit can be determined by providing a valve to deliver a metered amount. For example, gel capsules and gel columns, for example, made of gelatin, for use in a dispenser can be formulated as a powder mix containing the compound of the invention and a suitable powder base, for example, lactose or starch.

[0360] The pharmaceutical compositions described herein can be formulated for parenteral administration, e.g., by push injection or continuous infusion. Multiple formulations for injection can be in the form of unit doses, e.g., in multiple ampoules or in multiple multi-dose containers. Optionally, there is an added preservative. The multiple compositions can be suspensions, solutions, or emulsions in oily or aqueous carriers, and can contain preparatants, e.g., suspending agents, stabilizers, and / or dispersants.

[0361] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in a water-soluble form. Additionally, suspensions of the active ingredients may be prepared into suitable oily or water-based injection suspensions, with suitable lipophilic solvents or carriers including fatty oils, such as sesame oil or synthetic fatty acid esters, such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may include substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also include suitable stabilizers or agents that increase the solubility of the active ingredient to prepare high concentration solutions.

[0362] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, a sterile, pyrogen-free water based solution, before use.

[0363] The pharmaceutical compositions of some embodiments of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, for example, conventional suppository bases such as cocoa butter or other glycerides.

[0364] Pharmaceutical compositions suitable for use in the context of some embodiments of the present invention include compositions comprising an effective amount of the active ingredient to achieve the intended purpose. More specifically, a therapeutically effective amount refers to an amount of the active ingredient(s) that is effective in preventing, alleviating or ameliorating the symptoms of a disease (e.g., cancer or metastatic cancer) or prolonging the survival of the individual being treated.

[0365] Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0366] For any formulation used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from in vitro and cell culture assays. For example, a dose can be formulated in animal models to achieve a desired concentration or titer, and this information can be used to more accurately determine useful doses in humans.

[0367] The toxicity and therapeutic efficacy of the multiple active ingredients described in this specification can be determined by multiple standard pharmaceutical methods in test tubes, multiple cell cultures or multiple experimental animals. The data obtained from these in vitro and multiple cell culture assays and multiple animal studies can be used to formulate a series of doses for humans. The dosage can vary depending on the dosage form used and the route of administration used, and the exact formulation, route of administration and dosage can be selected by each physician according to the patient's condition (see, for example: Fingl et al. (1975), "The Pharmacological Basis of Therapeutics", Chapter 1, page 1).

[0368] Dosage and interval can be adjusted individually to provide multiple inhibition levels of the protein (e.g., SDF-1 and / or CXCR4) of the active ingredient sufficient to induce or inhibit a biological effect (minimum effective concentration, MEC). The MEC will vary for each formulation, but can be estimated from in vitro data, for example, based on the results on chemokine-induced (e.g., SDF-1-induced) migration inhibition described in this specification. Multiple doses required to achieve the MEC depend on multiple individual characteristics and the route of administration, and multiple assays can be used to determine multiple plasma concentrations.

[0369] In some embodiments of any of the embodiments described in this specification, an effective amount of the compound is less than 100 micromolar. In some embodiments, an effective amount is less than 10 micromolar. In some embodiments, an effective amount is less than 5 micromolar. In some embodiments, an effective amount is less than 1 micromolar. In some embodiments, an effective amount is less than 0.5 micromolar. In some embodiments, an effective amount is less than 0.1 micromolar.

[0370] In some embodiments of any of the embodiments described in this specification, an effective amount is at least 100% of the IC50 of the compound for a chemokine that tends to be inhibited (e.g., SDF-1). In some embodiments, an effective amount is at least 200% of the IC50 of the compound for a chemokine. In some embodiments, an effective amount is at least 300% of the IC50 of the compound for a chemokine. In some embodiments, an effective amount is at least 500% of the IC50 of the compound for a chemokine. In some embodiments, an effective amount is at least 1000% of the IC50 of the compound for a chemokine.

[0371] In some embodiments of any of the embodiments described in this specification, an effective amount is at least 100% of the IC50 of the compound for inducing cell death of multiple cancer cells to be inhibited. In some embodiments, an effective amount is at least 200% of the IC50 of the compound for the multiple cancer cells. In some embodiments, an effective amount is at least 300% of the IC50 of the compound for the multiple cancer cells.

[0372] Depending on the severity and responsiveness of the condition to be treated, administration may be single or multiple administrations, with the course of treatment lasting from several days to several weeks or until a cure is achieved or a diminution of the disease state is achieved.

[0373] The amount of the composition administered will, of course, be dependent upon the individual being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, and the like.

[0374] If desired, multiple compositions of some embodiments of the present invention may be present in a package or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, include metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by multiple administration instructions. The package or dispenser may also include a notice associated with the container, the form of which is prescribed by a government agency that manages the manufacture, use or sale of multiple drugs, and the notice reflects the form of administration of the composition or human or animal approved by the agency. For example, such a notice may be a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Multiple compositions formulated in a formulation of the present invention in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, as further described in detail in this specification, and labeled for treatment of a specified condition.

[0375] It is to be understood that the various compounds described in this specification may be provided alone or in combination with other active ingredients that are well known in the art for the relief of medical conditions.

[0376] Thus, for example, the compounds may be administered together with an immunomodulator, either in a common formulation or in a separate formulation.

[0377] According to one embodiment, cancer (and other hyperproliferative diseases) is treated in combination with an anti-cancer immunomodulatory agent.

[0378] As used herein, the term "anti-cancer immunomodulator" refers to an agent that can induce an immune response against a cancer cell, the immune response (eg, T cells, NK cells).

[0379] According to a specific embodiment, the agent is selected from cancer antigens, cancer vaccines, anti-cancer antibodies, a cytokine capable of inducing T cell activation and / or proliferation, and an immune checkpoint regulator.

[0380] Alternatively or additionally, such modulators may be immunostimulatory agents, for example immune checkpoint modulators, which are of particular value in cancer treatment.

[0381] As used herein, the term "immune checkpoint regulator" refers to a molecule that regulates the activity of one or more immune checkpoint proteins in an agonistic or antagonistic manner to lead to the activation of an immune cell.

[0382] As used in this specification, the term "immune checkpoint protein" refers to a protein that regulates the activation or function of immune cells. Multiple immune checkpoint proteins can be co-stimulatory proteins (i.e., transmitting a stimulatory signal, resulting in the activation of an immune cell) or multiple inhibitory proteins (i.e., transmitting an inhibitory signal, resulting in the inhibition of the activity of an immune cell). According to a specific embodiment, the immune checkpoint protein regulates the activation or function of a T cell. Many 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).

[0383] According to a specific embodiment, the immune checkpoint regulator is selected from anti-CTLA4, anti-PD-1 and CD40 agonist.

[0384] According to a specific embodiment, the immune checkpoint regulator is selected from anti-CTLA4, anti-PD-1, anti-PDL-1, CD40 agonist, 4-IBB agonist, GITR agonist and OX40 agonist.

[0385] CTLA4 is a member of the immunoglobulin superfamily. CTLA4 is expressed on the surface of helper T cells and transmits an inhibitory signal to multiple T cells when the ligand binds. As used in this specification, the term "anti-CTLA4" refers to an antagonist molecule that binds to CTLA4 (CD152) and inhibits its inhibitory activity. Therefore, anti-CTLA4 prevents the transmission of the inhibitory signal, thereby acting on a co-stimulatory molecule. According to a specific embodiment, the anti-CDLA4 molecule is an antibody.

[0386] PD-1 (Programmed Death 1) is a member of the extended CD28 / CTLA-4 family of T cell regulatory factors. PD-1 is expressed on the surface of multiple activated T cells, B cells and macrophages, and transmits an inhibitory signal when the ligand binds. As used in this specification, the term "anti-PD1" refers to an antagonist molecule that binds to PD-1 and inhibits its inhibitory activity. Therefore, anti-PD-1 prevents the transmission of the inhibitory signal, thereby acting on a co-stimulatory molecule. According to a specific embodiment, the anti-PD1 molecule is an antibody. Many anti-PD-1 antibodies are known in the art, see, for example, Topalian et al., The New England Journal of Medicine (NEJM) 2012.

[0387] PDL-1 is a ligand of PD-1, and the binding of PDL-1 to its receptor PD-1 transmits an inhibitory signal to cells expressing the PD-1. As used in this specification, the term "anti-PDL-1" refers to an antagonist molecule that inhibits the signal transduction of PD-1 by binding to or inhibiting PD-L1 to avoid the binding and / or activation of PD-1. Therefore, anti-PD-1 prevents the transmission of the inhibitory signal, thereby acting on a co-stimulatory molecule. According to a specific embodiment, 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., The New England Journal of Medicine (NEJM) 2012.

[0388] CD40 (CD154) is a co-stimulatory receptor found on multiple 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), thereby inducing activation of the antigen presenting cell.

[0389] OX40 belongs to the TNF receptor superfamily and leads to the expansion of CD4-positive and CD8-positive T cells. As used herein, the term "OX40 agonist" refers to an agonist molecule that binds to and activates OX40.

[0390] GITR (glucocorticoid-induced tumor necrosis factor receptor) is a surface receptor molecule that has been shown to be involved in inhibiting the suppressive activity of multiple T regulatory cells and prolonging the survival of multiple T effector cells. As used in this specification, the term "GITR agonist" refers to an agonist molecule that binds to and activates GITR. According to a specific embodiment, the GITR agonist is an antibody.

[0391] The compounds may be administered together with an additional anticancer agent as described herein in any corresponding example, either in a common formulation (eg, in the same pharmaceutical composition) or in a separate formulation.

[0392] According to one embodiment, treatment of cancer (and other hyperproliferative diseases) is performed in combination with an additional anticancer agent as described herein in any corresponding embodiment.

[0393] The pharmaceutical compositions as described herein may further comprise any additional pharmaceutical agent as described herein, or be identified for use in combination with any additional pharmaceutical agent as described herein.

[0394] According to another aspect described in the present specification, a kit for treating a condition described in the present specification (e.g., treating cancer or preventing tumor metastasis or treating non-cancerous proliferative diseases or disorders or treating inflammation) is provided, wherein the kit includes a packaging material for packaging the compound described in the present specification.

[0395] In some of these embodiments, the kit further comprises an additional reagent as described herein in any corresponding embodiment, and the two reagents are packaged separately within the kit.

[0396] In some of these embodiments, the kit further comprises instructions for using the compound in any corresponding embodiment in combination with an additional agent (e.g., an additional anti-cancer agent) as described herein.

[0397] In some embodiments, the compound is identified as an inhibitor of an SDF-1 and / or CXCR4 activity associated with the onset or progression of the condition, as described herein.

[0398] In some embodiments, the compounds are identified as inducing apoptosis and / or cell growth arrest associated with the condition, as described herein.

[0399] According to one aspect of some embodiments of the present invention, there is provided a pharmaceutical composition comprising the small molecule compound described herein in any corresponding embodiment, optionally in combination with a pharmaceutically acceptable carrier, and further optionally in combination with other active substances as described in each embodiment.

[0400] According to an aspect of some embodiments of the present invention, there is provided a small molecule compound described in any corresponding embodiment for use as a medicament or in the manufacture of a medicament.

[0401] The medicament may be a pharmaceutical composition as described herein in any of the various embodiments.

[0402] The medicament may be used to treat any of the medical conditions, diseases and / or disorders described herein.

[0403] Multiple definitions:

[0404] As used in this specification, the term "treat" includes eliminating, substantially inhibiting, slowing or reversing the progression of a condition, substantially improving the clinical or aesthetic symptoms of a condition, or substantially preventing the appearance of clinical or aesthetic symptoms of a condition. For example: in the context of preventing metastasis and / or angiogenesis, the term "prevention" refers to stagnation, stopping, inhibiting the process or progression of metastasis and / or angiogenesis and subsequent metastasis and / or angiogenesis.

[0405] As used herein, the term "subject" refers to a mammal (eg, a human), for example, a mammal that has been diagnosed with a disease (eg, cancer) described herein.

[0406] The terms "comprises," "comprising," "includes," "including," "having" and their conjugations mean "including but not limited to."

[0407] The term "consisting of" means "including and not limited to".

[0408] The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and / or components, but only when the additional ingredients, steps and / or components do not substantially change the basic and novel characteristics of the claimed composition, method or structure.

[0409] As used in this specification, the singular forms "a", "an" and "the" may include plural references unless the context clearly indicates otherwise. For example, the term "a compound" or "at least one compound" may include multiple compounds, including mixtures thereof.

[0410] Throughout this application, multiple embodiments of the present invention may be presented in a range format in conjunction with references. It should be understood that the description in range format is only for convenience and brevity and should not be interpreted as a strict limitation on the scope of the present invention. Therefore, the description of the range should be considered to be specifically disclosed all possible sub-ranges and each numerical value within the range, for example: describing a range such as "from 1 to 6" should be understood to disclose multiple sub-ranges such as "from 1 to 3", "from 1 to 4", "from 1 to 5", "from 2 to 4", "from 2 to 6", "from 3 to 6", etc.; also disclose each number within this range, such as: 1, 2, 3, 4, 5 and 6. Regardless of the width of the range, this applies here.

[0411] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integer) within the indicated range. The terms "range between" a first indicated numeral and a second indicated numeral and "range from" a first indicated numeral to a second indicated numeral are interchangeable herein and are meant to include the first and second indicated numerals, and all fractions and integers therebetween.

[0412] The term "method" as used herein refers to manner, means, technique and procedures for accomplishing a particular task, wherein the given task includes but is not limited to those manners, means, techniques and procedures which are known or which are readily developed by practitioners in the chemical, pharmacological, biological, biochemical and medical fields from known manners, means, techniques or procedures.

[0413] In this specification, the term "linking group" describes a group (substituent) that is connected to another part in a compound through two or more of its atoms. In order to distinguish a linking group from a substituent that is connected to another part in a compound through one of its atoms, the latter is referred to as a "terminal group" in this specification.

[0414] As used herein, the term "amine" describes a -NR'R" terminal group as well as a -NR'- linking group, wherein R' and R" are each independently hydrogen, alkyl, cycloalkyl, aryl, as those terms are defined below.

[0415] 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 R' and R' and each R" are independently alkyl, cycloalkyl or aryl.

[0416] Alternatively, R′ and R″ are each independently hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphate, 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, amidino, guanidine, and hydrazine.

[0417] The term "amine" is used in this specification to describe a -NR'R" group where the amine is a terminal group as defined below, and is used in this specification to describe a -NR'- group where the amine is or forms part of a linking group.

[0418] The term "alkyl" describes a saturated aliphatic hydrocarbon, including straight and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms. Any numerical range; for example, in this specification, "1 to 20" represents the group, in which case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. In some embodiments, the alkyl group is a medium-sized alkyl group having 1 to 10 carbon atoms. Unless otherwise specified, the alkyl group is a low alkyl group having 1 to 4 carbon atoms. In some embodiments, the alkyl group has at least 4 carbon atoms, for example: the alkyl group has 4 to 12 or 4 to 10 or 4 to 8 carbon atoms. The alkyl group may be substituted or unsubstituted. The substituted alkyl group may have one or more substituents, wherein each substituent may independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphate, 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, amidino, guanidine and hydrazine.

[0419] The alkyl group may be a terminal group, as defined above in the phrase, wherein the terminal group is connected to a single adjacent atom or a linking group, as defined above in the phrase, wherein the terminal group connects two or more moieties through at least two carbon atoms in its chain. When the alkyl group is a linking group, it is also referred to as "alkylene" in this specification, such as methylene, ethylene, propylene, etc.

[0420] The term "alkenyl" describes an alkyl group as defined in this specification wherein at least one pair of carbon atoms are linked to each other by a double bond.

[0421] The term "alkynyl" or "alkyne" describes an alkyl group as defined in this specification wherein at least one pair of carbon atoms are linked to each other by a triple bond.

[0422] The term "cycloalkyl" describes a group of all-carbon monocyclic or fused rings (i.e., multiple rings that share a pair of adjacent carbon atoms), wherein one or more of the multiple rings do not have a completely conjugated pi electron system, and may be further substituted or unsubstituted. Substituted cycloalkyl groups may have one or more substituents, whereby each substituent may independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphate, 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, amidino, guanidine, and hydrazine. The cycloalkyl group may be a terminal group, the phrase being as defined above, the cycloalkyl group being attached to a single adjacent atom or linking group. The phrase being as defined above, the cycloalkyl group being attached to two or more moieties at two or more positions thereof.

[0423] As used herein, the term "heteroalicyclic" describes a monocyclic or fused ring group having one or more atoms, such as nitrogen, oxygen and sulfur, in the ring(s). The rings may also have one or more double bonds. However, the rings do not have a completely conjugated π electron system, and the heteroalicyclic ring may be substituted or unsubstituted. Substituted heteroalicyclics may have one or more substituents, whereby each substituent may independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphate, hydroxyl, 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, amidino, guanidine and hydrazine. The heteroalicyclic group can be a terminal group, the phrase is as defined above, and the heteroalicyclic group is connected to a single adjacent atom or a linking group. The phrase is as defined above, and the heteroalicyclic group is connected to two or more parts at two or more positions thereof. A plurality of representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino, etc.

[0424] The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (i.e., multiple rings sharing a pair of adjacent carbon atoms) group having a completely conjugated pi electron system. Aryl groups may be substituted or unsubstituted. Substituted aryl groups may have one or more substituents, whereby each substituent may independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphate, 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, amidino, guanidine, and hydrazine. The aryl group may be a terminal group, the phrase being as defined above, the aryl group being attached to a single adjacent atom or linking group. The phrase being as defined above, the aryl group being attached to two or more moieties at two or more positions thereof. Preferably, the aryl group is a phenyl group. Alternatively, the aryl group is a naphthyl group.

[0425] The term "heteroaryl" describes a group having one or more atoms in the ring, such as, for example, nitrogen, oxygen and sulfur, and additionally a monocyclic or fused ring (i.e., multiple rings sharing a pair of adjacent carbon atoms) group having a completely conjugated pi electron system. Examples of heteroaryl groups include, but are not limited to: pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, triazine, tetrazine, quinoline, isoquinoline and purine. The heteroaryl group can be substituted or unsubstituted. The substituted heteroaryl may have one or more substituents, whereby each substituent may be independently, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfinate, sulfate, sulfonate, sulfoxide, phosphate, hydroxyl, 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, amidino, guanidine and hydrazine. The heteroaryl may be a terminal group, the phrase being as defined above, the cycloalkyl being attached to a single adjacent atom or linking group. The phrase being as defined above, the heteroaryl is attached to two or more parts at two or more positions thereof.

[0426] The term "alkaryl" describes an alkyl group as defined in this specification, substituted with one or more aryl or heteroaryl groups. An example of an alkaryl group is benzyl.

[0427] The terms "halide" and "halogen" describe fluorine, chlorine, bromine or iodine.

[0428] The term "haloalkyl" describes an alkyl group as defined above, further substituted with one or more halides.

[0429] The term "sulfate" describes a terminal group of -OS(=O)2-OR', as that term is defined above, or a linking group of -OS(=O)2-O-, as those phrases are defined above, wherein R' is defined above.

[0430] The term "thiosulfate" describes a terminal group of -OS(=S)(=O)-OR' or a linking group of a -OS(=S)(=O)-O- group as these phrases are defined above wherein R' is as defined above.

[0431] The term "sulfite" describes a terminal group of -OS(=O)-O-R' or a linking group of a -OS(=O)-O- group, these phrases being as defined above, wherein R' is as defined above.

[0432] The term "thiosulfite" describes a terminal group of -OS(=S)-O-R' or a linking group of a -OS(=S)-O- group, these phrases being as defined above, wherein R' is as defined above.

[0433] The term "sulfinate" or "sulfinyl" describes a terminal group of -S(=O)-OR' or a linking group of a -S(=O)-O- group, as these phrases are defined above, wherein R' is defined above.

[0434] The term "sulfoxide" describes a -S(=O)R' terminal group or a -S(=O)- linking group, these phrases being as defined above, wherein R' is as defined above.

[0435] The term "sulfonate" or "sulfonyl" describes a terminal group of -S(=O)2-OR' (also referred to herein as -SO3R' or -SO3H) or a linking group of -OS(=O)2-. These phrases are as defined above, wherein R' is as defined above.

[0436] The term "S-sulfonamide" describes a -S(=O)2-NR'R" terminal group or a -S(=O)2-NR'- linking group, as these phrases are defined above, wherein R' and R" are as defined herein.

[0437] The term "N-sulfonamide" describes a R'S(=O)2-NR"-terminal group or a -S(=O)2-NR'-linking group, as these phrases are defined above, wherein R' and R" are as defined in this specification.

[0438] The term "disulfide" refers to an -S-SR' terminal group or a -SS- linking group, as these phrases are defined above, wherein R' is as defined in this specification.

[0439] The term "phosphate" describes a -P(=O)(OR')(OR") terminal group or a -P(=O)(OR')(O)- linking group, as these phrases are defined above, with R' and R" being as defined in this specification.

[0440] The term "phosphorothioate" describes a -P(=S)(OR')(OR") terminal group or a -P(=S)(OR')(O)- linking group, these phrases being as defined above, with R' and R" being as defined in this specification.

[0441] The term "carbonyl" or "carbonate" or "ketone" as used in this specification describes a -C(=O)-R' terminal group or a -C(=O)- linking group, these phrases being defined above and R' being defined in this specification.

[0442] The term "thiocarbonyl" as used herein describes a -C(=S)-R' terminal group or a -C(=S)- linking group, as these phrases are defined above, with R' being as defined herein.

[0443] The term "oxo" as used in this specification describes an a=0 terminal group.

[0444] The term "thioxo" as used in this specification describes an a=S terminal group.

[0445] The term "oxime" describes an a=N-OH terminal group or an a=NO-linking group, these phrases being defined above.

[0446] The term "hydroxy" or "hydroxyl" describes an -OH group.

[0447] The term "alkoxy" describes both -O-alkyl and -O-cycloalkyl groups as defined in this specification.

[0448] The term "aryloxy" describes both -O-aryl and -O-heteroaryl groups as defined in this specification.

[0449] The term "thiol" or "thio" describes a -SH group.

[0450] The term "thioalkoxy" describes an -S-alkyl as well as an -S-cycloalkyl group as defined in this specification.

[0451] The term "thioaryloxy" describes both -S-aryl and -S-heteroaryl groups as defined in this specification.

[0452] The term "cyano" or "nitrile" describes a -C≡N group.

[0453] The term "isocyanate" describes a -N=C=O group.

[0454] The term "nitro" describes a -NO2 group.

[0455] The term "carboxylate" as used in this specification includes C-carboxylates as well as O-carboxylates.

[0456] The term "C-carboxylate" describes a -C(=O)-OR' terminal group or a -C(=O)-O- linking group, these phrases being defined above, wherein R' is as defined herein.

[0457] The term "O-carboxylate" describes a -OC(=O)R' terminal group or a -OC(=O)- linking group, these phrases being defined above, wherein R' is as defined herein.

[0458] The term "thiocarboxylate" used in the present specification includes "C-thiocarboxylate as well as O-thiocarboxylate".

[0459] The term "C-thiocarboxylate" describes a -C(=S)-OR' terminal group or a -C(=S)-O- linking group, as these phrases are defined above, wherein R' is as defined in this specification.

[0460] The term "O-thiocarboxylate" describes a terminal -OC(=S)R' group or a -OC(=S)- linking group, as these phrases are defined above, wherein R' is as defined herein.

[0461] The term "carbamate" used in this specification includes N-carbamate as well as O-carbamate.

[0462] The term "N-carbamate" describes an R"OC(=O)-NR'-terminal group or a -OC(=O)-NR'-linking group, these phrases being as defined above, with R' and R" being as defined in this specification.

[0463] The term "O-carbamate" describes a -OC(=O)-NR'R" terminal group or a -OC(=O)-NR'- linking group, these phrases being as defined above, with R' and R" being as defined herein.

[0464] The term "thiocarbamate" as used in the present specification includes N-thiocarbamate as well as O-thiocarbamate.

[0465] The term "O-thiocarbamate" describes a -OC(=S)-NR'R" terminal group or a -OC(=S)-NR'- linking group, these phrases being as defined above, with R' and R" being as defined herein.

[0466] The term "N-thiocarbamate" describes an R"OC(=S)NR"-terminal group or a -OC(=S)NR'-linking group, these phrases being as defined above, wherein R' and R" are as defined herein.

[0467] The term "dithiocarbamate" as used in this specification includes N-dithiocarbamate and S-dithiocarbamate.

[0468] The term "S-dithiocarbamate" describes a -SC(=S)-NR'R" terminal group or a -SC(=S)NR'- linking group, these phrases being defined above, wherein R' and R" are as defined herein.

[0469] The term "N-dithiocarbamate" describes a R"SC(=S)NR'-terminal group or a -SC(=S)NR'-linking group, these phrases being defined above, wherein R' and R" are as defined herein.

[0470] The term "urea" is also referred to herein as "urea group" to describe a -NR'C(=O)-NR"R"' terminal group or a -NR'C(=O)-NR"- linking group, these phrases being defined above, wherein R' and R" are as defined herein, and R"' is as defined herein for R' and R".

[0471] The term "thiourea" is also referred to herein as "thiourea group" and describes a -NR'-C(=S)-NR"R"' terminal group or a -NR'-C(=S)-NR"- linking group, with R', R" and R"' as defined herein.

[0472] The term "amide" as used in this specification includes C-amide as well as N-amide.

[0473] The term "C-amide" describes a -C(=O)-NR'R" terminal group or a -C(=O)-NR'- linking group, these phrases being defined above, wherein R' and R" are as defined herein.

[0474] The term "N-amide" describes an R'C(=O)-NR"-terminal group or an R'C(=O)-N-linking group, these phrases being defined above, wherein R' and R" are as defined herein.

[0475] The term "amidino" describes a R'R"NC(=N)-terminal group or a -R'NC(=N)- linking group, these phrases being defined above, wherein R' and R" are as defined herein.

[0476] The term "guanidine" describes a -R'NC(=N)-NR"R"' terminal group or a -R'NC(=N)-NR"- linking group, these phrases being defined above, wherein R', R" and R'" are as defined in this specification.

[0477] The term "hydrazine" describes a -NR'-NR"R"' terminal group or a -NR'-NR"- linking group, these phrases being as defined above, with R', R", and R'" being as defined in this specification.

[0478] As used herein, the term "hydrazide" describes a -C(=O)-NR'-NR"R"' terminal group or a -C(=O)-NR'-NR"- linking group, these phrases being as defined above, wherein R', R" and R'" are as defined herein.

[0479] As used herein, the term "thiohydrazide" describes a -C(=S)-NR'-NR"R"' terminal group or a -C(=S)-NR'-NR"- linking group, these phrases being as defined above, wherein R', R" and R'" are as defined herein.

[0480] For any embodiment described in this specification, the compound described in this specification may be in the form of a salt thereof, for example: a pharmaceutically acceptable salt thereof and / or a prodrug form of the compound.

[0481] As used herein, the phrase "pharmaceutically acceptable salt" refers to a charged species of the parent compound and a counter ion of the charged species, which counter ion is generally used to modify the solubility characteristics of the parent compound and / or reduce any significant irritation to an organism without abolishing the biological activity and various properties of the administered compound.

[0482] In the context of some embodiments of the present invention, a pharmaceutically acceptable salt of a compound described herein is optionally a base addition salt, wherein the base addition salt comprises at least one acidic (e.g., phenolic and / or carboxylic acid) group of the compound. The acidic group is in a negatively charged form (e.g., wherein the acidic group is deprotonated) and is combined with at least one counterion derived from the selected base to form a pharmaceutically acceptable salt.

[0483] Therefore, the base addition salt of the compound described in the present specification may be a complex formed between one or more acidic groups of the drug and one or more equivalent bases.

[0484] The multiple base addition salts can include various organic and inorganic counterions and bases, such as, but not limited to, sodium (e.g., by adding NaOH), potassium (e.g., by adding KOH), calcium (e.g., by adding Ca(OH)2, magnesium (e.g., by adding Mg(OH)2), aluminum (e.g., by adding Al(OH)3, and ammonium (e.g., by adding ammonia). These terms are defined in this specification, and each of these acid addition salts can be a single addition salt or multiple addition salts.

[0485] In the context of some embodiments of the present invention, a pharmaceutically acceptable salt of a compound described herein may optionally be an acid addition salt comprising at least one base (e.g., an amine or amide group) of the compounds, which is in a positively charged form (e.g., wherein the -NH- group is protonated), combined with at least one counter ion derived from a selected acid to form a pharmaceutically acceptable salt.

[0486] Therefore, the acid addition salts of the compounds described in the present specification may be complexes formed between one or more basic groups of the drug and one or more equivalent acids.

[0487] The plurality of acid addition salts may include various organic and inorganic acids such as, but not limited to, hydrochloric acid to provide hydrochloric acid addition salts, hydrobromic acid to provide hydrobromic acid addition salts, acetate to provide acetic acid addition salts, ascorbic acid to provide ascorbic acid addition salts, benzenesulfonic acid to provide benzenesulfonic acid addition salts, camphorsulfonic acid to provide camphorsulfonic acid addition salts, citric acid to provide citric acid 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 the acid addition salts may be a mono-addition salt or a poly-addition salt, as such terms are defined herein.

[0488] The acid addition salts may be mono-addition salts or poly-addition salts depending on the stoichiometric ratios between the charged group(s) in the compound and the counterion in the salt.

[0489] As used herein, the phrase "mono-addition salt" refers to a salt wherein the stoichiometric ratio between the counterion and the charged form of the compound is 1:1, such that the addition salt contains 1 molar equivalent of the counterion per molar equivalent of compound.

[0490] The phrase "multiple addition salt" as used herein refers to a salt wherein the stoichiometric ratio between the counter ion and the charged form of the compound is greater than 1:1, and is, for example, 2:1, 3:1, 4:1, etc., such that the addition salt contains 2 or more molar equivalents of the counter ion per molar equivalent of the compound.

[0491] As used herein, the term "prodrug" refers to a drug that is converted into the active compound (the active parent drug) in vivo. Prodrugs are generally designed to facilitate administration, for example, by enhancing absorption. A prodrug may include, for example, the active compound modified with multiple ester groups, for example, wherein any one or more hydroxyl groups of a compound are modified with acyl groups, optionally with (C 1-4 ) acyl (e.g., acetyl) group to form an ester group, and / or any one or more carboxylic acid groups of the compound are modified with an alkoxy or aryloxy group, optionally with (C 1-4 ) alkoxy (eg, methyl, ethyl) groups are modified to form ester groups.

[0492] In addition, each of the compounds described in the present specification, including salts of the compounds, may be in the form of a solvate or a hydrate of the compounds.

[0493] The term "solvate" refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, etc.) consisting of a solute (the compound of the invention) and a solvent, such that the solvent does not affect the biological activity of the solute.

[0494] The term "hydrate" refers to a solvate as defined above wherein the solvent is water.

[0495] The various compounds described in the present specification may be used as polymorphs, and embodiments of the present invention also include any isomorphs of the various compounds and any combination thereof.

[0496] Embodiments of the present invention also include any enantiomers and diastereomers of the compounds described herein.

[0497] The term "enantiomer" as used herein refers to a stereoisomer of a compound that is superimposable with its counterpart only by complete inversion / reflection (mirror image) of each other. Since they correspond to each other like the right hand and the left hand, enantiomers are said to have "chirality". Enantiomers have the same chemical and physical properties except when present in an environment that has chirality itself, such as all living systems. In the context of multiple embodiments of the present invention, a compound can exhibit one or more chiral centers, each of which exhibits an R configuration or an S configuration and any combination, and multiple compounds according to some embodiments of the present invention can have any of their chiral centers and present an R configuration or an S configuration.

[0498] The term "diastereomer" as used herein refers to stereoisomers that are not enantiomers of each other. Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more but not all of the equal (related) stereocenters, and are not mirror images of each other. When two diastereomers differ from each other at only one stereocenter, they are epimers. Each stereocenter (chiral center) produces two different configurations, thus producing two different stereoisomers. In the context of the present invention, multiple embodiments of the present invention encompass compounds with multiple chiral centers, and the multiple compounds appear in any combination of stereoconfigurations, i.e., any diastereomers.

[0499] Throughout this document, the term "about" describes ±10% or ±5%.

[0500] It is understood that certain features of the present invention, which for clarity are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present invention, which for brevity are described in the context of a single embodiment, may also be provided separately, or in any suitable subcombination, or in any other described embodiment applicable to the present invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment does not function without those elements.

[0501] 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 multiple examples.

[0502] Multiple examples:

[0503] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.

[0504] Example 1

[0505] Multiple chemical syntheses

[0506] According to the exemplary compound of this embodiment, represented as BKT300-N1, Figure 1 Prepared as shown and described below.

[0507] The chemical structure of BKT300-N1 can be represented as two tautomers:

[0508]

[0509] The chemical name of the ketone tautomer is 8-(4-hydroxy-2-methoxyphenoxy)-6-methoxy-3-pentylquinoline-2,4(1H,3H)-dione.

[0510] The chemical name of the enol tautomer is 4-hydroxy-8-(4-hydroxy-2-methoxyphenoxy)-6-methoxy-3-pentylquinolin-2(1H)-one.

[0511] For simplicity, hereinafter, only the enol tautomer is mentioned. However, it should be noted that the two tautomers may exist in equilibrium or as one of the multiple tautomers depending on environmental conditions.

[0512] Preparation of 4-(Benzyloxy)-2-methoxybenzaldehyde (S2):

[0513]

[0514] At 0 ° C, K was added to a DMF (1.0 L) solution of 4-hydroxy-2-methoxybenzaldehyde (S1) (150.0 g, 985 mmol), and the resulting mixture was stirred for 30 minutes. BnBr (270 g, 1576 mmol, 1.6 eq) was added to the reaction mixture at 0 ° C. The reaction mixture was allowed to reach room temperature and stirred overnight. TLC showed that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (EA) (800 ml x 3). The organic layer was washed with water (1000 ml x 2) and brine (800 ml), dried over Na2SO4, filtered and concentrated to obtain a residue. The residue was purified by column to obtain the product 4- (benzyloxy) -2-methoxybenzaldehyde (S2) (215.0 g, 90% yield) in a colorless oil.

[0515] Preparation of 4-methoxy-3-(trifluoromethoxy)phenol (S3):

[0516]

[0517] To a suspension of 4-(benzyloxy)-2-methoxybenzaldehyde (S2) (200.0 g, 825 mmol) and H2O2 (150 ml, 4412 mmol, 5 eq) in MeOH (1250 ml) was added H2SO4 (15.0 ml, 248 mmol). The reaction mixture was stirred at room temperature overnight. TLC indicated that the reaction was complete. The reaction mixture was diluted with water (1000 ml) and extracted with EA (500 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column to give the product 4-methoxy-3-(trifluoromethoxy)phenol (S3) (136.8 g, 72% yield) as a colorless oil.

[0518] Preparation of 4-(Benzyloxy)-2-methoxy-1-(5-methoxy-2-nitrophenoxy)benzene (2):

[0519]

[0520] NaH (60%) (23.8 g, 594 mmol) was added to a solution of 4-(benzyloxy)-2-methoxyphenol (S3) (125 g, 540 mmol) in THF (2.0 liters) in batches. The reaction mixture was stirred at 0 ° C for 30 minutes. Then 2-fluoro-4-methoxy-1-nitrobenzene (1) (93.0 g, 540 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature overnight. TLC showed that the reaction was complete (using petroleum ether (PE): ethyl acetate 10: 1 as eluent). The reaction mixture was poured into ice water and extracted with EA (800 ml x 3). The organic layer was washed with brine (500 ml x 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography, eluted with PE: EA 10: 1, to give product 2 (155.0 g, 72% yield) as a brown oil.

[0521] LC-MS: m / z = 382.1 (M + +H)

[0522] Preparation of 2-(4-(Benzyloxy)-2-methoxyphenoxy)-4-methoxyaniline (3):

[0523]

[0524] HCl (850 ml, 6N) was added to a mixture of 4-(benzyloxy)-2-methoxy-1-(5-methoxy-2-nitrophenoxy)benzene (2) (155 g, 275 mmol) and SnCl2 · 2HO (372 g, 1655 mmol, 6.0 eq) in EtOH (900 ml). The reaction mixture was heated to reflux and stirred overnight under reflux. LC-MS showed that the reaction was complete (using PE: EA2: 1 as eluent). The reaction mixture was diluted with water (1000 ml) and washed with saturated Na2CO3, filtered and the filtrate was extracted with EA (600 ml x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to obtain a residue. The residue was purified by silica gel chromatography, eluted with (PE: EA 4: 1) to obtain product 3 (100.0 g, 83% yield) as a black oil.

[0525] LC-MS: m / z 352.4 (M + +H)

[0526] Preparation of ethyl 2-((2-(4-(Benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoate (4):

[0527]

[0528] A mixture of 2-(4-(benzyloxy)-2-methoxyphenoxy)-4-methoxyaniline (3) (100 g, 285 mmol), diethyl 2-pentamalonate (SM-1) (39 g, 855 mmol, 3.0 eq) and pyridine (45.0 mL, 575 mmol, 2.0 eq) in toluene (300 mL) was stirred at reflux for 72 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with (PE:EA 7:1) to give the product 4 (100 g, 67% yield) as a brown oil.

[0529] LC-MS: m / z 536.3 (M + +H)

[0530] Preparation of 2-((2-(4-(Benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoic acid (5):

[0531]

[0532] To a solution of ethyl 2-((2-(4-(benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoic acid methyl ester (4) (100 g, 187 mmol) in a mixed solution of THF (500 ml) and H2O (300 ml) was added LiOH (22 g, 920 mmol, 5.0 eq). The reaction was stirred at room temperature overnight. TLC showed that the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was dissolved in H2O (300 ml) and acidified to pH 2-3 using concentrated HCl. The reaction mixture was extracted with EA (500 ml x 3). The organic layer was washed with brine (500 ml), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the product 5 (90 g, 96% yield) as a brown oil.

[0533] Preparation of 8-(4-(Benzyloxy)-2-methoxyphenoxy)-4-hydroxy-6-methoxy-3-pentylquinoline-2(1H)-one (6):

[0534]

[0535] 2-((2-(4-(Benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoic acid (5) (30 g, 59.1 mmol) was added to a solution of Eaton's reagent (42 g, 177.3 mmol, 3.0 eq) 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 H2O (50 mL) and washed with saturated NaHCO3 and extracted with EA (100 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by column to give product 6 (10.1 g, 35.1% yield) as a light yellow solid.

[0536] Preparation of 4-hydroxy-8-(4-hydroxy-2-methoxyphenoxy)-6-methoxy-3-pentylquinolin-2(1H)-one (BKT300-N1):

[0537]

[0538] 2-((2-(4-(Benzyloxy)-2-methoxyphenoxy)-4-methoxyphenyl)carbamoyl)heptanoic acid (6) (30 g, 59.1 mmol) was added to a solution of trifluoroacetic acid (150 mL) and stirred at room temperature for 12 hours. LC-MS showed that compound 6 had been completely consumed. The TFA solution was removed under vacuum at 30°C. The residue was diluted with H2O (250 mL) and extracted with EA (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by column to give the final product, BKT300-N1, as a white solid (10.5 g, 44.7% yield).

[0539] 1 H NMR (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, 1H) ), 6.38(m,1H), 6.12(s,1H), 3.69(s,3H), 3.68(s,3H), 2.56(m,2H), 1.45(m,2H), 1.28(s,4H), 0.87(t,3H).

[0540] HPLC purity: 97.8% (254nm), 97.7% (214nm)

[0541] MS m / z (ESI): m / z = 400.1 (M + +H).

[0542] Using the gist of the above procedure, other compounds of formula Ia and / or Ib or formula IIa and / or IIb can be synthesized by selecting corresponding compounds corresponding to compounds S3, 1 and SM-1, as described herein and Figure 1 shown.

[0543] Example 2

[0544] In vitro migration and invasion assays

[0545] Migration assay:

[0546] 600 μl of RPMI medium containing 1% fetal calf serum (FCS) was added to multiple lower chambers of multiple migration plates, and 100 μg / ml (ng / ml) of SDF-1 was added. In addition to multiple control samples, BKT300-N1 was added to the multiple lower chambers at the specified concentration. Before the migration assay began, the SDF-1 and BKT300-N1 were incubated at room temperature for 30 minutes. After 30 minutes of incubation, 2×10 5 Jurkat cells were added to the upper chambers of the migration plate in a total volume of 100 μl. Cells that migrated to the lower chambers of the plate within 3 hours were counted using a FACScalibur™ flow cytometer.

[0547] The results are shown in Figure 2 In the figure, it was shown that BKT300-N1 at a concentration of 0.5 μM, 1 μM, or 5 μM significantly inhibited the migration of lymphocyte Jurkat cells toward SDF-1.

[0548] These results demonstrate that BKT300-N1 is a potent inhibitor of SDF-1 function and suggest that the compound is effective in treating conditions associated with the activity of SDF-1 and CXCR4, the receptor for SDF-1.

[0549] Scratch analysis:

[0550] Scratch assays were performed to evaluate the effects of BKT300-N1 and BKT300-3-C5 on cell invasion and migration. The system measures scratch closure in real time and automatically calculates the relative wound density and wound width within the initial blank area at each time point. The relative wound density is the ratio of the occupied area to the total area of ​​the initial scratch area.

[0551] Cells were plated in 96-well ImageLock plates (Essen Bioscience) and grown overnight to form a spatially uniform monolayer.

[0552] By using the 96-well tool WoundMakerTM (Essen BioScience) to create uniform, reproducible scratches in all wells of the 96-well plate. After the scratch, the medium was aspirated and the wells were washed twice with fresh medium to remove any cells from the scratched area. After washing, fresh medium containing different concentrations of the test compound was added to the wells. After adding fresh medium, the plate was placed in the IncuCyte ZOOM TM In the device, images of collective cell spreading were recorded every 4 h for a total duration of 60 h.

[0553] Data processing and analysis were performed using the IncuCyte S3 Live Cell Analysis System.

[0554] Scratch assay was performed using HCC SNU449 cells. Cells were scratched and incubated with 0.05, 0.1, 0.5, 1, and 10 μM of BKT300-N1 or BKT300-3-C5.

[0555] Figure 3 The relative wound area at 24 hours is shown and demonstrates the ameliorative effect of BKT300-N1 at a concentration of 0.1 μM.

[0556] Figure 4A -E presents a comparative graph showing wound width values ​​(micrometers) analyzed by IncuCyte when incubated with 0.05, 0.1, 0.5, 1 and 10 μM BKT300-N1 (denoted as N1 for simplicity) and when incubated with 0.05, 0.1, 0.5, 1 and 10 μM BKT300-3-C5 (denoted as BKT300 for simplicity), respectively, and compared with the control, further demonstrating the improved effect of BKT300-N1 over BKT300-3-C5, especially at lower concentrations.

[0557] In another scratch assay, MSTO cells were scratched 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.

[0558] Figure 5A A comparative graph is presented showing relative wound width values ​​(micrometers) analyzed by IncuCyte.

[0559] Figure 5B Shown are wound width images acquired with the IncuCyte Live Cell Imaging System at 48 h for control, and cells cultured with BKT300-N1 at concentrations of 0.1 μM and 0.5 μM.

[0560] Example 3

[0561] In vitro cell viability assay

[0562] Annexin-V cell apoptosis detection:

[0563] Apoptosis was determined by flow cytometry analysis using the Annexin-V kit.

[0564] U937 cancer cells were cultured at 1×10 6 The cells were cultured in a final volume of 1 ml in a 24-well plate at a concentration of 10 cells / well. Test compounds (BKT300-N1 or BKT300-3-C5) were added to the cells at the indicated concentrations. After 24 hours of culture, the medium and cells were collected and centrifuged, and then stained with Annexin-V and propidium iodide (PI) kits according to the manufacturer's instructions. The number 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 evaluated by flow cytometry (FACS).

[0565] Fig. 6A -B presents the data obtained in the assay. Fig. 6A is a bar graph showing the effects of BKT300-N1 and BKT300-3-C5 (25-1000 nM) on U937 cell viability, as well as the number of Annexin-V- / PI-living cells, and demonstrating the improving effect of BKT300-N1 at all tested concentrations. Figure 6B is a bar graph showing the effect of BKT300-N1 and BKT300-3-C5 (25-1000 nM) on apoptosis of U937 cells by presenting the percentage of Annexin V+ cells.

[0566] The data obtained clearly showed a significantly higher effect of BKT300-N1 in reducing the percentage of viable cells via apoptosis.

[0567] Western blot of cleaved caspase-3:

[0568] CASP-3 (caspase-3) protein is a member of the cysteine-aspartic acid protease (caspase) family. The sequential activation of multiple caspases plays a central role in the execution phase of apoptosis. Multiple caspases exist as inactive zymogens, which are proteolytically processed at conserved aspartic acid residues to produce two large and small subunits that dimerize to form active enzymes. The active enzyme cleaves and activates multiple caspases 6 and 7, and is processed and activated by multiple caspases 8, 9, and 10.

[0569] The role of caspase-3 (CASP3) in BKT300-N1-induced apoptosis of the AML cell line U937 cells was tested. Cells were incubated with BKT300-N1 (0.1, 0.5, and 1 μM) for 24 hours and then tested for the presence of cleaved caspase 3 by Western blot analysis using mAb to human cleaved caspase 3.

[0570] Fig. 7A Western blots showing the effect of 24-hour incubation of BKT300-N1 (0.1, 0.5 and 1 μM) on the presence of cleaved caspase-3 in U937 cells are presented.

[0571] Figure 7B is a bar graph showing the effect of 24 h incubation with BKT300-N1 (0.1, 0.5 and 1 μM) on the presence of cleaved caspase-3 in U937 cells (expressed by optical density (OD) and normalized to actin).

[0572] The data obtained clearly demonstrated that BKT300-N1-induced apoptosis was via caspase-3 activation.

[0573] Cell cycle analysis by 7-AAD staining:

[0574] To evaluate the effect of BKT300-N1 on cell cycle distribution, the 7-aminoactinomycin D (7-AAD) protocol was used. Cells were seeded in 24 wells of a microtiter plate at a density of 1 × 10 6 Cells / well were added and exposed to different concentrations of the test compounds BKT300-N1 or BKT300-3-C5 for 24 or 48 hours in a CO2 incubator at 37°C. After the incubation time, cells were collected and washed with cold PBS. Cells were fixed at 4°C for 20 minutes and processed according to the 7-AAD labeling protocol. The intensity of the dye in the stained cells was measured by flow cytometry. Cell cycle analysis G0 / G1, G2 / M, and sub-G0 phases were calculated from the 7-AAD area histogram.

[0575] Using the above protocol, U937 cells were treated with different concentrations of BKT300-N1 or BKT300-3-C5 (0.05, 0.1, 0.5, and 1 μM) for 24 h, and then the cell cycle phase was analyzed by flow cytometry using 7-AAD.

[0576] Fig. 8A -B presents BKT300-N1( Fig. 8A ) and BKT300-3-C5( Figure 8B) on the cell cycle of U937 cells and further supports the ameliorative effect of BKT300-N1 over BKT300-3-C5, which was more pronounced at the lower concentrations tested. Fig. 8A As shown, treatment with BKT300-N1 at all tested concentrations resulted in cell cycle arrest and induced multiple cell death, whereby, as Figure 8B As shown, treatment with BKT300-3-C5 at concentrations below 0.5 μM did not induce multiple cell death.

[0577] Using the above protocol, multiple H69 cells were treated with different concentrations of BKT300-N1 for 48 hours, and then the cell cycle phase was analyzed by flow cytometry using 7-AAD. Cells were gated according to the cell cycle phase: P1 for G0 / G1 phase; P2- apoptotic cells in the sub-G0 phase; and P3 for G2 / M phase. The data obtained are presented in Fig. 9 middle.

[0578] The data obtained showed that BKT300-N1 arrested growth and induced apoptosis in the G2M phase of the cell cycle.

[0579] Fig. 8A -B and Fig. 9 The data presented in further show the improved activity of BKT300-N1 in cell cycle arrest of mutable cancer cells.

[0580] Example 4

[0581] Multiple in vivo studies

[0582] The effects of BKT300-N1 on cancer cell proliferation and survival in vivo were examined in NOD Scid gamma (NSG) mice or C57BL / 6 mice.

[0583] C57BL / 6 mice were transplanted SC with the murine pancreatic cell line Panc02, 5x10 6 cells / mouse.

[0584] NSG mice were transplanted SC with human hepatocellular carcinoma cell line SNU449 or human AML cell line U937, 5x10 6 cells / mouse.

[0585] When the tumors reached considerable size and were clearly visible, the treatment groups were injected with BKT300-N1. BKT300-N1 (30 mg / mL prepared in Cremophor EL 49.7% (V / V) dehydrated ethanol and further diluted 1:6 with 0.9% NaCl to 5 mg / mL) was injected subcutaneously at a dose of 2.5 mg / mouse per injection for 3-4 consecutive days. Some mice were treated with intratumoral injection of BKT300-N1 (30 mg / mL prepared in Cremophor EL 49.7% (V / V) dehydrated ethanol) at a dose of 0.6 mg / mouse per injection for 2-4 consecutive days. Mice were sacrificed 24 hours after the last treatment, and tumor size was assessed and weighed.

[0586] C57BL6 mice bearing Panc02 SC tumors were treated with BKT300-N1 (30 mg / mL formulated in CremophorEL 49.7% (v / v) dehydrated ethanol and further diluted to 5 mg / mL with 0.9% NaCl 1:6). BKT300-N1 was injected subcutaneously at a dose of 2.5 mg / mouse or intratumorally at a dose of 0.6 mg / mouse. BKT300-N1 was injected 4 times per day.

[0587] Fig.10 is a bar graph showing the in vivo effect of BKT300-N1 on pancreatic cancer in mice by displaying tumor weight (mg) after treatment (*p<0.05).

[0588] NSG mice bearing U937 SC tumors were treated with BKT300-N1 (30 mg / mL formulated in Cremophor EL4 9.7% (v / v) dehydrated ethanol and further diluted 1:6 with 0.9% NaCl to 5 mg / mL). BKT300-N1 was injected subcutaneously at a dose of 2.5 mg / mouse per day for 4 days or intratumorally at a dose of 0.6 mg / mouse per day for 2 days.

[0589] Fig.11 is a bar graph showing the in vivo effect of BKT300-N1 on mouse AML by displaying tumor weight (mg) after treatment (*p<0.05).

[0590] NSG mice bearing SNU449 SC tumors were treated with BKT300-N1 (30 mg / mL formulated in Cremophor EL4 9.7% (v / v) dehydrated ethanol and further diluted 1:6 with 0.9% NaCl to 5 mg / mL). BKT300-N1 was injected subcutaneously at a dose of 2.5 mg / mouse per day for 3 days.

[0591] Fig.12is a bar graph showing the in vivo effect of BKT300-N1 on mouse hepatocellular carcinoma by displaying tumor weight (mg) after treatment (*p<0.05).

[0592] In additional experiments, BKT300-N1 was tested in female immunocompromised mice subcutaneously, in low-generation Champions' In vivo efficacy in patient-derived human non-small cell lung cancer (CTG-0198), colorectal cancer (CTG-0923), and ovarian cancer (CTG-1086) xenograft (PDX) models grown.

[0593] 6-8 week old athymic Nude-Foxn1nu (Immunocompromised) female mice were implanted with 1-1.5 cm 3 Harvested tumors. When tumors reached an average volume of 200 mm3, the control group was treated daily with vehicle, and the treatment group was treated with 2.5 mg per mouse per injection (low dose) or 5 mg per mouse per injection (high dose) of BKT300-N1. The control group was injected subcutaneously (SC) with vehicle (Cremophore EL and ethanol 50% / 50% vol / vol) diluted 1:6 with 0.9% sodium chloride.

[0594] For the low-dose treatment group, a stock solution of 30 mg / mL BKN300-N1 was prepared in vehicle and further diluted 1:6 with 0.9% NaCl to a final concentration of 5 mg / mL. Animals received 0.5 mL subcutaneous (SC) injections every 12 hours (2.5 mg / injection = 5 mg daily dose).

[0595] For the high-dose treatment group, a 30 mg / mL stock solution of BKN300-N1 was prepared 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 (SC) injections every 12 hours (5 mg / injection = 10 mg daily dose)

[0596] The data obtained are presented in Fig.13A -C, and clearly shows a significant reduction or even stagnation of tumor growth in the treated groups compared to the control in all tumors tested.

[0597] These results further suggest that BKT300-N1 can effectively inhibit tumor growth in multiple cancer types.

[0598] Example 5

[0599] Combination therapy of BKT300-N1 and irinotecan

[0600] H460 cells (1x10 6cells / ml) were cultured in 12-well plates containing 10% FCS (fetal calf serum). After 24 h, 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) were added, respectively.

[0601] After 24 or 48 hours of culture, the culture medium and cells were collected and centrifuged, and then stained with propidium iodide (PI; 1:100) kit according to the manufacturer's instructions. After 24 or 48 hours of culture, the number of live cells (PI negative) and dead cells (PI positive) was assessed by flow cytometry (FACS).

[0602] The data obtained are shown in Fig.14A -D, Fig.14A -B shows the data obtained after 24 hours of culture, Fig. 14C -D shows data obtained after 48 h of culture. Results are presented as mean ± SD. Statistical differences were determined by two-tailed Student's t-test analysis. Values ​​of p < 0.05 were considered statistically significant. Data are mean ± SD of replicate cell numbers per group. *p < 0.05 compared to control; **p < 0.05 compared to irinotecan alone.

[0603] like Fig.14A -D, the combination treatment of BKT300-N1 and irinotecan showed a beneficial effect on the survival of the tested lung cancer cells. The combination treatment induced more cell death than each treatment alone, indicating a synergistic effect. This synergistic effect allows the use of smaller amounts of irinotecan and may reduce acquired resistance to irinotecan treatment.

[0604] Example 6

[0605] Paclitaxel-resistant cancer cells

[0606] Paclitaxel is a chemotherapeutic agent that acts by directly interacting with microtubules and stabilizing them to prevent depolymerization, thereby causing mitotic arrest and cell death. However, its clinical efficacy has been hampered by the development of drug resistance. Paclitaxel resistance is a major challenge in the treatment of various cancers.

[0607] Therefore, the effect of BKT300-N1 on paclitaxel-resistant cells was tested using the following protocol.

[0608] Cells (1x10 6 Cells were cultured in 12-well plates in 10% FCS (10 cells / ml). After 24 hours, the medium was replaced with 1% FCS and BKT300-N1 or paclitaxel (250-3.75 nM) was added.

[0609] After 24 hours of incubation, the cells were harvested and washed with PBS. The pellet was fixed by adding 200 μl of Fix / Perm buffer and vortexing. The fixed cells were incubated at 4°C for 20 minutes, and then 1 ml of Perm / Wash buffer was added. After centrifugation, the supernatant was removed and the cells were resuspended in 100 μl of Perm / Wash and 4 μl of 7-AAD and vortexed. The cells were then incubated in the dark at 4°C for 20 minutes, and then 300 μl of PBS was added. Flow cytometric analysis was performed by collecting 20,000 events per sample. The cells were analyzed based on their distribution in the three main phases of the cycle: G0 / G1 (blue), S (purple), G2 / M (green), and apoptotic cells (red), as shown in Figure 2. Figure 15 to 1 8.

[0610] All results are presented as mean ± SD. Statistical differences were determined by two-tailed Student's t-test analysis. Values ​​of p < 0.05 were considered statistically significant.

[0611] In the first set of experiments, two ovarian cancer cell lines, OVCAR8 and HEY-T30, were tested for their sensitivity to paclitaxel.

[0612] Cells were cultured in different doses of paclitaxel (30, 15, 7.5, 3.75 nM) for 24 h and then analyzed as described above.

[0613] The data obtained for Hey-T30 cells are shown in Fig.15 As can be seen, no effect on the cell cycle was observed in HEY-T30 cells after treatment with paclitaxel, indicating that these cells are resistant to paclitaxel at concentrations up to 30 nM.

[0614] The data obtained with OVCAR8 cells are shown in Fig.16 It can be seen that the effect on the cell cycle was already significant at the lowest concentration of paclitaxel, 3.75 nM, indicating that OVCAR8 cells are sensitive to paclitaxel.

[0615] Fig.17A -C is a graphical representation comparing the effects of paclitaxel on cell viability, percentage of cells in G0 / G1 phase, and level of cells in G2 / M phase in the two tested cell lines, further demonstrating the resistance of HEY-T30 cells to paclitaxel compared with the sensitivity of OVCAR8 cells to paclitaxel.

[0616] Next, the effect of BKT300-N1 on paclitaxel-resistant cells was tested. Both ovarian cancer cell lines were cultured with BKT300-N1 (250, 125, 62.5, 31.25, 15.6 nM). For comparison, the effect of the same amount of paclitaxel was also tested.

[0617] The data obtained are shown in Fig.18A -C. It was found that BKT300-N1 increased the level of dead cells at a concentration of 62.5 nM ( Fig.18A ; red line) and decreased the percentage of cells in G0 / G1 phase significantly affected the paclitaxel-resistant HEY-T30 cells at a concentration of 125 nM ( Fig.18B ; red line), while at a concentration of 125 nM the cell level in the G2 / M phase was increased ( Fig. 18C ; red line).

[0618] In contrast, no significant effect of paclitaxel on HEY-T30 resistant cells was observed at any concentration tested ( Fig.18A -C; green line).

[0619] These data demonstrate the therapeutic potential of BKT300-N1 in affecting (blocking) the growth and viability of cancer cells that are resistant to paclitaxel.

[0620] Although the present invention has been described in conjunction with its specific embodiments, it is apparent that many alternatives, modifications and variations are apparent to those skilled in the art. Therefore, the present invention is intended to encompass all such alternatives, modifications and variations that fall within the spirit and scope of the claims.

[0621] All publications, patents and patent applications mentioned in this specification are incorporated into this specification in their entirety as references, to the same extent as if each independent publication, patent or patent application was clearly and individually marked as being incorporated herein by reference. In addition, the citation or identification of any reference in this application should not be construed as an admission that the reference can be used as prior art of the present invention. The title part in this application is used herein to make this specification easy to understand and should not be construed as a necessary limitation.

[0622] Furthermore, any priority documents of the present application are hereby incorporated by reference in their entirety.

Claims

1. Use of a compound represented by the following structural formula Ia and / or Ib in the preparation of a medicament for treating a disease or condition selected from the following in a subject in need thereof: in: A is a monoalkyl group having a length of at least 4 carbon atoms; B is an alkoxy group; D and G are each independently selected from hydrogen, alkoxy and alkyl, provided that at least one of D and G is hydrogen and the other is alkoxy or alkyl, wherein the alkyl is at least 4 carbon atoms in length; E is hydroxyl; R1 is selected from hydrogen and alkyl; and R2 to R5 are hydrogen; Tuberculosis, human immunodeficiency virus type 1, proliferative glomerulonephritis, neural tube defects, xanthogranulomatous pyelonephritis, scleritis, rapidly progressive glomerulonephritis, pneumoconiosis, encephalitis, peritonitis, atherosclerosis, psoriasis, dengue shock syndrome, temporal arteritis, relapsing polychondritis, type II diabetes, diabetic angiopathy, mesangial proliferative glomerulonephritis, sympathetic ophthalmia, ureteral disease, lupus nephritis, pneumonia, periapical granuloma, Edheim-Chester disease, glomerulonephritis, arterial disease, viral encephalitis, primary cutaneous amyloidosis, arteriosclerosis , nonspecific interstitial pneumonia, acute post-streptococcal glomerulonephritis, coronary artery disease, Venezuelan equine encephalitis, diabetic macular edema, extrapulmonary tuberculosis, nephritis, rheumatoid arthritis, Kawasaki disease, arthritis, malaria, obesity, mental illness, neurodegenerative diseases, age-related maculopathy, Whim syndrome, bursitis, tuberculosis, intraocular lymphoma, cytomegalovirus retinitis, chronic inflammatory demyelinating polyneuropathy, ocular hypertension, polyradiculoneuropathy, dendritic cell tumors, retinal hemangioblastoma, malaria, endotheliitis, prostatitis, pancreas Inflammation, neuronitis, lung cancer, osteoarthritis, hypoxia, astrocytoma, periodontitis, preeclampsia, hepatitis, esophagitis, myeloma, eclampsia, cervicitis, periodontal disease, systemic lupus erythematosus, asthma, myocardial infarction, lupus erythematosus, premature ovarian failure, peritonitis, vascular disease, alcoholic hepatitis, kidney disease, cutaneous leishmaniasis, encephalitis, alopecia areata, oligodendroglioma, whooping cough, ischemia, uveal melanoma, gingivitis, pituitary adenoma, bronchiolitis, neuromyelitis optica, mesothelioma, alopecia, bronchiolitis obliterans, brain injury, colorectal adenoma, tongue squamous cell carcinoma, Traumatic brain injury, cerebral ischemia, allergic asthma, tick-borne encephalitis, plasmacytoid dendritic cells, oligoastrocytoma, childhood dermatomyositis, optic neuritis, seminoma, Sjögren's syndrome, pleurisy, neuritis, inflammatory bowel disease, cytomegalovirus infection, skeletal muscle regeneration, dominant Ehrlich-Derrickson muscular dystrophy, fibrosis, idiopathic pulmonary fibrosis, scleroderma, multiple sclerosis, Waldenstrom's macroglobulinemia, opioid-induced hyperalgesia, cirrhosis, infectious diseases, autoimmune diseases, allergy-related inflammation, transplant rejection, injury, and skin inflammation.

2. The use according to claim 1, characterized in that: One of D and G is an alkoxy group.

3. The use according to claim 1, characterized in that: R1 is hydrogen.

4. The use according to claim 1, characterized in that: The compound is: and / or 5. The use according to any one of claims 1 to 4, characterized in that: The disease or disorder is selected from psoriasis, rheumatoid arthritis, multiple sclerosis, atherosclerosis, glomerulonephritis, epilepsy, Alzheimer's disease, cerebral ischemia, traumatic brain injury, type II diabetes, and age-related maculopathy.

6. The use according to any one of claims 1 to 4, characterized in that: The disease or disorder is selected from the group consisting of unwanted angiogenesis, tumor metastasis, WHIM syndrome, Waldenstrom's macroglobulinemia, and opioid-induced hyperalgesia.

7. The use according to any one of claims 1 to 4, characterized in that: The disease or disorder is selected from infectious diseases, autoimmune diseases, allergy-related inflammation, transplant rejection, and injury.

8. The use according to any one of claims 1 to 4, characterized in that: The disease or condition is skin inflammation.

9. The use according to any one of claims 1 to 4, characterized in that: The disease or condition is selected from dermatitis, atopic dermatitis, contact dermatitis, dermatitis herpetiformis, systemic exfoliative dermatitis, seborrheic dermatitis, drug eruption, erythema multiforme, erythema nodosum, granuloma annulare, poison ivy, poison oak, toxic epidermal necrolysis, roseola, psoriasis, and acne.

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