JP2019519573A - Methods for treating cancer - Google Patents

Abstract

A therapeutically effective amount of at least one compound selected from a compound of Formula A and a compound of Formula B, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing And a compound of formula C, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. 68. A method comprising administering an amount of at least one second compound, and a kit comprising them.

Description

  The present application is directed to U.S. Provisional Patent Application No. 62 / 355,410 filed on June 28, 2016, U.S. Provisional Patent Application No. 62 / 506,929, filed on May 16, 2017, and 2017 Claims the benefit of priority of US Provisional Patent Application No. 62 / 514,059 filed on Jun. 2, 2012 under 特許 119 of the United States Patent Act, the contents of which are hereby incorporated by reference in their entirety. Is incorporated by reference.

  As used herein, a method for treating cancer in a subject comprising a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and A therapeutically effective amount of at least one first compound selected from any of the solvates; and kinase inhibitors, prodrugs thereof, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and Disclosed is a method comprising the step of administering a therapeutically effective amount of at least one second compound selected from a solvate of any of

In certain embodiments, at least one first compound selected from cancer stem cell inhibitors is, for example, a compound having the formula A:
, A prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing.

In certain embodiments, at least one first compound selected from cancer stem cell inhibitors is, for example, a compound having Formula B:
, A prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing.

In certain embodiments, at least one second compound selected from kinase inhibitors is, for example, a compound having the formula C:
, A prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing.

  The National Cancer Institute estimates that 1,685,210 new cancer cases will be diagnosed in the United States in 2016, and 595,690 people will die from the disease. The most common cancers are breast cancer, lung and bronchial cancer, prostate cancer, colon and rectum cancer, bladder cancer, skin melanoma, non-Hodgkin's lymphoma, thyroid cancer, kidney and renal pelvis cancer, leukemia Endometrial cancer, as well as pancreatic cancer. Despite advances in the treatment of certain forms of cancer through surgery, radiation and chemotherapy, many types of cancer are essentially uncurable. Even when an effective treatment for a particular cancer is available, the side effects of such treatment can have a significant detrimental effect on the patient's quality of life.

  Most conventional chemotherapeutic agents are toxic and have limited efficacy, especially for patients with advanced solid tumors. Conventional chemotherapeutic agents cause cytotoxicity against both healthy non-cancerous cells as well as cancerous cells. The therapeutic index (ie, a measure of therapeutic ability to distinguish between cancerous and normal cells) of these chemotherapeutic compounds can be very low. Often, doses of chemotherapeutic agents effective to kill cancer cells also kill normal cells, particularly normal cells that divide frequently, such as epithelial cells and bone marrow cells. When normal cells are subjected to chemotherapy, side effects such as hair loss, suppression of hematopoiesis causing anemia and immunodeficiency, and nausea often occur. Depending on the patient's overall health, such side effects may together prevent administration of the chemotherapy, or at least cause significant discomfort to the cancer patient, which reduces the quality of life. There is a risk of giving Even in cancer patients who respond to chemotherapy with tumor regression, cancer often relapses, progresses rapidly, and propagates through metastasis after the initial response to chemotherapy. Such recurrent cancers are often highly refractory to additional rounds of chemotherapy treatment.

  Progressive hepatocellular carcinoma (HCC) is the disease's resistance to chemotherapy, the toxicity profile of currently available systemic chemotherapeutic agents, and poor overall health of patients with HCC and underlying liver dysfunction Due to, it remains a major clinical challenge. The Sorafenib Hepatocellular Carcinoma Assessment Protocol (SHARP) trial is still the only randomized controlled trial of systemic chemotherapeutic agents to demonstrate a statistically significant survival benefit in patients with progressive unresectable HCC. In this study, 602 patients were randomly assigned to receive sorafenib (400 mg, twice daily) or placebo. For the treatment arm (arm), a median overall survival (OS) of 10.7 months was observed, compared to 7.9 months for placebo. The time to tumor progression (TTP) for the sorafenib and placebo groups was 5.5 and 2.8 months, respectively.

  The benefits realized with sorafenib monotherapy are important but not large. Disease control does not occur in many patients, and disease control can also be temporary in patients whose disease control is achieved by treatment. Unfortunately, there are no other drugs that have proved to be more effective. Recent Phase III trials with other regimens (eg, FOLFOX, brivanib, sunitinib and linifanib) all fail to demonstrate a statistically significant improvement in OS compared to treatment with sorafenib alone ing.

  Several studies have also been conducted on combination therapies using sorafenib and additionally drugs or regimens. However, few combinations have proven to be robust enough to be evaluated further in the Phase III, pivotal situation. Those evaluated in the phase III trial, such as brivanib, FOLFOX, and erlotinib, failed to show an advantage over sorafenib alone. Increased toxicity and inferior quality of life were observed in the BRISK-FL study, and increased incidence of hand-foot syndrome was observed in combination studies with treatment with 5-FU or 5-FU derivatives. There is a huge, yet unmet medical need for active systemic treatment of HCC.

  Cancer stem cells (CSC) or cancer cells with high stemness (high stem cell cancer cells) are considered to contribute to rapid tumor recurrence and resistance. CSCs are considered to have at least the following four properties:

1. Stemness As used herein, “stemgenic” refers to the ability of a stem cell population to self-replicate and transform into cancer cells (Gupta PB et al. Nat. Med. 2009; 15 ( 9): 1010 to 1012). CSCs form a small fraction of the total cancer cell population in tumors (Clarke MF, Biol. Blood Marrow Transplant. 2009; 11 (No. 2, Appendix 2): 14-16) Produces a heterogeneous lineage of differentiated cancer cells that make up the majority (see Gupta et al., 2009). Furthermore, CSCs have the ability to spread to other sites in the body by metastasis, where they have the ability to produce new tumor growth (Jordan CT et al., N. Engl. J. Med. 2006; 355 (12)): 1253-1261).

2. Aberrant Signaling Pathway CSC stemness can also be associated with dysregulation of signaling pathways, which can contribute to the ability to metastasize. In normal stem cells, the stem cell signaling pathway is tightly regulated and genetically intact. In contrast, aberrant regulation of stem cell signaling pathways in CSCs plays an important role in the uncontrolled self-replication of these cells and their transformation into cancer cells (Ajani et al., Semin. Oncol. Oncol. (2015) 42, Appendix 1: S3-17). Dysregulation of the stem cell signaling pathway also contributes to CSC resistance to chemotherapy and radiation as well as cancer recurrence and metastasis. Exemplary stem cell signaling pathways involved in the induction and maintenance of stem cell properties in CSCs include, but are not limited to: Janus kinase / signaling and transcriptional activator (JAK / STAT), Hedgehog (Desert) (DHH), Indian (IHH), and Sonic (SHH)) / PATCHED / (PTCH1) / SMOOTHENED (SMO), NOTCH / DELTA-LIKE (DLL1, DLL3, DLL4) / JAGGED (JAG1, JAG2) / CSL (CBF1) / Su (H) / Lag-1), WNT / APC / GSK3 / .beta.-catenin / TCF4 and NANOG (Boman BM et al., J. Clin. Oncol. 2008; 26 (17): 2828-2838) including.

3. Resistance to Conventional Treatment Unfortunately, cancers that respond early to chemotherapy and radiation treatment often relapse in a form that is resistant to these conventional treatments. The underlying detailed mechanism of such resistance is not well understood, but with regard to the tumor microenvironment (Borovski T. et al. Cancer Res. 2011: 71 (3): 634-639). Page), aberrant regulation of CSC stem cell signaling pathways (see Boman et al., 2008), may play an important role in the acquisition of such resistance.

4. Ability to Contribute to Tumor Recurrence and Metastasis Chemotherapy and radiation kill the majority of rapidly dividing cancer cells within the tumor, but CSCs do not die and survive by acquiring resistance (See Jordan et al., 2006). The ability to radiation / chemoresistant CSCs also metastasize to different sites in the body and maintain stemness through interaction with the microenvironment at these locations, thereby allowing the spread of metastatic tumor growth Can also be earned (see Boman et al., 2008). Interestingly, the enhanced tumorigenicity of this CSC correlates with the expression of genes normally expressed in adult stem cells, such as cell surface markers like CD44, CD133 and CD166.

  Because CSC survival may be the main reason for cancer to relapse after treatment with chemotherapy and / or radiation, anti-cancer therapies that specifically target CSC's aberrant signaling pathways are tumors. It can help prevent metastasis and provide viable treatment options for patients with recurrent disease that can no longer be treated using conventional therapies. Thus, such an approach can improve the survival and quality of life of cancer patients, particularly patients suffering from metastatic disease. Unleashing this untapped potential requires the identification and validation of pathways essential for CSC self-replication and survival. Although many signaling pathways that regulate the proliferation and differentiation of embryonic or adult stem cells are known, it remains unclear whether these same pathways are required for self-renewal and survival of cancer stem cells.

  The transcription factor signal transduction and transcription activation factor 3 (also known as acute phase response factor, APRF, DNA binding proteins APRF, ADMIO3, HIES and referred to herein as STAT3) includes STAT5a and STAT5b , A member of the family of seven transcription factors, STAT1 to STAT6. STAT is either by receptor associated tyrosine kinase like Janus kinase (JAK) or by receptor with endogenous tyrosine kinase activity such as PDGFR, EGFR, FLT3, EGFR, ABL, KDR, c-MET or HER2 Activated. When tyrosine is phosphorylated by a receptor-related kinase, the phosphorylated STAT protein ("pSTAT") dimerizes as a homodimer or heterodimer and translocates from cytoplasm to nucleus, where the target gene It binds to the specific DNA response element of the promoter of and induces gene expression. STAT2, 4 and 6 mainly regulate the immune response, STAT3 together with STAT1 and STAT5, genes that control the cell cycle (cyclins D1, D2 and c-MYC), genes that control cell survival (BCL- Regulates the expression of XL, BCL-2, MCL-1) and genes that control angiogenesis (HIF1α, VEGF) (Furqan et al., Journal of Hematology & Oncology (2013) 6: 90).

  In normal cells, STAT3 activation is transient and tightly regulated, for example, lasting about 30 minutes to several hours. However, STAT3 has been found to be abnormally active in a wide variety of human cancers, including all major carcinomas as well as some hematological tumors. Persistently active STAT3 is present in all breast and lung cancers and in more than half of colorectal cancer (CRC), ovarian cancer, hepatocellular carcinoma, multiple myeloma, all head / neck It is present in more than 95% of head cancer. Thus, STAT3 appears to play a central role in cancer progression and may be one of the major mechanisms by which cancer cells acquire drug resistance. STAT3 includes but is not limited to BCL-XL, c-MYC, cyclin D1, VEGF, MMP-2, and survivin, in cell cycle, cell survival, carcinogenesis, tumor invasion, and metastasis It is a potent transcriptional regulator that targets the genes involved. STAT3 is also a very important negative regulator of tumor immune surveillance and immune cell recruitment. Thus, STAT3 can enable the survival and self-replication ability of CSCs across a wide range of cancers. For example, pharmaceutical compounds having activity against CSC, through STAT3 inhibition, are very promising as treatment options for cancer patients with advanced disease.

In certain embodiments, at least one compound selected from compounds having Formula A can be, for example, an inhibitor of CSC growth and survival. No. 8,877,803 describes compounds having the formula A that inhibit STAT3 pathway activity with a cell IC ₅₀ of about 0.25 μM. Example 13 of US Pat. No. 8,877,803 presents an exemplary method of synthesizing a compound having at least one Formula A. In certain embodiments, at least one compound selected from compounds having Formula A can be used, for example, in a method for treating cancer. In Example 6 of PCT Patent Application No. PCT / US2014 / 033566, at least one compound selected from the compounds having Formula A was selected to enter into clinical trials for patients with advanced cancer. The disclosures of US Pat. No. 8,877,803 and PCT Patent Application No. PCT / US2014 / 033566 are hereby incorporated by reference in their entirety.

  Protein kinases are a family of enzymes that regulate a wide variety of cellular processes, including cell growth, cell proliferation, cell differentiation, and metabolism. Protein kinases transmit cell growth signals through sequential phosphorylation of pathway partners. Thus, pharmacological inhibition of any kinase on a given signal transduction cascade can block transmission along the entire pathway. In addition, protein kinases are known to play a role in disease states and disorders, for example, kinase mutations and / or overexpression of kinases frequently occur in many cancers, so that often there is no control. A hyperactivated activity is provided which correlates with cell growth. Thus, cancer stem cell pathway kinase (CSCPK) is an important therapeutic target for the treatment of various cancers (see, eg, US Pat. No. 8,299,106). Non-limiting examples of CSCPK include STK33, MELK, AXL, p70S6K, and PDGFRα.

  PDGF ligand activation of the receptor tyrosine kinase (RTK), CSCPK PDGFRα, triggers a signal transduction cascade that activates gene expression necessary for cell proliferation, angiogenesis, and apoptosis. PDGFRα is a class III receptor tyrosine kinase that is associated with CFS-1 receptor / c-fms and stem cell growth factor / c-kit proto-oncogene family. The PDGFRα pathway, active in early fetal development, includes hepatocellular carcinoma (HCC), head and neck cancer, brain tumors, gastrointestinal tumors, skin cancer, prostate cancer, ovarian cancer, breast cancer, sarcomas, and leukemia. Is also reactivated in cancer. Furthermore, PDGFRα activation has recently been shown to play an important role in bone metastasis of prostate cancer. Specific targeting of PDGFRα using monoclonal antibodies leads to a marked reduction of tumor cell growth and survival with minimal toxicity. Blockade of PDGFRα signaling may be a viable target to treat a wide range of cancers with minimal toxicity.

CSCPK STK 33 or human serine / threonine kinase 33 is a member of the Ca ²⁺ / calmodulin dependent kinase family (CAMK). Although its function in normal biology is not well understood, STK33 may play a specific role in the dynamic behavior of the intermediate filament cytoskeleton through the phosphorylation of vimentin. STK33 knockdown reduces tumor-related gene expression, inhibits cell migration, invasion, and EMT, and indicates that STK33 may be a mediator of signal transduction pathways involved in cancer. For example, STK33 has been implicated in tumor development and progression of hypopharyngeal squamous cell carcinoma (HSCC) (Huang et al., BMC Cancer. (2015) 15: 13).

  Maternal embryonic leucine zipper kinase (or MELK) is a serine / threonine-CSCPK involved in the regulation of cell cycle, stem cell self-renewal, apoptosis and splicing. MELK has a broad range of substrate specificities. For example, MELK acts as an activator of apoptosis by phosphorylation and activation of MAP3K5 / ASK1. MELK also regulates cell cycle by phosphorylation of CDC25B, which triggers the localization of CDC25B to centrosomes and mitotic spindle poles during mitosis. MELK also phosphorylates and inhibits BCL2L14, which indicates that it may play a role in carcinogenesis in the breast by inhibiting the proapoptotic function of BCL2L14.

The CSCPK AXL receptor tyrosine kinase (or AXL) is a member of the Tyro 3-Axl-Mer (TAM) receptor tyrosine kinase subfamily. The encoded protein has an extracellular domain composed of two immunoglobulin-like (IgL) motifs at the N-terminus followed by two fibronectin type III motifs (FNIII). It transmits signals from the extracellular matrix into the cytoplasm by binding to vitamin K dependent protein growth arrest specific 6 (Gas 6). Downregulation of AXL suppresses cell growth and invasion of brain tumors (Vajkoczy et al., Proc. Natl. Acad. Sci. US A., November 2006; 103 (15): 5799-804). Thus, AXL is a potential mediator of motility and can control the invasiveness of breast cancer cells (Zhang et al., Cancer Res. (2008) 15; 68 (6): 1905-15).
p70S6K (or p70 S6 kinase) is a serine / threonine CSCPK that is part of the PI3K / Akt / mTOR / P70S6K signaling pathway. Activation of p70S6K triggers phosphorylation of the S6 ribosomal protein and induces protein synthesis. p70 S6 kinase (p70 S6K) is frequently activated in high grade malignant human ovarian cancer, suggesting a possible role in metastasis.
In certain embodiments, at least one compound selected from compounds having Formula B can be, for example, an inhibitor of CSCPK (eg, compound BBI 503). As disclosed in US Pat. No. 8,299,106, compounds of Formula B inhibit CSC proliferation and / or survival. Examples 1-5 of US Pat. No. 8,299,106 further provide exemplary methods of synthesizing at least one compound selected from compounds having Formula B. U.S. Patent No. 8,299,106 is incorporated herein by reference in its entirety.

U.S. Patent No. 8,877,803 U.S. Patent No. 8,299,106

Gupta PB et al., Nat. Med. 2009; 15 (9): 1010-1012 Clarke MF, Biol. Blood Marrow Transplant. 2009; 11 (No. 2, Appendix 2): 14-16 Jordan CT et al., N. Engl. J. Med. 2006; 355 (12): 1253-1261. Ajani et al., Semin. Oncol. (2015) Vol. 42, Appendix 1: S3-17. Boman BM et al., J. Clin. Oncol. 2008; 26 (17): 2828-2838. Borovski T. et al., Cancer Res. 2011: 71 (No. 3): 634-639. Furqan et al., Journal of Hematology & Oncology (2013) 6: 90 Huang et al., BMC Cancer. (2015) 15: 13 Vajkoczy et al., Proc. Natl. Acad. Sci. U.S. A., November 2006; 103 (15): 5799-804. Zhang et al., Cancer Res. (2008) 15; 68 (6): 1905-15.

  The present disclosure provides that the combination of the treatment of at least one compound selected from the compounds of formula A and the treatment of at least one compound selected from the compounds of formula C adds the effect of each compound acting alone We report the surprising discovery that it had the effect of reducing the number of cancer cells, including cancer stem cells, which is larger. For example, the combination of treatments of the present disclosure results in in vitro and in comparison to the effect observed after treatment with the compound of Formula A alone and after treatment with the compound of Formula C alone. Enhanced inhibition of expression of cancer cell stem cell related factors both in vivo and enhanced reduction of the number of cancer stem cells in both in vitro and in vivo was provided.

  In one example, a combination of at least one compound selected from compounds of Formula A (eg, BBI 608) and at least one compound selected from compounds of Formula C (eg, Sorafenib) is used to generate HCC cell lines Treatment resulted in an enhanced reduction in the number of bulk tumor cells (FIG. 1) and a reduction in the number of spheres formed by CSCs after culture in nonadherent stem cell medium (FIG. 2). FIG. 3 also shows that as a result of treatment with at least one compound of Formula A (eg, BBI 608), there is a reduction in tumor volume in the HepG2 mouse xenograft mouse model as compared to treatment with a control. Indicates

  The present disclosure provides that the combination treatment of at least one compound selected from compounds having Formula B and at least one compound selected from compounds having Formula C (sorafenib) acts with either compound alone. We further report the surprising finding that it had the effect of reducing the growth and / or survival of cancer cells, including cancer stem cells, which is greater than the sum of the effects. For example, the combination of treatments of the present disclosure adds the effect of treating a tumor using a compound of Formula B (eg, BBI 503) alone and a compound of Formula C (eg, Sorafenib) alone. Enhanced inhibition of expression of cancer cell stem cell related factors in vitro and in vivo resulted in enhanced reduction of the number of cancer stem cells in vitro and in vivo.

  In another example, compounds of Formula B were active against CSCs derived from HCC cell lines, both alone and in combination with compounds of Formula C (eg, sorafenib). The compounds of Formula B not only inhibited the growth and / or survival of cancer stem cells, but also reduced the ability of CSCs to form characteristic spheres in non-adherent stem cell media. In contrast, the equivalent treatment with the compound of Formula C did not have any significant inhibitory activity on CSC sphere formation ability or on proliferation and / or survival of cancer cells. In contrast, treatment of cancer cells with a combination of a compound of Formula B and a compound of Formula C enhanced the reduction of colony formation (FIG. 4, FIG. 5 and FIG. 6). Compounds of Formula B, eg, BBI 503, have also been shown to inhibit the expression of cancer stem cell markers such as CD133 and CD44.

  In another example, treating a tumor with a compound of Formula B (e.g., BBI 503) in a mouse xenograft model of human liver cancer (HepG2) significantly inhibited tumor growth relative to controls. . FIG. 7 shows that the mean tumor volume of animals treated with the compound of formula B was less than 50% of the mean tumor volume obtained in the control.

  Without being limited to any particular knowledge or hypothesis, it is believed that components of the combination of treatments of the present disclosure act on different pathways associated with cancer cells (eg, CSCs). A combination of a compound of Formula A and a compound of Formula C or a compound of Formula B and a compound of Formula C in a treatment that is greater than the sum of the effects observed after treatment with either compound alone An inhibition of cell proliferation and / or survival is provided (sometimes referred to as "enhanced" or "synergistic" effects). Compounds of formula A may work by inhibiting the STAT3 signaling pathway. Specifically, the compound of formula A binds directly to activated STAT3 (eg phosphorylated STAT3) and inhibits its activity, thereby causing the stemness associated transcription factor c-MYC, OCT4, SOX2, And can prevent transcription of STAT3-dependent target genes, including and .beta.-catenin. Compounds of Formula B can inhibit the activity of multiple malignancy-associated serine-threonine kinases (or cancer stem cell pathway kinases (CSCPKs)).

In certain embodiments, a method for treating cancer, comprising:
Compounds having the formula A:
A therapeutically effective amount of at least one compound selected from a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing, and a compound having the Formula C:
Treating cancer with a therapeutically effective amount of at least one compound selected from the prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing Disclosed herein are methods comprising administering to a subject in need thereof.

In certain embodiments, a method for treating cancer, comprising:
Compounds having Formula B:
A therapeutically effective amount of at least one compound selected from a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing, and a compound having the Formula C:
Treating cancer with a therapeutically effective amount of at least one compound selected from the prodrugs, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing Disclosed herein are methods comprising administering to a subject in need thereof.

  In certain embodiments, a method of treating cancer comprising: (a) a cancer stem cell inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing. And a therapeutically effective amount of at least one first compound selected from any of the aforementioned solvates; and (b) a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, any of the foregoing Administering to a subject in need of treating cancer a therapeutically effective amount of at least one second compound selected from a pharmaceutically acceptable salt of and a solvate of any of the foregoing A method is disclosed including the step of

  In certain embodiments, the cancer stem cell inhibitor may be, for example, a STAT3 pathway inhibitor.

  In certain embodiments, the cancer stem cell inhibitor is, for example, 2- (1-hydroxyethyl) -naphtho [2,3-b] furan-4,9-dione, 2-acetyl-7-chloro-. Naphtho [2,3-b] furan-4,9-dione, 2-acetyl-7-fluoro-naphtho [2,3-b] furan-4,9-dione, 2-acetylnaphtho [2,3-b A furan-4,9-dione, 2-ethyl-naphtho [2,3-b] furan-4,9-dione, a prodrug of any of the foregoing, a derivative of any of the foregoing, a pharmaceutical of any of the foregoing It may be selected from pharmaceutically acceptable salts and solvates of any of the foregoing.

In certain embodiments, the cancer stem cell inhibitor may be, for example, a cancer stem cell pathway kinase (CASPK) inhibitor. In certain embodiments, cancer stem cell inhibitors include, for example, compounds having the following formula:
Or any of the aforementioned prodrugs, any of the aforementioned derivatives, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates.

  In certain embodiments, from (1) a compound of Formula A, a compound of Formula B, a prodrug, a derivative, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing From at least one first compound selected, and (2) a compound of formula C, a prodrug, a derivative, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing Disclosed are kits comprising at least one second compound selected together with instructions for administration and / or use.

  In certain embodiments, (1) at least one selected from a compound of Formula A, a prodrug, a derivative, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing And at least one selected from compounds having formula C, prodrugs, derivatives, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. A kit is disclosed comprising a second compound of claim together with instructions for administration and / or use.

  In certain embodiments, (1) at least one selected from a compound of Formula B, a prodrug, a derivative, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing And at least one selected from compounds having formula C, prodrugs, derivatives, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. A kit is disclosed comprising a second compound of claim together with instructions for administration and / or use.

  In certain embodiments, (1) cancer stem cell inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing And (2) a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and any of the foregoing. Disclosed is a kit comprising at least one second compound selected from the solvates of (1) together with instructions for administration and / or use.

  Aspects and embodiments of the present disclosure have been described or will be readily apparent from the following detailed description. It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not intended to limit the scope of the claims.

FIG. 1 illustrates the enhanced inhibition of HCC colony formation by the Hep3B cell line after treating the cells with a combination of a compound of Formula A and a compound of Formula C.

FIG. 2 shows an example of enhanced inhibition of Sk-Hep1, Huh7, and HepG2 CSC viability following treatment of cells with a combination of a compound of Formula A and a compound of Formula C.

FIG. 3 shows an example of inhibition of tumor growth in a mouse xenograft model of HCC after treatment with a compound of Formula A.

FIG. 4 illustrates the enhanced inhibition of HCC colony formation by the Hep3B cell line after treating the cells with a combination of a compound of Formula B and a compound of Formula C.

FIG. 5 illustrates the enhanced inhibition of HCC colony formation by the Hub7 cell line after treating cells with a combination of a compound of Formula B and a compound of Formula C.

FIG. 6 shows an example of enhanced inhibition of Skhep1, Hep3B, and HepG2 CSC viability following treatment of cells with a combination of a compound of Formula B and a compound of Formula C.

FIG. 7 shows an example of inhibition of tumor growth in a mouse xenograft model of HCC after treatment with a compound of Formula B.

FIG. 8A shows the assessment of patients with progressive HCC treated with napabukacin (BBI 608, Compound A) and sorafenib (Compound C), evaluated according to RECIST 1.1 and Modified RECIST (mRECIST).

FIG. 8B shows the assessment of patients with advanced HCC treated with amkaceltiv (BBI 503, compound B) and sorafenib (compound C), evaluated according to RECIST 1.1 and modified RECIST (mRECIST).

  The following is a definition of terms used herein. The initial definitions provided for a group or term herein apply throughout the specification to the group or term individually or as part of another group, unless otherwise indicated.

  When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below those numerical values. Generally, as used herein, the term "about" is used to modify a numerical value above and below the stated value by a 20%, 10%, 5%, or 1% dispersion. In certain embodiments, the term "about" is used to correct a numerical value above and below the stated value by a 10% dispersion. In certain embodiments, the term "about" is used to modify a numerical value above and below the stated value by a 5% dispersity. In certain embodiments, the term "about" is used to correct a numerical value above and below the stated value by a 1% dispersity.

  Where a range of values is recited herein, the range of values is intended to encompass each value and subrange within that range. For example, "1 to 5 mg" is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 1 to 2 mg, 1 to 3 mg, 1 to 4 mg, 1 to 5 mg, 2 to 3 mg, 2 to 4 mg, 2 to 5 mg, 3 to 4 mg , 3-5 mg, and 4-5 mg are intended to be included.

  The terms "administer", "administering" or "administration" are used herein in their broadest sense. These terms refer to any method of introducing a compound or pharmaceutical composition described herein into a subject, eg, introducing the compound systemically, locally or in situ into a subject May include. Thus, a compound of the present disclosure (whether or not the composition comprises a compound) produced from the composition in a subject is encompassed by these terms. These terms, when used in conjunction with the terms "systemic" or "systemically", generally refer to the in vivo systemic absorption or accumulation of a compound or composition in the bloodstream, followed by systemic distribution Point to

  The term "subject" generally refers to an organism to which a compound or pharmaceutical composition described herein may be administered. The subject may be a mammal or mammalian cells, including human or human cells. The term also refers to an organism comprising a cell, or a donor or recipient of such a cell. In certain embodiments, the term "subject" is a human, a mammal and a non-mammal, such as a non-human primate, a mouse, to be a recipient of a compound or pharmaceutical composition described herein. Refers to any animal (eg, a mammal) including, but not limited to, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, fish, nematodes, and insects. In certain contexts, the terms "subject" and "patient" referring to a human subject are used interchangeably herein.

  The terms "effective amount" and "therapeutically effective amount" are not limited thereto but are sufficient to provide the intended results, including the treatment of diseases exemplified below. Refers to the amount of a compound or pharmaceutical composition as described in In certain embodiments, a "therapeutically effective amount" is a detectable death or inhibition of growth or spread of cancer cells, the size or number of tumors, and / or the level, stage, progression and / or progress of cancer. An effective amount for other measures of severity. In certain embodiments, a "therapeutically effective amount" refers to an amount administered systemically, locally or in situ (eg, an amount of a compound generated in situ in a subject). The therapeutically effective amount will vary depending on the intended application (in vitro or in vivo) or the subject being treated and the disease state, eg, weight and age of the subject, severity of the disease state, mode of administration, etc. These can be easily determined by one skilled in the art. The terms also apply to specific responses in target cells, such as doses that induce a reduction in cell migration. Specific doses may be, for example, the weight of the subject, the particular pharmaceutical composition, the subject and the subject's age and risk for existing health or wellness, the dosing regimen to be followed, the severity of the disease, other agents It may vary depending on whether it is administered in combination with, the timing of administration, the tissue to which it is administered, as well as the physical delivery system with which it is delivered.

  A "therapeutically effective amount" referring to treatment of a subject's cancer means, for example, an amount capable of eliciting one or more of the following effects: (1) reduction in the progression of cancer in the subject or Some inhibition of cancer or tumor growth, including rest; (2) reduction in the number of cancer or tumor cells; (3) reduction in tumor size; (4) infiltration of cancer or tumor cells into peripheral organs (5) inhibition of metastasis, such as reduction or arrest; (6) enhancement of anti-tumor immune response, which may but need not result in regression or rejection of tumor, or (7) cancer Or some degree of elimination of one or more symptoms associated with the tumor. The therapeutically effective amount may vary according to factors such as the medical condition, age, sex and weight of the individual, and the ability of the one or more anti-cancer agents to elicit the desired response in the individual. A "therapeutically effective amount" can be, for example, an amount of a compound that has a therapeutically beneficial effect that outweighs any toxic or detrimental effects caused by the administration of the compound.

  As used herein, the terms "treatment", "treating", "recovering" and "promoting" are used interchangeably herein. These terms refer to techniques for obtaining beneficial or desired results, including, but not limited to, therapeutic and / or prophylactic benefits. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, the therapeutic benefit is realized in the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, and thus the subject may still suffer from the underlying disorder. Also, improvement is observed in the subject. For prophylactic benefit, the pharmaceutical composition may be a subject at risk of developing a particular disease, or possibly one or more of the physiological symptoms of the disease, if not diagnosed. Can be administered to a subject who has been reported.

  The terms "combination", "combination" or "combination treatment" as used herein are used to treat at least two disorders, conditions or symptoms, for example a cancer condition. (For example, at least one first compound selected from a compound having Formula A and a compound having Formula B, and at least one second compound selected from a compound having Formula C, and 1 Refers to administration of the species or plurality of additional agents). Such combination / combination treatment may involve administration before, during, and / or after administration of one agent of a second agent. The first agent and the second agent can be administered to the subject in separate pharmaceutical compositions, together, separately or sequentially. The first agent and the second agent can be administered to the subject by the same or different administration routes. In certain embodiments, the combination of treatments is a treatment selected from a therapeutically effective amount of at least one first compound selected from a compound having Formula A and a compound having Formula B and a compound having Formula C An effective amount of at least one second compound is included.

  For example, at least one first compound selected from cancer stem cell inhibitors and at least one second compound selected from a kinase inhibitor may have different mechanisms of action. In certain embodiments, the combination treatment comprises preventing or treating at least one first compound selected from a cancer stem cell inhibitor and at least one second compound selected from a kinase inhibitor. The effects are improved by working together to have additive, synergistic or enhanced effects. In certain embodiments, the combination treatments of the present disclosure relate to at least one first compound selected from cancer stem cell inhibitors and at least one second compound selected from kinase inhibitors. Side effects are reduced. Administration of at least one first compound selected from a cancer stem cell inhibitor and at least one second compound selected from a kinase inhibitor may be separated by up to several weeks. It is better, but more generally within 48 hours, most commonly within 24 hours.

  As used herein, the term "prodrug" refers to a derivative of a parent drug molecule that needs to be biotransformed naturally or by an enzyme in an organism to release the active drug. . For example, a prodrug or prodrug is a variant or derivative of a compound of formula A, B or C, which has a cleavable group under certain metabolic conditions, which when cleaved results in the compound of formula A, B or C, respectively. is there. Thus, such prodrugs are pharmaceutically inactive in vivo until they are active under physiological conditions, for example as a result of solvolysis or enzymatic degradation. The prodrug compounds described herein are single, double, depending on the number of biotransformation steps required to release the biologically active drug, and the number of functionalities present in the precursor form. It may be called a triple etc.

  Prodrug forms often provide the advantage of solubility, tissue compatibility, or delayed release in mammalian organisms. Prodrugs generally known in the art are, for example, well-known acid derivatives, such as esters prepared by reaction of a parent acid and a suitable alcohol, amides prepared by reaction of a parent acid compound and an amine, Or a basic group which reacts to form an acylated base derivative, but is not limited thereto. Other prodrug derivatives can also be combined with other features disclosed herein to enhance bioavailability. It is understood by those skilled in the art that certain disclosed compounds having free amino, amido, hydroxy, or carboxyl groups can be converted to prodrugs. Prodrugs include two or more (eg, two, three, etc.) covalently joined by a peptide bond to an amino acid residue, or the free amino, hydroxy, or carboxylic acid group of a compound of the disclosure Or compounds having a polypeptide chain of 4 amino acid residues. As amino acid residues, 20 naturally occurring amino acids generally indicated by a three letter symbol, as well as, for example, 4-hydroxyproline, hydroxylysine, demosine, isodesmosine, 3-methylhistidine, norvaline, Included are beta-alanine, gamma aminobutyric acid, citrulline homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs may also include compounds having a carbonate, carbamate, amide, or alkyl ester moiety covalently linked to any of the above-described substituents disclosed herein.

  The terms "synergism", "synergistic", "synergistic" or "enhanced" as used herein refer to the interaction of two or more components or a combination effect resulting in a combined effect It refers to the combined effect exceeding the sum (or "additive effect") of their separate effects. The synergistic effect is that the compounds are (1) co-formulated and simultaneously administered or delivered as a combined preparation; (2) delivered alternately or in parallel as separate preparations; or (3) some other This can be achieved if the regimen of When delivered in an alternating therapy, synergistic effects may be achieved when the compounds are administered or delivered sequentially, for example, in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternating treatment an effective dose of each active ingredient may be administered, for example sequentially or sequentially, while in combination treatment two or more of the effective doses are administered. The active ingredients are co-administered. A synergistic anti-cancer effect refers to an anti-cancer effect which is greater than the expected pure additive effect of the individual compounds of the separately administered combination.

  As used herein, the term "cancer stem cell inhibitor" refers to at least one cancer stem cell or expression of a plurality of cancer stem cell genes (eg, production of a functional product, eg, a protein) A molecule capable of targeting, reducing, inhibiting, interfering or modulating at least one of the pathways involved in The expressed or expressed protein can be used as a biomarker for the corresponding cancer stem cell gene. Examples of these biomarkers include, but are not limited to, β-catenin, NANOG, SMO, SOX2, STAT3, AXL, ATM, c-MYC, KLF4, survivin, or BMI-1. Cancer stem cell inhibitors can alter the growth of cancer stem cells as well as the growth of heterogeneous cancer cells.

  In certain embodiments, a cancer stem cell inhibitor can be, for example, a small molecule that binds to a protein encoded by a cancer stem cell gene. In certain embodiments, a cancer stem cell inhibitor is, for example, a biological, eg, recombinant binding protein or peptide that binds to a protein encoded by a cancer stem cell gene (eg, APTSTAT3; Kim et al .; Cancer Res. (2014) 74 (8): 2144-51) or nucleic acids (e.g. STAT3 aiRNA; U.S. Patent No. 9, 328, the entire contents of which are incorporated herein). See 345), or a conjugate thereof. In certain embodiments, the cancer stem cell inhibitor may be, for example, a cell. In certain embodiments, the cancer stem cell inhibitor may be, for example, a STAT3 inhibitor (eg, binds STAT3 and inhibits its biological activity (Furtek et al., ACS Chem. Biol., 2016) 11 (2nd), pages 308-318)). In certain embodiments, a cancer stem cell inhibitor may be, for example, a CSCPK inhibitor.

  In certain embodiments, the cancer stem cell inhibitor is, for example, 2- (1-hydroxyethyl) -naphtho [2,3-b] furan-4,9-dione, 2-acetyl-7-chloro-. Naphtho [2,3-b] furan-4,9-dione, 2-acetyl-7-fluoro-naphtho [2,3-b] furan-4,9-dione, 2-acetylnaphtho [2,3-b ] Furan-4,9-dione, or 2-ethyl-naphtho [2,3-b] furan-4,9-dione, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, And at least one compound selected from any of the aforementioned solvates.

In certain embodiments, for example, a cancer stem cell inhibitor is a compound having, for example, the following formula:
Or at least one compound selected from any of the aforementioned prodrugs, any of the aforementioned derivatives, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates .

  In certain embodiments, the cancer stem cell inhibitors of the present disclosure may be administered in an amount ranging from about 300 mg to about 700 mg. In certain embodiments, the cancer stem cell inhibitor may be administered in an amount ranging from about 700 mg to about 1200 mg. In certain embodiments, a cancer stem cell inhibitor may be administered in an amount ranging from about 800 mg to about 1100 mg. In certain embodiments, the cancer stem cell inhibitor may be administered in an amount ranging from about 850 mg to about 1050 mg. In certain embodiments, the cancer stem cell inhibitor may be administered in an amount ranging from about 960 mg to about 1000 mg.

  In certain embodiments, the total amount of cancer stem cell inhibitor may be administered once daily. In certain embodiments, a cancer stem cell inhibitor may be administered daily at a dose of about 480 mg. In certain embodiments, a cancer stem cell inhibitor may be administered daily at a dose of about 960 mg. In certain embodiments, a cancer stem cell inhibitor may be administered daily at a dose of about 1000 mg. In certain embodiments, the total amount of cancer stem cell inhibitor may be administered in divided doses more than once daily, such as twice daily (BID) or more frequently. In certain embodiments, a cancer stem cell inhibitor may be administered twice daily at a dose of about 240 mg. In certain embodiments, a cancer stem cell inhibitor may be administered twice daily at a dose of about 480 mg. In certain embodiments, a cancer stem cell inhibitor may be administered twice daily at a dose of about 500 mg. In certain embodiments, cancer stem cell inhibitors can be administered orally.

In certain embodiments, the cancer stem cell inhibitor may be, for example, at least one compound selected from compounds having Formula A. As used herein, the terms "compound having Formula A", "compounds having Formula A", and "Compound A" refer to Compounds which can be used interchangeably and each have the formula A:
By its prodrugs, their derivatives, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing are meant compounds.

  In certain embodiments, prodrugs and derivatives of compounds having Formula A can be, for example, STAT3 inhibitors. Non-limiting examples of prodrugs of compounds having Formula A include, for example, phosphate esters and phosphate diesters described as compound numbers 4011 and 4012 in U.S. Pre-Grant Patent Application Publication No. 2012/0252763, and Also suitable are the compounds described in US Pat. No. 9,150,530. Non-limiting examples of derivatives of compounds having Formula A include, for example, those disclosed in US Pat. No. 8,977,803. The disclosures of US Patent Application Publication No. 2012/0252763 and US Patent Nos. 9,150,530 and 8,977,803 are hereby incorporated by reference in their entirety.

A compound having the formula A shown below,
May also be known as 2-acetyl naphtho [2,3-b] furan-4,9-dione, napubucacin, BBI 608, or BB 608, including its tautomers.

  Suitable methods of preparing 2-acetylnaphtho [2,3-b] furan-4,9-dione, including its crystalline form, and additional cancer stem cell inhibitors are described in WO2009 / 036099, WO2009 / 036101. WO 2011/116398, WO 2011/116399, and co-owned PCT applications published as WO 2014/169078, the contents of each of which are incorporated herein by reference in their entirety.

  In certain embodiments, Compound A can be administered in an amount ranging from about 80 mg to about 1500 mg. In certain embodiments, Compound A can be administered in an amount ranging from about 160 mg to about 1000 mg. In certain embodiments, Compound A can be administered in an amount ranging from about 300 mg to about 700 mg daily. In certain embodiments, Compound A can be administered in an amount ranging from about 700 mg to about 1200 mg. In certain embodiments, Compound A can be administered in an amount ranging from about 800 mg to about 1100 mg. In certain embodiments, Compound A can be administered in an amount ranging from about 850 mg to about 1050 mg. In certain embodiments, Compound A can be administered in an amount ranging from about 960 mg to about 1000 mg. In certain embodiments, the total amount of Compound A can be administered, for example, once daily. In certain embodiments, Compound A can be administered daily, for example, at a dose of about 480 mg. In certain embodiments, Compound A can be administered daily, for example, at a dose of about 960 mg. In certain embodiments, Compound A can be administered daily, for example, at a dose of about 1000 mg. In certain embodiments, the total amount of Compound A may be administered, for example, more than once daily, for example, twice daily (BID) or more frequently, in divided doses. In certain embodiments, Compound A can be administered in amounts ranging from about 80 mg twice daily to about 750 mg twice daily. In certain embodiments, Compound A can be administered in amounts ranging from about 80 mg twice daily to about 500 mg twice daily. In certain embodiments, Compound A can be administered twice a day, for example, at a dose of about 240 mg. In certain embodiments, Compound A can be administered twice daily, for example, at a dose of about 480 mg. In certain embodiments, Compound A may be administered twice daily at a dose of, for example, about 500 mg. In certain embodiments, Compound A can be administered, for example, orally.

In certain embodiments, the cancer stem cell inhibitor may be, for example, at least one compound selected from compounds having Formula B. As used herein, the terms "a compound having Formula B", "compounds having Formula B" and "Compound B" refer to Compounds which can be used interchangeably and each have the formula B:
Or a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate selected from any of the foregoing solvates.

  In certain embodiments, the cancer stem cell inhibitor is, for example, a cancer stem cell pathway kinase (CSCPK) inhibitor, a STK33 inhibitor, a MELK inhibitor, an AXL inhibitor, a p70S6K inhibitor, a PDGFRα inhibitor, or a NANOG It may be an inhibitor. In certain embodiments, the cancer stem cell inhibitor may be, for example, a cancer stem cell pathway kinase (CSCPK) inhibitor. In certain embodiments, the cancer stem cell inhibitor can be, for example, an STK33 inhibitor. In certain embodiments, the cancer stem cell inhibitor may be, for example, a MELK inhibitor. In certain embodiments, the cancer stem cell inhibitor may be, for example, an AXL inhibitor. In certain embodiments, the cancer stem cell inhibitor may be, for example, a p70 S6K inhibitor. In certain embodiments, the cancer stem cell inhibitor may be, for example, a PDGFRα inhibitor. In certain embodiments, the cancer stem cell inhibitor can be, for example, a NANOG inhibitor.

  In certain embodiments, compounds having Formula B and derivatives thereof may be, for example, cancer stem cell pathway kinase (CSCPK) inhibitors. In certain embodiments, compounds having Formula B and derivatives thereof may include, for example, inhibitors of STK33, MELK, AXL, p70S6K, and PDGFRα. In certain embodiments, at least one compound selected from compounds having Formula B and derivatives thereof may be, for example, STK33 inhibitors. In certain embodiments, at least one compound selected from compounds having Formula B and its derivatives can be, for example, a MELK inhibitor. In certain embodiments, at least one compound selected from compounds having Formula B and its derivatives can be, for example, an AXL inhibitor. In certain embodiments, at least one compound selected from compounds having Formula B and a derivative thereof can be, for example, a p70 S6K inhibitor. In certain embodiments, at least one compound selected from compounds having Formula B and its derivatives can be, for example, a PDGFRα inhibitor. In certain embodiments, at least one compound selected from compounds having Formula B and derivatives thereof can inhibit NANOG expression. Non-limiting examples of compounds having Formula B and derivatives thereof can include, for example, derivatives disclosed in US Pat. No. 8,299,106 and PCT Patent Application Publication No. WO 2014160401. The disclosures of US Pat. No. 8,299,106 and PCT Patent Application Publication No. WO 2014160401 are incorporated herein by reference in their entirety.

In certain embodiments, the CSCPK inhibitor is, for example, a compound having the following formula:
, A prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing.

  In certain embodiments, the CSCPK inhibitor can be, for example, at least one compound selected from a compound having Formula B.

  Suitable methods of preparing compounds of Formula B and derivatives thereof are described in US Patent No. 8,299,106 and PCT Patent Application Publication No. WO 2014 160 401; the contents of each application are herein incorporated by reference in their entirety. Incorporated into the book.

  In certain embodiments, CSCPK inhibitors may be administered in amounts ranging from about 20 mg to about 600 mg. In certain embodiments, CSCPK inhibitors may be administered in amounts ranging from about 50 mg to about 500 mg. In certain embodiments, CSCPK inhibitors may be administered in amounts ranging from about 80 mg to about 400 mg. In certain embodiments, a CSCPK inhibitor may be administered in an amount ranging from about 80 mg to about 300 mg. In certain embodiments, a CSCPK inhibitor can be administered, for example, once daily. In certain embodiments, a CSCPK inhibitor can be administered daily, for example, at a dose of about 100 mg. In certain embodiments, a CSCPK inhibitor can be administered daily, for example, at a dose of about 200 mg. In certain embodiments, a CSCPK inhibitor can be administered daily, for example, at a dose of about 300 mg. In certain embodiments, the total amount of CSCPK inhibitor can be administered, for example, in a single daily dose. In certain embodiments, the total amount of CSCPK inhibitor may be administered, for example, more than once daily, for example, twice daily (BID) or more often in divided doses. In certain embodiments, a CSCPK inhibitor can be administered, for example, once daily at a dose of about 100 mg. In certain embodiments, a CSCPK inhibitor can be administered, for example, once daily at a dose of about 200 mg. In certain embodiments, CSCPK inhibitors can be administered, for example, orally.

  In certain embodiments, Compound B can be administered in an amount ranging from about 20 mg to about 600 mg. In certain embodiments, Compound B can be administered in an amount ranging from about 50 mg to about 500 mg. In certain embodiments, Compound B can be administered in an amount ranging from about 80 mg to about 400 mg. In certain embodiments, Compound B can be administered in an amount ranging from about 80 mg to about 300 mg. In certain embodiments, Compound B can be administered, for example, once daily. In certain embodiments, Compound B can be administered daily, for example, at a dose of about 100 mg. In certain embodiments, Compound B can be administered daily, for example, at a dose of about 200 mg. In certain embodiments, Compound B can be administered daily, for example, at a dose of about 300 mg. In certain embodiments, the total amount of Compound B can be administered, for example, in a single daily dose. In certain embodiments, the total amount of Compound B may be administered, for example, more than once daily, eg, twice daily (BID) or more frequently, in divided doses. In certain embodiments, Compound B can be administered, for example, once daily at a dose of about 100 mg. In certain embodiments, Compound B can be administered once daily at a dose of, for example, about 200 mg. In certain embodiments, Compound B can be administered, for example, orally.

  As used herein, the terms "kinase inhibitor" or "kinase inhibitors" target, reduce, inhibit, target at least one activity of multiple protein kinases Refers to molecules that can, interfere or modulate. Examples of these protein kinases include intracellular kinases (eg c-CRAF, BRAF and mutant BRAF) and cell surface kinases (eg KIT, FLT-3, RET, RET / PTC, VEGFR-1, VEGFR) -2, VEGFR-3, and PDGFR-β), but is not limited thereto. Examples of kinase inhibitors include afatinib (EGFR / ErbB2 inhibitor), axitinib, (VEGFR1 / VEGFR2 / VEGFR3 / PDGFRB / c-KIT inhibitor), bosutinib (Bcr-Abl / SRC inhibitor), cetuximab (EGFR inhibition) Agents), cobimetinib (MEK inhibitor), crizotinib (ALK / Met inhibitor), cabozantinib (RET / MET / VEGFR2 inhibitor), dasatinib (multiple kinase inhibitors), entretinib (TrkA / TrkB / TrkC / ROS1 / ALK) Inhibitor), erlotinib (EGFR inhibitor), fostamatinib (Syk inhibitor), gefitinib (EGFR inhibitor), ibrutinib (BTK inhibitor), imatinib (Bcr-Abl inhibitor), lapatinib (EGFR / ErbB2) Harms), lenvatinib (VEGFR2 inhibitor), mubritinib, nilotinib (Bcr-Abl inhibitor), pazopanib (VEGFR2 / PDGFR / c-kit inhibitor), pegaptanib (VEGF inhibitor), lucsolitinib (JAK inhibitor), sorafenib (Multiple kinase inhibitors), sunitinib (multiple kinase inhibitors), SU6656 (Src inhibitors), vandetanib (RET / VEGFR / EGFR inhibitors) or Vemurafenib (BRAF inhibitors), but it is limited to them I will not.

In certain embodiments, the kinase inhibitor may be, for example, at least one compound selected from compounds having Formula C. As used herein, the terms "compound having formula C (a compound having Formula C)", "compounds having Formula C (compound C having formula C)" and "compound C (Formula C)" Compounds which can be used interchangeably and each have the formula C:
Or a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate selected from any of the foregoing solvates. Compound C is also known as 4- [4-[[4-chloro-3- (trifluoromethyl) phenyl] carbamoylamino] phenoxy] -N-methyl-pyridine-2-carboxamide, nexavar, or sorafenib There is a case.

  In certain embodiments, Compound C can be administered in an amount ranging from about 80 mg to about 1500 mg. In certain embodiments, Compound C can be administered in an amount ranging from about 100 mg to about 1200 mg. In certain embodiments, Compound C can be administered in an amount ranging from about 200 mg to about 1000 mg daily. In certain embodiments, Compound C can be administered in an amount ranging from about 400 mg to about 900 mg. In certain embodiments, Compound C can be administered in an amount ranging from about 600 mg to about 900 mg. In certain embodiments, Compound C can be administered in an amount ranging from about 700 mg to about 900 mg. In certain embodiments, Compound C can be administered in an amount of about 800 mg. In certain embodiments, the total amount of Compound C can be administered, for example, once daily. In certain embodiments, the total amount of Compound C may be administered, for example, more than once daily, eg, twice daily (BID) or more frequently, in divided doses. In certain embodiments, Compound C can be administered in amounts ranging from about 80 mg twice daily to about 750 mg twice daily. In certain embodiments, Compound C can be administered in amounts ranging from about 80 mg twice daily to about 600 mg twice daily. In certain embodiments, Compound C can be administered, for example, twice daily at a dose of about 200 mg. In certain embodiments, Compound C may be administered twice daily, for example, at a dose of about 400 mg. In certain embodiments, Compound C can be administered, for example, orally. In certain embodiments, Compound C can be administered, for example, on an empty stomach. In certain embodiments, Compound C can be administered, for example, either about 1 hour before or about 2 hours after a meal.

  The terms "advance", "advanced" and "progression" as used herein refer to at least one of the following: (1) prior treatment of progressive disease (PD) (eg, (2) appearance of one or more new lesions after treatment with previous treatment (eg, chemotherapy); and (3) minimal sum by study, which is based on study If the line total is minimal, increase by at least 5% (e.g., 10%, 20%) of the total target lesion diameter with reference to the baseline sum).

  As used herein, “sensitizing” refers to the treatment of a subject who has already been resistant, non-responsive or somewhat responsive to a therapeutic (eg, chemotherapy) regimen For example, it can be meant to be sensitive, responsive or more responsive to a chemotherapy) regimen.

  The term "cancer" in a subject is typical for cells that cause cancer, such as uncontrolled growth, immortality, metastatic potential, rapid growth and growth rates, and certain morphological features. Refers to the presence of cells with features. Often, the cancer cells may be in the form of a tumor or mass, but such cells may be present alone in the subject, or in the bloodstream as independent cells such as leukemia or lymphoma cells. May circulate. As used herein, examples of cancer include lung cancer, pancreatic cancer, bone cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, breast cancer, uterine cancer, Ovarian cancer, peritoneal cancer, colon cancer, rectal cancer, colorectal adenocarcinoma, cancer of the anal area, stomach cancer, gastric cancer, gastrointestinal cancer, gastric adenocarcinoma, adrenocorticoid Cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophagus cancer, gastroesophageal junction cancer, gastroesophageal adenocarcinoma, chondrosarcoma, small intestine Cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, Ewing sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer Testicular cancer, ureteral cancer, renal pelvic carcinoma, mesothelioma, hepatocellular carcinoma, biliary tract Cancer, renal cell carcinoma, chronic or acute leukemia, lymphocytic lymphoma, neoplasm of central nervous system (CNS), spinal axis tumor, brain stem glioma, polymorphic glioblastoma, astrocytoma Schwann cell carcinoma, ependymoma, medulloblastoma, meningioma, squamous cell carcinoma, pituitary adenomas, refractory of any of the above mentioned cancers, or one or more of the above mentioned cancers A plurality of combinations are included, but not limited to them. Some of the exemplified cancers are included in the general term and included in this term. For example, the generic term urinary cancer may include bladder cancer, prostate cancer, kidney cancer, testicular cancer, etc. Another common term, hepatobiliary cancer, is liver cancer ( As such, it is a general term including hepatocellular carcinoma or cholangiocarcinoma), gallbladder carcinoma, biliary tract carcinoma, or pancreatic carcinoma. Both urological cancer and hepatobiliary cancer are contemplated by the present disclosure and are included in the term "cancer".

  As used herein, "cancer" may also include the term "solid tumor." As used herein, the term "solid tumor" refers to conditions such as cancer that form abnormal tumor masses such as sarcomas, carcinomas, and lymphomas. Examples of solid tumors include, but are not limited to, non-small cell lung cancer (NSCLC), neuroendocrine tumors, thymomas (thyomas), fibrotic tumors, metastatic colorectal cancer (mCRC) and the like. In certain embodiments, solid tumor disease may be, for example, adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and the like.

  In certain embodiments, the cancer is, for example, esophageal cancer, gastroesophageal junction cancer, gastroesophageal adenocarcinoma, gastric cancer, chondrosarcoma, colorectal adenocarcinoma, breast cancer, ovarian cancer, head and neck Head cancer, melanoma, gastric adenocarcinoma, lung cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, cervical cancer, brain cancer, multiple myeloma, leukemia, lymphoma, prostate cancer, cholangiocarcinoma, endometrium It may be cancer, small intestinal adenocarcinoma, uterine sarcoma, or adrenocorticoid cancer. In certain embodiments, the cancer is, for example, esophageal cancer, gastroesophageal junction cancer, gastroesophageal adenocarcinoma, colorectal adenocarcinoma, breast cancer, ovarian cancer, head and neck cancer, melanoma, gastric adenocarcinoma , Lung cancer, pancreatic cancer, renal cell cancer, hepatocellular carcinoma, cervical cancer, brain cancer, multiple myeloma, leukemia, lymphoma, prostate cancer, cholangiocarcinoma, endometrial cancer, small intestine adenocarcinoma, uterine sarcoma Or adrenocorticoid cancer. In certain embodiments, the cancer may be, for example, breast cancer. In certain embodiments, the cancer can be, for example, a colorectal adenocarcinoma. In certain embodiments, the cancer can be, for example, a small intestine adenocarcinoma. In certain embodiments, the cancer can be, for example, a hepatocellular carcinoma. In certain embodiments, the cancer may be, for example, head and neck cancer. In certain embodiments, the cancer can be, for example, renal cell carcinoma. In certain embodiments, the cancer may be, for example, ovarian cancer. In certain embodiments, the cancer may be, for example, prostate cancer. In certain embodiments, the cancer may be, for example, lung cancer. In certain embodiments, the cancer can be, for example, uterine sarcoma. In certain embodiments, the cancer may be, for example, esophageal cancer. In certain embodiments, the cancer may be, for example, endometrial carcinoma. In certain embodiments, the cancer can be, for example, cholangiocarcinoma. In certain embodiments, each cancer may be, for example, unresectable, progressive, refractory, relapsed, or metastatic.

  The term "salt (s)", as used herein, includes acidic and / or basic salts formed with inorganic and / or organic acids and bases. As used herein, the term "pharmaceutically acceptable salt" refers to a subject without undue toxicity, irritation, allergic response and / or the like within the scope of good medical judgment. These salts are suitable for use in contact with the organization of the above, and have a reasonable profit / loss ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., Describe pharmaceutically acceptable salts in J. Pharmaceutical Sciences (1977) 66: 1-19.

  Pharmaceutically acceptable salts may be formed with inorganic acids or organic acids. Non-limiting examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Non-limiting examples of suitable organic acids include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. Other non-limiting examples of suitable pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzene sulfonates, besylates, benzoates, bisulfates , Borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptanoic acid Salt, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethane sulfonate, lactobionate, lactate, laurate, lauryl sulfate Salt, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, Hydrate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinic acid Salts, sulphates, tartrates, thiocyanates, p-toluenesulphonates, undecanoates and valerates can be mentioned. In certain embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, trifluoroacetic acid, malonic acid, succinic acid The acids, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid are included.

The salts may be prepared in situ during isolation and purification of the disclosed compounds or may be prepared separately, such as by reacting the compounds with the appropriate base or acid, respectively. Non-limiting examples of pharmaceutically acceptable salts derived from bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N ⁺ (C _1-4 alkyl) ₄ salts. Nonlimiting examples of suitable alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. It can be mentioned. As further non-limiting examples of suitable pharmaceutically acceptable salts, where appropriate, non-toxic ammonium, quaternary ammonium and counter ions (eg halide ions, hydroxide ions, carboxylate ions, Sulfate ion, phosphate ion, nitrate ion, lower alkyl sulfonate ion, and amine cation formed using aryl sulfonate ion) can be mentioned. Non-limiting examples of suitable organic bases from which salts can be derived: primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ions Exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine are included. In certain embodiments, the pharmaceutically acceptable base addition salt may be selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

  The term "solvate" refers to an aggregate comprising one or more molecules of a compound of the present disclosure with one or more molecules of one or more solvents. Solvates of the compounds of the present disclosure include, for example, hydrates.

  At least one compound disclosed herein may be in the form of a pharmaceutical composition. In certain embodiments, the pharmaceutical composition may comprise at least one compound of Formula A and at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition may comprise at least one compound of Formula B and at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition may comprise at least one compound of Formula C and at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition can comprise one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds are at least It is possible to convert to a compound having one Formula A (ie, a prodrug). In certain embodiments, the pharmaceutical composition can comprise one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds are at least It can be converted to a compound having one Formula B (ie, a prodrug). In certain embodiments, the pharmaceutical composition can comprise one or more compounds and at least one pharmaceutically acceptable carrier, wherein the one or more compounds are at least It is possible to convert to one compound of formula C (ie a prodrug).

  The term "carrier" as used herein refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, a diluent, an excipient, a solvent, or a target pharmaceutical compound. Or an encapsulation material or the like involved in or capable of transporting or transporting from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Non-limiting examples of pharmaceutically acceptable carriers, carriers and / or diluents, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose Maltose; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; For example, propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; Agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; water without pyrogens; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other compatible non-toxic substances used in pharmaceutical formulations Substances can be mentioned. Wetting agents, emulsifying agents and lubricants, such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring and flavoring agents, preservatives, and Antioxidants may also be present in the composition.

  The pharmaceutical composition disclosed herein, suitable for oral administration, comprises a capsule, a cachet, a pill, a tablet, a lozenge, each containing a predetermined amount of at least one compound of the present disclosure. Bases (usually using sucrose and acacia or tragacanth), powders, granules, aqueous or non-aqueous liquid solutions, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, water-in-oil emulsions, elixirs, syrups The agent may be in the form of an agent (pastille) (using an inert base such as gelatin, glycerin, sucrose and / or acacia) and / or a gargle.

  The pharmaceutical compositions disclosed herein can be administered as boluses, lozenges, or pastes.

  Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules etc.) are one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate And / or any of the following: fillers or fillers, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or Moisturizing agents such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate and sodium starch glycolate; dissolution retarders such as paraffin; Promoters such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and polyethylene oxide-polypropylene oxide copolymers, etc. Absorbents such as kaolin and bentonite clays; Lubricants such as talc, calcium stearate Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets and pills, the pharmaceutical composition may also comprise buffering agents. Solid types of similar compositions can also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

  Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms, in addition to the active ingredient, inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (in particular, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan And fatty acid esters of the above, as well as mixtures thereof. Additionally, cyclodextrins, such as hydroxypropyl-beta-cyclodextrin, may be used to solubilize the compound.

  Pharmaceutical compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, flavoring agents, and preservatives. Suspending agents, in addition to the compounds according to the disclosure, suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, As well as mixtures thereof.

  The pharmaceutical composition disclosed herein for rectal or vaginal administration may be presented as a suppository, which suppository contains one or more compounds according to the present disclosure, for example cocoa butter, polyethylene One or more suitable non-irritants, including glycols, suppositories waxes or salicylates, which are solid at room temperature but become liquid at body temperature and thus melt in the rectum or vaginal cavity and release the compounds of the disclosure It can be prepared by mixing with a sex excipient or carrier. Pharmaceutical compositions suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing a carrier known to be suitable in the art. obtain.

  Dosage forms for topical or transdermal administration of the pharmaceutical composition or pharmaceutical tablet of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants May be included. The pharmaceutical composition or tablet may be mixed under aseptic conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers or sprays that may be required.

  Ointments, pastes, creams and gels, in addition to the pharmaceutical compositions or tablets of the present disclosure, animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones Excipients can be included such as bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

  Powders and sprays contain, in addition to the pharmaceutical composition or tablets of the present disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances It can. In addition, the spray may contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

  Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this disclosure.

  Compositions suitable for parenteral administration can be injected immediately prior to use of at least one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions, emulsions, or Sterile powders or solutions which can be reconstituted into various sterile solutions or dispersions, which may be antioxidants, buffers, bacteriostatics, solutes which render the formulation isotonic with the blood of the intended recipient, or It may contain suspending agents or thickening agents.

  In certain embodiments, the compositions described herein comprise at least one compound selected from a compound of Formula A and pharmaceutically acceptable salts and solvates thereof, and one or more Containing a surfactant of the species. In certain embodiments, the surfactant can be, for example, sodium lauryl sulfate (SLS), sodium dodecyl sulfate (SDS), or one or more polyoxyglycerides. For example, the polyoxyglyceride can be lauroyl polyoxyglyceride (sometimes called GelucireTM) or linoleoyl polyoxyglyceride (sometimes called LabrafilTM). An example of such a composition is shown in PCT Patent Application No. PCT / US2014 / 033566, the entire contents of which are incorporated herein.

  The present invention provides further embodiments of suitable pharmaceutical formulations having a selected particle size distribution, as well as optimum particle size distribution, appropriate drug regimens, methods for identifying dosages and intervals, including their crystalline forms 2- Suitable methods of preparing acetyl naphtho [2,3-b] furan-4,9-diones, as well as the entire contents thereof are incorporated herein by reference WO 2009/036099, WO 2009/036101, WO 2011/116398, WO 2011 Additional specific suitable cancer stem cell inhibitors and kinase inhibitors are provided as described in co-owned PCT applications published as WO / 116399, WO 2014/169078, and WO 2009/033033.

  In certain embodiments, the compositions described herein comprise at least one compound selected from a compound of Formula B and pharmaceutically acceptable salts and solvates thereof, and one or more The surfactant may be included. In certain embodiments, the surfactant may be, for example, sodium lauryl sulfate (SLS), sodium dodecyl sulfate (SDS), or one or more polyoxyl glycerides. For example, the polyoxyl glyceride can be lauroyl polyoxyl glyceride (sometimes called GelucireTM) or linoleoyl polyoxyl glyceride (sometimes called LabrafilTM).

  In certain embodiments, the compounds or pharmaceutical compositions described herein are known variously, including, for example, chemotherapeutic agents and other antineoplastic agents, anti-inflammatory compounds, and / or immunosuppressive compounds. Can be administered in combination with any of the therapeutic agents of In certain embodiments, the compounds, products, and / or pharmaceutical compositions described herein are, by way of non-limiting example, surgical treatments and methods, radiation therapy, chemotherapy, and / or hormones or It is useful in conjunction with any of a variety of known treatments, including other endocrine related treatments.

  In certain embodiments, a method of treating cancer in a subject in need of treating cancer comprising: (a) a cancer stem cell inhibitor, a prodrug of the foregoing, a derivative of the foregoing A therapeutically effective amount of at least one first compound selected from any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates; and (b) a kinase inhibitor, as described above Administering a therapeutically effective amount of at least one second compound selected from a prodrug thereof, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing Methods including steps are disclosed herein. In certain embodiments, at least one selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing The first compound of may be included in the pharmaceutical composition. In certain embodiments, at least one selected from a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. A second compound of a species may be included in the pharmaceutical composition.

  In certain embodiments, a method of treating cancer cells comprising: (a) a cancer stem cell inhibitor, a prodrug of the foregoing, a derivative of the foregoing, pharmaceutically acceptable of any of the foregoing And a therapeutically effective amount of at least one first compound selected from any of the foregoing solvates; and (b) a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, any of the foregoing Disclosed herein is a method comprising the step of administering a therapeutically effective amount of at least one second compound selected from any of the aforementioned pharmaceutically acceptable salts and solvates of any of the foregoing. Ru. In certain embodiments, the cancer cells are in a subject. In certain embodiments, at least one selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing The first compound of may be included in the pharmaceutical composition. In certain embodiments, at least one selected from a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. A second compound of a species may be included in the pharmaceutical composition.

  In certain embodiments, a method of inhibiting, reducing and / or reducing the survival and / or self-renewal of cancer stem cells, comprising: (a) a cancer stem cell inhibitor, a prodrug of the foregoing, A therapeutically effective amount of at least one first compound selected from derivatives of any of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing; and (b) a kinase inhibitor Or a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a therapeutically effective amount of at least one second compound selected from the solvates of any of the foregoing. Disclosed herein is a method comprising the step of administering In certain embodiments, the cancer stem cells are in a subject. In certain embodiments, at least one selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing The first compound of may be included in the pharmaceutical composition. In certain embodiments, at least one selected from a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. A second compound of a species may be included in the pharmaceutical composition.

  In certain embodiments, a method of treating cancer refractory to conventional chemotherapy and / or targeted therapy in a subject, comprising: (a) a cancer stem cell inhibitor, a prodrug of the foregoing, A therapeutically effective amount of at least one first compound selected from derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing; and (b) kinase inhibition A therapeutically effective amount of at least one second selected from an agent, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. Disclosed herein are methods comprising administering a compound. In certain embodiments, at least one selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing The first compound of may be included in the pharmaceutical composition. In certain embodiments, at least one selected from a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. A second compound of a species may be included in the pharmaceutical composition. In certain embodiments, conventional chemotherapies and / or targeted therapies include kinase inhibitors, prodrugs thereof, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvents of any of the foregoing. It may comprise the step of administering at least one compound selected from a solvate. In certain embodiments, conventional chemotherapy and / or targeted therapy may comprise administering sorafenib.

  In certain embodiments, a method of treating recurrent cancer in a subject who has failed surgery, oncology treatment (eg, chemotherapy), and / or radiation treatment, comprising: (a) cancer stem cell inhibition A therapeutically effective amount of at least one first selected from an agent, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. A therapeutically effective amount selected from the compounds; and (b) kinase inhibitors, prodrugs of the foregoing, derivatives of the foregoing, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing Disclosed herein are methods comprising the step of administering at least one second compound. In certain embodiments, at least one selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing The first compound of may be included in the pharmaceutical composition. In certain embodiments, at least one selected from a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. A second compound of a species may be included in the pharmaceutical composition.

  In certain embodiments, a method of treating or preventing cancer metastasis in a subject comprising: (a) a cancer stem cell inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutical of any of the foregoing And a therapeutically effective amount of at least one first compound selected from any of the foregoing solvates; and (b) a kinase inhibitor, a prodrug of the foregoing, of A method comprising administering a therapeutically effective amount of at least one second compound selected from a derivative, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing is provided It is disclosed in the specification. In certain embodiments, at least one selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing The first compound of may be included in the pharmaceutical composition. In certain embodiments, at least one selected from a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. A second compound of a species may be included in the pharmaceutical composition.

  In certain embodiments, a method of preventing cancer relapse or suppressing regrowth or relapse in a subject, comprising: (a) a cancer stem cell inhibitor, a prodrug of any of the foregoing, A therapeutically effective amount of at least one first compound selected from a derivative, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing; and (b) a kinase inhibitor, as described above Administration of a therapeutically effective amount of at least one second compound selected from a prodrug of any of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing Disclosed herein is a method comprising the steps of: In certain embodiments, at least one selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing The first compound of may be included in the pharmaceutical composition. In certain embodiments, at least one selected from a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. A second compound of a species may be included in the pharmaceutical composition. In certain embodiments, the method is part of an adjuvant treatment. In certain embodiments, the method comprises administering a combination of treatments of the present disclosure after or in conjunction with primary cancer treatment. In certain embodiments, the primary treatment is selected from chemotherapy, radiation therapy, hormonal therapy, targeted therapy, or biological therapy.

  In certain embodiments, a method for sensitizing or resensitizing cells to at least one kinase inhibitor, comprising: a cancer stem cell inhibitor, a prodrug of the foregoing, a derivative of the foregoing, A method comprising administering a therapeutically effective amount of at least one first compound selected from any of the pharmaceutically acceptable salts of any of the foregoing and the solvates of any of the foregoing, as described herein Disclosed. In certain embodiments, at least one kinase inhibitor is sorafenib. In certain embodiments, the method is selected from a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. Administering a therapeutically effective amount of at least one second compound. In certain embodiments, at least one selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing The first compound of may be included in the pharmaceutical composition. In certain embodiments, at least one selected from a kinase inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. A second compound of a species may be included in the pharmaceutical composition.

  In certain embodiments, the cancer can be, for example, a hepatocellular carcinoma. In certain embodiments, the cancer can be, for example, cholangiocarcinoma.

  In certain embodiments, the cancer may be unresectable. In certain embodiments, the cancer may be progressive. In certain embodiments, the cancer may be refractory. In certain embodiments, the cancer may be relapsed. In certain embodiments, the cancer may be metastatic. In certain embodiments, the cancer may be associated with overexpression of STAT3. In certain embodiments, the cancer may be associated with nuclear β-catenin localization.

  In the following, examples are provided to further illustrate the various features of the present disclosure. These examples also illustrate methodologies useful for practicing the present invention. These examples do not limit the claimed invention.

  The methods disclosed herein combine a therapeutically effective amount of at least one compound selected from cancer stem cell inhibitors with a therapeutically effective amount of at least one compound selected from kinase inhibitors, Administering to a subject in need thereof.

Example 1
Treatment with a combination of Compound A (BBI 608) and Compound C (sorafenib) enhanced inhibition of bulk cancer cell colony formation in vitro

  The ability of bulk cancer cells to undergo increased clonogenicity after treatment with a combination of Compound A and Compound C was investigated using a colony formation assay. For these studies, human HCC cell lines (HepG2, 1000 cells per well) were seeded in 6 well plates. Twenty-four hours after seeding, cells were either DMSO (as control), Compound A alone (0.15 μM), Compound C alone (2 μM), or a combination of Compound A (0.15 μM) and Compound C (2 μM) It was treated with The cells were then cultured for 7-10 days until visible colonies formed.

  As shown in Figure 1, treatment with a combination of Compound A and Compound C ("combo") results in treatment with Compound A (BBI 608) alone or Compound C (sorafenib) alone. In comparison there was an enhanced inhibition of HCC colony formation.

(Example 2)
Treatment with a combination of Compound A (BBI 608) and Compound C (sorafenib) enhanced the inhibition of cancer stem cell sphere formation in vitro

  After treating cancer cells with a combination of Compound A (BBI 608) and Compound C (sorafenib) ("combo"), cancer stem cell sphere formation (ie, spherogenesis) was investigated. Single Sk-Hep1, Huh7, and HepG2 cells were grown in suspension for 48 hours in the presence of either Compound A alone (BBI 608; 1.6 μM), Compound C alone (sorafenib; 2 μM) Or with the combination of Compound A (BBI 608) and Compound C (sorafenib) at concentrations of 1.6 μM and 2 μM, respectively, for 24 hours. The cells were then washed and cultured for another 24 hours in standard cell culture medium. Cells were then examined and photographed using a differential interference (DIC) microscope. The blue coloration of the cells is due to Tryphan Blue, which indicates the presence of dead cells.

  As shown in Figure 2, treatment with a combination of Compound A (BBI 608) and Compound C (sorafenib) ("combo") results in Compound A (BBI 608) alone or Compound C (sorafenib) alone. There was a significant increase in inhibition of Sk-Hep1, Huh7, and HepG2 CSC viability as compared to the treatment used in

  In summary, the studies described in Examples 1 and 2 demonstrate that Compound A and Compound C act synergistically in vitro, and these data used Compound A and Compound C to HCC. , A significant potential for combined treatment is suggested.

(Example 3)
Treatment of mouse xenograft model of human cancer with Compound A (BBI 608)

In a mouse xenograft model of human HCC, HepG2 cells were inoculated subcutaneously into male athymic nude mice (8 × 10 ⁶ cells per mouse) to form a palpable tumor. As shown in FIG. 3, when tumors reach approximately 500 mm ³ , animals are orally treated with either vehicle (control) or Compound A (BBI 608; 10 mg / kg, iv) It was treated. The animals received a total of 5 doses. Treatment with Compound A (BBI 608) inhibited tumor growth as compared to control animals.

(Example 4)
Treatment with a combination of Compound B (BBI 503) and Compound C (sorafenib) enhanced inhibition of bulk cancer cell colony formation in vitro

  The ability of bulk cancer cells to undergo increased clonogenicity after treatment with a combination of Compound B (BBI 503) and Compound C (sorafenib) was investigated using a colony formation assay. For these studies, human HCC cell lines (Hep3B and Hub7, 1000 cells per well) were seeded in 6 well plates. Twenty four hours after seeding, cells were either DMSO (as control), Compound B alone (0.3 μM), Compound C alone (2 μM), or a combination of Compound B (0.3 μM) and Compound C (2 μM). It was treated with The cells were then cultured for 7-10 days until visible colonies formed.

  As shown in FIGS. 4 and 5, treatment with a combination of Compound B (BBI 503) and Compound C (sorafenib) results in the use of Compound A (BBI 503) alone or Compound C (sorafenib) alone. This resulted in enhanced inhibition of HCC colony formation as compared to the treatment given.

(Example 5)
Treatment with a combination of Compound B (BBI 503) and Compound C (sorafenib) enhanced the inhibition of cancer stem cell sphere formation in vitro

  After treating cancer cells with a combination of Compound B (BBI 503) and Compound C (sorafenib) ("combo"), cancer stem cell sphere formation (ie, sphere formation) was investigated. Single Sk-Hep1, Huh7, and HepG2 cells were grown in suspension for 48 hours in the presence of either Compound B alone (BBI 503; 1 μM), Compound C alone (sorafenib; 2 μM) Alternatively, the cells were cultured for 24 hours with the combination of Compound A (BBI 608) and Compound C (sorafenib) at concentrations of 1 μM and 2 μM, respectively. The cells were then washed and cultured for another 24 hours in standard cell culture medium. Cells were then examined and photographed using a differential interference (DIC) microscope. The blue coloration of the cells is due to Tryphan Blue, which indicates the presence of dead cells.

  As shown in FIG. 6, Compound B (BBI 503) alone or Compound C (sorafenib) alone was treated with a combination of Compound B (BBI 503) and Compound C (sorafenib) (“combo”). There was a significant increase in inhibition of Sk-Hep1, Huh7, and HepG2 CSC viability as compared to the treatment used in

  In summary, the studies described in Examples 4 and 5 demonstrate that Compound B and Compound C act synergistically in vitro, and these data used Compound A and Compound C to HCC. , A significant potential for combined treatment is suggested.

(Example 6)
Treatment of mouse xenograft model of human cancer with compound B (BBI 503)

In a mouse xenograft model of human HCC, HepG2 cells were inoculated subcutaneously into male athymic nude mice (8 × 10 ⁶ cells per mouse) to form a palpable tumor. As shown in FIG. 7, when tumors reach approximately 500 mm ³ , animals are orally treated with either vehicle (control) or Compound B (BBI 503; 100 mg / kg, po) It was treated. The animals received a total of 5 doses. Treatment with compound B (BBI 503) inhibited tumor growth compared to control animals.

(Example 7)
Clinical trial using combination treatment of Compound A (BBI 608) and Compound C (sorafenib) or Compound B (BBI 503) and Compound C (sorafenib)

  Combination of two treatments in patients with advanced hepatocellular carcinoma in a phase IB / II study to assess the safety, tolerability, and preliminary anti-cancer activity of the drug combination disclosed herein I studied the effects of The first treatment combination included Compound A (BBI 608) and Compound C (sorafenib), and the second treatment combination included Compound B (BBI 503) and Compound C (sorafenib).

  This open-label, phase IB / II study has determined the safety and efficacy of the combination of drugs described above for a population of adult patients with advanced hepatocellular carcinoma who have not received systemic chemotherapy. The phase IB portion may be administered with increasing doses of Compound A (BBI 608) in combination with fixed starting compound C (sorafenib) (Group 1) and fixed increasing doses of Compound B (BBI 503) at the starting dose Administration in combination with compound C (sorafenib) (group 2). The fixed starting dose level of sorafenib was 400 mg twice daily (800 mg total daily dose) for both groups. Eligible patients were randomized to either Group 1 or Group 2.

  In Group 1, increasing doses of Compound A (BBI 608), in cohorts of 3 to 6 patients, according to established criteria for determining dose-limiting toxicity (DLT) and dose escalation (RP2D) Was administered until it was determined.

  In group 2, increasing doses of Compound B (BBI 503) in a cohort of 3 to 6 patients according to established criteria for determining dose-limiting toxicity (DLT) and dose escalation (RP2D) Was administered until it was determined.

  Before commencing combination therapy in each group, Compound C (sorafenib) was administered as monotherapy for cycle 14 starting on the first day for 14 days. Adjustment of the dose of sorafenib according to the approved product label was observed. After the sorafenib induction period, the combination regimen was initiated on cycle 1, day 15. Protocol treatment continued on a 28-day cycle until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

  Pharmacokinetic (PK) studies were performed on cycles 1, 15 and 2, 15 for both groups. Additional pharmacokinetic studies were also performed as needed to confirm exposure after dose modification. Once the Phase II recommended dose (RP2D) was established for both study groups, the Phase II portion was initiated.

  The phase II portion was an open-label, three-group, randomized phase II trial of patients with advanced HCC who did not receive prior systemic treatment. Patients were treated with Group 1: Compound C (sorafenib) (in combination with BBI 608 plus RP2D determined for sorafenib during the phase IB portion) administered in combination with Compound A (BBI 608); Group 2: Compound B (BBI 503) Compound C (sorafenib) (with RP2D determined for BBI 503 + sorafenib during the phase IB portion), or group 3: receiving either Compound C (sorafenib) alone, 400 mg, twice daily starting dose It was randomized. The starting dose of sorafenib was the same in all study groups.

  A total of approximately 90 patients were enrolled in the Phase II portion of the study, or approximately 30 patients were enrolled in each study group.

  Pharmacodynamic assessments were performed on patients with tumors readily available via optional study tumor biopsies. Storage tissue was taken from all patients if available.

  The safety and tolerability of Compound A (BBI 608) in combination with Compound C (Sorafenib) and Compound B (BBI 503) in combination with Compound C (Sorafenib) throughout the study, over the duration of study treatment, and as study drug It was continuously assessed up to 30 days after cessation (either Compound A or Compound B).

  Evaluation of anti-tumor activity was carried out at regular 8-week intervals, and the first assessment was made after cycle 1 day 8 weeks (56 days). Radiological assessment for HCC patients was assessed according to RECIST 1.1 and modified RECIST (mRECIST). Alpha-fetoprotein (AFP) measurements were performed at baseline, at the end of the two week sorafenib monotherapy induction, and at the beginning of each subsequent study cycle.

Clinical Trials Patients should go beyond the progression determined by the RECIST criteria (either RECIST 1.1 or mRECIST for patients with HCC), provided that in the investigator's view the patient gains potential clinical benefit. Protocol treatment continued. If sorafenib is discontinued due to the toxicity associated with sorafenib, patients continue to receive study drug (BBI 608 or BBI 503), provided that there are no signs of toxicity and the patient gains clinical benefit from the drug I did.
Patient characteristics
Combination regimen safety profile-Grade 1 and 2 diarrhea observed with napabkacin and amkasertiv were manageable-1 group had discontinuation at level I due to toxicity with sorafenib in each group Three died during the study, all of them in group 2; 1 caused by MI at the time of sorafenib introduction, 2 caused by disease progression (1 upper GI hemorrhage, 1 acute abdominal complication) )
The safety profiles of napabukacin and amcasertib in combination with sorafenib were consistent with the safety profiles of the monotherapy drugs. RP2D was 240 mg BID in group 1 and 100 mg QD in group 2 based on clinical tolerance. It has been determined. The maximum tolerated dose (MTD) has not been determined-napavkasin and amkaceltiv were safe in combination with the recommended dose of sorafenib
Pharmacokinetics

Of the 17 patients that were evaluable by RECIST, 9 were group 1 and 8 were group 2 patients. DCR was observed in 100% of evaluable patients in both groups 1 and 2, 9 in group 1 with SD and 8 in group 2 with SD. RECIST 1.1 for napabukacin + sorafenib and akkacaseib + sorafenib. The first results of and mRECIST are shown in FIGS. 8A and 8B, respectively.

  Napavcasin and amkaceltiv were safely combined with sorafenib at full dose, with no unexpected adverse events. Promotion of anti-cancer activity was observed in patients with HCC who did not receive prior systemic treatment. The RP2D dose was determined to be 240 mg BID for napubucacin and 100 mg QD for amkaceltiv. The randomized phase II of this study currently enrolls patients in the following three groups: Group I: Napubucacin + Sorafenib, Group II: Amkaceltiv + Sorafenib and Group III: Sorafenib alone.

  The many features and advantages of the present disclosure will be apparent from the detailed description and thus, all such features of the present disclosure which fall within the true spirit and scope of the present disclosure as set forth in the appended claims. And is intended to encompass the benefits. Moreover, since numerous modifications and alterations will readily occur to those skilled in the art, it is not desired that the present disclosure be limited to the exact configuration and operation thus illustrated and described, and all that is within the scope of the present disclosure. Appropriate modifications and equivalents of may be used.

Claims (34)

A method for treating cancer in a subject in need thereof for treating cancer comprising:
(A) at least one therapeutically effective amount selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing And (b) a kinase inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. Administering at least one second compound. A method for treating a cancer refractory or resistant to a kinase inhibitor in a subject, comprising:
(A) at least one therapeutically effective amount selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing And (b) a kinase inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. Administering at least one second compound. A method for preventing cancer relapse in a subject, comprising:
(A) at least one therapeutically effective amount selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing And (b) a kinase inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. Administering at least one second compound. A method for inhibiting cancer regrowth or recurrence in a subject, comprising:
(A) at least one therapeutically effective amount selected from a cancer stem cell inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing And (b) a kinase inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing. Administering at least one second compound. The method according to any one of claims 1 to 4, wherein the cancer stem cell inhibitor comprises a STAT3 pathway inhibitor. The cancer stem cell inhibitor is 2- (1-hydroxyethyl) -naphtho [2,3-b] furan-4,9-dione, 2-acetyl-7-chloro-naphtho [2,3-b] Furan-4,9-dione, 2-acetyl-7-fluoro-naphtho [2,3-b] furan-4,9-dione, 2-acetylnaphtho [2,3-b] furan-4,9-dione And a method according to any one of the preceding claims comprising 2-ethyl-naphtho [2,3-b] furan-4,9-dione. The compound wherein the cancer stem cell inhibitor has Formula A:
The method according to any one of claims 1 to 6, which comprises The method according to any one of claims 1 to 7, wherein the cancer stem cell inhibitor comprises an inhibitor of at least one kinase selected from cancer stem cell pathway kinase (CSCPK). 9. The method of claim 8, wherein the at least one kinase is selected from STK33, MELK, AXL, p70S6K, and PDGFRα. The cancer stem cell inhibitor is
10. A method according to any one of the preceding claims, comprising The compound wherein the cancer stem cell inhibitor has Formula B:
The method according to any one of claims 1 to 10, comprising The compound wherein the kinase inhibitor has formula C
The method according to any one of claims 1 to 11, comprising 13. The method according to any one of the preceding claims, wherein the cancer is selected from liver cancer. The method according to any one of claims 1 to 13, wherein the cancer is selected from hepatocellular carcinoma and cholangiocarcinoma. The method according to any one of claims 1 to 14, wherein the cancer is progressive, refractory, relapsed or metastatic. A method for sensitizing or resensitizing cancer cells to a kinase inhibitor, comprising administering to the cancer cells a cancer stem cell-type inhibitor, a prodrug thereof, a derivative thereof, or any one of the aforementioned pharmacologically Administering an acceptable salt, and at least one first compound selected from any of the aforementioned solvates. A method for treating cancer cells, comprising a cancer stem cell inhibitor, a prodrug of the foregoing, a derivative of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, and any of the foregoing. Administering a therapeutically effective amount of at least one first compound selected from solvates. The method according to any one of claims 16 to 17, wherein the cancer cell is in a subject. 19. The method of any one of claims 16-18, wherein the cancer stem cell inhibitor comprises a STAT3 pathway inhibitor. The cancer stem cell inhibitor is 2- (1-hydroxyethyl) -naphtho [2,3-b] furan-4,9-dione, 2-acetyl-7-chloro-naphtho [2,3-b] Furan-4,9-dione, 2-acetyl-7-fluoro-naphtho [2,3-b] furan-4,9-dione, 2-acetylnaphtho [2,3-b] furan-4,9-dione 20. The method according to any one of claims 16-19, and comprising 2-ethyl-naphtho [2,3-b] furan-4,9-dione. The compound wherein the cancer stem cell inhibitor has Formula A:
The method according to any one of claims 16 to 20, comprising The method according to any one of claims 16 to 18, wherein the cancer stem cell inhibitor comprises a cancer stem cell pathway inhibitor. The cancer stem cell is
23. A method according to any one of claims 16-18 and 22 comprising The compound wherein the cancer stem cell inhibitor has Formula B:
24. The method of any one of claims 16-18, 22, and 23, comprising: A therapeutically effective amount of at least one second compound selected from a kinase inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing 24. The method of any one of claims 16-23, comprising the step of administering. The compound wherein the kinase inhibitor has Formula C:
26. A method according to any one of the claims 16-25, comprising 27. The method according to any one of claims 16 to 26, wherein the cancer is selected from liver cancer. 28. The method of any one of claims 16-27, wherein the cancer is selected from hepatocellular carcinoma and cholangiocarcinoma. 29. The method of any one of claims 16-28, wherein the cancer is progressive, refractory, relapsed or metastatic. A method for treating cancer in a subject, comprising a compound of formula A:
And compounds having the formula B:
A therapeutically effective amount of at least one first compound selected from a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing; Compounds having:
Treating the cancer with a therapeutically effective amount of at least one second compound selected from the prodrug, its derivative, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates Administering to a subject in need of treatment. A method for treating a cancer refractory or resistant to at least one kinase inhibitor in a subject, comprising a compound having the formula A:
And compounds having the formula B:
A therapeutically effective amount of at least one first compound selected from a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and a solvate of any of the foregoing; Compounds having:
Treating the cancer with a therapeutically effective amount of at least one second compound selected from the prodrug, its derivative, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates Administering to a subject in need of treatment. A method for sensitizing a cancer to at least one kinase inhibitor in a subject, comprising a compound of formula A:
And compounds having the formula B:
Treating a cancer with a therapeutically effective amount of at least one first compound selected from the prodrug, its derivative, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates Administering to a subject in need of sensitizing at least one kinase inhibitor. A method for resensitizing a cancer to at least one kinase inhibitor in a subject, comprising a compound of formula A:
And compounds having the formula B:
Treating a cancer with a therapeutically effective amount of at least one first compound selected from the prodrug, its derivative, any of the aforementioned pharmaceutically acceptable salts, and any of the aforementioned solvates Administering to a subject in need of resensitization to at least one kinase inhibitor. (A) at least one first selected from cancer stem cell inhibitors, prodrugs thereof, derivatives thereof, pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing (B) a kinase inhibitor, a prodrug thereof, a derivative thereof, a pharmaceutically acceptable salt of any of the foregoing, and at least one second compound selected from a solvate of any of the foregoing And (c) a kit comprising instructions for administration and / or use of the at least one first compound and the at least one second compound.