Co-therapy comprising metastasis inhibitor

Abstract

The present invention relates to co-therapies comprising a metastasis inhibitor. The present invention provides the use of a compound having the following structure, or a tautomer thereof, and / or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for increasing the response to a chemotherapeutic agent in a patient in need thereof: # imgabs0 # wherein the patient is or is about to undergo chemotherapy; and wherein the chemotherapeutic agent is paclitaxel, cyclophosphamide, or doxorubicin. The invention also provides the use of the above-mentioned substances in the preparation of a medicament for treating cancer in a patient in need thereof and for administration in combination with a chemotherapeutic agent, the use of the above-mentioned substances in the preparation of a medicament for increasing the response to an immunotherapeutic agent in a patient in need thereof, and the use of the above-mentioned substances in the manufacture of a medicament for the treatment of cancer in a patient in need thereof and for administration in combination with an immunotherapeutic agent.

Description

[0001] This application is a divisional application of the Chinese patent application with the application date of November 20, 2018, application number 201880087485.9, and invention name “Co-therapy including metastasis inhibitors”. Technical Field

[0002] The present technology generally relates to compounds, compositions, and methods for treating or preventing cancer. Background Art

[0003] Tumor metastasis is the main cause of death in cancer patients. Inhibiting tumor metastasis will significantly improve the survival rate of cancer patients. Metastasis is a multistep process in which the primary tumor spreads from its initial site to secondary tissues / organs. Weiss, L. Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer Metastasis Rev 19, I-XI, 193-383 (2000); Fidler, IJ The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3, 453-458 (2003); Valastyan, S. & Weinberg, R A Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275-292, (2011). Tumor cell migration and organ invasion are key steps in metastasis. Andeelis, J., Singer, RH & Segall, JE The great escape: when cancer cells hijack the genes for chemotaxis and motility. Annu Rev Cell Dev Biol 21, 695-718 (2005). Migration provides tumor cells with the ability to leave the primary tumor bed (local invasion), enter blood vessels, then leave the circulation and infiltrate distant tissues / organs. Important new insights into the biology of local tumor growth are being used as new targets for treatment. However, understanding and interrupting the process of tumor metastasis is also crucial because it is ultimately the terminal event that leads to cancer death.

[0004] In order for cells to migrate and invade, the actin cytoskeleton must reorganize by forming polymers and bundles to cause dynamic changes in cell shape. Same as above; Mogilner, A. & Rubinstein, B. The physics of filopodial protrusion. Biophys J 89, 782-795 (2005); Pollard, TD & Cooper, JA Actin, a central player in cell shape and movement. Science 326, 1208-1212, (2009). Among the morphological structures supported by actin filaments, one of the most prominent protruding organelles is the filopodia, which is the basis of cell shape and motility events. Mattila, PK & Lappalainen, P. Filopodia: molecular architecture and cellular functions. Nat Rev Mol Cell Biol 9, 446-454, (2008). Filopodia are finger-like plasma membrane protrusions formed when the actin cytoskeleton is remodeled below the plasma membrane. They can be considered as the cell's sensory organs for detecting and assimilating signals and exploring and navigating the surrounding microenvironment. avenport,RW,Dou,P.,Rehder,V.&Kater,SBA sensory role for neuronal growth conefilopodia.Nature 361,721-724,doi:10.1038 / 361721a0(1993);Bentley,D.&Toroian-Raymond,A.Disoriented pathfinding by pioneer neurone growth cones deprived offilopodia by cytochalasin treatment. Nature 323,712-715, doi:10.1038 / 323712a0(1986); Sanders, TA, Llagostera, E. & Barna, M. Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning. Nature 497, 628-632, doi:10.1038 / nature12157(2013). They contain long actin filaments cross-linked into parallel bundles by fasciclin.Metastatic tumor cells are rich in filopodia, and the number of filopodia is correlated with their invasiveness. Filopodia-like protrusions have also been shown to be crucial for metastatic tumor cells to interact with the metastatic microenvironment and grow in secondary tissues. ue, T., Brooks, MW, Inan, MF, Reinhardt, F. & Weinberg, RA The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer discovery 2, 706-721 (2012).

[0005] Fascin is the major actin cross-linker in filopodia and shows no amino acid sequence homology to other actin-binding proteins. JJ,Kane,RE&Bryan,J.Formation of filopodia incoelomocytes:localization of fascin,a 58,000dalton actin cross-linkingprotein.Cell 17,285-293(1979);Bryan,J.&Kane,RESeparation and interaction of the major components of sea urchin actin gel.J Mol Biol 125, 207-224 (1978); Yamashiro-Matsumura, S. & Matsumura, F. Purification and characterization of an F-actin-bundling 55-kilodalton protein from HeLa cells. J Biol Chem 260, 5087-5097 (1985); Vignjevic, D. et al., Formation of filopodia-like bundles in vitro froma dendritic network.J Cell Biol 160, 951-962 (2003); Vignjevic, D. et al., Role of fascin in filopodial protrusion. J Cell Biol 174, 863-875 (2006); Adams, JC Loes of fascin in cell adhesion and motility. Curr Opin Cell Biol 16, 590-596 (2004). It has a molecular weight of approximately 55 kDa and is used as a monomer. It binds 10 to 30 parallel actin filaments together into straight, compact, and rigid bundles to form filopodia (60 nm to 200 nm in diameter) and imparts varying mechanical stiffness to actin bundles.Tilney, LG, Connelly, PS, Vranich, KA, Shaw, MK & Guild, GM Why are two different cross-linkers necessary for actin bundle formation in vivo and what does each cross-link contribute? J Cell Biol 143, 121-133 (1998); Claessens, MM, Bathe, M., Frey, E. & Bausch, A.R. Actin-binding proteins sensitively mediate F-actin bundle stiffness. Nat Mater 5, 748-753 (2006). When ectopically expressed in tumor cells, fascins promote tumor cell migration, invasion and metastasis. Shimoto, Y., Kim, DJ & Adams, JC The roles of fascins in health and disease. The Journal of Pathology 224, 289-300 (2011). It has been proposed that upregulation of fascins is part of the epithelial-to-mesenchymal transition program that confers motility and invasiveness to tumor cells. Machesky, LM & Li, A. Fascin: Invasive filopodia promoting metastasis. Commun Integr Biol 3, 263-270 (2010).

[0006] Studies of samples from human cancer patients have shown that fascin is a biomarker of metastasis and that fascin is a good therapeutic target.Darnel, A.D. et al., Fascin regulates prostate cancer cell invasion and is associated with metastasis and biochemical failure in prostate cancer. Clin Cancer Res 15, 1376 - 1383, doi:15 / 4 / 1376[pii]10.1158 / 1078 - 0432.CCR - 08 - 1789(2009); Pelosi, G et al., Independent value of fascin immunoreactivity for predicting lymph node metastases in typical and atypical pulmonary carcinoids. Lung cancer 42, 203 - 213(2003); Hashimoto, Y., Shimada, Y., Kawamura, J., Yamasaki, S. & Imamura, M. The prognostic relevance of fascin expression in human gastric carcinoma. Oncology 67, 262 - 270(2004); Cao, D., Ji, H. & Ronnett, B.M. Expression of mesothelin, fascin, and prostate stem cell antigen in primary ovarian mucinous tumors and their utility in differentiating primary ovarian mucinous tumors from metastatic pancreatic mucinous carcinomas in the ovary. Int J Gynecol Pathol 24, 67 - 72(2005); Rodriguez - Pinilla, S.M. et al., Prognostic significance of basal - like phenotype and fascin expression in node - negative invasive breast carcinomas. Clin Cancer Res 12, 1533 - 1539(2006).Elevated levels of fascin are found in many types of metastatic tumors and are associated with a clinically aggressive phenotype, poor prognosis, and shorter survival. Tan, VY, Lewis, SJ, Adams, JC & Martin, RM. Association of fascin-1 with mortality, disease progression, and metastasis in carcinomas: a systematic review and meta-analysis. BMC Med 11, 52 (2013). Human fascin expression is low or absent in normal adult epithelial cells but is highly expressed in metastatic tumors. Rothey, A., Hashizume, R., Sahin, AA & McCrea, PDF Fascin, an actin-bundling protein associated with cell motility, is upregulated in hormone receptor-negative breast cancer. Br J Cancer 83, 870-873 (2000); Hashimoto, Y., Skacel, M. & Adams, JC Roles of fascin in human carcinoma motility and signaling: prospects for a novel biomarker? The international journal of biochemistry & cell biology 37, 1787-1804 (2005). A systematic review and meta-analysis of 26 immunohistochemical studies (totaling approximately 9,000 cancer patients) revealed that high levels of fascin are associated with an increased risk of death, lymph node metastasis, distant metastasis, and disease progression, and may provide a novel biomarker for early identification of aggressive and metastatic tumors. Furthermore, another systematic review and meta-analysis of 73 immunohistochemistry studies totaling approximately 5,000 cancer patients revealed that multiple biomarkers, including fascin, were prognostic for overall survival.Ruys, AT et al., Prognostic Biomarkers in Patients with Resected Cholangiocarcinoma: A Systematic Review and Meta-analysis. Annals of surgical oncology 21, 487-500, doi: 10.1245 / s10434-013-3286-x (2014). In addition, a study from 122 pancreatic cancer patients showed that higher levels of fasciclin were associated with poor outcomes, time to recurrence, and reduced overall survival. Li, A. et al., Fascin is regulated by slug, promotes progression of pancreatic cancer in mice, and is associated with patient outcomes. Gastroenterology 146, 1386-1396 (2014). In summary, these data from human cancer patients may indicate the role of fasciclin in cancer progression and metastasis.

[0007] Mouse genetic studies have shown that mice with fascin gene knockout are normal, which may be due to functional compensation of other actin-bundling proteins during embryonic development. Yamakita, Y., Matsumura, F. & Yamashiro, S. Fascin 1 is dispensable for mouse development but is favorable for neonatal survival. Cell Motil Cytoskeleton 66, 524-534 (2009).

[0008] Cancer immunotherapy with checkpoint inhibitors has had a significant impact on the treatment of many types of cancer. Sharma, P. & Allison, JP The future of immune checkpoint therapy. Science 348, 56-61 (2015). When successful, immunotherapy (such as antibody inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1)) extends the patient's lifespan by months or years compared to chemotherapy and radiotherapy. However, only about 25% to 30% of patients benefit from immunotherapy, and it is known that immunotherapy produces significant immune-related side effects in some patients.

[0009] Therefore, new treatments that improve upon existing cancer treatments are needed. Summary of the Invention

[0010] Embodiments disclosed herein include methods of increasing the response to a chemotherapeutic or immunotherapeutic agent in a patient in need thereof, comprising: administering to the patient a compound represented by formula (I):

[0011] or its tautomers, and / or its pharmaceutically acceptable salts; wherein, R 2 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 R 4 Substitute, where each R 4 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、SO2NR 10 R 10 , phenyl (optionally substituted by lower alkyl, halo or lower haloalkyl or -OH) and -NR 10 SO2R 7 ; Each R 3 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR10 R 10 、-NR 10 COR 10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、SO2NR 10 R 10 and -NR 10 SO2R 7 ; m is 0, 1, 2 or 3; R 7 is a lower alkyl group; and each R 10 are independently hydrogen or lower alkyl, or two R 10 Together with the one or more atoms to which it is attached, it forms a 4- to 6-membered ring; Y is selected from the group consisting of: CF3, Cl, F, and Me, wherein the patient is undergoing or is about to undergo chemotherapy or immunotherapy.

[0012] In some embodiments, the patient is undergoing or is about to undergo immunotherapy. In some embodiments, immunotherapy is selected from immune checkpoint inhibitors, such as anti-PD-1 antibodies or anti-CTLA-4 antibodies. In some embodiments, the patient is undergoing or is about to undergo chemotherapy. In some embodiments, chemotherapy is selected from paclitaxel, cyclophosphamide or doxorubicin. In some embodiments, the compound represented by formula (I) and chemotherapeutic agents or immunotherapeutic agents are administered within one year or up to 18 months of each other. In some embodiments, the compound represented by formula (I) and chemotherapeutic agents or immunotherapeutic agents are administered within one month of each other. In some embodiments, the compound represented by formula (I) and chemotherapeutic agents or immunotherapeutic agents are co-administered together. In some embodiments, the patient suffers from cancer. In some embodiments, the cancer is selected from the group consisting of carcinoma, lymphoma, sarcoma, melanoma, astrocytoma, mesothelioma, colon cancer, pancreatic cancer, esophageal cancer, stomach cancer, urinary system cancer, bladder cancer, breast cancer, gastric cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, kidney cancer, prostate cancer, liver cancer, head and neck cancer, thyroid cancer, brain cancer, oral cancer, gallbladder cancer, ampullary cancer, bile duct cancer and laryngeal cancer. In some embodiments, in the compound of formula I, R 2 is optionally replaced by 1 to 4 R 4 In some embodiments, in the compound of formula I, R 2 Optionally 1 to 4 R4 Replace, and R 2 is selected from the group consisting of furan, benzofuran, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, imidazole, pyrrole and pyrazole. In some embodiments, in the compound of Formula I, R 2 Selected from the group consisting of:

[0013] In some embodiments, in the compound of formula I, R 4 is not optional and is selected from the group consisting of lower alkyl, halo, lower haloalkyl, -OH, -OR 7 , cyano and phenyl (optionally substituted with methyl), wherein R 7 In some embodiments, in the compound of formula I, m is 0. In some embodiments, the compound of formula I is selected from:

[0014] or its tautomers, and / or its pharmaceutically acceptable salts. In some embodiments, the compound of formula I is

[0015] or a tautomer thereof, and / or a pharmaceutically acceptable salt thereof. In some embodiments, the method is a method for increasing a response to a chemotherapeutic agent. In some embodiments, the method is a method for increasing a response to an immunotherapeutic agent. In some embodiments, the patient is an adult.

[0016] Other embodiments include methods of treating cancer in a patient in need thereof, comprising administering to the patient a chemotherapeutic or immunotherapeutic agent and a compound represented by formula (I):

[0017] or its tautomers, and / or its pharmaceutically acceptable salts; wherein, R 2 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 R 4 Substitute, where each R 4 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、SO2NR 10 R 10 , phenyl (optionally substituted by lower alkyl, halo or lower haloalkyl or -OH) and -NR 10 SO2R 7 ; Each R 3 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、SO2NR 10 R 10 and -NR 10 SO2R 7 ; m is 0, 1, 2 or 3; R 7 is a lower alkyl group; and each R 10 are independently hydrogen or lower alkyl, or two R 10 Together with the one or more atoms to which it is attached, it forms a 4- to 6-membered ring; Y is selected from the group consisting of: CF3, Cl, F, and Me.

[0018] In some embodiments, the patient is undergoing or is about to undergo immunotherapy. In some embodiments, immunotherapy is selected from immune checkpoint inhibitors, such as anti-PD-1 antibodies or anti-CTLA-4 antibodies. In some embodiments, the patient is undergoing or is about to undergo chemotherapy. In some embodiments, chemotherapy is selected from paclitaxel, cyclophosphamide or doxorubicin. In some embodiments, the compound represented by formula (I) and chemotherapeutic agents or immunotherapeutic agents are administered within one year or at most 18 months of each other. In some embodiments, the compound represented by formula (I) and chemotherapeutic agents or immunotherapeutic agents are administered within one month of each other. In some embodiments, the compound represented by formula (I) and chemotherapeutic agents or immunotherapeutic agents are administered together. In some embodiments, the cancer is selected from the group consisting of: malignant epithelial tumors, lymphomas, sarcomas, melanomas, astrocytomas, mesotheliomas, colon cancer, pancreatic cancer, esophageal cancer, gastric cancer, urinary system cancer, bladder cancer, breast cancer, gastric cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, kidney cancer, prostate cancer, liver cancer, head and neck cancer, thyroid cancer, brain cancer, oral cancer, gallbladder cancer, ampullary cancer, bile duct cancer, and laryngeal cancer. In some embodiments, the cancer is selected from the group consisting of: neuroendocrine prostate cancer, diffuse large B-cell lymphoma of the activated B-cell subtype, and triple-negative breast cancer. In some embodiments, in the compound of Formula I, R 2 is optionally replaced by 1 to 4 R 4 In some embodiments, in the compound of formula I, R 2 Optionally 1 to 4 R 4 Replace, and R 2 is selected from the group consisting of furan, benzofuran, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, imidazole, pyrrole and pyrazole. In some embodiments, in the compound of Formula I, R 2 Selected from the group consisting of:

[0019] In some embodiments, in the compound of Formula I, R 4 is not optional and is selected from the group consisting of lower alkyl, halo, lower haloalkyl, -OH, -OR 7 , cyano and phenyl (optionally substituted with methyl), wherein R 7 In some embodiments, in the compound of formula I, m is 0. In some embodiments, the compound of formula I is selected from: or its tautomers, and / or its pharmaceutically acceptable salts. In some embodiments, the compound of formula I is

[0020] or a tautomer thereof, and / or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering a chemotherapeutic agent to the patient. In some embodiments, the method comprises administering an immunotherapeutic agent to the patient. In some embodiments, the patient is an adult. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 .Pharmacokinetic (PK) and pharmacodynamic (PD) studies of the fasciclin inhibitor NP-G2-044 in mice. (a) Chemical structure of NP-G2-044. (b) PK curves of NP-G2-044 in mice. NP-G2-044 was administered intravenously (at 20 mg / kg, left panel) or orally (at 20 mg / kg, middle panel; at 50 mg / kg, right panel) to mice. Blood samples were collected at different time points. Plasma samples were then extracted and the concentration of NP-G2-044 was determined by LC-MS / MS. Concentration-time curves are shown. (c to f) NP-G2-044 blocked tumor metastasis as a single agent. (c and d) MDA-MB-231 human breast tumor cells were implanted in the mammary fat pad and metastasis to the lungs was quantified. QD: once daily. BID: twice daily, treated with different concentrations of NP-G2-044. There were 3 to 4 mice in each group. Data are shown as mean ± SEM. (e) Representative images of hematoxylin and eosin staining show that after the mice were sacrificed, lung tissue sections of mice injected with MDA-MB-231 cells treated with control solvent or 100mg / kg NP-G2-044 were used. (f and g) 4T1 mouse mammary tumor cells were implanted in mammary fat pads and quantified for metastasis to the lungs. Each group had 3 to 4 mice. Data are shown as mean ± SEM. (h and i) The effect of NP-G2-044 on tumor metastasis when applied at different time points. 4T1 mammary tumor cells were implanted in fat pads. Chemotherapy with paclitaxel (20mg / kg, twice a week) was given on the 8th day. The primary tumor was surgically removed on the 15th day. Metastatic tumors in the lungs were quantified on the 32nd day. 100mg / kg of NP-G2-044 was given to mice once a day starting on the 4th, 8th or 15th day. Each group had 2 to 4 mice. Data are shown as mean ± SEM.

[0022] Figure 2.The fascin inhibitor NP-G2-044 improves the overall survival of tumor-bearing mice. NSG mice implanted with MDA-MB-231 tumor cells were treated with a fascin inhibitor, chemotherapy, or a combination of fascin inhibitor and chemotherapy. The primary tumor was surgically removed on day 29. Chemotherapy treatment continued for 4 weeks (as marked). NP-G2-044 started on day 1. (a and b) The fascin inhibitor, chemotherapy, and combination all improved the overall survival of tumor-bearing mice. (a) Experimental scheme for the data shown in (b). (b) Overall survival curves of mice from four groups of mice. (c and d) In the combination therapy, earlier treatment with NP-G2-044 (starting on day 1 or day 8) was more effective than later treatment starting on day 15. (c) Experimental scheme for the data shown in (d). (d) Overall survival curves of mice from three different groups. The group starting on day 1 is the same group as the fourth group in (b). Death was used as the endpoint. There were 3 to 5 mice in each group.

[0023] Figure 3 .Brannin inhibitors enhance immunotherapy response. (a) Effect on primary tumor growth. Primary tumor volume was measured weekly until all mice in the control group died. Data are shown as mean ± SEM. (b and c) Brannin inhibitors, immunotherapy (anti-PD-1 antibody and anti-CTLA-4 antibody), and the combination all improved the overall survival of tumor-bearing mice. (b) Experimental scheme for the data shown in (c). (c) Overall survival curves of mice from four groups of mice. (d and e) In the combination therapy, both early treatment (starting on day 8) and late treatment (starting on day 22) with NP-G2-044 enhanced the immunotherapy response. (d) Experimental scheme for the data shown in (e). (e) Overall survival curves of mice from two different groups. The group starting on day 8 is the same group as the fourth group in (c). Death was used as the endpoint. There were 7 to 10 mice in each group. DETAILED DESCRIPTION

[0024] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols generally identify similar components unless the context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein.

[0025] definition

[0026] As set forth throughout this specification, several definitions are used herein to describe the technology.

[0027] The use of the terms "a," "an," and "the" and similar referents in the context of describing elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0028] As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there is a use of a term that is unclear to one of ordinary skill in the art, "about" means up to plus or minus 10% of the particular term given the context in which it is used.

[0029] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached through a carbon atom.

[0030] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. For any group containing one or more substituents, those skilled in the art will understand that these groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically infeasible, and / or inherently unstable.

[0031] " alkyl " has encompassed straight and branched chains of carbon atoms with a specified number, typically 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as approximately 1 to 6 carbon atoms. For example, C1-C6 alkyl has encompassed straight and branched chains of 1 to 6 carbon atoms. The example of an alkyl group includes methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl etc. Alkylene is another subset of alkyl, refers to the same residue as alkyl, but has two attachment points. Alkylene groups will typically have 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as 2 to 6 carbon atoms. For example, C0 alkylene indicates a covalent bond and C1 alkylene is a methylene group. When an alkyl residue having a particular number of carbon atoms is named, all geometric isomers having that number of carbon atoms are encompassed; thus, for example, "butyl" is intended to include n-butyl, sec-butyl, isobutyl, and tert-butyl; "propyl" includes n-propyl and isopropyl. "Lower alkyl" refers to an alkyl group having from 1 to 4 carbon atoms.

[0032] "Alkenyl" refers to a straight or branched hydrocarbon group having a specified number of carbon atoms (typically 1 to 8 carbon atoms, such as 2 to 4 carbon atoms) and having at least 1 and preferably 1 to 2 vinyl (>C=C<) unsaturated bond sites. Such groups are exemplified by vinyl, allyl, and but-3-en-1-yl. The term includes cis- and trans-isomers or mixtures of these isomers. "Lower alkenyl" refers to an alkenyl group having 1 to 4 carbon atoms, which can be indicated by C2-C4 alkenyl.

[0033] " cycloalkyl " refers to the non-aromatic part saturated or fully saturated carbocycle with specified carbon ring number of atoms (such as 3 to 10 or 3 to 8 or 3 to 6 ring carbon atoms).Cycloalkyl group can be monocyclic or polycyclic (such as, bicyclic, tricyclic).The example of cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl and cyclohexyl, and the cyclic group (such as norbornane, bicyclo [2.2.2] octane) of bridged and caged.In addition, one ring of polycyclic cycloalkyl group can be aromatic, and condition is that this polycyclic cycloalkyl group is combined with parent structure via non-aromatic carbon.For example, 1,2,3,4-tetrahydronaphthalene-1-yl group (wherein this part is combined to parent structure via non-aromatic carbon atom) is cycloalkyl group, and 1,2,3,4-tetrahydronaphthalene-5-yl (wherein this part is combined to parent structure via aromatic carbon atom) is not considered as cycloalkyl group. Examples of the polycyclic cycloalkyl group consisting of a cycloalkyl group condensed with an aromatic ring are described below.

[0034] "Aryl" refers to an aromatic carbocyclic ring with a specified number of carbon atoms (e.g., 6 to 12 or 6 to 10 carbon atoms) in the ring. Aryl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, a polycyclic aryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the aromatic ring, provided that the polycyclic aryl group is bound to the parent structure via the atoms in the aromatic ring. Therefore, 1,2,3,4-tetrahydronaphthalene-5-yl groups (wherein the moiety is bound to the parent structure via an aromatic carbon atom) are considered to be aryl groups, while 1,2,3,4-tetrahydronaphthalene-1-yl groups (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) are considered not to be aryl groups. Similarly, 1,2,3,4-tetrahydroquinolin-8-yl groups (wherein the moiety is bound to the parent structure via an aromatic carbon atom) are considered to be aryl groups, while 1,2,3,4-tetrahydroquinolin-1-yl groups (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) are considered not to be aryl groups. However, the term "aryl" does not encompass "heteroaryl" as defined herein or overlaps with "heteroaryl" as defined herein, regardless of point of attachment (e.g., quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In some cases, aryl is phenyl. Other examples of aryl groups comprising aromatic carbocyclic rings fused to non-aromatic rings are described below.

[0035] "Carboxy" or "carboxyl" refers to -COOH or a salt thereof.

[0036] "Heteroaryl" refers to an aromatic ring (e.g., a 5- to 12-membered or 5- to 10-membered heteroaryl) containing a specified number of ring atoms consisting of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms being carbon. A 5-membered heteroaryl is a heteroaryl having 5 ring atoms. A 6-membered heteroaryl is a heteroaryl having 6 ring atoms. The heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is not greater than 1. Unless otherwise indicated, a heteroaryl group may be bound to the parent structure through a carbon atom or nitrogen atom, where valence permits. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups. When nitrogen is present in a heteroaryl ring, it may be in an oxidized state (i.e., N + -O -) is present. Additionally, when sulfur is present in a heteroaryl ring, it may be in an oxidized state (i.e., S + -O - The heteroaryl group may be monocyclic or polycyclic (eg, bicyclic, tricyclic).

[0037] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

[0038] In certain instances, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzooxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c] Pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3- c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0039] In other cases, the polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is bound to the parent structure via atoms in the aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered to be a heteroaryl group, while a 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered to be a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of heteroaryl rings fused to non-aromatic rings are described below.

[0040] " Heterocycloalkyl " refers to a ring atom consisting of one or more heteroatoms (for example, 1,2,3 or 4 heteroatoms) selected from N, O and S and the remaining ring atoms are non-aromatic partially saturated or fully saturated rings (for example, 3 yuan to 10 yuan heterocycloalkyl or 3 yuan to 7 yuan heterocycloalkyl) of carbon with a specified number. 5 yuan of heterocycloalkyl is a heterocycloalkyl with 5 ring atoms. 6 yuan of heterocycloalkyl is a heterocycloalkyl with 6 ring atoms. Heterocycloalkyl groups can be monocyclic or polycyclic (for example, bicyclic, tricyclic). The example of heterocycloalkyl groups includes oxiranyl, aziridine, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. When nitrogen is present in the heterocycloalkyl ring, it can be in an oxidized state (i.e., N) if the properties of the adjacent atoms and groups allow. + -O - ) exists. Examples include piperidinyl N-oxide and morpholinyl-N-oxide. In addition, when sulfur is present in the heterocycloalkyl ring, it may be in an oxidized state (i.e., S) if the properties of the adjacent atoms and groups permit. + -O - Or -SO2-) exist.Example includes thiomorpholine S-oxide and thiomorpholine S, S-dioxide.In addition, one ring of polycyclic heterocycloalkyl group can be aromatic (for example, aryl or heteroaryl), and condition is that this polycyclic heterocycloalkyl group is attached to parent structure via non-aromatic carbon or nitrogen atom.For example, 1,2,3,4-tetrahydroquinoline-1-base group (wherein this part is attached to parent structure via non-aromatic nitrogen atom) is considered to heterocycloalkyl group, and 1,2,3,4-tetrahydroquinoline-8-base group (wherein this part is attached to parent structure via aromatic carbon atom) is considered to not heterocycloalkyl group.The example of the polycyclic heterocycloalkyl group consisting of the heterocycloalkyl group fused to aromatic ring is described hereinafter.

[0041] "Alkoxy" means an alkyl group of a specified number of carbon atoms attached by an oxygen bridge, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. Alkoxy groups are also meant to encompass cycloalkyl groups as defined above that are also attached by an oxygen bridge. Alkoxy groups will typically have 1 to 6 carbon atoms attached by an oxygen bridge. "Lower alkoxy" refers to an alkoxy group with 1 to 4 carbon atoms.

[0042] The term "halo" includes fluoro, chloro, bromo and iodo and the term "halogen" includes fluorine, chlorine, bromine and iodine.

[0043] As used herein, the term "substituted" means that any one or more hydrogens on a designated atom or group are replaced by a selection in a designated group, provided that the normal valence of the designated atom is not exceeded. When the substituent is an oxo group (i.e., =O), then two hydrogens on the atom are replaced. Such combinations are permitted only when the combination of substituents and / or variables produces a stable compound or a useful synthetic intermediate. A stable compound or stable structure is intended to refer to a compound that is robust enough to survive separation from a reaction mixture and subsequently formulated into a reagent with at least practical application value. Unless otherwise indicated, the substituent is named as a core structure. For example, it should be understood that when (cycloalkyl) alkyl is listed as a possible substituent, the point of attachment of the substituent to the core structure is in the alkyl portion.

[0044] "Haloalkyl" refers to an alkyl group substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are as defined herein. Lower haloalkyl refers to a C1-C4 alkyl group substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups.

[0045] "Lower alkylphenyl" refers to a C1-C4 alkyl-phenyl group.

[0046] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the symbol "(±)" can be used to represent a racemic mixture. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. "Meso compounds" or "mesomers" are non-optically active members of a group of stereoisomers. Meso isomers contain two or more stereocenters but are not chiral (i.e., there is a plane of symmetry within the molecule). Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. According to the direction (right-handed or left-handed) of the rotation plane polarized light at the wavelength of the sodium D line, the unknown split compound of its absolute configuration can be designated as (+) or (-). Some compounds disclosed and / or described herein contain one or more asymmetric centers, and therefore can produce enantiomers, diastereomers, mesoisomers and other stereoisomeric forms. Unless otherwise indicated, the compounds disclosed and / or described herein include all such possible enantiomers, diastereomers, mesoisomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures. Enantiomers, diastereomers, mesoisomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or split using conventional techniques. Unless otherwise specified, when the compounds disclosed and / or described herein contain olefinic double bonds or other geometric asymmetric centers, it is meant that the compound includes both E and Z isomers.

[0047] "Tautomers" are structurally different isomers that interconvert by tautomerization. Tautomerization is a form of isomerization and includes prototropy or proton-shift tautomerization, which is considered a subset of acid-base chemistry. Prototropy or proton-shift tautomerization involves the migration of a proton, accompanied by a change in bond order, usually the interchange of a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. When a compound described herein contains a moiety capable of tautomerization, and unless otherwise specified, the compound is intended to include all possible tautomers.

[0048] Pharmaceutically acceptable forms of the compounds described herein include pharmaceutically acceptable salts and mixtures thereof.

[0049] "Pharmaceutically acceptable salts" include, but are not limited to, salts formed with inorganic acids such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and the like; and salts formed with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoates such as acetate, HOOC-(CH2) n -COOH, wherein n is 0 to 4, and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0050] In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0051] The compounds disclosed and / or described herein may be in isotopically enriched forms, e.g., 2 H. 3 H. 11 C. 13 C and / or 14In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be prepared, for example, by the procedures described in U.S. Patent No. 5,846,514 and U.S. Patent No. 6,334,997. Such deuterated compounds can improve the efficacy and increase the duration of action of the compounds disclosed and / or described herein. Deuterium-substituted compounds can be synthesized using a variety of methods, such as those described in Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0052] As used herein, the terms "group," "radical," or "fragment" are synonymous and are intended to refer to a functional group or fragment of a molecule that can be attached to a bond or other fragment of a molecule.

[0053] The term "active agent" is used to refer to a substance that has biological activity. In some embodiments, an "active agent" is a substance that has pharmaceutical utility. For example, an active agent can be an anti-metastatic therapeutic agent.

[0054] The term "therapeutically effective amount" or "effective amount" means an amount that, when administered to a human or non-human subject, is effective to provide a therapeutic benefit (such as improving symptoms, slowing disease progression, or preventing disease) or is effective to inhibit fasciclin activity in vitro or in vivo. For example, a therapeutically effective amount can be an amount sufficient to alleviate the symptoms of a disease that is responsive to inhibition of fasciclin activity.

[0055] "Inhibition of fasciclin activity" refers to a decrease in fasciclin activity, either directly or indirectly, in response to the presence of at least one compound described herein, or a pharmaceutically acceptable salt thereof, relative to fasciclin activity in the absence of at least one compound described herein, or a pharmaceutically acceptable salt thereof. The decrease in activity can be due to a direct interaction of at least one compound described herein, or a pharmaceutically acceptable salt thereof, with fasciclin or with one or more other factors that in turn affect fasciclin activity.

[0056] In some embodiments, the IC of a compound described herein or a pharmaceutically acceptable salt thereof is 50 (the concentration that inhibits 50% of fasciclin activity) value is about 500 micromolar, about 100 micromolar, about 10 micromolar, about 1 micromolar, about 500 nanomolar, about 400 nanomolar, about 300 nanomolar, about 200 nanomolar, about 100 nanomolar, about 50 nanomolar, about 10 nanomolar, less than about 10 nanomolar, or a range between and including any two of these values.

[0057] A "disease responsive to inhibition of fascin activity" is a disease in which inhibition of fascin provides a therapeutic benefit, such as alleviation of symptoms, reduction in disease progression, prevention or delay of disease onset, prevention or alleviation of an inflammatory response, or inhibition of the abnormal activity and / or death of certain cell types (such as cancer cells).

[0058] "Treatment" or "treating" means any treatment of a disease in a patient, including:

[0059] a) Preventing disease, i.e. preventing the development of clinical symptoms of the disease;

[0060] b) inhibiting the progression of the disease;

[0061] c) slow down or prevent the development of clinical symptoms; and / or

[0062] d) Alleviate the disease, i.e. cause regression of clinical symptoms.

[0063] A "subject" or "patient" refers to an animal, such as a mammal, that has been or is to be the subject of treatment, observation, or experimentation. The methods described herein can be used in both human therapy and veterinary applications. In some embodiments, the subject is a mammal; and in some embodiments, the subject is a human.

[0064] As used herein, the term "cancer" includes solid mammalian tumors as well as hematological malignancies. The terms "tumor cell" and "cancer cell" are used interchangeably herein.

[0065] "Solid mammalian tumors" include cancers of the head and neck, lung, mesothelioma, mediastinum, esophagus, stomach, pancreas, hepatobiliary system, small intestine, colon, colorectum, rectum, anus, kidney, urethra, bladder, prostate, urethra, penis, testicles, gynecological organs, ovary, breast, endocrine system, skin, central nervous system; sarcomas of soft tissue and bone; and melanoma of cutaneous and intraocular origin.

[0066] The term "hematologic malignancies" includes childhood leukemias and lymphomas, Hodgkin's disease, lymphomas of lymphocytic and cutaneous origin, acute and chronic leukemias, plasma cell neoplasms, and AIDS-related cancers.

[0067] Furthermore, in these instances and elsewhere, abbreviations have the following meanings:

[0068]

[0069]

[0070] Metastasis inhibitor compounds

[0071] The present technology provides compounds for co-therapy including metastasis inhibitors (such as the fascin inhibitors described in US Patent Application Nos. 13 / 972,649 and 14 / 626,791, as well as US Patent No. 9,573,946, each of which is incorporated by reference in its entirety).

[0072] In some embodiments, the metastasis inhibitor is a compound selected from Formula I, Formula Ia, or Formula Ib:

[0073]

[0074] or its tautomers, and / or its pharmaceutically acceptable salts;

[0075] in,

[0076] A 1 、A 2 、A 3 、A 4 、A 5 and A 6 independently CH, CR 3 or N, if A 1 、A 2 、A 3 、A 4 、A 5 and A 6 No more than four of them are N;

[0077] R 1 is phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein the phenyl, 5-membered heteroaryl or 6-membered heteroaryl is optionally substituted by 1 to 3 R 6 replace;

[0078] L 2 Selected from the group consisting of: -NR 8 -、-C(O)NR 8 -、-NR 8C(O)-、-C(O)CR 8 2-, -CR 8 2C(O)-、-NR 8 CR 8 2-and-CR 8 2NR 8 -;

[0079] R 2 is hydrogen, lower alkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 R 4 Substitute, where each R 4 are independently selected from the group consisting of lower alkyl, lower haloalkyl, phenyl (optionally substituted with lower alkyl, halo, lower haloalkyl or -OH), -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 7 、-NR 10 CO2R 7 、-SOR 7 、-SO2R 7 、-SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0080] Each R 3 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR10 R 10 、-NR 10 COR 7 、-NR 10 CO2R 7 、-SOR 7 、-SO2R 7 、-SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0081] m is 0, 1, 2, or 3;

[0082] q is 1, 2, or 3;

[0083] Each R 6 independently selected from the group consisting of cyano, halo, lower alkyl (such as methyl or ethyl), lower haloalkyl and -CH2OH;

[0084] R 7 is lower alkyl (such as methyl or ethyl) or lower haloalkyl;

[0085] R 8 is hydrogen or lower alkyl (such as methyl or ethyl);

[0086] Each R 10 are independently hydrogen or lower alkyl (such as methyl or ethyl), or two R 10 together with the one or more atoms to which it is attached, form a 4- to 6-membered ring; and

[0087] R 11 is hydrogen or R 3 ;

[0088] with the proviso that the compound is not N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

[0089] In some embodiments, the metastasis inhibitor is a compound selected from compounds of Formula II:

[0090]

[0091] or its tautomers, and / or its pharmaceutically acceptable salts;

[0092] in,

[0093] R 1 is phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein the phenyl, 5-membered heteroaryl or 6-membered heteroaryl is optionally substituted by 1 to 3 R 6 replace;

[0094] L 2 Selected from the group consisting of: -C(O)NH-, -NHC(O)-, -C(O)CH2-, -CH2C(O)-, -NHCH2-, and -CH2NH-;

[0095] R 2 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 R 4 Substitute, where each R 4 are independently selected from the group consisting of lower alkyl, lower haloalkyl, phenyl (optionally substituted with lower alkyl, halo or lower haloalkyl or -OH), -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 7 、-NR 10 CO2R 7 、-SOR 7 、-SO2R 7 、-SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0096] Each R 3 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、-SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0097] m is 0, 1, 2, or 3;

[0098] n is 0, 1, 2, or 3;

[0099] q is 1, 2, or 3;

[0100] Each R 6 independently selected from the group consisting of halo, cyano, lower alkyl (preferably methyl or ethyl) and lower haloalkyl;

[0101] R 7 is lower alkyl (preferably methyl or ethyl) or lower haloalkyl; and

[0102] Each R 10 are independently hydrogen or lower alkyl (preferably methyl or ethyl), or two R 10 Together with the one or more atoms to which it is attached, it forms a 4- to 6-membered ring;

[0103] with the proviso that the compound is not N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

[0104] In some embodiments, the metastasis inhibitor is a compound selected from the group consisting of compounds of Formula IIIa, Formula IIIb, Formula IIIc, or Formula IIId.

[0105]

[0106] or its tautomers, and / or its pharmaceutically acceptable salts;

[0107] in,

[0108] R 2 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 R 4 Substitute, where each R 4 are independently selected from the group consisting of lower alkyl, lower haloalkyl, phenyl (optionally substituted with lower alkyl, halo or lower haloalkyl or -OH), -OH, -OR 7 、-SH、-SR 7 、-NR10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 7 、-NR 10 CO2R 7 、-SOR 7 、-SO2R 7 、-SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0109] Each R 3 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 7 、-NR 10 CO2R 7 、-SOR 7 、-SO2R 7 、-SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0110] m is 0, 1, 2, or 3;

[0111] n is 0, 1, 2, or 3;

[0112] Each R 6 independently selected from the group consisting of halo, cyano, lower alkyl (preferably methyl or ethyl) and lower haloalkyl;

[0113] R 7 is lower alkyl (preferably methyl or ethyl); and

[0114] Each R 10 are independently hydrogen or lower alkyl (preferably methyl or ethyl), or two R 10 Together with the one or more atoms to which it is attached, it forms a 4- to 6-membered ring;

[0115] with the proviso that the compound is not N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

[0116] In some embodiments, the metastasis inhibitor is a compound selected from the group consisting of Formula IVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, Formula IVh:

[0117]

[0118] or its tautomers, and / or its pharmaceutically acceptable salts;

[0119] in,

[0120] R 2 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 R 4 Substitute, where each R 4 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、-SO2NR 10 R 10 , phenyl (optionally substituted by lower alkyl, halo or lower haloalkyl or -OH) and -NR 10 SO2R7 ;

[0121] Each R 3 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、-SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0122] m is 0, 1, 2, or 3;

[0123] R 7 is lower alkyl (preferably methyl or ethyl); and

[0124] Each R 10 are independently hydrogen or lower alkyl (preferably methyl or ethyl), or two R 10 Together with the one or more atoms to which it is attached, it forms a 4- to 6-membered ring;

[0125] with the proviso that the compound is not N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-3-yl)furan-2-carboxamide.

[0126] In some embodiments, the metastasis inhibitor is a compound of Formula VIII, Formula VIIIa, or Formula VIIIb:

[0127]

[0128] or its tautomers, and / or its pharmaceutically acceptable salts;

[0129] in,

[0130] L 2 Selected from the group consisting of: -NR 8-、-C(O)NR 8 -、-NR 8 C(O)-、-C(O)CR 8 2-, -CR 8 2C(O)-、-NR 8 CR 8 2-and-CR 8 2NR 8 -;

[0131] R 2a is hydrogen or -NHC(O)R 2 , where R 2 is a lower alkyl, a 6-membered aryl or a 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 R 4 Substitute, where each R 4 are independently selected from the group consisting of lower alkyl, lower haloalkyl, phenyl (optionally substituted with lower alkyl, halo, lower haloalkyl or -OH), -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 7 、-NR 10 CO2R 7 、-SOR 7 、-SO2R 7 、-SO2NR 10 R 10 and -NR 10 SO2R 7 ;and

[0132] Each R 3 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 7 、-NR 10 CO2R 7 、-SOR 7 、-SO2R 7 、-SO2NR 10 R 10 and -NR 10 SO2R 7 .

[0133] In some embodiments, L 2 It is -C(O)NH-, -C(O)CH2- or -CH2NH-.

[0134] In some embodiments, A 1 It is N and A 2 、A 3 、A 4 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 2 It is N and A 1 、A 3 、A 4 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 3 It is N and A 1 、A 2 、A 4 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 4 It is N and A 1 、A 2 、A 3 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 5 It is N and A 1 、A 2 、A 3 、A 4 and A 6 are independently CH or CR 3In some embodiments, A 6 It is N and A 1 、A 2 、A 3 、A 4 and A 5 are independently CH or CR 3 .

[0135] In some embodiments, A 1 and A 2 Is N. In some embodiments, A 3 、A 4 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 3 It is N and A 4 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 4 It is N and A 3 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 5 It is N and A 3 、A 4 and A 6 are independently CH or CR 3 In some embodiments, A 6 It is N and A 3 、A 4 and A 5 are independently CH or CR 3 In some embodiments, A 3 and A 4 It is N and A 5 and A 6 are independently CH or CR 3 In some embodiments, A 3 and A 5 It is N and A 4 and A 6 are independently CH or CR 3 In some embodiments, A 3 and A 6 It is N and A 4 and A 5 are independently CH or CR 3 In some embodiments, A 4 and A 5 It is N and A 3 and A6 are independently CH or CR 3 In some embodiments, A 4 and A 6 It is N and A 3 and A 5 are independently CH or CR 3 In some embodiments, A 5 and A 6 It is N and A 3 and A 4 are independently CH or CR 3 .

[0136] In some embodiments, A 1 and A 3 Is N. In some embodiments, A 2 、A 4 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 4 It is N and A 2 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 5 It is N and A 2 、A 4 and A 6 are independently CH or CR 3 In some embodiments, A 6 It is N and A 2 、A 4 and A 5 are independently CH or CR 3 In some embodiments, A 2 and A 4 It is N and A 5 and A 6 are independently CH or CR 3 In some embodiments, A 2 and A 5 It is N and A 4 and A 6 are independently CH or CR 3 In some embodiments, A 2 and A 6 It is N and A 4 and A 5 are independently CH or CR 3 In some embodiments, A 4 and A 5 It is N and A 2and A 6 are independently CH or CR 3 In some embodiments, A 4 and A 6 It is N and A 2 and A 5 are independently CH or CR 3 In some embodiments, A 5 and A 6 It is N and A 2 and A 4 are independently CH or CR 3 .

[0137] In some embodiments, A 1 and A 4 Is N. In some embodiments, A 2 、A 3 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 3 It is N and A 2 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 5 It is N and A 2 、A 3 and A 6 are independently CH or CR 3 In some embodiments, A 6 It is N and A 2 、A 3 and A 5 are independently CH or CR 3 In some embodiments, A 2 and A 3 It is N and A 5 and A 6 are independently CH or CR 3 In some embodiments, A 2 and A 5 It is N and A 3 and A 6 are independently CH or CR 3 In some embodiments, A 2 and A 6 It is N and A 3 and A 5 are independently CH or CR 3 In some embodiments, A 3 and A 5 It is N and A2 and A 6 are independently CH or CR 3 In some embodiments, A 3 and A 6 It is N and A 2 and A 5 are independently CH or CR 3 In some embodiments, A 5 and A 6 It is N and A 2 and A 3 are independently CH or CR 3 .

[0138] In some embodiments, A 1 and A 5 Is N. In some embodiments, A 2 、A 4 、A 3 and A 6 are independently CH or CR 3 In some embodiments, A 4 It is N and A 2 、A 3 and A 6 are independently CH or CR 3 In some embodiments, A 3 It is N and A 2 、A 4 and A 6 are independently CH or CR 3 In some embodiments, A 6 It is N and A 2 、A 4 and A 3 are independently CH or CR 3 In some embodiments, A 2 and A 4 It is N and A 3 and A 6 are independently CH or CR 3 In some embodiments, A 2 and A 3 It is N and A 4 and A 6 are independently CH or CR 3 In some embodiments, A 2 and A 6 It is N and A 4 and A 3 are independently CH or CR 3 In some embodiments, A 4 and A 3It is N and A 2 and A 6 are independently CH or CR 3 In some embodiments, A 4 and A 6 It is N and A 2 and A 3 are independently CH or CR 3 In some embodiments, A 3 and A 6 It is N and A 2 and A 4 are independently CH or CR 3 .

[0139] In some embodiments, A 1 and A 6 Is N. In some embodiments, A 2 、A 4 、A 5 and A 3 are independently CH or CR 3 In some embodiments, A 4 It is N and A 2 、A 5 and A 3 are independently CH or CR 3 In some embodiments, A 5 It is N and A 2 、A 4 and A 3 are independently CH or CR 3 In some embodiments, A 3 It is N and A 2 、A 4 and A 5 are independently CH or CR 3 In some embodiments, A 2 and A 4 It is N and A 5 and A 3 are independently CH or CR 3 In some embodiments, A 2 and A 5 It is N and A 4 and A 3 are independently CH or CR 3 In some embodiments, A 2 and A 3 It is N and A 4 and A 5 are independently CH or CR 3 In some embodiments, A 4 and A5 It is N and A 2 and A 3 are independently CH or CR 3 In some embodiments, A 4 and A 3 It is N and A 2 and A 5 are independently CH or CR 3 In some embodiments, A 5 and A 3 It is N and A 2 and A 4 are independently CH or CR 3 .

[0140] In some embodiments, A 2 Is N. In some embodiments, A 1 Is CH or CR 3 In some embodiments, A 3 、A 4 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 3 It is N and A 4 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 4 It is N and A 3 、A 5 and A 6 are independently CH or CR 3 In some embodiments, A 5 It is N and A 3 、A 4 and A 6 are independently CH or CR 3 In some embodiments, A 6 It is N and A 3 、A 4 and A 5 are independently CH or CR 3 In some embodiments, A 3 and A 4 It is N and A 5 and A 6 are independently CH or CR 3 In some embodiments, A 3 and A 5 It is N and A 4 and A 6 are independently CH or CR3 In some embodiments, A 3 and A 6 It is N and A 4 and A 5 are independently CH or CR 3 In some embodiments, A 4 and A 5 It is N and A 3 and A 6 are independently CH or CR 3 In some embodiments, A 4 and A 6 It is N and A 3 and A 5 are independently CH or CR 3 In some embodiments, A 5 and A 6 It is N and A 3 and A 4 are independently CH or CR 3 .

[0141] In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is 4-trifluoromethylphenyl. In some embodiments, R 1 Is 4-fluorophenyl. In some embodiments, R 1 is 4-chlorophenyl. In some embodiments, R 1 In some embodiments, R 1 is optionally replaced by 1 to 3 R 6 Substituted pyridyl.

[0142] In some embodiments, R 2 is optionally replaced by 1 to 4 R 4 In some embodiments, R 2 is optionally replaced by 1 to 4 R 4 In some embodiments, R 2 is optionally replaced by 1 to 4 R 4 In some embodiments, R 2 It is 2 R 4 In some embodiments, R 2 It is 2 R 4 In some embodiments, R 2 It is 2 R 4 In some embodiments, R2 Is 1 R 4 In some embodiments, R 2 Is 1 R 4 In some embodiments, R 2 Is 1 R 4 Substituted 6-membered heteroaryl.

[0143] In some embodiments, R 2 is phenyl, chlorophenyl, methylfuran. In some embodiments, R 2 is selected from the group consisting of thiophene, thiazole, isoxazole, oxazole, 1,2,5-oxadiazole, pyrazole, pyrimidine and pyridazine, which are optionally substituted with methyl. 2 is pyridazine, isoxazole or oxazole.

[0144] In some embodiments, R 2 is optionally replaced by 1 to 4 R 4 substituted 5-membered heteroaryl or 6-membered heteroaryl, wherein the heteroaryl group contains two heteroatoms selected from N, O and S. In some embodiments, R 2 is optionally replaced by 1 to 4 R 4 A substituted 5-membered or 6-membered heteroaryl group, wherein the heteroaryl group contains two heteroatoms selected from N and S.

[0145] In some embodiments, R 2 It is phenyl.

[0146] In some embodiments, R 2 Selected from the group consisting of:

[0147]

[0148] In some embodiments, R 2 yes In some embodiments, R 2 yes

[0149] In some embodiments, R 2 yes

[0150] In some embodiments of Formula VIIIa, Formula VIIIb, or Formula VIIIc, R 2 In some embodiments of Formula VIIIa, Formula VIIIb or Formula VIIIc, R 2 yes

[0151] In some embodiments, R 2is optionally replaced by 1 to 4 R 4 Replaced R 5 , where R 5 is selected from the group consisting of furan, benzofuran, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, imidazole, pyrrole, and pyrazole. 2 Is 1 R 4 Replaced R 5 In some embodiments, R 2 It is 2 R 4 Replaced R 5 In some embodiments, R 2 It is the 3 R 4 Replaced R 5 In some embodiments, R 2 It is the 4 R 4 Replaced R 5 .

[0152] In some embodiments, R 4 Selected from the group consisting of lower alkyl (such as methyl), halo, lower haloalkyl, -OH, -OR 7 , cyano and phenyl (optionally substituted with methyl), wherein R 7 It is a lower alkyl group or a lower halogenated alkyl group.

[0153] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, R 3 In some embodiments, R 3 It is a lower alkyl group.

[0154] In some embodiments, n is 1.

[0155] In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 is 4-trifluoromethyl. In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 is 4-methyl. In some embodiments, R 6 It is 4-cyano.

[0156] In some embodiments, the metastasis inhibitor is a compound selected from the group consisting of:

[0157]

[0158]

[0159]

[0160]

[0161] or its tautomers, and / or pharmaceutically acceptable salts.

[0162] In some embodiments, the group in any of the above compounds quilt Alternative.

[0163] In some embodiments, the metastasis inhibitor is a compound selected from the group consisting of:

[0164]

[0165]

[0166]

[0167]

[0168]

[0169] or its tautomers, and / or pharmaceutically acceptable salts.

[0170] In some embodiments, the group in any of the above compounds quilt Alternative.

[0171] In some embodiments, the metastasis inhibitor is a compound selected from Table 2, or a tautomer, and / or a pharmaceutically acceptable salt thereof:

[0172] Table 2

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180] In one embodiment, the present technology provides a metastasis inhibitor that is a fascin inhibitory IC 50 In some embodiments, the fasciclin inhibitor has an IC50 of no greater than 100 μM. 50 In some embodiments, the fasciclin inhibitor has an IC for fasciclin inhibition of no greater than 20 μM. 50 In some embodiments, the fasciclin inhibitor has an IC for fasciclin inhibition of no greater than 8 μM. 50 .

[0181] Also provided is a method for evaluating a therapeutically effective dose of a compound described herein or a pharmaceutically acceptable salt thereof for treating cancer (e.g., inhibiting metastasis), the method comprising determining the IC of the agent in vitro. 50 This method allows calculation of the approximate amount of agent per volume required to inhibit cancer cell migration. Such amounts can be determined, for example, by standard microdilution methods. In some embodiments, the compounds or compositions described herein can be administered in multiple doses over an extended period of time or intermittently.

[0182] Second medicine

[0183] The metastasis inhibitors of the present disclosure can be part of a co-therapy with a second agent useful in treating cancer. For example, in some embodiments, the second agent is a chemotherapeutic agent or an immunotherapeutic agent.

[0184] In some embodiments, the second agent is a chemotherapeutic agent. The chemotherapeutic agent can be, for example, a known chemotherapeutic agent, such as an FDA-approved chemotherapeutic agent. Examples of suitable chemotherapeutic agents include taxanes, such as docetaxel, paclitaxel, albumin-bound paclitaxel, and the like; cyclophosphamide or anthracyclines, such as doxorubicin, daunorubicin, pirarubicin, aclarubicin, and mitoxantrone.

[0185] In some embodiments, the second agent is an immunotherapeutic agent. The immunotherapeutic agent can be, for example, a known immunotherapeutic agent, such as an FDA-approved immunotherapeutic agent. Examples of suitable immunotherapeutic agents include immune checkpoint inhibitors, such as anti-PD-1 antibodies or anti-CTLA-4 antibodies.

[0186] Patient population

[0187] The patient treated by the methods described herein may have one or more cancers. The cancer may be selected from the group consisting of lymphoma, sarcoma, melanoma, astrocytoma, mesothelioma, colon cancer, pancreatic cancer, esophageal cancer, gastric cancer, urinary system cancer, bladder cancer, breast cancer, gastric cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, kidney cancer, prostate cancer, liver cancer, head and neck cancer, thyroid cancer, brain cancer, oral cancer, gallbladder cancer, ampullary cancer, bile duct cancer and laryngeal cancer, lymphoma, sarcoma, melanoma, astrocytoma, mesothelioma, colon cancer, pancreatic cancer, esophageal cancer, gastric cancer, urinary system cancer, bladder cancer, breast cancer, gastric cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, kidney cancer, prostate cancer, liver cancer, head and neck cancer, thyroid cancer, brain cancer, oral cancer, gallbladder cancer, ampullary cancer, bile duct cancer and laryngeal cancer.

[0188] In some embodiments, the cancer can be selected from a cancer that exhibits high levels of fascin. For example, this can be a subset of specific cancers that have high levels of fascin, such as those described in the following table, each of which is incorporated by reference in its entirety.

[0189]

[0190] In some embodiments, the cancer can be the cancer described in: Strong association of fascin expression with triple negative breast cancer and basal-like phenotype in African-American women. Journal of Clinical Pathology. 2014; Prognostic Significance of Basal-Like Phenotype and Fascin Expression in Node-Negative Invasive Breast Carcinomas Clinical Cancer Research, 2006; Fascin expression predicts an aggressive clinical course in patients with advanced breast cancer Oncol Lett. July 2015; 10(1):121-130. Epub May 8, 2015; Fascin Is a Key Regulator of Breast Cancer Invasion That Acts via the Modification of Metastasis-Associated Molecules PLoS One. 2011; 6(11):e27339; Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K / Akt pathway British Journal of Cancer (2014) 111, 1552-1561; Fascin is Expressed in Basal-Liketype Triple Negative Breast Cancer Associated with High Malignant Potential in Japanese Women Int J Cancer Clin Res 2015, 2:5; Fascin expression in colorectal carcinomas Clinics Volume 65, Number 2 Paulo 2010; Fascin-1 as a biomarker and prospective therapeutic target in colorectal cancer. Expert Rev Mol Diagn. January 2015; 15(1):41-8; Overexpression of fascin-1 in advanced colorectal adenocarcinoma: Tissue microarray analysis of immunostaining scores with clinicopathological parameters, Disease Markers 23(2007)153-160; Prognostic Impact of Fascin-1 Expression is More Significant in Advanced Colorectal Cancer Journal of Surgical Research Vol. 172, No. 1, January 2012, pp. 102-108; Fascin overexpression promotes neoplastic progression in oral squamous cell carcinoma BMC Cancer 2012 12:32; Fascin upregulation in primary head and neck squamous cell carcinoma is associated with lymphatic metastasis Oncology Letters Vol. 7, No. 6, June 2014; OP050: Expression of fascin in squamous cell carcinoma of the oral cavity: Clinicopathological, prognostic significance and cell line study Oral Oncology Vol. 49, Supplement 1, May 1, 2013, pp. S24-S25;Fascin在口腔鳞状细胞癌中的表达:一项免疫组织化学技术研究《牙颌面放射学、病理学与外科学杂志》,第4卷,第2期,2015年夏季刊;Fascin免疫反应性在I期非小细胞肺癌中的独立预后价值。《英国癌症杂志》。2003年2月24日;88(4):537 - 47;Fascin在非小细胞肺癌中临床意义的血清学研究,《肺癌》。2013年11月;82(2):346 - 52。doi:10.1016 / j.lungcan.2013.08.017;Fascin在非小细胞肺癌患者中的表达及诊断价值《中华医学杂志》。2013年8月20日;93(31):2505 - 7;Fascin - 1在人肺癌及癌旁组织中的表达及其与肺癌患者临床病理特征的关系,《肿瘤靶点与治疗》2015年9月15日第2015卷:8:2571 - 2576;EMMPRIN和Fascin在非小细胞肺癌中的表达《中欧医学杂志》,2010年12月,第5卷,第6期,第659 - 665页;Fascin和Caveolin-1免疫组化表达在非小细胞肺癌中的意义 《国际癌症研究杂志》10(1):14 - 26·2013年12月;Fascin 1通过激活YAP / TEAD信号促进非小细胞肺癌细胞的生长和迁移,《肿瘤生物学》;2016年8月;肌动蛋白束蛋白Fascin的表达及其与卵巢浆液性肿瘤中E - cadherin和β - catenin表达改变的关系,《韩国病理学杂志》2005;39:258 - 64;Fascin(一种运动相关蛋白)在卵巢癌来源的细胞培养物以及交界性和癌性卵巢肿瘤中的表达增加,《临床与实验转移》2000年1月,第18卷,第1期,第83 - 88页;Fascin表达在晚期低分化浆液性卵巢癌中的预后意义,《抗癌研究》。2008年5月 - 6月;28(3B):1905 - 10;Fascin受slug调控,促进小鼠胰腺癌进展,并与患者预后相关,《胃肠病学》。2014年5月;146(5):1386 - 96.e1 - 17;Fascin调节前列腺癌细胞侵袭,并与前列腺癌转移和生化失败相关。临床癌症研究。2009年2月15日;15(4):1376 - 83。doi:10.1158 / 1078 - 0432.CCR - 08 - 1789;Fascin - 1表达与肝细胞癌(HCC)细胞中E - cadherin表达的抑制相关,并与基质金属蛋白酶联合增强其侵袭性,癌症科学。2011年3月14日;Fascin表达与胃癌患者的不良生存相关,国际病理学杂志。第62卷,第12期,2012年12月,第777 - 784页;肾细胞癌中Fascin表达增加与侵袭性的临床病理参数相关,组织学与组织病理学[2006年12月1日,21(12):1287 - 1293;Fascin的磷酸化降低食管鳞状细胞癌患者不良生存的风险,组织化学与细胞化学杂志。2010年11月;58(11):979 - 988;靶向Fascin的小干扰RNA对人食管鳞状细胞癌细胞系的影响,诊断病理学20105:41;Fascin and CK4 as Biomarkers for Esophageal Squamous Cell Carcinoma, Anticancer Res. Author manuscript; Available from PMC 2011 December 12; The Role of Fascinin the Migration and Invasiveness of Malignant Glioma Cells, Neoplasia, Volume 10, Issue 2 - February 2008, Pages 149-159; Fascin-1 knock-down of human glioma cells reduces their microvilli / filopodia while improving their susceptibility to lymphocyte-mediated cytotoxicity, Am J Transl Res. 2015; 7(2):271-284; Fascin-1 expression in papillary and invasive urothelial carcinomas of the urinarybladder,Human Pathology, Vol. 36, No. 7 - July 2005, pp. 741-746; The Role of Fascinin Migration and Invasion of Urothelial Carcinoma of the Bladder, Urologia Internationalis, 2013; 91: 227-235; Fascin Regulates Nuclear Movement and Deformation in Migrating Cells Developmental Cell. Vol. 38, No. 4, pp. 371-383, August 22, 2016, each of which is incorporated by reference in its entirety.

[0191] In some embodiments, the cancer is one for which chemotherapy or immunotherapy has been shown to be effective. Some embodiments include subsets in which the patient is suffering from one of the above cancers, e.g., neuroendocrine prostate cancer, diffuse large B-cell lymphoma of the activated B-cell subtype, triple-negative breast cancer.

[0192] In some embodiments, the patient is currently undergoing or about to undergo chemotherapy. In other embodiments, the patient has undergone chemotherapy, e.g., within the past 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, or 24 months. In some embodiments, the patient is currently undergoing or about to undergo immunotherapy. In other embodiments, the patient has undergone immunotherapy, e.g., within the past 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, or 24 months.

[0193] method

[0194] The present disclosure includes methods of treating cancer in a patient in need thereof, comprising administering to the patient a chemotherapeutic or immunotherapeutic agent and a metastasis-suppressing compound as described herein.

[0195] In some embodiments, the second agent is a chemotherapeutic agent. The chemotherapeutic agent can be, for example, a known chemotherapeutic agent, such as an FDA-approved chemotherapeutic agent. Examples of suitable chemotherapeutic agents include taxanes, such as docetaxel, paclitaxel, albumin-bound paclitaxel, etc.; cyclophosphamide; anthracyclines, such as doxorubicin, daunomycin, pirarubicin, aclarubicin, and mitoxantrone; platinum-based drugs, such as carboplatin or cisplatin. The chemotherapeutic agent can be a combination of agents as known in the art. For example, a clinical oncologist combines a platinum-based drug (such as carboplatin or cisplatin) with a taxane (such as paclitaxel or docetaxel). Additional chemotherapeutic agents include carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, cabazitaxel, anastrozole, capecitabine, cyclophosphamide, doxorubicin, exemestane, 5-fluorouracil, gemcitabine, ixabepilone, letrozole, estramustine, mitoxantrone, etoposide, vinorelbine, or pemetrexed.

[0196] In some embodiments, the second agent is an immunotherapeutic agent. The immunotherapeutic agent can be, for example, a known immunotherapeutic agent, such as an FDA-approved immunotherapeutic agent. Examples of suitable immunotherapeutic agents include immune checkpoint inhibitors, such as anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-CTLA-4 antibodies.

[0197] In some embodiments, the compound represented by formula (I):

[0198]

[0199] or its tautomers, and / or its pharmaceutically acceptable salts; wherein,

[0200] R2 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 R 4 Substitute, where each R 4 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、SO2NR 10 R 10 , phenyl (optionally substituted by lower alkyl, halo or lower haloalkyl or -OH) and -NR 10 SO2R 7 ;

[0201] Each R 3 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、SO2NR 10 R 10and -NR 10 SO2R 7 ;

[0202] m is 0, 1, 2, or 3;

[0203] R 7 is lower alkyl; and

[0204] Each R 10 are independently hydrogen or lower alkyl, or two R 10 Together with the one or more atoms to which it is attached, it forms a 4- to 6-membered ring;

[0205] Y is selected from the group consisting of CF3, Cl, F and Me.

[0206] In some embodiments, in the compound of formula I, R 2 Optionally 1 to 4 R 4 Replace, and R 2 is selected from the group consisting of furan, benzofuran, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, imidazole, pyrrole and pyrazole. In some embodiments, in the compound of formula I, R 2 Selected from the group consisting of:

[0207] In some embodiments, in the compound of formula I, R 4 is not optional and is selected from the group consisting of lower alkyl, halo, lower haloalkyl, -OH, -OR 7 , cyano and phenyl (optionally substituted with methyl), wherein R 7 In some embodiments, in the compound of formula I, m is 0. In some embodiments, the compound of formula I is selected from:

[0208] or its tautomer, and / or its pharmaceutically acceptable salt.

[0209] In some embodiments, the cancer can be selected from the group consisting of lymphoma, sarcoma, melanoma, astrocytoma, mesothelioma, colon cancer, pancreatic cancer, esophageal cancer, gastric cancer, urinary system cancer, bladder cancer, breast cancer, stomach cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, kidney cancer, prostate cancer, liver cancer, head and neck cancer, thyroid cancer, brain cancer, oral cancer, gallbladder cancer, ampullary cancer, bile duct cancer and laryngeal cancer.

[0210] In some embodiments, the cancer is one for which chemotherapy or immunotherapy has been shown to be effective. Some embodiments include subsets in which the patient is suffering from one of the above cancers, e.g., neuroendocrine prostate cancer, diffuse large B-cell lymphoma of the activated B-cell subtype, triple-negative breast cancer.

[0211] In some embodiments, the patient is currently undergoing or about to undergo chemotherapy. In other embodiments, the patient has undergone chemotherapy, e.g., in the past 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, or 24 months. In some embodiments, the patient is currently undergoing or about to undergo immunotherapy. In other embodiments, the patient has undergone immunotherapy, e.g., in the past 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, or 24 months.

[0212] Other embodiments include methods of increasing the response to a chemotherapeutic or immunotherapeutic agent in a patient in need thereof, comprising: administering to the patient a metastasis-suppressing compound as described herein.

[0213] In some embodiments, the second agent is a chemotherapeutic agent. The chemotherapeutic agent can be, for example, a known chemotherapeutic agent, such as an FDA-approved chemotherapeutic agent. Examples of suitable chemotherapeutic agents include taxanes, such as docetaxel, paclitaxel, albumin-bound paclitaxel, and the like; cyclophosphamide or anthracyclines, such as doxorubicin, daunorubicin, pirarubicin, aclarubicin, and mitoxantrone.

[0214] In some embodiments, the second agent is an immunotherapeutic agent. The immunotherapeutic agent can be, for example, a known immunotherapeutic agent, such as an FDA-approved immunotherapeutic agent. Examples of suitable immunotherapeutic agents include immune checkpoint inhibitors, such as anti-PD-1 antibodies or anti-CTLA-4 antibodies.

[0215] In some embodiments, the compound represented by formula (I):

[0216]

[0217] or its tautomers, and / or its pharmaceutically acceptable salts; wherein,

[0218] R 2 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; wherein the 6- to 10-membered aryl or the 5- to 10-membered heteroaryl is optionally substituted by 1 to 4 R 4 Substitute, where each R 4 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7 、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、SO2NR 10 R 10 , phenyl (optionally substituted by lower alkyl, halo or lower haloalkyl or -OH) and -NR 10 SO2R 7 ;

[0219] Each R 3 Independently selected from the group consisting of lower alkyl, lower haloalkyl, -OH, -OR 7 、-SH、-SR 7 、-NR 10 R 10 , halogenated, cyano, nitro, -COH, -COR 7、-CO2H、-CO2R 7 、-CONR 10 R 10 、-OCOR 7 、-OCO2R 7 、-OCONR 10 R 10 、-NR 10 COR 10 、-NR 10 CO2R 10 、-SOR 7 、-SO2R 7 、SO2NR 10 R 10 and -NR 10 SO2R 7 ;

[0220] m is 0, 1, 2, or 3;

[0221] R 7 is lower alkyl; and

[0222] Each R 10 are independently hydrogen or lower alkyl, or two R 10 Together with the one or more atoms to which it is attached, it forms a 4- to 6-membered ring;

[0223] Y is selected from the group consisting of CF3, Cl, F and Me.

[0224] In some embodiments, in the compound of formula I, R 2 Optionally 1 to 4 R 4 Replace, and R 2 is selected from the group consisting of furan, benzofuran, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, imidazole, pyrrole and pyrazole. In some embodiments, in the compound of formula I, R 2 Selected from the group consisting of:

[0225] In some embodiments, in the compound of formula I, R 4 is not optional and is selected from the group consisting of lower alkyl, halo, lower haloalkyl, -OH, -OR 7 , cyano and phenyl (optionally substituted with methyl), wherein R 7 In some embodiments, in the compound of formula I, m is 0. In some embodiments, the compound of formula I is selected from:

[0226]

[0227]

[0228] or its tautomer, and / or its pharmaceutically acceptable salt.

[0229] In some embodiments, increasing the response to a chemotherapeutic or immunotherapeutic agent means increasing the prognosis survival rate, for example, the average survival rate of a patient population and / or increasing the reduction of tumor growth or presence in a patient or patient population compared to a therapy with a chemotherapeutic or immunotherapeutic agent and no metastasis inhibitory compound. In some embodiments, the increase in response to a chemotherapeutic or immunotherapeutic agent is synergistic, meaning that the effect is greater than when a chemotherapeutic or immunotherapeutic agent is administered alone, and greater than when a metastasis inhibitory compound is administered alone. The efficacy of treating or preventing a disease can be assessed by, for example, measuring disease progression, disease remission, symptom severity, pain relief, quality of life, the dose of drug required to maintain the therapeutic effect, the level of a disease marker, or any other measurable parameter applicable to a given disease being treated or targeted for prevention. Monitoring the efficacy of treatment or prevention by measuring any one of these parameters or any combination of parameters is entirely within the capabilities of those skilled in the art.

[0230] The amount of metastasis inhibition compound disclosed herein can be determined by medical professionals. The daily dose of the product can change in the wide range of 10 mg to 2,000 mg per adult per day or any range thereof. For oral administration, the composition is preferably provided in the form of tablets, capsules or other oral administration forms, containing 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 50.0 mg, 100 mg, 150 mg, 200 mg, 250 mg and 500 mg of active ingredient, for symptomatic dose adjustment of patients to be treated. The effective amount of the drug is usually supplied with a dosage level of about 0.01 mg / kg body weight to about 100 mg / kg body weight or any range thereof per day. Preferably, the scope is about 0.01 mg / kg body weight per day to about 50.0 mg / kg body weight per day or any range thereof. More preferably, the dosage is from about 0.01 mg / kg body weight to about 10.0 mg / kg body weight per day, or any range thereof. More preferably, the dosage is from about 0.01 mg / kg body weight to about 1.0 mg / kg body weight per day, or any range thereof. The metastasis-suppressing compound can be administered on a schedule of 1 to 4 times per day. For example, the metastasis-suppressing compound of the present disclosure can be administered in one or more doses of from about 0.1 mg / kg to about 100 mg / kg. For example, the disclosed metastasis-suppressing compounds can be administered at a dose of about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg g, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, about 5 mg / kg, about 5.1mg / kg, about 5.2mg / kg, about 5.3mg / kg, about 5.4mg / kg, about 5.5mg / kg, about 5.6mg / kg, about 5.7mg / kg, about 5.8mg / kg, about 5.9mg / kg, about 6mg / kg, about 6.1mg / kg, about 6.2mg / kg, about 6.3mg / kg, about 6.4mg / kg, about 6.5mg / kg, about 6.6mg / kg, about 6.7mg / kg, about 6.8mg / kg, about 6.9mg / kg, about 7mg / kg, about 7.1mg / kg, about 7.2mg / kg, about 7.3mg g / kg, about 7.4 mg / kg, about 7.5 mg / kg, about 7.6 mg / kg, about 7.7 mg / kg, about 7.8 mg / kg, about 7.9 mg / kg, about 8 mg / kg, about 8.1 mg / kg, about 8.2 mg / kg, about 8.3 mg / kg, about 8.4 mg / kg, about 8.5 mg / kg, about 8.6 mg / kg, about 8.7 mg / kg, about 8.8 mg / kg, about 8.9 mg / kg, about 9 mg / kg, about 9.1 mg / kg, about 9.2 mg / kg, about 9.3 mg / kg, about 9.4 mg / kg, about 9.5 mg / kg, about 9.6 mg / kg, about 9.7 mg / kg, about 9.8 mg / kg, about 9.9 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11 mg / kg, about 11.5 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 13.5 mg / kg, about 14 mg / kg, about 14.5 mg / kg, about 15 mg / kg, about 15.5 mg / kg, about 16 mg / kg, about 16.5 mg / kg, about 17 mg / kg, about 17.5 mg / kg, about 18 mg / kg, about 18.5 mg / kg g / kg, about 19 mg / kg, about 19.5 mg / kg, about 20 mg / kg, about 20.5 mg / kg, about 21 mg / kg, about 21.5 mg / kg, about 22 mg / kg, about 22.5 mg / kg, about 23 mg / kg, about 23.5 mg / kg, about 24 mg / kg, about 24.5 mg / kg, about 25 mg / kg, about 25.5 mg / kg, about 26 mg / kg, about 26.5 mg / kg, about 27 mg / kg, about 27.5 mg / kg, about 28 mg / kg, about 28.5 mg / kg, about 29 mg / kg, about 29.The present invention also provides the present invention with respect to the present invention.In some embodiments, the present invention provides the present invention with respect to the present invention with respect to the present invention.In some embodiments, the present invention provides the present invention with respect to the present invention with respect to the present invention with respect to the present invention. These values ​​apply to intravenous infusion and / or subcutaneous delivery. Other delivery methods described herein may also be administered at these doses. Dosages may vary depending on the patient's requirements, the severity of the condition being treated, and the metastasis-inhibiting compound being used. Daily administration or post-periodic dosing may be employed.

[0231] The metastasis-suppressing compound can be administered concurrently with the chemotherapeutic or immunotherapeutic agent, or can be administered within a year or up to 18 months of administration of the chemotherapeutic or immunotherapeutic agent, for example within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, or within 1 week, 2 weeks, 3 weeks, 4 weeks, or within 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months.

[0232] Composition

[0233] The compounds described herein (e.g., metastasis-inhibiting compounds) can be formulated as pharmaceutical compositions and administered to a mammalian host (such as a human patient) in a variety of forms suitable for the chosen route of administration (i.e., orally or parenterally, by intravenous, intramuscular, topical, transdermal, intrathecal, ocular, intranasal, intraperitoneal, or subcutaneous routes).

[0234] The compounds described herein (e.g., metastasis-inhibiting compounds) can be systemically (e.g., orally) administered in combination with a pharmaceutically acceptable vehicle (such as an inert diluent or an absorbable edible carrier). They can be placed in hard or soft shell gelatin capsules, compressed into tablets, or directly mixed with the food of the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% active compound. The percentage of the composition and preparation can of course vary and can conveniently be from about 2% to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

[0235] Tablets, lozenges, pills, capsules, etc. may also contain the following: binders such as gum tragacanth, gum arabic, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavorings such as peppermint, wintergreen oil, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to the above-mentioned types of materials, a liquid carrier such as a vegetable oil or polyethylene glycol. Various other materials may be present as a coating or otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar. Syrups or elixirs may contain the active compound, sucrose or fructose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavorings such as cherry or orange flavor. The materials used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. Additionally, the active compound may be incorporated into sustained-release preparations and devices.

[0236] The active compounds described herein can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salt can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersants can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, and in oils. Under conventional storage and use conditions, these formulations contain a preservative to prevent the growth of microorganisms.

[0237] The pharmaceutical dosage form suitable for injection or infusion can include a sterile aqueous solution or dispersant or sterile powder comprising active ingredient, which is suitable for temporary preparation of sterile injectable or infusible solutions or dispersants optionally encapsulated in liposomes. In all cases, the final dosage form should be sterile, fluid and stable under manufacturing and storage conditions. The liquid carrier or vehicle can be a solvent or liquid dispersion medium, which comprises, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides and their applicable mixtures. Suitable fluidity can be, for example, by forming liposomes, by maintaining the required particle size in the case of dispersants, or by using surfactants to maintain. The effect of microorganisms can be prevented by various antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In many cases, it is preferred to include isotonic agents, such as sugar, buffer or sodium chloride. By using the reagent (such as aluminum monostearate and gelatin) that delays absorption in the composition, the absorption of the injectable composition can be extended.

[0238] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in an appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in a previously sterile-filtered solution.

[0239] For topical administration, the compounds of the invention can be applied in pure form (ie, when they are liquids). However, it will generally be desirable to administer them to the skin as compositions or formulations in combination with a dermatologically acceptable carrier (which may be a solid or liquid).

[0240] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silicon dioxide, aluminum oxide, and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the compounds of the present invention can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and other antimicrobial agents can be added to optimize performance for a given application. The resulting liquid composition can be applied from an absorbent pad, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump or aerosol sprayer.

[0241] Thickening agents such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with the liquid carrier to form spreadable pastes, gels, ointments, soaps, and the like for application directly to the user's skin.

[0242] Examples of useful dermatological compositions that can be used to deliver the compounds described herein, or pharmaceutically acceptable salts thereof, to the skin are known in the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157), and Wortzman (U.S. Pat. No. 4,820,508).

[0243] By comparing the in vitro and in vivo activity of the compounds described herein or their pharmaceutically acceptable salts in animal models, their useful dosages can be determined. Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; for example, see U.S. Patent No. 4,938,949.

[0244] Typically, the concentration of a compound as described herein, or a pharmaceutically acceptable salt thereof, in a liquid composition such as a lotion will be about 0.01%, about 0.1%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 10.0%, about 25.0%, or a range between and including any two of these values. The concentration in a semisolid or solid composition such as a gel or powder will be about 0.01%, about 0.1%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 10.0%, about 25.0%, or a range between and including any two of these values.

[0245] The amount for treating required compound or its active salt or derivative not only changes because of selected particular salt, but also changes with route of administration, the character of the illness treated and the age and situation of the patient, and will finally be determined by the attending physician or clinician.Usually, however, suitable dosage will be in the scope of about 1.0mg / kg to about 200mg / kg, for example, about 1mg / kg body weight / day to about 100mg / kg body weight / day, such as about 2.0mg / kg body weight / day to about 100mg / kg body weight / day, such as about 3.0mg / kg recipient body weight / day to about 50mg / kg recipient body weight / day, or in the scope of about 5mg / kg / days to 20mg / kg / days.Alternatively, compositions can be used five times in a week for five consecutive days, wherein rest two days, or use four times in a week for four consecutive days, wherein rest three days, or once every other day.

[0246] Methods for extrapolating effective doses in mice and other animals to humans are known in the art (see, for example, U.S. Patent No.: 4,938,949). For example, in some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof (e.g., those used to treat colon cancer and / or ovarian cancer), can be administered at dosage levels of about 0.01 mg / kg to about 300 mg / kg, about 0.1 mg / kg to about 250 mg / kg, about 1 mg / kg to about 200 mg / kg, about 1 mg / kg to about 150 mg / kg, about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 90 mg / kg, about 1 mg / kg to about 80 mg of the subject's body weight per day. / kg, about 1 mg / kg to about 70 mg / kg, about 1 mg / kg to about 60 mg / kg, about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 40 mg / kg, about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 100 mg / kg, about 5 mg / kg to about 90 mg / kg, about 5 mg / kg to about 80 mg / kg, about 5 mg / kg to about 70 mg / kg, about 5 mg / kg to about 60 mg / kg, about 5 mg / kg to about 80 mg / kg. / kg to about 50 mg / kg, about 5 mg / kg to about 40 mg / kg, about 5 mg / kg to about 30 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 100 mg / kg, about 10 mg / kg to about 90 mg / kg, about 10 mg / kg to about 80 mg / kg, about 10 mg / kg to about 70 mg / kg, about 10 mg / kg to about 60 mg / kg, about 10 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 10 mg / kg to about 50 mg / kg. / kg to about 30 mg / kg, about 10 mg / kg to about 20 mg / kg, about 20 mg / kg to about 100 mg / kg, about 20 mg / kg to about 90 mg / kg, about 20 mg / kg to about 80 mg / kg, about 20 mg / kg to about 70 mg / kg, about 20 mg / kg to about 60 mg / kg, about 20 mg / kg to about 50 mg / kg, about 20 mg / kg to about 40 mg / kg, about 20 mg / kg to about 30 mg / kg, once or more a day to achieve the desired therapeutic effect.In some embodiments, the compound can be administered at a dose of about 1 mg / kg or more, 5 mg / kg or more, 10 mg / kg or more, 15 mg / kg or more, 20 mg / kg or more, 25 mg / kg or more, 30 mg / kg or more, 35 mg / kg or more, 40 mg / kg or more, 45 mg / kg or more, 50 mg / kg or more, 60 mg / kg or more, 70 mg / kg or more of body weight. It will also be understood that a dose of less than 0.01 mg / kg or greater than 70 mg / kg (e.g., 70 mg / kg to 200 mg / kg) can be administered to a subject.

[0247] In some embodiments, the compounds described herein can be used in chemotherapy (i.e., to inhibit metastasis) and can be administered at higher doses. For example, the compound to be used in chemotherapy can be administered at about 100 mg / kg to about 300 mg / kg, about 120 mg / kg to about 280 mg / kg, about 140 mg / kg to about 260 mg / kg, about 150 mg / kg to about 250 mg / kg, about 160 mg / kg to about 240 mg / kg of the subject's body weight per day, once or more times a day to achieve the desired therapeutic effect.

[0248] In certain other embodiments, the compounds described herein can be used in supportive therapy (e.g., as an adjuvant to surgery or irradiation within the context of common tumor types) and can be administered at lower doses. For example, the compound to be used in supportive therapy can be administered at about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg of the subject's body weight per day, once or more a day to achieve the desired therapeutic effect.

[0249] In certain other embodiments, the compounds described herein can be used to treat metastatic cancers (e.g., ovarian cancer and / or colon cancer) and can be administered at intermediate doses. For example, the compound to be used in supportive therapy can be administered at about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 80 mg / kg, about 5 mg / kg to about 70 mg / kg, about 10 mg / kg to about 70 mg / kg, about 10 mg / kg to about 60 mg / kg, about 20 mg / kg to about 70 mg / kg, about 20 mg / kg to about 60 mg / kg, once or more a day to achieve the desired therapeutic effect.

[0250] The compound is conveniently administered in unit dosage form; for example, each unit dosage form contains 45 mg to 3000 mg, conveniently 90 mg to 2250 mg, and most conveniently 450 mg to 1500 mg of active ingredient. In some embodiments, the compound is administered in a dosage of about 1 mg / kg to about 100 mg / kg.

[0251] Ideally, the active ingredient should be administered so as to achieve a peak plasma concentration of the active compound of about 0.5 nM to about 10 μM, or about 1 nM to 1 μM, or about 10 nM to about 0.5 μM. This can be achieved, for example, by intravenous injection of a 0.05% to 5% solution of the active ingredient (optionally in saline), or by oral administration of a bolus containing about 20 mg to 2000 mg of the active ingredient. The desired blood level can be maintained by continuous infusion to provide about 0.2 mg / kg / h to 1.0 mg / kg / h of one or more active ingredients, or by intermittent infusion containing about 0.4 mg / kg to 20 mg / kg of one or more active ingredients. The desired dose may conveniently be presented as a single dose or divided doses administered at appropriate intervals, for example, two, three, four, or more sub-doses per day. The sub-doses themselves can be further divided, for example, into a plurality of separate, loosely spaced administrations; such as multiple inhalations from an insufflator or by applying multiple drops to the eye.

[0252] The compounds described herein, or pharmaceutically acceptable salts thereof, can be used as therapeutic agents for inhibiting cell migration and treating metastatic cancers. Such cancers include, but are not limited to, cancers of the head, neck, lung, mesothelioma, mediastinum, esophagus, stomach, pancreas, hepatobiliary system, small intestine, colon, colorectum, rectum, anus, kidney, ureter, bladder, prostate, urethra, penis, testicles, gynecological organs, ovary, breast, endocrine system, skin, or central nervous system of an animal. Thus, for example, the cancer can be breast cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, or prostate cancer.

[0253] Additionally, the compounds described herein, or pharmaceutically acceptable salts thereof (such as the exemplary salts described herein), can be used as pharmacological tools to further study the inhibition of cell migration.

[0254] The compounds described herein, or pharmaceutically acceptable salts thereof, may also be administered in combination with other therapeutic agents effective in treating or controlling the spread of cancer cells or tumor cells.

[0255] In addition, the compounds described herein, or pharmaceutically acceptable salts thereof, can be tested in appropriate animal models. For example, the compounds described herein, or pharmaceutically acceptable salts thereof, can be tested in animals with known tumors, or in animals in which tumor cells have been injected into a local area. The extent or number of secondary tumors formed over time is a measure of metastasis, and the ability of the compound to inhibit such metastasis can be evaluated relative to control animals with primary tumors that have not received the test compound.

[0256] The compounds described herein, or pharmaceutically acceptable salts thereof, will also be useful in treating brain disorders (Kraft et al., J. Neurosci. 2006 Aug 23;26(34):8734-47); Hodgkin's disease (Pinkus et al., Am J Pathol. 1997 Feb;150(2):543-62); viral infections (Mosialos et al., Am J Pathol. 1996 Feb;148(2):593-600); neuronal degeneration (Fulga et al., Nat Cell Biol. 2007 Feb;9(2):139-48); lymphoid hyperplasia (Said et al., Mod Pathol. 1997 May;10(5):421-7); and ischemia (Meller et al., J Neurosci. 2008 Jan 2;28(1):50-9).

[0257] General synthetic methods

[0258] The metastasis inhibition compounds described herein are commercially available or can be prepared from readily available raw materials using the following general methods and procedures. It should be understood that where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary with the specific reactants or solvents used, but these conditions can be determined by those skilled in the art through conventional optimization procedures.

[0259] In addition, it is obvious to those skilled in the art that conventional blocking groups may be necessary to prevent certain functional groups from carrying out undesirable reactions. The blocking groups that are applicable to various functional groups and the conditions for protecting and deprotecting specific functional groups are well known in the art. For example, various blocking groups are described in TW Greene and GM Wuts, Protecting Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999 and the references cited therein.

[0260] In addition, the metastasis inhibition compounds described herein may contain one or more chiral centers. Therefore, if desired, such compounds can be prepared or separated into pure stereoisomers (i.e., individual enantiomers or diastereomers), or into mixtures enriched in stereoisomers. Unless otherwise specified, all of these stereoisomers (and enriched mixtures) are included within the scope of the present invention. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active raw materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0261] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or their obvious variations. For example, many starting materials can be obtained from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by the procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious variations thereof.

[0262] Where appropriate, conventional techniques (such as precipitation, filtration, crystallization, evaporation, distillation and chromatography) can be used to separate and purify the various raw materials, intermediates and compounds described herein. Conventional methods (such as by melting point, mass spectrometry, nuclear magnetic resonance and various other spectroscopic analyses) can be used to characterize these compounds.

[0263] Amide coupling reagents are known in the art and may include, but are not limited to, ammonium-based and phosphonium-based reagents. Ammonium salts include N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU), N-[(1H-6-chlorobenzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HCTU), N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (TBTU), and N-[(1H-6-chlorobenzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (TCTU). Phosphonium salts include 7-azabenzotriazol-1-yl-N-oxy-tris(pyrrolidinone)phosphonium hexafluorophosphate (PyAOP) and benzotriazol-1-yl-N-oxy-tris(pyrrolidinone)phosphonium hexafluorophosphate (PyBOP). The amide formation step can be carried out in a polar solvent such as dimethylformamide (DMF) and can also include an organic base such as diisopropylethylamine (DIEA) or dimethylaminopyridine (DMAP).

[0264] Cross-coupling reactions are well known in the art and are reported, for example, in Anna Roglans, et al., Diazonium Salts as Substrates in Palladium-Catalyzed Cross-Coupling Reactions, Chem. Rev., 2006, 106(11):4622-4643; Brad M. Rosen, et al., Nickel-Catalyzed Cross-Couplings Involving Carbon-Oxygen Bonds, Percec Chem. Rev., 2011, 111(3):1346-1416; Jean-Pierre Corbet, et al., Selected Patented Cross-Coupling Reaction Technologies, Chem. Rev., 2006, 106(7):2651-2710; Gwilherm Evano et al., Copper-Mediated Coupling Reactions and Their Applications in Natural Products and Designed Biomolecules Synthesis, Chem. Rev., 2008, 108 (8): 3054-3131; BennyBogoslavsky, et al., Formation of a Carbon-Carbon Triple Bond by CouplingReactions In Aqueous Solution, Science 308 (5719): 234-235 (2005); and M. Lafrance, et al., Catalytic Intermolecular Direct Arylation of Perfluorobenzenes, J.Am.Chem.Soc.128(27):8754-8756(2006); Norio Miyaura, et al., "Anew stereospecific cross-coupling by the palladium-catalyzed reaction of1-alkenylboranes with 1-alkenyl or 1-alkynyl halides," Tetrahedron Letters,1979,20(36):3437-3440;PEFanta, "The Ullmann Synthesis of Biaryls", Synthesis, 1974, 1974:9-21; M. Gomberg and WE Bachmann, J. Am. Chem. Soc., 1924, 42 (10): 2339-2343; RJ PCorriu and Masse, JP "Activation of Grignard reagents by transition-metal complexes. A new and simple synthesis of trans-stilbenes and polyphenyls,” Journal of the Chemical Society, Chemical Communications, 1972, (3): 144a. .

[0265] In some aspects, compounds of Formula I can be prepared according to Scheme 1 or other methods described herein.

[0266] Solution 1

[0267]

[0268] In some aspects, the compound of formula IIIa (wherein R 3 is hydrogen (compound 2-3) can be prepared from 1H-indazol-3-amine (compound 2-1, available from, for example, Enamine LLC) according to Scheme 2 or other methods described herein.

[0269] Option 2

[0270]

[0271] In some aspects, the compound of Formula VIIIa (wherein R 3 4-chloro (compound 3-2 or compound 3-3) from 4-chloro-1H-pyrazolo[3,4-c]pyridin-3-amine (compound 3-1, available from, for example, Novasyn Organics PVT. Ltd.) can be prepared according to Scheme 3 or other methods described herein. Compounds of formula 2-4 are generally available from commercial sources or can be prepared by methods known in the art. For example, 4-(bromomethyl)benzonitrile, 3-(bromomethyl)benzonitrile, 2-fluorobenzyl bromide, 3-fluorobenzyl bromide, 3-chlorobenzyl bromide, 4-chlorobenzyl bromide, 4-fluorobenzyl bromide, 4-methylbenzyl bromide, 3,4-difluorobenzyl bromide and 2,3-difluoro-4-methylbenzyl bromide, etc. are available from Sigma-Aldrich Co. LLC.

[0272]

[0273] All publications, patent applications, issued patents, and other documents mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in text incorporated by reference are excluded to the extent they conflict with definitions in this disclosure.

[0274] The present technology, thus generally described, will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to limit the present technology. Other compounds may be prepared analogously or by methods known in the art.

[0275] Example

[0276] Mouse colonies

[0277] Female BALB / c mice (female 6 to 8 weeks old) were purchased from a commercial source. NSG immunodeficient mice (female 6 to 10 weeks old) were purchased from a commercial source.

[0278] Cell culture

[0279] Mouse 4T1 breast tumor cells and human MDA-MB-231 breast cancer cells were obtained from the American Type Culture Collection. 4T1 cells and MDA-MB-231 cells were cultured in DMEM supplemented with 10% FBS as described previously. Chen, L., Yang, S., Jakoncic, J., Zhang, JJ, and Huang, XY. Migrastatin analogues target fascin to block tumor metastasis. Nature 464, 1062-1066 (2010); Huang, FK et al., Targeted inhibition of fascin function blocks tumor invasion and metastatic colonization. Nat Commun 6, 7465 (2015); Han, S. et al., Improving fascin inhibitors to block tumor cell migration and metastasis. Mol Oncol 10, 966-980 (2016).

[0280] Pharmacokinetic study of compound A in mice

[0281] High performance liquid chromatography-tandem mass spectrometry (LC MS / MS) was used to determine the concentration of compound A in plasma. All blood samples were transferred to commercial tubes containing potassium EDTA (K2) and processed to obtain plasma. Within one hour of collection, the sample was centrifuged (3000x g for 10 minutes at 2°C to 8°C). The assay used a Sciex API 4000 detector and nifedipine as internal standard. The calibration range of compound A was 5.00ng / mL to 5000ng / mL. By using Phoenix WinNonlin software (version 6.3, Pharsight, Mountain View, California), non-compartmental pharmacokinetic analysis was performed on the plasma concentration of compound A in mice. Nominal dose levels and nominal sampling times were used for the calculation of all pharmacokinetic parameters. The linear / logarithmic trapezoidal method was applied to obtain PK parameters. It was observed that compound A was stable after freeze-thaw and during storage, processing and analysis.

[0282] 4T1 mammary tumor metastasis in mice

[0283] Female BALB / c mice (6 to 8 weeks old) were purchased from Charles River. On day 0, 4T1 tumor cells (1×10 5=The mice were injected subcutaneously with 100 mg / kg, 30 mg / kg, 100 mg / kg or 300 mg / kg of compound A or a control solvent once or twice daily until the 27th day. On day 28, mice were sacrificed. This dose regimen was well tolerated with no obvious signs of toxicity. The number of metastatic 4T1 cells in the lungs was determined by clonogenic assay. Briefly, the lungs were removed from each mouse, minced, and digested in 5 ml of an enzyme mixture containing 1x PBS and 1 mg / ml type IV collagenase at 37°C on a platform shaker for 2 hours. After incubation, the samples were filtered through a 70-μm nylon cell strainer and washed twice with PBS. The resulting cells were suspended and plated in a series of dilutions in DMEM medium containing 60 μM thioguanine in 10 cm tissue culture dishes for clonogenic growth. Since 4T1 tumor cells are resistant to 6-thioguanine, the metastatic tumor cells formed lesions after 14 days, at which time they were fixed with 4% paraformaldehyde and stained with crystal violet stain for counting.

[0284] for Figure 1 In the experiment, on day 1, 4T1 tumor cells (1×10 5 Starting from day 4, day 8 or day 15, compound A was administered once a day at 100 mg / kg. -1 The control group of mice was given the vehicle solvent by oral gavage once a day. Starting on day 8, paclitaxel was administered at 20 mg / kg twice a week. -1The mice were given 100 mg / mL of dapoxetine by intraperitoneal injection for two weeks. The primary tumors were removed on day 15. On day 35, all mice were killed for clonogenic assay.

[0285] MDA-MB-231 human breast tumor metastasis in mice

[0286] On day 1, MDA-MB-231 cells (subclone LM2) (1×10 5 The mice were injected subcutaneously into the abdominal mammary region of the mice as described above. Chen, L., Yang, S., Jakoncic, J., Zhang, JJ and Huang, XY Migrastatin analogues target fascin to block tumor metastasis. Nature 464, 1062-1066 (2010); Huang, FK et al. Targeted inhibition of fascin function blocks tumor invasion and metastatic colonization. Nat Commun 6, 7465 (2015); Han, S. et al. Improving fascin inhibitors to block tumor cell migration and metastasis. Mol Oncol 10, 966-980 (2016). Starting from the 8th day, compound A or control solvent was administered by gavage once or twice a day for 6 days a week until the eighth week. On the first day of the ninth week, the mice were killed. The dosage regimen was well tolerated with no obvious signs of toxicity. The number of metastatic MDA-MB-231 cells in the lungs was determined by a colony formation assay. Briefly, once sacrificed, the lungs were removed from each mouse, minced, and digested in 5 ml of an enzyme mixture containing 1x PBS and 1 mg / ml type IV collagenase at 37°C on a platform shaker for 2 hours. After incubation, the samples were filtered through a 70-μm nylon cell strainer and washed twice with PBS. The resulting cells were suspended and plated in a 10 cm tissue culture dish with a series of dilutions in a culture medium containing 2.0 μg / ml puromycin for colony formation growth. Since these MBA-MB-231 tumor cells were stably transfected with the vector pSuper-puro, the metastatic tumor cells formed lesions after 14 days, at which point they were fixed with 4% paraformaldehyde and stained with crystal violet staining solution for counting.

[0287] For combined treatment with chemotherapy, MDA-MB-231 tumor cells (1×105 The mice were injected subcutaneously with Compound A (Sigma) (2 mg / kg) and cyclophosphamide monohydrate (Sigma) (60 mg / kg) into the abdominal mammary gland area of ​​the mice. From the 1st day, the 8th day, and the 15th day, Compound A was administered to the mice by oral gavage at 300 mg / kg / mouse once a day for 6 days a week. The control mice were given vehicle solvent once a day for 6 days a week. From the 15th day, doxorubicin hydrochloride (Sigma) (2 mg / kg) and cyclophosphamide monohydrate (Sigma) (60 mg / kg) were administered to the mice once a week for four weeks. The primary tumor was removed on the 29th day. The death of the mice was used as the endpoint.

[0288] Combination treatment with Compound A and immunotherapy

[0289] Female BALB / c mice (6 to 8 weeks old) were purchased from Charles River Laboratories. On day 0, 4T1 breast tumor cells (1×10 5The mice were injected subcutaneously with 100 mg / kg / mouse of Compound A once daily for 5 days starting on day 8 or day 22. Tumor-bearing mice were given 10 mg / kg anti-PD-1 antibody and 10 mg / kg anti-CTLA-4 antibody ip on days 11, 13, 15, and 17, as described previously. Kim, K. et al., Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA 111, 11774-11779 (2014). Control mice were also given control mouse IgG. Primary tumor volume was calculated as length × width 2 ×π / 6.

[0290] Equivalent solutions

[0291] The embodiments exemplarily described herein can be appropriately practiced in the absence of any one or more elements, one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprise," "include," "contain," etc. should be understood broadly and without restriction. In addition, the terms and expressions employed herein have been used as descriptive and non-restrictive terms, and are not intended to exclude any equivalents of the features shown and described or parts thereof using such terms and expressions, but it is recognized that various modifications can be made within the scope of the claimed technology. In addition, the phrase "essentially consisting of..." will be understood to include those elements specifically recited and those additional elements that do not substantially affect the basic and novel features of the claimed technology. The phrase "consisting of..." excludes any elements that are not specified.

[0292] The present disclosure is not limited to the specific embodiments described in this application, which are intended to serve as illustrations of various aspects. As will be apparent to those skilled in the art, many modifications and variations can be made without departing from its spirit and scope. From the foregoing, in addition to those enumerated herein, functionally equivalent compositions, devices and methods within the scope of the present disclosure will be apparent to those skilled in the art. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is limited only by the terms of the appended claims and the full scope of equivalents authorized by such claims. It should be understood that the present disclosure is not limited to specific methods, reagents, compounds, compositions or biological systems, which can certainly vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to be limiting.

[0293] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0294] As will be understood by those skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily identified as fully described, and the same range can be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be easily broken down into a lower third, a middle third, and an upper third, etc. As will be understood by those skilled in the art, all terms such as "at most," "at least," "greater than," "less than," etc. include the recited numbers and refer to ranges that can be subsequently broken down into subranges as discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member.

[0295] While certain embodiments have been shown and described, it will be understood that changes and modifications may be made therein by those skilled in the art without departing from the technology in its broader aspects as defined in the appended claims.

Claims

1. Use of a compound having the following structure, or a tautomer thereof, and / or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for increasing the response to a chemotherapeutic agent in a patient in need thereof: in, The patient is currently undergoing or is about to undergo chemotherapy; and wherein the chemotherapeutic agent is paclitaxel, cyclophosphamide, or doxorubicin.

2. The use according to claim 1, wherein The compound and the chemotherapeutic agent are administered within one year of each other.

3. The use according to claim 1, wherein The compound and the chemotherapeutic agent are administered within one month of each other.

4. The use according to claim 1, wherein The compound is administered together with the chemotherapeutic agent.

5. The use according to claim 1, wherein The patient suffers from cancer.

6. The use according to claim 5, wherein The cancer is selected from the group consisting of: malignant epithelial tumors, lymphomas, sarcomas, melanomas, astrocytomas, mesotheliomas, colon cancer, pancreatic cancer, esophageal cancer, gastric cancer, urinary system cancer, bladder cancer, breast cancer, stomach cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, kidney cancer, prostate cancer, liver cancer, head and neck cancer, thyroid cancer, brain cancer, oral cancer, gallbladder cancer, ampullary cancer, bile duct cancer and laryngeal cancer.

7. The use according to claim 1, wherein The drug is used to increase the response to chemotherapeutic agents.

8. The use according to any one of claims 1 to 7, wherein The patient is an adult.

9. Use of a compound having the following structure, or a tautomer thereof, and / or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer in a patient in need thereof and for administration in combination with a chemotherapeutic agent: in, The chemotherapeutic agent is paclitaxel, cyclophosphamide or doxorubicin.

10. The use according to claim 9, wherein The patient is currently undergoing or will be undergoing chemotherapy.

11. The use according to claim 9, wherein The compound and the chemotherapeutic agent are administered within one year of each other.

12. The use according to claim 9, wherein The compound and the chemotherapeutic agent are administered within one month of each other.

13. The use according to claim 9, wherein The compound is administered together with the chemotherapeutic agent.

14. The use according to claim 9, wherein The cancer is selected from the group consisting of: malignant epithelial tumors, lymphomas, sarcomas, melanomas, astrocytomas, mesotheliomas, colon cancer, pancreatic cancer, esophageal cancer, gastric cancer, urinary system cancer, bladder cancer, breast cancer, stomach cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, kidney cancer, prostate cancer, liver cancer, head and neck cancer, thyroid cancer, brain cancer, oral cancer, gallbladder cancer, ampullary cancer, bile duct cancer and laryngeal cancer.

15. The use according to claim 14, wherein The cancer is selected from the group consisting of neuroendocrine prostate cancer, diffuse large B-cell lymphoma of the activated B-cell subtype, and triple-negative breast cancer.

16. The use according to any one of claims 9 to 15, wherein The patient is an adult.

17. Use of a compound having the following structure, or a tautomer thereof, and / or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for increasing the response to an immunotherapeutic agent in a patient in need thereof: in, The patient is currently undergoing or will be undergoing immunotherapy, and The immunotherapeutic agent is an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-CTLA-4 antibody, or both an anti-PD-1 antibody and an anti-CTLA-4 antibody.

18. The use according to claim 17, wherein The compound and the immunotherapeutic agent are administered within one year of each other.

19. The use according to claim 17, wherein The compound and the immunotherapeutic agent are administered within one month of each other.

20. The use according to claim 17, wherein The compound and the immunotherapeutic agent are administered together.

21. The use according to claim 17, wherein The patient suffers from cancer.

22. The use according to claim 21, wherein The cancer is selected from the group consisting of: malignant epithelial tumors, lymphomas, sarcomas, melanomas, astrocytomas, mesotheliomas, colon cancer, pancreatic cancer, esophageal cancer, gastric cancer, urinary system cancer, bladder cancer, breast cancer, stomach cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, kidney cancer, prostate cancer, liver cancer, head and neck cancer, thyroid cancer, brain cancer, oral cancer, gallbladder cancer, ampullary cancer, bile duct cancer and laryngeal cancer.

23. The use according to claim 17, wherein The drug is used to increase the response to immunotherapeutic agents.

24. The use according to any one of claims 17 to 23, wherein The patient is an adult.

25. Use of a compound having the following structure, or a tautomer thereof, and / or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer in a patient in need thereof and for administration in combination with an immunotherapeutic agent: in, The immunotherapeutic agent is an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-CTLA-4 antibody, or both an anti-PD-1 antibody and an anti-CTLA-4 antibody.

26. The use according to claim 25, wherein The patient is currently undergoing or will be undergoing immunotherapy.

27. The use according to claim 25, wherein The compound and the immunotherapeutic agent are administered within one year of each other.

28. The use according to claim 25, wherein The compound and the immunotherapeutic agent are administered within one month of each other.

29. The use according to claim 25, wherein The compound and the immunotherapeutic agent are administered together.

30. The use according to claim 25, wherein The cancer is selected from the group consisting of: malignant epithelial tumors, lymphomas, sarcomas, melanomas, astrocytomas, mesotheliomas, colon cancer, pancreatic cancer, esophageal cancer, gastric cancer, urinary system cancer, bladder cancer, breast cancer, stomach cancer, leukemia, lung cancer, colon cancer, central nervous system cancer, ovarian cancer, kidney cancer, prostate cancer, liver cancer, head and neck cancer, thyroid cancer, brain cancer, oral cancer, gallbladder cancer, ampullary cancer, bile duct cancer and laryngeal cancer.

31. The use according to claim 30, wherein The cancer is selected from the group consisting of neuroendocrine prostate cancer, diffuse large B-cell lymphoma of the activated B-cell subtype, and triple-negative breast cancer.

32. The use according to any one of claims 25 to 31, wherein The patient is an adult.

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