Treatment of ASCT2-dependent cancer

Abstract

The present disclosure provides a method of treating or preventing cancer associated with elevated ASCT2 expression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a Na + / K +-ATPase (NKA) inhibitor. Additional methods of using the Na + / K +-ATPase (NKA) inhibitors are also provided.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 384,062, filed on November 16, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates generally to the fields of chemistry, biology and medicine. Specifically, the present disclosure describes the use of Na + / K + -ATPase inhibitors for the treatment of ASCT2-dependent cancers. Background Art

[0004] Cancer can be viewed as a breakdown in the communication between tumor cells and their environment, including their normal neighboring cells. Both growth-stimulating and growth-inhibiting signals are routinely exchanged between cells within a tissue. Typically, cells will not divide in the absence of stimulatory signals, and similarly, will stop dividing in the presence of inhibitory signals. In a cancerous or tumorous state, cells acquire the ability to "override" these signals and proliferate under conditions where normal cells cannot grow.

[0005] Cardiotonic steroids such as digoxin and digitoxin are naturally derived compounds that bind to and inhibit Na + / K + -ATPase (sodium pump). Members of this family have been used for many years to treat heart failure and arrhythmias. Recent discoveries have revealed that these compounds may be involved in the regulation of several important cellular processes. Several cardiotonic steroids, such as digitoxin and oleandrin, have shown inhibitory effects on the growth of human tumor cells. Summary of the Invention

[0006] In some aspects, the present disclosure provides a method of treating or preventing a cancer associated with elevated ASCT2 expression in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of Na + / K + -ATPase (NKA) inhibitors.

[0007] In some aspects, the present disclosure provides methods of treating a cancer associated with dysregulated glutamine metabolism in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.

[0008] In some aspects, the present disclosure provides methods of stabilizing or reducing the volume of a solid tumor in a cancer associated with elevated ASCT2 expression in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.

[0009] In some aspects, the present disclosure provides methods of reducing solid tumor volume in a cancer associated with elevated ASCT2 expression in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.

[0010] In some aspects, the present disclosure provides methods of modulating the concentration of one or more biomarkers of cancer associated with elevated ASCT2 expression in a cell, the method comprising contacting the cell with an NKA inhibitor.

[0011] In some aspects, the present disclosure provides methods of inhibiting expression of an ASCT2 protein in a cell, the method comprising contacting the cell with an NKA inhibitor.

[0012] In some aspects, the present disclosure provides a method of reducing the proliferation rate of a cancer cell, the method comprising contacting the cell with an NKA inhibitor, wherein the cancer is associated with elevated ASCT2 expression.

[0013] In some embodiments, the NKA inhibitor is a bufadienolide derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the NKA inhibitor is a compound of formula (I):

[0014]

[0015] in:

[0016] Each dashed bond independently represents a single or double bond;

[0017] n, p and q are independently selected from 0 and 1; and

[0018] R1, R2, R3, R4, R5, R6, R9, R 10 、R 11 and R 12 independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy

[0019] and optionally substituted amino; or

[0020] R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); or

[0021] R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0022] R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;

[0023] R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0024] R 13 is selected from hydrogen, optionally substituted alkyl and formyl;

[0025] L1 is selected from a covalent bond, * -C(O)O-, * -[C(R a )(R b )] s -O- and * -[C(R a )(R b )] s -C(O)O-,

[0026] wherein * denotes the connection point between L1 and Z, further wherein:

[0027] R a and R b is independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0028] R a and R b together with any intervening atoms to form an optionally substituted cycloalkyl ring or an optionally substituted heterocycloalkyl ring; or

[0029] R 15 and R appears once a taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0030] Z is selected from -OR 14 and -NR 15 R 16 ,in:

[0031] R 14 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkoxycarbonyl, and -P(=O)(OR 17 )(OR 18 ),in:

[0032] R 17 and R 18 are independently selected from hydrogen and optionally substituted alkyl; and

[0033]

[0034] R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0035] and

[0036] R 16 is selected from hydrogen, hydroxy, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, -COR 19 、-CO2R 19 、-

[0037] CONR 20 R 21 、-C(NR 22 )NR 20 R 21 、-C(NCN)NR 20 R 21 、-SO2R 19 and -SO2NR 20 R 21 , where R 19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 20 、R 21 and R 22 R is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or 20 and R 21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or

[0038] R 15 and R 16 Together with any intervening atoms, W1 forms an optionally substituted heterocycloalkyl ring; W1 is selected from the following moieties:

[0039]

[0040] in:

[0041] m is selected from 0, 1, 2 and 3;

[0042] Y is selected from O and NR24 ;

[0043] R 23 is selected from cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl,

[0044] optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl,

[0045] optionally substituted aminosulfonyl, optionally substituted amidino

[0046] (carbaminodoyl) and optionally substituted alkynyl;

[0047] R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0048] W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0049] or a pharmaceutically acceptable salt thereof.

[0050] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, as various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] The following drawings form part of this specification and are included to further illustrate certain aspects of the present disclosure. The present disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0052] Figures 1A-1D show the effects of RX108 on Na + / K + -ATPase activity and its effects on human HCC cell proliferation in vitro and tumorigenesis in a xenograft mouse model. + / K +-ATPase inhibitory activity (Figure 1B). After exposure to different doses of RX108 for different periods of time, the percentage inhibition of Huh7 (Figure 1C1), Hep3B (Figure 1C2), and LO2 (Figure 1C3) cell growth in culture is shown. Tumor growth curves (Figure 1D1) and tumor weights (Figure 1D2) of Huh7 xenografts in nude mice after treatment with different doses of RX108 (n=10 / group) are shown. Data are expressed as mean (±SD) values. **p<0.01 relative to control.

[0053] Figure 2A & Figure 2B show Annexin V-FITC / PI double staining and flow cytometric analysis of HCC cells treated with RX108. Hep3B cells exposed to different doses of RX108 for 48 hours were subjected to Annexin V-FITC / PI double staining, followed by flow cytometry. (Figure 2A) PI after RX108 treatment - / Annexin-V + ,PI + / Annexin-V + ,PI + / Annexin-V - and PI - / Annexin-V - Figure 2B: Representative histograms of Hep3B cells treated with vehicle control or RX108. Data are presented as mean (±SD).

[0054] Figures 3A & 3B show the effects of RX108 on HCC cell metabolism. Glutamine and TCA cycle metabolite concentrations in Huh7 cells (Figure 3A) and Hep3B cells (Figure 3B) after exposure to different doses of RX108, as measured using LC-MS / MS. Data are presented as mean (±SE) values.

[0055] Figures 4A-4G show the effects of RX108 on energy metabolism in Hep3B and Huh7 cells. Hep3B cells were treated with RX108 and then 13 C5-glutamine and 15 N2-glutamine or 13C6-glucose culture medium was incubated at 37 ° C for 24 h. Then, cell samples were harvested for ion chromatography-MS analysis. The mass distribution vector of each isotopologue of citrate from glutamine (Fig. 4A) and glucose (Fig. 4B) in Hep3B cells from two separate experiments. After being treated with RX108 for 2 h in triplicate samples, the GSH content in Hep3B cells (Fig. 4C) and Huh7 cells (Fig. 4D). After the cells were treated with RX108 for 2 h, the cellular NADH (Fig. 4E) and NADPH (Fig. 4F) concentrations in Hep3B cells and Huh7 cells were measured. (Fig. 4G) The oxygen consumption rate (OCR) level in Huh7 cells treated with RX108 was measured using Seahorse mitochondrial stress assay and normalized to cell number. NP, RX108. Data are expressed as mean (± SD) values. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

[0056] Figures 5A-5DThe effect of ASCT2 on the antiproliferative activity in HCC cells triggered by RX-108 and the overall survival of HCC patients is shown. Western blot analysis (Figure 5A1) and quantification of ASCT2 protein expression (Figure 5A2) in Hep3B cells after exposure to RX108 for 48 hours. ASCT2 siRNA transfection downregulated ASCT2 protein expression in Hep3B cells (Figure 5B1 & Figure 5B2) and significantly reduced Hep3B cell growth, as determined by total cell number or viable cell count (Figure 5B3 & Figure 5B4). Treatment with RX108 also reduced cell growth, but no cumulative cell growth inhibition was observed in cells subjected to a combination of ASCT2 siRNA transfection and RX108 (Figure 5B3 & Figure 5B4). HCC cells are addicted to glutamine for proliferation: Growth of Huh7 cells (Figure 5C1) and Hep3B cells (Figure 5C2) after treatment with medium containing 0.2 mM or 2 mM glutamine for 24, 48, 72, and 96 hours. Data are expressed as mean (±SD) values. ***p < 0.001; ****p < 0.0001, relative to control. Survival data of HCC patients were extracted from publicly available databases as shown (Figure 5D1, Human Protein Atlas: https: / / www.proteinatlas.org / ENSG00000105281-SLC1A5 / pathology / liver+cancer; cBioPortal for Cancer Genomics: Figure 5D2, TCGA, Pan-Cancer Atlas, and Figure 5D3, TCGA Liver Hepatocellular Carcinoma, source data from GDAC Firehose).

[0057] Figures 6A-6D The effects of RX108 on protein expression and glutamine metabolism in xenograft models are shown. Immunohistochemical analysis of ASCT2 (Figure 6A1, representative staining images; Figure 6A2, quantitative staining data), Ki67 (Figure 6B1, representative staining images; Figure 6B2, quantitative staining data), and cleaved caspase 3 (Figure 6C1, representative staining images; Figure 6C2, quantitative staining data) in Huh7 cell xenograft tumors after RX108 exposure. (Figure 6D) LC-MS / MS measurement of glutamine metabolite concentrations in the same tumor samples. Data are expressed as mean (±SD) values. *p < 0.05, relative to control. DETAILED DESCRIPTION

[0058] The poor prognosis and limited treatment options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify additional therapeutic modalities.+ / K + -Antitumor activity and potential molecular mechanisms of the ATPase inhibitor RX108 in human HCC cells and their xenograft models. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in xenograft mouse models, and this inhibition was associated with the induction of cell apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine ​​transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentrations in HCC cells and tumors. In addition, RX108 exposure led to a significant decrease in cellular energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate (OCR). In addition, HCC cells showed evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCC is associated with adverse survival. In summary, these findings reveal a novel approach to treat HCC by inhibiting Na + / K + -ATPase to target glutamine metabolism and provide a rationale for using RX108 to treat HCC in patients whose tumors express high levels of ASCT2.

[0059] Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Liver cancer is the fourth most common cause of cancer-related death and ranks sixth in cancer incidence worldwide. In the United States, liver cancer is the second most deadly cancer, and its incidence has tripled since 1980 (Siegel et al., 2019; Villanueva, 2019). Early surgical resection is the only curative treatment option, but over 80% of HCCs are diagnosed at an advanced stage with inoperable distant metastases (Yang and Roberts, 2010). Patients with unresectable HCC can benefit from multimodal treatment options, including percutaneous ethanol injection, radiofrequency ablation, and magnetic resonance-guided laser thermal ablation (Villanueva, 2019; Slotta et al., 2015). However, the 5-year survival rate for HCC is only 18%, as the effectiveness of systemic agents used to treat HCC is limited (Villanueva, 2019). Recently, immune-based therapies for HCC have emerged, but the overall response rates of these therapies are much lower than those of other tumor types, such as melanoma and lung cancer (Kudo, 2019). Therefore, the discovery of new therapeutic targets and additional effective compounds for HCC treatment is crucial to improving the outcomes of this cancer.

[0060] Metabolic reprogramming is one of the hallmarks of cancer. Many cancer cells (including HCC cells) show an oncogenic-driven addiction to the neutral amino acid glutamine, which is used as a carbon and nitrogen source for protein and nucleotide synthesis and a substrate for energy production, cell signaling, and oxidative protection (Schulte et al., 2018). In fact, studies have shown that tumor cells take up glutamine much faster than they take up glucose (Reinfeld et al., 2021). Targeting glutaminase reduces the stemness of HCC (Li et al., 2019). Sorafenib-resistant HCC cells show much higher glutamine metabolic activity than non-resistant cells regulated by peroxisome proliferator-activated receptor G (Kim et al., 2017). Rapidly proliferating cancer cells consume glutamine at a significantly higher rate than normal cells (Wang et al., 2018), and this consumption is driven by glutamine transporters such as Na + The upregulation of ASCT2 in HCC cells is driven by elevated expression of the alanine serine cysteine ​​transporter 2 (ASCT2 / SLC1A5). The authors reported that ASCT2 is upregulated in HCC cells and that this upregulation is negatively correlated with survival (Sun et al., 2016). Accumulating evidence has shown that disruption of ASCT2 expression in cancer cells by small interfering RNA (siRNA), short hairpin RNA, or CRISPR can significantly reduce glutamine uptake and lead to inhibition of cell growth (Lin et al., 2018), suggesting that ASCT2 is a promising therapeutic target for cancer (Wahi and Holst, 2019). Notably, several ASCT2 inhibitors have been developed or tested in vitro and in preclinical animal models and have demonstrated antitumor activity, including glutamine analogs (Esslinger et al., 2005; Schulte et al., 2016), V-9302 (a competitive small molecule antagonist of transmembrane glutamine flux; Schulte et al., 2018), and ASCT2-blocking antibodies (Osanai-Sasakawa et al., 2018; Kasai et al., 2017). However, due to their low affinity and lack of specificity, these amino acid analogs and V-9302 are not suitable for specifically targeting glutamine addiction via ASCT2 in tumor cells. Notably, MEDI7247, an ASCT2-blocking antibody conjugated to a pyrrolobenzodiazepine, is currently in Phase 1 clinical trials in patients with relapsed / refractory hematological malignancies (ClinicalTrials.gov identifier: NCT03106428) or advanced or metastatic solid tumors, including lung, head and neck, pancreatic, colorectal, and prostate cancers (ClinicalTrials.gov identifier: NCT03811652). Meanwhile, the search for drugs that can inhibit ASCT2 remains urgent.

[0061] HCC remains a global healthcare burden, with an increasing incidence and poor prognosis, largely due to the lack of early detection methods and effective treatments. Efforts to improve outcomes for patients with HCC depend on a thorough understanding of the molecular pathogenesis of this tumor and the development of mechanism-based drugs to treat it. The liver's primary function is systemic metabolic regulation, in which it coordinates the clearance of toxins; balances glucose, lipid, and amino acid uptake; and maintains metabolic homeostasis. HCC onset and progression are often accompanied by reprogramming of metabolic pathways, leading to metabolic dysregulation (Nwosu et al., 2017; Murakami et al., 2015; Fitian et al., 2014; Gao et al., 2015; Huang et al., 2013). Targeting dysregulated metabolic pathways in HCC cells offers untapped opportunities for prevention and treatment (De Matteis et al., 2018; Stine et al., 2022).

[0062] One of the hallmarks of metabolic dysregulation in cancer is glutamine addiction for cell proliferation, as demonstrated by overexpression of the plasma membrane transporter ASCT2 in various cancers, forming the molecular basis for targeting overexpressed ASCT2 for cancer therapy (Scalise et al., 2017).

[0063] Strategies targeting dysregulated glutamine metabolism in cancer include inhibiting glutaminolysis by treatment with glutaminase inhibitors, depleting glutamine supply, using glutamine analogs, and blocking glutamine uptake. Given that glutamine (a non-essential amino acid with an amine functional group) is the most abundant amino acid circulating in the bloodstream and contributes to almost every biosynthetic pathway in proliferating cells (DeBerardinis and Cheng, 2010), depleting glutamine supply and using glutamine analogs for cancer therapy are huge challenges. Elevated ASCT2 is a prognostic marker for HCC (Sun et al., 2016), and the different levels of ASCT2 expression in cancer and normal cells make targeting overexpressed ASCT2 a promising approach for cancer therapy (Wahi and Holst, 2019; Broer, 2018). Different ASCT2 inhibitors are being developed and tested, but have not yet been used clinically (Schulte et al., 2018; Broer et al., 2018; Ndaru et al., 2019). It is conceivable that progress in the structural characterization of substrate recognition by ASCT2 will greatly facilitate the development of new specific ASCT2 inhibitors (Scopelliti et al., 2018).

[0064] ASCT2 expression is reportedly regulated by the availability of glutamine, which induces the formation of FXR / RXR dimers that bind to the IR-1 repeats in the putative promoter region of ASCT2, leading to ASCT2 activation (Bungard and McGivan, 2004). Inactivation of tumor suppressors and activation of oncogenes are driving forces in cancer development and progression. For example, downregulation of the tumor suppressor Rb can lead to overexpression of ASCT2 through the transcription factor E2F-3 (Reynolds et al., 2014), while activation of the key oncogenes EphA2 and c-Myc in HCC carcinogenesis activates transcriptional ASCT2 expression (Edwards et al., 2017; Liu et al., 2017). ASCT2 protein expression increases with activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, which affects the stability of ASCT2 in the plasma membrane of cancer cells (Avissar et al., 2008). Recently, researchers discovered that ASCT2 is an epidermal growth factor receptor (EGFR)-related protein, and that targeting EGFR with cetuximab leads to downregulation of ASCT2 via cetuximab-mediated EGFR endocytosis in an EGFR expression-dependent manner (Lu et al., 2016). These previous findings may help explore the mechanistic effects of RX108 on ASCT2 expression regulation and are also valuable for designing mechanism-based combination therapies for the treatment of HCC.

[0065] RX108

[0066] RX108 is Na + / K + -ATPase is a synthetic small molecule inhibitor. It is derived from bufalin, and its synthesis has been previously reported (U.S. Patent 8,334,376B2). RX108 is currently in clinical trials for the treatment of HCC, glioblastoma multiforme, and other solid tumors (ClinicalTrials.gov identifier: NCT03646071). The present disclosure discloses the anti-tumor activity of RX108 in HCC cells. In some embodiments disclosed herein, RX108 has an anti-proliferative effect in both HCC cells and related xenograft HCC models by inducing apoptosis and reducing glutamine metabolism by downregulating the expression and function of the glutamine transporter in tumors.

[0067] In some embodiments, the present disclosure provides several lines of evidence supporting the use of Na + / K + -ATPase (NKA) inhibitors such as RX108 target the subgroup of HCC with dysregulated glutamine metabolism.

[0068] In some embodiments, Na + / K + The use of N-ATPase (NKA) inhibitors, such as RX108, impairs glutamine metabolism and is a potential therapy for patients with HCC whose tumors have high levels of ASCT2 expression and glutamine dependence. + / K + -ATPase (NKA) inhibitors (such as RX108) inhibit HCC cell proliferation in vitro. In some embodiments, Na + / K + The use of N-ATPase (NKA) inhibitors (such as RX108) inhibits tumorigenesis in vivo. In some embodiments, the inhibition of tumorigenesis is accompanied by significant induction of apoptosis. In some embodiments, Na + / K + -ATPase (NKA) inhibitors (such as RX108) significantly downregulate ASCT2 (glutamine transporter) in HCC cells. In some embodiments, Na + / K + The use of N-ATPase (NKA) inhibitors (such as RX108) reduces the concentration of glutamine and its metabolites in HCC cells and tumors. In some embodiments, Na + / K + -ATPase (NKA) inhibitors (such as RX108) inhibit the energy metabolism pathway in HCC cells. In some embodiments, HCC cells are addicted to glutamine for proliferation, and knockdown of ASCT2 significantly reduces HCC cell growth, and Na + / K + The anti-tumor effects of -ATPase (NKA) inhibitors, such as RX108, are dependent on glutamine transport. In some embodiments, high levels of ASCT2 mRNA expression in human HCC are associated with unfavorable survival.

[0069] In some aspects, the present disclosure provides a method of treating or preventing a cancer associated with elevated ASCT2 expression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Na + / K + -ATPase (NKA) inhibitors.

[0070] In some aspects, the present disclosure provides methods of treating a cancer associated with dysregulated glutamine metabolism in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.

[0071] In some aspects, the present disclosure provides methods of stabilizing or reducing the volume of a solid tumor in a cancer associated with elevated ASCT2 expression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.

[0072] In some aspects, the present disclosure provides a method for reducing the volume of a solid tumor of a cancer associated with elevated ASCT2 expression in a patient in need thereof, comprising administering a therapeutically effective amount of an NKA inhibitor to the patient. In some embodiments, the volume is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments, the volume is reduced by at least 25%. In some embodiments, the volume is reduced by at least 50%.

[0073] In some aspects, the present disclosure provides a method for regulating the concentration of one or more biomarkers of cancer associated with elevated ASCT2 expression in a cell, comprising contacting the cell with an NKA inhibitor. In some embodiments, the regulation reduces the concentration of one or more biomarkers. In some embodiments, the regulation reduces the concentration of one or more biomarkers by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In some embodiments, the regulation reduces the concentration of one or more biomarkers by at least 25%. In some embodiments, the regulation reduces the concentration of one or more biomarkers by at least 50%. In some embodiments, the regulation reduces the concentration of one or more biomarkers and the regulation increases the concentration of one or more biomarkers. In some embodiments, the modulation increases the concentration of one or more biomarkers by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0074] In some embodiments, the one or more biomarkers are selected from the group consisting of glutamine, glutamate, α-ketoglutarate (α-KG), 2-hydroxyglutarate (2HG), glutathione (GSH), malate, pyruvate, lactate, and fumarate. In some embodiments, the modulation decreases the concentration of one or more biomarkers selected from the group consisting of glutamine, glutamate, α-ketoglutarate (α-KG), 2-hydroxyglutarate (2HG), glutathione (GSH), malate, pyruvate, and lactate. In some embodiments, the modulation increases the concentration of fumarate.

[0075] In some embodiments, the level of NADH or NADPH is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments, the level of NADH or NADPH is reduced by at least 50%.

[0076] In some aspects, the present disclosure provides methods of inhibiting ASCT2 protein expression in a cell, comprising contacting the cell with an NKA inhibitor.

[0077] In some aspects, the present disclosure provides a method for reducing the proliferation rate of cancer cells, comprising contacting the cells with an NKA inhibitor, wherein the cancer is associated with elevated ASCT2 expression. In some embodiments, the proliferation rate is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In some embodiments, the proliferation rate is reduced by at least 10%. In some embodiments, the proliferation rate is reduced by at least 30%.

[0078] In some embodiments, the cellular concentration of the NKA inhibitor is from about 0.1 ng / mL to about 100 ng / mL, from about 1 ng / mL to about 50 ng / mL, or from about 0.1 ng / mL, 0.2 ng / mL, 0.3 ng / mL, 0.4 ng / mL, 0.5 ng / mL, 0.6 ng / mL, 0.7 ng / mL, 0.8 ng / mL, 0.9 ng / mL, 1 ng / mL, 2 ng / mL, 3 ng / mL, 4 ng / mL, 5 ng / mL, 6 ng / mL, 7 ng / mL, 8 ng / mL, 9 ng / mL, 10 ng / mL, 15 ng / mL, 20 ng In some embodiments, the cell concentration of the NKA inhibitor is about 3 ng / mL. In some embodiments, the cell concentration of the NKA inhibitor is about 30 ng / mL.

[0079] In some embodiments, the cancer is cancer of the bile duct, bladder, brain, breast, cervix, colon, esophagus, kidney, liver, lung, lymph node, mouth, ovary, pancreas, prostate, rectum, skin, stomach, throat, thymus, thyroid, or uterus. In some embodiments, the cancer is bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), bile duct carcinoma (CHOL), colon adenocarcinoma (COAD), lymphoid neoplasms diffuse large B-cell lymphoma (DLBC), esophageal cancer (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), brain low-grade glioma (LGG), liver hepatocellular carcinoma (LIHC / HCC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectal adenocarcinoma (READ), sarcoma (SARC), cutaneous melanoma (SKCM), gastric adenocarcinoma (STAD), thyroid carcinoma (THCA), thymoma (THYM), uterine corpus endometrial carcinoma (UCEC), or uterine carcinosarcoma (UCS). In some embodiments, the cancer is a cancer of the bile duct, brain, liver, oral cavity, or throat. In some embodiments, the cancer is a cancer of the bile duct. In some embodiments, the cancer is cholangiocarcinoma (CHOL). In some embodiments, the cancer is a cancer of the brain. In some embodiments, the cancer is glioblastoma multiforme (GBM). In some embodiments, the cancer is a cancer of the liver. In some embodiments, the cancer is hepatocellular carcinoma of the liver (LIHC / HCC). In some embodiments, the cancer is a cancer of the oral cavity or throat. In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSC).

[0080] In some embodiments, the NKA inhibitor is a bufadienolide derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the NKA inhibitor is a compound of formula (I):

[0081]

[0082] in:

[0083] Each dashed bond independently represents a single or double bond;

[0084] n, p and q are independently selected from 0 and 1; and

[0085] R1, R2, R3, R4, R5, R6, R9, R 10 、R 11 and R 12is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or

[0086] R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); or

[0087] R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0088] R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;

[0089] R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0090] R 13 is selected from hydrogen, optionally substituted alkyl and formyl;

[0091] L1 is selected from a covalent bond, * -C(O)O-, * -[C(R a )(R b )] s -O- and * -[C(R a )(R b )] s -C(O)O-,

[0092] wherein * denotes the connection point between L1 and Z, further wherein:

[0093] R a and R b is independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0094] R a and R b together with any intervening atoms to form an optionally substituted cycloalkyl ring or an optionally substituted heterocycloalkyl ring; or

[0095] R 15 and R appears once a taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0096] Z is selected from -OR 14 and -NR 15 R 16 ,in:

[0097] R 14 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkoxycarbonyl, and -P(=O)(OR 17 )(OR 18 ),in:

[0098] R 17 and R 18 are independently selected from hydrogen and optionally substituted alkyl; and

[0099]

[0100] R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0101] and

[0102] R 16 is selected from hydrogen, hydroxy, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, -COR 19 、-CO2R 19 、-

[0103] CONR 20 R 21 、-C(NR 22 )NR 20 R 21 、-C(NCN)NR 20 R 21 、-SO2R 19 and -SO2NR 20 R 21 , where R 19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 20 、R 21 and R 22R is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or 20 and R 21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or

[0104] R 15 and R 16 taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0105] W1 is selected from the following:

[0106]

[0107] in:

[0108] m is selected from 0, 1, 2 and 3;

[0109] Y is selected from O and NR 24 ;

[0110] R 23 is selected from cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy,

[0111] optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl,

[0112] optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl,

[0113] optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl;

[0114] R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0115] W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0116] or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the NKA inhibitor is a compound of formula (I):

[0118]

[0119] in:

[0120] Each dashed bond independently represents a single or double bond;

[0121] n, p and q are independently selected from 0 and 1; and

[0122] R1, R2, R3, R4, R5, R6, R9, R 10 、R 11 and R 12 is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or

[0123] R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); or

[0124] R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0125] R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;

[0126] R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0127] R 13 is selected from hydrogen, optionally substituted alkyl and formyl;

[0128] L1 is selected from a covalent bond, * -C(O)O-, * -[C(R a )(R b )] s -O- and * -[C(R a )(R b )] s -C(O)O-,

[0129] wherein * denotes the connection point between L1 and Z, further wherein:

[0130] R a and Rb is independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0131] R a and R b together with any intervening atoms to form an optionally substituted cycloalkyl ring or an optionally substituted heterocycloalkyl ring; or

[0132] R 15 and R appears once a taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0133] Z is selected from -OR 14 and -NR 15 R 16 ,in:

[0134] R 14 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkoxycarbonyl, and -P(=O)(OR 17 )(OR 18 ),in:

[0135] R 17 and R 18 are independently selected from hydrogen and optionally substituted alkyl; and

[0136]

[0137] R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0138] and

[0139] R 16 is selected from hydrogen, hydroxy, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, -COR 19 、-CO2R 19 、-

[0140] CONR 20 R 21 、-C(NR 22 )NR 20 R 21 、-C(NCN)NR 20 R 21 、-SO2R 19and -SO2NR 20 R 21 , where R 19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 20 、R 21 and R 22 R is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or 20 and R 21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or

[0141] R 15 and R 16 Together with any intervening atoms, W1 forms an optionally substituted heterocycloalkyl ring; W1 is selected from the following moieties:

[0142]

[0143] in:

[0144] m is selected from 0, 1, 2 and 3;

[0145] Y is selected from O and NR 24 ;

[0146] R 23 is selected from cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy,

[0147] optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl,

[0148] optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl,

[0149] optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl;

[0150] R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0151] W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0152] or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the NKA inhibitor is a compound of Formula (IA):

[0154]

[0155] in:

[0156] Each dashed bond independently represents a single or double bond;

[0157] n, p and q are independently selected from 0 and 1; and

[0158] R1, R2, R3, R4, R5, R6, R9, R 10 、R 11 and R 12 is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or

[0159] R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); or

[0160] R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0161] R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;

[0162] R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl

[0163] and optionally substituted alkynyl;

[0164] R 13 is selected from hydrogen, optionally substituted alkyl and formyl;

[0165] L1 is selected from a covalent bond, * -C(O)O-, * -[C(R a )(R b )] s -O- and * -[C(Ra )(R b )] s -C(O)O-,

[0166] wherein * denotes the connection point between L1 and Z, further wherein:

[0167] R a and R b is independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or

[0168] R a and R b together with any intervening atoms to form an optionally substituted cycloalkyl ring or an optionally substituted heterocycloalkyl ring; or

[0169] R 15 and R appears once a taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0170] Z is selected from -OR 14 and -NR 15 R 16 ,in:

[0171] R 14 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkoxycarbonyl, and -P(=O)(OR 17 )(OR 18 ),in:

[0172] R 17 and R 18 are independently selected from hydrogen and optionally substituted alkyl;

[0173] R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0174] and

[0175] R 16 is selected from hydrogen, hydroxy, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, -COR 19 、-CO2R 19 、-

[0176] CONR 20 R 21、-C(NR 22 )NR 20 R 21 、-C(NCN)NR 20 R 21 、-SO2R 19 and -SO2NR 20 R 21 , where R 19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 20 、R 21 and R 22 R is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or 20 and R 21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or

[0177] R 15 and R 16 Together with any intervening atoms, W1 forms an optionally substituted heterocycloalkyl ring; W1 is selected from the following moieties:

[0178]

[0179] in:

[0180] m is selected from 0, 1, 2 and 3;

[0181] Y is selected from O and NR 24 ;

[0182] R 23 is selected from cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl,

[0183] optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl;

[0184] R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0185] W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0186] or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, the NKA inhibitor is a compound of formula (II):

[0188]

[0189] in:

[0190] Each dashed line represents a single or double bond;

[0191] n, p and q are each independently selected from 0 and 1; and

[0192] R1, R2, R3, R4, R5, R6, R9, R 10 、R 11 and R 12 is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or

[0193] R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); or

[0194] R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0195] R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;

[0196] R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0197] R 13 is selected from hydrogen, optionally substituted alkyl and formyl;

[0198] R 15is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0199] R 16 is selected from hydrogen, hydroxy, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, -COR 19 、-CO2R 19 、-CONR 20 R 21 、-C(NR 22 )NR 20 R 21 、-C(NCN)NR 20 R 21 、-SO2R 19 and -SO2NR 20 R 21 , where R 19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 20 、R 21 and R 22 R is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or 20 and R 21 Can be linked with any intervening atoms to form

[0200] an optionally substituted heterocycloalkyl ring;

[0201] W1 is selected from the following:

[0202]

[0203] in:

[0204] m is selected from 0, 1, 2 and 3;

[0205] wherein Y is selected from O and NR 24 ;

[0206] R 23 is selected from cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy,

[0207] optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl,

[0208] optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl,

[0209] optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl;

[0210] R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0211] W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0212] or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the NKA inhibitor is a compound of formula (II-A):

[0214]

[0215] in:

[0216] R1, R2, R3, R4, R5, R6, R9, R 10 、R 11 and R 12 is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or

[0217] R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); or

[0218] R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0219] R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;

[0220] R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0221] R 13 is selected from hydrogen, optionally substituted alkyl and formyl;

[0222] R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0223] R 16 Yes-CONR 20 R 21 , where R 20 and R 21 are joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0224] W1 is selected from the following:

[0225]

[0226] in:

[0227] m is selected from 0, 1, 2 and 3;

[0228] Y is selected from O and NR 24 ;

[0229] R 23 is selected from the group consisting of cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl; and

[0230] R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0231] W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0232] or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the NKA inhibitor is a compound of formula (III):

[0234]

[0235] in:

[0236] Dashed lines represent single or double bonds;

[0237] n is selected from 0 and 1;

[0238] R1, R2, R3, R5, R6, R9, R 10 、R 11 and R 12 is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or

[0239] R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O);

[0240] R4 is hydroxy, or R4 and R5 may be optionally joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0241] R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;

[0242] R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0243] R 13 is selected from hydrogen, optionally substituted alkyl and formyl;

[0244] Z is selected from OR 14 and NR 15 R 16 ;in:

[0245] R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0246] R 15is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0247] R 16 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0248] or R 15 and R 16 may be optionally joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0249] W1 is selected from the following:

[0250]

[0251] in:

[0252] m is selected from 0, 1, 2 and 3;

[0253] Y is selected from O and NR 24 ;

[0254] R 23 is selected from cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl;

[0255] R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0256] W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;

[0257] or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments, the NKA inhibitor is a compound of formula (III), or a pharmaceutically acceptable salt thereof, provided that when R4 is OH, R 13 is methyl, W1 is (2-oxo-2H-pyran-5-yl), and R1, R2, R3, R5, R6, R7, R8, R9, R 10、R 11 and W2 is hydrogen, then R 12 Not hydrogen.

[0259] In some embodiments, the NKA inhibitor is a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein:

[0260] Dashed lines represent single or double bonds;

[0261] n is selected from 0 and 1;

[0262] R1, R2, R6, R8, R 10 、R 11 、R 12 and W2 is hydrogen; R3 and R9 are independently hydrogen or OH;

[0263] R4 is hydroxy and R5 is hydrogen, or R4 and R5 may be optionally joined together with any intervening atoms to form an oxirane ring;

[0264] R7 is -OCOCH3;

[0265] R 13 It is a methyl group;

[0266] Z is NR 15 R 16 ,in:

[0267] R 15 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;

[0268] R 16 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;

[0269] or R 15 and R 16 together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; and

[0270] W1 is selected from:

[0271]

[0272] In some embodiments, the NKA inhibitor is a compound of formula (III), or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not a compound of formula III wherein: R4 is OH, R 13 is methyl, W1 is (2-oxo-2H-pyran-5-yl), and R1, R2, R3, R5, R6, R7, R8, R9, R 10 、R 11 、R 12and W2 is hydrogen.

[0273] In some embodiments, the NKA inhibitor is:

[0274] (a) Compounds of formula (IV-A):

[0275]

[0276] in:

[0277] Z is selected from OR 14 and NR 15 R 16 ,in:

[0278] R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0279] R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0280] R 16 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0281] or R 15 and R 16 may be optionally joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0282] (b) Compounds of formula (IV-B):

[0283]

[0284] in:

[0285] R 15 and R 16 R1 and R2 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R1 and R2 may be optionally joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;

[0286] R a and R b is independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R a and R btogether with any intervening atoms to form an optionally substituted cycloalkyl ring or an optionally substituted heterocycloalkyl ring;

[0287] or R 15 and R appears once a taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; and

[0288] s is selected from 1, 2, 3, 4, 5 and 6; or (c) a compound of formula (IV-C):

[0289]

[0290]

[0291] in:

[0292] R a is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0293] R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkoxycarbonyl, and -P(=O)(OR7)(OR8), wherein R7 and R8 are independently selected from hydrogen and optionally substituted alkyl;

[0294] or a pharmaceutically acceptable salt of a compound of any of these formulae.

[0295] In some embodiments, the NKA inhibitor is a compound of formula (IV-A) or a pharmaceutically acceptable salt thereof. In some embodiments, Z is OR 14 In some embodiments, R 14 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 15 R 16 In some embodiments, R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted heterocycloalkyl, and R 16 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 15 is hydrogen and R 16 is an optionally substituted alkyl. 15 is hydrogen and R 16 In some embodiments, R 15 and R 16 Together they form a 5- to 7-membered heterocycloalkyl ring.15 and R 16 Together with the atoms to which they are attached they form a 4-piperazinyl group.

[0296] In some embodiments, the compound of Formula IV-A is selected from:

[0297] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0298] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0299] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

[0300] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate;

[0301] 4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid; and

[0302] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[0303] or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the NKA inhibitor is a compound of formula (IV-B) or a pharmaceutically acceptable salt thereof. In some embodiments, the NKA inhibitor is a compound of formula (IV-C) or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the NKA inhibitor is a compound selected from the group consisting of:

[0306] 2-Aminoethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0307] 2-Hydroxyethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0308] 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0309] 2-((R)-3-hydroxypyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0310] 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate;

[0311] 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0312] 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)urea;

[0313] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-hydroxyethyl)urea;

[0314] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0315] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0316] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0317] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea;

[0318] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0319] 4-(3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid;

[0320] N-((5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0321] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0322] (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0323] (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0324] (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0325] (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0326] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide;

[0327] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0328] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide;

[0329] (S)-3-Hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0330] (R)-3-hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0331] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0332] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea;

[0333] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0334] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0335] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0336] 2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)acetamide;

[0337] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(pyrrolidin-1-yl)acetamide;

[0338] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-morpholinoacetamide;

[0339] (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide;

[0340] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide;

[0341] (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide;

[0342] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide;

[0343] (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide;

[0344] (S)-2-amino-N1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide;

[0345] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)amino)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0346] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)amino)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0347] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)amino)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0348] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0349] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-morpholinoethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0350] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methylpiperazine-1-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0351] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0352] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0353] 4-(3-((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)ureido)butanoic acid;

[0354] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(piperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0355] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(1,4-diazepane-1-carboxamido)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0356] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-1,4-diazepan-1-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0357] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-oxopiperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0358] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(2-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0359] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0360] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0361] 2-Aminoethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0362] 2-(Pyrrolidin-1-yl)ethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0363] 2-Morpholinoethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate;

[0364] 2-(3-oxopiperazin-1-yl)ethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0365] 1-(2-aminoethyl)-3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)urea;

[0366] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0367] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0368] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0369] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea;

[0370] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0371] 4-(3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-

[0372] (2-Oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0373] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepane-1-carboxamide;

[0374] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0375] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide;

[0376] (S)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-

[0377] (2-Oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0378] (R)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-

[0379] (2-Oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0380] (S)-3-amino-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0381] (R)-3-amino-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0382] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0383] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea;

[0384] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0385] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0386] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0387] 2-(Pyrrolidin-1-yl)ethyl ((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0388] 2-Morpholinoethyl ((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate;

[0389] 2-(3-oxopiperazin-1-yl)ethyl ((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0390] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0391] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0392] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0393] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea;

[0394] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0395] 4-(3-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid

[0396] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0397] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide;

[0398] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0399] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide;

[0400] (S)-3-Hydroxy-N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0401] (R)-3-Hydroxy-N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0402] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0403] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea;

[0404] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0405] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0406] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0407] 2-(Pyrrolidin-1-yl)ethyl ((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)carbamate;

[0408] 2-Morpholinoethyl ((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)carbamate;

[0409] 2-(3-oxopiperazin-1-yl)ethyl ((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)carbamate;

[0410] 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-methylurea;

[0411] 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0412] 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-morpholinoethyl)urea;

[0413] N-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-4-methylpiperazine-1-carboxamide;

[0414] 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea;

[0415] N-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0416] N-((1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)morpholine-4-carboxamide;

[0417] 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0418] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)amino)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiranyl 2-yl acetate;

[0419] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)amino)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0420] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)amino)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0421] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0422] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-morpholinoethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0423] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(4-methylpiperazine-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0424] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0425] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(morpholine-4-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0426] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(4-methyl-1,4-diazepan-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0427] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-oxopiperazine-1-carboxamido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0428] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0429] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0430] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)amino)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0431] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)amino)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0432] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)amino)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0433] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0434] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-morpholinoethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0435] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(4-methylpiperazine-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0436] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0437] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(morpholine-4-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0438] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(4-methyl-1,4-diazepan-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0439] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-oxopiperazine-1-carboxamido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0440] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0441] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0442] 2-Aminoethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0443] 2-Hydroxyethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0444] 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0445] 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0446] 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0447] 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)urea;

[0448] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-hydroxyethyl)urea;

[0449] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0450] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0451] N-((5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0452] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0453] (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0454] (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0455] (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0456] (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0457] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea;

[0458] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0459] 4-(3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo

[0460] 1-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0461] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide;

[0462] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0463] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide;

[0464] (S)-3-Hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0465] (R)-3-hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0466] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0467] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea;

[0468] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0469] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0470] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0471] 2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-

[0472] (5-Oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)acetamide;

[0473] (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide;

[0474] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide;

[0475] (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide;

[0476] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide;

[0477] (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide;

[0478] (S)-2-Amino-N1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide;

[0479] 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0480] 2-Morpholinoethyl ((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0481] 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0482] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0483] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0484] N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0485] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea;

[0486] N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide

[0487] 4-(3-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid

[0488] N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0489] N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide;

[0490] N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0491] (S)-N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0492] (R)-N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0493] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0494] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0495] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0496] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0497] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)amino)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0498] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)amino)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0499] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)amino)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0500] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0501] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-morpholinoethyl)ureido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0502] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(piperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0503] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(piperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0504] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0505] 4-(3-((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid

[0506] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methylpiperazine-1-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0507] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(1,4-diazepane-1-carboxamido)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0508] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-1,4-diazepan-1-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0509] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(2-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0510] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0511] 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0512] 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate;

[0513] 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0514] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0515] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0516] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0517] 4-(3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid

[0518] N-((5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0519] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0520] (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0521] (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0522] (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0523] (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0524] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide;

[0525] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0526] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0527] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0528] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0529] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetrahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-(pyrrolidin-1-yl)acetamide;

[0530] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-morpholinoacetamide;

[0531] (R)-2-Amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide

[0532] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide;

[0533] (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide;

[0534] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide;

[0535] (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide;

[0536] (S)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide;

[0537] 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0538] 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0539] 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate;

[0540] 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)urea;

[0541] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-hydroxyethyl)urea;

[0542] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0543] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0544] N-((5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0545] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0546] (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0547] (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0548] (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0549] (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0550] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea;

[0551] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0552] 4-(3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid;

[0553] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0554] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide;

[0555] (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0556] (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0557] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0558] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0559] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0560] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0561] 2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)acetamide;

[0562] (2R)-2-amino-N-((3S,5R,8R,9S,10S,13S,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide;

[0563] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide;

[0564] (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide;

[0565] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide;

[0566] (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide,

[0567] (S)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide;

[0568] (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-2-carboxamide;

[0569] (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-2-carboxamide;

[0570] (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-3-carboxamide,

[0571] (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-3-carboxamide;

[0572] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthrene-16-yl acetate,

[0573] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0574] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0575] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0576] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate;

[0577] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0578] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[0579] 4-(((((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoic acid;

[0580] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0581] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0582] (3S,5S,8R,9S,10R,13R,14S,16S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0583] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate;

[0584] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[0585] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(piperazin-1-yl)ethyl)carbamate;

[0586] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[0587] 4-(((((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid;

[0588] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0589] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0590] (3S,8R,9S,10R,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0591] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate;

[0592] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[0593] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(piperazin-1-yl)ethyl)carbamate;

[0594] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[0595] 4-(((((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid;

[0596] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0597] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl) carbonate;

[0598] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

[0599] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl)carbamate;

[0600] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate;

[0601] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate;

[0602] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate;

[0603] 4-(((((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid;

[0604] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0605] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0606] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0607] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0608] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate;

[0609] Acetic acid (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-

[0610] (4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl ester;

[0611] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate;

[0612] 4-(((((1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid;

[0613] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethylacetate

[0614] -1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl ester;

[0615] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethylacetate

[0616] -7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl ester;

[0617] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethylacetate

[0618] -1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl ester;

[0619] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethylacetate

[0620] -7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl ester;

[0621] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate;

[0622] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethylacetate

[0623] -7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl ester;

[0624] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate;

[0625] 4-(((((1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid;

[0626] Carbonic acid (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo

[0627] -2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) ester;

[0628] Carbonic acid (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo

[0629] -2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) ester;

[0630] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

[0631] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate;

[0632] Piperazine-1-carboxylic acid (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-piperazine

[0633] (5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3-yl ester; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(piperazin-1-yl)ethyl)carbamate;

[0634] Morpholine-4-carboxylic acid (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-

[0635] (5-Oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl ester; 4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid;

[0636] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0637] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0638] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

[0639] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate;

[0640] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[0641] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(piperazin-1-yl)ethyl)carbamate;

[0642] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[0643] 4-(((((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid;

[0644] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0645] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0646] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0647] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethyl)carbamoyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0648] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[0649] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(piperazin-1-yl)ethyl)carbamoyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0650] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate,

[0651] 4-(((((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid;

[0652] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0653] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0654] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

[0655] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[0656] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate;

[0657] 4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid;

[0658] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl valine;

[0659] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl alanine;

[0660] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl leucine;

[0661] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-(piperidin-1-yl)acetate;

[0662] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-(pyrrolidin-1-yl)acetate;

[0663] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl asparagine;

[0664] Proline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl ester; and

[0665] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-morpholinoacetate;

[0666] or a pharmaceutically acceptable salt thereof.

[0667] In some embodiments, the NKA inhibitor is a compound selected from the group consisting of:

[0668] 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)urea;

[0669] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-hydroxyethyl)urea;

[0670] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0671] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0672] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0673] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea;

[0674] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0675] 4-(3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid;

[0676] N-((5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0677] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0678] (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0679] (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0680] (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0681] (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0682] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide;

[0683] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0684] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide;

[0685] (S)-3-Hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0686] (R)-3-hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0687] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0688] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea;

[0689] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0690] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0691] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0692] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0693] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-morpholinoethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0694] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methylpiperazine-1-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0695] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0696] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0697] 4-(3-((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)ureido)butanoic acid;

[0698] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(piperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0699] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(1,4-diazepane-1-carboxamido)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0700] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-1,4-diazepan-1-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0701] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-oxopiperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0702] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(2-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0703] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0704] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0705] 1-(2-aminoethyl)-3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)urea;

[0706] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0707] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0708] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0709] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea;

[0710] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0711] 4-(3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid;

[0712] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0713] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepane-1-carboxamide;

[0714] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0715] N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide;

[0716] (S)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0717] (R)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0718] (S)-3-amino-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0719] (R)-3-amino-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0720] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0721] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea;

[0722] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0723] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0724] 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0725] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0726] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0727] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0728] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea;

[0729] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0730] 4-(3-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid;

[0731] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0732] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide;

[0733] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0734] N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide;

[0735] (S)-3-Hydroxy-N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0736] (R)-3-Hydroxy-N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0737] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0738] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea;

[0739] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0740] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0741] 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0742] 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-methylurea;

[0743] 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0744] 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-morpholinoethyl)urea;

[0745] N-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-4-methylpiperazine-1-carboxamide;

[0746] 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea;

[0747] N-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0748] N-((1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)morpholine-4-carboxamide;

[0749] 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0750] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0751] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-morpholinoethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0752] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(4-methylpiperazine-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0753] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0754] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(morpholine-4-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0755] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(4-methyl-1,4-diazepan-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0756] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-oxopiperazine-1-carboxamido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0757] Acetic acid (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-

[0758] (4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl ester;

[0759] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0760] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0761] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-morpholinoethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0762] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(4-methylpiperazine-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0763] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0764] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(morpholine-4-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0765] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(4-methyl-1,4-diazepan-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0766] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-oxopiperazine-1-carboxamido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0767] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0768] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0769] 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)urea;

[0770] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-hydroxyethyl)urea;

[0771] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0772] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0773] N-((5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0774] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0775] (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0776] (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0777] (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0778] (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0779] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea;

[0780] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0781] 4-(3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid;

[0782] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0783] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide;

[0784] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0785] N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide;

[0786] (S)-3-Hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0787] (R)-3-hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide;

[0788] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0789] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea;

[0790] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0791] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0792] 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0793] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0794] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0795] N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0796] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea;

[0797] N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0798] 4-(3-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid;

[0799] N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0800] N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide;

[0801] N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide;

[0802] (S)-N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0803] (R)-N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0804] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0805] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0806] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0807] 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0808] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0809] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-morpholinoethyl)ureido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0810] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(piperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0811] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(piperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0812] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0813] 4-(3-((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid;

[0814] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methylpiperazine-1-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0815] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(1,4-diazepane-1-carboxamido)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0816] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-1,4-diazepan-1-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0817] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(2-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0818] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0819] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0820] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0821] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0822] 4-(3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)ureido)butanoic acid;

[0823] N-((5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0824] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0825] (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0826] (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0827] (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0828] (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0829] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide;

[0830] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0831] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0832] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0833] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0834] 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)urea;

[0835] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-hydroxyethyl)urea;

[0836] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea;

[0837] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea;

[0838] N-((5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0839] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide;

[0840] (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0841] (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide;

[0842] (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0843] (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide;

[0844] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea;

[0845] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide;

[0846] 4-(3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid;

[0847] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide;

[0848] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide;

[0849] (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0850] (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

[0851] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea;

[0852] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea;

[0853] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; and

[0854] 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea;

[0855] or a pharmaceutically acceptable salt thereof.

[0856] In some embodiments, the NKA inhibitor is a compound selected from the group consisting of:

[0857] 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0858] 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate;

[0859] 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0860] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetrahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-(pyrrolidin-1-yl)acetamide;

[0861] N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-morpholinoacetamide;

[0862] (R)-2-Amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide

[0863] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide;

[0864] (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide;

[0865] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide;

[0866] (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide;

[0867] (S)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide;

[0868] 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0869] 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate;

[0870] 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate;

[0871] 2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)acetamide;

[0872] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide;

[0873] (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide;

[0874] (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide;

[0875] (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide,

[0876] (S)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide;

[0877] or a pharmaceutically acceptable salt thereof.

[0878] In some embodiments, the NKA inhibitor is a compound selected from the group consisting of:

[0879] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate;

[0880] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate;

[0881] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate;

[0882] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate;

[0883] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate;

[0884] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[0885] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[0886] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate;

[0887] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate;

[0888] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate;

[0889] (S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[0890] (R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[0891] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[0892] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[0893] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate;

[0894] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate;

[0895] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-,acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate;

[0896] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate;

[0897] (S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; and

[0898] (R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[0899] or a pharmaceutically acceptable salt thereof.

[0900] In some embodiments, the NKA inhibitor is a compound selected from the group consisting of:

[0901] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0902] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl) carbonate;

[0903] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0904] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0905] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0906] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0907] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0908] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0909] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0910] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0911] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0912] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate;

[0913] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0914] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0915] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate;

[0916] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0917] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0918] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate;

[0919] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0920] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0921] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate;

[0922] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0923] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate,

[0924] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0925] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

[0926] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl)carbamate;

[0927] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate;

[0928] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate;

[0929] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate;

[0930] 4-(((((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid;

[0931] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0932] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0933] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0934] 4-(((((1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid;

[0935] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0936] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0937] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0938] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0939] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; and

[0940] 4-(((((1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid;

[0941] or a pharmaceutically acceptable salt thereof.

[0942] In some embodiments, the NKA inhibitor is a compound selected from the group consisting of:

[0943] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0944] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl) carbonate;

[0945] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0946] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0947] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0948] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0949] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0950] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0951] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0952] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0953] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0954] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate;

[0955] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0956] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0957] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate;

[0958] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0959] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0960] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate;

[0961] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[0962] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[0963] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate;

[0964] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0965] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate,

[0966] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate;

[0967] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

[0968] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl)carbamate;

[0969] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate;

[0970] 4-(((((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid;

[0971] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0972] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0973] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0974] 4-(((((1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid;

[0975] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0976] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate;

[0977] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; and

[0978] 4-(((((1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid;

[0979] or a pharmaceutically acceptable salt thereof.

[0980] In some embodiments, the NKA inhibitor is a compound selected from the group consisting of:

[0981] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate;

[0982] (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate;

[0983] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate;

[0984] (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate;

[0985] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate;

[0986] (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate;

[0987] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate;

[0988] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[0989] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[0990] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate;

[0991] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate;

[0992] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate;

[0993] (S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[0994] (R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[0995] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[0996] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[0997] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate;

[0998] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate;

[0999] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate;

[1000] (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate;

[1001] (S)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[1002] (R)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[1003] (S)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-aminopyrrolidine-1-carboxylate;

[1004] (R)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-aminopyrrolidine-1-carboxylate;

[1005] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[1006] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[1007] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate;

[1008] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate;

[1009] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate;

[1010] (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate;

[1011] (S)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[1012] (R)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[1013] (S)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-aminopyrrolidine-1-carboxylate;

[1014] (R)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-aminopyrrolidine-1-carboxylate;

[1015] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[1016] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[1017] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate;

[1018] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate;

[1019] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate;

[1020] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate;

[1021] (S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[1022] (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[1023] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[1024] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[1025] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate;

[1026] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate;

[1027] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate;

[1028] (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate;

[1029] (S)-(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[1030] (R)-(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[1031] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[1032] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[1033] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate;

[1034] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate;

[1035] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-,acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate;

[1036] (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate;

[1037] (S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; and

[1038] (R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate;

[1039] or a pharmaceutically acceptable salt thereof.

[1040] In some embodiments, the NKA inhibitor is a compound selected from:

[1041] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[1042] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[1043] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

[1044] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate;

[1045] 4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid;

[1046] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[1047] or a pharmaceutically acceptable salt thereof.

[1048] In some embodiments, the NKA inhibitor is a compound selected from:

[1049] (((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)methyl dihydrogen phosphate;

[1050] (((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)methyl acetate;

[1051] 1-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)ethyl acetate;

[1052] (((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)methyl pivalate;

[1053] Ethyl carbonate ((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)methyl) ester;

[1054] Ethyl carbonate (1-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)ethyl) ester;

[1055] or a pharmaceutically acceptable salt thereof.

[1056] In some embodiments, the NKA inhibitor is a compound selected from the group consisting of:

[1057] (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-aminopropanoate;

[1058] (S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-aminopropanoate;

[1059] (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-amino-3-methylbutanoate;

[1060] (S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-amino-3-methylbutanoate;

[1061] (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-amino-4-methylpentanoate;

[1062] (S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-amino-4-methylpentanoate;

[1063] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate;

[1064] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;

[1065] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

[1066] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate;

[1067] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[1068] 4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid; and

[1069] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate;

[1070] or a pharmaceutically acceptable salt thereof.

[1071] In some embodiments, the NKA inhibitor is a compound selected from the group consisting of:

[1072] (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate;

[1073] or a pharmaceutically acceptable salt thereof.

[1074] In some embodiments, the NKA inhibitor is a compound selected from digoxin and digitoxin, or a pharmaceutically acceptable salt thereof. In some embodiments, the NKA inhibitor is a compound disclosed in US 2013 / 0005696 or WO 2013 / 000286, or a pharmaceutically acceptable salt thereof.

[1075] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless otherwise indicated by the context in which they are used.

[1076] The following abbreviations and terms have the indicated meanings throughout the text:

[1077]

[1078]

[1079] As used herein, when any variable occurs more than one time in a formula, its definition on each occurrence is independent of its definition at every other occurrence.

[1080] As used herein, 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.

[1081] As used herein, "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 the event or circumstance does not occur. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art that for any group containing one or more substituents, such group is not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically infeasible, and / or inherently unstable.

[1082] As used herein, "alkyl" refers to straight and branched chains with a specified number of carbon atoms (typically from 1 to 20 carbon atoms, for example, 1 to 8 carbon atoms, such as 1 to 6 carbon atoms). For example, C1-C6 alkyl encompasses straight and branched alkyl groups with from 1 to 6 carbon atoms. When an alkyl residue with a specific number of carbons is named, it is intended to encompass all straight and branched forms of carbon with that number; thus, for example, "butyl" means including n-butyl, sec-butyl, isobutyl and tert-butyl; "propyl" includes n-propyl and isopropyl. "Lower alkyl" refers to an alkyl group with 1 to 6 carbons. Examples of alkyl groups include 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 a subset of alkyl and refers to a group that is the same as alkyl but has two points of attachment. An alkylene group typically has from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. For example, C0 alkylene represents a covalent bond, and C1 alkylene is a methylene group.

[1083] As used herein, "alkenyl" refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon double bond, wherein the double bond is obtained by removing one molecule of hydrogen from the adjacent carbon atoms of the parent alkyl group. The group can be in a cis or trans configuration around the double bond. Typical alkenyl groups include, but are not limited to, vinyl; propenyl, such as prop-1-ene-1-yl, prop-1-ene-2-yl, prop-2-ene-1-yl (allyl), prop-2-ene-2-yl; butenyl, such as but-1-ene-1-yl, but-1-ene-2-yl, 2-methyl-prop-1-ene-1-yl, but-2-ene-1-yl, but-2-ene-1-yl, but-2-ene-2-yl, but-1,3-diene-1-yl, but-1,3-diene-2-yl; etc. Alkenyl groups have from 2 to 20 carbon atoms in certain embodiments, and from 2 to 6 carbon atoms in other embodiments. "Lower alkenyl" refers to alkenyl groups having 2 to 6 carbons.

[1084] As used herein, "alkynyl" refers to an unsaturated branched or straight chain alkyl group having at least one carbon-carbon triple bond, the triple bond being obtained by removing two molecules of hydrogen from adjacent carbon atoms of the parent alkyl group. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like. Alkynyl groups have from 2 to 20 carbon atoms in certain embodiments, and from 3 to 6 carbon atoms in other embodiments. "Lower alkynyl" refers to alkynyl groups having from 2 to 6 carbon atoms.

[1085] As used herein, "cycloalkyl" refers to a non-aromatic carbocyclic ring typically having from 3 to 8 ring carbon atoms. The ring may be saturated or have one or more carbon-carbon double bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, as well as bridged and caged ring groups such as norbornane.

[1086] As used herein, the term "alkoxy" refers to an alkyl group having a specified number of carbon atoms connected by an oxygen bridge, 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 typically have from 1 to 7 carbon atoms connected by an oxygen bridge. "Lower alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms.

[1087] As used herein, "acyl" refers to the groups HC(O)-; (alkyl)-C(O)-; (cycloalkyl)-C(O)-; (aryl)-C(O)-; (heteroaryl)-C(O)-; and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through a carbonyl functional group, and wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein. The acyl group has the specified number of carbon atoms, wherein the carbon of the keto group is included in the numbered carbon atoms. For example, a C2 acyl group is an acetyl group having the formula CH3(C=O)-.

[1088] As used herein, "acyloxy" refers to the group -O-acyl.

[1089] As used herein, "formyl" refers to the group -C(O)H.

[1090] As used herein, "alkoxycarbonyl" refers to a radical of the formula (alkoxy)(C=O)- linked through the carbonyl carbon, wherein the alkoxy group has the indicated number of carbon atoms. Thus, a C1-C6 alkoxycarbonyl radical is an alkoxy radical having from 1 to 6 carbon atoms linked through its oxygen to a carbonyl linker.

[1091] As used herein, "alkoxycarbonyloxy" refers to the group -O-alkoxycarbonyl.

[1092] As used herein, "azido" refers to the group -N3.

[1093] As used herein, "amino" refers to the group -NH2.

[1094] As used herein, "mono- and di-alkylamino" refers to secondary and tertiary alkylamino groups, wherein the alkyl group is as defined above and has the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and dialkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.

[1095] As used herein, "aminocarbonyl" refers to the group -C(O)NR b R c ,in:

[1096] R b is selected from H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, optionally substituted alkoxy; and

[1097] R c is selected from hydrogen and optionally substituted C1-C4 alkyl; or

[1098] R b and R ctogether with the nitrogen to which they are attached form an optionally substituted 5- to 8-membered nitrogen-containing heterocycloalkyl group optionally comprising 1 or 2 additional heteroatoms selected from O, N and S in the heterocycloalkyl ring;

[1099] wherein each substituted group is independently substituted by one or more substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl, heterocycloalkyl or heteroaryl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C -C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C4 haloalkyl).

[1100] As used herein, "aminocarbonyloxy" refers to the group -O-aminocarbonyl.

[1101] As used herein, "aryl" refers to: a 6-membered carbocyclic aromatic ring, such as benzene; a bicyclic ring system in which at least one ring is carbocyclic and aromatic, such as naphthalene, indane, and tetralin; and a tricyclic ring system in which at least one ring is carbocyclic and aromatic, such as fluorene.

[1102] For example, aryl includes a 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O, and S. For such fused bicyclic ring systems in which only one ring is a carbocyclic aromatic ring, the point of attachment can be on the carbocyclic aromatic ring or the heterocycloalkyl ring. Divalent radicals formed from substituted benzene derivatives and having free valences on ring atoms are referred to as substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose names end in "radical" by removing a hydrogen atom from a carbon atom having free valences are named by adding a "cross" to the name of the corresponding monovalent radical; for example, a naphthyl radical with two points of attachment is referred to as naphthylidene. However, aryl does not in any way encompass or overlap with heteroaryl, which is defined separately below. Thus, if one or more carbocyclic aromatic rings are fused to a heterocycloalkyl aromatic ring, the resulting ring system is a heteroaryl rather than an aryl radical, as defined herein.

[1103] As used herein, "aryloxy" refers to the group -O-aryl.

[1104] As used herein, "aralkyl" refers to the group -alkyl-aryl.

[1105] As used herein, "carbamimidoyl" refers to the group -C(=NH)-NH2.

[1106] As used herein, "substituted carbamimidoyl" refers to a group -C(=NR e )-NR f R g ,in

[1107] R e is selected from hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; and

[1108] R f and R g are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl,

[1109] The condition is R e 、R f and R g wherein at least one of the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups is not hydrogen and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups refer to alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups, respectively, in which one or more (such as up to 5, for example up to 3) hydrogen atoms are replaced by substituents independently selected from:

[1110] -R a 、-OR b, optionally substituted amino (including -NR c COR b 、-NR c CO2R a 、-NR c CONR b R c 、-NR b C(NR c )NR b R c 、-NR b C(NCN)NR b R c and -NR c SO2R a ), halo, cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl and heteroaryl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO2R b ), aminocarbonyl (such as -CONR b R c ),-OCOR b 、-OCO2R a 、-OCONR b R c 、-OP(O)(OR b )OR c , sulfanyl (such as SR b ), sulfinyl (such as -SOR a ) and sulfonyl groups (such as -SO2R a and -SO2NR b R c ),

[1111] where R a is selected from optionally substituted C1-C6 alkyl, optionally substituted aryl and optionally substituted heteroaryl;

[1112] R b is selected from H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[1113] R c is selected from hydrogen and optionally substituted C1-C4 alkyl; or

[1114] R b and R c and the nitrogen to which they are attached form an optionally substituted heterocycloalkyl group; and

[1115] wherein each optionally substituted group is unsubstituted or independently substituted with one or more (such as one, two or three) substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl, heterocycloalkyl or heteroaryl), -CO2H, -C(O)OC1-C4 alkyl -C1-C4 alkyl), -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 phenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C4 haloalkyl).

[1116] As used herein, "halo" refers to fluoro, chloro, bromo and iodo, and the term "halogen" includes fluorine, chlorine, bromine and iodine.

[1117] As used herein, "haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogen atoms (up to the maximum permitted number of halogen atoms) and having a specified number of carbon atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

[1118] As used herein, "heteroaryl" refers to:

[1119] a 5- to 7-membered aromatic monocyclic ring containing one or more (e.g., from 1 to 4, or in certain embodiments, from 1 to 3) heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon;

[1120] bicyclic heterocycloalkyl rings containing one or more (e.g., from 1 to 4, or in certain embodiments, from 1 to 3) heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon and wherein at least one heteroatom is present in an aromatic ring; and

[1121] A tricyclic heterocycloalkyl ring containing one or more (e.g., from 1 to 5, or in certain embodiments, from 1 to 4) heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon and wherein at least one heteroatom is present in an aromatic ring.

[1122] For example, heteroaryl includes a 5- to 7-membered heterocycloalkyl aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring. For such fused bicyclic heteroaryl ring systems in which only one ring contains one or more heteroatoms, the point of attachment can be on either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In certain embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuranyl, benzimidazolinyl, indolinyl, pyridazinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl (as numbered from the attachment position designated as priority 1). Divalent radicals derived from monovalent heteroaryl radicals whose names end in "radical" by removing one hydrogen atom from the atom having the free valences are named by adding a "cross" to the name of the corresponding monovalent radical, for example, a pyridyl radical having two points of attachment is a pyridylidene radical. Heteroaryl does not encompass or overlap with aryl, cycloalkyl, or heterocycloalkyl, as defined herein.

[1123] Substituted heteroaryl groups also include those substituted by one or more oxides (-O - ) substituents, such as pyridyl N-oxides.

[1124] As used herein, "heteroaryloxy" refers to the group -O-heteroaryl.

[1125] As used herein, "heteroaralkyl" refers to the group -alkyl-heteroaryl.

[1126] As used herein, "heterocycloalkyl" refers to a single non-aromatic ring, typically having 3 to 8 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and combinations comprising at least one of the foregoing heteroatoms. The ring may be saturated or have one or more carbon-carbon double bonds. Suitable heterocycloalkyl groups include, for example (as numbered from the attachment position designated as priority 1) 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-piperazinyl and 2,5-piperazinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (oxygen is designated as priority 1 in the numbering). Substituted heterocycloalkyl groups also include those replaced by one or more oxo (=O) or oxygen radicals (-O) groups. - ) substituents such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

[1127] “Heterocycloalkyl” also includes bicyclic ring systems in which one of the non-aromatic rings (typically having 3 to 8 ring atoms) contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and combinations comprising at least one of the foregoing heteroatoms; and the other ring (typically having 3 to 8 ring atoms) optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen and is non-aromatic.

[1128] As used herein, "heterocycloalkoxy" refers to the group -O-heterocycloalkyl.

[1129] As used herein, "sulfanyl" refers to the following groups: -S-(optionally substituted (C1-C6)alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl). Thus, sulfanyl includes the group C1-C6 alkylsulfanyl.

[1130] As used herein, "sulfinyl" refers to the following groups: -S(O)-(optionally substituted (C1-C6)alkyl), -S(O)-(optionally substituted aryl), -S(O)-(optionally substituted heteroaryl), -S(O)-(optionally substituted heterocycloalkyl); and -S(O)-(optionally substituted amino).

[1131] As used herein, "sulfonyl" refers to the following groups: -S(O2)-(optionally substituted (C1-C6)alkyl), -S(O2)-(optionally substituted aryl), -S(O2)-(optionally substituted heteroaryl), -S(O2)-(optionally substituted heterocycloalkyl) and -S(O2)-(optionally substituted amino).

[1132] As used herein, "aminosulfonyl" refers to the group -S(O)2NR b R c ,in:

[1133] R b is selected from H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, optionally substituted alkoxy; and

[1134] R c is selected from hydrogen and optionally substituted C1-C4 alkyl; or

[1135] R b and R c together with the nitrogen to which they are attached form an optionally substituted 5- to 8-membered nitrogen-containing heterocycloalkyl group optionally comprising 1 or 2 additional heteroatoms selected from O, N and S in the heterocycloalkyl ring;

[1136] wherein each substituted group is independently substituted by one or more substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl, heterocycloalkyl or heteroaryl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C -C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C4 haloalkyl).

[1137] As used herein, "substituted" refers to any one or more hydrogens on a designated atom or group that are replaced by a substituent selected from 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. Combinations of substituents and / or variables are permitted only when such combinations produce stable compounds or useful synthetic intermediates. A stable compound or stable structure is intended to represent a compound that is sufficiently strong to withstand separation from a reaction mixture and subsequently formulated into a reagent that is at least practical. Unless otherwise indicated, the substituents are named into the 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.

[1138] Unless expressly defined otherwise, the terms "substituted" alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl as used herein refer to alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups, respectively, in which one or more (such as up to 5, for example up to 3) hydrogen atoms are replaced by substituents independently selected from:

[1139] -R a 、-OR b , optionally substituted amino (including -NR c COR b 、-NR c CO2R a 、-NR c CONR b R c 、-NR b C(NR c )NR b R c 、-NR b C(NCN)NR b R c and -NR c SO2R a ), halo, cyano, azido, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO2R b ), aminocarbonyl (such as -CONR b R c ),-OCOR b 、-OCO2R a 、-OCONR b R c 、-OP(O)(OR b )OR c , sulfanyl (such as SR b), sulfinyl (such as -SOR a ) and sulfonyl groups (such as -SO2R a and -SO2NR b R c ),in

[1140] R a R is selected from optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl; b is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[1141] R c is selected from hydrogen and optionally substituted C1-C4 alkyl; or

[1142] R b and R c and the nitrogen to which they are attached form an optionally substituted heterocycloalkyl group; and

[1143] wherein each optionally substituted group is unsubstituted or independently substituted by one or more (such as one, two or three) substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4 alkyl, - CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C4 haloalkyl).

[1144] As used herein, "substituted acyl" refers to the groups (substituted alkyl)-C(O)-; (substituted cycloalkyl)-C(O)-; (substituted aryl)-C(O)-; (substituted heteroaryl)-C(O)-; and (substituted heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through a carbonyl functionality, and wherein substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl refer to alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups, respectively, in which one or more (such as up to 5, e.g., up to 3) hydrogen atoms are replaced by substituents independently selected from:

[1145] -R a 、-OR b , optionally substituted amino (including -NR c COR b 、-NR c CO2R a 、-NR c CONR b R c、-NR b C(NR c )NR b R c 、-NR b C(NCN)NR b R c and -NR c SO2R a ), halo, cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO2R b ), aminocarbonyl (such as -CONR b R c ),-OCOR b 、-OCO2R a 、-OCONR b R c 、-OP(O)(OR b )OR c , sulfanyl (such as SR b ), sulfinyl (such as -SOR a ) and sulfonyl groups (such as -SO2R a and -SO2NR b R c ),

[1146] where R a is selected from optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[1147] R b is selected from H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[1148] R c is selected from hydrogen and optionally substituted C1-C4 alkyl; or

[1149] R b and R c and the nitrogen to which they are attached form an optionally substituted heterocycloalkyl group; and

[1150] wherein each optionally substituted group is unsubstituted or independently substituted by one or more (such as one, two or three) substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4 alkyl, - CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C4 haloalkyl).

[1151] As used herein, the term "substituted alkoxy" refers to an alkoxy group in which the alkyl component is substituted (i.e., -O-(substituted alkyl)), wherein "substituted alkyl" refers to an alkyl group in which one or more (such as up to 5, for example up to 3) hydrogen atoms are replaced by substituents independently selected from:

[1152] -R a 、-OR b , optionally substituted amino (including -NR c COR b 、-NR c CO2R a 、-NR c CONR b R c 、-NR b C(NR c )NR b R c 、-NR b C(NCN)NR b Rc and -NR c SO2R a ), halo, cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO2R b ), aminocarbonyl (such as -CONR b R c ),-OCOR b 、-OCO2R a 、-OCONR b R c 、-OP(O)(OR b )OR c , sulfanyl (such as SR b ), sulfinyl (such as -SOR a ) and sulfonyl groups (such as -SO2R a and -SO2NR b R c ),

[1153] where R a is selected from optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[1154] R b is selected from H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[1155] R c is selected from hydrogen and optionally substituted C1-C4 alkyl; or

[1156] R b and R c and the nitrogen to which they are attached form an optionally substituted heterocycloalkyl group; and

[1157] wherein each optionally substituted group is unsubstituted or independently substituted by one or more (such as one, two or three) substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4 alkyl, - CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C4 haloalkyl).

[1158] In some embodiments, a substituted alkoxy group is a "polyalkoxy" or -O-(optionally substituted alkylene)-(optionally substituted alkoxy) and includes groups such as -OCH2CH2OCH3, and residues of glycol ethers such as polyethylene glycol, and -O(CH2CH2O) x CH3, wherein x is an integer from 2 to 20, such as 2 to 10, for example 2 to 5. Another substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2) y OH, wherein y is an integer from 1 to 10, such as 1 to 4.

[1159] As used herein, "substituted alkoxycarbonyl" refers to the group (substituted alkyl)-OC(O)-, wherein the group is attached to the parent structure via the carbonyl functionality, and wherein substituted refers to an alkyl group in which one or more (such as up to 5, for example up to 3) hydrogen atoms are replaced by substituents independently selected from:

[1160] -R a 、-ORb , optionally substituted amino (including -NR c COR b 、-NR c CO2R a 、-NR c CONR b R c 、-NR b C(NR c )NR b R c 、-NR b C(NCN)NR b R c and -NR c SO2R a ), halo, cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO2R b ), aminocarbonyl (such as -CONR b R c ),-OCOR b 、-OCO2R a 、-OCONR b R c 、-OP(O)(OR b )OR c , sulfanyl (such as SR b ), sulfinyl (such as -SOR a ) and sulfonyl groups (such as -SO2R a and -SO2NR b R c ),

[1161] where R a is selected from optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[1162] R b is selected from H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[1163] R c is selected from hydrogen and optionally substituted C1-C4 alkyl; or

[1164] R b and R c and the nitrogen to which they are attached form an optionally substituted heterocycloalkyl group; and

[1165] wherein each optionally substituted group is unsubstituted or independently substituted by one or more (such as one, two or three) substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4 alkyl, - CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C4 haloalkyl).

[1166] As used herein, "substituted amino" refers to the group -NHR d or -NR d R e , where R d is selected from hydroxy, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted amidino, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein R e is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocycloalkyl, and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl refer to alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, respectively, in which one or more (such as up to 5, for example up to 3) hydrogen atoms are replaced by substituents independently selected from:

[1167] -R a 、-ORb , optionally substituted amino (including -NR c COR b 、-NR c CO2R a 、-NR c CONR b R c 、-NR b C(NR c )NR b R c 、-NR b C(NCN)NR b R c and -NR c SO2R a ), halo, cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO2R b ), aminocarbonyl (such as -CONR b R c ),-OCOR b 、-OCO2R a 、-OCONR b R c 、-OP(O)(OR b )OR c , sulfanyl (such as SR b ), sulfinyl (such as -SOR a ) and sulfonyl groups (such as -SO2R a and -SO2NR b R c ),

[1168] where R a is selected from optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;

[1169] R b is selected from H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[1170] R c is selected from hydrogen and optionally substituted C1-C4 alkyl; or

[1171] R b and R c and the nitrogen to which they are attached form an optionally substituted heterocycloalkyl group; and

[1172] wherein each optionally substituted group is unsubstituted or independently substituted by one or more (such as one, two or three) substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4 alkyl, -C ON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl); and

[1173] wherein optionally substituted acyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.

[1174] The term "substituted amino" also refers to the groups -NHR, each as described above. d and NR d R d N-oxides can be prepared by treating the corresponding amino group with, for example, hydrogen peroxide or m-chloroperbenzoic acid. Those skilled in the art are familiar with the reaction conditions for carrying out N-oxidation.

[1175] Compounds as described herein include but are not limited to their optical isomers, racemates and other mixtures thereof. In those cases, single enantiomers or diastereomers, that is, optically active forms, can be obtained by asymmetric synthesis or by splitting racemates. For example, the splitting of racemates can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or using, for example, a chromatogram of a chiral high pressure liquid chromatography (HPLC) column. In addition, compounds include Z forms and E forms (or cis and trans forms) of compounds with carbon-carbon double bonds. When compounds as described herein exist in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the compound.

[1176] The compounds or salts disclosed herein also include crystalline and amorphous forms of those compounds or salts, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof. "Crystalline form," "polymorph," and "novel form" are used interchangeably herein and are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is mentioned. Similarly, "pharmaceutically acceptable salts" of compounds of Formula I also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of pharmaceutically acceptable salts, and mixtures thereof.

[1177] A "solvate" is formed by the interaction of a solvent and a compound. The term "compound" is intended to include solvates of the compound. Similarly, a "pharmaceutically acceptable salt" includes solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemihydrates.

[1178] The compounds disclosed herein also include other pharmaceutically acceptable forms of the compounds, including chelates, non-covalent complexes, prodrugs, and mixtures thereof.

[1179] A "chelate" is formed by the coordination of a compound to a metal ion at two (or more) points. The term "compound" is intended to include chelates of the compound. Similarly, a "pharmaceutically acceptable salt" includes chelates of pharmaceutically acceptable salts.

[1180] A "non-covalent complex" is formed by the interaction of a compound with another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also known as ionic bonding). Such non-covalent complexes are included in the term "compound." Similarly, "pharmaceutically acceptable salts" include "non-covalent complexes" of pharmaceutically acceptable salts.

[1181] The term "hydrogen bond" refers to a form of association between an electronegative atom (also called a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also called a hydrogen bond donor). Suitable hydrogen bond donors and acceptors are well known in medicinal chemistry.

[1182] "Hydrogen bond acceptors" refer to groups containing oxygen or nitrogen, such as sp 2 - a hybridized oxygen or nitrogen, an ether oxygen, or the oxygen of a sulfoxide or N-oxide.

[1183] The term "hydrogen bond donor" refers to an oxygen, nitrogen, or heteroaromatic carbon, a ring nitrogen containing group, or a ring nitrogen containing heteroaryl group that carries a hydrogen.

[1184] The compounds disclosed herein may be present in different isotopically enriched forms (e.g. 2 H. 3 H. 11 C. 13 C and / or 14 In certain embodiments, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve efficacy and increase the duration of action of the drug.

[1185] Deuterium-substituted compounds can be synthesized using various methods such as those described in Dean, Dennis C., ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[1186] "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) wherein n is 0-4, n -COOH and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[1187] Furthermore, 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, an 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.

[1188] "Prodrugs" as described herein include any compound that becomes a compound of Formula I when administered to a subject (e.g., after metabolic processing of the prodrug). Similarly, "pharmaceutically acceptable salts" include "prodrugs" of pharmaceutically acceptable salts. Examples of prodrugs include derivatives of functional groups (such as carboxylic acid groups) in compounds of Formula I. Exemplary prodrugs of carboxylic acid groups include, but are not limited to, carboxylate esters, such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters, such as ethyl esters; acyloxyalkyl esters, such as pivaloyloxymethyl (POM); glycosides; and ascorbic acid derivatives.

[1189] Other exemplary prodrugs include amides of carboxylic acids. Exemplary amide prodrugs include, for example, metabolically unstable amides formed with amines and carboxylic acids. Exemplary amines include NH2, primary amines, and secondary amines, such as NHR x and NR x R y , where R x is hydrogen, (C1-C 18 )-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl-, (C6-C 14 )-aryl, which is unsubstituted or substituted by residues (C1-C2)-alkyl, (C1-C2)-alkoxy, fluorine or chlorine; heteroaryl-, (C6-C 14 )-aryl-(C1-C4)-alkyl-, wherein aryl is unsubstituted or substituted by a residue (C1-C2)-alkyl, (C1-C2)-alkoxy, fluorine or chlorine; or heteroaryl-(C1-C4)-alkyl-, and wherein R y With R x The meanings specified (except hydrogen), or wherein R x and R y Together with the nitrogen to which they are attached, they form an optionally substituted 4- to 8-membered heterocycloalkyl ring optionally containing one or two additional heteroatoms selected from nitrogen, oxygen, and sulfur. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, the ACSSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985.

[1190] 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.

[1191] As used herein, "modulate" refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity in the absence of the chemical entity. The change can be an increase in activity or a decrease in activity and can be attributable to a direct interaction of the compound with the target or to an interaction of the compound with one or more other factors that in turn affect the activity of the target. For example, the presence of a chemical entity can increase or decrease the activity of a target, for example, by directly binding to the target, causing another factor to increase or decrease the activity of the target (directly or indirectly), or increasing or decreasing the amount of the target present in a cell or organism (directly or indirectly).

[1192] As used herein, "active agent" is used to refer to a chemical entity with biological activity. In certain embodiments, an "active agent" is a compound with pharmaceutical utility. For example, an active agent can be an anticancer therapeutic agent.

[1193] As used herein, "significant" refers to any detectable change that is statistically significant in a standard parametric test of statistical significance, such as Student's T-test, where p < 0.05.

[1194] As used herein, a "pharmaceutically acceptable" component is one that is suitable for use in humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio.

[1195] As used herein, a "therapeutically effective amount" of a chemical entity described herein refers to an amount effective to provide a therapeutic benefit, such as amelioration of symptoms, delay of disease progression, or prevention of disease, when administered to a human or non-human subject.

[1196] "Treating" or "treatment" encompasses the administration of at least one compound of Formula I or a pharmaceutically acceptable salt thereof to a mammalian subject, particularly a human subject, in need of such administration, and includes (i) arresting the development of clinical symptoms of a disease, such as cancer, (ii) causing regression of clinical symptoms of a disease, such as cancer, and / or (ii) prophylactic treatment for preventing the onset of a disease, such as cancer.

[1197] As used herein, "cancer" refers to all types of cancers or neoplasms or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancer are brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, and medulloblastoma.

[1198] As used herein, a "subject" refers to a mammal that is or will be the subject of treatment, observation, or experiment. The methods described herein can be used for both human therapeutic and veterinary applications. In some embodiments, the subject is a human.

[1199] The term "mammal" is intended to have its standard meaning and encompasses, for example, humans, dogs, cats, sheep, and cattle.

[1200] The chemical entities described herein can be synthesized from commercially available starting materials and reagents using techniques well known in the art.

[1201] The chemical entities described herein can be prepared in substantially pure form, typically by standard chromatography, prior to formulation into a pharmaceutically acceptable form.

[1202] The chemical entities described herein can be used to treat a variety of cancers. Cancers that can be prevented and / or treated by the chemical entities, compositions, and methods described herein include, but are not limited to, human sarcomas and carcinomas, such as carcinomas, for example, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, enchondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovialoma, mesothelioma, Ewing's tumor, and / or sarcoma. tumor), leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung tumor, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma , neuroblastoma, retinoblastoma, leukemias (e.g., acute lymphocytic leukemia and acute myeloid leukemia (myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, and erythroleukemia)); chronic leukemias (chronic myeloid (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphomas (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease.

[1203] In some embodiments, the chemical entities described herein are used to treat cancers of:

[1204] (i) digestive system, including but not limited to the esophagus, stomach, small intestine, colon (including colorectum), liver and intrahepatic bile ducts, gallbladder and other bile ducts, pancreas and other digestive organs;

[1205] (ii) respiratory system, including but not limited to the larynx, lungs and bronchi and other respiratory organs;

[1206] (iii) mammary gland;

[1207] (iv) reproductive system, including but not limited to the cervix, ovaries, and prostate;

[1208] (v) the urinary system, including but not limited to the bladder and the kidneys and renal pelvis; and

[1209] (vi) Oral cavity & pharynx, including but not limited to the tongue, oral cavity, pharynx and other oral parts.

[1210] In some embodiments, the chemical entities described herein are used to treat colorectal cancer, liver cancer, lung cancer, breast cancer, and oral cancer.

[1211] In some embodiments, as described herein, the chemical entities described herein having the desired pharmacological activity can be administered to a patient in the form of a pharmaceutically acceptable composition comprising a pharmaceutical excipient. Depending on the mode of introduction, the chemical entity can be formulated in various ways as discussed below. The concentration of at least one chemical entity in the formulation can vary from about 0.01 to 100% by weight.

[1212] Administration of the chemical entities described herein can be carried out in a variety of ways, including, but not limited to, orally, subcutaneously, intravenously, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonary, vaginally, rectally, or intraocularly.

[1213] Pharmaceutical dosage forms include at least one chemical entity as described herein and one or more pharmaceutical excipients. As known in the art, pharmaceutical excipients are minor components that play a role in enabling a drug or medicament to be delivered or enhancing its delivery in a variety of dosage forms (e.g., oral dosage forms such as tablets, capsules, and liquids; topical dosage forms such as skin, eye, and ear dosage forms; suppositories; injection dosage forms; respiratory dosage forms, etc.). Pharmaceutical excipients include inert or inactive ingredients, synergists or chemicals that substantially promote the pharmaceutical effects of active ingredients. For example, pharmaceutical excipients can play a role in improving flow characteristics, product uniformity, stability, taste, or appearance, making the handling and application of dosages easier to use or control bioavailability. Although pharmaceutical excipients are generally described as inert or inactive, it should be understood in the art that there is a relationship between the properties of pharmaceutical excipients and the dosage forms containing them.

[1214] Pharmaceutical excipients suitable for use as carriers or diluents are well known in the art and can be used in a variety of formulations. See, for example, Remington's Pharmaceutical Sciences, 18th edition, A.R. Gennaro, ed., Mack Publishing Company (1990); Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins (2005); Handbook of Pharmaceutical Excipients, 3rd edition, A.H. Kibbe, ed., American Pharmaceutical Association, and Pharmaceutical Press (2000); and Handbook of Pharmaceutical Additives, compiled by Michael and Irene Ash, Gower (1995), each of which is incorporated herein by reference for all purposes.

[1215] Oral solid dosage forms such as tablets typically contain one or more pharmaceutical excipients that, for example, can help impart satisfactory processing and tableting properties, or provide the tablet with additional desired physical properties. Such pharmaceutical excipients can be selected from diluents, binders, glidants, lubricants, disintegrants, colorants, flavorings, sweeteners, polymers, waxes, or other dissolution-delaying materials.

[1216] Compositions for intravenous administration typically contain intravenous fluids, ie, sterile solutions of simple chemicals (such as sugars, amino acids, or electrolytes) that are easily carried and absorbed by the circulatory system.

[1217] Dosage forms for parenteral administration typically contain fluids, particularly intravenous fluids, i.e., sterile solutions of simple chemicals (such as sugars, amino acids, or electrolytes) that are easily carried and absorbed by the circulatory system. Such fluids are typically prepared with USP water for injection. Fluids typically used for intravenous (IV) use are disclosed in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins (2005). As known in the art, the pH of such IV fluids can vary, and is typically from 3.5 to 8.

[1218] The chemical entities described herein may also be used in combination with other well-known therapeutic agents that are selected for their specific usefulness against the condition being treated. For example, the chemical entities described herein may be used in combination with at least one additional anticancer agent and / or cytotoxic agent. In addition, the chemical entities described herein may also be used in combination with other inhibitors of portions of the signaling pathway that connect cell surface growth factor receptors to nuclear signals that trigger cell proliferation.

[1219] Such known anticancer and / or cytotoxic agents that can be used in combination with the chemical entities described herein include:

[1220] (i) other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines, such as doxorubicin, bleomycin, , doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, dactinomycin, and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as paclitaxel and taxotere, and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin);

[1221] (ii) cytostatic agents, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole, and exemestane), and inhibitors of 5a-reductase such as finasteride;

[1222] (iii) anti-invasive agents [e.g., inhibitors of the c-Src kinase family, such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 66586661), and bosutinib (SK1-606), as well as metalloproteinase inhibitors such as marimastat, urokinase plasminogen activator receptor function inhibitors, or antibodies to heparanase];

[1223] (iv) Growth factor function inhibitors: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin TM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor antibody or growth factor receptor antibody disclosed in Stem et al. Critical reviews in oncology / haematology, 2005, volume 54, pages 11-29); such inhibitors also include tyrosine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (Erlotinib, ZD1839), tinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, for example, sorafenib (BAY107); 43-9006), tipifarnib (RI15777) and lonafarnib (SCH66336)), inhibitors of cell signaling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, P13 kinase inhibitors, Plt3 kinase inhibitors, CSF-IR kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors;

[1224] (v) anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin) TM) and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034) and 4-{4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00 / 47212), such as those disclosed in International Patent Applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compounds acting by other mechanisms (e.g., linomide, inhibitors of integrin av-3 function and angiostatin));

[1225] (vi) Vascular damaging agents such as Compretin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[1226] (vii) endothelin receptor antagonists, for example, zibotentan (ZD4054) or atrasentan;

[1227] (viii) antisense therapies, e.g., those directed against the targets listed above, such as ISIS2503 (an anti-ras antisense agent);

[1228] (ix) gene therapy approaches, including, for example, approaches that replace abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2), GDEPT (gene-directed enzyme prodrug therapy) approaches (such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase), and approaches that enhance a subject's tolerance to chemotherapy or radiation therapy (such as multidrug resistance gene therapy); and

[1229] (x) Immunotherapy methods, including, for example, ex vivo and in vivo methods for enhancing the immunogenicity of tumor cells in a subject, such as transfection with cytokines (such as interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor), methods for reducing T cell anergy, methods using transfected immune cells (such as cytokine-transfected dendritic cells), methods using cytokine-transfected tumor cell lines, and methods using anti-idiotypic antibodies.

[1230] In certain embodiments, at least one chemical entity is administered in combination with one or more agents selected from the group consisting of paclitaxel, bortezomib, dacarbazine, gemcitabine, trastuzumab, bevacizumab, capecitabine, docetaxel, erlotinib, aromatase inhibitors such as, TM (exemestane)) and estrogen receptor inhibitors (such as FASLODEX TM (fulvestrant)).

[1231] When administering the chemical entities described herein to human subjects, the daily dosage will generally be determined by the prescribing physician, with the dosage generally varying according to the age, weight, and response of the individual subject and the severity of the subject's symptoms.

[1232] In one exemplary application, an appropriate amount of at least one chemical entity is administered to a mammal undergoing cancer (e.g., breast cancer) treatment. Typically, an amount of about 0.01 mg / kg body weight to about 100 mg / kg body weight per day (administered in a single dose or in separate doses) is administered, such as at least about 0.1 mg / kg body weight per day. A specific therapeutic dose may include, for example, a chemical entity from about 0.01 mg to about 1000 mg, such as, for example, from about 1 mg to 1000 mg. In a unit dose formulation, the amount of at least one chemical entity may vary or be adjusted from about 0.1 mg to 1000 mg, such as from about 1 mg to 300 mg, for example, between 10 mg and 200 mg, depending on the specific application. The amount administered will be based on the specific IC of the at least one chemical entity used. 50 The values ​​and the judgment of the attending clinician will vary considering factors such as health, weight and age. In combination applications where at least one chemical entity described herein is not the sole active ingredient, it is possible to administer smaller amounts of at least one chemical entity and still have a therapeutic or prophylactic effect.

[1233] In some embodiments, the pharmaceutical preparation is in unit dosage form. In such dosage form, the preparation is subdivided into unit doses containing appropriate quantities (e.g., an effective amount to achieve the desired purpose) of the active ingredient.

[1234] The actual dosage employed may vary depending on the needs of the subject and the severity of the condition being treated. Determination of the appropriate dosage for a particular situation is within the skill of the art. Typically, treatment is initiated with a smaller dose that is less than the optimal dose of at least one chemical entity. Thereafter, the dose is increased in small amounts until the optimal effect for the situation is achieved. For convenience, the total daily dose may be divided and administered in portions over the day, if desired.

[1235] The amount and frequency of administration of the at least one chemical entity described herein, and if applicable, other chemotherapeutic agents and / or radiation therapy, will be adjusted according to the judgment of the attending clinician (physician), taking into account factors such as the age, condition, and size of the subject and the severity of the disease being treated.

[1236] Chemotherapeutic agents and / or radiotherapy can be administered according to treatment regimens well known in the art. It will be apparent to those skilled in the art that the administration of chemotherapeutic agents and / or radiotherapy can vary depending on the disease being treated and the known effects of the chemotherapeutic agent and / or radiotherapy on the disease. In addition, according to the knowledge of a skilled clinician, treatment regimens (e.g., dosage and number of administrations) can vary in view of the observed effects of the administered therapeutic agent (i.e., antitumor agent or radiation) on the subject and in view of the observed response of the disease to the administered therapeutic agent.

[1237] Moreover, generally at least one chemical entity described herein need not be administered in the same pharmaceutical composition as the chemotherapeutic agent and, due to different physical and chemical properties, may be administered by different routes. For example, the chemical entity / composition may be administered orally to produce and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the desirability of administration (where possible, in the same pharmaceutical composition) is well within the knowledge of a skilled clinician. Initial administration may be performed according to established protocols known in the art, followed by adjustment of dosage, mode of administration, and number of administrations by a skilled clinician based on the observed effects.

[1238] The particular choice of chemical entity (and, where appropriate, chemotherapeutic agent and / or radiation) will depend on the diagnosis of the attending physician and their judgment of the subject's condition and the appropriate treatment regimen.

[1239] The chemical entities described herein (and, where appropriate, the chemotherapeutic agent and / or radiation) may be administered concurrently (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially, depending on the nature of the proliferative disease, the condition of the subject, and the actual choice of chemotherapeutic agent and / or radiation to be administered in combination with the chemical entity / composition (i.e., within a single treatment regimen).

[1240] In combined applications and uses, the chemical entity / composition and the chemotherapeutic agent and / or radiation need not be administered simultaneously or substantially simultaneously, and the order in which the chemical entity / composition and the chemotherapeutic agent and / or radiation are initially administered may not be important. Thus, at least one chemical entity described herein may be administered first, followed by the chemotherapeutic agent and / or radiation; or the chemotherapeutic agent and / or radiation may be administered first, followed by the at least one chemical entity described herein. This alternating administration may be repeated during a single treatment regimen. Determination of the order of administration and the number of repeated administrations of each therapeutic agent during a treatment regimen is well within the knowledge of the skilled physician, after evaluating the disease being treated and the condition of the subject. For example, the chemotherapeutic agent and / or radiation may be administered first, followed by the continued treatment by administering at least one chemical entity described herein, followed by the administration of the chemotherapeutic agent and / or radiation (if determined to be beneficial), and so on until the treatment regimen is complete.

[1241] Thus, based on experience and knowledge, the practicing physician will be able to adjust the various administration regimens of the chemical entities / compositions used in treatment to the needs of the individual subject as treatment progresses.

[1242] The attending clinician will consider the subject's overall health and more specific physical signs, such as alleviation of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis, when judging whether treatment is effective at the administered dose. The size of the tumor can be measured by standard methods such as radiological studies (e.g., CAT or MRI scans), and serial measurements can be used to judge whether tumor growth has been delayed or even reversed. Relief of disease-related symptoms (such as pain) and improvement in overall condition can also be used to help judge the effectiveness of treatment.

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[1290] Example

[1291] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[1292] Example 1A: Materials and Methods.

[1293] Materials. All methods were performed according to the guidelines and regulations of The University of Texas MD Anderson Cancer Center. RX108 was provided by NeuPharma. + / K + -ATPase (isolated from pig cerebral cortex) was purchased from Sigma-Aldrich. + / K + The ATPase assay kit was purchased from Genmed Scientifics. Anti-ASCT2, anti-Ki67, and anti-cleaved caspase 3 antibodies were purchased from Cell Signaling Technology. GSH, NADH, and NADPH assay kits were purchased from Promega. E-actin, anti-GAPDH antibody, NADH, NADPH, and all other reagents were purchased from Sigma-Aldrich.

[1294] Cell culture. HepB3, Huh7, and PLC / RF5 cells were obtained from ATCC and maintained at 37°C in a humidified atmosphere containing 5% CO2. Hep3B and Huh7 cells were routinely cultured in Dulbecco's modified Eagle's medium (DMEM) / F12 medium. PLC / RF5 cells were cultured in minimum essential medium. All media were supplemented with 10% heat-inactivated fetal bovine serum (Hyclone Laboratories), penicillin (10 IU / mL; Invitrogen / Thermo Fisher Scientific) and streptomycin (10 μg / mL; Invitrogen / Thermo Fisher Scientific), L-glutamine (2 mM; Gibco), sodium pyruvate (1 mM; Gibco), minimum essential medium nonessential amino acids (1%; Gibco), and antibiotics (1% antibiotics: 10,000 U / mL penicillin, 10,000 μg / mL streptomycin, and 25 μg / mL amphotericin B; Gibco).

[1295] Cell proliferation. HCC cells (1×10 4 ) were plated in 96-well plates. After 24 hours of incubation, cells were treated with various concentrations of RX108. Inhibition of cell proliferation was assessed using the MTT assay (Yang et al., 2019) for an additional 72 hours. Absorbance was read using a Vmax microplate reader (Molecular Devices) at a wavelength of 570 nm and a reference wavelength of 650 nm.

[1296] Animal studies. All animal experiments were approved by the University of Texas MD Anderson Cancer Center Animal Care and Use Committee. Six-week-old female BALB / c athymic (Nu / Nu) mice were purchased from the Department of Experimental Radiation Oncology at MD Anderson and acclimated to the institutional animal care facility for 1 week. Mice were injected subcutaneously with Huh7 cells (5 × 10 6Each group of mice was treated with 100% RX108 (n = 8 / mouse) and placed in one of three treatment groups (n = 8 / group): control, 2 mg / kg RX108, and 4 mg / kg RX108. Starting the day after tumor cell inoculation, mice in each group were given subcutaneous injections of the study agent twice a week. The tumor uptake rate was 100%. Tumor growth was then measured for 3 weeks. The length and width of the tumors (in millimeters) were measured twice a week using a caliper. The formula (L×W 2 ) × 0.5, where L and W represent length and width, respectively. At the end of the experiment, mice were sacrificed, and their tumors were dissected and weighed. Tumor tissues were then fixed with formalin or snap-frozen for use in related experiments.

[1297] Cell apoptosis was detected by Annexin V-FITC / PI double staining. For apoptosis analysis, Hep3B cells (2.5×10 6 Cells were treated with RX108 (0, 3, and 30 ng / mL) for 48 hours. The cells were trypsinized and centrifuged, and the pellet was suspended in 1× phosphate-buffered saline (PBS) and washed therein. The cells were then double-stained with fluorescein isothiocyanate-conjugated annexin V and PI according to the manufacturer's instructions (BD Biosciences). Fluorescence was detected using a BD FACS Calibur flow cytometer and analyzed using CellQuest Pro software (BD Biosciences).

[1298] Glutamine-dependent cell growth assay. Hep3B, Huh7, and PLC-RF5 cells were cultured at 2×10 3 Cells / well were plated in 96-well flat-bottom plates and cultured in DMEM containing 10% fetal bovine serum or minimal essential medium containing high glucose in the presence of 0, 0.2, or 2 mM glutamine. After incubation at 37°C for 24, 48, 72, and 96 h, viable cells were detected using the CellTiter-Glo luminescent cell viability assay (Promega) according to the manufacturer's instructions.

[1299] Metabolic analysis using LC-MS / MS. Huh7 and Hep3B cells were cultured at 2 × 10 6Cells / mL were cultured in high-glucose DMEM supplemented with 10% fetal bovine serum and 2 mM glutamine. After incubation at 37°C for 24 hours, RX108 at its IC25 and IC50 levels or vehicle was added to the cells and incubated for 24 hours. The cells were then trypsinized, washed twice with PBS, and subjected to LC-MS / MS using a modified version of a previously described method (Chuang et al., 2009). Briefly, cells for analysis of citrate, isocitrate, 2HG, D-KG, malate, and fumarate were mixed with methanol / water (80:20), while cells for analysis of lactate, glutamine, and glutamate were extracted with acetonitrile / water (50:50). Glutamine and tricarboxylic acid (TCA) cycle metabolites were determined using an Agilent 1200 HPLC system coupled to an Agilent 6460 Triple Quad MS detector. Citrate, isocitrate, 2HG, D-KG, malate and fumarate were separated on a Phenomenex Synergi Hydro-RP column (2.5 μm, 2 × 50 mm) using 2HG-d3 as an internal standard. The mobile phase consisted of an aqueous solution of 0.1% formic acid and was delivered at a flow rate of 0.2 mL / min. Lactate, pyruvate, glutamine and glutamate were separated on an Agilent XDB-C18 column (5 μm, 4.6 × 150.0 mm) using 2HG-d3 as an internal standard. Mobile phase A consisted of an aqueous solution of 0.1% formic acid, and mobile phase B consisted of an acetonitrile solution of 0.1% formic acid. Lactate, pyruvate, glutamine, and glutamate were eluted using the following gradient: starting at 5% B at 0 min, holding for 1 min; changing to 10% B at 6 min, holding for 1 min; changing to 90% B at 7.1 min, holding until 12 min; and then changing back to 5% B at 12.1 min. All metabolites were detected using negative electrospray ionization and multiple reaction monitoring of transition ions of the metabolites and their internal standards. The MRM transitions for the above metabolites are m / z 89-43 for lactate, m / z 87-43 for pyruvate, m / z 146-102 for glutamate, m / z 145-127 for glutamine, m / z 191-111 for citrate, m / z 191-111 for isocitrate, m / z 147-129 for 2HG, m / z 144.9-57.1 for D-KG, 133-115 for malate, 115-71 for fumarate, and 150-132 for 2HG-D3. The results for glucose and glutamine metabolites were normalized according to the amount of protein.

[1300] TCA cycle metabolite analysis using ion chromatography-high resolution MS (IC-MS). To determine the carbon from glucose and glutamine carbon and the nitrogen from glutamine ( 13 C6-glucose and 13 C5-glutamine and 15 N2-glutamine) incorporation into the TCA cycle and intracellular amino acids in HCC cells, extracts were prepared and analyzed using high-resolution MS. Hep3B cells at approximately 80% confluence were seeded in triplicate in 10-cm culture dishes. 13 C5-glutamine and 15 Before incubation in fresh medium supplemented with N2-glutamine for 24 hours, cells were washed with DMEM without glutamine. Cells were quickly washed with ice-cold PBS to remove additional culture medium components. Metabolites were extracted using cold 80 / 20 (v / v) methanol / water. The samples were centrifuged at 17,000g for 5 min at 4°C, and the supernatant was transferred to a clean tube and subsequently evaporated to dryness using nitrogen gas. The samples were reconstituted in deionized water, and 5 μL aliquots were injected into a Thermo Fisher Scientific Dionex ICS-5000+ capillary ion chromatography system containing a Thermo Fisher Scientific IonPac AS11 column (250×2 mm, 4 μm) for TCA cycle metabolite analysis. The ion chromatography flow rate was 360 μl / min (at 30°C), and the gradient conditions were: starting from 1 mM KOH, increasing to 35 mM at 25 min, then increasing to 99 mM at 39 min, and continuing at 99 mM for 10 min. The total run time was 50 min. To aid desolvation and increase sensitivity, methanol was delivered using an external pump and combined with the eluent using a low dead volume mixing tee. Metabolic data were acquired using a Thermo Fisher Scientific Orbitrap Fusion Tribrid mass spectrometer in electrospray ionization-negative mode.

[1301] NADP / NADPH and GSH assays. For NADP / NADPH assays, Hep3B and Huh7 cells (6 × 10 3) were plated in a white 96-well transparent flat-bottom white plate overnight. They were then treated with RX108 (3 and 30 ng / mL) for 4 h. After incubation for 24 h, the cell culture medium was aspirated and 50 μL PBS was added to each well. Cell samples were prepared directly in 96-well plates by adding 50 μL of alkaline solution (0.2 N NaOH, final concentration of 1% DTAB; #D8638, Sigma), with a total of 100 μL per sample. The cell samples were lysed and divided into two 50 μL aliquots. In order to measure the NADP level in the culture medium, 25 μL 0.4 N HCl was added to 50 μL of the cell sample lysed with 0.2 N NaOH and heated at 60 ° C for 15 minutes, followed by incubation at room temperature for 10 min. 25 μL Trizma alkaline solution was added to each well. To measure NADPH levels, cell lysates were heated at 60°C for 15 min and incubated at room temperature for 10 min, and 50 μL of HCl / Trizma alkaline solution was added to each well containing samples treated with alkaline solution. The detection reagent was prepared according to the manufacturer's protocol. The wells were briefly mixed on a platform shaker and incubated at room temperature for 30-60 min. At this point, the total volume per well was 100 μL for NADP and NADPH samples. To perform the NADP / NADPH-Glo assay, 100 μL of NADP / NADPH-Glo detection reagent was added directly to each well. Standard curves for NADP (#N8035, Sigma) and NADPH (#N9910, Sigma) were generated according to the manufacturer's instructions. The standard curve allows luminescence (in RLU) to be converted to NADP+ or NADPH concentration. The net luminescence value was used to generate a standard curve and perform linear regression analysis. The amount of NADP or NADPH was interpolated by comparing the net luminescence value of the experimental sample with the value in the standard curve. Luminescence was read using a Vmax Molecular Probe Plate Reader (Molecular Devices).

[1302] GSH assay was performed using the GSH-Glo kit (#V6611, Promega). Hep3B and Huh7 cells were plated in black 96-well plates (1×10 4Cells were plated at 4 °C for 24 h at 37 °C (400 cells / well). The cells were treated with 3 and 30 ng / mL of RX108 for 24 h. The cell culture medium was then removed and 100 μL of 1×GSH-Glo reagent was added to each well and incubated on a shaker at room temperature for 30 min. 100 μL of reconstituted luciferin detection reagent was added to each well and briefly mixed on a plate shaker. The plate was incubated at room temperature for 15 min. Luminescence was measured using a microplate reader (Molecular Devices). A standard GSH solution (5 mM) was used to generate a standard curve for GSH according to the manufacturer's instructions to facilitate conversion of luminescence (in relative light units) to GSH concentration.

[1303] Mitochondrial metabolism. Huh7 cells were plated (approximately 8000 cells / well) in XF96 well plates (Seahorse Bioscience, Massachusetts, USA) and treated with vehicle and RX108 (3 and 30 ng / ml) for 24 h. Immediately before the respiratory assay, the culture medium was replaced with unbuffered DMEM containing glucose (10 mM), pyruvate (10 mM) and GlutaMAX (2 mM; Invitrogen). Mitochondrial respiration oxygen consumption rate (OCR) was measured by Seahorse Extracellular Flux Analyzer XF96 (Seahorse Bioscience) according to the manufacturer's instructions. First, basal respiration was measured in unbuffered culture medium. Oligomycin (2 μg / ml) was then added to inhibit ATP synthesis and detect respiration associated with ATP production. The uncoupling agent carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP, 2 μM) was used to measure respiratory reserve capacity and maximum respiration. Finally, a combination of rotenone and antimycin A (rot & AA, 4 μM) was added to inhibit complexes III and I in order to completely block mitochondrial oxygen consumption. The plate was read by a Seahorse XFe96 analyzer (Seahorse Bioscience). Data were calculated and generated by the Seahorse XFMito stress assay report generator.

[1304] Immunoblotting. Cellular protein samples were extracted using sodium dodecyl sulfate buffer. Total protein (25 μg / well) was separated on a 10-15% sodium dodecyl sulfate gel and transferred to a polyvinylidene difluoride membrane. The membrane was blocked with 5% skim milk in Tris-buffered saline solution and then probed with primary antibodies overnight at 4°C. The membrane was visualized using SuperSignal substrate (Pierce ECL Plus; Thermo Fisher Scientific). E-actin or GAPDH was detected to normalize the results.

[1305] siRNA transfection. Hep3B cells were plated in six-well plates and allowed to adhere overnight. Nonspecific siRNA (control siRNA) and ASCT2 siRNA (Origene Technologies) were transiently transfected into the cells using Lipofectamine RNAiMAX reagent (Thermo Fisher Scientific) according to the manufacturer's instructions. Starting 48 hours after transfection, cells were treated with vehicle control or RX108 for 24 hours. Protein was collected for Western blot analysis.

[1306] Histopathology and Immunohistochemistry. Formalin-fixed tumor samples were waxed for biomarker identification using immunohistochemical staining. For this staining, the slides were baked at 60°C for more than 2 hours, then dewaxed and rehydrated. Antigens were exposed via heat-induced antigen retrieval. The slides were then immersed in a 3% H2O2-methanol solution and subsequently blocked with 5% goat serum in 0.3% Triton X-100 PBS. The slides were stained with antibodies against ASCT2, cleaved caspase 3, or Ki67 at 4°C in a humidified chamber overnight. The slides were then washed three times with PBS and incubated with secondary antibodies for 45 minutes at room temperature. Slides were incubated with avidin-biotin complex (Vector Laboratories), followed by incubation with 3,3′-diaminobenzidine substrate to visualize the antibodies, counterstained with Mayer's hematoxylin, dehydrated, and mounted using Clear Mount mounting medium (American Master Tech; Al-Hassan et al., 2021).

[1307] Statistical analysis. Student's t-test was used to determine the significance of differences between the control and treatment groups. P values ​​of up to 0.05 were considered significant. One-way ANOVA was used to determine significant differences in the mean values ​​of more than two groups. All analyses were performed using Prism software (version 9.0; GraphPad software).

[1308] Example 1B: Results.

[1309] To Na + / K + The inhibitory activity of RX108 (chemical structure in Figure 1A) on Na-ATPase was measured using an enzyme-linked assay. + / K + -ATPase (isolated from porcine cerebral cortex). RX108 showed inhibitory activity against Na + / K +1B), and its potency (IC50, 25.7 nM) was greater than that of ouabain (IC50, 232.5 nM), a known Na + / K + -ATPase inhibitors.

[1310] Antiproliferative effects on HCC cells and in xenograft models. To determine the sensitivity of HCC cells to RX108, human HCC Huh7 and Hep3B cells were treated with different doses of RX108 at different time points, while immortalized human liver LO2 cells were used as control cells. As shown in Figure 1C, RX108 exposure significantly inhibited the growth of Huh7 and Hep3B cells in a time- and dose-dependent manner, with median inhibitory concentrations (IC50) in Huh7 cells greater than 100.0, 2.2, and 0.8 ng / ml when administered for 24, 48, and 72 hours, respectively, and median inhibitory concentrations (IC50) in Hep3B cells greater than 100.0, 3.4, and 0.8 ng / ml (Figure 1C1 & Figure 1C2). In contrast, treatment with 3.2 ng / mL of RX108 for 72 h slowed the growth of LO2 cells by 54.5%, but even at concentrations as high as 100 ng / ml, the inhibition rate of cell growth remained at a similar level (Figure 1C3). To further evaluate the anti-tumor effect of RX108 on HCC, anti-tumor efficacy studies were performed using a human Huh7 cell HCC mouse xenograft model. RX108 (4 mg / kg) exposure significantly inhibited tumor growth in a dose-dependent manner, as shown by reduced tumor volume and weight (Figure 1D1 & Figure 1D2).

[1311] Induction of apoptosis in HCC cells. To examine the potential mechanism by which RX108 inhibits the growth of Hep3B cells, Annexin V staining was performed, and these cells were subsequently subjected to flow cytometric analysis. Treatment with RX108 dose-dependently induced apoptosis and necrosis in Hep3B cells, as shown by 1.59% ± 0.58%, 2.98% ± 1.10%, and 5.50% ± 1.43% propidium iodide (PI)- / Annexin V expression levels after treatment with 0, 3, and 30 ng / ml of RX108, respectively. + The percentage of cells, and 6.40% ± 1.36%, 9.13% ± 1.06% and 16.82% ± 2.39% of PI+ / Annexin V + Representative flow cytometry chromatograms of Hep3B cells treated with different doses of RX108 are shown in Figure 2B.

[1312] Effect of RX108 on HCC cell metabolism. To further...

Claims

1. A method for treating or preventing cancer associated with elevated ASCT2 expression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Na + / K + -ATPase (NKA) inhibitors.

2. A method of treating a cancer associated with dysregulated glutamine metabolism in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.

3. A method of stabilizing or reducing the volume of a solid tumor in a cancer associated with elevated ASCT2 expression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.

4. A method of reducing the volume of a solid tumor in a cancer associated with elevated ASCT2 expression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an NKA inhibitor. The method of claim 4 , wherein the volume is reduced by at least 25%.

6. A method according to claim 4 or claim 5, wherein the volume is reduced by at least 50%.

7. A method of modulating the concentration of one or more biomarkers of cancer associated with elevated ASCT2 expression in a cell, comprising contacting the cell with an NKA inhibitor.

8. The method of claim 7, wherein modulation results in a decrease in the concentration of the one or more biomarkers.

9. The method of claim 7 or claim 8, wherein the modulation reduces the concentration of the one or more biomarkers by at least 25%.

10. The method of any one of claims 7-9, wherein the modulation reduces the concentration of the one or more biomarkers by at least 50%.

11. The method of any one of claims 7-10, wherein modulation increases the concentration of the one or more biomarkers.

12. The method of any one of claims 7-11, wherein the one or more biomarkers are selected from the group consisting of: glutamine, glutamate, α-ketoglutarate (α-KG), 2-hydroxyglutarate (2HG), glutathione (GSH), malate, pyruvate, lactate, and fumarate.

13. The method of any one of claims 7-12, wherein the modulation results in a decrease in the concentration of the one or more biomarkers selected from the group consisting of glutamine, glutamate, α-ketoglutarate (α-KG), 2-hydroxyglutarate (2HG), glutathione (GSH), malate, pyruvate, and lactate.

14. The method of any one of claims 7 to 13, wherein the adjustment results in an increased concentration of fumarate.

15. The method of any one of claims 7-14, wherein the level of NADH or NADPH is reduced by at least 50%.

16. A method for inhibiting ASCT2 protein expression in a cell, comprising contacting the cell with an NKA inhibitor.

17. A method of reducing the proliferation rate of cancer cells comprising contacting the cells with an NKA inhibitor, wherein the cancer is associated with elevated ASCT2 expression.

18. The method of claim 17, wherein the proliferation rate is reduced by at least 10%.

19. The method of claim 17 or claim 18, wherein the proliferation rate is reduced by at least 30%.

20. The method of any one of claims 7-19, wherein the cellular concentration of the NKA inhibitor is from about 0.1 ng / mL to about 100 ng / mL.

21. The method of any one of claims 7-20, wherein the cellular concentration of the NKA inhibitor is from about 1 ng / mL to about 50 ng / mL.

22. The method of any one of claims 7-21, wherein the cellular concentration of the NKA inhibitor is about 3 ng / ml.

23. The method of any one of claims 7-21, wherein the cellular concentration of the NKA inhibitor is about 30 ng / ml.

24. The method of any one of claims 1-23, wherein the cancer is of the bile duct, bladder, brain, breast, cervix, colon, esophagus, kidney, liver, lung, lymph node, oral cavity, ovary, pancreas, prostate, rectum, skin, stomach, throat, thymus, thyroid, or uterus.

25. The method of any one of claims 1-24, wherein the cancer is bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), bile duct carcinoma (CHOL), colon adenocarcinoma (COAD), lymphoid tumor diffuse large B-cell lymphoma (DLBC), esophageal cancer (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), brain low-grade glioma (LGG), liver hepatocellular carcinoma (LIHC / HCC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectal adenocarcinoma (READ), sarcoma (SARC), cutaneous melanoma (SKCM), gastric adenocarcinoma (STAD), thyroid cancer (THCA), thymoma (THYM), uterine corpus endometrial carcinoma (UCEC), or uterine carcinosarcoma (UCS).

26. The method of any one of claims 1-25, wherein the cancer is a cancer of the bile duct, brain, liver, oral cavity, or throat.

27. The method of any one of claims 1-26, wherein the cancer is cancer of the bile duct.

28. The method of any one of claims 1-27, wherein the cancer is cholangiocarcinoma (CHOL).

29. The method of any one of claims 1-26, wherein the cancer is a cancer of the brain.

30. The method of any one of claims 1-26 and 29, wherein the cancer is glioblastoma multiforme (GBM).

31. The method of any one of claims 1-26, wherein the cancer is a cancer of the brain.

32. The method of any one of claims 1-26 and 29, wherein the cancer is glioblastoma multiforme (GBM).

33. The method of any one of claims 1-26, wherein the cancer is cancer of the liver.

34. The method of any one of claims 1-26 and 33, wherein the cancer is liver hepatocellular carcinoma (LIHC / HCC).

35. The method of any one of claims 1-26, wherein the cancer is a cancer of the oral cavity or throat.

36. The method of any one of claims 1-26 and 35, wherein the cancer is head and neck squamous cell carcinoma (HNSC).

37. The method of any one of claims 1-36, wherein the NKA inhibitor is a bufadienolide derivative or a pharmaceutically acceptable salt thereof.

38. The method of any one of claims 1-37, wherein the NKA inhibitor is a compound of formula (I): in: Each dashed bond independently represents a single or double bond; n, p and q are independently selected from 0 and 1; and R1, R2, R3, R4, R5, R6, R9, R 10 、R 11 and R 12 is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); or R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 13 is selected from hydrogen, optionally substituted alkyl and formyl; L1 is selected from a covalent bond, * -C(O)O-, * -[C(R a )(R b )] s -O- and * -[C(R a )(R b )] s -C(O)O-, wherein * represents the point of attachment of L1 to Z, further wherein: R a and R b is independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R a and R b together with any intervening atoms to form an optionally substituted cycloalkyl ring or an optionally substituted heterocycloalkyl ring; or R 15 and R appears once a taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; Z is selected from -OR 14 and -NR 15 R 16 ,in: R 14 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkoxycarbonyl and - P(=O)(OR 17 )(OR 18 ), wherein: R 17 and R 18 are independently selected from hydrogen and optionally substituted alkyl; and R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 16 is selected from hydrogen, hydroxy, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, -COR 19 、-CO2R 19 、-CONR 20 R 21 、-C(NR 22 )NR 20 R 21 、-C(NCN)NR 20 R 21 、-SO2R 19 and -SO2NR 20 R 21 , where R 19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 20 、R 21 and R 22 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 20 and R 21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or R 15 and R 16 taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; W1 is selected from the following: in: m is selected from 0, 1, 2 and 3; Y is selected from O and NR 24 ; R 23 is selected from cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl; R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.

39. The method of any one of claims 1-38, wherein the NKA inhibitor is a compound of formula (IA): in: Each dashed bond independently represents a single or double bond; n, p, and q are independently selected from 0 and 1; and R1, R2, R3, R4, R5, R6, R9, R 10 、R 11 and R 12 is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); or R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 13 is selected from hydrogen, optionally substituted alkyl and formyl; L1 is selected from a covalent bond, * -C(O)O-, * -[C(R a )(R b )] s -O- and * -[C(R a )(R b )] s -C(O)O-, wherein * represents the point of attachment of L1 to Z, further wherein: R a and R b is independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R a and R b together with any intervening atoms to form an optionally substituted cycloalkyl ring or an optionally substituted heterocycloalkyl ring; or R 15 and R appears once a taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; Z is selected from -OR 14 and -NR 15 R 16 ,in: R 14 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkoxycarbonyl and - P(=O)(OR 17 )(OR 18 ), wherein: R 17 and R 18 are independently selected from hydrogen and optionally substituted alkyl; R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 16 is selected from hydrogen, hydroxy, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, -COR 19 、-CO2R 19 、-CONR 20 R 21 、-C(NR 22 )NR 20 R 21 、-C(NCN)NR 20 R 21 、-SO2R 19 and -SO2NR 20 R 21 , where R 19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 20 、R 21 and R 22 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 20 and R 21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or R 15 and R 16 taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; W1 is selected from the following: in: m is selected from 0, 1, 2 and 3; Y is selected from O and NR 24 ; R 23 is selected from cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl; R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.

40. The method of any one of claims 1-39, wherein the NKA inhibitor is a compound of formula (II): in: Each dashed line represents a single or double bond; n, p and q are each independently selected from 0 and 1; and R1, R2, R3, R4, R5, R6, R9, R 10 、R 11 and R 12 is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); or R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 13 is selected from hydrogen, optionally substituted alkyl and formyl; R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and and R 16 is selected from hydrogen, hydroxy, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, -COR 19 、-CO2R 19 、-CONR 20 R 21 、-C(NR 22 )NR 20 R 21 、-C(NCN)NR 20 R 21 、-SO2R 19 and -SO2NR 20 R 21 , where R 19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 20 、R 21 and R 22 R is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or 20 and R 21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; W1 is selected from the following: in: m is selected from 0, 1, 2 and 3; wherein Y is selected from O and NR 24 ; R 23 is selected from cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl; R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.

41. The method of any one of claims 1-40, wherein the NKA inhibitor is a compound of formula (II-A): in: R1, R2, R3, R4, R5, R6, R9, R 10 、R 11 and R 12 is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); or R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 13 is selected from hydrogen, optionally substituted alkyl and formyl; R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 16 Yes-CONR 20 R 21 , where R 20 and R 21 are joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; W1 is selected from the following: in: m is selected from 0, 1, 2 and 3; Y is selected from O and NR 24 ; R 23 is selected from the group consisting of cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl; and R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.

42. The method of any one of claims 1-39, wherein the NKA inhibitor is a compound of formula (III): in: Dashed lines represent single or double bonds; n is selected from 0 and 1; R1, R2, R3, R5, R6, R9, R 10 、R 11 and R 12 is independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or R1 and R2, or R5 and R6, or R7 and R8, or R9 and R 10 , or R 11 and R 12 independently of one another and in each case together represent an oxo group (=O); R4 is hydroxy, or R4 and R5 may be optionally joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 13 is selected from hydrogen, optionally substituted alkyl and formyl; Z is selected from OR 14 and NR 15 R 16 ; in: R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 16 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 15 and R 16 may be optionally joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; W1 is selected from the following: in: m is selected from 0, 1, 2 and 3; Y is selected from O and NR 24 ; R 23 is selected from cyano, halo, hydroxy, azido, nitro, carboxyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted amidino, and optionally substituted alkynyl; R 24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.

43. The method of any one of claims 1-39 and 42, wherein the NKA inhibitor is a compound of formula (III), or a pharmaceutically acceptable salt thereof, with the proviso that when R4 is OH, R 13 is methyl, W1 is (2-oxo-2H-pyran-5-yl), and R1, R2, R3, R5, R6, R7, R8, R9, R 10 、R 11 and W2 is hydrogen, then R 12 Not hydrogen.

44. The method of any one of claims 1-39, 42, and 43, wherein the NKA inhibitor is a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein: Dashed lines represent single or double bonds; n is selected from 0 and 1; R1, R2, R6, R8, R 10 、R 11 、R 12 and W2 is hydrogen; R3 and R9 are independently hydrogen or OH; R4 is hydroxy and R5 is hydrogen, or R4 and R5 may be optionally joined together with any intervening atoms to form an oxirane ring; R7 is -OCOCH3; R 13 It is a methyl group; Z is NR 15 R 16 ,in: R 15 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; R 16 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; or R 15 and R 16 together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; and W1 is selected from:

45. The method of any one of claims 1-39 and 42-44, wherein the NKA inhibitor is a compound of formula (III), or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not a compound of formula III wherein: R4 is OH, R 13 is methyl, W1 is (2-oxo-2H-pyran-5-yl), and R1, R2, R3, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 and W2 is hydrogen.

46. ​​The method of any one of claims 1-39, wherein the NKA inhibitor is: (a) Compounds of formula (IV-A): in: Z is selected from OR 14 and NR 15 R 16 ,in: R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 16 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 15 and R 16 may be optionally joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; (b) Compounds of formula (IV-B): in: R 15 and R 16 R1 and R2 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R1 and R2 may be optionally joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; R a and R b is independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R a and R b together with any intervening atoms to form an optionally substituted cycloalkyl ring or an optionally substituted heterocycloalkyl ring; or R 15 and R appears once a taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; and s is selected from 1, 2, 3, 4, 5 and 6; or (c) Compounds of formula (IV-C): in: R a is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkoxycarbonyl, and -P(=O)(OR7)(OR8), wherein R7 and R8 are independently selected from hydrogen and optionally substituted alkyl; or a pharmaceutically acceptable salt of a compound of any of these formulae.

47. The method of any one of claims 1-39 and 46, wherein the NKA inhibitor is a compound of formula (IV-A) or a pharmaceutically acceptable salt thereof.

48. The method of any one of claims 1-39, 46, and 47, wherein the NKA inhibitor is a compound of formula (IV-B) or a pharmaceutically acceptable salt thereof.

49. The method of any one of claims 1-39 and 46, wherein the NKA inhibitor is a compound of formula (IV-C) or a pharmaceutically acceptable salt thereof.

50. The method of any one of claims 1-49, wherein the NKA inhibitor is a compound selected from the group consisting of: 2-Aminoethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Hydroxyethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-((R)-3-hydroxypyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate; 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-hydroxyethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide; (S)-3-Hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; (R)-3-hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)acetamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(pyrrolidin-1-yl)acetamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-morpholinoacetamide; (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide; (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide; (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide; (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide; (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide; (S)-2-amino-N1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)amino)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)amino)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)amino)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-morpholinoethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methylpiperazine-1-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; 4-(3-((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)ureido)butanoic acid; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(piperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(1,4-diazepane-1-carboxamido)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-1,4-diazepan-1-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-oxopiperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(2-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; 2-Aminoethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-(Pyrrolidin-1-yl)ethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Morpholinoethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate; 2-(3-oxopiperazin-1-yl)ethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 1-(2-aminoethyl)-3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepane-1-carboxamide; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide; (S)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-3-amino-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; (R)-3-amino-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 2-(Pyrrolidin-1-yl)ethyl ((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Morpholinoethyl ((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate; 2-(3-oxopiperazin-1-yl)ethyl ((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-4-methyl-1,4-diazepan-1-carboxamide; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide; (S)-3-Hydroxy-N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; (R)-3-Hydroxy-N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 2-(Pyrrolidin-1-yl)ethyl ((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)carbamate; 2-Morpholinoethyl ((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)carbamate; 2-(3-oxopiperazin-1-yl)ethyl ((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)carbamate; 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-methylurea; 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-morpholinoethyl)urea; N-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-4-methylpiperazine-1-carboxamide; 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea; N-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-4-methyl-1,4-diazepan-1-carboxamide; N-((1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)morpholine-4-carboxamide; 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)amino)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiranyl 2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)amino)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)amino)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-morpholinoethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(4-methylpiperazine-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(morpholine-4-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(4-methyl-1,4-diazepan-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-oxopiperazine-1-carboxamido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)amino)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)amino)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)amino)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-morpholinoethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(4-methylpiperazine-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(morpholine-4-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(4-methyl-1,4-diazepan-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-oxopiperazine-1-carboxamido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; 2-Aminoethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Hydroxyethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-hydroxyethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide; (S)-3-Hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; (R)-3-hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)acetamide; (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide; (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide; (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide; (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide; (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide; (S)-2-Amino-N1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide; 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Morpholinoethyl ((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea; N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide 4-(3-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide; N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)amino)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)amino)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)amino)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-morpholinoethyl)ureido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(piperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(piperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; 4-(3-((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methylpiperazine-1-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(1,4-diazepane-1-carboxamido)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-1,4-diazepan-1-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(2-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate; 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid N-((5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetrahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-(pyrrolidin-1-yl)acetamide; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-morpholinoacetamide; (R)-2-Amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide; (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide; (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide; (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide; (S)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide; 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate; 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-hydroxyethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)acetamide; (2R)-2-amino-N-((3S,5R,8R,9S,10S,13S,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide; (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide; (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide; (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide; (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide, (S)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide; (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-2-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-2-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-3-carboxamide, (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-3-carboxamide; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthrene-16-yl acetate, (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; 4-(((((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoic acid; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5S,8R,9S,10R,13R,14S,16S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(piperazin-1-yl)ethyl)carbamate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; 4-(((((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,8R,9S,10R,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(piperazin-1-yl)ethyl)carbamate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; 4-(((((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl) carbonate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl)carbamate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl)carbamate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate; 4-(((((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate; 4-(((((1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate; 4-(((((1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(piperazin-1-yl)ethyl)carbamate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; 4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(piperazin-1-yl)ethyl)carbamate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; 4-(((((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethyl)carbamoyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(piperazin-1-yl)ethyl)carbamoyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate, 4-(((((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate; 4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl valine; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl alanine; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl leucine; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-(piperidin-1-yl)acetate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-(pyrrolidin-1-yl)acetate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl asparagine; Proline (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl ester; and (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-morpholinoacetate; or a pharmaceutically acceptable salt thereof.

51. The method of any one of claims 1-50, wherein the NKA inhibitor is a compound selected from the group consisting of: 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-hydroxyethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide; (S)-3-Hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; (R)-3-hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-morpholinoethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methylpiperazine-1-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; 4-(3-((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)ureido)butanoic acid; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(piperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(1,4-diazepane-1-carboxamido)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-1,4-diazepan-1-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-oxopiperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(2-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; 1-(2-aminoethyl)-3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepane-1-carboxamide; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide; N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide; (S)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-3-amino-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; (R)-3-amino-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-4-methyl-1,4-diazepan-1-carboxamide; N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide; (S)-3-Hydroxy-N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; (R)-3-Hydroxy-N-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-methylurea; 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-morpholinoethyl)urea; N-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-4-methylpiperazine-1-carboxamide; 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea; N-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-4-methyl-1,4-diazepan-1-carboxamide; N-((1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)morpholine-4-carboxamide; 1-((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-morpholinoethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(4-methylpiperazine-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(morpholine-4-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(4-methyl-1,4-diazepan-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-oxopiperazine-1-carboxamido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-morpholinoethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(4-methylpiperazine-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-(4-methylpiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(morpholine-4-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(4-methyl-1,4-diazepan-1-carboxamido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-oxopiperazine-1-carboxamido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)ureido)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-hydroxyethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-oxopiperazine-1-carboxamide; (S)-3-Hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; (R)-3-hydroxy-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)pyrrolidine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea; N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide; N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methyl-1,4-diazepan-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(pyrrolidin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-morpholinoethyl)ureido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(piperazine-1-carboxamido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(piperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; 4-(3-((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methylpiperazine-1-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(1,4-diazepane-1-carboxamido)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-1,4-diazepan-1-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(2-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(3-(2-(3-oxopiperazin-1-yl)ethyl)ureido)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)ureido)butanoic acid; N-((5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-1,4-diazepan-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; 1-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-hydroxyethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(pyrrolidin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-morpholinoethyl)urea; N-((5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(hydroxymethyl)piperazine-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-2-(hydroxymethyl)piperazine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-1-yl)ethyl)urea; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)morpholine-4-carboxamide; 4-(3-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)ureido)butanoic acid; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-4-methylpiperazine-1-carboxamide; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-1,4-diazepan-1-carboxamide; (S)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-hydroxypyrrolidine-1-carboxamide; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(2-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)urea; 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)urea; and 1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)urea; or a pharmaceutically acceptable salt thereof.

52. The method of any one of claims 1-50, wherein the NKA inhibitor is a compound selected from the group consisting of: 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate; 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetrahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-(pyrrolidin-1-yl)acetamide; N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-morpholinoacetamide; (R)-2-Amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide; (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide; (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide; (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide; (S)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide; 2-(3-oxopiperazin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-(Pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)carbamate; 2-Morpholinoethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate; 2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)acetamide; (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)propanamide; (R)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide; (S)-2-amino-N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)-3-methylbutanamide; (R)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide, (S)-2-amino-N1-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)succinamide; or a pharmaceutically acceptable salt thereof.

53. The method of any one of claims 1-49, wherein the NKA inhibitor is a compound selected from the group consisting of: (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate; (S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-,acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate; (S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; and (R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

54. The method of any one of claims 1-49, wherein the NKA inhibitor is a compound selected from the group consisting of: (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl) carbonate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate, (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl)carbamate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl)carbamate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate; 4-(((((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; 4-(((((1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; and 4-(((((1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid; or a pharmaceutically acceptable salt thereof.

55. The method of any one of claims 1-49, wherein the NKA inhibitor is a compound selected from the group consisting of: (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl) carbonate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(3-oxopiperazin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate, (3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexahydro-1H-cyclopenta[a]phenanthren-16-yl acetate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(pyrrolidin-1-yl)ethyl)carbamate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-morpholinoethyl)carbamate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl (2-(4-methylpiperazin-1-yl)ethyl)carbamate; 4-(((((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; 4-(((((1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-2-yl acetate; and 4-(((((1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl)oxy)carbonyl)amino)butanoic acid; or a pharmaceutically acceptable salt thereof.

56. The method of any one of claims 1-49, wherein the NKA inhibitor is a compound selected from the group consisting of: (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate; (1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate; (1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl 4-methylpiperazine-1-carboxylate; (1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexahydronaphtho[1',2':6,7]indeno[1,7a-b]oxiran-7-yl morpholine-4-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate; (S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate; (3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate; (S)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (R)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (S)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-aminopyrrolidine-1-carboxylate; (R)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-aminopyrrolidine-1-carboxylate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate; (3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate; (S)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (R)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (S)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-aminopyrrolidine-1-carboxylate; (R)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-aminopyrrolidine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate; (S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate; (3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate; (S)-(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (R)-(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methylpiperazine-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 1,4-diazacycloheptane-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-,acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 4-methyl-1,4-diazepane-1-carboxylate; (3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-oxopiperazine-1-carboxylate; (S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; and (R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 3-hydroxypyrrolidine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

57. The method of any one of claims 1-49, wherein the NKA inhibitor is a compound selected from the group consisting of: (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate; 4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

58. The method of any one of claims 1-49, wherein the NKA inhibitor is a compound selected from the group consisting of: (((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)methyl dihydrogen phosphate; (((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)methyl acetate; 1-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)ethyl acetate; (((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)methyl pivalate; Ethyl carbonate ((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)methyl) ester; Ethyl carbonate (1-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)ethyl) ester; or a pharmaceutically acceptable salt thereof.

59. The method of any one of claims 1-49, wherein the NKA inhibitor is a compound selected from the group consisting of: (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-aminopropanoate; (S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-aminopropanoate; (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-amino-3-methylbutanoate; (S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-amino-3-methylbutanoate; (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-amino-4-methylpentanoate; (S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-amino-4-methylpentanoate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl (2-morpholinoethyl)carbamate; (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; 4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)butanoic acid; and (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl morpholine-4-carboxylate; or a pharmaceutically acceptable salt thereof.

60. The method of any one of claims 1-49, wherein the compound is: (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexahydro-1H-cyclopenta[a]phenanthrene-3-yl piperazine-1-carboxylate; or a pharmaceutically acceptable salt thereof.

61. The method of any one of claims 1-38, wherein the NKA inhibitor is a compound selected from digoxin and digitoxin, or a pharmaceutically acceptable salt thereof.

62. The method of any one of claims 1-49, wherein the NKA inhibitor is a compound disclosed in US 2013 / 0005696 or WO 2013 / 000286, or a pharmaceutically acceptable salt thereof.

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