Treatment of asct2-dependent cancers

Abstract

The present disclosure provides methods 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 a Na+ / K+-ATPase (NKA) inhibitor. Additional methods employing Na+ / K+-ATPase (NKA) inhibitors are also provided.

Description

TREATMENT OF ASCT2-DEPENDENT CANCERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims 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.FIELD OF THE INVENTION

[0002] The present disclosure generally relates to the fields of chemistry, biology, and medicine. In particular, the present disclosure describes methods for the treatment of ASCT2-dependent cancers using Na+ / K+-ATPase inhibitors.BACKGROUND

[0003] Cancer can be viewed as a breakdown in the communication between tumor cells and their environment, including their normal neighboring cells. Signals, both growth-stimulatory and growth-inhibitory, are routinely exchanged between cells within a tissue. Normally, cells do not divide in the absence of stimulatory signals, and likewise, will cease dividing in the presence of inhibitory signals. In a cancerous, or neoplastic state, a cell acquires the ability to “override” these signals and to proliferate under conditions in which normal cells would not grow.

[0004] Cardiotonic steroids like digoxin and digitoxin are a class of naturally derived compounds that bind to and inhibit Na+ / K+-ATPase (sodium pump). Members of this family have been used for the treatment of heart failure and arrhythmia for many years. Recent findings 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 effect on the growth of human tumor cells.SUMMARY OF THE INVENTION

[0005] In some aspects, the present disclosure provides methods 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 a Na+ / K+-ATPase (NKA) inhibitor.

[0006] 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.

[0007] In some aspects, the present disclosure provides methods of stabilizing or reducing the volume of a solid tumor of a cancer associated with elevated ASCT2 expression in a patient inneed thereof comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.

[0008] In some aspects, the present disclosure provides methods of reducing the volume of a solid tumor of 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. In some aspects, the present disclosure provides methods of modulating the concentration of one or more biomarkers of a cancer associated with elevated ASCT2 expression in a cell comprising contacting the cell with an NKA inhibitor.

[0009] In some aspects, the present disclosure provides methods of suppressing ASCT2 protein expression in a cell comprising contacting the cell with an NKA inhibitor.In some aspects, the present disclosure provides methods of reducing the rate of proliferation of a cancer cell comprising contacting the cell with an NKA inhibitor, wherein the cancer is associated with elevated ASCT2 expression.

[0010] 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):wherein: each dashed bond independently represents a single bond or a double bond; n, p, and q are independently selected from 0 and 1; andRi, R2, R3, R4, R5, Re, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Re, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0); orR4 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;Li is selected from a covalent bond, *-C(O)O-, *-[C(Ra)(Rb)]s-O-, and *-[C(Ra)(Rb)]s- C(O)O-, wherein * indicates the point of attachment of Li to Z, further wherein: Raand Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; orRaand Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; orR15 and one occurrence of R3 are together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Z is selected from -OR14 and -NR15R16, wherein:R14 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)(ORi7)(ORis), wherein:R17 and Ris are independently selected from hydrogen and optionally substituted alkyl; andRis is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, -CO2R19, -CONR20R21, -C(NR22)NR2oR2i, -C(NCN)NR2oR2i, -SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R20 and R21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; orR15 and Ri6 are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3;Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, 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 carbaminodoyl, 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; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.[OH] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The 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.

[0013] FIG. 1A-1D shows the effect of RX108 on Na+ / K+-ATPase activity and human HCC cell proliferation in vitro and tumorigenesis in a xenograft mouse model. The chemical structure of RX108 (FIG. 1A) and its inhibitory activity against Na+ / K+-ATPase (FIG. IB). The percent suppression of Huh7 (FIG. 1 C 1), Hep3B (FIG. 1C2), and LO2 (FIG. 1C3) cell growth in culture after exposure to different doses of RX108 for different times as indicated. Tumor growth curve (FIG. ID 1 ) and tumor weights (FIG. 1D2) for Huh7 xenografts in nude mice after treatment with different doses of RX108 (n = 10 / group). The data are presented as mean (± SD) values. ** p < 0.01 versus control.

[0014] FIG. 2A & 2B show Annexin V-fluorescein isothiocyanate / PI double staining and flow cytometric analysis of HCC cells treated with RX108. Hep3B cells exposed to different doses of RX108 for 48 h were subjected to Annexin V-fluorescein isothiocyanate / PI double staining followed by flow cytometry. (FIG. 2A) The differences in the percentages of PI7Annexin-V+, PI+ / Annexin- V+, PI+ / Annexin- V, and PI7Annexin-V cells after treated with RX108. (FIG. 2B) Representative histograms of Hep3B cells treated with vehicle control or RX108. The data are presented as mean (± SD) values.

[0015] FIG. 3A & 3B show the effect of RX108 on HCC cell metabolism. Glutamine and TCA cycle metabolite concentrations in Huh7 (FIG. 3 A) and Hep3B (FIG. 3B) cells after exposure todifferent doses of RX108 as measured using LC-MS / MS. The data are presented as mean (± SE) values.

[0016] FIG. 4A-4G show the effect of RX108 on energy metabolism in Hep3B and Huh7 cells. Hep3B cells were treated with RX108 and incubated with a medium containing13Cs- and15N2- glutamine or13Ce-glucose at 37 °C for 24 h. Afterward, cell samples were harvested for ion chromatography -MS analysis. The mass distribution vector for each isotopologue for citrate from glutamine (FIG. 4A) and glucose (FIG. 4B) in the Hep3B cells from two separate experiments. GSH content in Hep3B (FIG. 4C) and Huh7 (FIG. 4D) cells after treatment with RX108 for 2 h in triplicate samples. Cellular NADH (FIG. 4E) and NADPH (FIG. 4F) concentrations in Hep3B cells and Huh7 cells after the cells were treated with RX108 for 2 h. (FIG. 4G) Oxygen Consumption Rate (OCR) levels in Huh7 cells treated with RX108 measured using a Seahorse mitochondrial stress test and normalized to cell number. NP, RX108. The data are presented as mean (± SD) values. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

[0017] FIG. 5A-5D show the effect of ASCT2 on RX-108 elicited antiproliferative activity in HCC cells and overall survival of HCC patients. Western blot analysis (FIG. 5A1) and quantification (FIG. 5A2) of ASCT2 protein expression in Hep3B cells after exposure to RX108 for 48 h. ASCT2 siRNA transfection downregulated ASCT2 protein expression in Hep3B cells (FIG. 5B1 & 5B2) and drastically reduced Hep3B cell growth as determined according to the total cell number or viable cell count (FIG. 5B3 & 5B4). Treatment with RX108 also reduced cell growth, but no additive cell growth-suppression effect was observed in cells subjected to the combination of ASCT2 siRNA transfection and RX108 (FIG. 5B3 & 5B4). HCC cell addiction to glutamine for proliferation: the growth of Huh7 (FIG. 5C1) and Hep3B (FIG. 5C2) cells after treatment with a medium containing 0.2 mM or 2 mM glutamine for 24, 48, 72, and 96 h. The data are presented as mean (± SD) values. *** p < 0.001; **** p < 0.0001 versus control. The survival data of HCC patients were extracted from public available database as indicated (FIG. 5D1, the human protein atlas: https: / / www.proteinatlas.org / ENSG00000105281- SLClA5 / pathology / liver+cancer; cBioPortal for Cancer Genomics: FIG. 5D2, TCGA, PanCancer Atlas, and FIG. 5D3, TCGA liver hepatocellular Carcinoma, with source data from GDAC Firehose).

[0018] FIG. 6A-6D show the effect of RX108 on protein expression and glutamine metabolism in xenograft model. Immunohistochemical analysis of ASCT2 (FIG. 6A1, representative staining image; FIG. 6A2, quantitative staining data), Ki67 (FIG. 6B1, representative staining image; FIG. 6B2, quantitative staining data), and cleaved caspase 3 (FIG. 6C1, representative staining image; FIG. 6C2, quantitative staining data) in huh7 cells xenograft tumors after RX108exposure. (FIG. 6D) LC-MS / MS measurement of the concentration of glutamine metabolites in the same tumor samples. The data are presented as mean (± SD) values. *p < 0.05 vs. control.DETAILED DESCRIPTION OF THE INVENTION

[0019] The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify additional therapeutic modalities. The present disclosure describes the antitumor activity and underlying molecular mechanisms of Na+ / K+-ATPase inhibitor RX108 in human HCC cells and its xenograft model. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in a xenograft mouse model, and that inhibition was associated with induction of apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentration in HCC cells and tumors. Additionally, RX108 exposure led to a significant decrease in cell energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate (OCR). Furthermore, HCC cells exhibited evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCCs was associated with unfavorable survival. Taken together, these findings reveal an additional approach to target glutamine metabolism through inhibiting Na+ / K+-ATPase and provide a rationale for using RX108 to treat HCC in patients whose tumors express ASCT2 at high levels.

[0020] Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Liver cancer is the fourth most common cause of cancer-related deaths and ranks sixth in terms of cancer incidence worldwide. In the United States, liver cancer is the second most lethal tumor, and its incidence has tripled since 1980 (Siegel et al., 2019; Villanueva, 2019). Surgical resection at an early stage is the only curative treatment option, but more than 80% of HCCs are diagnosed at an advanced stage with inoperable distant metastases (Yang and Roberts, 2010). Patients with unresectable HCC can benefit from multimodality 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% because the effectiveness of agents used in systematic treatment of HCC is limited (Villanueva, 2019). More recently, immune-based therapies for HCC have emerged, but the overall response rate for these therapies is much lower than the rates for other tumor types, such as melanoma and lung cancer (Kudo, 2019). Thus, discovering new therapeutic targets and additional effective compounds for HCC treatment is critical to improving the outcomes of this cancer.

[0021] Metabolic reprogramming is one of the hallmarks of cancer. Many cancer cells, including HCC cells, exhibit an oncogenetically 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, a study suggested that tumor cells take up glutamine much faster than they do glucose (Reinfeld et al., 2021). Targeting glutaminase decreases the sternness of HCC (Li et al.,2019). Sorafenib-resistant HCC cells exhibited much higher glutamine metabolic activity than did nonresistant cells regulated by peroxisome proliferator-activated receptor G (Kim et al., 2017). Rapidly proliferating cancer cells consume glutamine at a dramatically greater rate than do normal cells (Wang et al., 2018), and this consumption is fueled by elevated expression of glutamine transporters such as Na+-dependent alanine serine cysteine transporter 2 (ASCT2 / SLC1 A5). Authors reported that ASCT2 was upregulated in HCC cells and that this upregulation was inversely associated with survival (Sun et al., 2016). Consistently, 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 result in inhibition of cell growth (Lin et al., 2018), suggesting that ASCT2 is a promising therapeutic target for cancer (Wahi and Holst, 2019). Significantly, several ASCT2 inhibitors have been developed or tested in vitro and in preclinical animal models and 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, the amino acid analogs and V- 9302 are not suitable for specific targeting of glutamine addiction via ASCT2 in tumor cells. Notably, MEDI7247, an ASCT2-blocking antibody conjugated with the toxic drug pyrrolobenzodiazepine, is currently entering 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, there remains an urgent need to continue searching for a drug that can inhibit ASCT2.

[0022] HCC remains a global medical burden with a rising incidence and has a dismal prognosis, largely due to a lack of early detection methods and effective therapeutic modalities. Efforts to improve the outcomes of 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 major function of the liver is whole-body metabolism regulation, in which it orchestrates the clearance of toxins; balances glucose, lipid, and amino acid uptake; andmaintains metabolic homeostasis. HCC onset and progression are frequently accompanied by reprogramming of metabolic pathways, leading to dysregulation of metabolism (Nwosu et al., 2017; Murakami et al., 2015; Fitian et al., 2014; Gao et al., 2015; Huang et al., 2013). Targeting the dysregulated metabolic pathway in HCC cells offers unexploited preventative and therapeutic opportunities (De Matteis et al., 2018; Stine et al., 2022).

[0023] One of the hallmarks of metabolic dysregulation in cancer is addiction to glutamine for cell proliferation, which is corroborated by overexpression of the plasma membrane transporter ASCT2 in a variety of cancers, thus forming the molecular basis for targeting overexpressed ASCT2 for cancer therapy (Scalise et al., 2017).

[0024] Strategies for targeting dysregulated glutamine metabolism in cancer include inhibition of glutaminolysis by treatment with glutaminase inhibitors, depletion of glutamine supply, use of glutamine analogs, and blockage of glutamine uptake. Given that glutamine, a nonessential amino acid with an amine functional group, is the most abundant amino acid circulating in the bloodstream and contributes to virtually every biosynthetic pathway in proliferating cells (DeBerardinis and Cheng, 2010), depleting the glutamine supply and using glutamine analogs for cancer therapy are great 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 makes 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 yet to be applied clinically (Schulte et al., 2018; Broer et al., 2018; Ndaru et al., 2019). Conceivably, advances in structural characterization of substrate recognition by ASCT2 will greatly facilitate the development of new specific ASCT2 inhibitors (Scopelliti et al., 2018).

[0025] It was reported that ASCT2 expression is regulated by the availability of glutamine, which induces the formation of an FXR / RXR dimer that binds to the IR-1 repeat in the putative promoter region of ASCT2, leading to activation of ASCT2 (Bungard and McGivan, 2004). Inactivation of tumor suppressors and activation of oncogenes are the 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), whereas activation of EphA2 and c-Myc, the key oncogenes in HCC carcinogenesis, activates transcriptional ASCT2 expression (Edwards et al., 2017; Liu et al., 2017). ASCT2 protein expression is increased under 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). More recently, investigators found that ASCT2 is an epidermal growth factor receptor (EGFR)-associated protein and that targeting EGFR by cetuximab led to downregulation of ASCT2 in an EGFR expression-dependent manner viacetuximab-mediated EGFR endocytosis (Lu et al., 2016). These previous findings may facilitate exploration of the mechanistic action of RX108 on ASCT2 expression regulation and are also valuable for the design of mechanism-based combinational therapy to treat HCC.RX108

[0026] RX108 is a synthetic small-molecule inhibitor of Na+ / K+-ATPase. It is derived from bufalin, and its synthesis was reported previously (U.S. Patent 8,334,376 B2). 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 antitumor activity of RX108 in HCC cells. In some embodiments disclosed herein, RX108 has antiproliferative effects in both HCC cells and relevant xenograft HCC model by inducing apoptosis and reducing glutamine metabolism by downregulating glutamine transporter expression and function in tumors.

[0027] In some embodiments, the present disclosure provides several lines of evidence supporting the use of a Na+ / K+-ATPase (NKA) inhibitor, such as RX108, to target a subgroup of HCCs with dysregulated glutamine metabolism.

[0028] In some embodiments, the use of a Na+ / K+-ATPase (NKA) inhibitor, 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 dependent. In some embodiments, the use of a Na+ / K+-ATPase (NKA) inhibitor, such as RX108, inhibits HCC cell proliferation in vitro. In some embodiments, the use of a Na+ / K+-ATPase (NKA) inhibitor, such as RX108, inhibits tumorigenesis in vivo. In some embodiments, the inhibition of tumorigenesis is accompanied by significant induction of apoptosis. In some embodiments, the use of a Na+ / K+-ATPase (NKA) inhibitor, such as RX108, significantly downregulates ASCT2, the transporter of glutamine, in HCC cells. In some embodiments, the use of a Na+ / K+-ATPase (NKA) inhibitor, such as RX108, reduces glutamine and its metabolite concentrations in HCC cells and tumors In some embodiments, the use of a Na+ / K+-ATPase (NKA) inhibitor, such as RX108, inhibits the energy metabolic pathway in HCC cells. In some embodiments, HCC cells are addicted to glutamine for proliferation, knockdown of ASCT2 drastically reduced HCC cell growth, and the antitumor effect of a Na+ / K+-ATPase (NKA) inhibitor, such as RX108, is dependent on glutamine transport. In some embodiments, a high level of ASCT2 mRNA expression in human HCC is associated with unfavorable survival.

[0029] In some aspects, the present disclosure provides methods of treating or preventing a cancer associated with elevated ASCT2 expression in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of a Na+ / K+-ATPase (NKA) inhibitor.

[0030] 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.

[0031] In some aspects, the present disclosure provides methods of stabilizing or reducing the volume of a solid tumor of 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.

[0032] In some aspects, the present disclosure provides methods of reducing the volume of a solid tumor of 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. 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 at least 25%. In some embodiments, the volume is reduced by at least 50%.

[0033] In some aspects, the present disclosure provides methods of modulating the concentration of one or more biomarkers of a cancer associated with elevated ASCT2 expression in a cell comprising contacting the cell with an NKA inhibitor. In some embodiments, modulating decreases the concentration of the one or more biomarkers. In some embodiments, the modulating decreases the concentration of the 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 modulating decreases the concentration of the one or more biomarkers by at least 25%. In some embodiments, the modulating decreases the concentration of the one or more biomarkers by at least 50%. In some embodiments, the modulating decreases the concentration of the one or more biomarkers modulating increases the concentration of the one or more biomarkers. In some embodiments, the modulating increases the concentration of the 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%, atleast 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%.

[0034] In some embodiments, the one or more biomarkers are selected from: glutamine, glutamate, a-ketoglutarate (a-KG), 2-hydroxyglutarate (2HG), glutathione (GSH), malate, pyruvate, lactate, and fumarate. In some embodiments, modulating decreases the concentration of the one or more biomarkers selected from: glutamine, glutamate, a-ketoglutarate (a-KG), 2- hydroxyglutarate (2HG), glutathione (GSH), malate, pyruvate, and lactate. In some embodiments, modulating increases the concentration of fumarate.

[0035] 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%.

[0036] In some aspects, the present disclosure provides methods of suppressing ASCT2 protein expression in a cell comprising contacting the cell with an NKA inhibitor.

[0037] In some aspects, the present disclosure provides methods of reducing the rate of proliferation of a cancer cell comprising contacting the cell with an NKA inhibitor, wherein the cancer is associated with elevated ASCT2 expression. In some embodiments, the rate of proliferation 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 rate of proliferation is reduced by at least 10%. In some embodiments, the rate of proliferation is reduced by at least at least 30%.

[0038] 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 / mL, 25 ng / mL, 30 ng / mL, 35 ng / mL, 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, 60 ng / mL, 65 ng / mL, 70 ng / mL, 75 ng / mL, 80 ng / mL, 90 ng / mL, 95 ng / mL, 100 ng / mL, 125 ng / mL, 150 ng / mL, 175 ng / mL, 200 ng / mL, 250 ng / mL, 300 ng / mL, 350 ng / mL, 400 ng / mL, 450 ng / mL, to about 500 ng / mL, or any range derivable therein. In some embodiments, the cellular concentration of the NKA inhibitor is about 3 ng / mL. In some embodiments, the cellular concentration of the NKA inhibitor is about 30 ng / mL.

[0039] In some embodiments, the cancer is 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), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC / HCC), lung adenocarcinoma (LU AD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), sarcoma (SARC), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), thyroid carcinoma (THCA), thymoma (THYM), uterine corpus endometrial carcinoma (UCEC), or uterine carcinosarcoma (UCS). In some embodiments, the cancer is of the bile duct, brain, liver, mouth, or throat. In some embodiments, the cancer is of the bile duct. In some embodiments, the cancer is cholangiocarcinoma (CHOL). In some embodiments, the cancer is of the brain. In some embodiments, the cancer is glioblastoma multiforme (GBM). In some embodiments, the cancer is of the liver. In some embodiments, the cancer is liver hepatocellular carcinoma (LIHC / HCC). In some embodiments, the cancer is of the mouth or throat. In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSC).

[0040] 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):wherein: each dashed bond independently represents a single bond or a double bond; n, p, and q are independently selected from 0 and 1; andRi, R2, R3, R4, R5, Re, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionallysubstituted alkloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Rs, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0); orR4 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;Li is selected from a covalent bond, *-C(0)0-, *-[C(Ra)(Rb)]s-O-, and *-[C(Ra)(Rb)]s- C(0)0-, wherein * indicates the point of attachment of Li to Z, further wherein: Raand Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; orRaand Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; orR15 and one occurrence of R3 are together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Z is selected from -OR14 and -NR15R16, wherein:R14 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(=0)(0Ri7)(0Ris), wherein: R17 and Ris are independently selected from hydrogen and optionally substituted alkyl; andRis is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, -CO2R19, -CONR20R21, -C(NR22)NR2oR2i, -C(NCN)NR2oR2i, -SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R20 and R21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; orR15 and Ri6 are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3;Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substitutedaryloxy, 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 carbaminodoyl, and optionally substituted alkynyl;R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the NKA inhibitor is a compound of formula (I):wherein: each dashed bond independently represents a single bond or a double bond; n, p, and q are independently selected from 0 and 1; andRi, R2, R3, R4, R5, Rs, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Rs, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0); orR4 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 substitutedheterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;Li is selected from a covalent bond, *-C(O)O-, *-[C(Ra)(Rb)]s-O-, and *-[C(Ra)(Rb)]s- C(O)O-, wherein * indicates the point of attachment of Li to Z, further wherein: Raand Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; orRaand Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; orR15 and one occurrence of Ra are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Z is selected from -ORu and -NR15R16, wherein:R14 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)(ORi7)(ORis), wherein:R17 and Ris are independently selected from hydrogen and optionally substituted alkyl; andR15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, -CO2R19, -CONR20R21, -C(NR22)NR2oR2i,-C(NCN)NR2oR.2i, -SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R20 and R21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; orR15 and Ri6 are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3;Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, 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 carbaminodoyl, and optionally substituted alkynyl;R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the NKA inhibitor is a compound of formula (I-A):(I-A) wherein: each dashed bond independently represents a single bond or a double bond; n, p, and q are independently selected from 0 and 1; andRi, R2, R3, R4, R5, Rs, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Rs, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0); orR4 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;Li is selected from a covalent bond, *-C(O)O-, *-[C(Ra)(Rb)]s-O-, and *-[C(Ra)(Rb)]s- C(O)O-, wherein * indicates the point of attachment of Li to Z, further wherein: Raand Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; orRaand Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; orR15 and one occurrence of Ra are together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Z is selected from -ORu and -NR15R16, wherein:R14 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)(ORi7)(ORis), wherein: R17 and Ris are independently selected from hydrogen and optionally substituted alkyl;R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, -CO2R19, -CONR20R21, -C(NR22)NR2oR2i, -C(NCN)NR2oR2i, -SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R20 and R21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; orR15 and Ri6 are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3;Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, 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 carbaminodoyl, and optionally substituted alkynyl;R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the NKA inhibitor is a compound of Formula (II):QI) wherein: each dotted line represents a single bond or a double bond; n, p, and q are each independently selected from 0 and 1; andRi, R2, R3, R4, R5, Re, R9, Rio, R11 and R12 are 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Re, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0); orR4 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, -CO2R19, -CONR20R21, -C(NR22)NR2oR2i, - C(NCN)NR2oR2i, -SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R20 and R21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3; wherein Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, 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 carbaminodoyl, and optionally substituted alkynyl;R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the NKA inhibitor is a compound of Formula (II- A):(II-A) wherein:Ri, R2, R3, R4, Rs, Rs, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionallysubstituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Rs, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0); orR4 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;Ri6 is -CONR20R21, where R20 and R21 are joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3;Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, 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 carbaminodoyl, and optionally substituted alkynyl; andR24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the NKA inhibitor is a compound of formula (III):QU) wherein: the dotted line represents a single bond or a double bond; n is selected from 0 and 1;Ri, R2, R3, R5, Re, R9, Rio, R11 and R12, are 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Re, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0);R4 is hydroxy, 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionallysubstituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;RB is selected from hydrogen, optionally substituted alkyl, and formyl;Z is selected from ORu and NR15R16; wherein:R14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;Ri6 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R15 and Ri6 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3;Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, 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 substitutedaminosulfonyl, optionally substituted carbaminodoyl, and optionally substituted alkynyl;R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the NKA inhibitor is a compound of formula (III), or a pharmaceutically acceptable salt thereof, provided that when R4 is OH, R13 is methyl, Wi isO(2-oxo-2H-pyran-5-yl), and Ri, R2, R3, Rs, Rs, R7, Rs, R9, Rio, R11, and W2 are hydrogen then R12 is not hydrogen.

[0047] In some embodiments, the NKA inhibitor is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents a single bond or a double bond; n is selected from 0 and 1;Ri, R2, Rs, Rs, Rio, R11, R12 and W2 are hydrogen; R3 and R9 are independently hydrogen or OH;R4 is hydroxy and Rs is hydrogen, or R4 and Rs may optionally be joined together with any intervening atoms to form an oxirane ring;R7is -OCOCH3;R13 is methyl;Z is NR15R16, wherein:Ris is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;Rie is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; or R15 and Rie are joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; andWi is selected from:

[0048] In some embodiments, the NKA inhibitor is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, provided that the compound is not a compound ofFormula III in which: R4 is OH, R13 is methyl,-oxo-2H-pyran-5-yl), and Ri, R2,R3, R5, Rs, R7, Rs, R9, Rio, R11, R12 and W2 are hydrogen.

[0049] In some embodiments, the NKA inhibitor is:(a) a compound of F ormula (IV -A) :wherein:Z is selected from OR14 and NR15R16, wherein:R14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi6 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R15 and Ri6 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;(b) a compound of Formula (IV-B):(IV-B) wherein:R15 and Ri6 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or Ri and R2 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Raand Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or Ra and Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; or R15 and one occurrence of Ra 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) a compound of Formula (I V-C):wherein:Rais selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi4 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)(ORs), where R7 and Rs are independently selected from hydrogen and optionally substituted alkyl; or a pharmaceutically acceptable salt of the compound of any of these formulae.

[0050] In some embodiments, the NKA inhibitor is a compound of Formula (IV-A) or a pharmaceutically acceptable salt thereof. In some embodiments, Z is OR14. In some embodiments, R14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, Z is NR15R16. In some embodiments, R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, and Ri6 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. In some embodiments, R15 is hydrogen and Ri6 is optionally substituted alkyl. In some embodiments, R15 is hydrogen and Ri6 is alkyl. In some embodiments, R15 and Ri6 are taken together to form a 5- to 7- membered heterocycloalkyl ring. In some embodiments, R15 and Ri6 are taken together with the atom to which they are attached to form a 4-piperazinyl.

[0051] In some embodiments, the compound of Formula IV-A is selected from: (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl)carbamate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl piperazine- 1 -carboxylate;or a pharmaceutically acceptable salt thereof.

[0052] 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.

[0053] In some embodiments, the NKA inhibitor is a compound selected from:2-aminoethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-hydroxy ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-(pyrrolidin-l-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-((R)-3-hydroxypyrrolidin-l-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-(3 -oxopiperazin- l-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate; l-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2 -hydroxy ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methylpiperazine-l- carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methylpiperazin-l- yl)ethyl)urea;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide;(R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4-diazepane-l-carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro- lH-cyclopenta[a]phenanthren-3 -yl)-4-methyl- 1 ,4-di azepane- 1 - carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-oxopiperazine-l-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-l- yl)ethyl)urea;l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-l- yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3-oxopiperazin-l- yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-l- yl)ethyl)urea;1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)acetamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-2-(pyrrolidin-l-yl)acetamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide;(R)-2-amino-Nl-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)succinamide;(S)-2-amino-Nl-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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-l-yl)ethoxy)carbonyl)amino)hexadecahydro-lH- 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)hexadecahydro-lH- 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- y 1 ) -3 -(((2-(3 -oxopiperazin- 1 -yl)ethoxy)carbonyl)amino)hexadecahy dro- 1 H- 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-l-yl)ethyl)ureido)hexadecahydro-lH-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)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3 S,5R,8R,9S, IOS, 13R,14S,16S,17R)-14-hy droxy-10,13-dimethyl-3-(4-m ethylpiperazine- 1- carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-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-l-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3 S, 5R, 8R,9S,1 OS, 13R,14S,16S,17R)-14-hy droxy-10,13-dimethyl-3-(morpholine-4- carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-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)hexadecahydro-lH-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-l-carboxamido)hexadecahydro-lH-cyclopenta[a]phenanthren-16-yl acetate;(3 S,5R,8R,9S, IOS, 13R,14S,16S, 17R)-3-(l,4-diazepane-l-carboxamido)-14-hy droxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-l,4- diazepane-l-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- 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-l-carboxamido)hexadecahydro-lH-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- y 1 ) -3 -(3 -(2-(2-oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[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-l-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- 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- y 1 ) -3 -(3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-(pyrrolidin-l-yl)ethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-(3 -oxopiperazin- l-yl)ethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate; l-(2-aminoethyl)-3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-l-yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-l-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methylpiperazine-l- carboxamide;N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4-diazepane-l -carboxamide;N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,4-diazepane-l- carboxamide;N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-oxopiperazine-l- carboxamide;(S)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-hydroxypyrrolidine-l- carboxamide;(R)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-hydroxypyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- carboxamide; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-l- yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-l- yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3-oxopiperazin-l- yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-l- yl)ethyl)urea;2-(pyrrolidin- 1 -yl)ethyl ((3 S,8R,9S, 1 OR, 13R, 14S, 17R)- 14-hydroxy- 10,13 -dimethyl- 17-(2- oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,l 1,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate;2-(3 -oxopiperazin- l-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-(py rrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3- yl)piperazine-l -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-(piperazin- 1 -yl)ethy l)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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3- yl)ureido)butanoic acidN-((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-lH-cy cl openta[a]phenanthren-3-yl)- 4-methylpiperazine-l -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-lH-cy cl openta[a]phenanthren-3-yl)- 1 ,4-diazepane- 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-lH-cy cl openta[a]phenanthren-3-yl)- 4-methyl- 1 ,4-diazepane- 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-lH-cy cl openta[a]phenanthren-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)pyrrolidine-l -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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)pyrrolidine-l -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3-(2-(4-methyl-2-oxopiperazin-l-yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-(3 -oxopiperazin- 1 -y l)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-((S)-3 -hy droxypy rrolidin- 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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-((R)-3 -hy droxypyrrolidin- 1 -yl)ethyl)urea;2-(pyrrolidin-l-yl)ethyl ((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2- oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)carbamate;2-morpholinoethyl ((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)carbamate;2-(3 -oxopiperazin- l-yl)ethyl ((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l- (2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)carbamate; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-methylurea; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(pyrroli din-1- yl)ethyl)urea; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2- morpholinoethyl)urea;N-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-4-methylpiperazine-l- carboxamide; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(4-methylpiperazin- l-yl)ethyl)urea;N-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl)-4-m ethyl- 1 ,4-diazepane- 1 -carboxamide;N-((lR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)morpholine-4- carboxamide; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl)-3 -(2-(3 -oxopiperazin- 1 - yl)ethyl)urea;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (((2-(pyrrolidin-l- yl)ethoxy)carbonyl)amino)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)amino)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (((2-(3 -oxopiperazin- 1 -yl)ethoxy)carbonyl)amino)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (3 -(2-(pyrrolidin- 1 -yl)ethyl)ureido)hexadecahydronaphtho[ 1 ',2' :6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2- morpholinoethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(4-methylpiperazine-l- carboxamido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2-(4-methylpiperazin-l- yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[ 1 ',2' : 6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(morpholine-4- carboxamido)- 1 -(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(4-methyl-l,4-diazepane-l- carboxamido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (3 -oxopiperazine- 1 -carboxamido)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren- 2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2-(4-methyl-2- oxopiperazin-l-yl)ethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)ureido)hexadecahydronaphtho[ 1 ',2' :6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethoxy)carbonyl)amino)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)amino)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5 -yl)-7-(((2-(3 -oxopiperazin- 1 - yl)ethoxy)carbonyl)amino)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(3-(2-(pyrrolidin-l- yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2- morpholinoethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(4- methylpiperazine- 1 -carb oxami do)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2-(4- methylpiperazin- 1 -yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5 - yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(morpholine-4- carboxamido)- 1 -(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(4-methyl-l,4- diazepane-l-carboxamido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5 -y 1) -7 - (3 -oxopiperazine- 1 - carboxamido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2-(4- methyl-2-oxopiperazin- 1 -yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5 -y 1) -7 - (3 -(2-(3 -oxopiperazin- 1 - yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-hydroxy ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo- 2,5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-(3 -oxopiperazin- l-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate;2-(pyrrolidin-l-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate;2-morpholinoethyl ((3 S,5R,8R,9S, IOS, 13R,14S,17R)-14-hy droxy-10,13 -dimethyl- 17-(5- oxo-2, 5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate; l-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5- oxo-2, 5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2- hydroxyethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin- l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2- morpholinoethyl)urea;N-((5R,8R,9S,1 OS, 13R,14S,17R)-14-hy droxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran- 3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l- carboxamide;(R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-2- (hydroxymethyl)piperazine- 1 -carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-l- 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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro- lH-cyclopenta[a]phenanthren-3 -yl)- 1 ,4-diazepane- 1 - carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,4- diazepane-1 -carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-oxopiperazine- 1 -carboxamide;(S)-3-hy droxy-N-((3S,5R, 8R,9S, IOS, 13R,14S,17R)-14-hy droxy-10,13 -dimethyl- 17-(5-oxo- 2,5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- carboxamide;l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3- hydroxypyrrolidin-l-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3- hydroxypyrrolidin-l-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 - methylbutanamide;(S)-2-amino-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 - methylbutanamide;(R)-2-amino-Nl-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2.5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)succinamide;(S)-2-amino-Nl-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)succinamide;2-(pyrrolidin-l-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)hexadecahydro-lH- cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate;2-(3 -oxopiperazin- l-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)hexadecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin- l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l- carboxamide; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)morpholine-4- carb oxami de4-(3-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)ureido)butanoic acidN-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro- lH-cyclopenta[a]phenanthren-3 -yl)- 1 ,4-diazepane- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,4- diazepane-1 -carboxamide;(S)-N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 - hydroxypyrrolidine- 1 -carboxamide; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3- hydroxypyrrolidin-l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3- hydroxypyrrolidin-l-yl)ethyl)urea;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihy drofuran-3 -y l)-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)hexadecahydro- lH-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- dihy drofuran-3 -yl)-3-(((2-(3 -oxopiperazin- 1 -yl)ethoxy)carbonyl)amino)hexadecahy dro- lH-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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(pyrrolidin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 H- 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)hexadecahydro-lH- 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 -y l)-3 -(piperazine- 1 -carboxamido)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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(piperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 H- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4- carboxami do)- 17-(5 -oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)ureido)butanoic acid(3 S, 5R, 8R, 9S,1 OS, 13R,14S,16S,17R)-14-hydroxy-l 0,13-dimethyl-3-(4-m ethylpiperazine- 1- carboxami do)- 17-(5 -oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(l,4-diazepane-l-carboxamido)-14-hydroxy-10,13- dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-l,4- diazepane-l-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH- 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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(2-oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 H- 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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 H- cyclopenta[a]phenanthren- 16-yl acetate;2-(pyrrolidin-l-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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3 - yl)carbamate;2-(3 -oxopiperazin- l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(pyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3- yl)ureido)butanoic acidN-((5R, 8R,9S, 1 OS, 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-lH-cy cl openta[a]phenanthren-3 - yl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3 - yl)piperazine-l -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-lH-cy cl openta[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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3-yl)- 1 ,4-diazepane- 1 -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(3 -oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-((S)-3 -hydroxypyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[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-tetradecahydro-lH-cy cl openta[a]phenanthren-3 -yl)-2- (pyrrolidin-l-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-lH-cy cl openta[a]phenanthren-3-yl)-2- morpholinoacetamide;(R)-2-amino-N-((3 S, 5R, 8R,9S, 1 OS, 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3- yl)propanamide;(R)-2-amino-N-((3 S, 5R, 8R,9S, 1 OS, 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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3-yl)-3- methylbutanamide;(R)-2-amino-Nl-((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-lH-cy cl openta[a]phenanthren-3- yl)succinamide;(S)-2-amino-Nl-((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-lH-cy cl openta[a]phenanthren-3- yl)succinamide;2-(3 -oxopiperazin- l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate;2-(pyrrolidin-l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate; l-(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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)urea; l-((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-lH-cy cl openta[a]phenanthren-3 -yl)-3- (2 -hydroxy ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(pyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3 - yl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3 - yl)piperazine-l -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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3 -yl)-2- (hydroxymethyl)piperazine- 1 -carboxamide; l-((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-lH-cy cl openta[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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3-yl)- 1 ,4-diazepane- 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3 -yl)-3- hydroxypyrrolidine-1 -carboxamide;l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(3 -oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-3- yl)-3-methylbutanamide;(R)-2-amino-Nl-((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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-3- yl)succinamide,(S)-2-amino-Nl-((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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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-l-yl)ethoxy)carbonyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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-l-yl)ethyl)carbamoyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methylpiperazine-l- carboxylate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-(4- methylpiperazin-l-yl)ethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro- lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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-l-yl)ethyl)carbamoyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro- lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoic acid;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3-yl (2-(pyrrolidin- 1 -yl)ethyl) carbonate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[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-l-yl)ethyl)carbamoyl)oxy)-2, 3, 6, 7, 8, 9, 10,11,12,13,14,15,16,17- tetradecahydro- lH-cyclopenta[a]phenanthren- 16-yl acetate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3-yl (2-morpholinoethyl)carbamate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3-yl piperazine- 1 -carboxylate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3-yl (2-(piperazin-l-yl)ethyl)carbamate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3- yl)oxy)carbonyl)amino)butanoic acid;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 -yl)ethyl) carbonate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2 -morpholinoethyl) carbonate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 - yl)ethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2- morpholinoethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl 4-m ethylpiperazine- 1 - carboxylate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2-(4-methylpiperazin-l- yl)ethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4-carboxylate;4-(((((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (((2-(pyrrolidin- 1 -yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (((2-(pyrrolidin- 1 -yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2-(4-methylpiperazin-l- yl)ethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4- carboxylate;4-(((((lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l-(2- oxo-2H-pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2-(4- methylpiperazin-l-yl)ethyl)carbamoyl)oxy)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l-(2- oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4-carboxylate;4-(((((lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l- (2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran- 3-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- yl)ethyl)carbamate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran- 3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- 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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(piperazin-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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-l-yl)ethoxy)carbonyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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-l-yl)ethyl)carbamoyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro- 1 Iley cl openta[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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- yl)ethyl)carbamate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl valinate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl alaninate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl leucinate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 2-(piperidin-l-yl)acetate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 2-(pyrrolidin-l-yl)acetate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl asparaginate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl prolinate; and(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 2-morpholinoacetate; or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the NKA inhibitor is a compound selected from: l-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2 -hydroxy ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methylpiperazine-l- carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methylpiperazin-l- yl)ethyl)urea;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide;(R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4-diazepane-l-carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro- lH-cyclopenta[a]phenanthren-3 -yl)-4-methyl- 1 ,4-di azepane- 1 - carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-oxopiperazine-l-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-l- yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-l- yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3-oxopiperazin-l- yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-l- yl)ethyl)urea;l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-l- 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-l-yl)ethyl)ureido)hexadecahydro-lH-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)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3 S,5R,8R,9S, IOS, 13R,14S,16S,17R)-14-hy droxy-10,13-dimethyl-3-(4-m ethylpiperazine- 1- carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-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-l-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3 S, 5R, 8R,9S,1 OS, 13R,14S,16S,17R)-14-hy droxy-10,13-dimethyl-3-(morpholine-4- carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-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)hexadecahydro-lH-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-l-carboxamido)hexadecahydro-lH-cyclopenta[a]phenanthren-16-yl acetate;(3 S,5R,8R,9S, IOS, 13R,14S,16S, 17R)-3-(l,4-diazepane-l-carboxamido)-14-hy droxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-l,4- diazepane-l-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- 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-l-carboxamido)hexadecahydro-lH-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- y 1 ) -3 -(3 -(2-(2-oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[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-l-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- 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- y 1 ) -3 -(3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[a]phenanthren- 16-yl acetate; l-(2-aminoethyl)-3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-l-yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-l-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methylpiperazine-l- carboxamide;N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4-diazepane-l -carboxamide;N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,4-diazepane-l- carboxamide;N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-oxopiperazine-l- carboxamide;(S)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-hydroxypyrrolidine-l- carboxamide;(R)-N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-hydroxypyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- carboxamide; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-l- yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2-oxopiperazin-l- yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3-oxopiperazin-l- yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3-hydroxypyrrolidin-l- yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3-hydroxypyrrolidin-l- yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-(py rrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3- yl)piperazine-l -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-(piperazin- 1 -yl)ethy l)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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3-yl)- 4-methylpiperazine-l -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-lH-cy cl openta[a]phenanthren-3-yl)- 1 ,4-diazepane- 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-lH-cy cl openta[a]phenanthren-3-yl)- 4-methyl- 1 ,4-diazepane- 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-lH-cy cl openta[a]phenanthren-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)pyrrolidine-l -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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)pyrrolidine-l -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-(2-oxopiperazin- 1 -yl)ethyl)urea;l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3-(2-(4-methyl-2-oxopiperazin-l-yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-(3 -oxopiperazin- 1 -y l)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-((S)-3 -hy droxypy rrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)- 3 -(2-((R)-3 -hy droxypyrrolidin- 1 -yl)ethyl)urea; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-methylurea; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(pyrrolidin-l- yl)ethyl)urea; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2- morpholinoethyl)urea;N-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-4-methylpiperazine-l- carboxamide; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(4-methylpiperazin- l-yl)ethyl)urea;N-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl)-4-m ethyl- 1 ,4-diazepane- 1 -carboxamide;N-((lR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)morpholine-4- carboxamide; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(3-oxopiperazin-l- yl)ethyl)urea;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (3 -(2-(pyrrolidin- 1 -yl)ethyl)ureido)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2- morpholinoethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(4-methylpiperazine-l- carboxamido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2-(4-methylpiperazin-l- yl)ethyl)ureido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(morpholine-4- carboxamido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(4-methyl-l,4-diazepane-l- carboxamido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7-(3-oxopiperazine-l-carboxamido)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren- 2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2-(4-methyl-2- oxopiperazin-l-yl)ethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7-(3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)ureido)hexadecahydronaphtho[ 1 ',2' :6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(3-(2-(pyrrolidin-l- yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2- morpholinoethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(4- methylpiperazine- 1 -carb oxami do)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2-(4- methylpiperazin- 1 -yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(morpholine-4- carboxamido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(4-methyl-l,4- diazepane-l-carboxamido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5 -y 1) -7 - (3 -oxopiperazine- 1 - carboxamido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2-(4- methyl-2-oxopiperazin- 1 -yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5 -y 1) -7 - (3 -(2-(3 -oxopiperazin- 1 - yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate; l-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5- oxo-2, 5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2- hydroxyethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin- l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l- carboxamide;(R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-2- (hydroxymethyl)piperazine- 1 -carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-l- 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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro- lH-cyclopenta[a]phenanthren-3 -yl)- 1 ,4-diazepane- 1 - carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,4- diazepane-1 -carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-oxopiperazine- 1 -carboxamide;(S)-3-hy droxy-N-((3S,5R, 8R,9S, IOS, 13R,14S,17R)-14-hy droxy-10,13 -dimethyl- 17-(5-oxo- 2,5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3- hydroxypyrrolidin-l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3- hydroxypyrrolidin-l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin- l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l- carboxamide;l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-l- 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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro- lH-cyclopenta[a]phenanthren-3 -yl)- 1 ,4-diazepane- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,4- diazepane-1 -carboxamide;(S)-N-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 - hydroxypyrrolidine- 1 -carboxamide; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3- hydroxypyrrolidin-l-yl)ethyl)urea;l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3- hydroxypyrrolidin-l-yl)ethyl)urea;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(pyrrolidin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2- morpholinoethyl)urei do)- 17-(5 -oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 Iley cl openta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihy drofuran-3 -y l)-3 -(piperazine- 1 -carboxamido)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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(piperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4- carboxami do)- 17-(5 -oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 Iley cl openta[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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)ureido)butanoic acid;(3 S,5R,8R,9S, IOS, 13R,14S,16S,17R)-14-hy droxy-10,13-dimethyl-3-(4-m ethylpiperazine- 1- carboxami do)- 17-(5 -oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 Iley cl openta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(l,4-diazepane-l-carboxamido)-14-hydroxy-10,13- dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-l,4- diazepane-l-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH- 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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(2-oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[a]phenanthren- 16-yl acetate; l-((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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3-yl)-3- (2-(pyrrolidin- 1 -yl)ethyl)urea; l-((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-tetradecahy dro- IH-cy cl openta[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-tetradecahy dro- IH-cy cl openta[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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl)ureido)butanoic acid;N-((5R, 8R,9S, 1 OS, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3 - yl)piperazine-l -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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3 - yl)piperazine-l -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-tetradecahy dro- IH-cy cl openta[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-tetradecahy dro- IH-cy cl openta[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-tetradecahy dro- IH-cy cl openta[a]phenanthren-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-tetradecahy dro- IH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3-yl)- 1 ,4-diazepane- 1 -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(3 -oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-((S)-3 -hydroxypyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-((R)-3 -hydroxypyrrolidin- 1 -yl)ethyl)urea; l-(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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)urea; l-((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-lH-cy cl openta[a]phenanthren-3 -yl)-3- (2 -hydroxy ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(pyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3 - yl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3 - yl)piperazine-l -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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3 -yl)-2- (hydroxymethyl)piperazine- 1 -carboxamide; l-((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-lH-cy cl openta[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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3-yl)- 1 ,4-diazepane- 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3 -yl)-3- hydroxypyrrolidine-1 -carboxamide;l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-(3 -oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-((S)-3 -hydroxypyrrolidin- 1 -yl)ethyl)urea; and1-((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-lH-cy cl openta[a]phenanthren-3-yl)-3- (2-((R)-3 -hydroxypyrrolidin- 1 -yl)ethyl)urea; or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the NKA inhibitor is a compound selected from:2-(pyrrolidin-l-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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3 - yl)carbamate;2-(3 -oxopiperazin- l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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-tetradecahydro-lH-cy cl openta[a]phenanthren-3 -yl)-2- (pyrrolidin-l-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-lH-cy cl openta[a]phenanthren-3-yl)-2- morpholinoacetamide;(R)-2-amino-N-((3 S, 5R, 8R,9S, 1 OS, 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3- yl)propanamide;(R)-2-amino-N-((3 S, 5R, 8R,9S, 1 OS, 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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3-yl)-3- methylbutanamide;(R)-2-amino-Nl-((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-lH-cy cl openta[a]phenanthren-3- yl)succinamide;(S)-2-amino-Nl-((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-lH-cy cl openta[a]phenanthren-3- yl)succinamide;2-(3 -oxopiperazin- l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate;2-(pyrrolidin-l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l 1,12,13,16,17-tetradecahydro-lH- 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-lH-cy cl openta[a]phenanthren-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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-3- yl)-3-methylbutanamide;(R)-2-amino-Nl-((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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-3- yl)succinamide,(S)-2-amino-Nl-((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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-3- yl)succinamide; or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the NKA inhibitor is a compound selected from:(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4- carboxylate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l-(2- oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l-(2- oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methylpiperazine-l- carboxylate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 1,4-diazepane-l- carboxylate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methyl-l,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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methyl-l,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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -yl 3 - hydroxypyrrolidine- 1 -carboxylate; or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the NKA inhibitor is a compound selected from:(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 -yl)ethyl) carbonate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2 -morpholinoethyl) carbonate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (((2-(pyrrolidin- 1 -yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[ 1 ',2' : 6,7]indeno[ 1 ,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-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-l-yl)ethoxy)carbonyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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- y 1 ) -3 -(((2-(3 -oxopiperazin- 1 -yl)ethoxy)carbonyl)oxy)hexadecahy dro- 1 Iley cl openta[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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(3 -oxopiperazin- l-yl)ethyl) carbonate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3-yl (2-(pyrrolidin- 1 -yl)ethyl) carbonate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3-yl (2 -morpholinoethyl) carbonate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3-yl (2-(3 -oxopiperazin- l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran- 3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran- 3-yl)hexadecahydro-lH-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- 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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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-l-yl)ethoxy)carbonyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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)hexadecahy dro- lH-cyclopenta[a]phenanthren-16-yl acetate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 - yl)ethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2- morpholinoethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl 4-m ethylpiperazine- 1 - carboxylate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2-(4-methylpiperazin-l- yl)ethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4-carboxylate;4-(((((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (((2-(pyrrolidin- 1 -yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2-(4-methylpiperazin-l- yl)ethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;4-(((((lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l-yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2-(4- methylpiperazin-l-yl)ethyl)carbamoyl)oxy)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate; and 4-(((((lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid; or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, wherein the NKA inhibitor is a compound selected from: (lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 -yl)ethyl) carbonate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2 -morpholinoethyl) carbonate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin- 1 -yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l-yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-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-l-yl)ethoxy)carbonyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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- y 1 ) -3 -(((2-(3 -oxopiperazin- 1 -yl)ethoxy)carbonyl)oxy)hexadecahy dro- 1 Iley cl openta[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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(3 -oxopiperazin- l-yl)ethyl) carbonate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3-yl (2-(pyrrolidin- 1 -yl)ethyl) carbonate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3-yl (2-morpholinoethyl) carbonate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3-yl (2-(3 -oxopiperazin- l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran- 3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran- 3-yl)hexadecahydro-lH-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- 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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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-l-yl)ethoxy)carbonyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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)hexadecahy dro- lH-cyclopenta[a]phenanthren-16-yl acetate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 - yl)ethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2- morpholinoethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2-(4-methylpiperazin-l- yl)ethyl)carbamate;4-(((((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)-7- (((2-(pyrrolidin- 1 -yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2-(4-methylpiperazin-l- yl)ethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;4-(((((lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2-(4- methylpiperazin-l-yl)ethyl)carbamoyl)oxy)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate; and4-(((((lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l- (2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid; or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the NKA inhibitor is a compound selected from: (lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl 4-m ethylpiperazine- 1 - carboxylate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4-carboxylate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4- carboxylate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l-(2- oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l-(2- oxo-2H-pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methylpiperazine-l- carboxylate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 1,4-diazepane-l- carboxylate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methyl-l,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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methylpiperazine-l -carboxylate;(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro- lH-cyclopenta[a]phenanthren-3 -yl 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) hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methyl-l,4-diazepane-l- carboxylate;(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -yl 3 -hy droxypyrrolidine- 1 - carboxylate;(R)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl) hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 3 -aminopyrrolidine- 1- carboxylate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3-yl piperazine- 1 -carboxylate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3-yl morpholine-4-carboxylate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3-yl 4-methylpiperazine-l -carboxylate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3-yl 1 ,4-diazepane- 1 -carboxylate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3-yl 4-methyl- 1 ,4-diazepane- 1 -carboxylate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3-yl 3 -hydroxypyrrolidine- 1 -carboxylate;(R)-(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3-yl 3 -aminopyrrolidine- 1 -carboxylate;(R)-(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 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) hexadecahydro- IH-cy cl openta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 3-oxopiperazine-l-carboxylate;(S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 1,4-diazepane-l- carboxylate;(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methyl-l,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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 3- hydroxypyrroli dine- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methyl-l,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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -yl 3 - hydroxypyrrolidine- 1 -carboxylate; or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the NKA inhibitor is a compound selected from: (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- yl)ethyl)carbamate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl piperazine- 1 -carboxylate;or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the NKA inhibitor is a compound selected from:(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)oxy)methyl acetate; l-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)oxy)methyl pivalate; ethyl ((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)oxy)methyl) carbonate; ethyl (l-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)oxy)ethyl) carbonate; or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the NKA inhibitor is a compound selected from:(R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- yl)ethyl)carbamate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl morpholine-4-carboxylate; or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the NKA inhibitor is a compound selected from: (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl piperazine- 1 -carboxylate; or a pharmaceutically acceptable salt thereof.

[0064] 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.

[0065] As used herein, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0066] The following abbreviations and terms have the indicated meanings throughout:

[0067] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0068] As used herein, a dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom.

[0069] As used herein, “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances wherein the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and / or inherently unstable.

[0070] As used herein, “alkyl” refers to straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For example, Ci-Ce alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl. “Lower alkyl” refers to alkyl groups having one to six 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, and the like. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment. Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. For example, Co alkylene indicates a covalent bond and Ci alkylene is a methylene group.

[0071] As used herein, “alkenyl” refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms of the parent alkyl. The group may be in either the cis or trans configuration about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en- 2-yl; butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but- 2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl; and the like. In certainembodiments, an alkenyl group has from 2 to 20 carbon atoms and in other embodiments, from 2 to 6 carbon atoms. “Lower alkenyl” refers to alkenyl groups having two to six carbons.

[0072] As used herein, “alkynyl” refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the parent alkyl. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-l-yn-l-yl, prop-2-yn-l-yl; butynyls such as but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl; and the like. In certain embodiments, an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 3 to 6 carbon atoms.“Lower alkynyl” refers to alkynyl groups having two to six carbons.

[0073] As used herein, “cycloalkyl” refers to a non-aromatic carbocyclic ring, usually having from 3 to 8 ring carbon atoms. The ring may be saturated or have one or more carboncarbon 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.

[0074] As used herein, “alkoxy” refers to an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3 -methylpentyloxy, and the like. Alkoxy groups will usually have from 1 to 7 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refers to alkoxy groups having one to six carbons.

[0075] As used herein, “acyl” refers to the groups H-C(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 the carbonyl functionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein. Acyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example, a C2 acyl group is an acetyl group having the formula CH3(C=O)-.

[0076] As used herein, “acyloxy” refers to the group -O-acyl.

[0077] As used herein, “formyl” refers to the group -C(O)H.

[0078] As used herein, “alkoxycarbonyl” refers to a group of the formula (alkoxy)(C=O)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus, a Ci-Ce alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.

[0079] As used herein, “alkoxycarbonyloxy” refers to the group -O-alkoxy carbonyl.

[0080] As used herein, “azido” refers to the group -N3.

[0081] As used herein, “amino” refers to the group -NH2.

[0082] As used herein, “mono- and di-(alkyl)amino” refers to secondary and tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.

[0083] As used herein, “aminocarbonyl” refers to the group -C(O)NRbRc, where:Rbis selected from H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, optionally substituted alkoxy; andRcis selected from hydrogen and optionally substituted C1-C4 alkyl; orRband Rctaken together with the nitrogen to which they are bound, form an optionally substituted 5- to 8-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, N, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NEE, -N(CI-C4 alkyl)(Ci-C4 alkyl), -NH(Ci-C4 alkyl), -N(CI-C4 alkyl)(Ci-C4 alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCi-C4 alkyl, -CON(CI-C4alkyl)(Ci-C4alkyl), -CONH(CI-C4alkyl), -CONH2, -NHC(O)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)Ci-C4alkyl, -SO2(Ci-C4alkyl), - SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(CI-C4alkyl), -SO2NH(phenyl), - NHSO2(CI-C4 alkyl), -NHSO2(phenyl), and -NHSO2(CI-C4 haloalkyl).

[0084] As used herein, “aminocarbonyloxy” refers to the group -O-aminocarbonyl.

[0085] As used herein, “aryl” refers to: 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

[0086] For example, aryl includes 6-membered carbocyclic aromatic rings fused to a 5- to 7- membered heterocycloalkyl ring containing 1 or more heteroatoms selected from N, O, and S. For such fused, bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the heterocycloalkyl ring. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of onehydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Aryl, however, does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.

[0087] As used herein, “aryloxy” refers to the group -O-aryl.

[0088] As used herein, “aralkyl” refers to the group -alkyl-aryl.

[0089] As used herein, “carbamimidoyl” refers to the group -C(=NH)-NH2.

[0090] As used herein, “substituted carbamimidoyl” refers to the group -C(=NRe)-NRfRswhereReis selected from hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; andRfand Rsare independently selected from hydrogen optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, provided that at least one of Re, Rf, and Rsis not hydrogen and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -C0NRbRc), -OCORb, -OCO2Ra, -0C0NRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SChR3and -SO2NRbRc), where Rais selected from optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;Rbis selected from H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRcis selected from hydrogen and optionally substituted C1-C4 alkyl; orRband Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; andwhere each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-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(CI-C4alkyl)(Ci-C4alkyl), -NH(CI-C4alkyl), -N(CI-C4alkyl)(Ci-C4alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCi-C4alkyl, -CON(CI-C4alkyl)(Ci-C4alkyl), -CONH(CI-C4alkyl), -CONH2, -NHC(O)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4phenyl, -C(O)Ci-C4haloalkyl, -OC(O)C1-C4alkyl, -SO2(CI-C4alkyl), -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(Ci-C4 alkyl), -SO2 NH(phenyl), -NHSO2(Ci-C4 alkyl), -NHSO2(phenyl), and -NHSO2(CI-C4haloalkyl).

[0091] As used herein, “halo” refers to fluoro, chloro, bromo, and iodo, and the term “halogen” includes fluorine, chlorine, bromine, and iodine.

[0092] As used herein, “haloalkyl” refers to alkyl as defined above having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, di fluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

[0093] As used herein, “heteroaryl” refers to:5- to 7-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; bicyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and tricyclic heterocycloalkyl rings containing one or more, for example, from 1 to 5, or in certain embodiments, from 1 to 4, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.

[0094] 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 wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not morethan 1. Examples of heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1), 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, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl, indolinyl, pyridazinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl. Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene. Heteroaryl does not encompass or overlap with aryl, cycloalkyl, or heterocycloalkyl, as defined herein.

[0095] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O') substituents, such as pyridinyl N-oxides.

[0096] As used herein, “heteroaryloxy” refers to the group -O-heteroaryl.

[0097] As used herein, “heteroaralkyl” refers to the group -alkyl-heteroaryl.

[0098] As used herein, “heterocycloalkyl” refers to a single, non-aromatic ring, usually with3 to 8 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms. The ring may be saturated or have one or more carboncarbon double bonds. Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2- piperidyl, 3-piperidyl, 4-piperidyl, 4-piperazinyl, and 2,5-piperizinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1). Substituted heterocycloalkyl also includes ring systems substituted with one or more oxo (=0) or oxide (-O') substituents, such as piperidinyl N-oxide, morpholinyl-N- oxide, 1-oxo-l-thiomorpholinyl and 1,1-dioxo-l-thiomorpholinyl.

[0099] “Heterocycloalkyl” also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 8 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 8 ring atoms, optionally contains 1-3 heteratoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.

[0100] As used herein, “heterocycloalkloxy” refers to the group -O-heterocycloalkyl.

[0101] As used herein, “sulfanyl” refers to the groups: -S-(optionally substituted (Ci-Ce)alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl). Hence, sulfanyl includes the group Ci-Ce alkyl sulfanyl.

[0102] As used herein, “sulfinyl” refers to the groups: -S(O)-(optionally substituted (Ci- Ce)alkyl), -S(O)-optionally substituted aryl), -S(O)-optionally substituted heteroaryl), -S(O)- (optionally substituted heterocycloalkyl); and -S(O)-(optionally substituted amino).

[0103] As used herein, “sulfonyl” refers to the groups: -S(O)2-(optionally substituted (Ci- Ce)alkyl), -S(O)2-optionally substituted aryl), -S(O)2-optionally substituted heteroaryl), -S(O)2- (optionally substituted heterocycloalkyl), and -S(O)2-(optionally substituted amino).

[0104] As used herein, “aminosulfonyl” refers to the group -S(O)2NRbRc, where:Rbis selected from H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, optionally substituted alkoxy; andRcis selected from hydrogen and optionally substituted C1-C4 alkyl; orRband Rctaken together with the nitrogen to which they are bound, form an optionally substituted 5- to 8-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, N, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-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(CI-C4 alkyl)(Ci-C4 alkyl), -NH(Ci-C4 alkyl), -N(CI-C4 alkyl)(Ci-C4 alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCi-C4 alkyl, -CON(CI-C4alkyl)(Ci-C4alkyl), -CONH(CI-C4alkyl), -CONH2, -NHC(O)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)Ci-C4alkyl, -SO2(Ci-C4alkyl), - SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(CI-C4alkyl), -SO2NH(phenyl), - NHSO2(CI-C4 alkyl), -NHSO2(phenyl), and -NHSO2(CI-C4 haloalkyl).

[0105] As used herein, “substituted” refers to any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom’s normal valence is not exceeded. When a substituent is oxo (i.e., =0) then 2 hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility. Unless otherwise specified, substituents are named into the core structure. For example, it is tobe understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.

[0106] As used herein, the terms “substituted” alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, unless otherwise expressly defined, refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcC0NRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, azido, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -C0Rb), optionally substituted alkoxycarbonyl (such as -C02Rb), aminocarbonyl (such as -C0NRbRc), -0C0Rb, -0C02Ra, -0C0NRbRc, -0P(0)(0Rb)0Rc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SChR3and -S02NRbRc), whereRais selected from optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; Rbis selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRcis selected from hydrogen and optionally substituted C1-C4 alkyl; orRbandRc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-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(CI-C4alkyl)(Ci-C4alkyl), -NH(CI-C4alkyl), -N(CI-C4alkyl)(Ci-C4alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OCi-C4alkyl, -CON(CI-C4alkyl)(Ci-C4alkyl), -C0NH(CI-C4alkyl), -C0NH2, -NHC(O)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)C1-C4alkyl, -SO2(Ci-C4alkyl), -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(Ci-C4 alkyl), -SO2NH(phenyl), -NHSO2(Ci-C4 alkyl), -NHSO2(phenyl), and -NHSO2(CI-C4haloalkyl).

[0107] 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 the carbonyl functionality and wherein substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, refer respectively to alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from:-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcC0NRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -C0Rb), optionally substituted alkoxycarbonyl (such as -C02Rb), aminocarbonyl (such as -C0NRbRc), -0C0Rb, -0C02Ra, -0C0NRbRc, -0P(0)(0Rb)0Rc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SChR3and -S02NRbRc), where Rais selected from optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;Rbis selected from H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRcis selected from hydrogen and optionally substituted C1-C4 alkyl; orRbandRc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-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(CI-C4alkyl)(Ci-C4alkyl), -NH(CI-C4alkyl), -N(CI-C4alkyl)(Ci-C4alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OCi-C4alkyl, -C0N(CI-C4alkyl)(Ci-C4alkyl), -C0NH(CI-C4alkyl), -C0NH2, -NHC(0)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)C1-C4alkyl, -SO2(Ci-C4alkyl), -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(Ci-C4 alkyl), -SO2NH(phenyl), -NHSO2(Ci-C4 alkyl), -NHSO2(phenyl), and -NHSO2(CI-C4haloalkyl).

[0108] As used herein, “substituted alkoxy” refers to alkoxy wherein the alkyl constituent is substituted (i.e. -©-(substituted alkyl)) wherein “substituted alkyl” refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -C0Rb), optionally substituted alkoxycarbonyl (such as -C02Rb), aminocarbonyl (such as -C0NRbRc), -0C0Rb, -0C02Ra, -0C0NRbRc, -0P(0)(0Rb)0Rc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SChR3and -S02NRbRc), where Rais selected from optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;Rbis selected from H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRcis selected from hydrogen and optionally substituted C1-C4 alkyl; orRbandRc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-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(CI-C4alkyl)(Ci-C4alkyl), -NH(CI-C4alkyl), -N(CI-C4alkyl)(Ci-C4alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OCi-C4alkyl, -C0N(CI-C4alkyl)(Ci-C4alkyl), -C0NH(CI-C4alkyl), -C0NH2, -NHC(0)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)C1-C4alkyl, -SO2(Ci-C4alkyl), -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(Ci-C4 alkyl), -SO2NH(phenyl), -NHSO2(Ci-C4 alkyl), -NHSO2(phenyl), and -NHSO2(CI-C4haloalkyl).

[0109] In some embodiments, a substituted alkoxy group is “polyalkoxy” or -©-(optionally substituted alkylene)-(optionally substituted alkoxy), and includes groups such as - OCH2CH2OCH3, and residues of glycol ethers such as polyethyleneglycol, and - O(CH2CH2O)XCH3, where x is an integer of 2-20, such as 2-10, and for example, 2-5. Another substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, where y is an integer of 1-10, such as 1-4.

[0110] As used herein, “substituted alkoxycarbonyl” refers to the group (substituted alkyl)- O-C(O)- wherein the group is attached to the parent structure through the carbonyl functionalityand wherein substituted refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -C0Rb), optionally substituted alkoxycarbonyl (such as -C02Rb), aminocarbonyl (such as -C0NRbRc), -0C0Rb, -0C02Ra, -0C0NRbRc, -0P(0)(0Rb)0Rc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SChR3and -S02NRbRc), where Rais selected from optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;Rbis selected from H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRcis selected from hydrogen and optionally substituted C1-C4 alkyl; orRbandRc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-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(CI-C4alkyl)(Ci-C4alkyl), -NH(CI-C4alkyl), -N(CI-C4alkyl)(Ci-C4alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OCi-C4alkyl, -C0N(CI-C4alkyl)(Ci-C4alkyl), -C0NH(CI-C4alkyl), -C0NH2, -NHC(0)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)C1-C4alkyl, -SO2(Ci-C4alkyl), -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(Ci-C4 alkyl), -SO2NH(phenyl), -NHSO2(Ci-C4 alkyl), -NHSO2(phenyl), and -NHSO2(CI-C4haloalkyl).

[0111] As used herein, “substituted amino” refers to the group -NHRdor -NRdRewherein Rdis selected from hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein Reis selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocycloalkyl, and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from:-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcC0NRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -C0Rb), optionally substituted alkoxycarbonyl (such as -C02Rb), aminocarbonyl (such as -C0NRbRc), -0C0Rb, -0C02Ra, -0C0NRbRc, -0P(0)(0Rb)0Rc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SChR3and -S02NRbRc), where Rais selected from optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;Rbis selected from H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRcis selected from hydrogen and optionally substituted C1-C4 alkyl; orRbandRc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-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(CI-C4alkyl)(Ci-C4alkyl), -NH(CI-C4alkyl), -N(CI-C4alkyl)(Ci-C4alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OCi-C4alkyl, -C0N(CI-C4alkyl)(Ci-C4alkyl), -C0NH(CI-C4alkyl), -C0NH2, -NHC(0)(CI-C4alkyl), -NHC(O)(phenyl), -N(CI-C4alkyl)C(O)(Ci-C4alkyl), -N(CI-C4alkyl)C(O)(phenyl), -C(O)Ci-C4alkyl, -C(O)Ci-C4alkylphenyl, -C(O)Ci-C4haloalkyl, -OC(O)C1-C4alkyl, -SO2(Ci-C4alkyl), -SO2(phenyl), -SO2(Ci-C4haloalkyl), -SO2NH2, -SO2NH(Ci-C4 alkyl), -SO2NH(phenyl), -NHSO2(Ci-C4 alkyl), -NHSO2(phenyl), and -NHSO2(Ci-C4 haloalkyl); and wherein optionally substituted acyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.

[0112] The term “substituted amino” also refers to N-oxides of the groups -NHRd, and NRdRdeach as described above. N-oxides can be prepared by treatment of the correspondingamino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.

[0113] Compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. In addition, compounds include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds. Where compounds described herein exist in various tautomeric forms, the term “compound” is intended to include all tautomeric forms of the compound.

[0114] 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, as well as mixtures thereof. “Crystalline form,” “polymorph,” and “novel form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. 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 the pharmaceutically acceptable salts, as well as mixtures thereof.

[0115] A “solvate” is formed by the interaction of a solvent and a compound. The term “compound” is intended to include solvates of compounds. Similarly, “pharmaceutically acceptable salts” includes solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemihydrates.

[0116] Compounds disclosed herein also include other pharmaceutically acceptable forms of the recited compounds, including chelates, non-covalent complexes, prodrugs, and mixtures thereof.

[0117] 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 compounds. Similarly, “pharmaceutically acceptable salts” includes chelates of pharmaceutically acceptable salts.

[0118] A “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term “compound’. Similarly, “pharmaceutically acceptable salts” includes “non-covalent complexes” of pharmaceutically acceptable salts.

[0119] The term “hydrogen bond” refers to a form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also known as a hydrogen bond donor). Suitable hydrogen bond donor and acceptors are well understood in medicinal chemistry.

[0120] “Hydrogen bond acceptor” refers to a group comprising an oxygen or nitrogen, such as an oxygen or nitrogen that is sp2-hybridized, an ether oxygen, or the oxygen of a sulfoxide or N-oxide.

[0121] The term “hydrogen bond donor” refers to an oxygen, nitrogen, or heteroaromatic carbon that bears a hydrogen. group containing a ring nitrogen or a heteroaryl group containing a ring nitrogen.

[0122] The compounds disclosed herein can be used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedure 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 the efficacy and increase the duration of action of drugs.

[0123] Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; 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.

[0124] “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxy ethyl sulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC- (CH2)n-COOH where n is 0-4, and like salts. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0125] In addition, if the compounds described herein are obtained as an acid addition salt, 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, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0126] “Prodrugs” described herein include any compound that becomes a compound of Formula I when administered to a subject, e.g., upon metabolic processing of the prodrug. Similarly, “pharmaceutically acceptable salts” includes “prodrugs” of pharmaceutically acceptable salts. Examples of prodrugs include derivatives of functional groups, such as a carboxylic acid group, in the compounds of Formula I. Exemplary prodrugs of a carboxylic acid group include, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives.

[0127] Other exemplary prodrugs include amides of carboxylic acids. Exemplary amide prodrugs include metabolically labile amides that are formed, for example, with an amine and a carboxylic acid. Exemplary amines include NEE, primary, and secondary amines such as NHRX, and NRxRy, wherein Rxis hydrogen, (Ci-Cis)-alkyl, (C3-C?)-cycloalkyl, (C3-C?)-cycloalkyl-(Ci- C4)-alkyl-, (Ce-Cuj-aryl which is unsubstituted or substituted by a residue (Ci-C2)-alkyl, (Ci- C2)-alkoxy, fluoro, or chloro; heteroaryl-, (Ce-Ci4)-aryl-(Ci-C4)-alkyl- where aryl is unsubstituted or substituted by a residue (Ci-C2)-alkyl, (Ci-C2)-alkoxy, fluoro, or chloro; or heteroaryl-(Ci-C4)-alkyl- and in which Ryhas the meanings indicated for Rxwith the exception of hydrogen or wherein Rxand Ry, together with the nitrogen to which they are bound, form an optionally substituted 4- to 8-membered heterocycloalkyl ring which optionally includes 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, Vol. 14 of the A.C.S. Symposium Series, in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergam on Press, 1987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[0128] As used herein the terms “group”, “radical” or “fragment” are synonymous and are intended to indicate functional groups or fragments of molecules attachable to a bond or other fragments of molecules.

[0129] As used herein, “modulation” 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 of in the absence of the chemical entity. The change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the compound with a target or due to the interaction of the compound with one or more other factors that in turn affect the target’s activity. For example, the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.

[0130] As used herein, “active agent” is used to indicate a chemical entity which has biological activity. In certain embodiments, an “active agent” is a compound having pharmaceutical utility. For example, an active agent may be an anti-cancer therapeutic.

[0131] 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.

[0132] As used herein, a “pharmaceutically acceptable” component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio.

[0133] As used herein, “therapeutically effective amount” of a chemical entity described herein refers to an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease.

[0134] “Treating” or “treatment” encompasses 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 an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringing about a regression in the clinical symptoms of the disease, such as cancer, and / or (iii) prophylactic treatment for preventing the onset of the disease, such as cancer.

[0135] As used herein, “cancer” refers to all types of cancer or neoplasm or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancer are cancer of the brain, breast, cervix, colon, head & neck, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and Medulloblastoma.

[0136] As used herein, “subject” refers to a mammal that has been or will be the object of treatment, observation or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a human.

[0137] The term “mammal” is intended to have its standard meaning, and encompasses humans, dogs, cats, sheep, and cows, for example.

[0138] The chemical entities described herein can be synthesized utilizing techniques well known in the art from commercially available starting materials and reagents.

[0139] The chemical entities described herein may be prepared in substantially pure form, typically by standard chromatographic methods, prior to formulation in a pharmaceutically acceptable form.

[0140] The chemical entities described herein may be used in treating 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, e.g. carcinomas, e.g., colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wiims’ tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias, e.g., acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin’s disease and non-Hodgkin’s disease), multiple myeloma, Waldenstrom’s macroglobulinemia, and heavy chain disease.

[0141] In some embodiments, the chemical entities described herein are used for the treatment of cancers of the(i) digestive system including, without limitation, the esophagus, stomach, small intestine, colon (including colorectal), liver & intrahepatic bile duct, gallbladder & other biliary, pancreas, and other digestive organs;Ill(ii) respiratory system, including without limitation, larynx, lung & bronchus, and other respiratory organs;(iii) breast;(iv) genital system, including without limitation, uterine cervix, ovary, and prostate;(v) urinary system, including without limitation, urinary bladder and kidney and renal pelvis; and(vi) oral cavity & pharynx, including without limitation, tongue, mouth, pharynx, and other oral cavity.

[0142] In some embodiments, the chemical entities described herein are used for the treatment of colorectal cancer, liver cancer, lung cancer, breast cancer and oral cancer.

[0143] Chemical entities described herein having the desired pharmacological activity may be administered, in some embodiments, as a pharmaceutically acceptable composition comprising a pharmaceutical excipient, to a patient, as described herein. Depending upon the manner of introduction, the chemical entities may be formulated in a variety of ways as discussed below. The concentration of the at least one chemical entity in the formulation may vary from about 0.01-100 wt.%.

[0144] The administration of the chemical entities described herein can be done in a variety of ways, including, but not limited to, orally, subcutaneously, intravenously, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonary, vaginally, rectally, or intraocularly.

[0145] Pharmaceutical dosage forms include at least one chemical entity described herein and one or more pharmaceutical excipients. As is known in the art, pharmaceutical excipients are secondary ingredients which function to enable or enhance the delivery of a drug or medicine in a variety of dosage forms (e.g.: oral forms such as tablets, capsules, and liquids; topical forms such as dermal, opthalmic, and otic forms; suppositories; injectables; respiratory forms and the like). Pharmaceutical excipients include inert or inactive ingredients, synergists or chemicals that substantively contribute to the medicinal effects of the active ingredient. For example, pharmaceutical excipients may function to improve flow characteristics, product uniformity, stability, taste, or appearance, to ease handling and administration of dose, for convenience of use, or to control bioavailability. While pharmaceutical excipients are commonly described as being inert or inactive, it is appreciated in the art that there is a relationship between the properties of the pharmaceutical excipients and the dosage forms containing them.

[0146] Pharmaceutical excipients suitable for use as carriers or diluents are well known in the art, and may be used in a variety of formulations. See, e.g., Remington’s PharmaceuticalSciences, 18th Edition, A. R. Gennaro, Editor, Mack Publishing Company (1990); Remington: The Science and Practice of Pharmacy, 21stEdition, Lippincott Williams & Wilkins (2005); Handbook of Pharmaceutical Excipients, 3rd Edition, A. H. Kibbe, Editor, 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.

[0147] Oral solid dosage forms such as tablets will typically comprise one or more pharmaceutical excipients, which may for example help impart satisfactory processing and compression characteristics, or provide additional desirable physical characteristics to the tablet. Such pharmaceutical excipients may be selected from diluents, binders, glidants, lubricants, disintegrants, colors, flavors, sweetening agents, polymers, waxes or other solubility -retarding materials.

[0148] Compositions for intravenous administration will generally comprise intravenous fluids, i.e., sterile solutions of simple chemicals such as sugars, amino acids or electrolytes, which can be easily carried by the circulatory system and assimilated.

[0149] Dosage forms for parenteral administration will generally comprise fluids, particularly intravenous fluids, i.e., sterile solutions of simple chemicals such as sugars, amino acids or electrolytes, which can be easily carried by the circulatory system and assimilated. Such fluids are typically prepared with water for injection USP. Fluids used commonly for intravenous (IV) use are disclosed in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins (2005). The pH of such IV fluids may vary, and will typically be from 3.5 to 8 as known in the art.

[0150] The chemical entities described herein may also be used in conjunction with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the chemical entities described herein may be useful in combination with at least one additional anti-cancer and / or cytotoxic agents. Further, the chemical entities described herein may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.

[0151] Such known anti-cancer and / or cytotoxic agents that may be used in combination with the chemical entities described herein include:(i) other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such asfluoropyrimidines like 5 -fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycinC, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;(iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran- 4yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2- chloro-6- methylphenyl)-2- {6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin-4ylamino}thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med. Chern., 2004, 47, 66586661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase];(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB 1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stem et al. Critical reviews in oncology / haematology, 2005, Vol. 54, pp 11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD 1839), N- (3 -ethynylphenyl)-6, 7-bis(2 -methoxy ethoxy)quinazolin-4- amine (erlotinib, OSI-774) and 6- acrylami do-N -(3 -chloro-4-fluorophenyl)-7-(3 - morpholinopropoxy)-quinazolin-4-amine (CI 1033), 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 (for example Ras / Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (RI15777) and lonafarnib (SCH66336)),inhibitors of cell signalling 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 (for example AZDI 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors;(v) anti angiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib(ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4 {4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3pyrrolidin-l- ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00 / 47212), compounds such as those disclosed in International Patent Applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin av~3 function and angiostatin));(vi) vascular damaging agents such as Combretastatin 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;(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan;(viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;(ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase subject tolerance to chemotherapy or radiotherapy such as multi -drug resistance gene therapy; and(x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of subject’s tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti -idiotypic antibodies.

[0152] In certain embodiments, the at least one chemical entity is administered in combination with one or more agents selected from pacliataxel, bortezomib, dacarbazine, gemcitabine, trastuzumab, bevacizumab, capecitabine, docetaxel, erlotinib, aromatase inhibitors,such as AROMASIN™ (exemestane), and estrogen receptor inhibitors, such as FASLODEX™ (fulvestrant).

[0153] When a chemical entity described herein is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual subject, as well as the severity of the subject’s symptoms.

[0154] In one exemplary application, a suitable amount of at least one chemical entity is administered to a mammal undergoing treatment for cancer, for example, breast cancer. Administration typically occurs in an amount of between about 0.01 mg / kg of body weight to about 100 mg / kg of body weight per day (administered in single or divided doses), such as at least about 0.1 mg / kg of body weight per day. A particular therapeutic dosage can include, e.g., from about 0.01 mg to about 1000 mg of the chemical entity, such as including, e.g., from about 1 mg to about 1000 mg. The quantity of the at least one chemical entity in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, such as from about 1 mg to 300 mg, for example 10 mg to 200 mg, according to the particular application. The amount administered will vary depending on the particular IC50 value of the at least one chemical entity used and the judgment of the attending clinician taking into consideration factors such as health, weight, and age. In combinational applications in which the at least one chemical entity described herein is not the sole active ingredient, it may be possible to administer lesser amounts of the at least one chemical entity and still have therapeutic or prophylactic effect.

[0155] In some embodiments, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0156] The actual dosage employed may be varied depending upon the requirements of the subject and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the at least one chemical entity. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0157] The amount and frequency of administration of the at least one chemical entities described herein, and if applicable other chemotherapeutic agents and / or radiation therapy, will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the subject as well as severity of the disease being treated.

[0158] The chemotherapeutic agent and / or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and / or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and / or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., antineoplastic agent or radiation) on the subject, and in view of the observed responses of the disease to the administered therapeutic agents.

[0159] Also, in general, the at least one chemical entities described herein need not be administered in the same pharmaceutical composition as a chemotherapeutic agent, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the chemical entities / compositions may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0160] The particular choice of chemical entity (and where appropriate, chemotherapeutic agent and / or radiation) will depend upon the diagnosis of the attending physicians and their judgment of the condition of the subject and the appropriate treatment protocol.

[0161] The chemical entities described herein (and where appropriate chemotherapeutic agent and / or radiation) may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon 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 conjunction (i.e., within a single treatment protocol) with the chemical entity / composition.

[0162] In combinational applications and uses, the chemical entity / composition and the chemotherapeutic agent and / or radiation need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the chemical entity / composition, and the chemotherapeutic agent and / or radiation, may not be important. Thus, the at least one chemical entity described herein may be administered first followed by the administration of the chemotherapeutic agent and / or radiation; or the chemotherapeutic agent and / or radiation may be administered first followed by the administration of the at least one chemical entity describedherein. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the subject. For example, the chemotherapeutic agent and / or radiation may be administered first, and then the treatment continued with the administration of the at least one chemical entity described herein followed, where determined advantageous, by the administration of the chemotherapeutic agent and / or radiation, and so on until the treatment protocol is complete.

[0163] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a chemical entity / composition for treatment according to the individual subject ‘s needs, as the treatment proceeds.

[0164] The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the subject as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease- related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.REFERENCES

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[0166] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.Example 1A: Material and Methods.

[0167] Materials. All methods were performed in accordance with the relevant guidelines and regulations of The University of Texas MD Anderson Cancer Center. RX108 was provided by NeuPharma. Na+ / K+-ATPase (isolated from porcine cerebral cortices was purchased from Sigma-Aldrich. Na+ / K+-ATPase assay kit was purchased from Genmed Scientifics. Anti-ASCT2, -Ki67, and -cleaved caspase 3 antibodies were purchased from Cell Signaling Technology. GSH, NADH, and NADPH assay kits were purchased from Promega. E- actin, anti-GAPDH antibodies, NADH, NADPH, and all other reagents were purchased from Sigma-Aldrich.

[0168] Cell culture. HepB3, Huh7, and PLC / RF5 cells were obtained from the ATCC and maintained in a humidified atmosphere containing 5% CO2 at 37 °C. 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 lU / mL; Invitrogen / Thermo Fisher Scientific), and streptomycin (10 pg / 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 pg / mL streptomycin, and 25 pg / mL amphotericin B; Gibco).

[0169] Cell proliferation. HCC cells (1 x 104) were plated in 96-well plates. After incubation for 24 h, cells were treated with various concentrations of RX108. After incubationfor an additional 72 h, inhibition of cellular proliferation was assessed using an MTT assay (Yang et al., 2019). Absorbance was read at a wavelength of 570 nm and reference wavelength of 650 nm using a VMax microplate reader (Molecular Devices).

[0170] Animal study. 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 x io6per mouse) and placed in one of three treatment groups (n = 8 per group): control, 2 mg / kg RX108, and 4 mg / kg RX108. Mice in each group were given subcutaneous injections of the study agents twice a week starting the day after tumor cell inoculation. The tumor take 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 calipers. The tumor volume was calculated using the formula (L x W2) x 0.5, where L and W represent length and width, respectively. At the end of the experiment, the mice were sacrificed, and their tumors were dissected and weighed. The tumor tissues were then processed as formalin fixative or flash frozen for related experiments.

[0171] Detection of apoptosis via Annexin V-fluorescein isothiocyanate / PI double staining. For apoptosis analysis, Hep3B cells (2.5 x 106) grown in 100-mm dishes were treated with RX108 (at 0, 3, and 30 ng / mL) for 48 h. The cells were subjected to trypsinization and centrifugation, and the pellets were suspended and washed in 1 x phosphate-buffered saline (PBS) solution and then double-stained with fluorescein isothiocyanate-conjugated Annexin V and PI as per the manufacturer’s instructions (BD Biosciences). Fluorescence was detected using a BD FACS Calibur flow cytometer and analyzed using CellQuest Pro software (BD Biosciences).

[0172] Glutamine-dependent cell growth assay. The Hep3B, Huh7 and PLC-RF5 cells were plated at 2 x io3cells / well in 96-well flat-bottom plates and cultured in DMEM or minimum essential medium with high glucose containing 10% fetal bovine serum in the presence of 0, 0.2, or 2 mM glutamine. After incubation for 24, 48, 72, and 96 h at 37 °C, viable cells were detected using a CellTiter-Glo Luminescent Cell Viability Assay (Promega) according to the manufacturer’s instructions.

[0173] Metabolic analysis using LC-MS / MS measurement. Huh7 and Hep3B cells were cultured at 2 x 106cells / mL in high-glucose DMEM supplemented with 10% fetal bovine serum and 2 mM glutamine. After incubation for 24 h at 37 °C, RX108 at its IC25 and IC50 or a vehicle was added to the cells, and they were incubated for 24 h. The cells were then trypsinized, washed with PBS twice, and subjected to LC-MS / MS using a modified version of a previously describedmethod (Chuang et al., 2009). Briefly, cells used for the analysis of citrate, isocitrate, 2HG, D- KG, malate, and fumarate were mixed with methanol / water (80:20), whereas cells used for the analysis of lactate, glutamine, and glutamate were extracted with acetonitrile / water (50:50). An Agilent 1200 HPLC system coupled with an Agilent 6460 Triple Quad MS detector was used for determining the glutamine and tricarboxylic acid (TCA) cycle metabolites. Citrate, isocitrate, 2HG, D-KG, malate, and fumarate were separated on a Phenomenex Synergi Hydro-RP column (2.5 pm, 2 x 50 mm) using 2HG-d3 as an internal standard. The mobile phase was composed of 0.1% formic acid in water 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 pm, 4.6 x 150.0 mm) using 2HG-d3 as an internal standard. Mobile phase A was composed of 0.1% formic acid in water, and mobile phase B was composed of 0.1% formic acid in acetonitrile. Lactate, pyruvate, glutamine, and glutamate were eluted using a gradient starting at 5% of B at 0 min, hold for 1 min; changed to 10% of B at 6 min, hold for 1 min; changed to 90% of B at 7.1 min, hold until 12 min; and then changed back to 5% of B at 12.1 min. All metabolites were detected using electrospray negative ionization and multiple-reaction monitoring of the transition ions for the metabolites and their internal standards. The MRM transitions for the aforementioned metabolites were 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 of glucose and glutamine metabolites were normalized according to the amount of protein.

[0174] TCA cycle metabolite analysis using ion chromatography-high-resolution MS (IC-MS). To determine the incorporation of carbon from glucose and glutamine carbon and nitrogen from glutamine (13C6-glucose and13C5- and15N2-glutamine) into the TCA cycle and intracellular amino acids in HCC cells, extracts were prepared and analyzed using high- resolution MS. About 80% confluent Hep3B cells were seeded in 10-cm dishes in triplicate. Cells were washed with glutamine-free DMEM before incubation in fresh medium containing 10 mM glucose and 2 mM13C5- and15N2-glutamine for 24 h. Cells were quickly washed with ice-cold PBS to remove extra medium components. Metabolites were extracted using cold 80 / 20 (v / v) methanol / water. Samples were centrifuged at 17,000 g for 5 min at 4 °C, and supernatants were transferred to clean tubes, which was followed by evaporation to dryness using nitrogen. Samples were reconstituted in deionized water, and 5 pL aliquot was injected into a Thermo Fisher Scientific Dionex ICS-5000+ capillary ion chromatography system containing a Thermo Fisher Scientific lonPac ASH column (250 x 2 mm, 4 pm) for TCA cycle metabolite analysis. The ion chromatography flow rate was 360 pL / min (at 30 °C), and the gradient conditionsstarted with 1 mM KOH, increased to 35 mM at 25 min and then to 99 mM at 39 min, and at 99 mM for 10 min. The total run time was 50 min. To assist the desolvation for increased sensitivity, methanol was delivered using an external pump and combined with the eluent using a low dead-volume mixing tee. The metabolic Data were acquired using a Thermo Fisher Scientific Orbitrap Fusion Tribrid mass spectrometer in electrospray ionization-negative mode.

[0175] NADP / NADPH and GSH assays. For the NADP / NADPH assay, Hep3B and Huh7 cells (6 x io3) were plated in white 96-well transparent, flat-bottom white plates overnight. They were then treated with RX108 (3 and 30 ng / mL) for 4 h. Following 24 h incubation, the cell culture medium was aspirated, and an aliquot of 50 pL of PBS was added to each well. Cell samples were prepared directly in the 96-well plates by adding 50 pL of base solution (0.2N NaOH with a final concentration of 1% DTAB; #D8638, Sigma) for a total of 100 pL per sample. The cell sample were lysed and divided into two aliquots of 50 pL. To measure the NADP levels in the medium, 25 pL of 0.4N HC1 was added to 50 pL of 0.2N NaOH lysed cell sample, and heated at 60°C for 15 min, followed by incubation at room temperature for 10 min. A 25 pL aliquot of Trizma base solution was added to each well. To measure the NADPH level, cell lysates were heated at 60°C for 15 min and incubated at room temperature for 10 min, and 50 pL of HCl / Trizma base solution was added to each well containing base solution -treated samples. A detection reagent was prepared as per 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 is 100 pL for NADP and NADPH samples. To perform the NADP / NADPH-Glo assay, 100 pL of NADP / NADPH-Glo Detection Reagent directly added to each well. Standard curves for NADP (#N8035, Sigma) and NADPH (#N9910, Sigma) were generated according to the manufacturer’s instructions. A standard curve allows conversion of luminescence (in RLU) to NADP+ or NADPH concentration. Net luminescence values were used to generate the standard curve and performed linear regression analysis. The amount of NADP or NADPH was interpolated by comparing net luminescence values of the experimental samples to the values in the standard curve. Luminescence was read using a VMax molecular probe plate reader (Molecular Devices).

[0176] A GSH assay was carried out using a GSH-Glo kit (#V6611, Promega). Hep3B and Huh7 cells were plated in black 96-well plates (1 x 104cells / well). Cells were treated with RX108 at 3 and 30 ng / mL for 24 h. The cell culture media were then removed, an aliquot of 100 pL of 1 x GSH-Glo reagent was added to each well and incubated at room temperature for 30 min on a shaker. An aliquot of 100 pL of reconstituted luciferin detection reagent was added to each well and mixed briefly on a plate shaker. The plate was incubated at room temperature for 15 min. Luminescence was measured using a microplate reader (Molecular Devices). Astandard curve of GSH was generated using a standard GSH solution (5 mM) to facilitate conversion of luminescence (in relative light units) to GSH concentration as per the manufacturer’s instructions.

[0177] Mitochondrial metabolism. Huh7 cells were plated (about 8000 cells per well) in an XF96-well plate (Seahorse Bioscience, Massachusetts, USA) and treated with vehicle and RX108 (3 and 30 ng / mL) for 24 hrs. Immediately before the respiration assay, the medium was changed to unbuffered DMEM containing glucose (10 mM), pyruvate (10 mM) and GlutaMAX (2 mM; Invitrogen). Mitochondrial respiration oxygen consumption rate (OCR) was measured by a Seahorse Extracellular Flux Analyzer XF96 (Seahorse Bioscience) according to the manufacturer’s instruction. Firstly, basal respiration was measured in an unbuffered medium. Then oligomycin (2 pg / mL) was added to inhibit ATP synthesis and to detect respiration linked to ATP production. The uncoupler carbonyl cyanide 4-(trufluoromethoxy) phenylhydrazone (FCCP, 2 pM) was applied to measure respiratory reserve capacity and maximal respiration. Finally, combination of rotenone and antimycin A (rot & AA, 4 pM) 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 was calculated and generated by Seahorse XF Mito Stress Test Report Generator.

[0178] Immunoblotting. Cellular protein samples were extracted using sodium dodecyl sulfate buffer. Total protein (25 pg / well) was separated on a 10-15% sodium dodecyl sulfate gel and transferred onto polyvinylidene fluoride membranes. The membranes were blocked with 5% nonfat milk in a Tris-buffered saline solution and then probed with primary antibodies at 4°C overnight. The membranes were visualized using SuperSignal substrate (Pierce ECL Plus; Thermo Fisher Scientific). E-actin or GAPDH was detected for normalization of results.

[0179] siRNA transfection. Hep3B cells were plated in six-well plates and allowed to attach overnight. Transient transfection of nonspecific siRNA (control siRNA) and ASCT2 siRNA (OriGene Technologies) into the cells was carried out using Lipofectamine RNAiMAX reagent (Thermo Fisher Scientific) following the manufacturer’s instructions. Beginning 48 h after transfection, cells were treated with a vehicle control or RX108 for 24 h. Protein was collected for Western blot analysis.

[0180] Histopathology and immunohistochemistry. Formalin-fixed tumor samples were paraffin-processed for biomarker identification using immunohistochemical staining. For this staining, slides were baked at 60°C for more than 2 h and then deparaffinized and rehydrated. Antigens were unmasked via heat-induced antigen retrieval. Slides were then immersed in a 3% H2O2-methanol solution followed by blocking with 5% goat serum in 0.3% Triton X-100 PBS. Slides were stained with antibodies against ASCT2, cleaved caspase 3, or Ki67 in a humidifiedchamber overnight at 4°C. Next, slides were washed three times with PBS and then incubated with a secondary antibody at room temperature for 45 min. Slides were incubated with avidinbiotin complex (Vector Laboratories) followed by 3,3 '-diaminobenzidine substrate for antibody visualization and counterstained with Mayer’s hematoxylin, dehydrated, and mounted using Clear Mount mounting medium (American Master Tech; Al-Hassan et al., 2021).

[0181] Statistical analysis. The Student Ltest was used to determine the significance of differences between control and treatment groups. P values of up to 0.05 were considered significant. One-way analysis of variance was used to determine Significant differences in mean values in more than two groups. All analyses were performed using Prism software (version 9.0; GraphPad Software).Example IB: Results.

[0182] Inhibitory activity against Na+ / K+-ATPase. The inhibitory activity of RX108 (Chemical structure in FIG. 1A) was measured against Na+ / K+-ATPase (isolated from porcine cerebral cortices) using an enzyme-linked assay. RX108 exhibited dose-dependent inhibition of Na+ / K+-ATPase (FIG. IB), and its potency (IC50, 25.7 nM) was greater than that of ouabain (IC50, 232.5 nM), a known inhibitor of Na+ / K+-ATPase.

[0183] Antiproliferative effect on HCC cells and in a xenograft model. 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, whereas using immortalized human hepatic LO2 cells as control cells. As shown in FIG. 1C, RX108 exposure significantly inhibited Huh7 and Hep3B cell growth in a time- and dose-dependent manner, with median inhibitory concentrations (IC50) of greater than 100.0, 2.2, and 0.8 ng / mL in Huh7 cells and greater than 100.0, 3.4, and 0.8 ng / mL in Hep3B cells when given for 24, 48, and 72 h, respectively (FIGS.1C1 &1C2). In contrast, treatment with RX108 at 3.2 ng / mL for 72 h slowed the growth of LO2 cells by 54.5%, but the inhibition rate of cell growth remained at similar levels even at concentrations as high as 100 ng / mL (FIG. 1C3). To further evaluate the antitumor effect of RX108 on HCC, an antitumor efficacy study was conducted using a human Huh7-cell HCC mouse xenograft model. RX108 (4 mg / kg) exposure significantly inhibited tumor growth in a dose-dependent manner as indicated by reduced tumor volume and weight (FIGS. 1D1 & 1D2).

[0184] Induction of apoptosis in HCC cells. To examine the potential mechanisms by which RX108 inhibits the growth of Hep3B cells, Annexin V staining was performed followed by flow cytometry analysis of these cells. Treatment with RX108 dose-dependently induced apoptosis and necrosis in Hep3B cells as indicated by propidium iodide (PI)- / Annexin V+cell percentages of 1.59% ± 0.58%, 2.98% ± 1.10%, and 5.50% ± 1.43% and PH7 Annexin V+cellpercentages of 6.40% ± 1.36%, 9.13% ± 1.06%, and 16.82% ± 2.39% after treatment with RX108 at doses at 0, 3, and 30 ng / mL, respectively (FIG. 2A). Representative flow cytometry chromatograms of the Hep3B cells treated with different doses of RX108 are shown in FIG. 2B.

[0185] Effect of RX108 on HCC cell metabolism. To further assess the effect of RX108 on HCC cell metabolism, Huh7 and Hep3B cells were treated with RX108 at 0 (vehicle control) and its IC25 and IC50 values for 24 h. The levels of metabolites involved in glycolysis, the TCA cycle, and glutamine metabolism were then measured using liquid chromatography (LC)-tandem mass spectrometry (MS / MS). As shown in FIG. 3 A, RX108 significantly decreased the concentrations of glutamine, glutamate, D-ketoglutarate (D-KG), 2-hydroxyglutarate (2HG), malate, pyruvate, and lactate and increased the concentration of fumarate in Huh7 cells in a dose-dependent manner. Drastic reduction of the glutamine concentration in Hep3B cells was also detected (FIG. 3B). Similar trends were observed for glutamate, D-KG, and 2HG. These data suggested that RX108 exerts its antitumor effect by interfering with glutamine-driven TCA cycling, thereby inhibiting a major source of cellular energy production (Li and Le, 2018; Yang et al., 2017).

[0186] Effect on cell energy metabolism. Considering that glutamine metabolism is critical for the energy of tumor cells (Reinfeld et al., 2021) and to further interrogate whether glutamine metabolism is essential for RX108-elicited inhibition of energy metabolism in HCC cells, metabolic flux analysis was performed using stable isotope-labeled energy substrates13C6- glucose and13C5,15N2-glutamine in Hep3B cells using ion-chromatography and mass spectrometry (IC-MS). As shown in FIG. 4A, the levels of glutamine-derived (M+5, M+4) citrate were markedly lower in RX108-treated Hep38 cells than in vehicle-treated control cells. Similarly, Hep3B cells cultured with13C6-glucose and treated with RX108 had 61% lower unlabeled glucose-derived (M+2) citrate levels than did the control cells (p < 0.0001) (FIG. 4B). Together, these observations indicate that RX108 affects both glucose- and glutamine-driven TCA cycling.

[0187] As glutamine is a main precursor of the antioxidant glutathione (GSH), which is important for cellular function and cancer cell metabolism, the levels of GSH in Hep3B and Huh7 cells after treatment with RX108 were then measured. FIG. 4C shows that RX108 significantly and dose-dependently decreased GSH levels in Hep3B cells after treatment for 4 h. Similar results were observed in Huh7 cells, although the percent reduction in GSH level was less pronounced than that in Hep3B cells (FIG. 4D). To determine whether RX108 affects both the TCA cycle and pentose phosphate pathway in HCC cells, the production of NADH and NADPH, respectively, was measured. The levels of NADH and NADPH in Hep3B and Huh7 cells were significantly decreased by at least 50% after treatment with RX108 (3 and 30 ng / mL)(FIGS. 4E & 4F). The decrease in NADH and NADPH level in these cells was concentration dependent. Finally, to determine the effect of RX108 on mitochondrial respiration function, a Seahorse mitochondrial stress test was performed with Hep3B cells after treatment with RX108. RX108-treated cells had lower basal / spare respiratory capacity than did vehicle-treated control cells as well as maximal respiratory capacity (FIG. 4G), suggesting that RX108 inhibits mitochondrial respiration. Taken together, these data strongly suggested that RX108 modulated mitochondrial function and redox metabolism through glycolysis, the TCA cycle, and the pentose phosphate pathway in HCC cells.

[0188] Effect of ASCT2 on RX108 elicited antiproliferative activity in HCC cells and overall survival of patients with HCC. Since glutamine uptake is dependent on ASCT2, a Na+- dependent neutral amino acid transporter encoded by solute-linked carrier family Al member 5 (Kekuda et al., 1996), it was determined whether RX108 affects the expression of ASCT2 in HCC cells. As shown in FIG. 5 A, RX108 significantly suppressed ASCT2 protein expression in both Hep3B and Huh7 cells as determined via Western blot analysis (FIG. 5A1), and the quantitative data on ASCT2 expression are shown in FIG. 5A2. Next, it was sought to define the effects of ASCT2 expression on HCC proliferation and response to treatment with RX108. As shown in FIG. 5B, transfection of ASCT2 siRNA drastically downregulated ASCT2 protein expression (FIGS. 5B1 & 5B2) and inhibited the growth of Hep3B cells (FIGS. 5B3 & 5B4), suggesting that ASCT2 and relevant reduction of the glutamine level are essential for the proliferation of Hep3B cells. Consistently, it was found that RX108 significantly inhibited the proliferation of control siRNA-transfected Hep3B cells by 31% but that the antiproliferative activity induced by RX108 (3 ng / mL) was lower in ASCT2-knockdown Hep3B cells than in vehicle control -treated ASCT2-knockdown cells (FIGS. 5B3 & 5B4). Taken together, these data demonstrated that the antiproliferative effect of RX108 is dependent on glutamine transport.

[0189] To further elaborate the essential role of glutamine in HCC proliferation, the effect of glutamine availability on the growth of HCC cells was investigated. HCC liver cell lines Huh7, Hep3B, and PLC / RF5 were cultured with media supplemented with different concentrations of glutamine for 24, 48, 72 and 96 h. While cell growth was induced in the presence of 0.2 or 2 mM glutamine, the growth was clearly decreased or stopped under glutamine-deprived conditions (control group) (FIGS. 5C1 & 5C2). These results suggested that glutamine is essential for the growth of these HCC cell lines.

[0190] To provide further evidence of the clinical significance and translational value of the findings on ASCT2 in HCC, multiple publicly available databases were searched, and it was consistently found that high ASCT2 mRNA expression was inversely correlated with survival of HCC (FIGS. 5D1-5D3), which is in line with the results of a previous study in whichresearchers used an immunohistochemical assay to analyze ASCT2 protein expression in HCC samples (Sun et al., 2016). These data suggested that the expression of ASCT2 is a prognostic marker and therapeutic target for HCC, which provides the rationale for using RX108 to target HCC in a subgroup of HCC patients with tumors that express ASCT2 protein at high levels.

[0191] Effect on glutamine metabolism and cell proliferation in xenograft model. To further understand the underlying mechanisms by which RX108 exerts its inhibitory effect on HCC tumorigenesis, expression of proteins related to ASCT2, Ki67 and cleaved caspase 3 were examined using immunohistochemical staining of xenograft tumors derived from mice receiving treatment with RX108 or a vehicle control. As shown in FIG. 6A, RX108 significantly reduced ASCT2 staining in Huh7 tumors in a dose-dependent manner. Similarly, RX108 resulted in markedly lower Ki67 staining intensity (FIG. 6B1) but higher cleaved caspase 3 staining intensity (FIG. 6C1) than did the control treatment; the quantitative staining data are shown in FIG. 6B2 and FIG. 6C2, respectively. Consistent with the in vitro data on glutamine metabolism (see FIG. 3), RX108 significantly reduced the concentrations of glutamine and glutamate in tumor tissues in a dose-dependent manner (FIG. 6D). A similar trend was also observed regarding the concentration of D-KG in tumor samples, but the difference was not statistically significant.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. 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 a Na+ / K+-ATPase (NKA) inhibitor.

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 of 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 of 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.

5. The method of claim 4, wherein the volume is reduced by at least 25%.

6. The method of either 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 a cancer associated with elevated ASCT2 expression in a cell comprising contacting the cell with an NKA inhibitor.

8. The method of claim 7, wherein modulating decreases the concentration of the one or more biomarkers.

9. The method of either claim 7 or claim 8, wherein the modulating decreases the concentration of the one or more biomarkers by at least 25%.

10. The method according to any one of claims 7-9, wherein the modulating decreases the concentration of the one or more biomarkers by at least 50%.

11. The method according to any one of claims 7-10, wherein modulating increases the concentration of the one or more biomarkers.

12. The method according to any one of claims 7-11, wherein the one or more biomarkers are selected from: glutamine, glutamate, a-ketoglutarate (a-KG), 2-hydroxy glutarate (2HG), glutathione (GSH), malate, pyruvate, lactate, and fumarate.

13. The method according to any one of claims 7-12, wherein modulating decreases the concentration of the one or more biomarkers selected from: glutamine, glutamate, a- ketoglutarate (a-KG), 2-hydroxyglutarate (2HG), glutathione (GSH), malate, pyruvate, and lactate.The method according to any one of claims 7-13, wherein modulating increases the concentration of fumarate. The method according to any one of claims 7-14, wherein the level of NADH or NADPH is reduced by at least 50%. A method of suppressing ASCT2 protein expression in a cell comprising contacting the cell with an NKA inhibitor. A method of reducing the rate of proliferation of a cancer cell comprising contacting the cell with an NKA inhibitor, wherein the cancer is associated with elevated ASCT2 expression. The method of claim 17, wherein the rate of proliferation is reduced by at least 10%. The method of either claim 17 or claim 18, wherein the rate of proliferation is reduced by at least 30%. The method according to 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. The method according to 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. The method according to any one of claims 7-21, wherein the cellular concentration of the NKA inhibitor is about 3 ng / mL. The method according to any one of claims 7-21, wherein the cellular concentration of the NKA inhibitor is about 30 ng / mL. The method according to 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, mouth, ovary, pancreas, prostate, rectum, skin, stomach, throat, thymus, thyroid, or uterus. The method according to 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), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC / HCC), lung adenocarcinoma (LU AD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), sarcoma (SARC), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), thyroid carcinoma(THCA), thymoma (THYM), uterine corpus endometrial carcinoma (UCEC), or uterine carcinosarcoma (UCS). The method according to any one of claims 1-25, wherein the cancer is of the bile duct, brain, liver, mouth, or throat. The method according to any one of claims 1-26, wherein the cancer is of the bile duct. The method according to any one of claims 1-27, wherein the cancer is cholangiocarcinoma (CHOL). The method according to any one of claims 1-26, wherein the cancer is of the brain. The method according to any one of claims 1-26 and 29, wherein the cancer is glioblastoma multiforme (GBM). The method according to any one of claims 1-26, wherein the cancer is of the brain. The method according to any one of claims 1-26 and 29, wherein the cancer is glioblastoma multiforme (GBM). The method according to any one of claims 1-26, wherein the cancer is of the liver. The method according to any one of claims 1-26 and 33, wherein the cancer is liver hepatocellular carcinoma (LH4C / HCC). The method according to any one of claims 1-26, wherein the cancer is of the mouth or throat. The method according to any one of claims 1-26 and 35, wherein the cancer is head and neck squamous cell carcinoma (HNSC). The method according to any one of claims 1-36, wherein the NKA inhibitor is a bufadienolide derivative, or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-37, wherein the NKA inhibitor is a compound of formula (I):wherein: each dashed bond independently represents a single bond or a double bond; n, p, and q are independently selected from 0 and 1; andRi, R2, R3, R4, R5, Re, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted alkloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Rs, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0); orR4 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;Li is selected from a covalent bond, *-C(0)0-, *-[C(Ra)(Rb)]s-O-, and *- [C(Ra)(Rb)]s-C(O)O-, wherein * indicates the point of attachment of Li to Z, further wherein:Raand Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; orRaand Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; orR15 and one occurrence of Ra are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Z is selected from -OR14 and -NR15R16, wherein:R14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionallysubstituted acyl, optionally substituted alkoxycarbonyl, and -P(=O)(ORi7)(ORis), wherein:R17 and Ris are independently selected from hydrogen and optionally substituted alkyl; andRis is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, - CO2R19, -CONR20R21, -C(NR22)NR2OR21, -C(NCN)NR2OR2I, - SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R20 and R21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; orR15 and Ri6 are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3;Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, 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 carbaminodoyl, and optionally substituted alkynyl;R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.The method according to any one of claims 1-38, wherein the NKA inhibitor is a compound of formula (I-A):(I-A) wherein: each dashed bond independently represents a single bond or a double bond; n, p, and q are independently selected from 0 and 1; andRi, R2, R3, R4, Rs, Rs, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkloxy, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Rs, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0); orR4 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;Li is selected from a covalent bond, *-C(0)0-, *-[C(Ra)(Rb)]s-O-, and *- [C(Ra)(Rb)]s-C(O)O-, wherein * indicates the point of attachment of Li to Z, further wherein:Raand Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; orRaand Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; orR15 and one occurrence of Ra are together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Z is selected from -OR14 and -NR15R16, wherein:R14 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(=0)(0Ri7)(0Ris), wherein:Ri7 and Ris are independently selected from hydrogen and optionally substituted alkyl;Ris is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, - CO2R19, -CONR20R21, -C(NR22)NR2OR21, -C(NCN)NR2OR2I, - SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R20 and R21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; orR15 and Ri6 are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3;Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substitutedalkoxycarbonyl, 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 carbaminodoyl, and optionally substituted alkynyl;R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-39, wherein the NKA inhibitor is a compound of Formula (II):wherein: each dotted line represents a single bond or a double bond; n, p, and q are each independently selected from 0 and 1; andRi, R2, R3, R4, R5, Rs, R9, Rio, R11 and R12 are 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted ammo; orRi and R2, or R5 and Rs, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0); orR4 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, -CO2R19, -CONR20R21, -C(NR22)NR2oR2i, -C(NCN)NR2oR2i, -SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R20 and R21 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein:m is selected from 0, 1, 2, and 3; wherein Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, 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 carbaminodoyl, and optionally substituted alkynyl;R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-40, wherein the NKA inhibitor is a(II-A) wherein:Ri, R2, R3, R4, Rs, Rs, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Rs, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0); orR4 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;Ri6 is -CONR20R21, where R20 and R21 are joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3;Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substitutedalkenyl, 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 carbaminodoyl, and optionally substituted alkynyl; andR24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.The method according to any one of claims 1-39, wherein the NKA inhibitor is a compound of formula (III):QU) wherein: the dotted line represents a single bond or a double bond; n is selected from 0 and 1;Ri, R2, R3, R5, Re, R9, Rio, R11 and R12, are 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; orRi and R2, or R5 and Re, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group (=0);R.4 is hydroxy, 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 heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;R13 is selected from hydrogen, optionally substituted alkyl, and formyl;Z is selected from OR14 and NR15R16; whereinR14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;Ri6 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R15 and Ri6 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Wi is selected from the following moi eties:wherein: m is selected from 0, 1, 2, and 3;Y is selected from O and NR24;R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substitutedalkoxycarbonyl, 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 carbaminodoyl, and optionally substituted alkynyl;R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andW2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-39 and 42, wherein the NKA inhibitor is a compound of formula (III), or a pharmaceutically acceptable salt thereof, provided that when R4 is OH, R13 is methyl,-oxo-2H-pyran-5-yl), and Ri, R2, R3, Rs, Rs,R7, Rs, R9, Rio, R11, and W2 are hydrogen then R12 is not hydrogen.The method according to 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: the dotted line represents a single bond or a double bond; n is selected from 0 and 1;Ri, R2, Rs, Rs, Rio, R11, R12 and W2 are hydrogen; R3 and R9 are independently hydrogen or OH;R4 is hydroxy and R5 is hydrogen, or R4 and R5 may optionally be joined together with any intervening atoms to form an oxirane ring;R7is -OCOCH3;R13 is methyl;Z is NR15R16, wherein:R15 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;Ri6 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; or R15 and Ri6 are joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; andWi is selected from:The method according to 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, provided that the compound is not a compound of Formula III in which: R4 is OH, R13 is methyl,-oxo-2H-pyran-5-yl), and Ri, R2, R3, R5, Rs, R7, Rs, R9, Rio, Ru, R12 and W2 are hydrogen. The method according to any one of claims 1-39, wherein the NKA inhibitor is:(a) a compound of F ormula (IV -A) :wherein:Z is selected from OR14 and NR15R16, wherein:R14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi6 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R15 and Ri6 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;(b) a compound of Formula (IV-B):(IV-B) wherein:R15 and Ri6 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or Ri and R2 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;Raand Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or Raand Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; or R15 and one occurrence of Ra 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) a compound of Formula (IV-C):(IV-C) wherein:Rais selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; andRi4 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)(OR?)(ORs), where R7 and Rs are independently selected from hydrogen and optionally substituted alkyl; or a pharmaceutically acceptable salt of the compound of any of these formulae. The method according to 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. The method according to 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. The method according to 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. The method according to any one of claims 1-49, wherein the NKA inhibitor is a compound selected from:2-aminoethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-hydroxy ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-(pyrrolidin-l-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate;2-((R)-3-hydroxypyrrolidin-l-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10, 13 -dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro- 1H- cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-(3 -oxopiperazin- l-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate; l-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2 -hydroxy ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-l- yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -yl)-4-m ethylpiperazine- 1 - carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methylpiperazin-l- yl)ethyl)urea;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide;(R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4-diazepane-l- carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,4-diazepane-l- carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-oxopiperazine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-l- yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3-oxopiperazin-l- yl)ethyl)urea;l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3- hydroxypyrrolidin-l-yl)ethyl)urea;1-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3- hydroxypyrrolidin-l-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)acetamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3- methylbutanamide;(R)-2-amino-Nl-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)succinamide;(S)-2-amino-Nl-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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-l-yl)ethoxy)carbonyl)amino)hexadecahydro-lH- 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)hexadecahydro-lH- 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 -y 1) - 3 -(((2-(3 -oxopiperazin- 1 -yl)ethoxy)carbonyl)amino)hexadecahy dro- 1 Iley cl openta[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-l-yl)ethyl)ureido)hexadecahydro-lH- 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)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4- methylpiperazine- 1 -carb oxami do)- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro- 1 Iley cl openta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(3-(2-(4- methylpiperazin-l-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4- carboxami do)- 17-(2-oxo-2H-pyran-5 -yl)hexadecahy dro- 1 Iley cl openta[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)hexadecahydro-lH-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-l-carboxamido)hexadecahydro-lH-cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(l,4-diazepane-l-carboxamido)-14-hydroxy-10, 13 -dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro- 1H- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-l,4- diazepane-l-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- 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-l-carboxamido)hexadecahydro-lH- 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-l-yl)ethyl)ureido)hexadecahydro-lH- 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-l-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- 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 -y 1) - 3 -(3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-(pyrrolidin-l-yl)ethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate;2-(3 -oxopiperazin- l-yl)ethyl ((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate; l-(2-aminoethyl)-3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5 -yl)hexadecahy dro- 1 H-cy cl openta[a]phenanthren-3 -yl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 ) -3 -(2-(pyrroli din- 1 - yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -yl)piperazine- 1 - carboxamide; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(piperazin-l- 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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4-diazepane-l- carboxamide;N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 ) -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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)pyrrolidine- 1 -carboxamide; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin- l-yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2- oxopiperazin- 1 -yl)ethyl)urea;l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3-oxopiperazin- l-yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3- hydroxypyrrolidin-l-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3- hydroxypyrrolidin-l-yl)ethyl)urea;2-(pyrrolidin- 1 -yl)ethyl ((3 S,8R,9S, 1 OR, 13R, 14S, 17R)- 14-hydroxy- 10,13 -dimethyl- 17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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- 1 Iley cl openta[a]phenanthren-3-yl)carbamate;2-(3 -oxopiperazin- l-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-lH-cyclopenta[a]phenanthren-3-yl)carbamate; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(pyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)piperazine-l -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -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,l l,12,13,14,15,16,17-tetradecahydro-lH- 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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)ureido)butanoic acidN-((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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)-4-methylpiperazine-l -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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)-l,4-diazepane-l-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cy cl openta[a]phenanthren-3-yl)-4-methyl-l,4-diazepane-l -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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)pyrrolidine-l -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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)pyrrolidine-l -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- yl)-3-(2-(4-methyl-2-oxopiperazin-l-yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((S)-3 -hy droxypyrrolidin- 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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((R)-3 -hy droxypyrrolidin- 1 -yl)ethyl)urea;2-(pyrrolidin-l-yl)ethyl ((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2- oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)carbamate;2-morpholinoethyl ((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo- 2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)carbamate;2-(3 -oxopiperazin- l-yl)ethyl ((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl- l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)carbamate; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-methylurea; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(pyrrolidin-l- yl)ethyl)urea; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2- morpholinoethyl)urea;N-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-4-methylpiperazine-l- carboxamide; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(4- methylpiperazin- 1 -yl)ethyl)urea;N-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl)-4-m ethyl- 1 ,4- diazepane-1 -carboxamide;N-((lR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)morpholine-4- carboxamide; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(3-oxopiperazin- l-yl)ethyl)urea;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(((2-(pyrrolidin- 1 - yl)ethoxy)carbonyl)amino)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-2- yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)amino)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(((2-(3 -oxopiperazin- 1 - yl)ethoxy)carbonyl)amino)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-2- yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(3-(2-(pyrrolidin-l-yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2- morpholinoethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(4-methylpiperazine-l- carboxamido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2-(4- methylpiperazin- 1 -yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5 - yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(morpholine-4- carboxamido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(4-methyl-l,4- diazepane-l-carboxamido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(3 -oxopiperazine- 1 -carboxamido)hexadecahydronaphtho[ 1 ',2' : 6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2-(4-methyl-2- oxopiperazin-l-yl)ethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(3 -(2-(3 -oxopiperazin- 1 - yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethoxy)carbonyl)amino)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2- yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)amino)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5 -yl)-7-(((2-(3 -oxopiperazin- 1 - yl)ethoxy)carbonyl)amino)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-2- yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5 -y 1 ) -7 - (3 -(2-(pyrrolidin- 1 - yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2- morpholinoethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(4- methylpiperazine- 1 -carb oxami do)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2-(4- methylpiperazin- 1 -yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5 - yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7- (morpholine-4-carboxamido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(4-methyl- 1 ,4-diazepane- 1 -carb oxami do)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(3 -oxopiperazine- 1- carboxamido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2-(4- methyl-2-oxopiperazin- 1 -yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5 -y 1 ) -7 - (3 -(2-(3 -oxopiperazin- 1 - yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-hydroxy ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5- oxo-2, 5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate;2-(3 -oxopiperazin- l-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate;2-(pyrrolidin-l-yl)ethyl ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)carbamate; l-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2- hydroxyethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2- (pyrrolidin-l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l- carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l- carboxamide;(R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-2- (hydroxymethyl)piperazine- 1 -carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4- diazepane-1 -carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,4- diazepane-1 -carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)pyrrolidine- 1 -carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4- methyl-2-oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3- hydroxypyrrolidin-l-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3- hydroxypyrrolidin-l-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3- methylbutanamide;(R)-2-amino-Nl-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5- oxo-2, 5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)succinamide;(S)-2-amino-Nl-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5- oxo-2, 5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)succinamide;2-(pyrrolidin-l-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)hexadecahydro-lH- cyclopenta[a]phenanthren-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)hexadecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate;2-(3 -oxopiperazin- l-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)hexadecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 -(2- (pyrrolidin-l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine- 1 -carboxamide; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 - yl)morpholine-4-carboxamide4-(3-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 - yl)ureido)butanoic acidN-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4- diazepane-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl- 1 ,4-diazepane- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3- hydroxypyrrolidine-1 -carboxamide; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 -(2-(2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 -(2-(3 - oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 -(2-((S)- 3 -hydroxypyrrolidin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 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- dihy drofuran-3 -yl)-3 -(((2-(pyrrolidin-l -yl)ethoxy)carbonyl)amino)hexadecahy dro- lH-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)hexadecahydro- lH-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- dihy drofuran-3 -y 1 ) -3 -(((2-(3 -oxopiperazin- 1 - yl)ethoxy)carbonyl)amino)hexadecahydro-lH-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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(pyrrolidin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 H- 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)hexadecahydro-lH- 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- dihy drofuran-3 -y l)-3 -(piperazine- 1 -carboxamido)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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(piperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 H- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4- carboxami do)- 17-(5 -oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)ureido)butanoic acid(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4- methylpiperazine-l-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro- lH-cyclopenta[a]phenanthren-16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(l,4-diazepane-l-carboxamido)-14-hydroxy- 10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-l,4- diazepane-l-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH- 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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(2-oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[a]phenanthren- 16-yl acetate;2-(pyrrolidin-l-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,l 1, 12, 13, 16,17-tetradecahy dro- 1H- cyclopenta[a]phenanthren-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,l 1, 12, 13, 16,17-tetradecahy dro- IH-cy cl openta[a]phenanthren-3-yl)carbamate;2-(3 -oxopiperazin- l-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,l l,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate; l-((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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(pyrrolidin- 1 -yl)ethyl)urea; l-((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-tetradecahy dro- IH-cy cl openta[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-tetradecahy dro- IH-cy cl openta[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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl)ureido)butanoic acidN-((5R, 8R,9S, 1 OS, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl)piperazine-l -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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-3-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-3-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-2-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-2-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)- 1 ,4-diazepane- 1 -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((S)-3 -hy droxypyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((R)-3 -hy droxypyrrolidin- 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-tetradecahydro-lH-cy cl openta[a]phenanthren-3- yl)-2-(pyrrolidin-l-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-lH-cy cl openta[a]phenanthren-3- yl)-2-morpholinoacetamide;(R)-2-amino-N-((3 S, 5R, 8R,9S, 1 OS, 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3- yl)propanamide;(R)-2-amino-N-((3 S, 5R, 8R,9S, 1 OS, 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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3- yl)-3-methylbutanamide;(R)-2-amino-Nl-((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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren- 3-yl)succinamide;(S)-2-amino-Nl-((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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren- 3-yl)succinamide;2-(3 -oxopiperazin- l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate;2-(pyrrolidin-l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate; l-(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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-hy droxy ethyl)urea;l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(pyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3- yl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-3-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-3-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-2-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-2-(hydroxymethyl)piperazine-l -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3- yl)-4-methylpiperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)- 1 ,4-diazepane- 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3- yl)-3 -hydroxypyrrolidine- 1 -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((S)-3 -hy droxypyrrolidin- 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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((R)-3 -hy droxypyrrolidin- 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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide;(R)-2-amino-Nl-((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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)succinamide,(S)-2-amino-Nl-((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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-3- carb oxami de,(R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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-l-yl)ethoxy)carbonyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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-l-yl)ethyl)carbamoyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4- methylpiperazine- 1 -carboxylate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-(4- methylpiperazin-l-yl)ethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5- yl)hexadecahydro- lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-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 -y 1 ) -3 -(((2-(pyrrolidin- 1 -yl)ethyl)carb amoyl)oxy)hexadecahy dro- 1 Iley cl openta[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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)oxy)carbonyl)amino)butanoic acid;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3- yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[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-l-yl)ethyl)carbamoyl)oxy)-2,3,6,7,8,9,10,11, 12, 13, 14, 15, 16,17-tetradecahydro-lH-cy cl openta[a]phenanthren- 16-yl acetate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3- yl (2-morpholinoethyl)carbamate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3- yl piperazine- 1 -carboxylate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-3- yl (2-(piperazin- 1 -yl)ethyl)carbamate;(3 S,8R,9S, 1 OR, 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-lH-cy cl openta[a]phenanthren-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoic acid;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 - yl)ethyl) carbonate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2-morpholinoethyl) carbonate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 - yl)ethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2- morpholinoethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4-m ethylpiperazine- 1- carboxylate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2-(4-methylpiperazin- 1 -yl)ethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4- carboxylate;4-(((((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(((2-(pyrrolidin- 1 - yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(((2-(pyrrolidin- 1 - yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2-(4-methylpiperazin- 1 -yl)ethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5 - yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4- carboxylate;4-(((((lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo- 2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l- (2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2-(4- methylpiperazin-l-yl)ethyl)carbamoyl)oxy)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l- (2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4-carboxylate;4-(((((lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la- dimethyl- 1 -(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1,7a- b]oxiren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin- l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin- l-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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- dihy drofuran-3 -y l)-3 -(((2-(pyrrolidin- 1 -yl)ethoxy)carbonyl)oxy)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)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro- lH-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- dihy drofuran-3 -y l)-3 -(((2-(pyrrolidin- 1 -yl)ethyl)carbamoyl)oxy)hexadecahy dro- 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)hexadecahydro- lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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-l-yl)ethyl)carbamoyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- yl)ethyl)carbamate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl valinate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl alaninate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl leucinate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 2-(piperidin-l-yl)acetate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 2-(pyrrolidin-l-yl)acetate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl asparaginate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl prolinate; and(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 2-morpholinoacetate; or a pharmaceutically acceptable salt thereof.The method according to any one of claims 1-50, wherein the NKA inhibitor is a compound selected from: l-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2 -hydroxy ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(pyrrolidin-l- yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -yl)-4-m ethylpiperazine- 1 - carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methylpiperazin-l- yl)ethyl)urea;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l-carboxamide;(R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4-diazepane-l- carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,4-diazepane-l- carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-oxopiperazine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin-l- yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3-oxopiperazin-l- yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3- hydroxypyrrolidin-l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3- hydroxypyrrolidin-l-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-l-yl)ethyl)ureido)hexadecahydro-lH- 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)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4- methylpiperazine- 1 -carb oxami do)- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro- 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-l-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4- carboxami do)- 17-(2-oxo-2H-pyran-5 -yl)hexadecahy dro- 1 Iley cl openta[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)hexadecahydro-lH-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-l-carboxamido)hexadecahydro-lH-cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(l,4-diazepane-l-carboxamido)-14-hydroxy-10, 13 -dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro- 1 Iley cl openta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-l,4- diazepane-l-carboxamido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- 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-l-carboxamido)hexadecahydro-lH- 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-l-yl)ethyl)ureido)hexadecahydro-lH- 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-l-yl)ethyl)ureido)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-lH- 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 -y 1) - 3 -(3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 Iley cl openta[a]phenanthren- 16-yl acetate; l-(2-aminoethyl)-3-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5 -yl)hexadecahy dro- 1 H-cy cl openta[a]phenanthren-3 -yl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 ) -3 -(2-(pyrroli din- 1 - yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -yl)piperazine- 1 - carboxamide; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 ) -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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4-diazepane-l- carboxamide;N-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 ) -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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)pyrrolidine-l- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)pyrrolidine- 1 -carboxamide; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2-oxopiperazin- l-yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4-methyl-2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3-oxopiperazin- l-yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3- hydroxypyrrolidin-l-yl)ethyl)urea; l-((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3- hydroxypyrrolidin-l-yl)ethyl)urea; l-((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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(pyrrolidin- 1 -yl)ethyl)urea;l-((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-lH-cy cl openta[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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)piperazine-l -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -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,l l,12,13,14,15,16,17-tetradecahydro-lH- 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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)-4-methylpiperazine-l -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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)-l,4-diazepane-l-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cy cl openta[a]phenanthren-3-yl)-4-methyl-l,4-diazepane-l -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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)pyrrolidine-l -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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)pyrrolidine-l -carboxamide;l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- yl)-3-(2-(4-methyl-2-oxopiperazin-l-yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((S)-3 -hy droxypyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((R)-3 -hy droxypyrrolidin- 1 -yl)ethyl)urea; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-methylurea; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(pyrrolidin-l- yl)ethyl)urea; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2- morpholinoethyl)urea;N-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-4-methylpiperazine-l- carboxamide; l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(4- methylpiperazin- 1 -yl)ethyl)urea;N-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl)-4-m ethyl- 1 ,4- diazepane-1 -carboxamide;N-((lR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)morpholine-4- carboxamide;l-((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl)-3-(2-(3-oxopiperazin- l-yl)ethyl)urea;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(3-(2-(pyrrolidin-l-yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2- morpholinoethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(4-methylpiperazine-l- carboxamido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2-(4- methylpiperazin- 1 -yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(morpholine-4- carboxamido)-l-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(4-methyl-l,4- diazepane-l-carboxamido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(3 -oxopiperazine- 1 -carboxamido)hexadecahydronaphtho[ 1 ',2' : 6,7]indeno[ 1,7a- b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(3-(2-(4-methyl-2- oxopiperazin-l-yl)ethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(3 -(2-(3 -oxopiperazin- 1 - yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5 -y 1 ) -7 - (3 -(2-(pyrrolidin- 1 - yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2- morpholinoethyl)ureido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(4- methylpiperazine- 1 -carb oxami do)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2-(4- methylpiperazin- 1 -yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7- (morpholine-4-carboxamido)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(4-methyl- 1 ,4-diazepane- 1 -carb oxami do)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(3 -oxopiperazine- 1- carboxamido)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(3-(2-(4- methyl-2-oxopiperazin- 1 -yl)ethyl)ureido)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5 -y 1 ) -7 - (3 -(2-(3 -oxopiperazin- 1 - yl)ethyl)ureido)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate; l-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2- hydroxyethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2- (pyrrolidin-l-yl)ethyl)urea;l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l- carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine-l- carboxamide;(R)-N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-2- (hydroxymethyl)piperazine- 1 -carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4- diazepane-1 -carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl-l,4- diazepane-1 -carboxamide;N-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)pyrrolidine- 1 -carboxamide; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(2- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(4- methyl-2-oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-(3- oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((S)-3- hydroxypyrrolidin-l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2-((R)-3- hydroxypyrrolidin-l-yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 -(2- (pyrrolidin-l-yl)ethyl)urea;l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)piperazine- 1 -carboxamide; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-l,4- diazepane-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-4-methyl- 1 ,4-diazepane- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3- hydroxypyrrolidine-1 -carboxamide; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 -(2-(2- oxopiperazin- 1 -yl)ethyl)urea;l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 -(2-(3 - oxopiperazin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 3 -(2-((S)- 3 -hydroxypyrrolidin- 1 -yl)ethyl)urea; l-((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -y 1 )- 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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(pyrrolidin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 H- 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)hexadecahydro-lH- 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- dihy drofuran-3 -y l)-3 -(piperazine- 1 -carboxamido)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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(piperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 H- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(morpholine-4- carboxami do)- 17-(5 -oxo-2, 5 -dihy drofuran-3 -yl)hexadecahy dro- 1 H- 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3- yl)ureido)butanoic acid;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4- methylpiperazine-l-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro- lH-cyclopenta[a]phenanthren-16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-3-(l,4-diazepane-l-carboxamido)-14-hydroxy- 10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH- cyclopenta[a]phenanthren- 16-yl acetate;(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(4-methyl-l,4- diazepane-l-carboxamido)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-lH- 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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(2-oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 H- 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- dihy drofuran-3 -y 1 ) -3 -(3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)ureido)hexadecahy dro- 1 H- cyclopenta[a]phenanthren- 16-yl acetate; l-((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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(pyrrolidin- 1 -yl)ethyl)urea; l-((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-tetradecahy dro- IH-cy cl openta[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-tetradecahy dro- IH-cy cl openta[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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl)ureido)butanoic acid;N-((5R, 8R,9S, 1 OS, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl)piperazine-l -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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl)piperazine-l -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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl)-3-(hydroxymethyl)piperazine-l -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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl)-3-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-2-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-2-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)- 1 ,4-diazepane- 1 -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((S)-3 -hy droxypyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((R)-3 -hy droxypyrrolidin- 1 -yl)ethyl)urea; l-(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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-hy droxy ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(pyrrolidin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3- yl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-3-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-3-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-2-(hydroxymethyl)piperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)-2-(hydroxymethyl)piperazine-l -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3- yl)-4-methylpiperazine-l -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-lH-cy cl openta[a]phenanthren-3- yl)- 1 ,4-diazepane- 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3- yl)-3 -hydroxypyrrolidine- 1 -carboxamide; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(2-oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-(3 -oxopiperazin- 1 -yl)ethyl)urea; l-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((S)-3 -hy droxypyrrolidin- 1 -yl)ethyl)urea; and1-((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-lH-cy cl openta[a]phenanthren-3- y 1 ) -3 -(2-((R)-3 -hy droxypyrrolidin- 1 -yl)ethyl)urea; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-50, wherein the NKA inhibitor is a compound selected from:2-(pyrrolidin-l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-3-yl)carbamate;2-(3 -oxopiperazin- l-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,l l,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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-tetradecahydro-lH-cy cl openta[a]phenanthren-3- yl)-2-(pyrrolidin-l-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-lH-cy cl openta[a]phenanthren-3- yl)-2-morpholinoacetamide;(R)-2-amino-N-((3 S, 5R, 8R,9S, 1 OS, 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-lH-cy cl openta[a]phenanthren-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-lH-cy cl openta[a]phenanthren-3- yl)propanamide;(R)-2-amino-N-((3 S, 5R, 8R,9S, 1 OS, 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-lH-cy cl openta[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-lH-cy cl openta[a]phenanthren-3- yl)-3-methylbutanamide;(R)-2-amino-Nl-((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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren- 3-yl)succinamide;(S)-2-amino-Nl -((3 S,5R, 8R,9 S, 1 OS, 13R, 17S)- 10, 13 -dimethyl- 17-(2-oxo-2H-pyran-5- yl)-2,3,4,5,6,7,8,9,10,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren- 3-yl)succinamide;2-(3 -oxopiperazin- l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)carbamate;2-(pyrrolidin-l-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l 1,12,13,16,17-tetradecahydro-lH- 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,l l,12,13,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren- 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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide;(R)-2-amino-Nl-((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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)succinamide,(S)-2-amino-Nl-((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,l 1,12,13,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl)succinamide; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-49, wherein the NKA inhibitor is a compound selected from: (lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4- carboxylate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l- (2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l- (2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methyl-l,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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 3- hydroxypyrrolidine-1 -carboxylate; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-49, wherein the NKA inhibitor is a compound selected from: (lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 - yl)ethyl) carbonate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2 -morpholinoethyl) carbonate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(((2-(pyrrolidin- 1 - yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-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-l-yl)ethoxy)carbonyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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 -y 1) - 3 -(((2-(3 -oxopiperazin- 1 -yl)ethoxy)carbonyl)oxy)hexadecahy dro- 1 Iley cl openta[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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -yl (2-(3 -oxopiperazin- 1 - yl)ethyl) carbonate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl (2-morpholinoethyl) carbonate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl (2-(3 -oxopiperazin- l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin- l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin- l-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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 -y l)-3 -(((2-(pyrrolidin- 1 -yl)ethoxy)carbonyl)oxy)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)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro- 1 H-cy clopenta[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)hexadecahy dro- lH-cyclopenta[a]phenanthren-16-yl acetate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 - yl)ethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2- morpholinoethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl 4-m ethylpiperazine- 1 - carboxylate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2-(4-methylpiperazin- 1 -yl)ethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4- carboxylate;4-(((((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(((2-(pyrrolidin- 1 - yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2-(4-methylpiperazin- 1 -yl)ethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5 - yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;4-(((((lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo- 2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2-(4- methylpiperazin-l-yl)ethyl)carbamoyl)oxy)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate; and 4-(((((lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la- dimethyl- 1 -(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1,7a- b]oxiren-7-yl)oxy)carbonyl)amino)butanoic acid; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-49, wherein the NKA inhibitor is a compound selected from:(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 - yl)ethyl) carbonate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2 -morpholinoethyl) carbonate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(((2-(pyrrolidin- 1 - yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethoxy)carbonyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-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-l-yl)ethoxy)carbonyl)oxy)hexadecahydro-lH- 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)hexadecahydro-lH- 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 -y 1) - 3 -(((2-(3 -oxopiperazin- 1 -yl)ethoxy)carbonyl)oxy)hexadecahy dro- 1 Iley cl openta[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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-3 -yl (2-(3 -oxopiperazin- 1 - yl)ethyl) carbonate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl (2-morpholinoethyl) carbonate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl (2-(3 -oxopiperazin- l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin- l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5- dihydrofuran-3-yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin- l-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)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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 -y l)-3 -(((2-(pyrrolidin- 1 -yl)ethoxy)carbonyl)oxy)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)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro- lH-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)hexadecahy dro- lH-cyclopenta[a]phenanthren-16-yl acetate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 - yl)ethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2- morpholinoethyl)carbamate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl (2-(4-methylpiperazin- 1 -yl)ethyl)carbamate;4-(((((lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5-yl)- 7-(((2-(pyrrolidin- 1 - yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-7-(((2-(4-methylpiperazin- 1 -yl)ethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5 - yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;4-(((((lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo- 2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7- yl)oxy)carbonyl)amino)butanoic acid;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)-7-(((2-(pyrrolidin-l- yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2- morpholinoethyl)carbamoyl)oxy)- 1 -(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-5a-hydroxy-9a,l la-dimethyl-7-(((2-(4- methylpiperazin-l-yl)ethyl)carbamoyl)oxy)-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-2-yl acetate; and 4-(((((lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la- dimethyl- 1 -(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1,7a- b]oxiren-7-yl)oxy)carbonyl)amino)butanoic acid; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-49, wherein the NKA inhibitor is a compound selected from:(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl 4-m ethylpiperazine- 1 - carboxylate;(lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4- carboxylate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-2-acetoxy-9a,l la-dimethyl-l-(2-oxo-2H- pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl morpholine-4- carboxylate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l- (2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[l',2':6,7]indeno[l,7a-b]oxiren-7-yl 4- methylpiperazine- 1 -carboxylate;(lR,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,l laR)-2-acetoxy-5a-hydroxy-9a,l la-dimethyl-l- (2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[r,2':6,7]indeno[l,7a-b]oxiren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methyl-l,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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro- IH-cy cl openta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 1,4-diazepane-l -carboxylate;(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl) hexadecahydro- IH-cy cl openta[a]phenanthren-3 -yl 4-m ethyl- 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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 3 -aminopyrrolidine- 1- carboxylate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl piperazine- 1 -carboxylate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl morpholine-4-carboxylate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl 4-methylpiperazine- 1 -carboxylate;(3 S,8R,9S, 1 OR, 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-tetradecahy dro- IH-cy cl openta[a]phenanthren-3- yl 1,4-diazepane-l -carboxylate;(3 S,8R,9S, 1 OR, 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- IH-cy cl openta[a]phenanthren-3- yl 4-m ethyl- 1 ,4-diazepane- 1 -carboxylate;(3 S,8R,9S, 1 OR, 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- IH-cy cl openta[a]phenanthren-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl 3 -hydroxypyrrolidine- 1 -carboxylate;(R)-(3 S,8R,9S, 1 OR, 13R, 14S, 17R)- 14-hydroxy- 10,13 -dimethyl- 17-(2-oxo-2H-pyran-5- yl)-2,3,6,7,8,9,10,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl 3 -aminopyrrolidine- 1 -carboxylate;(R)-(3 S,8R,9S, 1 OR, 13R, 14S, 17R)- 14-hydroxy- 10,13 -dimethyl- 17-(2-oxo-2H-pyran-5- yl)-2,3,6,7,8,9,10,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-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) hexadecahydro- IH-cy cl openta[a]phenanthren-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) hexadecahydro- IH-cy cl openta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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) hexadecahydro- IH-cy cl openta[a]phenanthren-3 -yl 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) hexadecahydro- IH-cy cl openta[a]phenanthren-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) hexadecahydro- IH-cy cl openta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 4-methyl-l,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)hexadecahydro-lH-cyclopenta[a]phenanthren-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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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 -dihy drofuran-3 -yl)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl 3- hydroxypyrrolidine-1 -carboxylate; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-49, wherein the NKA inhibitor is a compound selected from: (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- yl)ethyl)carbamate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl piperazine- 1 -carboxylate; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-49, wherein the NKA inhibitor is a compound selected from: (((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)oxy)methyl acetate; l-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)oxy)methyl pivalate; ethyl ((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)oxy)methyl) carbonate; ethyl (l-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)oxy)ethyl) carbonate; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-49, wherein the NKA inhibitor is a compound selected from:(R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l- yl)ethyl)carbamate;(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-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)hexadecahy dro- 1 H-cy clopenta[a]phenanthren-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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl morpholine-4-carboxylate; or a pharmaceutically acceptable salt thereof. The method according to 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)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl piperazine- 1 -carboxylate; or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1-38, wherein the NKA inhibitor is a compound selected from digoxin and digitoxin, or a pharmaceutically acceptable salt thereof. The method according to 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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