Bufadienolide compounds substituted by a nitrogen heterocycle

Abstract

The invention relates inter alia to compounds of formula (I) and their use in treating or preventing cancer, including metastasis of cancer.

Description

[0001] PAG-P3656PCT Application as filed FINAL

[0002] Novel Compounds

[0003] Field of the invention

[0004] The present invention relates to compounds and their use in treating or preventing cancer, including metastasis of cancer, and to related compositions, methods and intermediate compounds.

[0005] Background of the invention Metastasis remains a leading cause of cancer-related deaths worldwide (Siegel, R. L. et al. 2022). Metastasis concerns the spread of tumour cells from a primary site to a different location in the body. Metastasis involves a multistep process whereby invasive cell clones in the primary tumour (or metastatic lesions) escape via intravasation and transit in the bloodstream or the lymphatic system as circulating tumour cells (CTCs) (Lambert A. W. et al. 2017).

[0006] Circulating tumour cells (CTCs) are considered to be precursors of metastasis in various cancer types, including breast cancer (Aceto N. et al. 2015; Alix-Panabieres C. and Pantel K. 2014). The CTCs are shed from primary and / or metastatic tumours and enter into the bloodstream to eventually seed new metastases. Many cancers display organ-specific metastasis (organ tropism). For instance, some cancer types predominantly spread to one organ (e.g. prostate cancer to bone, pancreatic cancer to liver), whilst other cancer types are able to colonise many different organ sites (e.g. breast cancer, lung cancer or melanoma). Several factors contribute to the observed preferences, such as the pattern and direction of blood flow or the intrinsic capabilities of primary cells for promoting tumour cell adhesion at secondary sites (Horak C. E. and Steeg P. S. 2005; Obenauf A. C. and Massague J. 2015).

[0007] CTCs are found in the blood of cancer patients as single CTCs and CTC clusters (Fidler I. J. Eur. J. Cancer 1973, 9, 223-227; Liotta L. A. et al. Cancer Res. 1976, 36, 889-894). CTC clustering has been shown to be a mechanism that enhances CTC survival in the harsh conditions (e.g. high shear stress) of the bloodstream (Liu X et al. 2019) and also leads to a higher capacity to seed metastasis versus single CTCs (Aceto N. et al. / 2014).

[0008] Targeting CTCs, in particular CTC clusters, through pharmacological inhibition of associated cellular functions or pathways is seen as a potential strategy to directly interfere with metastatic progression in cancer patents. For instance, the present inventors have previously shown that Na+ / K+ ATPase inhibitors (for example, digoxin) can reduce cluster size, dissociate clusters into single cells, and reverse methylation patterns on key sternness genes, ultimately leading to PAG-P3656PCT Application as filed FINAL metastasis suppression in mice (Gkountela, S. et al. 2019; W02020127943).

[0009] Na+ / K+ ATPase is a transmembrane protein complex located in the plasma of animal cells. The function of the enzyme is to maintain ionic and osmotic balance in cells by pumping sodium ions out of cells and pumping potassium ions into cells. A single cycle involves three sodium ions being exported and two potassium ions being imported. Both ions are actively pumped against their electrochemical gradient utilising energy from ATP hydrolysis.

[0010] Na+ / K+ ATPase is composed of a dimer of alpha and beta subunits. The alpha subunit is the catalytic site of the enzyme and executes all processes connected to the Na+ and K+ ion transport across the cell plasma membrane. The beta subunit affects the affinity of Na+ and K+ ions to their binding sites (Hilbers, F. et al. 2016).

[0011] Each subunit exists as a multiplicity of isoforms. The alpha isoforms are ATP1A1 (alpha 1), ATP1A2 (alpha 2), ATP1A3 (alpha 3), and ATP1A4 (alpha 4) and the beta isoforms are ATP1 B1

[0012] (beta 1), ATP1 B2 (beta 2), ATP1 B3 (beta 3) and ATP1 B4 (beta 4). Subunit isoforms are known to perform different roles and are expressed at differing levels and in different alpha / beta combinations in various cell types. Cardiac glycosides and their aglycone derivatives, such as digoxin and bufalin, bind to the extracellular part of the Na+ / K+ ATPase that binds potassium to transfer it inside the cell. Inhibition of Na+ / K+ ATPase results in an intracellular increase of Na+. The Na+ / Ca2+ exchanger pumps calcium out of the cell and sodium into the cell down their concentration gradient. A decrease in the concentration gradient of sodium into the cell reduces the ability of the Na+ / Ca2+ exchanger to function, resulting in an increase of intracellular calcium levels. In the context of CTC clusters, inhibition of the Na+ / K+ ATPase, either directly or indirectly, is thought to lead to CTC cluster disruption through suppression of functional cell-cell junction assembly.

[0013] W02009 / 064657 indicates that cardiac glycosides and their aglycone derivatives have been suggested as having potential value in the treatment of various cancers and reports some apparent anti-cancer effects of the cardiac glycoside oleandrin in vivo. McConkey et al, 2000 reports that cardiac glycosides including digoxin induce apoptosis in androgen-independent human prostate cancer cell lines in vitro. Digoxin is widely used as a drug for the treatment of heart problems, including congestive heart failure, atrial fibrillation or flutter, and certain cardiac arrhythmias. The compound is considered a potentially toxic substance due to its unpredictable pharmacodynamic and pharmacokinetic PAG-P3656PCT Application as filed FINAL properties and has common side effects such as dizziness, nausea, diarrhoea, blurred vision and skin rash.

[0014] Digoxin contains a digoxigenin steroid core with a trisaccharide glycoside chain attached at the C3 oxo position.

[0015] A related natural product, digitoxin, lacks the OH group in position C12 of the steroid core.

[0016] Bufalin is an aglycone derivative of a cardiac glycoside containing a steroid core which, like digitoxin, lacks an OH group in position 012. However, bufalin further lacks a glycoside chain in position 03 and contains a 6-membered pyrone group in position 017 rather than a furanone group.

[0017] There remains a need to identify and develop alternative compounds for use in treating or preventing cancer, including metastasis of cancer, preferably with advantageous properties compared to existing therapies.

[0018] Summary of the invention

[0019] The present inventors have now discovered, surprisingly, that certain bufalin derivatives are effective at reducing CTO cluster formation. These properties make them potentially suitable for treating or preventing cancer, including metastasis of cancer in cancer patients.

[0020] The present invention provides a compound of formula (I): PAG-P3656PCT Application as filed FINAL or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

[0021] V is H or -C(RARB)C(=O)NRIR2;

[0022] RA and RB are each independently selected from the group consisting of H, Ci-ealkyl and Ci-ehaloalkyl;

[0023] Re is selected from the group consisting of halo, -NH2, Ci-ehaloalkyl, Ci-ealkyl, Ci-ealkoxy and cyano;

[0024] RD is selected from the group consisting of H, Ci-ealkyl and Ci-ehaloalkyl; k is 0 or 1 ;

[0025] I is an integer 0 to 2; m is an integer 0 to 4; n is 0 or 1 ; and:

[0026] Ri is H or Ci-ealkyl;

[0027] R2is H or Ci-salkyl, wherein Ci-salkyl is (i) optionally substituted with 1 or 2 R3, (ii) is substituted with 1 Cyci and is optionally substituted with 1 R3, or (iii) is substituted by 1 R3 and by 2 further substituent groups which when taken together with the C atom to which they are attached form Cs-ecycloalkyl or 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O;

[0028] R3 is independently selected from the group consisting of -ORsa, -NRpRqand - C(=O)-R3d;

[0029] Cyci is selected from the group consisting of Cs-scycloalkyl, 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, 7-11 membered heterobicyclyl or heterospirobicyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, 5 membered heteroaryl, 7-11 membered heteroaryl and An, wherein Cyci is optionally substituted in any position with 1 to 3 Rcyci;

[0030] An is phenyl or 6 membered heteroaryl;

[0031] R3ais H or Ci-ealkyl; PAG-P3656PCT Application as filed FINAL

[0032] Rp and Rqare (i) each independently H or Ci-4alkyl, (ii) Rpand Rqtaken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O, or (iii) Rpis H or Ci-4alkyl and Rqis selected from -C(=O)Ci- salkyl and -K-Cyc2;

[0033] K is -C(=0)(CH2)O-2- or -(CH2)o-3-;

[0034] R3CI is hydroxy or -NRmn;

[0035] Rmand Rnare (i) each independently H or Ci-4alkyl, (ii) Rmand Rntaken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O, or (iii) Rmis H or Ci-4alkyl and Rnis -(CH2)o-3-Cyc2;

[0036] Cyc2is selected from the group consisting of Cs-ecycloalkyl, 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, 5-7 membered heteroaryl and phenyl, wherein Cyc2is optionally substituted in any position with 1 to 3 RcyC2;

[0037] Rcyd and RcyC2 are independently selected from the group consisting of halo, -NRgRh, Ci-ehaloalkyl, Ci-ealkyl optionally substituted by hydroxy, Ci- ealkoxy and cyano; and when Cyci is An, An may also be optionally substituted with RAM ;

[0038] RAM is selected from the group consisting of -(CH2)-Q-C(=O)-(CH2)t-RAr3, -(CH2)- NRx-S(=O)2-(CH2)t-RAr3 and -(CH2)-NRx-C(=O)-C(=O)-NRs-RAr3;

[0039] RAF3 is selected from the group consisting of phenyl, naphthyl, 5-6 membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O and S, C4-7cycloalkyl and 5-6 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, wherein RAPS is optionally substituted with 1 or 2 RAM;

[0040] RA is selected from the group consisting of halo, -NRgRh, Ci-ehaloalkyl, Ci^alkyl optionally substituted by hydroxy, Ci-ealkoxy and cyano;

[0041] Q is selected from the group consisting of bond, -O- and -NRX-;

[0042] Rgand Rh are each independently H or Ci^alkyl or Rgand Rh taken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O;

[0043] Rxand Rsare each independently H or methyl; and t is 0 or 1 ; PAG-P3656PCT Application as filed FINAL or:

[0044] Ri and R2 taken together with the N atom to which they are attached form (i) a 4-7 membered heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, (ii) a 4-7 membered heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein the 4-7 membered heterocyclyl or 7-11 membered heterospirobicyclyl of (i)-(iii) are optionally substituted with 1 R4 and optionally substituted with 1 or 2 R5;

[0045] R4 is Ci-ealkyl or Co-ealkylene-NRyRs, wherein the Ci-ealkyl is optionally substituted with 1 or 2 substituents selected from the group consisting of hydroxy, fluoro, cyano, -OCi-4alkyl, -NHCi-4alkyl and -N(Ci-4alkyl)2;

[0046] Re is selected from the group consisting of -C(=O)-X-(CH2)v-R7, -S(=O)2- (CH2)W-R7and -C(=O)-C(=O)-NRZ-R8;

[0047] X is selected from the group consisting of bond, -O- and -NR11-;

[0048] R? is Ci-ealkyl or Cyca;

[0049] Cyca is selected from the group consisting of phenyl, naphthyl, 5-6 membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, S and O, C4-7cycloalkyl and 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, wherein Cyca is optionally substituted with 1 to 4 R9;

[0050] Rs represents C4-7cycloalkyl optionally substituted with 1 to 4 Rw;

[0051] R9 and R10 are each independently selected from the group consisting of halo, -NRjRj, Ci-ehaloalkyl, Ci-ealkyl, Ci-ealkoxy, Ci-salkyl-C(=O)-, cyano and S(=O)2(Ci-6alkyl);

[0052] Rs is selected from the group consisting of halo, -NH2, Ci-ehaloalkyl, Ci-ealkyl, C1- ealkoxy, -CH2OH, hydroxy and cyano;

[0053] Ry, Rzand Rn are each independently H or methyl; v and w are each independently 0 or 1 ; and

[0054] Ri and Rj are each independently H or Ci-4alkyl; or a pharmaceutically acceptable salt and / or solvate thereof. PAG-P3656PCT Application as filed FINAL

[0055] Detailed description of the invention

[0056] Brief Description of the Figures

[0057] Figure 1 : Dot plots showing the number of (a) homotypic and (b) heterotypic CTC clusters in 750 pl of blood from HCT116 xenografts following administration of Control (vehicle), Digoxin or Example 4. Each dot represents one mouse. Dotted line represents the mean value of the controls. P value relative to Control is shown on top of each condition.

[0058] Figure 2: Representative images of CTC clusters captured with microchip technology from the blood of mice treated with Control (left) versus treated with Example 4 (right).

[0059] Figure 3: Representative images of metastases in (a) the lung and (b) the brain from HCT116 xenografts following administration of Control (left) versus Example 4 (right).

[0060] Compounds of formula (I)

[0061] Embodiments and preferences set out herein with respect to the compound of formula (I) apply equally to the pharmaceutical composition, compound or pharmaceutically acceptable salt and / or solvate thereof for use, pharmaceutical composition for use, use and method aspects of the invention, as well as intermediates used in the synthesis of the compounds of formula (I).

[0062] The term “alkyl” (e.g. Ci-salkyl , Ci-ealkyl or Ci-4alkyl) as used herein refers to a straight or branched fully saturated hydrocarbon group having the specified number of carbon atoms. The term encompasses methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 2,3- dimethylbutyl, n-pentyl, isopentyl, neopentyl, 3-methyl pentyl, n-hexyl, isohexyl, neohexyl, heptyl, 2-methylhexyl, 3-methylhexyl, 2, 2, dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, 2,2,3- trimethylbutyl, 2-methylheptyl, 3-methyl heptyl, 4-methylheptyl, 2,2-dimethylhexyl, 2,3- dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 3,3-dimethylhexyl, 3-ethylhexyl, and 2,2,3- trimethylpentyl. The term “alkyl” also encompasses “alkylene” which is a bifunctional straight or branched fully saturated hydrocarbon group having a specified number of carbon atoms. Example “alkylene” groups include methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, n-heptylene and n-octylene.

[0063] The term “halo” as used herein refers to fluoro, chloro, bromo and iodo. Particular examples of halo are fluorine and chlorine, especially fluorine.

[0064] The term “alkoxy” (e.g. Ci-ealkoxy) as used herein refers to an alkyl group (e.g. Ci-ealkyl) as defined above, singularly bonded via an oxygen atom. The term encompasses methoxy, ethoxy, PAG-P3656PCT Application as filed FINAL

[0065] 1-propoxy, 2-propoxy, 2, 2-dimethyl-1 -propoxy, 1-butoxy, 2-butoxy, iso-butoxy, tert-butoxy, 3- methyl-1 -butoxy, 3-methyl-2-butoxy, 2-methyl-1-butoxy, 2-methyl-2-butoxy, 2,3-dimethyl-2- butoxy, 3, 3-dimethyl-1 -butoxy, 1 -pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-1 -pentoxy, 3-methyl-1- pentoxy, 4-methyl-1 -pentoxy, 2-methyl-2-pentoxy, 3-methyl-2-pentoxy, 4-methyl-2-pentoxy, 2- methyl-3-pentoxy and 3-methyl-3-pentoxy.

[0066] The term “haloalkyl” (e.g. Ci-ehaloalkyl) as used herein refers to an alkyl group (e.g. Ci-ealkyl) as defined above bearing at least one halogen atom, such as fluoro or chloro, especially fluoro. An alkyl group may bear one halogen atom or may bear two or three (or more) atoms, for example a terminal carbon atom may bear three carbon atoms. An example of haloalkyl is CF3.

[0067] The term “cycloalkyl” (e.g. C^cycloalkyl or Cs-ecycloalkyl) as used herein refers to a fully saturated cyclic hydrocarbon group having the specified number of carbon atoms. The term encompasses cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, as well as bridged and fused systems such as bicyclo[1.1.1]pentyl.

[0068] The term “heterocyclyl” (e.g. 4-7 membered heterocyclyl) as used herein refers to a non-aromatic cyclic group having the specified number of ring atoms, at least one of which is a heteroatom selected from N, O and S, such as N or O, e.g. N. In some circumstances heterocyclyl represents a ring comprising S(=O)2. Heterocyclyl groups for example, may contain one ring heteroatom e.g. O, N or S especially O or N such as N or may contain two ring heteroatoms e.g. two N atoms or a N atom and an O or S atom. The term encompasses oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl and thiomorpholinyl. When heterocyclyl represents a ring which comprises S(=O)2 the term embraces tetrahydro-1 , 1 -dioxidothiopyran-4-yl .

[0069] The term “heterobicyclyl” (e.g. 7-11 membered heterocyclyl) as used herein refers to a non- aromatic cyclic group having the specified number of ring atoms formed in two fused rings, at least one of which atoms is a heteroatom selected from N, O and S, such as N or O, e.g. N. In some circumstances heterobicyclyl represents a ring comprising S(=O)2. Heterobicyclyl groups for example, may contain one ring heteroatom e.g. O, N or S especially O or N such as N or may contain two ring heteroatoms e.g. two N atoms or a N atom and an O or S atom. An example of a heterobicyclyl is decahydroquinolinyl: 111 I 111 wherein I represents the site of attachment to the rest of the compound. PAG-P3656PCT Application as filed FINAL

[0070] The term “heterospirobicyclyl” (e.g. 7-11 membered heterospirobicyclyl) as used herein refers to a non-aromatic bicyclic group wherein the two rings are connected through a single C atom and having the specified number of ring atoms, at least one of which is a heteroatom selected from N, O, S and B such as N or O, e.g. N. The two rings of the heterospirocyclyl can be of the same size (e.g. [4.4], [5.5] or [6.6]) or can be different sizes (e.g. [4.5] or [5.6]). An example of a heterospirobicyclylyl is 2-azaspiro[3.3]heptanyl: 111 I 111 wherein I represents the site of attachment to the rest of the compound.

[0071] The term “heteroaryl” (e.g. 5-11 membered heteroaryl, 5-6 membered heteroaryl, 6 membered heteroaryl, 7-11 membered heteroaryl) as used herein refers to an aromatic cyclic group having the specified number of ring atoms, at least one of which is a heteroatom selected from N, O, S and B such as N or O, e.g. N. Heteroaryl groups for example, may contain one ring heteroatom e.g. O, N or S especially O or N such as N or may contain two ring heteroatoms e.g. two N atoms or a N atom and an O or S atom. The term encompasses pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, isoxazolyl, oxazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyradizinyl and pyrazinyl.

[0072] In one aspect, V represents H. In another aspect, V represents -C(RARB)C(=O)NRIR2.

[0073] In a first such latter aspect, Ri and R2 taken together with the N atom to which they are attached do not form a ring structure.

[0074] Thus, in an embodiment R1 represents H. Alternatively in an embodiment R1 represents Ci-ealkyl. For example, R1 represents unsubstituted methyl. Most suitably R1 represents H.

[0075] Thus, in an embodiment R2 represents H. Alternatively in an embodiment R2 represents optionally substituted Ci-salkyl such as optionally substituted Ci-ealkyl or Ci-4alkyl. In an embodiment R2 is selected from optionally substituted alkyl wherein alkyl is selected from Ci-salkyl, C alkyl, Ci- ealkyl, Ci-salkyl, Ci-4alkyl, Ci-3alkyl, Ci-2alkyl, C2-salkyl, C2-?alkyl, C2-ealkyl, C2-salkyl, C2-4alkyl, C2- salkyl, Cs-salkyl, Cs yalkyl, Cs-ealkyl, Cs-salkyl, C3-4alkyl, C4-salkyl, C4-?alkyl, C4-salkyl, C4-salkyl, C5- salkyl, Cs-yalkyl, Cs-ealkyl, Ce-salkyl and Cy-salkyl. In an embodiment R2 represents optionally substituted methyl. In another embodiment R2 represents optionally substituted ethyl. In another embodiment R2 represents optionally substituted n-propyl. In another embodiment R2 represents PAG-P3656PCT Application as filed FINAL optionally substituted isopropyl. In another embodiment R2 represents optionally substituted butyl. In another embodiment R2 represents optionally substituted 3-methylbutan-2-yl. In an embodiment R2 is selected from ^ ' (methyl), (ethyl), (n-propyl),

[0076] (isopropyl), ^\(butan-2-yl) , ^\(3-methylbutan-2-yl) and (S.S-dimethylbutan^-yl) 111 I 111 each of which groups are optionally substituted, wherein I represents the site of attachment to the rest of the compound.

[0077] In an embodiment R2 represents Ci-salkyl which is unsubstituted. Alternatively in an embodiment R2 represents Ci-salkyl which is substituted by one R3 (e.g. one ORsa e.g. one OH) such as, when R2 represents ethyl, one ORsa e.g. OH is in the B position. In another embodiment R2 represents Ci-salkyl such as ethyl which is substituted by two R3 (e.g. two ORsa e.g. two OH) such as, when R2 represents ethyl, one ORsa e.g. OH in the a position and one ORsa e.g. OH in the B position. In another embodiment R2 represents Ci-salkyl which is substituted by one Cyci and is not substituted by one R3. In another embodiment R2 represents Ci-salkyl which is substituted by one Cyci and is substituted by one R3 (e.g. ORsa e.g. OH). For example, when R2 represents ethyl, one Cyci is in the a position and one R3 e.g. ORsa e.g. OH is in the B position. In another embodiment R2 represents Ci-salkyl which is substituted by 1 R3 (e.g. ORsa e.g. OH) and by 2 further substituent groups which when taken together with the C atom to which they are attached form Cs-ecycloalkyl or 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O. For example, R2 represents methyl substituted by one Cyci and one R3 (e.g. -C(=O)-R3d e.g. -C(=O)-OH or -C(=O)-NH2). For example, when R2 represents ethyl, one R3 e.g. ORsa e.g, OH is in the B position and 2 further substituent groups which when taken together with the C atom to which they are attached form Cs-ecycloalkyl or 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O are in the a position.

[0078] For example, R2 represents methyl substituted by one R3. e.g. represents -CH2OH. For example, ^0 / I I I I

[0079] R2 represents ethyl substituted by one R3 e.g. in the B position e.g. HO ' wherein I represents the site of attachment to the rest of the compound. For example, R2 represents 1 isopropyl substituted by one R3 e.g. in the B position e.g. wherein I represents the site of attachment to the rest of the compound. For example, R2 represents butan-2-yl substituted PAG-P3656PCT Application as filed FINAL 111 I 111 by one R3 e.g. in the B position e.g. wherein I represents the site of attachment to the rest of the compound. For example, R2 represents tert-butyl substituted by one R3 e.g. in the

[0080] B position e.g. wherein I represents the site of attachment to the rest of the compound. For example, R2 represents 3-methylbutan-2-yl substituted by one R3 e.g. in the B

[0081] I position e.g. wherein I represents the site of attachment to the rest of the compound. For example, R2 represents 3,3-dimethylbutan-3-yl substituted by one R3 e.g. in the

[0082] B position e.g. wherein I represents the site of attachment to the rest of the compound. For example R2 represents isopropyl substituted by two R3 e.g. one R3 in the B

[0083] I position and one R3 in the a position e.g. wherein I represents the site of attachment to the rest of the compound. For example, R2 represents ethyl substituted by 1 R3 wherein R3 is hydroxy e.g. in the B position and by 2 further substituent groups which when taken together form a 6 membered cycloalkyl e.g. in the a position e.g. wherein I represents the site of attachment to the rest of the compound. For example, R2 represents ethyl substituted by 1 R3 wherein one R3 is hydroxy e.g. in the B position and by 2 further substituent groups which when taken together form a 4-6 membered heterocyclyl e.g. in the a position e.g. wherein I represents the site of attachment to the rest of the compound. For example, R2 is ethyl substituted with 1 R3 (especially in the B position) and by 2 further substituent groups (especially in the a position) which when taken together with the C atom to which they are attached form a ring selected from cyclohexyl, oxetanyl and tetrahydropyranyl.

[0084] In an embodiment R3 represents ORsa. For example, R3 represents OH (i.e. Rsa is H). For example, R3 represents OMe (i.e. Rsa is methyl).

[0085] Alternatively in an embodiment R3 represents -NRpRqwherein Rpand Rqare (i) each independently H or Ci-4alkyl, or (ii) Rpand Rqtaken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O, or (iii) Rpis H or Ci-4alkyl and Rqis selected from -C(=O)Ci-3alkyl and -K-Cyc2. PAG-P3656PCT Application as filed FINAL

[0086] In an embodiment Rpand Rqeach represent H. In an embodiment one of Rpor Rqrepresent H and the other represents Ci-4alkyl. In an embodiment Rpand Rqboth represent Ci-4alkyl. For example, one of Rpor Rqrepresents H and the other represents methyl, ethyl or isopropyl. For example, one of Rpor Rqrepresents H and the other represents methyl or ethyl. For example, Rpand Rqboth represent methyl or ethyl.

[0087] In an embodiment Rpand Rqtaken together with the N atom to which they are attached form a 4 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O. In an embodiment Rpand Rqform a 5 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O. In an embodiment Rpand Rqform a 6 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O. In an embodiment Rpand Rqform a 7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O.

[0088] In an embodiment Rprepresents H and Rqis selected from -C(=O)Ci-3alkyl and -K-Cyc2. In an embodiment, Rprepresents Ci-4alkyl and Rqis selected from -C(=O)Ci-3alkyl and -K-Cyc2. In an embodiment Rprepresents H and Rqrepresents C(=O)Ci-3alkyl. For example, Rprepresents H and Rqrepresents C(=O)-Et. In an embodiment Rprepresents Ci-4alkyl and Rqrepresents C(=O)Ci-3alkyl. In an embodiment Rprepresents H and Rqrepresents -K-Cyc2. In an embodiment

[0089] Rprepresents Ci-4alkyl and Rqrepresents -K-Cyc2.

[0090] In an embodiment K represents -C(=0)(CH2)o-2-. In an embodiment K represents -(CH2)o-3- such as -(CH2)I-3- e.g. -CH2-. For example, K represents -C(=O)(CH2)-. For example, K represents - C(=O)-.

[0091] Alternatively in an embodiment R3 represents -C(=O)-R3d wherein Rsd represents hydroxy or - NRmRn wherein Rmand Rnare (i) each independently H or Ci-4alkyl, or (ii) Rmand Rntaken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O or (iii) Rmis H or Ci-4alkyl and Rnis - (CH2)o-3-Cyc2. For example, R3 represents -C(=O)-OH (i.e. Rsd is OH). In an embodiment R3 represents -C(=O)-NRmRn (i.e. Rsd is -NRmRn).

[0092] In an embodiment Rmand Rnboth represent H. In an embodiment one of Rmor Rnrepresents H and the other represents Ci-4alkyl. In an embodiment Rmand Rnboth represent Ci-4alkyl. For example, one of Rmor Rnrepresents H and the other represents methyl or ethyl. For example, Rmand Rnboth represent methyl or ethyl. PAG-P3656PCT Application as filed FINAL

[0093] In an embodiment Rmand Rntaken together with the N atom to which they are attached form 4 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O. In an embodiment Rmand Rnform a 5 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O. In an embodiment Rmand Rnform a 6 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O. In an embodiment Rmand Rnform a 7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O.

[0094] In an embodiment Rmrepresents H and Rnrepresents -(CH2)o-3-Cyc2. In an embodiment, Rmrepresents Ci-4alkyl and Rnrepresents -(CH2)o-3-Cyc2.

[0095] In an embodiment Cyc2 represents optionally substituted Cs-ecycloalkyl (such as cyclohexyl). Alternatively, in an embodiment Cyc2 represents optionally substituted 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2 (such as piperidinyl). Alternatively, in an embodiment Cyc2 represents optionally substituted 5-7 membered heteroaryl (such as pyridinyl). Alternatively, in an embodiment Cyc2 represents optionally substituted phenyl.

[0096] In an embodiment Cyc2 is unsubstituted. Alternatively, in an embodiment Cyc2 is substituted by one Rcyc2. Alternatively, in an embodiment Cyc2 is substituted by two RcyC2. Alternatively, in an embodiment Cyc2 is substituted by three RcyC2.

[0097] In an embodiment Cyci represents optionally substituted Cs-ecycloalkyl (such as cyclohexyl). Alternatively in an embodiment Cyci represents optionally substituted 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2. Alternatively in an embodiment Cyci represents optionally substituted 7-11 membered heterobicyclyl or heterospirobicyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2. Alternatively in an embodiment Cyci represents optionally substituted 5 membered heteroaryl (such as imidazolyl). Alternatively in an embodiment Cyci represents optionally substituted 7-11 membered heteroaryl (such as indolyl). Alternatively, Cyci represents optionally substituted An.

[0098] In an embodiment An represents optionally substituted phenyl. Alternatively, in an embodiment An represents optionally substituted 6 membered heteroaryl. For example, 6 membered PAG-P3656PCT Application as filed FINAL heteroaryl represents pyridinyl (pyridin-4-yl), (pyridin-3-yl) or (pyridin-2- yl), wherein represents the site of attachment to the rest of the compound.

[0099] In an embodiment Cyci is unsubstituted. Alternatively, in an embodiment Cyci is substituted by one Rcyd. Alternatively, in an embodiment Cyci is substituted by two Rcyci. Alternatively, in an embodiment Cyci is substituted by three Rcyd.

[0100] In an embodiment Rcyciand RcyC2 are independently selected from the group consisting of halo, -NRgRh, Ci-ehaloalkyl, Ci-ealkyl optionally substituted by hydroxy, Ci-ealkoxy and cyano. Rcyciand RcyC2 may also represent -NRgRh wherein Rgand Rh taken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O such as a 5 or 6 especially a 6 membered heterocyclyl optionally comprising a further heteroatom selected from N and O e.g morpholinyl. Suitably, Rcyciis selected from halo, -NRgRh, Ci-ehaloalkyl, Ci-ealkyl optionally substituted by hydroxy, Ci-ealkoxy and cyano. Suitably, Rcyciis selected from -NRgRh, Ci-ehaloalkyl, Ci-ealkyl optionally substituted by hydroxy, Ci-ealkoxy and cyano. For example, Rcyciis selected from fluoro, morpholinyl, trifluoromethyl, methyl, methoxy and cyano. For example, Rcyciis selected from morpholinyl, trifluoromethyl, methyl, methoxy and cyano.

[0101] For example, R2 represents methyl substituted by one Cyci and said methyl is not substituted by R3. For example, R2 represents methyl substituted by one Cyci and one R3. For example, R2 represents ethyl substituted by one Cyci. For example, R2 represents ethyl substituted by one Cyci and one R3. For example, Cyci represents cyclohexyl, imidazolyl, indolyl or An and R3 represents OH.

[0102] In an embodiment, R2 represents methyl, which methyl is substituted by (i) Cyci (which may optionally be substituted) and (ii) R3, to formCyci wherein represents the site of attachment to the rest of the compound.

[0103] In an embodiment, R2 represents methyl which methyl is substituted by (i) Cyci (which may PAG-P3656PCT Application as filed FINAL optionally be substituted) and (ii) R3 wherein R3 is -C(=O)-R3d to form Cyci wherein I represents the site of attachment to the rest of the compound. In an example of one such embodiment Rsc is hydroxy; or -NRmRn where Rmand Rnare independently selected from H and Ci-4alkyl, such as -NH2, -NHMe and NMe2.

[0104] In an embodiment, R2 represents ethyl which ethyl is substituted by (i) Cyci (which may optionally be substituted) in the alpha position and (ii) R3 in the beta position, to formCyClwherein 111 I 111

[0105] I represents the site of attachment to the rest of the compound.

[0106] In an example of one such embodiment R3 is hydroxy. In another example of one such embodiment R3 is -NRpRqsuch as -NH2, -NHCi-4alkyl e.g. -NHMe, -NHEt or -NH'Pr; -NHCH2CyC2 e.g. where Cyci is An especially optionally substituted phenyl; or -NHC(=O)Ci-4akyl e.g. - NHC(=O)Me, -NHC(=O)Et or -NHC(=O)'Pr. In another example of one such embodiment R3 is - NRpRqsuch as -NH2, -NHCi-4alkyl e.g. -NHMe or -NHEt; -NHCH2CyC2 e.g. where Cyci is An especially optionally substituted phenyl; or -NHC(=O)Ci-4akyl e.g. -NHC(=O)Me.

[0107] In an embodiment, R2 represents n-propyl which n-propyl is substituted by (i) Cyci (which may optionally be substituted) in the alpha position and (ii) R3 in the gamma position, to form

[0108] Cyci wherein I represents the site of attachment to the rest of the compound. In an example of one such embodiment R3 is hydroxy.

[0109] In an embodiment, R2 represents isopropyl which isopropyl is substituted by (i) Cyci (which may optionally be substituted) in the beta position and (ii) R3 in the beta’ position, to form 111 I 111 wherein I represent the site of attachment to the rest of the compound. In an example of one such embodiment R3 is hydroxy.

[0110] In an alternative embodiment R2 is Ci-salkyl which is substituted by one Cyci (which may optionally be substituted) which Cyci is An and R2 is not substituted by one R3. In an embodiment R2 represents methyl substituted by one Cyci which Cyci is An and An is phenyl substituted by PAG-P3656PCT Application as filed FINAL

[0111] RAM to form wherein1I represents the site of attachment to the rest of the compound.

[0112] In an embodiment when Cyci is An, An is substituted with RAM .

[0113] In an embodiment, RAM represents -(CH2)-Q-C(=O)-(CH2)t-RAr3. In an embodiment Q represents a bond. Alternatively, in an embodiment Q represents -O-. Alternatively, in an embodiment Q represents -NRX- wherein Rxrepresents H or methyl. In an embodiment t is 0. Alternatively, in an embodiment t is 1. In an embodiment Q represents -NRX- wherein Rxrepresents H and t is 0. In an embodiment Q represents -NRX- wherein Rxrepresents H and t is 1. Alternatively, in an embodiment RAM represents -(CH2)-NRx-S(=O)2-(CH2)t-RAr3. In an embodiment Rxrepresents H. Alternatively, in an embodiment Rxrepresents methyl. In an embodiment t is 0. Alternatively, in an embodiment t is 1. In an embodiment Rxrepresents H and t is 0. Alternatively, in an embodiment RAM represents -(CH2)-NRx-C(=O)-C(=O)-NRs-RAr3. In an embodiment Rxand Rsboth represent H. Alternatively, in an embodiment one of Rxand Rsrepresents H and the other represents methyl. Alternatively, in an embodiment Rxand Rsboth represent methyl.

[0114] In an embodiment RAM is selected from the group consisting of phenyl, pyridinyl, imidazolyl, isoxazolyl, tetrahydropyranyl, cyclopentyl and cyclohexyl. In an embodiment RAM is unsubstituted. In an embodiment RAM is substituted, for example, with one RA .

[0115] In an embodiment RA is independently selected from the group consisting of halo (such as Cl or F), -NRgRh (such as -NH2), Ci-ehaloalkyl (such as trifluoromethyl), Ci-ealkyl optionally substituted by hydroxy (such as methyl) and Ci-ealkoxy (such as methoxy). In an embodiment, RA represents cyano.

[0116] In a second such latter aspect, R1 and R2 taken together with the N atom to which they are attached form (i) a 4-7 membered heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, (ii) a 4-7 membered heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein the 4-7 membered heterocyclyl or 7-11 membered heterospirobicyclyl of (i)-(iii) are optionally substituted with 1 R4 and optionally substituted with 1 or 2 R5. PAG-P3656PCT Application as filed FINAL

[0117] When Ri and R2 taken together with the N atom to which they are attached form a 4-7 membered heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O which is optionally substituted, said 4-7 membered heterocyclyl is suitably a 5-6 membered heterocyclyl. For example, the 4-7 membered heterocyclyl which is optionally substituted is a 6 membered heterocyclyl which is optionally substituted. In an embodiment the 4-7 membered heterocyclyl does not contain any further heteroatom. For example, the 6 membered heterocyclyl is optionally substituted piperidinyl. In an alternative embodiment the 4-7 membered heterocyclyl comprises 1 additional heteroatom. For example, the 6 membered heterocyclyl is optionally substituted 1 ,4- piperazinyl and is substituted e.g. in the 4 position.

[0118] In an embodiment R1 and R2 taken together with the N atom to which they are attached form a 4- 7 membered heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, wherein the 4-7 membered heterocyclyl is optionally substituted with 1 R4 and optionally substituted with 1 or 2 (e.g. 1) R5.

[0119] Alternatively in an embodiment R1 and R2 taken together with the N atom to which they are attached form a 4-7 membered heterocyclyl fused to C^cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein the 7-11 membered heterospirobicyclyl is optionally substituted with 1 R4 and optionally substituted with 1 or 2 (e.g. 1) R5.

[0120] In an embodiment, the 4-7 membered heterocyclyl which is optionally substituted is a 4 membered heterocyclyl which is optionally substituted and which is fused to a 4 membered cycloalkyl ring through a single C atom to form an 7 membered heterospirobicyclyl which is optionally substituted.

[0121] Alternatively in an embodiment R1 and R2 taken together with the N atom to which they are attached form a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein the 7-11 membered heterospirobicyclyl is optionally substituted with 1 R4 and optionally substituted with 1 or 2 (e.g. 1) Rs.

[0122] In an embodiment, the 4-7 membered heterocyclyl which is optionally substituted is a 4 membered heterocyclyl which is optionally substituted and which is fused to a 4 membered heterocyclyl ring through a single C atom to form a 7 membered heterospirobicyclyl which is optionally substituted.

[0123] In an embodiment, the 4-7 membered heterocyclyl or 7-11 membered heterospirobicyclyl is substituted with 1 R4 and not any R5. For example, the 4-7 membered heterocyclyl is a 6 PAG-P3656PCT Application as filed FINAL membered heterocyclyl which is substituted by R4 in the 4-position of the 6 membered heterocyclyl.

[0124] In an embodiment, the 4-7 membered heterocyclyl or 7-11 membered heterospirobicyclyl is substituted with 1 R4 and is substituted by 1 R5. For example, the 4-7 membered heterocyclyl is a 6 membered heterocyclyl which is substituted by R4 in the 4-position of the 6 membered heterocyclyl and in the 3-position by R5.

[0125] In a particular embodiment, R1 and R2 taken together with the N atom to which they are attached form a piperidine ring substituted with one R4 in the para position and suitably not substituted with R5.

[0126] In an embodiment, R4 represents Ci-ealkyl optionally substituted with 1 or 2 hydroxy groups. For example, R4 is unsubstituted methyl. Alternatively in an embodiment R4 is ethyl substituted with 1 hydroxy group e.g. R4 is -CH2CH2OH. Alternatively in an embodiment R4 is Co-ealkylene-NHRe. For example in an embodiment R4 represents -NHRe. Alternatively in an embodiment R4 represents -(CH2)i-3-NRyR6.

[0127] In an embodiment, R5 is selected from is selected from the group consisting of Cl, F, -NH2, CF3, methyl, methoxy, -CH2OH, hydroxy and cyano and for example is selected from the group consisting of methyl, -CH2OH and hydroxy.

[0128] In an embodiment Ryis H.

[0129] In an embodiment Re represents -C(=O)-X-(CH2)v-R7. In an embodiment X is a bond. In an alternative embodiment X represents -O-. In an alternative embodiment X represents -NRn- wherein Rn represents H or methyl, particularly H. In an embodiment v is 0. In an alternative embodiment v is 1. In an embodiment X represents bond and v is 0. In an embodiment X represents bond and v is 1 .

[0130] In a particular embodiment, R4 represents -NHC(=O)-CH2-R?.

[0131] Alternatively, in an embodiment Re represents -S(=O)2-(CH2)W-R7. In an embodiment w is 0. Alternatively in an embodiment w is 1.

[0132] In an embodiment R7 represents Ci-ealkyl e.g. methyl. Alternatively, in an embodiment R7 represents Cycs. In an embodiment Cycs is selected from the group consisting of phenyl, naphthyl PAG-P3656PCT Application as filed FINAL and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, S and O, wherein Cyca is optionally substituted with 1 to 4 Rg. For example, Cyca is optionally substituted phenyl. Alternatively Cycs is optionally substituted 5-6 membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, S and O. For example, Cycs is selected from the group consisting of pyridinyl, pyrimidinyl, tetrahydropyranyl and isoxazolyl, each of which is optionally substituted. Alternatively, Cycs represents optionally substituted imidazolyl. Alternatively, Cycs represents optionally substituted 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2 for example a 5-6 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2. When Cycs represents a optionally substituted 4-7 membered heterocyclyl suitably it comprises at least one N atom. For example, Cycs represents azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl or tetrahydropyranyl, each of which are optionally substituted. Alternatively, Cycs represents optionally substituted tetrahydro- 1 ,1-dioxidothiopyran-4-yl. Alternatively, Cycs represents optionally substituted C4-7cycloalkyl.

[0133] In an embodiment Cycs is unsubstituted. Alternatively in an embodiment Cycs is substituted with one Rg. Alternatively in an embodiment Cycs is substituted with two Rg.

[0134] In an embodiment Rg independently represents halo (such as Cl or F), -NRjRj (such as -NH2, - NHMe or -NMe2), Ci-ehaloalkyl (such as trifluoromethyl), Ci-ealkyl (such as methyl), Ci-salkoxy (such as methoxy), Ci-salkyl-C(=O)- (such as -CH3C(=O)-) or cyano e.g. independently represents halo (such as Cl or F) or Ci^alkyl (such as methyl). In an embodiment Rg is selected or independently selected from the group consisting of halo (such as Cl or F), -NRjRj (e.g. -NH2, - NHMe or -NMe2), Ci-ehaloalkyl (such as trifluoromethyl), Ci-ealkyl (such as methyl) and Ci^alkoxy (such as methoxy). In an embodiment Rg represents chloro or fluoro. Alternatively in an embodiment Rg represents trifluoromethyl, methyl or methoxy. Alternatively in an embodiment Rg represents -NRjRj, and, for example, Rj and Rj are selected from H and methyl e.g. Rj and Rj are both H.

[0135] In an embodiment Re represents -C(=O)-C(=O)-NRZ-R8. In an embodiment Rzis H. In an embodiment Rs represents optionally substituted C^cycloalkyl. In an embodiment Rs represents optionally substituted cyclopentyl or cyclohexyl.

[0136] In an embodiment Rs is unsubstituted. Alternatively, in an embodiment Rs is substituted with 1 R10. Alternatively, in an embodiment Rs is substituted with 2 Rw. Alternatively, in an embodiment Rs is substituted with 3 Rw. Alternatively, in an embodiment Rs is substituted with 4 Rw. PAG-P3656PCT Application as filed FINAL

[0137] In an embodiment R independently represents halo (such as Cl or F), Ci-ehaloalkyl (such as trifluoromethyl), Ci-ealkyl (such as methyl), Ci-ealkoxy (such as methoxy), Ci-salkyl-C(=O)- (such as CH3C(=O)) or cyano e.g. independently represents halo (such as Cl or F) or Ci^alkyl (such as methyl).

[0138] In an embodiment RA is H. In an embodiment RB is H. In compounds of particular interest RA and RB are both H.

[0139] In an embodiment Rc is halo (such as Cl or F), Ci-ehaloalkyl (such as trifluoromethyl), Ci-ealkyl (such as methyl), Ci^alkoxy (such as methoxy) or cyano, for example, Rc is Ci-ealkyl (such as methyl).

[0140] In a particular embodiment m is 0. Alternatively, in an embodiment m is 1. Alternatively, in an embodiment m is 2, particularly, when Rc represents methyl.

[0141] In an embodiment n is 0. Alternatively in an embodiment n is 1.

[0142] In a particular embodiment RD is H.

[0143] In an embodiment k is 1. In an embodiment I is 1.

[0144] In compounds of particular interest m is 0 and I and k are both 1.

[0145] In a particular embodiment, compounds of formula (I) are compounds of formula (la): or a pharmaceutically acceptable salt and / or solvate thereof, wherein n, Ri and R2 are as defined elsewhere herein. PAG-P3656PCT Application as filed FINAL

[0146] By reference to compounds of formula (la), exemplary NR1R2 moieties include -NHMe, -NMe2, - NH-benzyl, -NH-2-hydroxy-1-(phenyl)ethyl, -NHCH2-phenyl-4-CH2NHC(=O)-pyridin-4-yl), - NHCH2-phenyl-4-CH2NHC(=O)-(2-aminopyrimidin-5-yl), -NHCH2-phenyl-4-CH2NHC(=O)-(4- trifluoromethylphenyl), -NHCH2-phenyl-4-CH2NHC(=O)-tetrahydropyran-4-yl, -NHCH2-phenyl-4- CH2NHC(=O)-(3-methylisoxazol-5-yl), -NHCH2-phenyl-4-CH2NHC(=O)-(4-fluorophenyl),

[0147] NHCH2-phenyl-4-CH2NHC(=O)-pyridin-2-yl, -NHCH2-phenyl-4-CH2NHC(=O)-pyridin-3-yl, NHCH2-phenyl-4-CH2NHS(=O)2-(1 ,2-dimethylimidazol-4-yl), -NHCH2-phenyl-3-CH2NHC(=O)- tetrahydropyran-4-yl, -NHCH2-phenyl-3-CH2NHC(=O)-(4-fluorophenyl), -NHCH2-phenyl-3- CH2NHC(=O)-pyrdin-3-yl, -NHCH2-phenyl-3-CH2NHS(=O)2-(1 ,2-dimethylimidazol-4-yl), -NHCH2- phenyl-3-CH2NHC(=O)-cyclopentyl, -NHCH2-phenyl-3-CH2NHC(=O)-cyclohexyl, -NHCH2- phenyl-4-CH2NHC(=O)-(4-chlorophenyl), -NHCH2-phenyl-4-CH2NHC(=O)-(4-methylphenyl), - NHCH2-phenyl-4-CH2NHC(=O)-(3-methoxyphenyl), -NHCH2-phenyl-3-CH2NHC(=O)-pyridin-3-yl, -NHCH2-phenyl-3-CH2NHC(=O)-(2-aminopyrimidin-5-yl), -NHCH2-phenyl-3-CH2NHC(=O)-(3- methyloxazol-5-yl), -NHCH2-phenyl-3-CH2NHC(=O)-pyridin-2-yl, -NH-(N-2-morpholinyl)benzyl, - NH--(N3-morpholinyl)benzyl, -NH-(N-4-morpholinyl)benzyl, -NH-2-(trifluoromethyl)benzyl, -NH-3- (trifluoromethyl)benzyl, -NH-(pyridin-4-yl)methyl, -NH-(pyridin-3-yl)methyl, -NH-(pyridin-2- yl)methyl, -NH-2-cyanobenzyl, -NH-4-cyanobenzyl, -NH-4-methoxybenzyl, -NH-3- methoxybenzyl, -NH-2-methoxybenzyl, -NH-4-methylbenzyl, -NH-3-methylbenzyl, -NH-2- methylbenzyl, and -NH-4-(trifluoromethyl)benzyl.

[0148] By reference to compounds of formula (la), further exemplary NR1R2 moieties include -NH- - NHCH2-phenyl-3-CH2NHC(=O)-pyridin-4-yl), -NHCH2-phenyl-4-CH2NHC(=O)CH2-(4- fluorophenyl), -NH-2-hydroxy-1-phenylethyl, -NH-ethyl-NHC(=O)-2-methyloxazol-5-yl, -NH-2- hydroxy-1-(4-fluorophenyl)ethyl, -NH-2-(hydroxymethyl)benzyl, -NH-2-hydroxy-1-(4- chlorophenyl)ethyl, -NH-2-hydroxy-1-(4-methoxyphenyl)ethyl, -NH-2-methoxy-1-phenylethyl, - NMe-2-hydroxy-1 -phenylethyl, -NH-1-phenylethyl, -NH-2-hydroxy-1-(2-fluorophenyl)ethyl, -NH-2- hydroxy-1-(cyclohexyl)ethyl, -NH-2-hydroxy-1-(pyridin-4-yl)ethyl, -NH-3-hydroxy-1 -phenylpropyl, -NH-2-amino-2-oxo-1-phenylethyl, -NH-1-hydroxy-3-(1 H-imidazol-4-yl)propan-2-yl, -NH-1- hydroxypropan-2-yl, -NH-2-hydroxy-1-(2-chlorophenyl)ethyl, -NH-2-hydroxy-1-(3- chlorophenyl)ethyl, -NH-1-hydroxybutan-2-yl, -NH-2-hydroxy-1-(p-tolyl)ethyl, -NH-1-hydroxy-3- (1 H-indol-3-yl)propan-2-yl, -NH-2-amino-1-phenylethyl, -NH-2-(methylamino)-1-phenylethyl, - NH-2-hydroxy-1-(3-fluorophenyl)ethyl, -NH-1-hydroxy-3-phenylpropan-2-yl, -NH-2-hydroxyethyl, -NH-2-hydroxy-1-(pyridin-2-yl)ethyl, -NH-2-hydroxy-1-(2-methoxyphenyl)ethyl, -NH-N-methyl-2- phenylacetamide, -NH-2-hydroxy-1-(pyridin-3-yl)ethyl, -NH-2-hydroxy-1-(3-methoxyphenyl)ethyl, -NH-2-hydroxy-1-(m-tolyl)ethyl, -NH-1-hydroxy-3-methylbutan-2-yl, -NH-2-hydroxy-2-oxo-1- phenylethyl, -NH-1-hydroxy-3,3,-dimethylbutan-2-yl, -NH-1 ,3-dihydroxypropan-2-yl, -NH-N,N- dimethyl-2-phenylacetamide, -NH-2-hydroxy-1-(4-tert-butylphenyl)ethyl, -NH-2-hydroxy-1-(3,5- PAG-P3656PCT Application as filed FINAL difluorophenyl)ethyl, -NH-2-hydroxy-1-(4-trifluoromethylphenyl)ethyl, -NH-1-hydroxy-2- methylpropan-yl, -NH-1-hydroxy-2-tetrahydropyran-4-yl, -NH-1-hydroxy-2-tetrahydropyran-4-yl, - NH-1-hydroxy-2-oxetan-3-yl and -NH-1-hydroxy-2-cyclohexyl.

[0149] By reference to compounds of formula (la), further exemplary NR1R2 moieties include -NH-1-(3,5- difluorophenyl)-2-hydroxyethyl, -NH-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl, -NH-1-hydroxy- 2-methylpropan-2-yl, -NH-3-(hydroxymethyl)oxetan-3-yl, -NH-4-(hydroxymethyl)tetrahydro-2H- pyran-4-yl, -NH-1-(hydroxymethyl)cyclohexyl, -NH-2-(ethylamino)-1-phenylethyl, -NH-2- phenylethyl)benzamide, -NH-2-(isopropylamino)-1 -phenylethyl, -NH-2- phenylethyl)propionamide, -NH-2-(benzylamino)-1-phenylethyl, and -NH-1-phenyl-2-(2- phenylacetamido)ethyl.

[0150] In a particular embodiment, compounds of formula (I) are compounds of formula (lb): or a pharmaceutically acceptable salt and / or solvate thereof, wherein n, RD, m, Rc, k, I, RA, RB and R4 are as defined elsewhere herein and wherein (i) R55 and R66 are both absent or (ii) R55 is absent and Ree as defined elsewhere herein for R5 or (iii) Ree is absent and R55 as defined elsewhere herein for R5. By reference to compounds of formula (lb), exemplary R4 moieties include -NHAc, -NHBz, - NHC(=O)-4-chlorophenyl, -NHC(=O)-pyridin-4-yl, -NHC(=O)-5-(2-pyrimidinamine), -NHC(=O)-4- trifluoromethylphenyl, -NHC(=O)-4-tetrahydropyranyl, -NHC(=O)-3-methyl-5-isoxazolyl.

[0151] NHC(=O)-4-fluorophenyl, -NHC(=O)CH2-4-fluorophenyl, -NHC(=O)-4-methylphenyl, -NHC(=O)- pyridin-2-yl, -NHC(=O)-pyridin-3-yl, -NHC(=O)CH2-3-methoxyphenyl, -NHS(=O)2-1 ,2-dimethyl4- imidazolyl, -NHC(=O)C(=O)NH-cyclopentyl, -NHC(=O)C(=O)NH-cyclohexyl, -NHC(=O)-phenyl, - NHC(=O)NH-phenyl, -NHC(=O)CH2-pyridin-3-yl, -NHC(=O)CH2-2-methylphenyl, -NHC(=O)NH- 4-methylphenyl, -NHC(=O)CH2-2-fluorophenyl, -NHC(=O)NH-4-fluorophenyl, -NHC(=O)CH2-2- chlorophenyl, -NHC(=O)CH2-2-methoxyphenyl, -NHC(=O)O-phenyl, -NHC(=O)O-4- PAG-P3656PCT Application as filed FINAL methylphenyl, -NHC(=O)CH2-pyridin-4-yl, -NHC(=O)O-4-fluorophenyl, -NHC(=O)CH2-4- methoxylphenyl, -NHC(=O)CH2-4-cyanophenyl, -NHC(=O)CH2-1-naphthyl, -CH2NH(C=O)- phenyl, -NHC(=O)-4-methylphenyl, -NHC(=O)CH2-pyridin-2-yl, -NHC(=O)-3-methoxyphenyl, - NHC(=O)-tetrahydropyran-4-yl, -NHC(=O)CH2-tetrahydropyran-4-yl, -NHC(=O)-(S)- tetrahydrofuran-3-yl, NHC(=O)-(R)-tetrahydrofuran-3-yl, NHC(=O)-oxetan-3-yl, and NHC(=O)CH2-tetrahydro-1 ,1-dioxidothiopyran-4-yl.

[0152] By reference to compounds of formula (lb) further exemplary R4 moieties include -NHC(=O)- pyridin-2-yl, -NHC(=O)CH2-morpholinyl, -NHC(=O)CH2-1-(methylsulfonyl)piperidin-4-yl, NHC(=O)-2-methyloxazol-5-yl, -NHC(=O)-2-methylthiazol-5-yl and -NHC(=O)-3-methylisoxazol- 5-yl.

[0153] In an embodiment R55 and Ree are both absent. In an embodiment, Ree is absent and R55 is selected from methyl, CH2OH and hydroxy. In an embodiment, R55 is absent and Ree is selected from methyl and CH2OH.

[0154] In a particular embodiment, compounds of formula (I) are compounds of formula (Ic): wherein n, RD, m, Rc, k, I, RA, RB, RI, R3 and Cyci (which may optionally be substituted) are as defined elsewhere herein.

[0155] By reference to compounds of formula (Ic), exemplary R3 groups include OH, OMe, -NH2, - NHMe, -NHC(=O)Me, -C(=O)OH, -C(=O)NH2, -C(=O)NHMe and -C(=O)NMe2, particularly OH, OMe, -NH2, -NHMe and -NHC(=O)Me, especially OH.

[0156] By reference to compounds of formula (Ic), further exemplary R3 groups include -NHEt, - NHC(=O)Ph, -NH'Pr, -NHC(=O)Et, -NHCH2Ph, and -NHC(=O)CH2Ph. PAG-P3656PCT Application as filed FINAL

[0157] In a particular embodiment, compounds of formula (I) are compounds of formula (Id): or a pharmaceutically acceptable salt and / or solvate thereof, wherein n, RD, m, Rc, k, I, RA, RB, RI, R3 and Cyci (which may optionally be substituted) are as defined elsewhere herein.

[0158] By reference to compounds of formula (Id), exemplary R3 groups include -C(=O)OH, -C(=O)NH2, -C(=O)NHMe and -C(=O)NMe2.

[0159] By reference to compounds of formulae (Ic) and (Id), exemplary Cyci groups include cyclohexyl, imidazolyl, indolyl; and An groups such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,5-difluorophenyl, 4-(tert-butyl)phenyl and 3- (hydroxymethyl)phenyl.

[0160] By reference to compounds of formulae (Ic) and (Id), further exemplary Cyci groups include cyclohexyl, imidazolyl, indolyl; and An groups such as 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,5-difluorophenyl, 4-(tert- butyl)phenyl and 3-(hydroxymethyl)phenyl.

[0161] In a particular embodiment, compounds of formula (I) are compounds of formula (le): PAG-P3656PCT Application as filed FINAL wherein n, RD, m, Rc, k, I, RA, RB, RI and Cyci (which may optionally be substituted) are as defined elsewhere herein.

[0162] By reference to compounds of formula (le), exemplary Cyci groups include An groups such as phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, which are i) unsubstituted, (ii) substituted by 1 Rcyd or (iii) substituted by 1 RAM.

[0163] By reference to compounds of formula (le), when Cyci is phenyl and substituted by 1 Rcyd, exemplary Rcycigroups include N-2-morpholinyl, N-3-morpholinyl, N-4-morpholinyl, 4- trifluoromethyl, 3-trifluoromethyl, 2-trifluoromethyl, 4-cyano, 2-cyano, 2-methoxy, 3-methoxy, 4- methoxy, 4-methyl, 3-methyl and 2-methyl.

[0164] By reference to compounds of formula (le), when Cyci is phenyl and substituted by 1 RAM, exemplary RAM groups include -CH2NHC(=O)-pyridin-4-yl, -CH2NHC(=O)-2-aminopyrimidin-5-yl, -CH2NHC(=O)-4-trifluoromethylphenyl, -CH2NHC(=O)-tetrahydro-2H-pyran-4-yl, -CH2NHC(=O)- 3-methylisoxazol-5-yl, -CH2NHC(=O)-4-fluorophenyl, -CH2NHC(=O)-pyridin-2-yl, -CH2NHC(=O)- pyridin-3-yl, -CH2NHS(=O)2-1 ,2-dimethyl-1 H-imidazol-4-yl, -CH2NHC(=O)CH2-4-fluorophenyl, - CH2NHC(=O)C(=O)NH-cyclopentyl, -CH2NHC(=O)C(=O)NH-cyclohexyl, -CH2NHC(=O)-4- chlorophenyl, -CH2NHC(=O)-4-tolyl, and -CH2NHC(=O)-3-methoxyphenyl.

[0165] In compounds of formulae (Ic), (Id) and (le), Ri suitably represents H.

[0166] In compounds of formulae (lb), (Ic), (Id), and (le): k and I suitably each represent 1.

[0167] RD and RE suitably each represent H.

[0168] RA and RB suitably each represent H. PAG-P3656PCT Application as filed FINAL m suitably represents 0.

[0169] In an embodiment the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is selected from the group consisting of: 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-(piperidin-4- yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one; and 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-(piperidin-4- ylmethoxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one; or a pharmaceutically acceptable salt and / or solvate of any one thereof.

[0170] In an embodiment the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is selected from the group consisting of:

[0171] 2-(4-fluorophenyl)-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)acetamide;

[0172] N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0173] N-(2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)-2- azaspiro[3.3]heptan-6-yl)benzamide;

[0174] N-(1-(2-(4-((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)methyl)piperidin-1- yl)acetyl)piperidin-4-yl)benzamide; 4-fluoro-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-

[0175] 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)benzamide;

[0176] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)isonicotinamide;

[0177] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)picolinamide;

[0178] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-

[0179] 3-methoxybenzamide; PAG-P3656PCT Application as filed FINAL

[0180] 2-amino-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)pyrimidine-5-carboxamide;

[0181] 4-chloro-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)benzamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0182] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-

[0183] 4-(trifluoromethyl)benzamide; N1-cyclopentyl-N2-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-

[0184] (2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)oxalamide; N1-cyclohexyl-N2-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)oxalamide;

[0185] N-(3-((2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran-

[0186] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)isonicotinamide; 2-amino-N-(3-((2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)pyrimidine-5-carboxamide; 2-(4-fluorophenyl)-N-(3-((2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)acetamide; N-(4-((2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran-

[0187] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)-3-methoxybenzamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(4-methoxyphenyl)acetamide;

[0188] N-benzyl-2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- morpholinobenzyl)acetamide; PAG-P3656PCT Application as filed FINAL

[0189] N-((R)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0190] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-

[0191] 4-methylbenzamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0192] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)nicotinamide; N-(4-((2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran-

[0193] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)-4-methylbenzamide;

[0194] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(pyridin-4-yl)acetamide;

[0195] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(tetrahydro-2H-pyran-4-yl)acetamide; 2-(4-cyanophenyl)-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)acetamide;

[0196] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-

[0197] 1-(methylsulfonyl)piperidine-4-carboxamide; 5-((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-3-((1 -(2-(4-(3-methylisoxazole-

[0198] 5-carbonyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)oxy)hexadecahydro-1 H- cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one;

[0199] 5-((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-3-((1 -(2-(6-(3-methylisoxazole- 5-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethyl)piperidin-4-yl)oxy)hexadecahydro-1 H- cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one;

[0200] N-(3-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)propyl)-3- methylisoxazole-5-carboxamide;

[0201] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-

[0202] 2-methyloxazole-5-carboxamide; PAG-P3656PCT Application as filed FINAL

[0203] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-methylthiazole-5-carboxamide;

[0204] N-((S)-1-(4-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0205] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- (hydroxymethyl)benzyl)acetamide; N-(4-cyanobenzyl)-2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamide;

[0206] N-((S)-1-(4-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0207] N-((S)-2-hydroxy-1-(4-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-

[0208] 3-yl)oxy)piperidin-1-yl)acetamide;

[0209] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2-methoxy-1- phenylethyl)acetamide;

[0210] 2-(4-fluorophenyl)-N-(4-((2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)acetamide; N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)-N-methylacetamide;

[0211] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)tetrahydro-2H-pyran-4-carboxamide;

[0212] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-

[0213] 3-methylisoxazole-5-carboxamide;

[0214] N-((S)-2-hydroxy-1-phenylethyl)-2-(4-((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)methyl)piperidin-1-yl)acetamide; PAG-P3656PCT Application as filed FINAL

[0215] N-((S)-2-acetamido-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0216] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((R)-1- phenylethyl)acetamide; N-((S)-1-(2-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0217] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-1-cyclohexyl-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0218] N-((S)-2-hydroxy-1-(pyridin-4-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0219] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0220] N-((R)-3-hydroxy-1-phenylpropyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0221] ((S)-2-amino-2-oxo-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0222] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxy-3-(1 H- imidazol-4-yl)propan-2-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1- hydroxypropan-2-yl)acetamide;

[0223] N-((S)-1-(2-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0224] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0225] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0226] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0227] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxybutan- 2-yl)acetamide; PAG-P3656PCT Application as filed FINAL

[0228] N-((S)-2-hydroxy-1-(p-tolyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxy-3-(1 H- indol-3-yl)propan-2-yl)acetamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(pyridin-2-yl)acetamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0229] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(pyridin-3-yl)acetamide; N-((S)-2-amino-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0230] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2-(methylamino)- 1 -phenylethyl)acetamide;

[0231] N-((S)-1-(3-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0232] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3- phenylpropan-2-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- hydroxyethyl)acetamide; N-((S)-2-hydroxy-1-(pyridin-2-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0233] N-((S)-2-hydroxy-1-(2-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-

[0234] 3-yl)oxy)piperidin-1-yl)acetamide;

[0235] (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-N-methyl- 2-phenylacetamide; N-((S)-2-hydroxy-1-(pyridin-3-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- PAG-P3656PCT Application as filed FINAL

[0236] 10, 13-d i methyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0237] N-((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren- 3-yl)oxy)piperidin-1-yl)acetamide;

[0238] N-((S)-2-hydroxy-1-(m-tolyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0239] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3- methylbutan-2-yl)acetamide; (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylacetic acid; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3, 3- dimethylbutan-2-yl)acetamide; N-(1 ,3-dihydroxypropan-2-yl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-N,N- dimethyl-2-phenylacetamide; N-((S)-1-(3,5-difluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-

[0240] 3-yl)oxy)piperidin-1-yl)acetamide; N-((S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren- 3-yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(1 -hydroxy-2- methylpropan-2-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(3- (hydroxymethyl)oxetan-3-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(4- PAG-P3656PCT Application as filed FINAL

[0241] (hydroxymethyl)tetrahydro-2H-pyran-4-yl)acetamide;

[0242] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(1- (hydroxymethyl)cyclohexyl)acetamide; N-((S)-2-(ethylamino)-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0243] N-((S)-2-(2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylethyl)benzamide;

[0244] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2- (isopropylamino)-1-phenylethyl)acetamide;

[0245] N-((S)-2-(2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylethyl)propionamide;

[0246] N-((S)-2-(benzylamino)-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; and 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-phenyl-2-(2- phenylacetamido)ethyl)acetamide; or a pharmaceutically acceptable salt and / or solvate of any one thereof. In an embodiment the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is selected from the group consisting of: 2-(4-fluorophenyl)-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)acetamide; N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0247] N-(2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)-2- azaspiro[3.3]heptan-6-yl)benzamide; PAG-P3656PCT Application as filed FINAL

[0248] N-(1-(2-(4-((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)methyl)piperidin-1- yl)acetyl)piperidin-4-yl)benzamide;

[0249] 4-fluoro-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)benzamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0250] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)isonicotinamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0251] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)picolinamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 3-methoxybenzamide;

[0252] 2-amino-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)pyrimidine-5-carboxamide;

[0253] 4-chloro-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)benzamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0254] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-

[0255] 4-(trifluoromethyl)benzamide; N1-cyclopentyl-N2-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-

[0256] (2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)oxalamide; N1-cyclohexyl-N2-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)oxalamide;

[0257] N-(3-((2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran-

[0258] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)isonicotinamide;

[0259] 2-amino-N-(3-((2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)pyrimidine-5-carboxamide; PAG-P3656PCT Application as filed FINAL

[0260] 2-(4-fluorophenyl)-N-(3-((2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)acetamide;

[0261] N-(4-((2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)-3-methoxybenzamide;

[0262] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(4-methoxyphenyl)acetamide; N-benzyl-2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- morpholinobenzyl)acetamide; N-((R)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 4-methylbenzamide;

[0263] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)nicotinamide;

[0264] N-(4-((2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)-4-methylbenzamide;

[0265] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(pyridin-4-yl)acetamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0266] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(tetrahydro-2H-pyran-4-yl)acetamide; 2-(4-cyanophenyl)-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)acetamide; PAG-P3656PCT Application as filed FINAL

[0267] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-

[0268] 1-(methylsulfonyl)piperidine-4-carboxamide;

[0269] 5-((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-3-((1 -(2-(4-(3-methylisoxazole- 5-carbonyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)oxy)hexadecahydro-1 H- cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one;

[0270] 5-((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-3-((1 -(2-(6-(3-methylisoxazole- 5-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethyl)piperidin-4-yl)oxy)hexadecahydro-1 H- cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one; N-(3-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0271] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)propyl)-3- methylisoxazole-5-carboxamide;

[0272] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-methyloxazole-5-carboxamide;

[0273] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-

[0274] 2-methylthiazole-5-carboxamide;

[0275] N-((S)-1-(4-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0276] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- (hydroxymethyl)benzyl)acetamide; N-(4-cyanobenzyl)-2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamide;

[0277] N-((S)-1-(4-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0278] N-((S)-2-hydroxy-1-(4-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-

[0279] 3-yl)oxy)piperidin-1-yl)acetamide;

[0280] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2-methoxy-1- phenylethyl)acetamide; PAG-P3656PCT Application as filed FINAL

[0281] 2-(4-fluorophenyl)-N-(4-((2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)acetamide;

[0282] N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)-N-methylacetamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)tetrahydro-2H-pyran-4-carboxamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0283] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-

[0284] 3-methylisoxazole-5-carboxamide;

[0285] N-((S)-2-hydroxy-1-phenylethyl)-2-(4-((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)methyl)piperidin-1-yl)acetamide;

[0286] N-((S)-2-acetamido-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0287] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((R)-1- phenylethyl)acetamide;

[0288] N-((S)-1-(2-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-1-cyclohexyl-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0289] N-((S)-2-hydroxy-1-(pyridin-4-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0290] N-((R)-3-hydroxy-1-phenylpropyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0291] ((S)-2-amino-2-oxo-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; PAG-P3656PCT Application as filed FINAL

[0292] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxy-3-(1 H- imidazol-4-yl)propan-2-yl)acetamide;

[0293] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1- hydroxypropan-2-yl)acetamide; N-((S)-1-(2-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0294] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0295] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxybutan- 2-yl)acetamide;

[0296] N-((S)-2-hydroxy-1-(p-tolyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0297] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxy-3-(1 H- indol-3-yl)propan-2-yl)acetamide;

[0298] N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(pyridin-2-yl)acetamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0299] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(pyridin-3-yl)acetamide;

[0300] N-((S)-2-amino-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0301] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2-(methylamino)- 1 -phenylethyl)acetamide;

[0302] N-((S)-1-(3-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0303] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- PAG-P3656PCT Application as filed FINAL yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3- phenylpropan-2-yl)acetamide;

[0304] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- hydroxyethyl)acetamide;

[0305] N-((S)-2-hydroxy-1-(pyridin-2-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0306] N-((S)-2-hydroxy-1-(2-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-

[0307] 3-yl)oxy)piperidin-1-yl)acetamide; (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-N-methyl- 2-phenylacetamide; N-((S)-2-hydroxy-1-(pyridin-3-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0308] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren- 3-yl)oxy)piperidin-1-yl)acetamide;

[0309] N-((S)-2-hydroxy-1-(m-tolyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0310] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3- methylbutan-2-yl)acetamide; (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylacetic acid; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3, 3- dimethylbutan-2-yl)acetamide; N-(1 ,3-dihydroxypropan-2-yl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; and (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-N,N- PAG-P3656PCT Application as filed FINAL dimethyl-2-phenylacetamide; or a pharmaceutically acceptable salt and / or solvate of any one thereof.

[0311] In an embodiment the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is selected from the group consisting of:

[0312] N-((S)-1-(3,5-difluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren- 3-yl)oxy)piperidin-1-yl)acetamide;

[0313] N-((S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren- 3-yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(1 -hydroxy-2- methylpropan-2-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(3- (hydroxymethyl)oxetan-3-yl)acetamide;

[0314] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(4- (hydroxymethyl)tetrahydro-2H-pyran-4-yl)acetamide;

[0315] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(1- (hydroxymethyl)cyclohexyl)acetamide;

[0316] N-((S)-2-(ethylamino)-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0317] N-((S)-2-(2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylethyl)benzamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2- (isopropylamino)-1-phenylethyl)acetamide;

[0318] N-((S)-2-(2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylethyl)propionamide;

[0319] N-((S)-2-(benzylamino)-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- PAG-P3656PCT Application as filed FINAL yl)oxy)piperidin-1 -yl)acetamide; and 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-phenyl-2-(2- phenylacetamido)ethyl)acetamide; or a pharmaceutically acceptable salt and / or solvate of any one thereof.

[0320] In an embodiment the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is selected from the group consisting of: N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0321] N-benzyl-2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- morpholinobenzyl)acetamide; N-((R)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-1-(4-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0322] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0323] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- (hydroxymethyl)benzyl)acetamide;

[0324] N-(4-cyanobenzyl)-2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamide;

[0325] N-((S)-1-(4-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

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

[0327] 3-yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2-methoxy-1- phenylethyl)acetamide; PAG-P3656PCT Application as filed FINAL

[0328] N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)-N-methylacetamide;

[0329] N-((S)-2-hydroxy-1-phenylethyl)-2-(4-((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)methyl)piperidin-1-yl)acetamide; N-((S)-2-acetamido-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((R)-1- phenylethyl)acetamide;

[0330] N-((S)-1-(2-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0331] N-((S)-1-cyclohexyl-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0332] N-((S)-2-hydroxy-1-(pyridin-4-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0333] N-((R)-3-hydroxy-1-phenylpropyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; ((S)-2-amino-2-oxo-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0334] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxy-3-(1 H- imidazol-4-yl)propan-2-yl)acetamide;

[0335] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1- hydroxypropan-2-yl)acetamide;

[0336] N-((S)-1-(2-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0337] N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- PAG-P3656PCT Application as filed FINAL

[0338] 10.13-d i methyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0339] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxybutan- 2-yl)acetamide;

[0340] N-((S)-2-hydroxy-1-(p-tolyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0341] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxy-3-(1 H- indol-3-yl)propan-2-yl)acetamide; N-((S)-2-amino-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2-(methylamino)- 1 -phenylethyl)acetamide; N-((S)-1-(3-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0342] 10.13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0343] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3- phenylpropan-2-yl)acetamide;

[0344] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- hydroxyethyl)acetamide; N-((S)-2-hydroxy-1-(pyridin-2-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0345] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-2-hydroxy-1-(2-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-

[0346] 3-yl)oxy)piperidin-1-yl)acetamide; (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-N-methyl- 2-phenylacetamide;

[0347] N-((S)-2-hydroxy-1-(pyridin-3-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0348] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- PAG-P3656PCT Application as filed FINAL yl)oxy)piperidin-1 -yl)acetamide;

[0349] N-((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren- 3-yl)oxy)piperidin-1-yl)acetamide; N-((S)-2-hydroxy-1-(m-tolyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0350] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3- methylbutan-2-yl)acetamide;

[0351] (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylacetic acid;

[0352] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3, 3- dimethylbutan-2-yl)acetamide;

[0353] N-(1 ,3-dihydroxypropan-2-yl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-

[0354] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-N,N- dimethyl-2-phenylacetamide;

[0355] N-((S)-1-(3,5-difluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren- 3-yl)oxy)piperidin-1-yl)acetamide;

[0356] N-((S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-

[0357] 3-yl)oxy)piperidin-1-yl)acetamide;

[0358] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(1 -hydroxy-2- methylpropan-2-yl)acetamide;

[0359] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(3- (hydroxymethyl)oxetan-3-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(4- (hydroxymethyl)tetrahydro-2H-pyran-4-yl)acetamide; PAG-P3656PCT Application as filed FINAL

[0360] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(1- (hydroxymethyl)cyclohexyl)acetamide;

[0361] N-((S)-2-(ethylamino)-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0362] N-((S)-2-(2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylethyl)benzamide;

[0363] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2- (isopropylamino)-1-phenylethyl)acetamide;

[0364] N-((S)-2-(2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylethyl)propionamide;

[0365] N-((S)-2-(benzylamino)-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0366] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; and 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-phenyl-2-(2- phenylacetamido)ethyl)acetamide; or a pharmaceutically acceptable salt and / or solvate of any one thereof.

[0367] In an embodiment the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is selected from the group consisting of: N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0368] N-benzyl-2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- morpholinobenzyl)acetamide;

[0369] N-((R)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0370] N-((S)-1-(4-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- PAG-P3656PCT Application as filed FINAL

[0371] 10.13-d i methyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0372] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- (hydroxymethyl)benzyl)acetamide; N-(4-cyanobenzyl)-2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamide;

[0373] N-((S)-1-(4-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-2-hydroxy-1-(4-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-

[0374] 3-yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2-methoxy-1- phenylethyl)acetamide; N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)-N-methylacetamide; N-((S)-2-hydroxy-1-phenylethyl)-2-(4-((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)methyl)piperidin-1-yl)acetamide; N-((S)-2-acetamido-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((R)-1- phenylethyl)acetamide; N-((S)-1-(2-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0375] 10.13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-1-cyclohexyl-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-2-hydroxy-1-(pyridin-4-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0376] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- PAG-P3656PCT Application as filed FINAL yl)oxy)piperidin-1 -yl)acetamide; N-((R)-3-hydroxy-1-phenylpropyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; ((S)-2-amino-2-oxo-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxy-3-(1 H- imidazol-4-yl)propan-2-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1- hydroxypropan-2-yl)acetamide; N-((S)-1-(2-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxybutan- 2-yl)acetamide; N-((S)-2-hydroxy-1-(p-tolyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxy-3-(1 H- indol-3-yl)propan-2-yl)acetamide; N-((S)-2-amino-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2-(methylamino)- 1 -phenylethyl)acetamide; N-((S)-1-(3-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0377] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; PAG-P3656PCT Application as filed FINAL

[0378] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3- phenylpropan-2-yl)acetamide;

[0379] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- hydroxyethyl)acetamide; N-((S)-2-hydroxy-1-(pyridin-2-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-2-hydroxy-1-(2-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-

[0380] 3-yl)oxy)piperidin-1-yl)acetamide; (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-N-methyl- 2-phenylacetamide;

[0381] N-((S)-2-hydroxy-1-(pyridin-3-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;

[0382] N-((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren- 3-yl)oxy)piperidin-1-yl)acetamide; N-((S)-2-hydroxy-1-(m-tolyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3- methylbutan-2-yl)acetamide; (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylacetic acid;

[0383] 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3, 3- dimethylbutan-2-yl)acetamide;

[0384] N-(1 ,3-dihydroxypropan-2-yl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; and (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- PAG-P3656PCT Application as filed FINAL

[0385] 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-N,N- dimethyl-2-phenylacetamide; or a pharmaceutically acceptable salt and / or solvate of any one thereof.

[0386] It will be appreciated that for use in therapy the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include acid addition salts, suitably salts of compounds of the invention comprising a basic group such as an amino group, formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid. Also included are salts formed with organic acids, e.g., succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid and 1 ,5-naphthalenedisulfonic acid. Other salts, e.g., oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention, as are basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts.

[0387] In one embodiment there is provided a compound of formula (I) in the form of a salt, such as a pharmaceutically acceptable salt. Alternatively, there is provided a compound of formula (I).

[0388] The compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g., as the hydrate. This invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water). Suitably, the compound of formula (I) is not in the form of a solvate. Suitably, the compound of formula (I) or salt and / or solvate thereof is a solvate of the compound of formula (I). Suitably the solvate of the compound of formula (I) is a pharmaceutically acceptable solvate.

[0389] The invention extends to a pharmaceutically acceptable derivative thereof, such as a pharmaceutically acceptable prodrug of compounds of formula (I).

[0390] It is to be understood that the present invention encompasses all isomers of compounds of formula (I) including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). In particular, the invention extends to all tautomeric forms of the compounds of formula (I). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional PAG-P3656PCT Application as filed FINAL methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0391] The present invention also includes all isotopic forms of the compound provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exist as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an “isotopically enriched variant form”). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0392] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36CI), chlorine-37 (37CI), fluorine-18 (18F) iodine-123 (123l), iodine-125 (125l) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0393] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon- 14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e.2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as11C,18F,15O and13N, and would be useful in positron emission topography (PET) studies for examining substrate receptor occupancy. PAG-P3656PCT Application as filed FINAL

[0394] In one embodiment, the compound of formula (I) is provided in a natural isotopic form. In one embodiment, the compound of formula (I) is provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e.2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of formula (I). In one embodiment, the atoms of the compound of formula (I) are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compound of formula (I) are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0395] In one embodiment, a compound of formula (I) is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of formula (I) is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0396] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples. Since the compound of formula (I) is intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compound may be used for preparing the purer forms used in the pharmaceutical compositions.

[0397] Synthetic processes

[0398] Compounds of formula (I) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by a number of routes, which include the methods described below and other similar methods and methods known to the skilled person.

[0399] Thus, compounds of formula (I) wherein V represents -C(RARB)C(=O)NRIR2, or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a protected derivative thereof may be prepared by reacting a compound of formula (I) wherein V represents H (a compound of formula (l-H)): PAG-P3656PCT Application as filed FINAL or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a protected derivative thereof; with a compound of formula (II): or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a protected derivative thereof, wherein LGi = leaving group (such as halo e.g. chloro); e.g. under basic conditions (such as Et3N or DIPEA) in a polar solvent (such as DMF, THF or DCM) in the presence of a catalytic amount of a halogen salt (such as KI or Nal).

[0400] Alternatively, compounds of formula (I) wherein V represents -C(RARB)C(=O)NRIR2 or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a protected derivative thereof may be prepared by reacting a compound of formula (III): or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a derivative thereof in which the carboxylic acid group is activated or a protected derivative thereof; with a compound of formula (IV):

[0401] R^

[0402] 1NH i R2 (IV) PAG-P3656PCT Application as filed FINAL or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a protected derivative thereof; under basic conditions (such as Et3N or DIPEA) in a polar solvent (such as DMF, THF or DCM).

[0403] Compounds of formula (I) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof wherein R2 is further substituted by R3 may be prepared by deprotecting a corresponding compound in which a terminal nitrogen atom (such as wherein R3 is -NRpRqor - C(=O)-NRmRn) is protected with a nitrogen protecting group (such as a carbamate forming group e.g. Alloc) or by deprotecting a corresponding compound in which a terminal oxygen atom (such as wherein R3 is -C(=O)-OH) is protected with an oxygen protecting group (such as an allyl ester forming group e.g. allyl alcohol). When the nitrogen protecting group is Alloc or the oxygen protecting group is allyl, deprotection is achieved by reaction with 1 ,3-dimethylbarbituric acid in a polar solvent (such as DCM) in the presence of a Pd(0) catalyst (such as Pd(PPh3)4).

[0404] The carboxylic acid of compounds of formula (II) is suitably activated e.g. as an acid halide (such as chloride) or anhydride and can be activated in situ by the presence of an activator (such as HATU, EDC, HOBt or BOP).

[0405] Alternatively, compounds of formula (I) wherein V represents -C(RARB)C(=O)NRIR2 or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a protected derivative thereof, wherein R1 and R2 taken together with the N atom to which they are attached form (i) a 4-7 membered heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, (ii) a 4-7 membered heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein the 4-7 membered heterocyclyl or 7-11 membered heterospirobicyclyl of (i)-(iii) are substituted with -Co-salkylene-NRyRs and optionally substituted with 1 or 2 Rs, may be prepared by reacting a compound of formula (V):

[0406] PAG-P3656PCT Application as filed FINAL or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a protected derivative thereof, wherein is (i) a 4-7 membered N-heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, (ii) a 4-7 membered N-heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein each of (i)-(iii) are optionally substituted with 1 or 2 Rs and Co-6 represents Co-6alkylene; with a compound of formula (VI):

[0407] OH-R6(VI) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a derivative thereof in which the acid group of the compound of formula (VI) is activated or a protected derivative thereof; under basic conditions (such as Et3N or DIPEA) in a polar solvent (such as DMF, THF or DCM).

[0408] Compounds of formula (VI) are suitably activated e.g. as an acid halide (such as chloride) or anhydride and can be activated in situ by the presence of an activator (such as HATLI, EDC, HOBt or BOP).

[0409] Compounds of formula (l-H) (i.e. compounds of formula (I) in which V represents H) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 1 below. PAG-P3656PCT Application as filed FINAL

[0410] Scheme 1 : Synthesis of compounds of formula (l-H) wherein PGi = alcohol protecting group (such as TMS) and PG2 = nitrogen protecting group (such as Alloc);

[0411] Step 1 : The compound of formula (VII), Bufalin, is reacted with an alcohol protecting reagent (such as TMSCI) in a polar solvent (such as DMF) in the presence of an activator (such as imidazole) to give compounds of formula (VIII).

[0412] Step 2: Compounds of formula (VIII) are reacted with an N-protected oxopiperidine or formyl piperidine (i.e. compounds of formula (X) or (XI) such as Intermediate 1 or Intermediate 11) in a polar solvent (such as MeCN) in the presence of a reducing agent (such as chlorodimethylsilane) to give compounds of formula (IX).

[0413] Step 3: Compounds of formula (IX) are first stirred at room temperature under basic conditions (such as NH3) in a polar solvent (such as MeOH) followed by reaction with 1 ,3-dimethylbarbituric acid in a polar solvent (such as DCM) in the presence of a Pd catalyst (such as Pd(PPha)4) to give compounds of formula (l-H).

[0414] Thus, compounds of formula (l-H) (i.e. compounds of formula (I) in which V represents H such as Example 1 or Example 2) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof (optionally wherein hydroxy groups are protected) may be prepared by deprotecting a corresponding compound in which the terminal nitrogen atom is protected with a nitrogen protecting group (such as a carbamate forming group e.g. Alloc). When the nitrogen protecting group is Alloc, deprotection is achieved by reaction with 1 ,3-dimethylbarbituric acid in a polar solvent (such as DCM) in the presence of a Pd(0) catalyst (such as Pd(PPha)4).

[0415] A compound of formula (l-H) (i.e. compounds of formula (I) in which V represents H) or a salt PAG-P3656PCT Application as filed FINAL and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a protected derivative thereof may be prepared by reacting a corresponding compound of formula (VIII) or a salt and / or solvate thereof with a corresponding compound of formula (X) or (XI): or a protected derivative thereof in the presence of a reducing agent to yield the compound of formula (l-H).

[0416] Suitably, the ring nitrogen of the compounds of formula (X) and (XI) may be protected with a nitrogen protecting group such as Alloc. Suitably, the alcohol on position 3 of the compound of formula (VIII) is protected with an alcohol protecting group such as TMS or TBS.

[0417] This reaction of the compound of formula (VIII) with a compound of formula (X) or (XI) may suitably be performed in the presence of an activating agent (such as trimethylsilyl trifluoromethanesulfonate to form a TMS derivative). Suitable reducing agent conditions include use of an alkyl silane or halogenated alkyl silane such as triethylsilane (TMS) or chlorodimethylsilane (DMCS).

[0418] The aforementioned reactions may take place in a polar organic solvent such as DCM or MeCN.

[0419] Compounds of formula (II) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be commercially available or may be prepared by reacting compounds of formula (IV) with compounds of formula (XII), in the presence of a nitrogen base (such as EtsN) in a polar solvent (such as THF) as outlined below in Scheme 2.

[0420] Scheme 2: Synthesis of compounds of formula (II)

[0421] (IV) (XII) (II) wherein LGi and LG2= leaving group (such as halo e.g. chloro);

[0422] Compounds of formula (III) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared from compounds of formula (l-H) by the synthetic route shown in Scheme 3 below. PAG-P3656PCT Application as filed FINAL

[0423] Scheme 3: Synthesis of compounds of formula (III) wherein LG3 = leaving group (such as halo e.g. bromo) and PG3 = carboxylic acid protecting group (such as allyl);

[0424] Step 1 : Compounds of formula (l-H) are reacted with compounds of formula (XIII) under basic conditions (such as DI PEA) in an apolar solvent (such as dioxane) to give compounds of formula (XIV).

[0425] Step 2: Compounds of formula (XI ) are reacted with 1 ,3-dimethylbarbituric acid in a polar solvent (such as DCM) in the presence of a Pd catalyst (such as Pd(PPhs)4) to give compounds of formula (III).

[0426] Compounds of formula (IV) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by methods disclosed herein or by methods known to a skilled person.

[0427] For example: a) Compounds of formula (IV) in which R1 and R2 taken together with the N atom to which they are attached form (i) a 4-7 membered heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O or (ii) a 4-7 membered heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered PAG-P3656PCT Application as filed FINAL heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein the 4-7 membered heterocyclyl or 7-11 membered heterospirobicyclyl of (i)-(iii) are substituted with 1 R4 wherein R4 is -Co-ealkylene-NRyRe may be prepared by reacting corresponding compounds of formula (XV): wherein O 'His (i) a 4-7 membered N-heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, (ii) a 4-7 membered N-heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, optionally substituted with 1 or 2 Rs and Co-6 represents Co-6alkylene; with compounds of formula (VI) or a derivative thereof in which the acid group of the compound of formula (VI) is activated e.g. as described above; under basic conditions (such as DI PEA) in a polar solvent (such as DCM); b) Compounds of formula (IV) in which R1 and R2 are each independently H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one phenyl or a 6 membered heteroaryl which is substituted with -(CH2)-NH-C(=O)-(CH2)t-RAr3, -(CH2)-NH-S(=O)2-(CH2)t-RAr3 or - (CH2)-NH-C(=O)-C(=O)-NRs-RAr3, may be prepared by reacting corresponding compounds of formula (XVI): wherein An is as defined elsewhere herein and C(i-s) represents Ci-salkyl; with HO-C(=O)-(CH2)t-RAr3, HO-S(=O)2-(CH2)t-RAr3 or HO-C(=O)-C(=O)-NRs-RAr3; under basic conditions (such as DI PEA) in a polar solvent (such as DCM) in the presence of an activator (such as EDC and HOBt).

[0428] Compounds of formula (V) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared from compounds of formula (III) via the synthetic route shown in Scheme 4 below. PAG-P3656PCT Application as filed FINAL

[0429] Scheme 4: Synthesis of compounds of formula (V)

[0430] Compounds of formula (III) are reacted with compounds of formula (XV) under basic conditions

[0431] (such as DIPEA) in a polar solvent (such as DMF) in the presence of activating agents (such as HATLI and HOBt) to give compounds of formula (V).

[0432] Compounds of formula (VI) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by methods disclosed herein or by methods known to a skilled person. For example, certain compounds wherein Re is -C(=O)-C(=O)-NRZ-R8 may be prepared by the synthetic route shown in Scheme 5 below.

[0433] Scheme 5: Synthesis of compounds of formula (VI) wherein Rs is -C(=O)-C(=O)-NRZ-R8. wherein PG4 = carboxylic acid protecting group (such as alkyl e.g. ethyl) and LG1 = as defined above.

[0434] Step 1 : Compounds of formula (XVII) are reacted with an alkyl oxalyl chloride a polar solvent (such as DCM) in the presence of a nitrogen base (such as DI PEA or Et2NMe) to give compounds of formula (XVIII).

[0435] Step 2: Compounds of formula (XVIII) are hydrolysed using a protic base (such as LiOH) in a polar solvent (such as THF) to give compounds of formula (VI).

[0436] Compounds of formula (VII), (X), (XI), (XII), (XIII), (XV), (XVI) (XVII), HO-C(=O)-(CH2)t-RAr3, HO- S(=O)2-(CH2)t-RAr3, and HO-C(=O)-C(=O)-NRs-RAr3 are either known or may be prepared by methods known to the skilled person.

[0437] If appropriate or convenient, compounds of formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), PAG-P3656PCT Application as filed FINAL

[0438] (XI), (XII), (XIII), (XIV), (XV), (XVI) (XVII), HO-C(=O)-(CH2)t-RAr3, HO-S(=O)2-(CH2)t-RAr3, and HO- C(=O)-C(=O)-NRs-RAr3 may be protected in the synthetic method to protect potentially reactive groups such as oxygen and nitrogen containing groups. Further, structures shown as containing protecting groups may be successfully deployed without such protecting groups. Salt interconversion may be performed as required.

[0439] Novel compounds, such as compounds of formula (III) and (V) and salts and / or solvates thereof e.g. pharmaceutically acceptable salts and / or solvated thereof are provided as an aspect of the invention.

[0440] The skilled person will appreciate that protecting groups may be used throughout the synthetic schemes described herein to give protected derivatives of any of the above compounds or generic formulae. Protective groups and the means for their removal are described in “Protective Groups in Organic Synthesis", by Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc; 4th Rev Ed., 2006, ISBN-10: 0471697540. Examples of nitrogen protecting groups include tert-butyloxycarbonyl (BOG), benzyloxycarbonyl (Cbz) and allyloxycarbonyl (Alloc) groups. Examples of oxygen protecting groups include benzyl, ethyl, chloro acetyl, and silyl ethers and esters (such as tert-butyldimethylsilyl (TBS). Specific examples of carboxylic acid protecting groups include alkyl esters (such as Ci-ealkyl e.g. Ci-4alkyl esters), benzyl esters and allyl esters.

[0441] Therapeutic indications

[0442] The invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicament.

[0443] In particular the invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing cancer, including metastasis of cancer. There is also provided use of compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing cancer, including metastasis of cancer. There is also provided a method of treating or preventing cancer, including metastasis of cancer, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. Cancer is PAG-P3656PCT Application as filed FINAL to be treated in a subject (e.g. a patient) in need thereof, especially a human subject. Cancer is to be prevented in a subject susceptible thereto, especially a human subject.

[0444] In one embodiment, the cancer is a solid cancer. For example, in one embodiment, the cancer is an epithelial tumour i.e. carcinoma, for example an adenocarcinoma, basal cell carcinoma, or squamous cell carcinoma. In an alternative embodiment, the cancer is a lymphoma. In a further alternative embodiment, the cancer is a melanoma. In an additional alternative embodiment, the cancer is a sarcoma, for example fibrosarcoma, Kaposi’s sarcoma, osteosarcoma, or rhabdomyosarcoma. In an alternative embodiment, the cancer is a blastoma.

[0445] In one embodiment, the cancer is bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, gallbladder cancer, liver cancer, oesophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer e.g. basal cell carcinoma, stomach cancer, thyroid cancer, or uterine cancer, In a particular embodiment, the cancer is breast cancer, colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, or skin cancer e.g. basal cell carcinoma and especially is breast cancer, colorectal cancer or prostate cancer.

[0446] In one embodiment, the cancer is a metastatic cancer. For example, in one embodiment, the cancer is a metastatic carcinoma. In an alternative embodiment, the cancer is a metastatic lymphoma. In a further alternative embodiment, the cancer is a metastatic melanoma. In an additional alternative embodiment, the cancer is a metastatic sarcoma. In an alternative embodiment, the cancer is a metastatic blastoma.

[0447] In one embodiment, the cancer is a metastatic cancer. For example, the cancer is metastatic bladder cancer, metastatic brain cancer, metastatic breast cancer, metastatic cervical cancer, metastatic colorectal cancer, metastatic gallbladder cancer, metastatic liver cancer, metastatic oesophageal cancer, metastatic ovarian cancer, metastatic pancreatic cancer, metastatic prostate cancer, metastatic renal cancer, metastatic skin cancer, metastatic stomach cancer, metastatic thyroid cancer, or metastatic uterine cancer, In a particular embodiment, the cancer is metastatic breast cancer, metastatic colorectal cancer, metastatic lung cancer, metastatic ovarian cancer, metastatic pancreatic cancer, metastatic prostate cancer, or metastatic skin cancer and especially is metastatic breast cancer, metastatic colorectal cancer or metastatic prostate cancer.

[0448] Administration

[0449] The compound of formula (I) may usually be administered as a pharmaceutical composition. Thus, in one embodiment, is provided a pharmaceutical composition comprising a compound of PAG-P3656PCT Application as filed FINAL formula (I) and one or more pharmaceutically acceptable diluents or carriers.

[0450] The compound of formula (I) may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical compositions adapted accordingly. Alternatively, parenteral administration may be used, such as subcutaneous, intravenous, intrahepatic or intramuscular injection forms.

[0451] The compound of formula (I) may be administered topically to the target organ e.g. topically to the eye, lung, nose or skin. The compound of formula (I) may be instilled into the bladder. Hence the invention provides a pharmaceutical composition comprising a compound of formula (I) and one or more topically acceptable diluents or carriers.

[0452] A compound of formula (I) intended for oral administration can be formulated as a liquid or solid, e.g. as a syrup, suspension, emulsion, tablet, capsule or lozenge.

[0453] A liquid composition will generally consist of a suspension or solution of the compound of formula (I) in a suitable liquid carrier(s). The carrier may be aqueous or non-aqueous e.g. polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and / or colouring agent.

[0454] A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.

[0455] A composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule.

[0456] Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A suitable sterile aqueous carrier is water for injection.

[0457] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels PAG-P3656PCT Application as filed FINAL and powders.

[0458] The compound of the invention may also be administered rectally, for example in the form of suppositories or enemas, which include aqueous or oily solutions as well as suspensions and emulsions and foams. Such compositions are prepared following standard procedures, well known by those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides.

[0459] The compositions administered according to the present invention may also include various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymer, preservatives, co-solvents and viscosity building agents.

[0460] Surfactants may optionally be employed to deliver higher concentrations of compound of the present invention. The surfactants function to solubilise the compound and stabilise colloid dispersion, such as micellar solution, microemulsion, emulsion and suspension. Examples of surfactants which may optionally be used include polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate.

[0461] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the compound of formula (I) is formulated with a carrier such as sugar and acacia, tragacanth, or gelatine and glycerine.

[0462] Compositions suitable for transdermal administration include ointments, gels and patches.

[0463] The composition may contain from 0.1 % to 100% by weight, for example from 10 to 60% by weight, of the compound of formula (I), depending on the method of administration. The composition may contain from 0% to 99.9% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain from 0.05 mg to 1000 mg, for example from 1.0 mg to 500 mg, such as from 1.0 mg to 50 mg, e.g. about 10 mg of the compound of formula (I), depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from 100 mg to 400 mg of the carrier, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 500 mg, such as from 1.0 mg to 50 mg, e.g. about 10 mg and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months. PAG-P3656PCT Application as filed FINAL

[0464] In one embodiment of the invention, the compound of formula (I) is used in combination with one or more further therapeutic agents, such as further therapeutic agents for the treatment or prevention of cancer (including metastasis of cancer). When the compound of formula (I) is used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. Alternatively, the compounds may be administered separately.

[0465] Further aspects of the invention

[0466] Aspects of the invention include those defined by the following clauses:

[0467] 1 . A compound of formula (I): or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

[0468] V is H or -C(RARB)C(=O)NRIR2;

[0469] RA and RB are each independently selected from the group consisting of H, Ci-ealkyl and Ci-ehaloalkyl;

[0470] Re is selected from the group consisting of halo, -NH2, Ci-ehaloalkyl, Ci-ealkyl, Ci-ealkoxy and cyano;

[0471] RD is selected from the group consisting of H, Ci-ealkyl and Ci-ehaloalkyl; k is 0 or 1 ;

[0472] I is an integer 0 to 2; m is an integer 0 to 4; n is 0 or 1 ; and:

[0473] Ri is H or Ci-ealkyl;

[0474] R2is H or Ci-salkyl, wherein Ci-salkyl is (i) optionally substituted with 1 or 2 R3, (ii) is substituted with 1 Cyci and is optionally substituted with 1 R3, or (iii) is substituted by 1 PAG-P3656PCT Application as filed FINAL

[0475] R3and by 2 further substituent groups which when taken together with the C atom to which they are attached form Cs-ecycloalkyl or 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O;

[0476] Rs is independently selected from the group consisting of -ORsa, -NRpRqand - C(=O)-R3d;

[0477] Cyci is selected from the group consisting of Cs-ecycloalkyl, 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, 7-11 membered heterobicyclyl or heterospirobicyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, 5 membered heteroaryl, 7-11 membered heteroaryl and An, wherein Cyci is optionally substituted in any position with 1 to 3 Rcyci;

[0478] An is phenyl or 6 membered heteroaryl;

[0479] R3ais H or Ci-ealkyl;

[0480] Rpand Rqare (i) each independently H or Ci-4alkyl, (ii) Rpand Rqtaken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N,

[0481] 5 and O, or (iii) Rpis H or Ci-4alkyl and Rqis selected from -C(=O)Ci- 3alkyl and -K-Cyc2;

[0482] K is -C(=0)(CH2)O-2- or -(CH2)o-3-;

[0483] R3d is hydroxy or -NRmRn;

[0484] Rmand Rnare (i) each independently H or Ci-4alkyl, (ii) Rmand Rntaken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O, or (iii) Rmis H or Ci-4alkyl and Rnis -(CH2)o-3-Cyc2;

[0485] Cyc2 is selected from the group consisting of C3-6cycloalkyl, 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, 5-7 membered heteroaryl and phenyl, wherein Cyc3is optionally substituted in any position with 1 to 3 RcyC2;

[0486] Rcyciand RcyC2 are independently selected from the group consisting of halo, -NRgRh, Ci-ehaloalkyl, Ci-ealkyl optionally substituted by hydroxy, C1-

[0487] 6 alkoxy and cyano; and when Cyci is An, An may also be optionally substituted with RAM ;

[0488] RAM is selected from the group consisting of -(CH2)-Q-C(=O)-(CH2)t-RAr3, -(CH2)- NRx-S(=O)2-(CH2)t-RAr3 and -(CH2)-NRx-C(=O)-C(=O)-NRs-RAr3;

[0489] RAF3 is selected from the group consisting of phenyl, naphthyl, 5-6 membered heteroaryl comprising 1 to 3 heteroatoms independently PAG-P3656PCT Application as filed FINAL selected from N, O and S, C^cycloalkyl and 5-6 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, wherein RAr3a is optionally substituted with 1 or 2 RAM;

[0490] RA is selected from the group consisting of halo, -NRgRh, Ci-ehaloalkyl, Ci-ealkyl optionally substituted by hydroxy, C1-6 alkoxy and cyano;

[0491] Q is selected from the group consisting of bond, -O- and -NRX-;

[0492] Rgand Rh are each independently H or Ci-4alkyl or Rgand Rh taken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O;

[0493] Rxand Rsare each independently H or methyl; and t is 0 or 1. or:

[0494] Ri and R2 taken together with the N atom to which they are attached form (i) a 4-7 membered heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O or (ii) a 4-7 membered heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein the 4-7 membered heterocyclyl or 7-11 membered heterospirobicyclyl of (i) to (iii) are optionally substituted with 1 R4 and optionally substituted with 1 or 2 R5;

[0495] R4 is Ci-ealkyl or Co-ealkylene-NRyRe, wherein the Ci-ealkyl is optionally substituted with 1 or 2 substituents selected from the group consisting of -OH, fluorine, -CN, -OCi-4alkyl, NHCi-4alkyl and N(Ci-4alkyl)2;

[0496] Re is selected from the group consisting of -C(=O)-X-(CH2)v-R7, -S(=O)2- (CH2)W-R7and -C(=O)-C(=O)-NRZ-R8;

[0497] X is selected from the group consisting of bond, O and NRn;

[0498] R7 is Ci-ealkyl or Cyca;

[0499] Cyca is selected from the group consisting of phenyl, naphthyl, 5 to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, S and O, C4-7cycloalkyl and 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, wherein Cyci is optionally substituted with 1 to 4 R9;

[0500] Rs represents C4-7cycloalkyl optionally substituted with 1 to 4 Rw; R9, and R10 are each independently selected from the group PAG-P3656PCT Application as filed FINAL consisting of halo, -NRjRj, Ci-ehaloalkyl, Ci-ealkyl, Ci-ealkoxy, Ci- salkyl-C(=O)-, cyano and S(=O)2(Ci-6alkyl);

[0501] Rs is selected from the group consisting of halo, -NH2, Ci-ehaloalkyl, Ci-ealkyl, C1- ealkoxy, -CH2OH, hydroxy and cyano;

[0502] Ry, Rzand Rn are each independently H or methyl; v and w are each independently 0 or 1 ; and

[0503] Ri and Rj are each independently H or Ci-4alkyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0504] 2. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 1 wherein m is 0.

[0505] 3. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 1 wherein m is 1.

[0506] 4. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 3 wherein n is 0.

[0507] 5. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 3 wherein n is 1 .

[0508] 6. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 5 wherein RD is H.

[0509] 7. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 6 wherein k and I are both 1.

[0510] 8. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 7 wherein V is H.

[0511] 9. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 7 wherein V is -C(RARB)C(=O)NRIR2.

[0512] 10. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 9 wherein RA and RB are both H.

[0513] 11 . The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 9 or clause 10 wherein R1 is H.

[0514] 12. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 9 or clause 10 wherein R1 is methyl.

[0515] 13. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 9 to 12 wherein R2 is optionally substituted Ci-salkyl.

[0516] 14. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 13 wherein R2 is selected from the group consisting of ' (methyl), (ethyl),

[0517] (n-propyl), (isopropyl), ^\(butan-2-yl) , ^\(3-methylbutan-2-yl) and PAG-P3656PCT Application as filed FINAL

[0518] 111 I 111 (3,3-dimethylbutan-2-yl) each of which groups are optionally substituted, wherein I represents the site of attachment to the rest of the compound.

[0519] 15. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 14 wherein R2 is selected from the group consisting of (methyl), (ethyl), , (butan-2-yl) each of which groups are optionally 111 I 111 substituted, wherein I represents the site of attachment to the rest of the compound .

[0520] 16. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 13 to 15 wherein R2 is unsubstituted.

[0521] 17. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 13 to 15 wherein R2 is substituted with (i) 1 or 2 R3, (ii) 1 Cyci and optionally substituted with 1 R3, or (iii) 1 R3 and by 2 further substituent groups which when taken together with the C atom to which they are attached form Cs-ecycloalkyl or 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N and O.

[0522] 18. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 17 wherein R2 is Ci-salkyl substituted with one R3, and R3 is hydroxy.

[0523] 19. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 17 wherein R2 is selected from the group consisting of ethyl, isopropyl and butan-2-yl substituted by one R3 in the B position.

[0524] 20. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 17 wherein R2 is substituted with 1 Cyci and with no R3.

[0525] 21 . The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 17 wherein R2 is substituted with 1 Cyci and 1 R3.

[0526] 22. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 20 or clause 21 wherein R3 is ORsaand Rsa is H or methyl.

[0527] 23. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 20 or clause 21 wherein R3 is -NRpRg.

[0528] 24. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 23 wherein Rpand Rgare both H or Rpis H and Rqis methyl.

[0529] 25. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 23 wherein Rpand Rgtaken together with the N atom to which they are attached form a 5 membered or 6 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O.

[0530] 26. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 23 wherein Rpis H and Rqis selected from -C(=O)Ci-3alkyl and -K-Cyc2 wherein K is - PAG-P3656PCT Application as filed FINAL

[0531] CH2- or -C(=O)-.

[0532] 27. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 26 wherein Cyc2is phenyl wherein Cyc2is optionally substituted in any position with 1 to 3 Rcyc2-

[0533] 28. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 21 wherein R3 is -C(=O)-R3d and Rsd is hydroxy.

[0534] 29. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 21 wherein R3 is -C(=O)-R3d and Rsd is -NRmRn and, for example, Rmand Rnare both H.

[0535] 30. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 20 or clause 21 wherein Cyci is selected from the group consisting of Cs-ecycloalkyl, 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, 7-11 membered heterobicyclyl or heterospirobicyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, 5 membered heteroaryl, 7-11 membered heteroaryl and An, wherein Cyci is optionally substituted in any position with 1 Rcyd.

[0536] 31 . The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 30 wherein Cyci is selected from the group consisting of Cs-ecycloalkyl, 5 membered heteroaryl and 711 membered heteroaryl and An, wherein Cyci is optionally substituted in any position with 1 Rcyd.

[0537] 32. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 30 or clause 31 wherein Cyci is unsubstituted.

[0538] 33. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 30 to 32 wherein Cyci is selected from the group consisting of cyclohexyl, imidazolyl and phenyl, each of which is optionally substituted with 1 Rcyd.

[0539] 34. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 33 wherein Cyci is unsubstituted.

[0540] 35. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 33 wherein Cyci is substituted with 1 Rcyciand Rcyciis halo (e.g. fluoro).

[0541] 36. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 21 and 30 to 35 wherein R2is methyl which methyl is substituted by (i) Cyci

[0542] 0 (which may optionally be substituted) and (ii) R3 wherein R3 is -C(=O)-R3d to form Cy^ 111 I 111 wherein I represents the site of attachment to the rest of the compound and Rsd is hydroxy or -NRmRn where Rmand Rnare, for example, both H.

[0543] 37. The compound or pharmaceutically acceptable salt and / or solvate thereof according to PAG-P3656PCT Application as filed FINAL any one of clauses 21 and 30 to 35 wherein R2 represents ethyl which ethyl is substituted by (i) Cyci in the alpha position which Cyci may optionally be substituted and (ii) R3 in the beta position, to formCyClwherein I represents the site of attachment to the rest of the compound.

[0544] 38. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 21 and 30 to 35 wherein R2 represents n-propyl which n-propyl is substituted by (i) Cyci (which may optionally be substituted) in the alpha position and (ii) R3 in the gamma position, to formCyci wherein I represents the site of attachment to the rest of the compound.

[0545] 39. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 21 and 30 to 35 wherein R1 represents H and R2 represents isopropyl which isopropyl is substituted by (i) Cyci (which may optionally be substituted) in the beta position and I

[0546] (ii) R3 in the beta’ position, to form wherein I represents the site of attachment to the rest of the compound.

[0547] 40. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 20 wherein R2 represents methyl substituted by one An, which An is phenyl substituted with RAM to form wherein I represents the site of attachment to the rest of the compound.

[0548] 41. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 40 wherein RAM is -(CH2)-Q-C(=O)-(CH2)t-RAr3.

[0549] 42. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 41 wherein Q is -NH- and t is 0 or 1.

[0550] 43. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 41 or clause 42 wherein RAM is optionally substituted phenyl or 5 to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O and S.

[0551] 44. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 41 to 43 wherein RAM is substituted with one RA .

[0552] 45. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 44 wherein RA is selected from the group consisting of halo, Ci-ealkyl and Ci-ealkoxy.

[0553] 46. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 9 wherein R1 and R2 taken together with the N atom to which they are attached form (i) a PAG-P3656PCT Application as filed FINAL

[0554] 4-7 membered heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, (ii) a 4-7 membered heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein the 4-7 membered heterocyclyl or 7-11 membered heterospirobicyclyl of (i)-(iii) are optionally substituted with 1 R4 and not any Rs.

[0555] 47. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 46 wherein R1 and R2 taken together with the N atom to which they are attached form a 4-7 membered heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, wherein the 4-7 membered heterocyclyl is optionally substituted with 1 R4 and not any R5.

[0556] 48. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 46 or clause 47 wherein the 4-7 membered heterocyclyl which a 6 membered heterocyclyl which is optionally substituted.

[0557] 49. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 48 wherein the 6 membered heterocyclyl is optionally substituted piperidinyl.

[0558] 50. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 49 wherein the 6 membered heterocyclyl is piperidinyl and is substituted in the 4 position with 1 R4 and not substituted with any R5.

[0559] 51 . The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 50 wherein R4 is Co-salkylene-NHRs.

[0560] 52. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 51 wherein R4 is -NHRs.

[0561] 53. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 51 or clause 52 wherein Re is -C(=O)-X-(CH2)v-R7.

[0562] 54. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 53 wherein X is bond and v is 1 .

[0563] 55. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 53 or clause 54 wherein R7 is Cyca.

[0564] 56. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 55 wherein Cyca is phenyl or 5-6 membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, S and O, wherein Cycs is optionally substituted with 1 R9.

[0565] 57. The compound or pharmaceutically acceptable salt and / or solvate thereof according to clause 56 wherein Cycs is pyridinyl, wherein Cycs is optionally substituted with 1 to 4 R9.

[0566] 58. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 55 to 57 wherein Cycs is unsubstituted.

[0567] 59. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to PAG-P3656PCT Application as filed FINAL clause 1 which is selected from the group consisting of: Examples 1-78 or a pharmaceutically acceptable salt and / or solvate of any one thereof.

[0568] 60. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to clause 1 which is selected from the group consisting of: Examples 79-90 or a pharmaceutically acceptable salt and / or solvate of any one thereof.

[0569] 61 . The compound or a pharmaceutically acceptable salt and / or solvate thereof according to clause 1 which is selected from the group consisting of: Examples 4, 6, 36, 53, 55 and 67 or a pharmaceutically acceptable salt and / or solvate of any one thereof.

[0570] 62. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 61 and one or more pharmaceutically acceptable diluents or carriers.

[0571] 63. A compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 61 or a pharmaceutical composition according to clause 62 for use as a medicament.

[0572] 64. A compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 61 or a pharmaceutical composition according to clause 62 for use in treating or preventing cancer, including metastasis of cancer.

[0573] 65. Use of a compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 61 or a pharmaceutical composition according to clause 62 in the manufacture of a medicament for treating or preventing cancer, including metastasis of cancer.

[0574] 66. A method of treating or preventing cancer, including metastasis of cancer, which comprises administering a compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of clauses 1 to 61 or a pharmaceutical composition according to clause 62.

[0575] 67. A compound of formula (III): or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a derivative thereof in which the carboxylic acid group is activated or a protected derivative thereof and wherein RA, B, RC, RD, k, I, m and n are as defined in any one of clauses 1 to 61.

[0576] 68. A compound of formula (V): PAG-P3656PCT Application as filed FINAL or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a protected derivative thereof, wherein is (i) a 4-7 membered N-heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, (ii) a 4-7 membered N-heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein each of (i)-(iii) are optionally substituted with 1 or 2 Rs and Co-6 represents Co-6alkylene and wherein RA, RB, RC, RD, Ry, k, I, m and n are as defined in any one of clauses 1 to 61 .

[0577] Potential desirable properties

[0578] The compounds of formula (I) are effective at reducing cell-cell interactions between cancer cells (e.g. as determined by the method of Biological Example 1) in cancer cell lines and are expected to be useful in treating or preventing cancer including metastasis of cancer (e.g. as demonstrated in the model described in Biological Example 2). They may display one or more of the following desirable properties: Good anti-proliferative activity, high kinetic solubility, good metabolic stability or other suitable adsorption, distribution, metabolism or excretion (ADME) property or other pharmacodynamic or pharmacokinetic properties (such as predictability of pharmacodynamic or pharmacokinetic properties) or favourable toxicity profile, which properties indicate suitability as a pharmaceutical agent. PAG-P3656PCT Application as filed FINAL

[0579] EXAMPLES

[0580] Chemical Examples Analytical Equipment

[0581] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance 400 or 500 MHz spectrometer unless otherwise noted. Spectra are given in ppm (5) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.

[0582] Chemical shifts are reported in ppm relative to Dimethyl sulfoxide (DMSO) (5 2.50), methanol (5 3.31), chloroform (5 7.26) or other solvent as indicated in NMR spectral data. A small amount of the dry sample (2-5 mg) is dissolved in an appropriate deuterated solvent (1 mL). The chemical names were generated using ChemBioDraw Ultra v12 from CambridgeSoft.

[0583] Mass spectra (ESI-MS) were collected using a Hitachi Chromaster HPLC system (Column: Zorbax XDB-C18 150x4.6 mm 5 pm; Flow Rate: 1 mL / min; 40°C) and on a Shimadzu UHPLC system with a 8045 Triple Quadrupole (Column: Eclipse Plus C18 50x4.6 mm 1.8 pm; Flow Rate: 1 mL / min; 24°C); all masses are the m / z of the protonated or deprotonated parent ion unless recorded otherwise. The sample was dissolved in a suitable solvent such as MeCN or MeOH and was injected directly into the column using an automated sample handler.

[0584] Commercial Materials All starting materials and solvents were obtained either from commercial sources or prepared according to the literature citation.

[0585] Abbreviations °C Degree Celsius

[0586] Ac Acetyl

[0587] Alloc Allyloxycarbonyl aq Aqueous

[0588] Boc Terf-Butyloxycarbonyl BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate br Broad

[0589] Bz Benzoyl PAG-P3656PCT Application as filed FINAL

[0590] Cbz Benzyloxycarbonyl

[0591] CV Column Volume

[0592] Cy Cyclohexyl

[0593] CyH Cyclohexane d Days / doublet (NMR)

[0594] DCM Dichloromethane dd Doublet of doublets ddd Doublet of doublet of doublets ddq Doublet of doublet of quartets ddt Doublet of doublet of triplets

[0595] DIPEA N,N-diisopropylethylamine

[0596] DMAP 4-Dimethylaminopyridine

[0597] DMF Dimethylformamide

[0598] DMSO Dimethyl sulfoxide dq Doublet of quartets dt Doublet of triplets dtd Doublet of triplet of doublets

[0599] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0600] Eq. or equiv. Equivalents ES Electrospray

[0601] Et Ethyl

[0602] EtOAc Ethyl acetate g Gram

[0603] H or hr Hour HATLI Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium hept Heptet

[0604] Hex Hexyl

[0605] HOBt Hydroxybenzotriazole

[0606] HPLC High performance liquid chromatography J Scalar coupling constant

[0607] LC-MS Liquid Chromatography-Mass Spectrometry

[0608] M Molarity m Multiplet m / Z Mass-to-Charge ratio Me Methyl

[0609] MeCN Acetonitrile

[0610] MeOH Methanol PAG-P3656PCT Application as filed FINAL mg Milligram

[0611] MHz Megahertz mL Millilitre mmol Millimole MS Mass spectrometry

[0612] N Normality

[0613] NMR Nuclear Magnetic Resonance

[0614] Ph Phenyl

[0615] Py Pyridinyl q Quartet qd Quartet of doublets quint Quintet t Triplet

[0616] TBS Tert-butyldimethylsilyl TBSCI Tert-Butyldimethylsilyl chloride td Triplet of doublets tdd Triplet of doublet of doublets THF Tetrahydrofuran TLC Thin Layer Chromatography tt Triplet of triplets ttd T riplet of triplet of doublets

[0617] PAG-P3656PCT Application as filed FINAL

[0618] General Procedures

[0619] The following General Procedures (A) to (B) are referred to in the foregoing methods of preparing certain Intermediates and Examples.

[0620] General procedure (A-1 and A-2)

[0621] General Procedure (A-1):

[0622] To a mixture of Example 1 or Example 2 (1 equiv), DIPEA (5.0 equiv.) and KI (0.2 equiv.), in DMF was added the alpha chloro amide (amount as stated in relevant Example). The reaction mixture was heated to 50 °C. After 20 h, the reaction mixture was cooled to room temperature diluted with EtOAC and washed with sat. NaHCCh (1x) and brine (3x). The organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, MeOH / EtOAc, 0% over 3 CVs, 0% to 100% over 10 CVs, 100% over 4 CVs). Fractions containing product were concentrated, redissolved in H2O / MeOH (10:1) and then lyophilized to give the desired product.

[0623] General Procedure (A-2):

[0624] To a mixture of Example 1 or Example 2 (1 equiv.), alpha chloro amide (amount as stated in relevant Example) and sodium iodide (0.2 equiv.) in DMF (1.7 mL) was added DIPEA (5 equiv.) and the reaction mixture was allowed to stir at room temperature. After 20 h (or the duration as stated in the relevant Example), water was added and the precipitated was filtered, collected, and then purified by column chromatography (20 g cartridge, EtOAc / MeOH, 0% to 40% over 12 CVs) to give the desired product PAG-P3656PCT Application as filed FINAL

[0625] General procedure (B-1 and B-2) lnt-15

[0626] General Procedure (B-1):

[0627] To a solution of Intermediate 15 (1.0 equiv.), HATLI (1.50 equiv.), HOBt (1.0 equiv.) in DMF was added DIPEA (4.0 equiv. or 5.0 equiv.; amount as stated in relevant Example). The mixture was cooled to 0 °C when RNHR’ or RNHR’HCI (amount as stated in relevant Example) was added in one portion and the reaction mixture was allowed to stir 20 h at room temperature. After 20 h (or the duration as stated in the relevant Example), the reaction mixture was diluted with DCM and washed with sat. NaHCCh (2 x), followed by brine. The organic solution was then dried, filtered, and concentrated. The crude product was purified by chromatography. The fractions containing product were concentrated under reduced pressure and the residue was purified further by reverse phase chromatography. Fractions containing product were lyophilized to give the title product.

[0628] General Procedure (B-2):

[0629] To a solution of Intermediate 15 (1.0 equiv.), HATU (1.50 equiv.), HOBt (1 equiv.) in DMF was added DIPEA (4 equiv.). The mixture was cooled to 0 °C when RNHR’ or RNHR’HCI (20 mg, 0.068 mmol, 1.2 equiv.) was added in one portion and the reaction mixture was allowed to stir at room temperature. After 20 h (or the duration as stated in the relevant Example), water (20 mL) was slowly added. The precipitate obtained was filtered, collected, and chromatographed (12g cartridge, [(DCM / EtOAc 1 :1) / MeOH] 0% for 2 CV, 0-15% for 6 CVs, 15% for 6 CV). Fractions which contained product were concentrated and then lyophilized from MeOH / H2O (30 mL / 2 mL) to give the title product.

[0630] Intermediates

[0631] Intermediate 1 (lnt-1): Allyl 4-oxopi peridin e-1 -carboxylate

[0632] Potassium carbonate (6.79 g, 49.1 mmol, 2 equiv.) was added to a solution of piperidin-4-one hydrochloride (3.33 g, 24.6 mmol, 1 equiv.) in THF (25 mL) / Water (8.3 mL) at ambient PAG-P3656PCT Application as filed FINAL temperature. The mixture was cooled to 0°C when allyl chloroformate (3.26 g, 2.87 mL, 27.0 mmol, 1.1 equiv.) was added dropwise. The cooling bath was removed and stirring continued at ambient temperature for 2 h. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic solution was dried over anhydrous Na2SO4, filtered, and concentrated to afford allyl 4-oxopiperidine-1 -carboxylate (Intermediate 1) (4.2 g, 93 %) as a colourless oil which was used in the next step without further purification.1H NMR (400 MHz, CDCh) 6 5.95 (ddt, J = 17.2, 10.4, 5.6 Hz, 1 H), 5.32 (dq, J = 17.2, 1.5 Hz, 1 H), 5.24 (dq, J = 10.4, 1.3 Hz, 1 H), 4.64 (dt, J = 5.6, 1 .4 Hz, 2H), 3.79 (t, J = 6.3 Hz, 4H), 2.46 (t, J = 6.3 Hz, 4H).

[0633] Intermediate 2 (lnt-2): 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3- ((trimethylsilyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one

[0634] To a mixture of bufalin (200 mg, 0.517 mmol, 1 equiv.) and imidazole (352 mg, 5.17 mmol, 10 equiv.) in anhydrous DMF (2.6 mL) at 0 °C was added trimethylsilylchloride (0.33 mL, 2.59 mmol, 5 equiv), dropwise, and the reaction mixture was allowed to warm to room temperature. After stirring for 18 h, the reaction mixture was cooled with an ice bath and distilled water was added. The resulting precipitate was filtered, washed with water (20 mL), stripped from MeCN (2x 10 mL) and then dried under reduced pressure. The residue was finally taken up in anhydrous toluene (50 mL) insoluble material was filtered off, and the solution then concentrated to give 5- ((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3- ((trimethylsilyl)oxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one (Intermediate 2) as a white solid (192 mg, 81 % yield).1H NMR (400 MHz, DMSO) 5 7.93 (dd, J = 9.8, 2.6 Hz, 1 H), 7.52 (s, 1 H), 6.29 (d, J = 9.7 Hz, 1 H), 4.14 (s, 1 H), 4.05 (s, 1 H), 2.25 - 0.94 (m, 22H), 0.86 (s, 3H), 0.59 (s, 3H), 0.06 (s, 9H).

[0635] Step 1 : To a solution of tetrahydro-2H-pyran-4-carboxylic acid (200 mg, 1.54 mmol, 1 equiv.) in DCM (6 mL) at 0 °C were added HOBt (259 mg, 1.69 mmol, 1.10 equiv.), EDC (442 mg, 2.31 PAG-P3656PCT Application as filed FINAL mmol, 1.50 equiv.) and tert-butyl 4-aminopiperidine-1 -carboxylate (323 mg, 1.61 mmol, 1.05 equiv.). The solution was stirred at 0 °C when DIPEA (1.07 mL, 6.15 mmol, 4 equiv.) was added. The reaction mixture was allowed to warm to room temperature. After 20 h, the solution was partitioned with distilled water (25 mL) and EtOAc (50 mL). The aqueous layer was taken out, and the organic layer was washed with half sat. aq. NH4CI sol. (25 mL), then sat. aq. NH4CI sol. (25 mL) then sat. aq. NaHCO3 sol. (25 mL) then brine (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 4-(tetrahydro- 2H-pyran-4-carboxamido)piperidine-1-carboxylate as a white solid (472 mg, 98% yield).1H NMR (400 MHz, CDCI3) 5 5.29 (d, J = 8.0 Hz, 1 H), 4.14 - 3.97 (m, 4H), 3.92 (dtt, J = 11.7, 8.2, 4.1 Hz, 1 H), 3.40 (td, J = 11.4, 3.0 Hz, 2H), 2.92 - 2.77 (m, 2H), 2.36 - 2.23 (m, 1 H), 1.90 (dd, J = 12.3, 3.6 Hz, 2H), 1.85 - 1 .69 (m, 4H), 1 .45 (s, 9H), 1.27 (qd, J = 11 .9, 4.4 Hz, 3H).

[0636] Step 2: To a solution of tert-butyl 4-(tetrahydro-2H-pyran-4-carboxamido)piperidine-1 -carboxylate (472 mg, 1.51 mmol, 1 equiv.) in DCM (10 mL) was added 4N HCI in dioxane (3.78 mL, 15.1 mmol, 10 equiv.). The reaction mixture was allowed to stir 20 h at room temperature when it was concentrated to give the crude HCI salt (Intermediate 3) that was used in the next step without further purification (359 mg, >99%).1H NMR (400 MHz, DMSO) 5 8.77 (s, 2H), 7.94 (s, 1 H), 3.85 (dt, J = 11.4, 3.5 Hz, 2H), 3.79 (d, J = 5.4 Hz, 1 H), 3.34 - 3.17 (m, 4H), 2.94 (d, J = 10.5 Hz, 2H), 2.41 - 2.27 (m, 1 H), 1.91 - 1.79 (m, 2H), 1.56 (tt, J = 8.3, 3.3 Hz, 6H).

[0637] Intermediate 4 (lnt-4): N-(1-(2-chloroacetyl)piperidin-4-yl)tetrahydro-2H-pyran-4- carboxamide

[0638] Chloroacetyl chloride (1.5 g, 14 mmol, 1.1 equiv.) was added to a mixture of N-(piperidin-4- yl)tetrahydro-2H-pyran-4-carboxamide hydrochloride (Intermediate 4) (3.1 g, 12 mmol, 1 equiv.) and triethylamine (5.2 mL, 37 mmol, 3 equiv.) in DCM (62 mL) at 0 °C. After warming to room temperature, the reaction mixture was diluted with DCM and washed with distilled water. The organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (40 g cartridge, 0-10% MeOH in DCM) to give a beige solid (Intermediate 4) (393 mg, 11 %).1H NMR (400 MHz, CDCI3) 5 5.45 (d, J = 7.9 Hz, 1 H), 4.57 - 4.47 (m, 1 H), 4.15 - 3.96 (m, 4H), 3.90 - 3.79 (m, 1 H), 3.40 (td, J = 11.4, 2.9 Hz, 2H), 3.21 (ddd, J = 14.2, 12.1 , 2.8 Hz, 1 H), 2.77 (ddd, J = 13.8, 12.3, 3.0 Hz, 1 H), 2.31 (tt, J = 11.0, 4.5 Hz, 1 H), 2.15 - 2.03 (m, 1 H), 2.00 - 1.90 (m, 1 H), 1.86 - 1.68 (m, 5H), 1.48 - 1.21 (m, 2H). PAG-P3656PCT Application as filed FINAL

[0639] Intermediate 5 (lnt-5): 3-methyl-N-(piperidin-4-yl)isoxazole-5-carboxamide hydrochloride

[0640] Step 1 : To a solution of 5-carboxy-3-methylisoxazole (150 mg, 1.18 mmol, 1 equiv.), EDC (339 mg, 1.77 mmol, 1.50 equiv.)), HOBt (199 mg, 1.30 mmol, 1.10 equiv.) in DCM (4.7 mL) was added DIPEA (1.03 mL, 5.90 mmol, 5 equiv.). The mixture was cooled to 0 °C when tert-butyl 4- aminopiperidine-1 -carboxylate (248 mg, 1.24 mmol, 1.05 equiv.) was added in one portion and the reaction mixture was allowed to stir overnight at room temperature. After 20 h, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between H2O (10 mL) and EtOAc (10 mL). The aqueous layer was taken out, and the organic layer was washed with half sat. aq. NH4CI sol. (10 mL), then sat. aq. NH4CI sol. (10 mL) then sat. aq. NaHCCh sol.

[0641] (10 mL) then brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 4-(3-methylisoxazole-5-carboxamido)piperidine-1- carboxylate as a white solid (168 mg, 46% yield). The product was used as such in the next step without further purification.1H NMR (400 MHz, CDCh) 6 6.74 (s, 1 H), 6.46 - 6.33 (m, 1 H), 4.20 - 3.99 (m, 5H), 2.91 (t, J = 12.7 Hz, 2H), 2.36 (s, 3H), 2.03 - 1.95 (m, 2H), 1.47 (s, 9H).

[0642] Step 2: To a mixture of tert-butyl 4-(3-methylisoxazole-5-carboxamido)piperidine-1 -carboxylate (100 mg, 0.323 mmol, 1.00 equiv.) in DCM (1 mL) was added 4N HCI in dioxane (0.808 mL, 3.23 mmol, 10.0 equiv.), and the reaction mixture was stirred 20 h at room temperature. The reaction mixture was then concentrated under reduced pressure to give the desired product (79.4 mg, >99% yield). The product (Intermediate 5) was used as such in the next step without further purification.1H NMR (400 MHz, DMSO) 6 8.99 (s, 1 H), 8.58 (d, J = 80.3 Hz, 2H), 6.96 (d, J = 2.5 Hz, 1 H), 4.11 - 3.97 (m, 1 H), 3.28 (s, 2H), 3.08 - 2.92 (m, 2H), 2.29 (s, 3H), 1.93 (d, J = 13.7 Hz, 2H), 1.77 (t, J = 13.0 Hz, 2H).

[0643] Intermediate 6 (lnt-6): N-( 1 -(2-chloroacetyl)piperidin-4-yl)-3-methylisoxazole-5- carboxamide

[0644] Chloroacetylchloride (0.14 mL, 1.75 mmol, 1.3 equiv.) was added to a mixture of 3-methyl-N- (piperidin-4-yl)isoxazole-5-carboxamide hydrochloride (Intermediate 5) (330 mg, 1.34 mmol, 1 PAG-P3656PCT Application as filed FINAL equiv.) and triethylamine (0.94 mL, 6.72 mmol, 5 equiv.) in DCM (8.6 mL) at 0 °C. After allowing to warm to room temperature overnight (ca. 20 h), the reaction mixture was diluted with DCM (50 mL) and the aqueous solution was extracted with DCM (3 x 20 mL). The combined organic solution was then washed with brine (10 mL), dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, EtOAc / MeOH, 0% over 3CVs, 0% to 100% over 10 CVs, 100% over 0.1 CVs). Fractions containing product were pooled and then concentrated to give the desired product (Intermediate 6) as an oil (60 mg, 16% yield).1H NMR (400 MHz, DMSO) 6 8.80 (d, J = 7.9 Hz, 1 H), 6.92 (s, 1 H), 4.60 - 4.19 (m, 3H), 4.08 - 3.95 (m, 1 H), 3.84 (d, J = 13.9 Hz, 1 H), 3.16 (t, J = 12.9 Hz, 1 H), 2.76 (t, J = 12.6 Hz, 1 H), 2.29 (s, 3H), 1.86 - 1.77 (m, 2H), 1.57 (td, J = 12.0, 4.0 Hz, 1 H), 1.47 - 1.35 (m, 1 H).

[0645] Step 1 : To a solution of 2-(4-fluorophenyl)acetic acid (200 mg, 1.30 mmol, 1.00 equiv.) in anhydrous DCM (5 mL) were consecutively added at 0°C, HOBt (219 mg, 1.43 mmol, 1.10 equiv.) and EDC (373 mg, 1.95 mmol, 1 .50 equiv.). The solution was stirred for 30 minutes at 0°C when DI PEA (1 .13 mL, 6.49 mmol, 5.00 equiv.) and tert-butyl 4-aminopiperidine-1 -carboxylate (273 mg, 1.36 mmol, 1.05 equiv.) were added to the mixture. The solution was stirred overnight at room temperature. After ca. 20 h, the solution was partitioned with distilled water (25 mL) and EtOAc (50 mL). The aqueous layer was taken out, and the organic layer was washed with half sat. aq.

[0646] NH4CI sol. (25 mL), then sat. aq. NH4CI sol. (25 mL) then sat. aq. NaHCO3 sol. (25 mL) then brine (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a white solid (345 mg, 79%).1H NMR (400 MHz, CDCI3) 6 7.24 - 7.18 (m, 2H), 7.08 - 7.00 (m, 2H), 5.19 (d, J = 7.9 Hz, 1 H), 4.05 - 3.83 (m, 3H), 3.52 (s, 2H), 2.92 - 2.75 (m, 2H), 1.84 (dd, J = 12.6, 3.7 Hz, 2H), 1.43 (s, 9H), 1.28 - 1.12 (m, 2H). 19F NMR (376

[0647] MHz, CDCI3) 6 -114.98 (m, J = 13.6, 8.2, 4.8 Hz).

[0648] Step 2: To a mixture of tert-butyl 4-(2-(4-fluorophenyl)acetamido)piperidine-1 -carboxylate (345 mg, 1.03 mmol, 1 equiv.) in DCM (7mL), was added 4N HCI in dioxane (2.56 mL, 10.3 mmol, 10 equiv.). The reaction mixture was stirred for 20 h at room temperature when it was concentrated to give the crude HCI salt (Intermediate 7) that was used in the next step without further characterization or purification (280 mg, 100%). PAG-P3656PCT Application as filed FINAL

[0649] Chloroacetyl chloride (0.07 mL, 0.86 mmol, 1.1 equiv.) was added to a mixture of 2-(4- fluorophenyl)-N-(piperidin-4-yl)acetamide hydrochloride (Intermediate 7) (212 mg, 0.78 mmol, 1 equiv.) and triethylamine (236 mg, 0.33 mL, 2.33 mmol, 3 equiv.) in DCM (4 mL) at 0 °C. After 2 h, the reaction mixture was diluted with DCM and washed 3 times with distilled water. The organic solution was then dried (Na2SO4), filtered, and concentrated to give the desired product (Intermediate 8) as a yellow solid (207 mg, 85%).1H NMR (400 MHz, CDCI3) 6 7.24 - 7.15 (m, 2H), 7.12 - 6.95 (m, 2H), 5.44 - 5.09 (m, 1 H), 4.45 (d, J = 13.8 Hz, 1 H), 4.24 - 3.91 (m, 3H), 3.80 (d, J = 14.6 Hz, 1 H), 3.52 (s, 2H), 3.19 (ddd, J = 14.1 , 12.0, 2.8 Hz, 1 H), 2.88 - 2.64 (m, 1 H), 2.11 - 1.77 (m, 2H), 1.47 - 1.11 (m, 3H).

[0650] Intermediate 9 (lnt-9): (S)-N-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-2- chloroacetamide

[0651] Step 1 : A solution of tert-butyldimethylchlorosilane (1.32 g, 8.75 mmol, 1.2 equiv.) in DCM (4.50 mL) was added drop-wise to a stirred solution of (2S)-2-Amino-2-phenylethanol (1.00 g, 7.29 mmol, 1 equiv.), 4-dimethylaminopyridine (9 mg, 0.073 mmol, 0.01 equiv.) and triethylamine (2.0 mL, 14.6 mmol, 2 equiv.) in DCM (4.50 mL). After stirring for 48 hours, saturated aqueous NH4CI solution was added, and the mixture was extracted with CH2CI2 (3 times) and washed once with brine. The organic solution was then dried over Na2SO4, filtered, and concentrated. The crude residue was then chromatographed (40 g cartridge, Hex / EtOAc, 0% for 3 CV, 0-50% for 2 CV 50% for 3 CV, 50-100% for 2 CV, 100% for 3 CV) to give (S)-2-((tert-butyldimethylsilyl)oxy)-1- phenylethan-1-amine (1.258 g, 5.00 mmol, 69 % yield) as a pale yellow oil.1H NMR (400 MHz, CDCI3) 5 7.45 - 7.25 (m, 5H), 4.12 (dd, J = 8.4, 3.9 Hz, 1 H), 3.77 (ddd, J = 9.8, 4.0, 0.9 Hz, 1 H), 3.56 (ddd, J = 9.4, 8.4, 0.9 Hz, 1 H), 1.76 (s, 2H), 0.94 (d, J = 0.9 Hz, 9H), 0.07 (t, J = 1.1 Hz, 6H). Step 2: To a mixture of (S)-2-((tert-butyldimethylsilyl)oxy)-1-phenylethan-1 -amine (330 mg, 1.31 mmol, 1 equiv.), triethylamine (0.92 mL, 6.56 mmol, 5 equiv.) in DCM (8.4 mL) was added chloroacetyl chloride at 0 °C (0.12 mL, 1.44 mmol, 1.1 equiv.) and the reaction mixture was allowed to warm to room temperature. After ca. 20 h, the reaction mixture was diluted with DCM (20 mL) and sat. NaHCO3 (20 mL). The aqueous solution was extracted with DCM (3 x 20 mL), PAG-P3656PCT Application as filed FINAL and the combined organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (40 g cartridge, Hex / EtOAc, 5% over 1 CV, 5% to 40% over 10 CVs, 40% over 2 CVs, 40% to 100% over 5 CVs, then EtOAc / MeOH, 0 to 100% over 5 CVs, 100% over 2 CVs) to give the desired product (Intermediate 9) as a yellow oil (184 mg, 43% yield). 1 H NMR (400 MHz, DMSO) 5 8.55 (d, J = 8.4 Hz, 1 H), 7.56 - 7.09 (m, 5H), 4.88 (dt, J = 8.3, 6.2 Hz, 1 H), 4.12

[0652] (s, 2H), 3.74 (d, J = 6.2 Hz, 2H), 0.80 (s, 9H), -0.05 (s, 3H), -0.06 (s, 3H).

[0653] Intermediate 10 (lnt-10): N-(2-(2-chloroacetyl)-2-azaspiro[3.3]heptan-6-yl)benzamide Step 1 : To a solution of 6-amino-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butylester (1 .00 g, 4.71 mmol, 1 equiv.), DMAP (57.56 mg, 0.47 mmol, 0.1 equiv.), and DIPEA (1.64 mL, 9.42 mmol, 2 equiv.) in DCM (19 mL) was added benzoic anhydride (1.23 g, 5.42 mmol, 1.15 equiv.). After stirring for ca. 20 h at room temperature, the reaction mixture was diluted with DCM (50 mL) and then washed with 10% citric acid (3 x 20 mL), sat. NaHCO3 (3 x 10 mL), dried (Na2SO4), filtered, concentrated and chromatographed (40 g cartridge, cyclohexane / EtOAc, 12% over 1 CVs, 12% to 90% over 8.8 CVs) to give tert-butyl 6-benzamido-2-azaspiro[3.3]heptane-2-carboxylate as a white solid (1.001 g, 67% yield).1H NMR (400 MHz, DMSO) 5 8.57 (d, J = 7.3 Hz, 1 H), 7.86 - 7.78 (m, 2H), 7.57 - 7.25 (m, 3H), 4.34 - 4.20 (m, 1 H), 3.91 (s, 2H), 3.79 (s, 2H), 2.51 - 2.44 (m, 2H), 2.24 (ddd, J = 12.4, 7.0, 2.5 Hz, 2H), 1.37 (s, 9H). Step 2: To a solution of tert-butyl 6-benzamido-2-azaspiro[3.3]heptane-2-carboxylate (290 mg, 0.92 mmol, 1 equiv.) in DCM (5 mL) was added trifluoroacetic acid (0.70 mL, 9.2 mmol 10 equiv.) and the reaction mixture was allowed to stir at room temperature. After 20 h, the reaction mixture was concentrated to give N-(2-azaspiro[3.3]heptan-6-yl)benzamide 2,2,2-trifluoroacetate an oil (422 mg). The crude material was used in the next step without further purification.1H NMR (400 MHz, DMSO) 5 8.59 (d, J = 7.3 Hz, 1 H), 7.87 - 7.78 (m, 2H), 7.56 - 7.37 (m, 3H), 4.46 - 4.16 (m, 1 H), 4.16 - 3.98 (m, 2H), 4.00 - 3.83 (m, 2H), 2.74 - 2.50 (m, 2H), 2.36 - 2.11 (m, 2H).

[0654] Step 3: To a mixture of N-(2-azaspiro[3.3]heptan-6-yl)benzamide 2,2,2-trifluoroacetate (330 mg, 1.00 mmol, 1 equiv.), triethylamine (0.70 mL, 5.00 mmol, 5 equiv.) in DCM (6.4 mL) was added chloroacetyl chloride at 0 °C (0.1 mL, 1.26 mmol, 1.26 equiv.) and the reaction mixture was allowed to warm to room temperature. After ca. 20 h, the reaction mixture was diluted with DCM (20 mL) and sat. NaHCO3 (20 mL). The aqueous solution was extracted with DCM (3 x 20 mL), and the combined organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (40 g cartridge, EtOAc / MeOH, 0% over 3 CVs, 0% to 50% over 15 CVs, 50% PAG-P3656PCT Application as filed FINAL over 2 CVs) to give the desired product (Intermediate 10) as a foam (116 mg, 40% yield).1H NMR (400 MHz, DMSO) 5 8.60 (t, J = 6.8 Hz, 1 H), 7.87 - 7.79 (m, 2H), 7.74 - 7.09 (m, 3H), 4.40 - 4.23 (m, 2H), 4.16 (s, 1 H), 4.10 (d, J = 5.0 Hz, 2H), 3.99 (s, 1 H), 3.88 (s, 1 H), 2.58 - 2.50 (m, 2H), 2.28 (td, J = 9.3, 2.2 Hz, 2H).

[0655] Intermediate 11: allyl 4-formylpiperidine-1 -carboxylate

[0656] Step 1 : To a cold (0 °C) solution of piperidin-4-yl methanol (2.70 g, 23.4 mmol, 1 equiv.) in DCM (30 mL) was added Et3N (9.80 mL, 70.3 mmol, 3 equiv.), followed by allyl chloroformate (3.11 g, 2.74 mL, 25.8 mmol, 1.1 equiv.). The mixture was stirred at O °C for 1 h when it was poured into water (50 mL). The aqueous phase was extracted with DCM (3 portions) and the combined organic solution was dried (Na2SO4), filtered, concentrated, and chromatographed (40 g cartridge, Hex / EtOAc, 10:1 to 2:1)). The fractions which contained product were combined and then concentrated to give allyl 4-(hydroxymethyl)piperidine-1 -carboxylate ((4.46 g, 96%) as a colourless oil. This Intermediate was used in the next step without further characterization or purification.

[0657] Step 2: A stirred solution of allyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.54 g, 7.73 mmol, 1 equiv.), DIPEA (4.00 g, 5.34 mL, 30.9 mmol, 4 equiv.), and DMSO (4.83 g, 4.40 mL, 8 equiv., 8 equiv.) in DCM (25 mL) was cooled to 0 °C when sulfur trioxide pyridine complex (3.08 g, 19.3 mmol, 2.5 equiv.) was added. After stirring for 1.5 h, the reaction mixture was concentrated, diluted with 2M aq. citric acid and extracted with Et20 (3 portions). The combined organic solution was then dried (Na2SO4), filtered, and concentrated to give the title compound () as a colourless oil (1.37 g, 6.95 mmol, 89.9 %). The compound was used in the next step without further purification.1H NMR (400 MHz, CDCI3) 6 9.67 (s, 1 H), 5.94 (ddt, J = 17.2, 10.4, 5.6 Hz, 1 H), 5.36 - 5.25 (m, 1 H), 5.24 - 5.17 (m, 1 H), 4.59 (dt, J = 5.5, 1.5 Hz, 2H), 4.23 - 3.88 (m, 2H), 3.02 (ddd, J = 13.8, 10.8, 3.2 Hz, 2H), 2.53 - 2.31 (m, 1 H), 1.93 (dt, J = 13.7, 3.9 Hz, 2H), 1.59 (dtd, J = 13.6, 10.7, 4.3 Hz, 2H).

[0658] Intermediate 12 (lnt-12): N-(1-(2-chloroacetyl)piperidin-4-yl)benzamide PAG-P3656PCT Application as filed FINAL

[0659] Step 1 : Tert-butyl 4-aminopiperidine-1 -carboxylate (1.00 g, 4.993 mmol, 1 equiv.) was dissolved in dichloromethane (20 mL) when triethylamine (1.010 g, 1.39 mL, 9.986 mmol, 2 equiv.) was added. The reaction mixture was cooled to 0°C and benzoic anhydride was added (1.243 g, 5.5 mmol, 1.1 equiv.). The ice bath was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (20 mL), washed with water (20 mL), dried (Na2SC>4), filtered, concentrated and chromatographed (40 g cartridge, 0% to 60% over 10 CVs). Fractions containing the intermediate product were combined and concentrated to give the intermediate Boc amine (1.28 g) as a solid that was used in the next step without characterization. Step 2: Tert-butyl 4-benzamidopiperidine-1-carboxylate (0.50 g, 1.6 mmol, 1 equiv.) was dissolved in DCM (8 mL), when a solution of hydrogen chloride 4M in dioxane (4.1 mL, 16 mmol, 10 equiv.) was added dropwise. After 2 h, the reaction mixture was concentrated to give the title compound as a white solid (336 mg, 85% yield).1H NMR (400 MHz, DMSO) 5 8.74 (s, 2H), 8.48 (d, J = 7.5 Hz, 1 H), 7.89 - 7.82 (m, 2H), 7.58 - 7.50 (m, 1 H), 7.49 - 7.41 (m, 2H), 4.10 - 4.00 (m, 1 H), 3.32 - 3.27 (m, 2H), 3.00 (td, J = 12.5, 3.1 Hz, 2H), 2.01 - 1.93 (m, 2H), 1.77 - 1.72 (m, 2H). Step 3: Chloroacetylchloride (0.060 mL, 0.75 mmol, 1 equiv.) was added to a mixture of N- (piperidin-4-yl)benzamide hydrochloride (180 mg, 0.75 mmol, 1 equiv.) and triethylamine (0.20 mL, 1.5 mmol, 2 equiv.) in THF (6 mL) at 0 °C. After allowing to warm to room temperature overnight (ca. 20 h), the reaction mixture was diluted with EtOAc (50 mL) and the aqueous solution was extracted with EtOAc (3 x 20 mL). The combined organic solution was then washed with brine (10 mL), dried (Na2SC>4), filtered, concentrated, and chromatographed (20 g cartridge, EtOAc / MeOH, 0% over 3CVs, 0% to 100% over 10 CVs, 100% over 0.1 CVs). Fractions containing product were pooled and then concentrated to give the desired product (Intermediate 12) as a white solid (61 mg, 29% yield).1H NMR (400 MHz, DMSO) 6 8.31 (d, J = 7.7 Hz, 1 H), 7.88 - 7.80 (m, 2H), 7.52 - 7.41 (m, 3H), 4.59 - 4.19 (m, 3H), 4.05 (dtt, J = 11.5, 8.2, 4.3 Hz, 1 H), 3.86 (d, J = 13.9 Hz, 1 H), 3.18 (t, J = 12.9 Hz, 1 H), 2.80 (t, J = 12.5 Hz, 1 H), 1.90 - 1.80 (m, 2H), 1.56 (qd, = 12.0, 4.1 Hz, 1 H), 1.41 (qd, = 12.1 , 4.2 Hz, 1 H).

[0660] Step 1 : To a solution of 4-fluorobenzoic acid (140 mg, 1.00 mmol, 1.00 equiv.) in anhydrous DCM (4 mL) were consecutively added at 0°C HOBt (168 mg, 1.10 mmol, 1.10 equiv.) and EDC (288 mg, 1.50 mmol, 1.50 equiv.). The solution was stirred for 30 minutes at 0°C when DIPEA (0.35 mL, 2.00 mmol, 2.00 equiv.) and 1-t-butoxycarbonyl-4-aminopiperidine (200 mg, 1.00 mmol, 1.00 equiv.) were added to the mixture. The solution was stirred overnight at room temperature. After PAG-P3656PCT Application as filed FINAL ca. 20 h, the mixture was washed with a solution of sat. NaHCCh and then brine. The organic phase was dried (Na2SO4), filtered, concentrated, and then chromatographed (12 g cartridge, Hex / EtOAc, 10% to 100%). Fractions containing product were then concentrated to give tertbutyl 4-(4-fluorobenzamido)piperidine-1-carboxylate as a white powder (232 mg, 72% yield).1H NMR (400 MHz, CDCI3) 5 7.81 - 7.72 (m, 2H), 7.15 - 7.04 (m, 2H), 6.04 (d, J = 7.9 Hz, 1 H), 4.18

[0661] - 4.04 (m, 3H), 2.89 (t, J = 12.6 Hz, 2H), 2.00 (dd, J = 12.5, 3.7 Hz, 2H), 1.55 - 1.29 (m, 11 H).19F NMR (376 MHz, Chloroform-d) 5 -108.43.

[0662] Step 2: To a solution of tert-butyl 4-(4-fluorobenzamido)piperidine-1 -carboxylate (610 mg, 1.89 mmol, 1 equiv.) in DCM (10 mL) was added 4N HCI in dioxane (14.2 mL, 56.8 mmol, 30.0 equiv.) and the reaction mixture was allowed to stir overnight. After 20 h, the reaction mixture was triturated with ether. The white precipitate was collected and used in the next step without further purification (527 mg, quant.).1H NMR (400 MHz, DMSO) 5 8.71 (s, 1 H), 8.57 (s, 1 H), 8.49 (d, J = 7.4 Hz, 1 H), 7.98 - 7.89 (m, 2H), 7.35 - 7.25 (m, 2H), 4.11 - 3.99 (m, 1 H), 3.31 (d, J = 13.1 Hz, 2H), 3.07 - 2.94 (m, 2H), 1.96 (dd, J = 14.1 , 3.9 Hz, 2H), 1.81 - 1.67 (m, 2H). Step 3: To a mixture of the product of step 2, 4-fluoro-N-(piperidin-4-yl)benzamide hydrochloride (230 mg, 0.89 mmol, 1 equiv.), and DIPEA (460 mg, 0.62 mL, 3.56 mmol, 4 equiv.) in DCM (4.4 mL) at 0 °C was added chloroacetylchloride dropwise (0.085 mL, 1.07 mmol, 1.2 equiv.) and the reaction mixture was allowed to warm to room temperature over 1 h. After stirring for an additional 1 h at room temperature, the reaction mixture was concentrated and chromatographed (40 g cartridge, EtOAc / MeOH, 0% to 10% over 15 CVs) to give the desired product (Intermediate 13) as a solid (57 mg, 21 % yield).1H NMR (400 MHz, CDCI3) 5 7.86 - 7.73 (m, 2H), 7.10 (t, J = 8.6 Hz, 2H), 6.26 - 6.20 (m, 1 H), 4.57 (dd, J = 13.9, 4.9 Hz, 1 H), 4.23 (tdt, J = 11.6, 8.0, 4.1 Hz, 1 H), 4.13 (d, J = 12.1 Hz, 1 H), 4.04 (d, J = 12.0 Hz, 1 H), 3.95 - 3.84 (m, 1 H), 3.27 (ddd, J = 14.3, 12.1 , 2.8 Hz, 1 H), 2.88 - 2.76 (m, 1 H), 2.23 - 2.13 (m, 1 H), 2.12 - 2.01 (m, 1 H), 1.62 - 1.32 (m, 2H).

[0663] Intermediate 14 (lnt-14): Allyl 2-(4-(((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)oxy)piperidin-1-yl)acetate

[0664] To a mixture of 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-(piperidin-4- yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one (Example 1) (850 mg, 1.81 mmol, 1 equiv.) and DIPEA (1.25 mL, 7.24 mmol, 4 equiv.) in dioxane (86 mL) was PAG-P3656PCT Application as filed FINAL added allyl 2-bromoacetate (486 mg, 2.71 mmol, 1.5 equiv.), and the reaction mixture was stirred at 23 °C. After 16 h, full consumption of starting material was indicated by TLC. The reaction mixture was concentrated, and chromatographed (80g cartridge), cHex / EtOAc 0% over 1 CV, 0% to 100% over 10 CVs, 100% over 8 CV) to give the title product (Intermediate 14) as a white solid (950 mg, 93 %).1H NMR (400 MHz, DMSO) 5 7.93 (dd, J = 9.8, 2.6 Hz, 1 H), 7.52 (dd, J =

[0665] 2.6, 1.2 Hz, 1 H), 6.29 (dd, J = 9.6, 1.2 Hz, 1 H), 5.91 (ddt, J = 17.3, 10.8, 5.5 Hz, 1 H), 5.30 (dq, J = 17.3, 1.6 Hz, 1 H), 5.21 (dq, J = 10.8, 1.6 Hz, 1 H), 4.56 (d, J = 5.4 Hz, 2H), 4.14 (s, 1 H), 3.70 (brs, 1 H), 3.28 (p, J = 4.8 Hz, 1 H), 3.22 (s, 2H), 2.76 - 2.68 (m, 2H), 2.47 - 2.41 (m, 2H), 2.28 (t, J = 9.4 Hz, 2H), 2.13 - 2.00 (m, 1 H), 1.85 - 1.67 (m, 5H), 1.67 - 1.54 (m, 4H), 1.53 - 1.22 (m, 12H), 1.14 - 0.98 (m, 2H), 0.85 (s, 3H), 0.59 (s, 3H).

[0666] Intermediate 15 (lnt-15): 2-(4-(((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)oxy)piperidin- 1-yl)acetic acid

[0667] To a solution of allyl 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetate (Intermediate 14) (950 mg, 1.67 mmol, 1 equiv.) in DCM (64 mL) was added 1 ,3- dimethylbarbituric acid (314 mg, 2.01 mmol, 1.2 equiv.) followed by tetrakis(triphenylphosphine)palladium(o) (193 mg, 167 pmol, 0.1 equiv.). After 30 minutes, full consumption of starting material was indicated by TLC. The reaction mixture was concentrated and the crude orange residue was purified by chromatography (40 g cartridge DCM / MeOH, 0% over 3 CVs, 0% to 50% over 10 CVs, then 50% over 8 CVs). The fractions containing the product were concentrated to give the title compound (Intermediate 15) as a white solid (870 mg, 99 %).1H NMR (400 MHz, DMSO) 5 7.93 (dd, J = 9.8, 2.6 Hz, 1 H), 7.52 (dd, J = 2.6, 1.1 Hz, 1 H), 6.29

[0668] (dd, J = 9.8, 1.1 Hz, 1 H), 4.14 (brs, 1 H), 3.70 (s, 1 H), 3.42 (dt, J = 5.9, 3.2 Hz, 1 H), 3.06 - 2.94 (m, 2H), 2.70 (t, J = 9.2 Hz, 2H), 2.48 - 2.39 (m, 2H), 2.17 - 1.91 (m, 2H), 1.91 - 1.67 (m, 6H), 1 .67 - 1 .22 (m, 16H), 1.22 - 0.95 (m, 3H), 0.86 (s, 3H), 0.59 (s, 3H). PAG-P3656PCT Application as filed FINAL

[0669] Step 1 : To a solution of isonicotinic acid (307 mg, 2.50 mmol, 1.00 equiv.) in anhydrous DCM (10 mL) were consecutively added at 0°C HOBt (421 mg, 2.75 mmol, 1.10 equiv.) and EDC (718 mg, 3.74 mmol, 1.50 equiv.). The solution was stirred for 30 minutes at O°C when DIPEA (2.17 mL, 12.5 mmol, 5.00 equiv.) and tert-butyl 4-aminopiperidine-1 -carboxylate (500 mg, 2.50 mmol, 1.00 equiv.) were added to the mixture. The solution was stirred overnight at room temperature. After ca. 20 h, the mixture was washed with a solution of sat. NaHCCh and then brine. The organic phase was dried (Na2SO4), filtered, concentrated, and then chromatographed (40 g cartridge, Hex / EtOAc, 10% to 75%). Fractions containing product were then concentrated to give tert-butyl 4-(isonicotinamido)piperidine-1-carboxylate as a solid (462 mg, 61%).1H N MR (400 MHz, DMSO) 5 8.74 - 8.68 (m, 2H), 8.55 (d, J = 7.8 Hz, 1 H), 7.77 - 7.71 (m, 2H), 4.31 - 3.76 (m, 3H), 2.94 - 2.77 (m, 2H), 1.82 - 1.75 (m, 2H), 1.64 - 1.29 (m, 11 H).

[0670] Step 2: To a solution of tert-butyl 4-(isonicotinamido)piperidine-1 -carboxylate (462 mg, 1.51 mmol, 1 equiv.) in DCM (7.6 mL) was added 4N HCI in dioxane (11.3 mL, 45.4 mmol, 30.0 equiv.) and the reaction mixture was allowed to stir overnight. After 20 h, the reaction mixture was triturated with ether. The white precipitate (Intermediate 16) was collected and used in the next step without further purification (428 mg, quant.)1H NMR (400 MHz, DMSO) 5 9.01 (d, J = 7.4 Hz, 1 H), 8.88 - 8.82 (m, 4H), 8.01 (d, J = 5.4 Hz, 2H), 4.14 - 4.02 (m, 2H), 3.35 - 3.27 (m, 2H), 3.07 - 2.97 (m, 2H), 2.02 - 1.93 (m, 2H), 1.88 - 1.73 (m, 2H).

[0671] Intermediate 17 (lnt-17): N-(1-(2-chloroacetyl)piperidin-4-yl)picolinamide

[0672] (1

[0673] Stepl : To a solution of picolinic acid (200 mg, 1.62 mmol, 1 equiv.), EDC. HCI (467 mg, 2.44 mmol, 1.50 equiv.)), HOBt (274 mg, 1.79 mmol, 1.10 equiv.) in DCM (6.5 mL) was added DIPEA (1.41 mL, 8.12 mmol, 5 equiv.). The mixture was cooled to 0 °C when tert-butyl 4-aminopiperidine- 1 -carboxylate (342 mg, 1.71 mmol, 1.05 equiv.) was added in one portion and the reaction mixture was allowed to stir overnight at room temperature. After 20 h, the reaction mixture was PAG-P3656PCT Application as filed FINAL concentrated under reduced pressure. The residue was partitioned between H2O (10 mL) and EtOAc (10 mL). The aqueous layer was taken out, and the organic layer was washed with half sat. aq. NH4CI sol. (10 mL), then sat. aq. NH4CI sol. (10 mL) then sat. aq. NaHCCh sol. (10 mL) then brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product as a white solid (395 mg, 80% yield). The product was used as such in the next step without further purification.1H NMR (400 MHz, CDCI3) 6 8.54 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.20 (dt, J = 7.8, 1.1 Hz, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), 7.86 (td, J = 7.7, 1.7 Hz, 1 H), 7.44 (ddd, J = 7.6, 4.8, 1.2 Hz, 1 H), 4.20 - 3.98 (m, 3H), 2.96 (t, J = 12.6 Hz, 2H), 2.04 - 1.94 (m, 2H), 1.52 (dd, J = 14.1 , 9.8 Hz, 2H), 1.47 (s, 9H). Step 2: To a mixture of tert-butyl 4-(picolinamido)piperidine-1 -carboxylate (395 mg, 1.29 mmol, 1.00 equiv.) in CH2CI2 (4 mL) was added 4N HCI in dioxane (3.23 mL, 12.9 mmol, 10.0 equiv.), and the reaction mixture was stirred 20 h at room temperature. The reaction mixture was then concentrated under reduced pressure to give N-(piperidin-4-yl)picolinamide dihydrochloride (313 mg, >99% yield). The product was used as such in the next step without further purification.1H NMR (400 MHz, DMSO) 5 9.09 (s, 1 H), 8.85 (d, J = 8.0 Hz, 2H), 8.66 (dt, J = 5.0, 1.3 Hz, 1H), 8.09 - 7.99 (m, 2H), 7.63 (ddd, J = 7.0, 4.8, 1.7 Hz, 1 H), 4.15 - 4.00 (m, 1 H), 3.29 (d, J = 12.8 Hz, 2H), 2.99 (q, J = 11.7 Hz, 2H), 1.99 - 1.76 (m, 4H).

[0674] Step 3: To a mixture of N-(piperidin-4-yl)picolinamide dihydrochloride (230 mg, 0.83 mmol, 1 equiv.) and DIPEA (534 mg, 0.72 mL, 4.13 mmol, 5 equiv.) in DCM (4.13 mL) at 0 °C was added chloroacetylchloride dropwise (0.079 mL, 0.992 mmol, 1.2 equiv.) and the reaction mixture was allowed to warm to room temperature over 1 h. After stirring for an additional 1 h at room temperature, the reaction mixture was concentrated and chromatographed (40 g cartridge, EtOAc / MeOH, 0% to 10% over 15 CVs) to give the desired product (Intermediate 17) as a solid (96 mg, 41% yield).1H NMR (400 MHz, DMSO) 5 8.71 - 8.61 (m, 2H), 8.07 - 7.95 (m, 2H), 7.60 (ddd, J = 7.3, 4.7, 1.5 Hz, 1H), 4.45 - 4.36 (m, 2H), 4.36 - 4.25 (m, 1H), 4.15 -4.01 (m, 1H), 3.85 (d, J = 14.0 Hz, 1 H), 3.18 (t, J = 12.9 Hz, 1 H), 2.78 (t, J = 12.6 Hz, 1H), 1.82 (t, J = 13.9 Hz, 2H), 1.73 - 1.47 (m, 2H).

[0675] Intermediate 18 (lnt-18): N-(1-(2-chloroacetyl)piperidin-4-yl)-3-methoxybenzamide PAG-P3656PCT Application as filed FINAL

[0676] Step 1 : To a solution of 3-methoxy benzoic acid (380 mg, 2.50 mmol, 1.00 equiv.) in anhydrous DCM (10 mL) were consecutively added at 0°C HOBt (421 mg, 2.75 mmol, 1.10 equiv.) and EDC (718 mg, 3.74 mmol, 1.50 equiv.). The solution was stirred for 30 minutes at 0°C when DIPEA (2.17 mL, 12.5 mmol, 5.00 equiv.) and tert-butyl 4-aminopiperidine-1 -carboxylate (500 mg, 2.50 mmol, 1.00 equiv.) were added to the mixture. The solution was stirred overnight at room temperature. After ca. 20 h, the mixture was washed with a solution of sat. NaHCCh and then brine. The organic phase was dried (Na2SO4), filtered, concentrated, and then chromatographed (40 g cartridge, Hex / EtOAc, 0% to 40% over 12 CVs). Fractions containing product were then concentrated to give tert-butyl 4-(3-methoxybenzamido)piperidine-1 -carboxylate as a solid (674 mg, 81%). 1 H NMR (400 MHz, DMSO) 5 8.23 (d, J = 7.9 Hz, 1 H), 7.45 - 7.32 (m, 3H), 7.08 (ddd, J = 8.1 , 2.8, 1.2 Hz, 1 H), 4.16 - 3.87 (m, 3H), 3.80 (s, 3H), 2.85 - 2.81 (m, 2H), 1.77 (d, J = 12.7 Hz, 2H), 1.53 - 1.31 (m, 11 H).

[0677] Step 2: To a solution of tert-butyl 4-(3-methoxybenzamido)piperidine-1 -carboxylate (674 mg, 2.02 mmol, 1 equiv.) in DCM (10 mL) was added 4N HCI in dioxane (15.1 mL, 60.5 mmol, 30.0 equiv.) and the reaction mixture was allowed to stir overnight. After 20 h, the reaction mixture was triturated with ether. The white precipitate was collected to give 3-methoxy-N-(piperidin-4- yl)benzamide hydrochloride which was used in the next step without further purification (576 mg, quant.)1H NMR (400 MHz, DMSO) 5 8.89 - 8.81 (m, 2H), 8.58 (d, J = 7.4 Hz, 1 H), 7.94 - 7.86 (m, 2H), 7.58 - 7.50 (m, 2H), 4.19 - 3.88 (m, 4H), 3.30 (d, J = 12.7 Hz, 2H), 2.99 (td, J = 12.4, 9.4 Hz, 2H), 2.00 - 1.91 (m, 2H), 1.84 - 1.70 (m, 2H).

[0678] Step 3: To a mixture of 3-methoxy-N-(piperidin-4-yl)benzamide hydrochloride (290 mg, 1.07 mmol, 1 equiv.) and DIPEA (692 mg, 0.93 mL, 5.36 mmol, 5 equiv.) in DCM (5.4 mL) at 0 °C was added chloroacetylchloride dropwise (0.10 mL, 1.29 mmol, 1.2 equiv.) and the reaction mixture was allowed to warm to room temperature over 1 h. After stirring for an additional 1 h at room temperature, the reaction mixture was concentrated and chromatographed (40 g cartridge, EtOAc / MeOH, 0% to 10% over 15 CVs) to give the desired product (Intermediate 18) as a solid (125 mg, 38% yield).1H NMR (400 MHz, DMSO) 5 8.28 (d, J = 7.7 Hz, 1 H), 7.46 - 7.32 (m, 3H), 7.08 (ddd, J = 8.0, 2.6, 1.1 Hz, 1 H), 4.43 (d, J = 12.9 Hz, 1 H), 4.37 - 4.22 (m, 2H), 4.13 - 3.99 (m, 1 H), 3.86 (d, J = 13.9 Hz, 1 H), 3.80 (s, 3H), 3.23 - 3.13 (m, 1 H), 2.79 (t, J = 12.5 Hz, 1 H), 1.87 - 1.82 (m, 2H), 1.67 - 1.33 (m, 2H). PAG-P3656PCT Application as filed FINAL

[0679] Intermediate 19 (lnt-19): 2-amino-N-( 1 -(2-chloroacetyl)piperidin-4-yl)pyrimidine-5- carboxamide

[0680] Step 1 : To a solution of 2-aminopyrimidine-5-carboxylic acid (347 mg, 2.50 mmol, 1.00 equiv.) in anhydrous DCM (10 mL) were consecutively added at 0°C HOBt (421 mg, 2.75 mmol, 1.10 equiv.) and EDC (718 mg, 3.74 mmol, 1.50 equiv.). The solution was stirred for 30 minutes at 0°C when DI PEA (2.17 mL, 12.5 mmol, 5.00 equiv.) and tert-butyl 4-aminopiperidine-1 -carboxylate (500 mg, 2.50 mmol, 1.00 equiv.) were added to the mixture. The solution was stirred overnight at room temperature. After ca. 20 h, the mixture was washed with a solution of sat. NaHCCh and then brine. The organic phase was dried (Na2SO4), filtered, concentrated, and then chromatographed (40 g cartridge, Hex / EtOAc, 0% to 40% over 12 CVs). Fractions containing product were then concentrated to give tert-butyl 4-(2-aminopyrimidine-5-carboxamido)piperidine-1 -carboxylate as a solid (210 mg, 26%).1H NMR (400 MHz, DMSO) 5 8.65 (s, 2H), 8.06 (d, J = 7.7 Hz, 1 H), 7.18 (s, 2H), 3.99 - 3.87 (m, 3H), 2.83 (s, 2H), 1.81 - 1.72 (m, 2H), 1.51 - 1.27 (m, 11 H).

[0681] Step 2: To a solution of tert-butyl 4-(2-aminopyrimidine-5-carboxamido)piperidine-1-carboxylate (210 mg, 0.65 mmol, 1 equiv.) in DCM (3.3 mL) was added 4N HCI in dioxane (4.90 mL, 19.6 mmol, 30.0 equiv.) and the reaction mixture was allowed to stir overnight. After 20 h, the reaction mixture was triturated with ether. The white precipitate was collected to give 2-amino-N- (piperidin-4-yl)pyrimidine-5-carboxamide dihydrochloride as a yellow solid which was used in the next step without further purification or characterization (225 mg, quant.).

[0682] Step 3: To a mixture of 2-amino-N-(piperidin-4-yl)pyrimidine-5-carboxamide dihydrochloride (195 mg, 0.66 mmol, 1 equiv.) and DIPEA (0.58 mL, 3.31 mmol, 5 equiv.) in DCM (3.3 mL) at 0 °C was added chloroacetylchloride dropwise (0.063 mL, 0.80 mmol, 1.2 equiv.) and the reaction mixture was allowed to warm to room temperature over 1 h. After stirring for an additional 1 h at room temperature, the reaction mixture was concentrated and chromatographed (40 g cartridge, EtOAc / MeOH, 0% to 10% over 15 CVs) to give the desired product (Intermediate 19) as a solid (92 mg, 47% yield).1H NMR (400 MHz, DMSO) 5 8.66 (s, 2H), 8.10 (d, J = 7.6 Hz, 1 H), 7.19 (s, 2H), 4.47 - 4.18 (m, 3H), 4.10 - 3.98 (m, 1 H), 3.84 (d, J = 13.8 Hz, 1 H), 3.18 (t, J = 12.8 Hz, 1 H), 2.80 (t, J = 12.2 Hz, 1 H), 1.90 - 1.72 (m, 2H), 1.60 - 1.27 (m, 2H). PAG-P3656PCT Application as filed FINAL

[0683] Step 1 : To a solution of 4-chlorobenzoic acid (391 mg, 2.50 mmol, 1.00 equiv.) in anhydrous DCM (10 mL) were consecutively added at 0 °C HOBt (421 mg, 2.75 mmol, 1.10 equiv.) and EDC (718 mg, 3.74 mmol, 1.50 equiv.). The solution was stirred for 30 minutes at 0 °C when DI PEA (2.17 mL, 12.5 mmol, 5.00 equiv.) and 1-t-butoxycarbonyl-4-aminopiperidine (500 mg, 2.50 mmol, 1.00 equiv.) were added to the mixture. The solution was stirred overnight at room temperature. After ca. 20 h, the mixture was washed with a solution of sat. NaHCCh and then brine. The organic phase was dried (Na2SO4), filtered, concentrated, and then chromatographed (40 g cartridge, Hex / EtOAc, 0% to 40% over 12CVs). Fractions containing product were then concentrated to give tert-butyl 4-(4-chlorobenzamido)piperidine-1 -carboxylate as a white powder (584 mg, 69 % yield).1H NMR (400 MHz, DMSO) 5 8.34 (d, J = 7.7 Hz, 1 H), 7.89 - 7.82 (m, 2H), 7.57 - 7.49 (m, 2H), 3.97 - 3.89 (m, 3H), 2.86 - 2.81 (m, 2H), 1.81 - 1.74 (m, 2H), 1.43 - 1.38 (m, 11 H).

[0684] Step 2: To a solution of tert-butyl 4-(4-chlorobenzamido)piperidine-1 -carboxylate (584 mg, 1.72 mmol, 1 equiv.) in DCM (8.6 mL) was added 4N HCI in dioxane (12.9 mL, 51.7 mmol, 30.0 equiv.) and the reaction mixture was allowed to stir overnight. After 20 h, the reaction mixture was triturated with ether. The white precipitate was collected to give 4-chloro-N-(piperidin-4- yl)benzamide hydrochloride as a white solid which was used in the next step without further purification (559 mg, quant.).1H NMR (400 MHz, DMSO) 5 8.90 - 8.86 (m, 2H), 8.59 (d, J = 7.4 Hz, 1 H), 7.94 - 7.86 (m, 2H), 7.58 - 7.50 (m, 2H), 4.10 - 4.07 (m, 1 H), 3.30 (d, J = 12.7 Hz, 2H), 2.99 (td, J = 12.4, 9.4 Hz, 2H), 1.95 (dd, J = 13.9, 3.7 Hz, 2H), 1.85 - 1.70 (m, 2H).

[0685] Step 3: To a mixture of 4-chloro-N-(piperidin-4-yl)benzamide hydrochloride (290 mg, 1.05 mmol, 1 equiv.) and DIPEA (0.92 mL, 5.27 mmol, 5 equiv.) in DCM (5.3 mL) at 0 °C was added chloroacetylchloride dropwise (0.10 mL, 1.26 mmol, 1.2 equiv.) and the reaction mixture was allowed to warm to room temperature over 1 h. After stirring for an additional 1 h at room temperature, the reaction mixture was concentrated and chromatographed (40 g cartridge, EtOAc / MeOH, 0% to 10% over 15 CVs) to give 4-chloro-N-(1-(2-chloroacetyl)piperidin-4- yl)benzamide (Intermediate 20) as a solid (194 mg, 58% yield). _1H NMR (400 MHz, DMSO) 5 7.57 (d, J = 7.7 Hz, 1 H), 7.08 - 7.00 (m, 2H), 6.75 - 6.67 (m, 2H), 3.61 (d, J = 12.8 Hz, 1 H), 3.57 - 3.39 (m, 2H), 3.34 - 3.12 (m, 1 H), 3.03 (d, J = 13.8 Hz, 1 H), 2.43 - 2.28 (m, 1 H), 1.98 (t, J = 12.6 Hz, 1 H), 1.03 (t, J = 12.6 Hz, 2H), 0.89 - 0.64 (m, 1 H), 0.58 (qd, J = 11.9, 4.1 Hz, 1 H). PAG-P3656PCT Application as filed FINAL

[0686] Step 1 : To a solution of 4-(trifluoromethyl)benzoic acid (475 mg, 2.50 mmol, 1.00 equiv.) in anhydrous DCM (10 mL) were consecutively added at 0 °C HOBt (421 mg, 2.75 mmol, 1.10 equiv.) and EDC (718 mg, 3.74 mmol, 1.50 equiv.). The solution was stirred for 30 minutes at O °C when DIPEA (2.17 mL, 12.5 mmol, 5.00 equiv.) and 1-t-butoxycarbonyl-4-aminopiperidine (500 mg, 2.50 mmol, 1.00 equiv.) were added to the mixture. The solution was stirred overnight at room temperature. After ca. 20 h, the mixture was washed with a solution of sat. NaHCCh and then brine. The organic phase was dried (Na2SO4), filtered, concentrated, and then chromatographed (40 g cartridge, Hex / EtOAc, 0% to 40% over 12CVs). Fractions containing product were then concentrated to give tert-butyl 4-(4-(trifluoromethyl)benzamido)piperidine-1- carboxylate as a white powder (654 mg, 70% yield).1H NMR (400 MHz, DMSO) 5 8.51 (d, J =

[0687] 7.8 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 4.06 - 3.81 (m, 3H), 2.97 - 2.72 (m, 2H), 1.80 (dd, J = 12.9, 3.7 Hz, 2H), 1.63 - 1.26 (m, 11 H).

[0688] Step 2: To a solution of tert-butyl 4-(4-(trifluoromethyl)benzamido)piperidine-1 -carboxylate (645 mg, 1.76 mmol, 1 equiv.) in DCM (8.8 mL) was added 4N HCI in dioxane (13.2 mL, 52.7 mmol, 30.0 equiv.) and the reaction mixture was allowed to stir overnight. After 20 h, the reaction mixture was triturated with ether. The white precipitate was collected to give N-(piperidin-4-yl)-4- (trifluoromethyl)benzamide hydrochloride as a white solid which was used in the next step without further purification or characterization (559 mg, quant.).

[0689] Step 3: To a mixture of N-(piperidin-4-yl)-4-(trifluoromethyl)benzamide hydrochloride (300 mg, 0.97 mmol, 1 equiv.) and DIPEA (0.85 mL, 4.86 mmol, 5 equiv.) in DCM (5 mL) at 0 °C was added chloroacetylchloride dropwise (0.093 mL, 1.17 mmol, 1.2 equiv.) and the reaction mixture was allowed to warm to room temperature over 1 h. After stirring for an additional 1 h at room temperature, the reaction mixture was concentrated and chromatographed (40 g cartridge, EtOAc / MeOH, 0% to 10% over 15 CVs) to give N-(1-(2-chloroacetyl)piperidin-4-yl)-4- (trifluoromethyl)benzamide (Intermediate 21) as a solid (198 mg, 58% yield).1H NMR (400 MHz, DMSO) 5 7.74 (d, J = 7.7 Hz, 1 H), 7.22 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.2 Hz, 2H), 3.62 (d, J =

[0690] 12.8 Hz, 1 H), 3.56 - 3.42 (m, 2H), 3.36 - 3.15 (m, 1 H), 3.04 (d, J = 14.0 Hz, 1 H), 2.37 (t, J = 12.8 Hz, 1 H), 1.99 (t, J = 12.5 Hz, 1 H), 1.12 - 0.94 (m, 2H), 0.84 - 0.65 (m, 1 H), 0.66 - 0.49 (m, 1 H). PAG-P3656PCT Application as filed FINAL

[0691] Intermediate 22 (lnt-22): 2-(cyclopentylamino)-2-oxoacetic acid

[0692] Step 1 : DIPEA (0.198 mL, 1.14 mmol, 1.00 equiv.) was added to a mixture of cyclopentylamine (100 mg, 1.14 mmol, 1.00 equiv.) in dichloromethane (3.8 mL) at room temperature. The mixture was cooled to 0 °C and ethyl 2-chloro-2-oxoacetate (0.143 mL, 1.25 mmol, 1.10 equiv.) was added at 0 °C dropwise and then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc (30 mL) and 1 M aq. HCI sol. (30 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3x30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed (20 g cartridge, EtOAc / CyH 0% over 1 CV, 0-35% over 10 CVs, 35-50% over 5 CVs) to give ethyl 2-(cyclopentylamino)-2-oxoacetate as a white solid (190 mg, 90%).

[0693] Step 2: Ethyl 2-(cyclopentylamino)-2-oxoacetate (62 mg, 0.33 mmol, 1.00 equiv.) was dissolved in THF (0.5 mL) and H2O (0.16 mL), and Lithium hydroxide monohydrate (70 mg, 1.7 mmol, 5.00 equiv.) was added. After stirring for 4 h at room temperature, the basic reaction mixture was washed with DCM (3 x 5 mL). The aqueous phase was separated and acidified with 1 M aq. HCI sol. (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 10 mL) and the combined organic layers (EtOAc) were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the product as a white solid (35 mg, 67%). The product (Intermediate 22) was used as such in the next step without further purification.1H NMR (400 MHz, DMSO) 5 8.71 (d, J = 7.6 Hz, 1 H), 4.09 - 3.93 (m, 1 H), 1.79 (q, J = 5.1 Hz, 2H), 1.69 - 1.57 (m, 2H), 1.52 - 1.44 (m, 4H).

[0694] Intermediate 23 (lnt-23): N1-cyclopentyl-N2-(piperidin-4-yl)oxalamide hydrochloride

[0695] Step 1 : To a solution of BOP (563 mg, 1.27 mmol, 1 equiv.), 2-(cyclopentylamino)-2-oxoacetic acid (Intermediate 23) (200 mg, 1.27 mmol, 1 equiv.), and tert-butyl 4-aminopiperidine-1- carboxylate (268 mg, 1.34 mmol, 1.05 equiv.) in anhydrous DCM (6.4 mL) at 0 °C was added DI PEA (0.27 mL,1.53 mmol, 1.2 equiv.) and the reaction mixture was allowed to warm to room PAG-P3656PCT Application as filed FINAL temperature.. After 20 h, the solution was concentrated and re-dissolved in EtOAc (100 mL). The organic phase was washed with 1 N aq. HCI solution (20 mL), 20 mL of water, 20 mL of NaHCCh and 20 mL of brine. The organic solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 4-(2-(cyclopentylamino)-2-oxoacetamido)piperidine-1- carboxylate (207 mg, 48%). The product was used in the next step without further purification or characterization.

[0696] Step 2: To a solution of tert-butyl 4-(2-(cyclopentylamino)-2-oxoacetamido)piperidine-1- carboxylate ( (207 mg, 0.61 mmol, 1 equiv.) in DCM (3.0 mL) was added 4N HCI in dioxane (4.6 mL, 18.3 mmol, 30.0 equiv.) and the reaction mixture was allowed to stir overnight. After 20 h, the reaction mixture was triturated with ether. The precipitate was collected to give N1- cyclopentyl-N2-(piperidin-4-yl)oxalamide hydrochloride as a yellow solid (Intermediate 23) which was used in the next step without further purification or characterization (168 mg, quant.).1H NMR (400 MHz, DMSO) 5 8.87 (d, J = 7.9 Hz, 1 H), 8.77 (br s, 1 H), 8.61 (d, J = 8.1 Hz, 1 H), 8.47 (br s, 1 H), 4.03 (h, J = 7.5 Hz, 1 H), 3.95 - 3.76 (m, 1 H), 3.26 (d, J = 12.9 Hz, 2H), 3.10 - 2.86 (m, 2H), 1.91 - 1.41 (m, 12H).

[0697] Intermediate 24 (lnt-24): 2-(cyclohexylamino)-2-oxoacetic acid

[0698] Step 1 : Performed similarly to Step 1 of Intermediate 22 with use of N-ethyl-N-methylethanamine in place of DI PEA to give ethyl 2-(cyclohexylamino)-2-oxoacetate as a white solid (502 mg, >99%).

[0699] Step 2: Performed similarly to Step 2 of Intermediate 22 to give the product (Intermediate 24) as a white solid (73 mg, 85%). The product was used as such in the next step without further purification.1H NMR (400 MHz, DMSO) 5 8.61 (d, J = 8.3 Hz, 1 H), 3.54 (s, 1 H), 1.69 (d, J = 9.6 Hz, 4H), 1.27 (q, J = 11.1 Hz, 6H). PAG-P3656PCT Application as filed FINAL

[0700] Step 1 : Performed similarly to Step 1 of Intermediate 23 give ethyl 2-(cyclohexylamino)-2- oxoacetate as a white solid (83 mg, 20%).

[0701] Step 2: Performed similarly to Step 2 of Intermediate 23 to give the product (Intermediate 25) as a yellow solid (68 mg, quant.). The product was used as such in the next step without further purification.1H NMR (400 MHz, DMSO) 5 8.89 (d, J = 8.2 Hz, 1 H), 8.69 (s, 1 H), 8.49 (d, J = 8.7

[0702] Hz, 1 H), 8.35 (s, 1 H), 3.94 - 3.81 (m, 1 H), 3.63 - 3.44 (m, 1H), 3.31 - 3.23 (m, 2H), 2.97 (q, J = 11.6 Hz, 2H), 1.90 - 0.99 (m, 14H).

[0703] Prepared similarly to Intermediate 33 to afford the expected product (Intermediate 26) as a white powder (347 mg).1H NMR (400 MHz, DMSO) 5 9.57 (t, J = 5.7 Hz, 1 H), 8.84 (d, J = 6.2 Hz, 2H),

[0704] 8.30 (s, 3H), 7.98 (d, J = 6.2 Hz, 2H), 7.43 (s, 1H), 7.42 - 7.32 (m, 3H), 4.52 (d, J = 5.9 Hz, 2H),

[0705] 4.01 (q, J = 5.9 Hz, 2H).

[0706] Intermediate 27 (lnt-27): 2-amino-N-(3-(aminomethyl)benzyl)pyrimidine-5-carboxamide

[0707] Prepared similarly to Intermediate 33 to afford the expected product (Intermediate 27) as a white powder (233 mg).1H NMR (400 MHz, DMSO) 5 9.15 (t, J = 5.9 Hz, 1 H), 8.85 (s, 2H), 8.47 (s, 2H), 7.70 (s, 1H), 7.44 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 6.2 Hz, 2H), 7.33 (d, J = 4.7 Hz, 1H), 7.20 (s, 1H), 4.45 (d, J = 5.8 Hz, 2H), 3.98 (d, J = 5.8 Hz, 2H).

[0708] Intermediate 28 (lnt-28): N-(3-(aminomethyl)benzyl)-2-(4-fluorophenyl)acetamide PAG-P3656PCT Application as filed FINAL

[0709] Prepared similarly to Intermediate 33 to afford the expected product (Intermediate 28) as a white powder (172 mg, yield in Step 2: quant).1H NMR (400 MHz, DMSO) 5 8.65 (t, J = 6.0 Hz, 1 H), 8.35 (s, 3H), 7.36 (d, J = 4.7 Hz, 2H), 7.34 - 7.28 (m, 3H), 7.23 (td, J = 4.6, 1.6 Hz, 1 H), 7.13 (t, J = 8.9 Hz, 2H), 4.27 (d, J = 5.9 Hz, 2H), 3.98 (q, J = 5.8 Hz, 2H), 3.49 (s, 2H).

[0710] Prepared similarly to Intermediate 33 to give the desired product (Intermediate 29) (290 mg, >99% yield in step 2). The product was used as such in the next step without further purification.1H NMR (400 MHz, DMSO) 5 9.08 (s, 1 H), 8.13 (d, J = 8.5 Hz, 3H), 7.49 - 7.33 (m, 7H), 7.13 - 7.07 (m, 1 H), 4.47 (d, J = 6.0 Hz, 2H), 4.00 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H). Step 1 : To a solution of 2-(4-methoxyphenyl)acetic acid (415 mg, 2.50 mmol, 1.00 equiv.) in anhydrous DCM (10 mL) were consecutively added at 0 °C HOBt (421 mg, 2.75 mmol, 1.10 equiv.) and EDC (718 mg, 3.74 mmol, 1.50 equiv.). The solution was stirred for 30 minutes at 0 °C when DIPEA (2.17 mL, 12.5 mmol, 5.00 equiv.) and 1-t-butoxycarbonyl-4-aminopiperidine (500 mg, 2.50 mmol, 1.00 equiv.) were added to the mixture. The solution was stirred overnight at room temperature. After ca. 20 h, the mixture was washed with a solution of sat. NaHCCh and then brine. The organic phase was dried (Na2SO4), filtered, concentrated, and then chromatographed (40 g cartridge, Hex / EtOAc, 0% to 40% over 12CVs). Fractions containing product were then concentrated to give tert-butyl 4-(2-(4-methoxyphenyl)acetamido)piperidine-1- carboxylate as a white powder (718 mg, 83% yield).1H NMR (400 MHz, DMSO) 5 7.95 (d, J = 7.6 Hz, 1H), 7.15 (dd, J = 8.3, 2.5 Hz, 2H), 6.89 - 6.81 (m, 2H), 3.95 - 3.74 (m, 2H), 3.77 - 3.55

[0711] (m, 4H), 3.30 - 3.27 (m, 2H), 3.05 - 2.68 (m, 2H), 1.82 - 1.54 (m, 2H), 1.39 (s, 9H), 1.30 - 1.10 (m, 2H). PAG-P3656PCT Application as filed FINAL

[0712] Step 2: To a solution of tert-butyl 4-(2-(4-methoxyphenyl)acetamido)piperidine-1 -carboxylate (718 mg, 2.06 mmol, 1 equiv.) in DCM (10 mL) was added 4N HCI in dioxane (15.5 mL, 61.8 mmol, 30.0 equiv.) and the reaction mixture was allowed to stir overnight. After 20 h, the reaction mixture was triturated with ether. The white precipitate was collected to give 2-(4-methoxyphenyl)-N- (piperidin-4-yl)acetamide hydrochloride (Intermediate 30) as a white solid which was used in the next step without further purification or characterization (559 mg, quant.).1H NMR (400 MHz, DMSO) 5 8.98 - 8.56 (m, 2H), 8.22 (d, J = 7.5 Hz, 1 H), 7.20 - 7.12 (m, 2H), 6.89 - 6.81 (m, 2H), 3.88 - 3.74 (m, 1 H), 3.72 (s, 3H), 3.32 (s, 2H), 3.27 - 3.14 (m, 2H), 3.08 - 2.83 (m, 2H), 1.86 (dd, J = 13.9, 3.9 Hz, 2H), 1.72 - 1.44 (m, 2H).

[0713] Step 1 : Performed similarly to Step 1 of Intermediate 30. Benzyl 4-(4- methylbenzamido)piperidine-1 -carboxylate was produced as a white powder (778 mg, 98% yield). TLC-MS (ES, m / Z): [M + H]+ = 319.0

[0714] Step 2: To a solution of tert-butyl 4-(4-methylbenzamido)piperidine-1-carboxylate (777 mg, 2.44 mmol, 1 equiv.) in DCM (12 mL) was added 4N HCI in dioxane (18.3 mL, 73.2 mmol, 30.0 equiv.) and the reaction mixture was allowed to stir overnight. After 20 h, the reaction mixture was triturated with ether. The white precipitate was collected to give 4-methyl-N-(piperidin-4- yl)benzamide hydrochloride as a white solid (Intermediate 31) which was used in the next step without further purification or characterization (622 mg, quant.).

[0715] Step 1 : Performed similarly to Step 1 of Intermediate 30. Tert-butyl 4-(nicotinamido)piperidine-1- carboxylate was produced as a white powder (600 mg, 79% yield). TLC-MS (ES, m / Z): [M + H]+ = 306.1

[0716] Step 2: To a solution of tert-butyl 4-(nicotinamido)piperidine-1-carboxylate (600 mg, 1.96 mmol, 1 equiv.) in DCM (10 mL) was added 4N HCI in dioxane (14.7 mL, 58.9 mmol, 30.0 equiv.) and the reaction mixture was allowed to stir overnight. After 20 h, the reaction mixture was triturated with ether. The white precipitate was collected to give N-(piperidin-4-yl)nicotinamide PAG-P3656PCT Application as filed FINAL dihydrochloride (Intermediate 32) as a white solid (430 mg, quant.). _1H NMR (400 MHz, DMSO) 5 9.07 (d, J = 2.2 Hz, 1 H), 8.93 - 8.48 (m, 4H), 8.32 (d, J = 8.2 Hz, 1 H), 7.61 (dd, J = 8.0, 4.9 Hz, 1 H), 4.13 - 4.03 (m, 1 H), 3.32 (d, J = 12.8 Hz, 2H), 3.02 (q, J = 11.5 Hz, 2H), 2.13 - 1.89 (m, 2H), 1.86 - 1.61 (m, 2H).

[0717] Step 1 : To a solution of 4-methylbenzoic acid (150 mg, 1.10 mmol, 1 equiv.), EDC (317 mg, 1.65 mmol, 1.5 equiv.), HOBt (186 mg, 1.21 mmol, 1.10 equiv.), and 4-(boc-aminomethyl)-benzylamine (273 mg, 1 ,16 mmol, 1.05 equiv.) was added DIPEA (0.96 mL, 5.5 mmol, 5 equiv.) at 0°C. After warming to room temperature overnight (ca. 20 h), the reaction mixture was diluted with DCM (50 mL), washed with 10% citric acid (3 x 20 mL), sat. NaHCCh (3 x 20 mL), dried (Na2SO4), filtered, and concentrated to give tert-butyl (4-((4-methylbenzamido)methyl)benzyl)carbamate as a white solid (321 mg, 82% yield).

[0718] Step 2: To a solution of tert-butyl (4-((4-methylbenzamido)methyl)benzyl)carbamate (270 mg, 0.762 mmol, 1 equiv.) in dioxane (5 mL), was added 4N HCI in dioxane (5 mL, 20.0 mmol, 26.25 equiv.) and the reaction mixture was allowed to stir overnight at room temperature. After ca. 20 h, the reaction mixture was concentrated to give the crude HCI salt (Intermediate 33) that was used in the next step without further purification (226 mg, 102 % yield).1H NMR (400 MHz, DMSO) 5 9.04 (t, J = 6.0 Hz, 1 H), 8.36 (s, 3H), 7.86 - 7.76 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.46 (d, J = 5.8 Hz, 2H), 3.98 (dq, J = 8.4, 3.8 Hz, 2H), 2.35 (s, 3H).

[0719] Step 1 : To a solution of 2-(pyridin-4-yl)acetic acid (173 mg, 1.00 mmol, 1 equiv.), EDC.HCI (287 mg, 1.50 mmol, 1.5 equiv.), HOBt (168 mg, 1.10 mmol, 1.10 equiv.), and 1-t-butoxycarbonyl-4- aminopiperidine (200 mg, 1.00 mmol, 1 equiv.) in DCM (4 mL) was added DIPEA (0.7 mL, 3.99 mmol, 4 equiv.) at 0°C. After warming to room temperature overnight (ca. 20 h), the reaction PAG-P3656PCT Application as filed FINAL mixture was diluted with DCM (50 mL), washed with sat. NaHCO3 (3 x 20 mL), dried (Na2SO4), filtered, concentrated, and chromatographed (40 g cartridge, EtOAc / MeOH, 0% over 3 CVs, 0% to 100% over 7 CVs). Fractions containing product were pooled and then concentrated to give the title compound as a white solid (224 mg, 70% yield). 1 H NMR (400 MHz, DMSO) 5 8.50 - 8.44 (m, 2H), 8.14 (d, J = 7.7 Hz, 1 H), 7.28 - 7.22 (m, 2H), 3.82 (d, J = 13.3 Hz, 2H), 3.70 (ddp,

[0720] J = 11.0, 7.9, 4.1 Hz, 1 H), 3.43 (s, 2H), 2.84 (s, 2H), 1.71 (dd, J = 12.9, 3.8 Hz, 2H), 1.39 (s, 9H), 1.23 (qd, J = 11.4, 4.2 Hz, 2H).

[0721] Step 2: To a solution of tert-butyl 4-(2-(pyridin-4-yl)acetamido)piperidine-1-carboxylate (125 mg, 0.392 mmol, 1 equiv.) in dioxane (2 mL), was added 4N HCI in dioxane (2 mL, 7.833 mmol, 20.0 equiv.) and the reaction mixture was allowed to stir overnight at room temperature. After ca. 20 h, the reaction mixture was concentrated and triturated from ether to give N-(piperidin-4-yl)-2- (pyridin-4-yl)acetamide dihydrochloride (Intermediate 34) as a white solid (94 mg, 82 % yield). 1 H NMR (400 MHz, DMSO) 5 9.49 - 8.95 (m, 2H), 8.85 - 8.76 (m, 3H), 7.95 - 7.89 (m, 2H), 3.87 - 3.82 (m, 3H), 3.29 - 3.20 (m, 2H), 2.94 (q, J = 11.0 Hz, 2H), 1.89 (dt, J = 14.2, 4.0 Hz, 2H), 1.68 (ddt, J = 13.9, 10.0, 5.2 Hz, 2H).

[0722] Intermediate 35 (lnt-35): N-(piperidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide hydrochloride

[0723] Prepared similarly to Intermediate 34 to give N-(piperidin-4-yl)-2-(tetrahydro-2H-pyran-4- yl)acetamide hydrochloride (Intermediate 35) as a white solid (242 mg, 89% yield over 2 steps).1H NMR (400 MHz, DMSO) 5 8.77 (s, 2H), 8.01 (d, J = 7.5 Hz, 1 H), 3.86 - 3.74 (m, 3H), 3.32 - 3.16 (m, 4H), 2.93 (d, J = 9.5 Hz, 2H), 2.00 (d, J = 7.1 Hz, 2H), 1.92 - 1.80 (m, 3H), 1.65 - 1.43 (m, 4H), 1.17 (qd, J = 11.9, 4.4 Hz, 2H). PAG-P3656PCT Application as filed FINAL

[0724] Step 1 : To a solution of 2-(4-cyanophenyl)acetic acid (161 mg, 1.00 mmol, 1 equiv.), EDC.HCI (288 mg, 1.50 mmol, 1.5 equiv.), HOBt (168 mg, 1.10 mmol, 1.10 equiv.), and 1-t-butoxycarbonyl- 4-aminopiperidine (200 mg, 1.00 mmol, 1 equiv.) in DCM (6 mL) was added DIPEA (0.35 mL, 2.00 mmol, 2 equiv.) at O°C. After warming to room temperature overnight (ca. 20 h), the reaction mixture was diluted with DCM (50 mL), washed with 10% citric acid (3 x 20 mL), sat. NaHCO3 (3 x 20 mL), dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, Hex / EtOAc, 25% over 1 CV, 25% to 100% over 4 CV's, 100% over 2.6 CVs, then EtOAc / MeOH, 0% to 6% over 1.4 CV's, 6% over 2.2 CV's). Fractions containing product were then concentrated to give the title compound as a white solid (250 mg, 73% yield). Step 2: To a mixture of tert-butyl 4-(2-(4-cyanophenyl)acetamido)piperidine-1 -carboxylate (250 mg, 0.73 mmol, 1 equiv.), in dioxane (2 mL) was added 4N HCI in dioxane (7.3 mL, 29.1 mmol, 40 equiv.). The reaction mixture was stirred overnight when it was concentrated to give the desired HCI salt (Intermediate 36) that was used in the next step without further purification (204 mg).1H NMR (400 MHz, DMSO) 5 8.99 (s, 2H), 8.52 (d, J = 7.4 Hz, 1 H), 7.80 - 7.72 (m, 2H), 7.49 - 7.43 (m, 2H), 4.00 - 3.42 (m, 3H), 3.23 (d, J = 12.6 Hz, 2H), 2.92 (q, J = 11.4 Hz, 2H), 1.92 -

[0725] 1.81 (m, 2H), 1.63 (dtd, J = 14.1 , 10.6, 3.8 Hz, 2H).

[0726] Intermediate 37 (lnt-37): 1-(methylsulfonyl)-N-(piperidin-4-yl)piperidine-4-carboxamide hydrochloride

[0727] Prepared similarly to Intermediate 34 to give 1-(methylsulfonyl)-N-(piperidin-4-yl)piperidine-4- carboxamide hydrochloride (Intermediate 37) as a white solid (119 mg, 51% yield over 2 steps).1H NMR (400 MHz, DMSO) 5 8.86 (s, 2H), 8.18 - 7.95 (m, 1 H), 3.77 (s, 1 H), 3.53 (s, 2H), 3.18 (m, 2H), 3.00 - 2.88 (m, 2H), 2.83 (m, 3H), 2.67 (s, 2H), 2.21 (s, 1 H), 1.77 (m, 4H), 1.57 (m, 4H).

[0728] Intermediate 38 (lnt-38): (3-methylisoxazol-5-yl)(piperazin-1-yl)methanone hydrochloride PAG-P3656PCT Application as filed FINAL

[0729] Step 1 : To a solution of 3-methylisoxazole-5-carboxylic acid (341 mg, 2.68 mmol, 1 equiv.), EDC (772 mg, 4.03 mmol, 1.5 equiv.), HOBt (452 mg, 2.95 mmol, 1 equiv.), and tert-butyl piperazine- 1-carboxylate (500 mg, 2.68 mmol, 1 equiv.) in DCM (11 mL) was added DIPEA (0.94 mL, 5.37 mmol, 2 equiv.) at 0°C. After warming to room temperature overnight (ca. 20 h), the reaction mixture was diluted with DCM (50 mL), washed with sat. NaHCCh (3 x 20 mL), dried (Na2SO4), filtered, concentrated, and chromatographed (40 g cartridge, DCM / MeOH, 0% MeOH over 2 CV, 0% to 5% over 15 CV's, 5% over 5 CV's). Fractions containing product were then concentrated to give tert-butyl 4-(3-methylisoxazole-5-carbonyl)piperazine-1 -carboxylate as a white solid (695 mg, 88% yield).1H NMR (400 MHz, DMSO) 5 6.80 (s, 1 H), 3.83 - 3.44 (m, 5H), 3.48 - 3.34 (m, 5H), 2.29 (s, 1 H), 1.41 (s, 9H).

[0730] Step 2: To a solution of tert-butyl 4-(3-methylisoxazole-5-carbonyl)piperazine-1-carboxylate (694 mg, 2.35 mmol, 1 equiv.) in dioxane (12 mL), was added 4N HCI in dioxane (5.87 mL, 23.5 mmol, 10.0 equiv.) and the reaction mixture was allowed to stir overnight at room temperature. After ca. 20 h, the reaction mixture was concentrated and triturated from ether to give (3-methylisoxazol- 5-yl)(piperazin-1-yl)methanone hydrochloride (Intermediate 38) as a white solid (482 mg, 89 % yield). _1H NMR (400 MHz, DMSO) 5 9.56 (s, 2H), 6.88 (s, 1 H), 3.83 (t, J = 5.2 Hz, 4H), 3.17 (t, J = 5.2 Hz, 4H), 2.30 (s, 3H).

[0731] Intermediate 39 (lnt-39): 2-chloro-1-(6-(3-methylisoxazole-5-carbonyl)-2,6- diazaspiro[3.3]heptan-2-yl)ethan-1-one

[0732] Step 1 : To a solution of 3-methylisoxazole-5-carboxylic acid (260 mg, 1 Eq, 2.05 mmol, 1 equiv.), EDC (589 mg, 3.07 mmol, 1.5 equiv.), HOBt (345 mg, 2.25 mmol, 1.1 equiv.), and tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate formate (500 mg, 2.05 mmol, 1 equiv.) in DCM (8.2 mL) was added DI PEA (0.71 mL, 4.09 mmol, 2 equiv.) at 0°C. After warming to room temperature overnight (ca. 20 h), the reaction mixture was diluted with DCM (50 mL), washed with sat. NaHCO3 (3 x 20 mL), dried (Na2SO4), filtered, concentrated, and chromatographed (40 g cartridge, DCM / MeOH, 0% MeOH over 2 CV, 0% to 5% over 15 CV's, 5% over 5 CV's). Fractions containing product were then concentrated to give the title compound as a white solid (436 mg, 69% yield).1H NMR (400 MHz, DMSO) 5 6.86 (s, 1 H), 4.59 (s, 2H), 4.18 (s, 2H), 4.01 (s, 4H), 2.28 (s, 3H), 1.37 (s, 9H). PAG-P3656PCT Application as filed FINAL

[0733] Step 2: To a solution of tert-butyl 6-(3-methylisoxazole-5-carbonyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (436 mg, 1.42 mmol, 1 equiv.) in DCM (5 mL), was added trifluoroacetic acid (2.16 mL, 28.4 mmol, 20.0 equiv.) and the reaction mixture was allowed to stir overnight at room temperature. After ca. 20 h, the reaction mixture was concentrated and triturated from ether to give (3-methylisoxazol-5-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone 2,2,2-trifluoroacetate as a white solid (418 mg, 92% yield).1H NMR (400 MHz, DMSO) 5 8.63 (s, 2H), 6.88 (s, 1 H), 4.64 (s, 2H), 4.22 (s, 2H), 4.15 (s, 4H), 2.29 (s, 3H).

[0734] Step 3: To a mixture of (3-methylisoxazol-5-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone 2,2,2- trifluoroacetate (130 mg, 0.41 mmol, 1 equiv.), triethylamine (0.30 mL, 2.02 mmol, 5 equiv.) in DCM (2.6 mL) was added chloroacetyl chloride at 0 °C (0.041 mL, 0.51 mmol, 1.26 equiv.) and the reaction mixture was allowed to warm to room temperature. After ca. 20 h, the reaction mixture was diluted with DCM (20 mL) and sat. NaHCO3 (20 mL). The aqueous solution was extracted with DCM (3 x 20 mL), and the combined organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (40 g cartridge, EtOAc / MeOH, 0% over 3 CVs, 0% to 50% over 15 CVs, 50% over 2 CVs) to give the desired product (Intermediate 39) as a foam (98 mg, 85% yield).1H NMR (400 MHz, DMSO) 5 6.87 (s, 1 H), 4.62 (s, 2H), 4.37 (s, 2H), 4.21 (s, 2H), 4.13 - 4.07 (m, 4H), 2.29 (s, 3H).

[0735] Intermediate 40 (lnt-40): N-(piperidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide hydrochloride

[0736] Prepared similarly to Intermediate 34 to give N-(3-aminopropyl)-3-methylisoxazole-5- carboxamide hydrochloride (Intermediate 40) as a white solid (479 mg, 76% yield over 2 steps).

[0737] 1H NMR (400 MHz, DMSO) 5 9.11 (t, J = 5.9 Hz, 1 H), 7.99 (s, 3H), 6.97 (s, 1 H), 3.32 - 3.22 (m, 2H), 3.00 - 2.70 (m, 2H), 2.29 (s, 3H), 1 .81 (p, J = 6.9 Hz, 2H).

[0738] Intermediate 41 (lnt-41): 2-methyl-N-(piperidin-4-yl)oxazole-5-carboxamide hydrochloride DCM, r.t. PAG-P3656PCT Application as filed FINAL

[0739] Prepared similarly to Intermediate 34 to give 2-methyl-N-(piperidin-4-yl)oxazole-5-carboxamide hydrochloride (Intermediate 41) as a white solid (157 mg, 52% yield over 2 steps).1H NMR (400 MHz, DMSO) 5 9.13 (s, 1 H), 8.66 (d, J = 7.6 Hz, 1 H), 7.72 (s, 1 H), 6.33 - 5.20 (m, 1 H), 4.00 (dtt, J = 11.1 , 7.9, 3.9 Hz, 1 H), 3.27 (d, J = 11.6 Hz, 2H), 2.94 (td, J = 9.6, 5.3 Hz, 2H), 2.46 (s, 3H), 2.01 - 1.68 (m, 4H).

[0740] Intermediate 42 (lnt-42): 2-methyl-N-(piperidin-4-yl)thiazole-5-carboxamide hydrochloride

[0741] Prepared similarly to Intermediate 34 to give 2-methyl-N-(piperidin-4-yl)thiazole-5-carboxamide hydrochloride (Intermediate 42) as a white solid (466 mg, 71 % yield over 2 steps).1H NMR (400 MHz, DMSO) 5 9.07 (s, 1 H), 8.74 (d, J = 7.3 Hz, 1 H), 8.35 (s, 1 H), 6.96 - 5.90 (m, 1 H), 4.37 - 3.80 (m, 1 H), 3.39 - 3.15 (m, 2H), 2.96 (q, J = 11.7 Hz, 2H), 2.66 (s, 3H), 2.04 - 1.61 (m, 4H).

[0742] Intermediate 43 (lnt-43): N-(4-(aminomethyl)benzyl)-2-(4-fluorophenyl)acetamide

[0743] Step 1 : To a solution of 2-(4-fluorophenyl)acetic acid (150 mg, 0.973 mmol, 1.00 equiv.), HATLI (444 mg, 1.17 mmol, 1.20 equiv.) and Et3N (0.543 mL, 3.89 mmol, 4.00 equiv.) in anhydrous DMF (3.9 mL) at 0 °C was added 4-(boc-aminomethyl)-benzylamine (241 mg, 1.02 mmol, 1.05 equiv.). After 1 h, the reaction mixture was diluted with DCM (50 mL), washed twice with sat. aq. NaHCCh sol. (25 mL), then with brine (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed (20 g cartridge, EtOAc / CyH 0% over 1 CV, 0-50% over 8 CVs, 50% over 1 CV, 50-100% over 8 CVs, 100% over 1 CV) to give tert-butyl (4-((2-(4-fluorophenyl)acetamido)methyl)benzyl)carbamate as a white solid (84 mg, 23%).

[0744] Step 2: To a mixture of tert-butyl (4-((2-(4-fluorophenyl)acetamido)methyl)benzyl)carbamate (84 mg, 0.23 mmol, 1.00 equiv.) in DCM (1.0 mL) was added 4N HCI in dioxane (0.56 mL, 2.3 mmol, 10 equiv.), and the reaction mixture was stirred 20 h at room temperature. The reaction mixture was then concentrated under reduced pressure to give the desired product (70 mg, >99% yield). The product (Intermediate 43) was used as such in the next step without further purification.1H NMR (400 MHz, DMSO) 5 8.60 (s, 1 H), 8.13 (s, 3H), 7.37 (d, J = 7.9 Hz, 2H), 7.30 (dd, J = 8.5, PAG-P3656PCT Application as filed FINAL

[0745] 5.6 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.13 (t, J = 8.8 Hz, 2H), 4.26 (d, J = 6.0 Hz, 2H), 3.98 (t, J = 5.8 Hz, 2H), 3.47 (s, 2H);19F NMR (376 MHz, DMSO) 5 -117.05.

[0746] Intermediate 44 (lnt-44): (S)-N-(2-amino-2-phenylethyl)acetamide hydrochloride

[0747] Step 1 : To a solution of tert-butyl (S)-(2-amino-1-phenylethyl)carbamate (200 mg, 0.846 mmol, 1 equiv.) in DCM (20 mL) at 24 °C was added triethylamine (0.12 mL, 0.85 mmol, 1.0 equiv.) followed by addition of acetic anhydride (0.160 mL, 1.69 mmol, 2.0 equiv.). the resulting mixture was stirred at rt for 16h. The reaction mixture was concentrated to dryness and then redissolved in DCM (10 ml). The obtained solution was washed with 1M HCI, sat. solution of NaHCO3 and finally with water, the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (20 g cartridge, Cyclohex. / EtOAc 0% over 1 CV, 0-60% over 18 CVs). The fractions containing product were concentrated under reduced pressure to give tert-butyl (S)-(2-acetamido-1- phenylethyl)carbamate (0.22 g, 93 %).1H NMR (400 MHz, CDCI3) 5 7.39 - 7.32 (m, 2H), 7.28 (dt, J = 6.5, 1 .9 Hz, 3H), 6.06 (s, 1 H), 5.40 (d, J = 7.5 Hz, 1 H), 4.78 (s, 1 H), 3.74 - 3.44 (m, 2H), 1 .98 (s, 3H), 1.51 - 1.30 (m, 9H).

[0748] Step 2: To a solution of tert-butyl (S)-(2-acetamido-1-phenylethyl)carbamate (0.215 g, 0.77 mmol, 1 equiv.) in DCM (18 mL) at room temperature was added 4N HCI in dioxane (0.97 mL, 3.86 mmol, 5 equiv.) in dioxane and the reaction mixture was stirred at room temperature for 16h. The reaction mixture was concentrated under reduced pressure to give the crude product which was used in the next step without further purification or characterization (0.148 g, 89%).1H NMR (400 MHz, DMSO) 5 8.60 (s, 3H), 8.18 (t, J = 5.7 Hz, 1 H), 7.52 - 7.33 (m, 5H), 4.32 (q, J = 6.2 Hz, 1 H), 3.56 (ddd, J = 13.1 , 7.2, 5.7 Hz, 1 H), 3.42 (dt, J = 13.8, 6.1 Hz, 1 H), 1.80 (s, 3H).

[0749] Step 1 : To a solution of tert-butyl 4-aminopiperidine-1 -carboxylate (500 mg, 2.50 mmol, 1 equiv.) in DCM (25 ml) was added EDC (718 mg, 3.74 mmol, 1.5 equiv.) and HOBt (421 mg, 2.75 mmol, 1.1 equiv.) at 0°C. After stirring for 30 mins, DIPEA (2.17 mL, 12.5 mmol, 5.0 equiv.) and 2- (pyridin-2-yl)acetic acid, HCI (455 mg, 2.62 mmol, 1.05 equiv.) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (15ml) and the layers were separated. The aqueous layer was extracted with DCM (3 x 10 mL). PAG-P3656PCT Application as filed FINAL

[0750] The combined organic solution was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (20 g cartridge, Cyclohex. / EtOAc 0% over 1 CV, 0-80% over 18 CVs). The fractions containing product were concentrated under reduced pressure to give tert-butyl 4-(2-(pyridin-2-yl)acetamido)piperidine-1- carboxylate (0.648 g, 81 %).1H NMR (400 MHz, CDCI3) 5 8.53 (dd, J = 4.8, 1.6 Hz, 1 H), 8.49 (d, J = 2.3 Hz, 1 H), 7.67 (dt, J = 7.8, 2.0 Hz, 1 H), 7.29 (ddd, J = 7.9, 4.8, 0.9 Hz, 1 H), 5.48 (d, J = 8.0 Hz, 1 H), 4.16 - 3.82 (m, 3H), 3.52 (s, 2H), 2.81 (t, J = 12.7 Hz, 2H), 1.94 - 1.78 (m, 2H), 1.43 (s, 9H), 1.24 (tt, J = 11.9, 6.7 Hz, 2H).

[0751] Step 2: To a solution of tert-butyl 4-(2-(pyridin-2-yl)acetamido)piperidine-1-carboxylate (0.648 g, 2.03 mmol, 1 equiv.) in DCM (25 mL) at room temperature was added 4N HCI in dioxane ( 2.54 mL, 10.1 mmol, 5 equiv.) and the reaction mixture was stirred at 24°C for overnight. The reaction mixture was concentrated to dryness under reduced pressure and the crude product (565 mg, 95%) was used in the next step without further purification.1H NMR (400 MHz, DMSO) 5 9.15 (d, J = 21.4 Hz, 2H), 8.90 - 8.80 (m, 2H), 8.75 (d, J = 7.4 Hz, 1 H), 8.50 (dt, J = 8.1 , 1.7 Hz, 1 H), 8.04 (dd, J = 8.1 , 5.7 Hz, 1 H), 3.80 (s, 3H), 3.24 (dt, J = 12.8, 3.6 Hz, 2H), 2.93 (q, J = 11.2 Hz, 2H),

[0752] 1.89 (dq, J = 13.0, 4.0 Hz, 2H), 1.68 (dtd, J = 14.0, 10.3, 3.9 Hz, 2H).

[0753] Intermediate 46 (lnt-46): 2-phenyl-N-(piperidin-4-yl)acetamide.2HCI

[0754] Step 1 : To a solution of tert-butyl 4-aminopiperidine-1 -carboxylate (500 mg, 2.50 mmol, 1 equiv.) in DCM (25 ml) was added EDC (718 mg, 3.74 mmol, 1.5 equiv.) and HOBt (421 mg, 2.75 mmol, 1.1 equiv.) at 0°C. After stirring for 30 mins, DIPEA was added (2.17 mL, 12.5 mmol, 5.0 equiv.) followed by 2-(pyridin-3-yl)acetic acid hydrochloride (455 mg, 2.62 mmol, 1.05 equiv.) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (15 ml) and the layers were separated. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic solution was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (20 g cartridge, Cyclohex. / EtOAc 0% over 1 CV, 0-80% over 18 CVs). The fractions containing product were concentrated under reduced pressure to give tert-butyl 4-(2-(pyridin-3-yl)acetamido)piperidine-1- carboxylate (0.682 g, 81 %).1H NMR (400 MHz, CDCI3) 5 8.55 (ddd, J = 5.0, 1.9, 1.0 Hz, 1 H), 7.68 (td, J = 7.7, 1.8 Hz, 1 H), 7.46 (d, J = 7.5 Hz, 1 H), 7.28 (d, J = 1.2 Hz, 1 H), 7.22 (ddd, J = 7.6, 4.9, 1.2 Hz, 1 H), 4.06 - 3.81 (m, 3H), 3.72 (s, 2H), 3.00 - 2.85 (m, 2H), 1.94 - 1.81 (m, 2H), 1.46 (s, 9H), 1.42 - 1.23 (m, 2H).

[0755] Step 2: To a solution of tert-butyl 4-(2-(pyridin-3-yl)acetamido)piperidine-1-carboxylate (0.648 g, 2.03 mmol, 1 equiv.) in DCM (25 mL) was added 4N HCI in dioxane (2.54 mL, 10.1 mmol, 5 equiv.) and the reaction mixture was stirred at room temperature overnight. The reaction mixture PAG-P3656PCT Application as filed FINAL was concentrated and the crude product was used in the next reaction without further purification.1H N MR (400 MHz, DMSO) 5 9.12 (s, 2H), 8.84 (d, J = 6.4 Hz, 2H), 8.52 (t, J = 7.9 Hz, 1 H), 8.05 - 7.85 (m, 2H), 4.10 (s, 3H), 3.93 - 3.70 (m, 2H), 3.56 (s, 1 H), 2.94 (p, J = 10.3 Hz, 2H), 1.90 (dq, J = 8.4, 4.2 Hz, 2H), 1.71 (dtd, J = 14.0, 10.2, 3.8 Hz, 2H).

[0756] Intermediate 47 (lnt-47): N-(piperidin-4-yl)-2-(pyridin-4-yl)acetamide.2HCI

[0757] Step 1 : To a solution of tert-butyl 4-aminopiperidine-1 -carboxylate (500 mg, 2.50 mmol, 1 equiv.) in DCM (25 ml) was added EDC (718 mg, 3.74 mmol, 1.5 equiv.) and HOBt (421 mg, 2.75 mmol, 1.1 equiv.) at 0°C. After 30 min, DIPEA (2.17 mL, 12.5 mmol, 5 equiv.) and 2-(pyridin-4-yl)acetic acid hydrochloride (455 mg, 2.62 mmol, 1.05 equiv.) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (15 ml) and the layers were separated. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to get crude. The crude product was purified by chromatography (20 g cartridge, Cyclohex. / EtOAc 0% over 1 CV, 0-80% over 18 CVs). The fractions containing product were concentrated under reduced pressure to give tert-butyl 4-(2-(pyridin-4-yl)acetamido)piperidine-1- carboxylate (0.577 g, 72 %).1H NMR (400 MHz, CDCI3) 5 8.60 - 8.52 (m, 2H), 7.29 - 7.20 (m, 3H), 5.47 (d, J = 7.9 Hz, 1 H), 4.16 - 3.84 (m, 3H), 3.53 (s, 2H), 2.82 (t, J = 12.7 Hz, 2H), 1.96 - 1.82 (m, 2H), 1.44 (s, 10H), 1.34 - 1.16 (m, 2H).

[0758] Step 2: To a solution of tert-butyl 4-(2-(pyridin-4-yl)acetamido)piperidine-1-carboxylate (0.577 g, 1.81 mmol, 1 equiv.) in DCM (25 mL) at room temperature was added 4N HCI in dioxane (2.26 mL, 9.03 mmol, 5 equiv.) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and the crude product was used in the next step without further purification.1H NMR (400 MHz, DMSO) 5 9.07 (d, J = 33.1 Hz, 2H), 8.87 - 8.83 (m, 2H), 8.81 (d, J = 7.4 Hz, 1 H), 8.02 - 7.90 (m, 2H), 5.75 (s, 1 H), 3.86 - 3.76 (m, 2H), 3.56 (s, 3H), 3.02 - 2.88 (m, 2H), 1.89 (dd, J = 13.9, 4.1 Hz, 2H), 1.67 (dtd, J = 14.1 , 10.5, 3.9 Hz, 2H).

[0759] Step 1 : To a solution of tert-butyl (S)-(2-amino-1-phenylethyl)carbamate (300 mg, 1.27 mmol, 1 equiv.) in DCM (20 mL) at 0 °C was added triethylamine (0.89 mL, 6.35 mmol, 5.0 equiv.) followed by drop-wise addition of allyl chloroformate (0.18 mL, 1.65 mmol, 1.3 equiv.) and the reaction PAG-P3656PCT Application as filed FINAL mixture was allowed to warm to room temperature. After 16h, the reaction mixture was quenched by addition of sat. NH4CI (10 mL) and then extracted with DCM (3 x 10 mL). The combined organic solution was then dried (Na2SO4), filtered, concentrated and chromatographed (20 g cartridge, Cyclohex. / EtOAc 0% over 1 CV, 0-40% over 18 CVs). The fractions containing product were concentrated under reduced pressure to give allyl tert-butyl (1-phenylethane-1 ,2-diyl)(S)- dicarbamate (155 mg, 38 %).1H NMR (400 MHz, CDCI3) 5 7.40 - 7.27 (m, 5H), 5.91 (ddt, J = 17.4, 10.9, 5.6 Hz, 1 H), 5.37 - 5.17 (m, 3H), 5.01 (s, 1 H), 4.78 (s, 1 H), 4.64 - 4.50 (m, 2H), 3.50 (d, J = 8.9 Hz, 2H), 1.42 (s, 9H).

[0760] Step 2: To a solution of allyl tert-butyl (1-phenylethane-1 ,2-diyl)(S)-dicarbamate (155 mg, 0.484 mmol, 1 equiv.) in DCM (7.7 mL) at room temperature was added 4N HCI in dioxane (0.61 mL,

[0761] 2.42 mmol, 5 equiv.). After 16 h, the reaction mixture was concentrated under reduced pressure to give allyl (S)-(2-amino-2-phenylethyl)carbamate hydrochloride (124 mg, 100% yield). This product was used in the next step without any further purification.1H NMR (400 MHz, DMSO) 5 8.49 (s, 3H), 7.53 - 7.33 (m, 5H), 5.87 (ddt, J = 17.3, 10.5, 5.3 Hz, 1 H), 5.29 - 5.11 (m, 2H), 4.45 (d, J = 5.3 Hz, 2H), 4.31 (s, 1 H), 3.58 - 3.35 (m, 2H).

[0762] Step 1 : To a solution of tert-butyl (S)-(2-amino-1-phenylethyl)carbamate (0.500 g, 2.12 mmol, 1 equiv) in methanol (10.6 mL) at room temperature were added benzaldehyde (449 mg, 4.23 mmol, 2.0 equiv), triethylamine (642 mg, 6.35 mmol, 3.0 equiv), and 1 g of 3 molecular sieves. The resulting suspension was stirred at room temperature for 1 hour. TLC showed complete consumption of the amine. The reaction mixture was then cooled to 0°C (ice bath), when sodium borohydride was added in portions (240 mg, 6.35 mmol, 3.0 equiv). After stirring for 2 h at 0 °C, the reaction mixture was concentrated. The crude residue was suspended in water and extracted with ethyl acetate (3 x 15 mL). The combined organic solution was then dried (Na2SC>4), filtered, and concentrated. The crude product (700 mg) was used in next step without further purification. TLC-MS (ES, m / z): [M + H]+ = 327.2.

[0763] Step 2: To a solution of tert-butyl (S)-(2-(benzylamino)-1-phenylethyl)carbamate (0.500 g, 1.53 mmol, 1.0 equiv) in 1 ,2-dichloroethane (15 mL) was added paraformaldehyde (230.0 mg, 7.66 mmol, 5.0 equiv) and sodium triacetoxyborohydride (974 mg, 4.60 mmol, 3.0 equiv) at room PAG-P3656PCT Application as filed FINAL temperature. After stirring for 16 hours, the reaction mixture was diluted with water, and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 15 mL). The combined organic solution was then dried (Na2SO4), filtered, and concentrated. The crude product (489 mg) was used in the next step without further purification. TLC-MS (ES, m / z): [M + H]+ = 341.

[0764] Step 3: To a solution of tert-butyl (S)-(2-(benzyl(methyl)amino)-1-phenylethyl)carbamate (186 mg, 0.55 mmol, 1.0 equiv.) in methanol (10 mL) was added palladium hydroxide (38 mg, 20 wt%, 0.055 mmol, 0.1 equiv). The suspension was stirred under 1 atm of hydrogen at room temperature. After 16 h, the reaction mixture was filtered through a pad of Celite, the Celite pad was washed with methanol, and the collected filtrate was concentrated. The crude product (120 mg) was used in the next step without further purification. (TLC-MS (ES, m / z): [M + H]+ = 251. Step 4: To a cold (0°C) solution of tert-butyl (S)-(2-(methylamino)-1-phenylethyl)carbamate (0.120 g, 0.479 mmol, 1 equiv) in DCM (7.6 mL) at was added triethylamine (0.33 mL, 2.40 mmol, 5.0 equiv), followed by allyl chloroformate (0.07 mL, 0.623 mmol, 1.3 equiv) and the mixture was stirred at room temperature. After 16 hours, the reaction was quenched by the addition of a saturated solution of NH4CI (10 mL) and extracted with DCM (3 x 10 mL). The combined organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, cyclohexane / ethyl acetate 0% over 1CV then 0% to 40% over 18 CVs). The fractions containing product were concentrated under reduced pressure to give allyl (S)-(2-((tert- butoxycarbonyl)amino)-2-phenylethyl)(methyl)carbamate (72 mg, 45% yield); mixture of rotamers.1H NMR (400 MHz, CDCI3) 5 7.59 - 7.15 (m, 5H), 5.94 (ddt, J = 16.1 , 10.7, 5.4 Hz, 1 H), 5.64 - 5.59 (m, 0.6H), 5.45 - 5.13 (m, 2H), 5.12 - 4.99 (m, 0.4H), 4.96 - 4.82 (m, 0.6H), 4.70 (d, J = 5.7 Hz, 1 H), 4.67 - 4.43 (m, 2H), 3.86 (t, J = 12.7 Hz, 0.6H), 3.77 - 3.63 (m, 0.4H), 3.34 (dd, J = 14.6, 5.4 Hz, 0.4H), 3.19 (dd, J = 14.4, 4.3 Hz, 0.6H), 2.95 - 2.89 (m, 3H), 1.46 - 1.34 (m, 9H).

[0765] Step 5: To a solution of allyl (S)-(2-((tert-butoxycarbonyl)amino)-2-phenylethyl)(methyl)carbamate (72 mg, 0.22 mmol, 1 equiv) in DCM (3.4 mL) at room temperature, HCI in dioxane (0.27 mL, 4 M, 1.1 mmol, 5 equiv) was added and the reaction mixture was stirred at room temperature. After 16 h, the reaction mixture was evaporated to dryness under reduced pressure to give a white solid. This solid was suspended in diethyl ether (50 mL) and subjected to sonication for 30 minutes. The resulting suspension was filtered, and the obtained white solid was air-dried to yield allyl (S)-(2-amino-2-phenylethyl)(methyl)carbamate hydrochloride (54 mg, 93% yield). The product was used in the next step without further purification or characterization. PAG-P3656PCT Application as filed FINAL

[0766] Intermediate 50 (lnt-50): (S)-2-amino-N-methyl-2-phenylacetamide hydrochloride

[0767] Step 1 : To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (500 mg, 1.99 mmol, 1.0 equiv.) in DCM (20 mL) at 0°C was added GDI (484.0 mg, 2.985 mmol, 1.5 equiv.), and the mixture was stirred at 0°C for 30 minutes. To this solution at 0°C, methylamine in methanol

[0768] (4.98 mL, 2 M, 9.95 mmol, 5.0 equiv) was added, and the reaction mixture was allowed to warm to room temperature. After 16 hours, the mixture was diluted with DCM and washed with 1 N HCI followed by sat. NaHCCh solution. The organic solution was then dried (Na2SO4), filtered, concentrated and chromatographed (40 g cartridge, cyclohexane / ethyl acetate, 0% over 1CV, 0% to 100% over 10 CVs, 100% over 3CVs) to give tert-butyl (S)-(2-(methylamino)-2-oxo-1- phenylethyl)carbamate (378 mg, 72 %).1H NMR (400 MHz, CDCI3) 6 7.41 - 7.28 (m, 5H), 5.79 (d, J = 32.1 Hz, 2H), 5.11 (s, 1 H), 2.79 (d, J = 4.9 Hz, 3H), 1.40 (s, 9H).

[0769] Step 2: To a solution of tert-butyl (S)-(2-(methylamino)-2-oxo-1-phenylethyl)carbamate (448 mg, 1.69 mmol, 1.0 equiv) in DCM (17 mL) at room temperature was added 4N HCI in dioxane (2.12 mL, 8.47 mmol, 5.0 equiv.). After 72 h, the reaction mixture was concentrated, triturated with ether (50 mL), and then sonicated during which a white precipitate formed. The precipitate was filtered and then air-dried to give (S)-2-amino-N-methyl-2-phenylacetamide hydrochloride (268 mg, 79%).1H NMR (400 MHz, DMSO) 5 8.71 (s, 3H), 8.60 (d, J = 5.0 Hz, 1 H), 7.56 - 7.35 (m, 5H), 4.91 (s,

[0770] 1 H), 2.61 (d, J = 4.6 Hz, 3H).

[0771] Intermediate 51 (lnt-51): allyl (S)-2-amino-2-phenylacetate

[0772] Step 1 : To a solution of (S)-2-amino-2-phenylacetic acid (1.00 g, 6.62 mmol, 1.0 equiv.) in 1 N NaOH (8.27 mL) and THF (8.27 mL) at room temperature was added BOC2O (1.82 mL, 7.94 mmol, 1.2 equiv.) in one portion. After 16h, the volatiles were removed under vacuum, and the remaining mixture was washed with ether (2 x 15 mL). The combined organic solution was discarded, and the aqueous layer was acidified to pH 2 with 1 N HCI. The acidic aqueous solution was extracted with ethyl acetate (3 x 15 mL) and the combined organic solution was dried (Na2SO4), filtered, and concentrated pressure to give the crude 2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (1 .68 g) which was used in the next step without further purification or characterization.

[0773] Step 2: To a solution of crude (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (500 mg, 1 .99 mmol, 1 .0 equiv) in DCM (20 mL) at 0°C was added DCC (411 mg, 1 .990 mmol, 1.0 equiv) and DMAP (12 mg, 0.10 mmol, 0.05 equiv), and the mixture was stirred at 0°C. After 30 min, allyl PAG-P3656PCT Application as filed FINAL alcohol (127 mg, 2.19 mmol, 1.1 equiv) was added slowly, and the resulting mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with DCM and filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography (40 g cartridge, Cyc / EtOAc, 0% over 1 CV, 0% to 60% over 10 CVs, 60% over 3 CVs) to give allyl (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate (487 mg, 84 %). LC-MS (ES, m / z): [M + H]+ = 292.

[0774] Step 3: To a solution of allyl (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate (300 mg, 1.030 mmol, 1.0 equiv) in DCM (10 mL) at room temperature was added 4N HCI in dioxane (2.6 mL, 5.15 mmol, 5.0 equiv.) and the reaction mixture was stirred at room temperature. After 16 h, the reaction mixture was concentrated. The crude residue was triturated with ether (50 mL), and then sonicated during which a white precipitate formed. The precipitate was filtered, collected and then air-dried to give allyl (S)-2-amino-2-phenylacetate hydrochloride as a white solid (164 mg, 70 %).1H NMR (400 MHz, MeOD) 51H NMR (400 MHz, MeOD) 5 7.50 (s, 5H), 6.19 - 5.66 (m, 1 H), 5.37 - 5.02 (m, 3H), 4.78 - 4.56 (m, 2H).

[0775] Intermediate 52 (lnt-52): (S)-2-amino-N,N-dimethyl-2-phenylacetamide hydrochloride

[0776] Step 1 : To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (500 mg, 1.990 mmol, 1.0 equiv.) in DCM (20 mL) at 0 °C in a sealed tube, was added CDI (484.0 mg, 2.985 mmol, 1 .5 equiv.), and the reaction mixture was stirred at 0°C for 30 minutes. To the cold solution was added dimethylamine (4.98 mL, 2 M in MeOH, 9.95 mmol, 5.0 equiv) and the reaction mixture was sealed and then stirred at 80 °C. After 16 h, the reaction mixture was cooled to room temperature and then concentrated. The crude residue was dissolved in DCM and washed with 1 N HCI, followed by saturated NaHCO3solution. The combined organic solution was then dried (Na2SC>4), filtered, concentrated and chromatographed (40 g cartridge cycHex / ethyl acetate, 0% over 1 CV, 0% to 60% over 10 CVs, 60% over 3 CVs) to give tert-butyl (S)-(2-(dimethylamino)-2- oxo-1 -phenylethyl)carbamate (400 mg, 70% yield).1H NMR (400 MHz, CDCI3) 5 7.44 - 7.25 (m, 5H), 6.06 (d, J = 8.0 Hz, 1 H), 5.56 (d, J = 8.0 Hz, 1 H), 2.97 (s, 3H), 2.89 (s, 3H), 1.40 (s, 9H).

[0777] Step 2: To a solution of tert-butyl (S)-(2-(dimethylamino)-2-oxo-1-phenylethyl)carbamate (400 mg, 1.4 mmol, 1.0 equiv.) in DCM (14 mL) at room temperature was added 4N HCI in dioxane (1.8 mL, 7.2 mmol, 5 equiv.). After 72 h, the reaction mixture was concentrated. The crude residue was triturated with ether (50 mL), and then sonicated during which a white precipitate formed. The precipitate was filtered, collected and then air-dried to give (S)-2-amino-N,N-dimethyl-2- PAG-P3656PCT Application as filed FINAL phenylacetamide hydrochloride (148 mg, 48%) as a white solid.1H NMR (400 MHz, DMSO) 5 8.65 (s, 3H), 7.54 - 7.42 (m, 5H), 5.49 (s, 1 H), 2.88 (s, 3H), 2.82 (s, 3H).

[0778] Intermediate 53 (lnt-53): Allyl (S)-(2-amino-2-phenylethyl)(ethyl)carbamate hydrochloride

[0779] Step 1 : To a stirred solution of tert-butyl (S)-(2-amino-1-phenylethyl)carbamate (1.500 g, 6.35 mmol, 1 equiv.) in methanol (32 mL) at room temperature were added benzaldehyde (1.29 mL, 1.35 g, 12.69 mmol, 2.0 equiv.), DIPEA (3.30 mL, 2.46 g, 19.0 mmol, 3.0 equiv.), and 3 g of 3 molecular sieves. The resulting suspension was stirred at room temperature for 1 hour when TLC showed complete consumption of the amine. The reaction mixture was then cooled to 0°C (ice bath) when sodium borohydride was added in portions (720 mg, 19.0 mmol, 3.0 equiv.). After warming to room temperature and then stirring for 2 h the reaction mixture was concentrated. The crude residue was suspended in water and extracted with ethyl acetate (3 x 15 mL). The combined organic solution was then dried (Na2SO4), filtered, and concentrated. The crude product of tert-butyl (S)-(2-(benzylamino)-1-phenylethyl)carbamate (700 mg) was used in next step without further purification. LCMS (ESI, m / z): [M + H]+ = 327.9.

[0780] Step 2: To a stirred solution of tert-butyl (S)-(2-(benzylamino)-1-phenylethyl)carbamate (0.415 g, 1.27 mmol, 1.0 equiv.) in dry DCM (12.7 mL) was added acetaldehyde (355 pL, 280 mg, 6.36 mmol, 5.0 equiv.). The reaction mixture was cooled to 0°C (ice bath) when sodium triacetoxyborohydride (2.16 g, 10.2 mmol, 8.0 equiv.) was added in portions and the reaction mixture was allowed to warm to room temperature. After stirring for 3 h, the reaction mixture was diluted with water, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic solution was then dried (Na2SO4), filtered, and concentrated. The crude product of tert-butyl (S)-(2-(benzyl(ethyl)amino)-1- phenylethyl)carbamate (390 mg) was used in the next step without further purification. LCMS (ESI, m / z): [M + H]+ = 355.2.

[0781] Step 3: To a stirred solution of tert-butyl (S)-(2-(benzyl(ethyl)amino)-1-phenylethyl)carbamate (390 mg, 1.10 mmol, 1 equiv.) in MeOH (25 mL) was added dihydroxypalladium (77.2 mg, 20% w / w, 0.110 mmol, 1 equiv.), and the suspension was placed under a positive pressure of hydrogen (1 atm). After stirring for 16 h, the reaction mixture was filtered through a pad of celite, and the PAG-P3656PCT Application as filed FINAL celite pad was washed with methanol. The collected filtrate was concentrated under reduced pressure to give the crude product of tert-butyl (S)-(2-(ethylamino)-1-phenylethyl)carbamate which was used in the next step without further purification or characterization.

[0782] Step 4: To a stirred solution of tert-butyl (S)-(2-(ethylamino)-1-phenylethyl)carbamate (0.20 g, 0.757 mmol, 1 equiv.) in DCM (7.6 mL) at 0 °C was added DIPEA (0.66 mL, 3.78 mmol, 5.0 equiv.), followed by allyl chloroformate (0.161 mL, 1.51 mmol, 2.0 equiv.) and the mixture was allowed to warm to room temperature. After 16 hours, the reaction was diluted with a saturated solution of NH4CI (10 mL) and extracted with DCM (3 * 10 mL). The combined organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, cyclohexane / ethyl acetate, 0% over 1CV then 0% to 40% over 18 CVs). The fractions containing product were pooled and then concentrated under reduced pressure to give allyl (S)-(2-((tert- butoxycarbonyl)amino)-2-phenylethyl)(ethyl)carbamate (180 mg, 68% yield).1H NMR (400 MHz, DMSO) 5 7.50 - 7.18 (m, 6H), 5.92 (ddt, J = 15.8, 10.1 , 5.2 Hz, 1 H), 5.35 - 5.11 (m, 2H), 4.79 (s, 1 H), 4.57 - 4.40 (m, 2H), 3.50 - 3.33 (m, 1 H), 3.28 - 3.07 (m, 2H), 1 .35 (s, 9H), 1 .29 - 1 .20 (m, 1 H), 0.99 (q, J = 6.9 Hz, 3H).

[0783] Step 5: To a stirred solution of allyl (S)-(2-((tert-butoxycarbonyl)amino)-2- phenylethyl)(ethyl)carbamate (180 mg, 0.517 mmol, 1 equiv.) in DCM (8.20 mL) at 0 °C was added HCI in dioxane (4M, 0.65 mL, 2.58 mmol, 5.0 equiv.) and the resulting reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was evaporated to dryness under reduced pressure to give a white solid. The obtained solid was suspended in ether (25 ml) and sonicated for 10 min. The supernatant was filtered off. The obtained white solid was dried under vacuum to give the title product (Intermediate 53) (140 mg, 95%).1H NMR (400 MHz, DMSO) 5 8.80 - 8.40 (m, 3H), 7.53 (d, J = 7.8 Hz, 2H), 7.48 - 7.35 (m, 3H), 5.99 - 5.77 (m, 1 H), 5.25 (d, J = 17.1 Hz, 1 H), 5.19 (dq, J = 10.5, 1.6 Hz, 1 H), 4.61 - 4.26 (m, 3H), 3.79 - 3.59 (m, 1 H), 3.54 - 3.43 (m, 1 H), 3.26 - 3.01 (m, 2H), 0.95 (t, J = 7.1 Hz, 3H).

[0784] Intermediate 54 (lnt-54): (S)-N-(2-amino-2-phenylethyl)benzamide

[0785] Stepl : To a stirred solution of tert-butyl (S)-(2-amino-1-phenylethyl)carbamate (0.150 g, 0.635 mmol, 1 equiv.) in DCM (3.2 mL) at 0 °C was added DIPEA (0.44 mL, 2.54 mmol, 4.0 equiv.), followed by benzoyl chloride (0.11 mL, 0.95 mmol, 1.5 equiv.) and the reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction was diluted with EtOAc (30 mL) and 1 M HCI (10 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, cyclohexane / ethyl acetate 0% over 1CV then 0% to 40% over 18 CVs). The fractions PAG-P3656PCT Application as filed FINAL containing product were pooled and then concentrated to give tert-butyl (S)-(2-benzamido-1- phenylethyl)carbamate (66 mg, 31% yield).1H NMR (400 MHz, DMSO) 5 8.50 - 8.41 (m, 1 H), 7.97 - 7.90 (m, 1 H), 7.74 (d, J = 7.0 Hz, 2H), 7.54 - 7.37 (m, 3H), 7.36 - 7.27 (m, 4H), 7.27 - 7.18 (m, 1 H), 4.83 (q, J= 6.8 Hz, 1 H), 3.54 - 3.42 (m, 2H), 1.33 (s, 9H).

[0786] Step 2: To a stirred solution of tert-butyl (S)-(2-benzamido-1-phenylethyl)carbamate (66 mg, 0.19 mmol) in DCM (1.0 mL) at 0 °C was added HCI in dioxane (4M, 0.20 mL, 0.78 mmol, 4.0 equiv.) and the resulting reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was evaporated to dryness to give a white solid. The obtained solid was suspended in ether (25 ml) and sonicated for 10 minutes. The supernatant was removed and dried under vacuum to give the title compound (Intermediate 54) as a white solid (45 mg, 84%).1H NMR (400 MHz, DMSO) 5 8.69 (t, J = 5.7 Hz, 1 H), 8.52 (brs, 3H), 7.92 - 7.71 (m, 2H), 7.59 - 7.35 (m, 8H), 4.51 (brs, 1 H), 3.87 - 3.73 (m, 1 H), 3.69 - 3.61 (m, 1 H).

[0787] Intermediate 55 (lnt-55): Allyl (S)-(2-((tert-butoxycarbonyl)amino)-2-

[0788] Step 1 : To a stirred solution of tert-butyl (S)-(2-amino-1-phenylethyl)carbamate (0.250 g, 1.06 mmol, 1 .0 equiv.) in DCM (6.0 mL) at 0 °C was added acetone (117 pL, 92 mg, 1 .59 mmol, 1.50 equiv.). The reaction mixture was then cooled to 0°C (ice bath) when sodium triacetoxyborohydride (0.380 g, 1.80 mmol, 1.7 equiv.) was added in portions and the resulting suspension was allowed to warm to room temperature. After 3h, TLC showed complete consumption of the amine. The reaction mixture was diluted with water, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic solution was then dried (Na2SC>4), filtered, and concentrated. The crude product, tert-butyl (S)-(2- (isopropylamino)-1-phenylethyl)carbamate (390 mg) was used in the next step without further purification. LCMS (ESI, m / z): [M + H]+ = 279.2.

[0789] Step 2: To a stirred solution of tert-butyl (S)-(2-(isopropylamino)-1-phenylethyl)carbamate (0.295 g, 1.06 mmol, 1 equiv.) in DCM (10.6 mL) at 0 °C was added DIPEA (0.92 mL, 5.30 mmol, 5.0 equiv.), followed by allyl chloroformate (0.225 mL, 2.12 mmol, 2.0 equiv.) and the mixture was allowed to warm to temperature. After 16 hours, the reaction was diluted with a saturated solution of NH4CI (10 mL) and extracted with DCM (3 x 10 mL). The combined organic solution was then dried (Na2SC>4), filtered, concentrated, and chromatographed (20 g cartridge, cyclohexane / ethyl acetate 0% over 1CV then 0% to 40% over 18 CVs). The fractions containing product were pooled PAG-P3656PCT Application as filed FINAL and then concentrated to give allyl (S)-(2-((tert-butoxycarbonyl)amino)-2- phenylethyl)(isopropyl)carbamate (350 mg, 91% yield over two steps).1H NMR (400 MHz, DMSO) 5 7.37 - 7.28 (m, 5H), 7.24 (h, J = 3.8 Hz, 1 H), 5.95 (ddt, J = 17.4, 10.5, 5.3 Hz, 1 H), 5.30 (d, J = 14.9 Hz, 1 H), 5.20 (d, J = 10.6 Hz, 1 H), 4.97 - 4.72 (m, 1 H), 4.62 - 4.43 (m, 2H), 3.85 (s, 1 H), 3.30 - 3.15 (m, 1 H), 1.35 (s, 9H), 1.30 - 1.21 (m, 1 H), 1.10 (d, J = 6.8 Hz, 3H), 1.04 - 0.91

[0790] (m, 3H).

[0791] Step 3: To a stirred solution of allyl (S)-(2-((tert-butoxycarbonyl)amino)-2- phenylethyl)(isopropyl)carbamate (350 mg, 0.966 mmol) in DCM (15.0 mL) at 0 °C was added HCI in dioxane (4M, 1.20 mL, 4.83 mmol, 5.0 equiv.) and the resulting reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was concentrated to dryness to give a white solid. The obtained solid was suspended in ether (25 ml) and sonicated for 10 min. The supernatant was removed and the solid collected and dried under vacuum to give the title product (Intermediate 55) (277 mg, 96%).1H NMR (400 MHz, DMSO) 5 8.67 (brs, 3H), 7.57 - 7.46 (m, 2H), 7.46 - 7.34 (m, 3H), 5.89 (brs, 1 H), 5.26 (dd, J = 17.3, 1.8 Hz, 1 H), 5.19 (dd, J = 10.5, 1.5 Hz, 1 H), 4.60 - 4.39 (m, 3H), 3.97 - 3.80 (m, 1 H), 3.67 (dd, J = 14.3, 6.6 Hz, 1 H), 1 .33 - 0.93 (m, 3H), 0.85 (d, J = 6.0 Hz, 3H).

[0792] Intermediate 56 (lnt-56): (S)-N-(2-amino-2-phenylethyl)propionamide hydrochloride

[0793] Step 1 : To a stirred solution of tert-butyl (S)-(2-amino-1-phenylethyl)carbamate (0.150 g, 0.635 mmol, 1 equiv.) in DCM (3.2 mL) at 0 °C was added DIPEA (0.44 mL, 2.54 mmol, 4.0 equiv.), followed by propionyl chloride (0.09 mL, 0.095 mmol, 1.5 equiv.) and the mixture was allowed to warm to room temperature. After 2 hours, the reaction was diluted with EtOAc (30 mL) and 1 M HCI (10 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, cyclohexane / ethyl acetate 0% over 1CV then 0% to 40% over 18 CVs). The fractions containing product were pooled and concentrated to give tert-butyl (S)-(1-phenyl-2- propionamidoethyl)carbamate (128 mg, 69% yield).1H NMR (400 MHz, DMSO) 5 7.78 (t, J = 5.8 Hz, 1 H), 7.39 - 7.09 (m, 6H), 4.63 (q, J = 7.8 Hz, 1 H), 3.25 (p, J = 7.1 Hz, 2H), 2.01 (q, J = 7.6 Hz, 2H), 1.36 (s, 9H), 0.94 (t, J = 7.6 Hz, 3H).

[0794] Step 2: To a stirred solution of tert-butyl (S)-(1-phenyl-2-propionamidoethyl)carbamate (128 mg, 0.438 mmol) in DCM (2.2 mL) at 0 °C was added HCI in dioxane (4M, 0.44 mL, 1.75 mmol, 4.0 equiv.) and the resulting reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was concentrated to dryness and the resulting white solid was suspended in PAG-P3656PCT Application as filed FINAL ether (25 ml) and sonicated for 10 minutes. The supernatant was removed, and the obtained white solid was dried under vacuum to give the desired product (Intermediate 56) (80 mg, 80%).1H NMR (400 MHz, DMSO) 5 8.64 (brs, 3H), 8.09 (t, J = 5.8 Hz, 1 H), 7.51 - 7.34 (m, 5H), 4.33 (t, J = 6.8 Hz, 1 H), 3.65 - 3.51 (m, 1 H), 3.48 - 3.41 (m, 1 H), 2.06 (q, J = 7.6 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H).

[0795] Intermediate 57 (lnt-57) Allyl (S)-(2-((tert-butoxycarbonyl)amino)-2- phenylethyl)(isopropyl)carbamate To a stirred solution of tert-butyl (S)-(2-(benzylamino)-1-phenylethyl)carbamate (0.415 g, 1.27 mmol, 1 equiv.) in DCM (20.0 mL) at 0 °C was added DIPEA (1.10 mL, 6.35 mmol, 5.0 equiv.), followed by allyl chloroformate (0.270 mL, 2.54 mmol, 2.0 equiv.) and the mixture was allowed to warm to room temperature. After 16 hours, the reaction was diluted with a saturated solution of NH4CI (10 mL) and extracted with DCM (3 * 10 mL). The combined organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, cyclohexane / ethyl acetate 0% over 1CV then 0% to 40% over 18 CVs). The fractions containing product were pooled and concentrated to give allyl (S)-benzyl(2-((tert-butoxycarbonyl)amino)-2- phenylethyl)carbamate (Intermediate 57) (493 mg, 95% yield).1H NMR (400 MHz, CDCI3) 57.43 - 7.10 (m, 11 H), 5.93 (ddt, J = 16.1 , 10.8, 5.3 Hz, 1 H), 5.84 - 5.62 (m, 1 H), 5.45 - 5.16 (m, 2H), 4.89 (s, 1 H), 4.78 - 4.48 (m, 3H), 3.90 - 3.52 (m, 1 H), 3.30 - 3.03 (m, 1 H), 1 .42 (s, 9H).

[0796] Intermediate 58 (lnt-58): allyl (S)-(2-amino-2-phenylethyl)(benzyl)carbamate, HCI

[0797] Step 1 : To a stirred solution of tert-butyl (S)-(2-(benzylamino)-1-phenylethyl)carbamate (0.415 g, 1.27 mmol, 1 equiv.) in DCM (20.0 mL) at 0 °C was added DIPEA (1.10 mL, 6.35 mmol, 5.0 equiv.), followed by allyl chloroformate (0.270 mL, 2.54 mmol, 2.0 equiv.) and the mixture was allowed to warm to room temperature. After 16 hours, the reaction was diluted with a saturated solution of NH4CI (10 mL) and extracted with DCM (3 * 10 mL). The combined organic solution was then dried (Na2SC>4), filtered, concentrated, and chromatographed (20 g cartridge, cyclohexane / ethyl acetate 0% over 1CV then 0% to 40% over 18 CVs). The fractions containing product were pooled and concentrated to give allyl (S)-benzyl(2-((tert-butoxycarbonyl)amino)-2- phenylethyl)carbamate (Intermediate 58) (493 mg, 95% yield).1H NMR (400 MHz, CDCI3) 57.43 PAG-P3656PCT Application as filed FINAL

[0798] - 7.10 (m, 11 H), 5.93 (ddt, J = 16.1 , 10.8, 5.3 Hz, 1 H), 5.84 - 5.62 (m, 1 H), 5.45 - 5.16 (m, 2H), 4.89 (s, 1 H), 4.78 - 4.48 (m, 3H), 3.90 - 3.52 (m, 1 H), 3.30 - 3.03 (m, 1 H), 1 .42 (s, 9H).

[0799] Step 2: To a stirred solution of allyl (S)-benzyl(2-((tert-butoxycarbonyl)amino)-2- phenylethyl)carbamate (490 mg, 1.19 mmol) in DCM (19.0 mL) at 0 °C was added HCI in dioxane (4M, 1.50 mL, 6.0 mmol, 5.0 equiv.) and the resulting reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was evaporated to dryness to give a white solid. The obtained solid was suspended in ether (25 ml) and sonicated for 10 minutes. The supernatant was removed, and the obtained white solid was dried under vacuum to give the title product (Intermediate 58) (350 mg, 84% yield).1H NMR (400 MHz, DMSO) 5 8.96 - 8.59 (m, 3H), 7.72 - 7.13 (m, 10H), 5.88 (ddt, J = 17.3, 10.5, 5.3 Hz, 1 H), 5.35 - 5.08 (m, 2H), 4.63 - 4.35 (m, 4H), 3.77 - 3.38 (m, 3H).

[0800] Intermediate 59 (lnt-59): (S)-N-(2-amino-2-phenylethyl)-2-phenylacetamide hydrochloride Step 1 : To a stirred solution of tert-butyl (S)-(2-amino-1-phenylethyl)carbamate (0.150 g, 0.635 mmol, 1 equiv.) in DCM (3.2 mL) at 0 °C was added DIPEA (0.44 mL, 2.54 mmol, 4.0 equiv.), followed by phenylacetyl chloride (0.126 mL, 0.095 mmol, 1 .5 equiv.) and the mixture was allowed to warm to room temperature. After 2 hours, the reaction mixture was diluted with EtOAc (30 mL) and 1 M HCI (10 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, cyclohexane / ethyl acetate 0% over 1CV then 0% to 40% over 18 CVs). The fractions containing product were pooled and concentrated to give tert-butyl (S)-(1-phenyl-2-(2- phenylacetamido)ethyl)carbamate (210 mg, 93% yield).1H NMR (400 MHz, DMSO) 5 8.06 (t, J = 5.8 Hz, 1 H), 7.40 - 7.09 (m, 11 H), 4.62 (q, J = 7.8 Hz, 1 H), 3.37 (s, 2H), 3.27 (p, J = 7.0 Hz, 2H), 1.36 (s, 9H).

[0801] Step 2: To a stirred solution of tert-butyl (S)-(1-phenyl-2-(2-phenylacetamido)ethyl)carbamate (210 mg, 0.59 mmol) in DCM (3.0 mL) at 0 °C was added HCI in dioxane (4M, 0.6 mL, 2.4 mmol, 4.0 equiv.) and the resulting reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was evaporated to dryness to give a white solid. The obtained solid was suspended in ether (25 ml) and sonicated for 10 minutes. The supernatant was removed and then dried under vacuum to give the title product (Intermediate 59) as a white solid (153 mg, 90% yield).1H NMR (400 MHz, DMSO) 5 8.67 (s, 3H), 8.40 (t, J = 5.8 Hz, 1 H), 7.48 - 7.32 (m, 5H), PAG-P3656PCT Application as filed FINAL

[0802] 7.32 - 7.06 (m, 5H), 4.34 (t, J = 6.8 Hz, 1 H), 3.66 - 3.56 (m, 1 H), 3.52 - 3.42 (m, 1 H), 3.39 (s, 2H).

[0803] Examples Example 1 (Ex-1): 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-

[0804] (piperidin-4-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one

[0805] Step 1 : A solution of 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3- ((trimethylsilyl)oxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one (Intermediate 2) (580 mg, 1.26 mmol, 1 equiv.) and allyl 4-oxopiperidine-1 -carboxylate (463 mg, 2.53 mmol, 2 equiv.) was dissolved in DCM (12.5 mL), when sodium sulfate was added (300 mg). The mixture was stirred for 2 minutes, sonicated, and then filtered directly into a microwave vial with a syringe and HPLC filter. The solution was cooled to -78°C when a solution of trimethylsilyl trifluoromethanesulfonate (0.11 mL, 0.63 mmol, 0.5 equiv.) in DCM (1.5 mL) was added slowly, followed by neat triethylsilane (0.23 mL, 1.45 mmol, 1.15 equiv.). The reaction mixture was allowed to slowly warm to -20°C over a period of 1 h, at which point TLC showed complete conversion (1 :1 Hex / EtOAc). The reaction mixture was then cooled to -78°C and quenched with a pre-cooled (-78°C) solution of MeOH / EtsN (1 :1 , 1 mL). The reaction mixture was then allowed to warm to room temperature, concentrated and chromatographed (40 g cartridge, Hex / EtOAc, 12% over 1CV, 12% to 86% over 8.3 CVs) to give allyl 4- (((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidine-1-carboxylate as a white solid (320 mg, 46% yield). LC-MS (ES, m / Z): [M +MeCN + H]+ = 595.4.

[0806] Step 2: To a solution of allyl 4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidine-1- carboxylate (336 mg, 0.61 mmol, 1 equiv.) and 1 ,3-dimethylbarbituric acid (114 mg, 0.73 mmol, 1.2 equiv.) in DCM (4 mL) and MeOH (0.4 mL) was added tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol, 0.10 equiv.) After stirring for 1 h at room temperature, the reaction mixture was concentrated and then chromatographed (20 g cartridge, EtOAc / MeOH, 0% over 3 CVs, 0% to 100% over 5 CVs, then 100% MeOH); once the UV active byproducts eluted, the column was flushed with 2.5N NH3 in MeOH until the product PAG-P3656PCT Application as filed FINAL eluted (ca. 5 CVs). The fractions containing the product were concentrated in vacuo to give the desired product (Example 1) as a solid (238 mg, 84% yield).1H NMR (400 MHz, CDCI3) 5 7.93 (dd, J = 9.7, 2.5 Hz, 1H), 7.52 (s, 1 H), 6.29 (d, J = 9.7 Hz, 1 H), 4.14 (s, 1 H), 3.72 (s, 1H), 2.97 - 2.82 (m, 2H), 2.46 - 2.31 (m, 2H), 2.20 - 0.93 (m, 28H), 0.85 (s, 3H), 0.59 (s, 3H).

[0807] Example 2 (Ex-2): 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-

[0808] (piperidin-4-ylmethoxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2- one

[0809] Step 1: A solution of 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3- ((trimethylsilyl)oxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one (Intermediate 2) (300 mg, 0.65 mmol, 1 equiv.) and allyl 4-formylpiperidine-1 -carboxylate (258 mg, 1.31 mmol, 2 equiv.) was dissolved in DCM (10 mL), when sodium sulfate was added (300 mg). The mixture was stirred for 2 minutes, sonicated, and then filtered directly into a microwave vial with a syringe and HPLC filter. The solution was cooled to -78 °C when a solution of trimethylsilyl trifluoromethanesulfonate (0.06 mL, 0.33 mmol, 0.5 equiv.) in DCM (1.5 mL) was added slowly, followed by neat triethylsilane (0.12 mL, 0.75 mmol, 1.15 equiv.). The reaction mixture was allowed to slowly warm to -20°C over 1 h, at which point TLC showed complete conversion (1 :1 Hex / EtOAc). The reaction mixture was then cooled to -78°C and quenched with a pre-cooled (-78°C) solution of MeOH / EtsN (1 :1, 1 mL). The reaction mixture was then allowed to warm to room temperature, concentrated and chromatographed (40 g cartridge, Hex / EtOAc, 12% over 1CV, 12% to 86% over 8.3 CVs) to give allyl 4-((((3S,5R,8R,9S,10S,13R,14S,17R)- 14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H- cyclopenta[a]phenanthren-3-yl)oxy)methyl)piperidine-1 -carboxylate as a white solid (309 mg, 83% yield). The product was used in the next step without further characterization or purification. Step 2: Allyl 4-((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)methyl)piperidine-1- carboxylate (309 mg, 0.544 mmol, 1 equiv.) and 1,3-dimethylbarbituric acid (102 mg, 0.65 mmol, 1.2 equiv.) in DCM (4 mL) and MeOH (0.4 mL) was added tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.054 mmol, 0.1 equiv.) After stirring for 1 h at room temperature, the reaction mixture was concentrated and then chromatographed (20 g PAG-P3656PCT Application as filed FINAL cartridge, EtOAc / MeOH, 0% over 3 CVs, 0% to 100% over 5 CVs, then 100% over 3 CVs); once the UV active byproducts eluted, the column was flushed with 3.5N NH3 in MeOH until the product eluted (ca. 5 CVs). The fractions containing the product were concentrated in vacuo to give the desired product (Example 2) as a solid (208 mg, 79% yield).1H NMR (400 MHz, CDCh) 6 7.93 (dd, J = 9.7, 2.6 Hz, 1 H), 7.52 (dd, J = 2.5, 1.1 Hz, 1 H), 6.32 - 6.25 (m, 1 H), 4.14 (s, 1 H), 3.53 -

[0810] 3.48 (m, 1 H), 3.19 - 3.09 (m, 2H), 2.91 (dd, J = 12.1 , 3.9 Hz, 2H), 2.48 - 2.37 (m, 3H), 2.13 - 1 .95 (m, 2H), 1.83 - 0.92 (m, 25H), 0.85 (s, 3H), 0.59 (s, 3H).

[0811] Example 3 (Ex-3): 2-(4-fluorophenyl)-N-(1-(2-(4-(((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)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)acetamide

[0812] Prepared according to General Procedure (A-1): To a mixture of 5-

[0813] ((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-3-(piperidin-4- yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one (Example 7) (20 mg, 0.043 mmol, 1 equiv.), DIPEA (0.037 mL, 0.21 mmol, 5 equiv.) and KI (1.4 mg, 0.085 mmol, 0.2 equiv.), in DMF (1.5 mL) was added N-(1-(2-chloroacetyl)piperidin-4-yl)-2-(4- fluorophenyl)acetamide (Intermediate 8) (15 mg, 0.048 mmol, 1.1 equiv.). The reaction mixture was heated to 50 °C. After 20 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with sat. NaHCO3 ( 1 x 10 mL) and brine (3 x 10 mL). The organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, EtOAc / MeOH, 0% over 3 CVs, 0% to 100% over 10 CVs, 100% over4 CVs). Fractions containing product were concentrated, redissolved in H2O / MeOH (10:1) and then lyophilized to give the desired product (Example 3) as a white solid (18 mg, 57 % yield). LC-MS (ES, m / Z): [M - H]- = 744.6.1H NMR (400 MHz, DMSO) 5 8.07 (d, J = 7.6 Hz, 1 H), 7.93 (dd, J = 9.7, 2.6 Hz,

[0814] 1 H), 7.52 (d, J = 2.4 Hz, 1 H), 7.32 - 7.22 (m, 2H), 7.16 - 7.06 (m, 2H), 6.29 (d, J = 9.7 Hz, 1 H), 4.22 - 4.12 (m, 2H), 3.98 (d, J = 13.3 Hz, 1 H), 3.71 (s, 2H), 3.38 (s, 2H), 3.27 (d, J = 24.8 Hz, 4H), 3.14 - 2.99 (m, 1 H), 2.90 (d, J = 13.1 Hz, 1 H), 2.76 - 2.64 (m, 3H), 2.50 - 2.42 (m, 2H), 2.23 - 0.99 (m, 28H), 0.85 (s, 3H), 0.59 (s, 3H). PAG-P3656PCT Application as filed FINAL

[0815] Example 4 (Ex-4): N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)- 14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H- Step 1 : To a mixture of 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3- (piperidin-4-yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one (Example 7) (70 mg, 0.15 mmol, 1 equiv.), DIPEA (0.13 mL, 0.75 mmol, 5 equiv.). and KI (5.0 mg, 0.03 mmol, 0.2 equiv.), in DMF (2.3 mL) was added (S)-N-(2-((tert-butyldimethylsilyl)oxy)-1- phenylethyl)-2-chloroacetamide (Intermediate 9) (64 mg, 0.19 mmol, 1.3 equiv.). The reaction mixture was heated to 50 °C. After 20 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with sat. NaHCO3 ( 1 x 10 mL) and brine (3 x 10 mL). The organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (20 g cartridge, Hex / EtOAc, 0% over 3 CVs, 0% to 100% over 10 CVs, 100% over 4 CVs). Fractions containing product were concentrated to give N-((S)-2-((tert- butyldimethylsilyl)oxy)-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0816] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide as an oil (94 mg, 83%). The product was used in the next step without further purification or characterization.

[0817] Step 2: To a solution of N-((S)-2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-2-(4- (((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamide (94 mg, 0.12 mmol, 1 equiv.) in THF (1.5 mL) and pyridine (0.80 mL) was added HF. pyridine (0.80 mL, 6.2 mmol, 50 equiv) and the reaction mixture was allowed to stir at room temperature. After 30 min, the reaction mixture was quenched by carefully adding sat. NaHCO3 (30 mL). The reaction mixture was then extracted with DCM (3 x 20 mL) and the combined organic solution was washed with sat. NaHCO3 (4 x 20 mL). The organic solution was then dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography (20 g cartridge, MeOH / EtOAc 0% over 1 CV, 0-25% over 8 CVs, 25% over 1 CV, 25-50% over 8 CVs, 50% over 1 CV). The fractions containing product were concentrated under reduced pressure and the residue was purified further by reverse phase (C18 column, 20-35 micron, 20g cartridge, 0.1% aq.

[0818] HCO2H / MeCN, 5% over 5 CVs, 5% to 95% over 20 CVs, 95% over 3 CVs). Fractions containing PAG-P3656PCT Application as filed FINAL product were lyophilized to give the title product (Example 4) (19 mg, 23% yield). LC-MS (ES, m / Z): [M - H]- = 645.1H NMR (400 MHz, DMSO) 5 8.03 (d, J = 8.3 Hz, 1 H), 7.93 (dd, J = 9.8, 2.6 Hz, 1H), 7.52 (dd, J = 2.5, 1.1 Hz, 1H), 7.35 - 7.18 (m, 5H), 6.32 - 6.26 (m, 1H), 4.93 (t, J = 5.4 Hz, 1H), 4.83 (dt, J = 8.2, 5.8 Hz, 1 H), 4.14 (s, 1H), 3.72 (s, 1H), 3.63 - 3.56 (m, 2H), 3.00 - 2.85 (m, 2H), 2.75 - 2.62 (m, 2H), 2.49 (s, 1H), 2.26 - 0.93 (m, 28H), 0.86 (s, 3H), 0.60 (s, 3H).

[0819] Example 5 (Ex-5): N-(2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-

[0820] 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-

[0821] This Example was prepared from 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-3-(piperidin-4-yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2- one (Example 1) (20 mg, 0.043 mmol, 1 equiv.) and N-(2-(2-chloroacetyl)-2-azaspiro[3.3]heptan- 6-yl)benzamide (Intermediate 10) (16 mg, 0.055 mmol, 1.3 equiv.) according to General Procedure (A-1) using DIPEA (0.037 mL, 0.21 mmol, 5 equiv.). and KI (1.4 mg, 0.085 mmol, 0.2 equiv.), in DMF (1.5 mL) to give the desired product (Example 5) as a white solid (12 mg, 39 % yield). LC-MS (ES, m / Z): [M - H]- = 724.4.1H NMR (400 MHz, DMSO) 5 8.59 (t, J = 6.4 Hz, 1H), 7.94 (dd, J = 9.8, 2.5 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.57 - 7.42 (m, 4H), 6.30 (d, J = 9.7 Hz, 1 H), 4.43 - 4.18 (m, 2H), 4.15 (s, 2H), 3.93 (s, 1 H), 3.82 (s, 1 H), 3.72 (s, 1 H), 2.94 (s, 2H), 2.68 (s, 2H), 2.50 - 2.42 (m, 2H), 2.42 - 0.92 (m, 31H), 0.86 (s, 3H), 0.60 (s, 3H).

[0822] PAG-P3656PCT Application as filed FINAL

[0823] Example 6 (Ex-6): N-(1-(2-(4-((((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-

[0824] This Example was prepared from 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-3-(piperidin-4-ylmethoxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H- pyran-2-one (Example 2) (13 mg, 0.027 mmol, 1 equiv.) and -(1-(2-chloroacetyl)piperidin-4- yl)benzamide (Intermediate 12) (9 mg, 0.032 mmol, 1.2 equiv.) according to General Procedure (A-1) using DIPEA (0.02 mL, 0.13 mmol, 5 equiv.). and KI (1 mg, 0.005 mmol, 0.2 equiv.), in DMF (0.5 mL) to give the desired product (Example 6) as a white solid (5 mg, 30 % yield). LC-MS (ES, m / Z): [M - H]- = 726.1H NMR (400 MHz, DMSO-d6) 5 8.28 (d, J = 7.8 Hz, 1 H), 7.93 (dd, J = 9.8, 2.6 Hz, 1 H), 7.83 (dt, J = 7.0, 1.5 Hz, 2H), 7.56 - 7.40 (m, 4H), 6.29 (d, J = 9.7 Hz, 1 H), 4.38 - 4.28 (m, 1 H), 4.25 - 3.88 (m, 3H), 3.51 (s, 1 H), 3.26 - 2.94 (m, 5H), 2.81 (d, J = 10.9 Hz, 2H), 2.74 - 2.59 (m, 1 H), 2.48 - 2.41 (m, 1 H), 2.19 - 0.94 (m, 32H), 0.83 (s, 3H), 0.59 (s, 3H).

[0825] Example 7 (Ex-7): 4-fluoro-N-(1-(2-(4-(((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-

[0826] Prepared according to General Procedure (A-2): To a mixture of 5- ((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-3-(piperidin-4- yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one (Example 7)(50 mg, 0.11 mmol, 1 equiv.) , N-(1-(2-chloroacetyl)piperidin-4-yl)-4-fluorobenzamide (Intermediate 13) (40 mg , 0.13 mmol, 1.25 equiv.) and sodium iodide (3.2 mg, 21 pmol, 0.2 equiv.) in DMF (1.7 mL) was added DI PEA (0.092 mL, 0.53- mmol, 5 equiv.) and the reaction mixture was allowed to PAG-P3656PCT Application as filed FINAL stir at room temperature. After 20 h, water was added and the precipitated was filtered, collected, and then purified by column chromatography (20 g cartridge, EtOAc / MeOH, 0% to 40% over 12 CVs) to give the desired product (Example 7) (47 mg, 60% yield) as an off-white solid. LC-MS (ES, m / Z): [M + H]+ = 732.4.1H NMR (400 MHz, DMSO) 5 8.32 (d, J = 7.5 Hz, 1 H), 7.92 (q, J = 8.0 Hz, 3H), 7.52 (s, 1 H), 7.33 - 7.24 (m, 2H), 6.29 (d, J = 9.7 Hz, 1 H), 4.32 (d, J = 13.2 Hz, 1 H),

[0827] 4.18 - 3.96 (m, 3H), 3.71 (s, 1 H), 3.27 (d, J = 13.2 Hz, 2H), 3.06 (t, J = 12.6 Hz, 1 H), 2.91 (d, J = 13.1 Hz, 1 H), 2.67 (s, 4H), 2.50 (h, J = 1.8 Hz, 1 H), 2.23 - 0.95 (m, 30H), 0.85 (s, 3H), 0.59 (s, 3H).

[0828] Example 8 (Ex-8): N-(1-(2-(4-(((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)oxy)piperidin-

[0829] Prepared according to General Procedure B-1: To a solution of 2-(4- (((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetic acid,

[0830] (Intermediate 15) (40 mg, 0.076 mmol, 1 equiv.) in DMF (1.5 mL) was added N-(piperidin-4- yl)isonicotinamide dihydrochloride (Intermediate 16) (32 mg, 0.11 mmol, 1.5 equiv.), HATLI (43 mg, 0.11 mmol, 1.5 equiv.) and HOBt (12 mg, 0.076 mmol, 1.0 equiv.). The mixture was cooled to 0 °C when DI PEA was added in one portion (0.052 mL, 0.30 mmol, 4 equiv.) and the reaction mixture was allowed to stir overnight at room temperature. After 24 h, the reaction mixture was diluted with DCM (25 mL) and washed with sat. NaHCCh (2 x 20 mL), followed by brine (1 x 10 mL). The organic solution was then dried (Na2SO4), filtered, concentrated, and chromatographed (20g cartridge, EtOAc / MeOH, 0% over 1 CV, 0% to 25% over 8 CVs, 25% for 1 CV, 25-50% for 8 CVs, 50% for 1 CV). Fractions containing product were combined and concentrated under reduced pressure. The residue was purified further by reverse phase chromatography (C 18 column, 20-35 micron, 20 g, 0.1% aq. HCOOH / MeCN, 5% over 5 CVs, 5% to 95% over 20 CVs, 95% over 3 CVs). Fractions containing product were lyophilized to give the desired product (Example 8) as a solid. LC-MS (ES, m / Z): [M + H]+ = 715.5.1H NMR (400 MHz, DMSO) 5 8.74 - 8.68 (m, 2H), 8.60 (d, J = 7.6 Hz, 1 H), 7.93 (dd, J = 9.7, 2.6 Hz, 1 H), 7.77 - 7.71 (m, 2H), 7.55 PAG-P3656PCT Application as filed FINAL

[0831] - 7.49 (m, 1 H), 6.29 (d, J = 10.0 Hz, 1H), 4.32 (d, J = 13.0 Hz, 1 H), 4.14 (s, 1 H), 4.08 - 4.04 (m, 2H), 3.73 - 3.69 (m, 1H), 3.32 (s, 2H), 3.16 - 3.04 (m, 1H), 2.95 - 2.91 (m, 1H), 2.51 - 2.42 (m, 2H), 2.46 (s, 2H), 2.08 - 1.03 (m, 31 H), 0.85 (s, 3H), 0.59 (s, 3H). Example 9 (Ex-9): N-(1-(2-(4-(((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)oxy)piperidin-

[0832] This Example was prepare from 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-3-(piperidin-4-yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2- one (Example 1) (50 mg, 0.11 mmol, 1 equiv.) and N-(1-(2-chloroacetyl)piperidin-4- yl)picolinamide (Intermediate 17) (37 mg , 0.13 mmol, 1.25 equiv.) according to General Procedure (A-2) using sodium iodide (3.2 mg, 21 pmol, 0.2 equiv.) and DIPEA (0.092 mL, 0.53 mmol, 5 equiv.) in DMF (1.7 mL) to give the desired product (Example 9) (48 mg, 63% yield) as an off-white solid. LC-MS (ES, m / Z): [M + H]+ = 715.5.1H NMR (400 MHz, DMSO) 5 8.71 (d, J = 8.3 Hz, 1 H), 8.64 (d, J = 4.5 Hz, 1 H), 8.07 - 7.90 (m, 3H), 7.62 - 7.50 (m, 1 H), 7.52 (s, 1 H), 6.29 (d, J = 9.7 Hz, 1 H), 4.34 (d, J = 13.0 Hz, 1 H), 4.25 - 3.89 (m, 3H), 3.71 (s, 1 H), 3.30 - 3.23 (m, 2H), 3.06 (t, J = 12.5 Hz, 1H), 2.91 (d, J = 13.2 Hz, 1 H), 2.76 - 2.60 (m, 2H), 2.21 - 0.94 (m, 33H), 0.85 (s, 3H), 0.59 (s, 3H).

[0833] Example 10 (Ex-10): N-(1-(2-(4-(((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- This Example was prepared from 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-3-(piperidin-4-yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2- PAG-P3656PCT Application as filed FINAL one (Example 7) (50 mg, 0.11 mmol, 1 equiv.) and N-(1-(2-chloroacetyl)piperidin-4-yl)-3- methoxybenzamide (Intermediate 18) (41 mg, 0.13 mmol, 1.25 equiv.) according to General Procedure (A-1) using sodium iodide (3.2 mg, 21 pmol, 0.2 equiv.) and DIPEA (0.09 mL, 0.53 mmol, 5 equiv.) in DMF (1.7 mL) to give the desired product (Example 10) (62 mg, 78 %) as a pale white solid. LC-MS (ES, m / Z): [M + H]+ = 744.5.1H NMR (400 MHz, DMSO) 5 8.27 (d, J =

[0834] 7.8 Hz, 1H), 7.93 (dd, J = 9.7, 2.6 Hz, 1 H), 7.55 - 7.49 (m, 1H), 7.45 - 7.32 (m, 3H), 7.12 - 7.04 (m, 1H), 6.29 (d, J = 9.7 Hz, 1 H), 4.32 (d, J = 13.2 Hz, 1 H), 4.21 - 3.95 (m, 3H), 3.80 (s, 3H), 3.71 (s, 1 H), 3.31 - 3.22 (m, 1 H), 3.12 - 3.01 (m, 1 H), 2.97 - 2.89 (m, 1H), 2.78 - 2.62 (m, 3H), 2.47 - 2.40 (m, 1H), 2.23 - 0.95 (m, 32H), 0.85 (s, 3H), 0.59 (s, 3H).

[0835] Example 11 (Ex-11): 2-amino-N-(1-(2-(4-(((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)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)pyrimidine-5-carboxamide This Example was prepared from 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-3-(piperidin-4-yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2- one (Example 1) (50 mg, 0.11 mmol, 1 equiv.) and 2-amino-N-(1-(2-chloroacetyl)piperidin-4- yl)pyrimidine-5-carboxamide (Intermediate 19) (40 mg, 0.13 mmol, 1.25 equiv.) according to General Procedure (A-2) using sodium iodide (3.2 mg, 21 pmol, 0.2 equiv.) and DIPEA (0.09 mL, 0.53 mmol, 5 equiv.) in DMF (1.7 mL) to give the desired product (Example 11) (15 mg, 20 %) as a white solid. LC-MS (ES, m / Z): [M + H]+ = 731.6.1H NMR (400 MHz, DMSO) 5 8.69 (s, 2H), 8.21 (s, 1H), 7.93 (dd, J = 9.8, 2.6 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.18 (s, 2H), 6.32 - 6.25 (m, 1 H), 4.29 (d, J = 13.0 Hz, 1 H), 4.17 (s, 1 H), 4.11 - 3.87 (m, 2H), 3.71 (s, 1 H), 3.31 - 3.27 (m, 2H), 3.05 (t, J = 12.4 Hz, 1 H), 2.95 - 2.90 (m, 1 H), 2.81 - 2.61 (m, 3H), 2.49 - 2.41 (m, 1H), 2.26 - 0.97 (m, 31 H), 0.85 (s, 3H), 0.59 (s, 3H). PAG-P3656PCT Application as filed FINAL

[0836] Example 12 (Ex-12): 4-chloro-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-

[0837] 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3- This Example was prepared from 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-3-(piperidin-4-yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2- one (Example 1) (50 mg, 0.11 mmol, 1 equiv.) and 4-chloro-N-(1-(2-chloroacetyl)piperidin-4- yl)benzamide (42 mg, 0.13 mmol, 1.25 equiv.) (Intermediate 20) according to General Procedure (A-2) using sodium iodide (3.2 mg, 21 pmol, 0.2 equiv.) and DIPEA (0.09 mL, 0.53 mmol, 5 equiv.) in DMF (1.7 mL) to give the desired product (Example 12) (42 mg, 53%) as a white solid. LC-MS (ES, m / Z): [M + H]+ = 748.6.1H NMR (400 MHz, DMSO) 5 8.38 (d, J = 7.6 Hz, 1 H), 7.93 (d, J = 9.9 Hz, 1 H), 7.86 (d, J = 8.1 Hz, 2H), 7.57 - 7.49 (m, 3H), 6.29 (d, J = 9.8 Hz, 1 H), 4.32 (d, J = 13.0 Hz, 1 H), 4.28 - 3.78 (m, 3H), 3.71 (s, 1H), 3.31 - 3.24 (m, 1 H), 3.06 (t, J = 12.5 Hz, 1H), 2.91 (d, J = 13.1 Hz, 1 H), 2.69 - 2.64 (m, 4H), 2.48 - 2.40 (m, 1 H), 2.24 - 0.95 (m, 31H), 0.85 (s, 3H), 0.59 (s, 3H).

[0838] Example 13 (Ex-13): N-(1-(2-(4-(((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)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-4-(trifluoromethyl)benzamide

[0839] This Example was prepared from 5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-3-(piperidin-4-yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2- one (Example 1) (50 mg, 0.11 mmol, 1 equiv.) and N-(1-(2-chloroacetyl)piperidin-4-yl)-4- (trifluoromethyl)benzamide (Intermediate 21) (46 mg, 0.13 mmol, 1.25 equiv.) according to General Procedure (A-2) using sodium iodide (3.2 mg, 21 pmol, 0.2 equiv.) and DIPEA (0.09 mL, 0.53 mmol, 5 equiv.) in DMF (1.7 mL) to give the desired product (Example 13) (53 mg, 64%) PAG-P3656PCT Application as filed FINAL as a white solid. LC-MS (ES, m / Z): [M + H]+ = 782.5.1H NMR (400 MHz, DMSO) 5 8.55 (d, J = 7.7 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 2H), 7.93 (dd, J = 9.8, 2.5 Hz, 1 H), 7.84 (d, J = 8.2 Hz, 2H), 7.55 - 7.49 (m, 1 H), 6.29 (d, J = 9.7 Hz, 1 H), 4.32 (d, J = 13.2 Hz, 1 H), 4.22 - 3.92 (m, 3H), 3.71 (s, 1 H), 3.31 - 3.25 (m, 2H), 3.07 (t, J = 11.7 Hz, 1 H), 2.91 (d, J = 13.1 Hz, 1 H), 2.71 - 2.64 (m, 3H), 2.20 - 0.94 (m, 32H), 0.85 (s, 3H), 0.59 (s, 3H).

[0840] Example 14 (Ex-14): N1-cyclopentyl-N2-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexade...

Claims

1. PAG-P3656PCT Application as filed FINALCLAIMS1. A compound of formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, wherein:V is H or -C(RARB)C(=O)NRIR2;RA and RB are each independently selected from the group consisting of H, Ci-ealkyl and Ci-ehaloalkyl;Re is selected from the group consisting of halo, -NH2, Ci-ehaloalkyl, Ci-ealkyl, Ci-ealkoxy and cyano;RD is selected from the group consisting of H, Ci-ealkyl and Ci-ehaloalkyl; k is 0 or 1 ;I is an integer 0 to 2; m is an integer 0 to 4; n is 0 or 1 ; and:Ri is H or Ci-ealkyl;R2is H or Ci-salkyl, wherein Ci-salkyl is (i) optionally substituted with 1 or 2 R3, (ii) is substituted 1 Cyci and is optionally substituted with 1 R3, or (iii) is substituted by 1 R3 and by 2 further substituent groups which when taken together with the C atom to which they are attached form Cs-ecycloalkyl or 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O;R3 is independently selected from the group consisting of -ORsa, -NRpRqand - C(=O)-R3d;Cyci is selected from the group consisting of Cs-scycloalkyl, 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, 7-11 membered heterobicyclyl or heterospirobicyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, orPAG-P3656PCT Application as filed FINAL comprising S(=O)2, 5 membered heteroaryl, 7-11 membered heteroaryl and An, wherein Cyci is optionally substituted in any position with 1 to 3 Rcyci;An is phenyl or 6 membered heteroaryl;R3ais H or Ci-ealkyl;Rpand Rqare (i) each independently H or Ci-4alkyl, (ii) Rpand Rqtaken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O, or (iii) Rpis H or Ci-4alkyl and Rqis selected from -C(=O)Ci- 3alkyl and -K-Cyc2;K is -C(=0)(CH2)O-2- or -(CH2)o-3-;Rsd is hydroxy or -NRmRn;Rmand Rnare (i) each independently H or Ci-4alkyl, (ii) Rmand Rntaken together with the N atom to which they are attached form 4-7 membered heterocyclyl optionally comprising a further heteroatom selected from N, S and O, or (iii) Rmis H or Ci-4alkyl and Rnis -(CH2)o-3-Cyc2;Cyc2 is selected from the group consisting of C3-6cycloalkyl, 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, 5-7 membered heteroaryl and phenyl, wherein Cyc2 is optionally substituted in any position with 1 to 3 RcyC2;Rcyciand RcyC2 are independently selected from the group consisting of halo, -NRgRh, Ci-ehaloalkyl, Ci-ealkyl optionally substituted by hydroxy, Ci- ealkoxy and cyano; and when Cyci is An, An may also be optionally substituted with RAM ;RAM is selected from the group consisting of -(CH2)-Q-C(=O)-(CH2)t-RAr3, -(CH2)- NRx-S(=O)2-(CH2)t-RAr3 and -(CH2)-NRx-C(=O)-C(=O)-NRs-RAr3;RAF3 is selected from the group consisting of phenyl, naphthyl, 5-6 membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O and S, C4-7cycloalkyl and 5-6 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, wherein RAPS is optionally substituted with 1 or 2 RAM;RA is selected from the group consisting of halo, -NRgRh, Ci-ehaloalkyl, Ci-ealkyl optionally substituted by hydroxy, Ci-ealkoxy and cyano;Q is selected from the group consisting of bond, -O- and -NRX-;Rgand Rh are each independently H or Ci-4alkyl or Rgand Rh taken together with the N atom to which they are attached form 4-7 memberedPAG-P3656PCT Application as filed FINAL heterocyclyl optionally comprising a further heteroatom selected from N, S and O;Rxand Rsare each independently H or methyl; and t is 0 or 1 ; or:Ri and R2 taken together with the N atom to which they are attached form (i) a 4-7 membered heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, (ii) a 4-7 membered heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein the 4-7 membered heterocyclyl or 7-11 membered heterospirobicyclyl of (i)-(iii) are optionally substituted with 1 R4 and optionally substituted with 1 or 2 R5;R4 is Ci-ealkyl or Co-ealkylene-NRyRs, wherein the Ci-ealkyl is optionally substituted with 1 or 2 substituents selected from the group consisting of hydroxy, fluoro, cyano, -OCi-4alkyl, -NHCi-4alkyl and -N(Ci-4alkyl)2;Re is selected from the group consisting of -C(=O)-X-(CH2)v-R7, -S(=O)2- (CH2)W-R7and -C(=O)-C(=O)-NRZ-R8;X is selected from the group consisting of bond, -O- and -NR11-;R? is Ci-ealkyl or Cyca;Cyca is selected from the group consisting of phenyl, naphthyl, 5-6 membered heteroaryl comprising 1 to 3 heteroatoms independently selected from N, S and O, C4-7cycloalkyl and 4-7 membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from N, S and O, or comprising S(=O)2, wherein Cyca is optionally substituted with 1 to 4 R9;Rs represents C4-7cycloalkyl optionally substituted with 1 to 4 Rw; R9 and R10 are each independently selected from the group consisting of halo, -NRjRj, Ci-ehaloalkyl, Ci-ealkyl, Ci-ealkoxy, C1- salkyl-C(=O)-, cyano and -S(=O)2(Ci-6alkyl);Rs is selected from the group consisting of halo, -NH2, Ci-ehaloalkyl, Ci-ealkyl, C1- ealkoxy, -CH2OH, hydroxy and cyano;Ry, Rzand Rn are each independently H or methyl; v and w are each independently 0 or 1 ; andRi and Rj are each independently H or Ci-4alkyl; or a pharmaceutically acceptable salt and / or solvate thereof.PAG-P3656PCT Application as filed FINAL2. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 1 wherein m is 0.

3. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 1 or claim 2 wherein n is 0.

4. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 3 wherein k and I are both 1.

5. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 4 wherein V is H.

6. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 4 wherein V is -C(RARB)C(=O)NRIR2.

7. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 6 wherein RA and RB are both H.

8. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 6 or claim 7 wherein Ri is H.

9. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 6 to 8 wherein R2 is Ci-salkyl.

10. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 9 wherein R2 is selected from the group consisting of(methyl),(ethyl),, , (butan-2-yl) ,(3-methylbutan-2-yl) and111 I 111 (3,3-dimethylbutan-2-yl) each of which groups are optionally substituted, wherein I represents the site of attachment to the rest of the compound.

11. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 6 to 10 wherein R2 is substituted with one R3, and R3 is hydroxy.

12. The compound or pharmaceutically acceptable salt and / or solvate thereof according to209PAG-P3656PCT Application as filed FINAL claim 6 wherein Ri is H and R2 is methyl which methyl is substituted by (i) Cyci (which may optionally be substituted) and (ii) R3 wherein R3 is -C(=O)-R3d to formwherein I represents the site of attachment to the rest of the compound and Rsc is hydroxy or -NRmRi where Rmand Rnare, for example, both H.

13. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 6 wherein R1 is H and R2 represents ethyl which ethyl is substituted by (i) Cyci in the alpha position which Cyci may optionally be substituted and (ii) R3 in the beta position, to formCyClwherein I represents the site of attachment to the rest of the compound.

14. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 6 wherein R1 is H and R2 represents n-propyl which n-propyl is substituted by (i) Cyci (which may optionally be substituted) in the alpha position and (ii) R3 in the gamma position, toJ formcYci wherein I represents the site of attachment to the rest of the compound.

15. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 4 wherein R1 is H and R2 represents isopropyl which isopropyl is substituted by (i) Cyci (which may optionally be substituted) in the beta position and (ii) R3 in the beta position, to formwherein I represents the site of attachment to the rest of the compound.

16. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 13 to 15 wherein R3 is ORsaand Rsa is H or methyl.

17. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 13 to 15 wherein R3 is -NRpRg.

18. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 17 wherein Rpand Rgare both H or Rpis H and Rqis methyl.

19. The compound or pharmaceutically acceptable salt and / or solvate thereof according to210PAG-P3656PCT Application as filed FINAL any one of claims 12 to 18 wherein Cyci is selected from 6 membered heterocyclyl (such as cyclohexyl), 5 membered heteroaryl (such as imidazolyl) and An, which An is phenyl, optionally substituted with 1 Rcyci.

20. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 19 wherein Cyci is An, which An is phenyl, optionally substituted with 1 Rcyci.

21. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 19 or claim 20 wherein Cyci is unsubstituted or is substituted with 1 Rcyciand Rcyciis halo (e.g. fluoro).

22. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 6 wherein Ri and R2 taken together with the N atom to which they are attached form a piperidinyl group which is optionally substituted, for example, the piperidinyl group is substituted in the 4-position with 1 R4 and is not substituted with any R5.

23. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 22 wherein R4 is -NRyRe and Ryis H.

24. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 23 wherein Re is -C(=O)-CH2-R?, wherein R? is Cyca, which Cyca is pyridinyl and is unsubstituted.

25. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 1 which is selected from the group consisting of:5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-(piperidin-4- yloxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one;5-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-(piperidin-4- ylmethoxy)hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one;2-(4-fluorophenyl)-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)acetamide;N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;211PAG-P3656PCT Application as filed FINALN-(2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)-2- azaspiro[3.3]heptan-6-yl)benzamide;N-(1-(2-(4-((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)methyl)piperidin-1- yl)acetyl)piperidin-4-yl)benzamide;4-fluoro-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)benzamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)isonicotinamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)picolinamide;N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-3-methoxybenzamide; 2-amino-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)pyrimidine-5-carboxamide;4-chloro-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)benzamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 4-(trifluoromethyl)benzamide; N1-cyclopentyl-N2-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17- (2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)oxalamide;N1-cyclohexyl-N2-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)oxalamide;N-(3-((2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)isonicotinamide;212PAG-P3656PCT Application as filed FINAL2-amino-N-(3-((2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo- 2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)pyrimidine-5-carboxamide;2-(4-fluorophenyl)-N-(3-((2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)acetamide;N-(4-((2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)-3-methoxybenzamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(4-methoxyphenyl)acetamide;N-benzyl-2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- morpholinobenzyl)acetamide; N-((R)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-4-methylbenzamide;N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)nicotinamide;N-(4-((2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)-4-methylbenzamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(pyridin-4-yl)acetamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(tetrahydro-2H-pyran-4-yl)acetamide;213PAG-P3656PCT Application as filed FINAL2-(4-cyanophenyl)-N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetyl)piperidin-4-yl)acetamide;N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;5-((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-3-((1 -(2-(4-(3-methylisoxazole- 5-carbonyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)oxy)hexadecahydro-1 H- cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one; 5-((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-3-((1 -(2-(6-(3-methylisoxazole-5-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethyl)piperidin-4-yl)oxy)hexadecahydro-1 H- cyclopenta[a]phenanthren-17-yl)-2H-pyran-2-one;N-(3-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)propyl)-3- methylisoxazole-5-carboxamide;N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-2-methyloxazole-5-carboxamide;N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)-2-methylthiazole-5-carboxamide;N-((S)-1-(4-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- (hydroxymethyl)benzyl)acetamide;N-(4-cyanobenzyl)-2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl) acetamide;N-((S)-1-(4-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;N-((S)-2-hydroxy-1-(4-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamide;214PAG-P3656PCT Application as filed FINAL2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2-methoxy-1- phenylethyl)acetamide; 2-(4-fluorophenyl)-N-(4-((2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1- yl)acetamido)methyl)benzyl)acetamide; N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)-N-methylacetamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4- yl)tetrahydro-2H-pyran-4-carboxamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 3-methylisoxazole-5-carboxamide;N-((S)-2-hydroxy-1-phenylethyl)-2-(4-((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)methyl)piperidin-1-yl)acetamide;N-((S)-2-acetamido-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((R)-1- phenylethyl)acetamide; N-((S)-1-(2-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-1-cyclohexyl-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;N-((S)-2-hydroxy-1-(pyridin-4-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;N-((R)-3-hydroxy-1-phenylpropyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;215PAG-P3656PCT Application as filed FINAL((S)-2-amino-2-oxo-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxy-3-(1 H- imidazol-4-yl)propan-2-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1- hydroxypropan-2-yl)acetamide; N-((S)-1-(2-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxybutan- 2-yl)acetamide;N-((S)-2-hydroxy-1-(p-tolyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-hydroxy-3-(1 H- indol-3-yl)propan-2-yl)acetamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(pyridin-2-yl)acetamide; N-(1-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetyl)piperidin-4-yl)- 2-(pyridin-3-yl)acetamide;N-((S)-2-amino-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2-(methylamino)- 1 -phenylethyl)acetamide; N-((S)-1-(3-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-216PAG-P3656PCT Application as filed FINAL10.13-d i methyl- 17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3- phenylpropan-2-yl)acetamide;2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- hydroxyethyl)acetamide;N-((S)-2-hydroxy-1-(pyridin-2-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;N-((S)-2-hydroxy-1-(2-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamide; (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-N-methyl-2-phenylacetamide;N-((S)-2-hydroxy-1-(pyridin-3-yl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10.13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;N-((S)-2-hydroxy-1-(3-methoxyphenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamide;N-((S)-2-hydroxy-1-(m-tolyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3- methylbutan-2-yl)acetamide; (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylacetic acid;2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1 -hydroxy-3,3- dimethylbutan-2-yl)acetamide;N-(1 ,3-dihydroxypropan-2-yl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-217PAG-P3656PCT Application as filed FINAL yl)oxy)piperidin-1 -yl)acetamide; and (S)-2-(2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran- 5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-N,N- dimethyl-2-phenylacetamide; or a pharmaceutically acceptable salt and / or solvate of any one thereof.

26. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 1 which is selected from the group consisting of: N-((S)-1-(3,5-difluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren- 3-yl)oxy)piperidin-1-yl)acetamide; N-((S)-2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14- hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren- 3-yl)oxy)piperidin-1-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(1 -hydroxy-2- methylpropan-2-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(3- (hydroxymethyl)oxetan-3-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(4- (hydroxymethyl)tetrahydro-2H-pyran-4-yl)acetamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(1- (hydroxymethyl)cyclohexyl)acetamide; N-((S)-2-(ethylamino)-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-((S)-2-(2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2- phenylethyl)benzamide; 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-2- (isopropylamino)-1-phenylethyl)acetamide; N-((S)-2-(2-(4-(((3S,5R,8R,9S, 10S, 13R, 14S, 17R)-14-hydroxy-10, 13-dimethyl-17-(2-oxo-2H- pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)acetamido)-2-218PAG-P3656PCT Application as filed FINAL phenylethyl)propionamide;N-((S)-2-(benzylamino)-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; and 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1-phenyl-2-(2- phenylacetamido)ethyl)acetamide; or a pharmaceutically acceptable salt and / or solvate of any one thereof.

27. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 1 which is selected from the group consisting of: N-((S)-2-hydroxy-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide; N-(1-(2-(4-((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)methyl)piperidin-1- yl)acetyl)piperidin-4-yl)benzamide; N-((S)-1-(4-fluorophenyl)-2-hydroxyethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy- 10, 13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;((S)-2-amino-2-oxo-1-phenylethyl)-2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13- dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3- yl)oxy)piperidin-1-yl)acetamide;2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-((S)-1- hydroxypropan-2-yl)acetamide; and 2-(4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-1 H-cyclopenta[a]phenanthren-3-yl)oxy)piperidin-1-yl)-N-(2- hydroxyethyl)acetamide; or a pharmaceutically acceptable salt and / or solvate of any one thereof.

28. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 27 and one or more pharmaceutically acceptable diluents or carriers.

29. A compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 27 or a pharmaceutical composition according to claim 28 for use as a219PAG-P3656PCT Application as filed FINAL medicament.

30. A compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 27 or a pharmaceutical composition according to claim 28 for use in treating or preventing cancer, including metastasis of cancer.

31. Use of a compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 27 or a pharmaceutical composition according to claims 28 in the manufacture of a medicament for treating or preventing cancer, including metastasis of cancer.

32. A method of treating or preventing cancer, including metastasis of cancer, which comprises administering a compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 27 or a pharmaceutical composition according to claim 28.

33. A compound which is a compound of formula (III):or a salt and / or solvate thereof or a derivative thereof in which the carboxylic acid group is activated ora protected derivative thereof and wherein RA, B, RC, RD, k, I, m and n are as defined in any one of claims 1 to 27.220PAG-P3656PCT Application as filed FINAL34. A compound of formula (V):or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof or a protected derivative thereof, whereinis (i) a 4-7 membered N-heterocyclyl optionally comprising 1 additional heteroatom selected from N, S and O, (ii) a 4-7 membered N-heterocyclyl fused to 4-7 membered cycloalkyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, or (iii) a 4-7 membered heterocyclyl fused to 4-7 membered heterocyclyl ring through a single C atom to form a 7-11 membered heterospirobicyclyl, wherein each of (i)-(iii) are optionally substituted with 1 or 2 Rs and Co-6 represents Co-6alkylene and wherein RA, RB, RC, RD, Ry, k, I, m and n are as defined in any one of claims 1 to 27.221

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