Compounds for the inhibition of cyclophilin d

Abstract

The invention provides novel inhibitor compounds of formula I as defined herein. The invention also provides the use of such compounds in treating cyclophilin D related disorders, such as acute pancreatitis, and processes for their synthesis.

Description

[0001] COMPOUNDS FOR THE INHIBITION OF CYCLOPHILIN D

[0002] Field of the Invention

[0003] The present invention relates to novel compounds, compositions comprising such compounds, and the use of such compounds and compositions in medicine. In particular, the present invention relates to the use of such compounds and compositions in methods for the treatment or prevention of diseases associated with cyclophilin D, such as acute pancreatitis, which treatment and prevention are thought to occur through inhibiting mitochondrial protein cyclophilin D.

[0004] Background of the Invention

[0005] Cyclophilins (Cyps) or peptidyl-prolyl isomerases (PPIases) are widely expressed enzymes which catalyse the conversion of proline residue peptide bonds from trans to cis conformation (Fischer, G. et al., Biomed Biochim Acta, 1984, 43, 1101; Fischer, G., et al., Biochemistry, 1990, 29, 2205). They play a critical role in important cellular processes and have been proposed as potential targets for the treatment for a range of inflammatory, infective, neurological, necrotic, and oncological diseases.

[0006] CypA was the first protein with Peptidyl-Prolyl cis-trans Isomerase (PPIase) activity to be identified and was initially known as PPIase (Fischer, G., et al., Nature, 1989, 337, 476). Additional Cyps have been discovered, including 17 individual Cyps found in humans (Wang, P., et al., Genome Biology, 2005, 6(7), 226). Cyps are a highly homogeneous family of proteins, as approximately 109 amino acids residues are shared across the family, and are classified as the cyclophilin-like domain. The molecular weight of this protein family ranges from 18-150 kDa, owing to the presence of other domains associated with sub-cellular compartmentalisation and specific functionalisation of each Cyp. Cyps are structurally conserved throughout evolution being present in bacteria, fungi, plants, insects and mammals, and all with PPIase activity (Wang, P., et al., Genome Biology, 2005, 6(7), 226).

[0007] CypD is the only Cyp present within the mitochondrial matrix, where this Cyp contributes to mitochondrial metabolism. The most researched activity of CypD is its PPIase-mediated opening of the mitochondrial permeability transition pore (MPTP), which forms in response to calcium overload and allows particles up to 1500 Da to pass through the inner mitochondrial membrane, causing loss of the mitochondrial membrane potential essential for adenosine triphosphate production. As the MPTP has a major role in many acute inflammatory and chronic degenerative diseases that include acute and chronic pancreatitis, CypD is an important drug target (Tazawa, H., et al., Archives of Biochemistry and Biophysics, 2009, 481(1), 59-64), CypD is an 18 kDa molecule consisting of the same 8 stranded antiparallel 0-barrel structure and hydrophobic core found in other Cyps, with an additional 13 amino acid mitochondrial signal sequence, Ala-Arg-Asp-Gly-Gly-Ala-Arg-Gly-Ala-Asn-Ser-Ser-Ser, which allows CypD to travel into the mitochondrial matrix. CypD has the highest amino acid sequence homology with CypA (81%) compared to all other Cyps, with an additional 42 amino acids (Connern, C. P., et al., Biochem J, 1992, 284, 381-385). Cyps are so named because of their binding affinity for the lipophilic cyclic peptide cyclosporine A (CsA), which inhibits their PPIase activity, and so inhibits CypD-mediated MPTP opening. Cyclosporine A is also known as cyclosporin, ciclosporin, cyclosporine, and CsA, and these are used interchangeably throughout.

[0008] The international patent application with publication no. WO 2017 / 173048 discloses urea and amide compounds having cyclophilin-inhibiting properties.

[0009] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0010] Detailed Description of the Invention

[0011] In a first aspect of the invention, there is provided a compound of formula I or a pharmaceutically-acceptable salt thereof, wherein:

[0012] R1represents phenyl or a 5 to 10-membered heterocyclyl group, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, -CN, benzyloxy, -C(O)O-R9, and -C(O)NH(R10);

[0013] R2represents H, Ci-4 alkyl, heteroaryl, or aryl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, Ci-4 alkyl, Ci-4 alkoxy, -O-C1-2 alkylene-R11and -aryl-CHi-2 alkylene-R13;

[0014] R3represents H, Ci-4 alkyl or a heterocyclic group;

[0015] R4and R5each represent H, or R4and R5are linked to form a 5- to 10-membered heterocyclic mono- or polycyclic ring optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, oxo and Ci-4 alkyl;

[0016] R6represents H or Ci-4 alkyl optionally substituted by a heterocyclic group;

[0017] R7represents H, halogen, or hydroxy;

[0018] R8aand R8beach independently represents H or Ci-4 alkyl optionally substituted by a heterocyclic group, which heterocyclic group is optionally substituted by one or more Ci-4 alkyl substituents;

[0019] R9represents H or C1-2 alkyl optionally substituted by R12;

[0020] R10represents H or C1-6 alkyl;

[0021] R11and R13independently represent a 5- or 6-membered heterocyclyl group optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl and oxo;

[0022] R12represents a 6-membered heterocyclyl or phenyl group, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, CH3 and CF3;

[0023] X1to X6each independently represents C, CH, CH2, N, O or NH, and the ring containing X1to X6is aromatic or contains 0, 1 or 2 double bonds; which compounds (including pharmaceutically acceptable salts) may be referred to herein as the "compounds of the invention". It has surprisingly been found that the compounds of the invention are inhibitors of cyclophilins, such as cyclophilin D, and thus have properties rendering them useful for the treatment or prevention of diseases associated with cyclophilins, such as cyclophilin D (e.g. acute pancreatitis).

[0024] For the avoidance of doubt, the skilled person will understand that references herein to compounds of particular aspects of the invention (such as the first aspect of the invention, i.e. referring to compounds of formula I as defined in the first aspect of the invention) will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention.

[0025] Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0026] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared using techniques known to those skilled in the art, such as by exchanging a counterion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

[0027] Particular acid addition salts that may be mentioned include carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, o-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxy benzoate, methoxybenzoate, dinitrobenzoate, o-acetoxy- benzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodide salts), sulphonate salts (e.g. benzenesulphonate, methyl-, bromo- or chlorobenzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxy-ethanesulphonate, 1- or 2- naphthalene-sulphonate or 1,5-naphthalene-disulphonate salts) or sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.

[0028] Particular base addition salts that may be mentioned include salts formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts.

[0029] For the avoidance of doubt, compounds of the invention may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof, and may also exist as oils. Where compounds of the invention exist in crystalline and part crystalline forms, such forms may include solvates, which are included in the scope of the invention.

[0030] For the avoidance of doubt, compounds of the invention may also exist in solution (i.e. in solution in a suitable solvent). For example, compounds of the invention may exist in aqueous solution, in which case compounds of the invention may exist in the form of hydrates thereof.

[0031] Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention (particularly those of sufficient stability to allow for isolation thereof).

[0032] Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and / or diastereoisomerism (i.e. existing in enantiomeric or diastereomeric forms). Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers (i.e. enantiomers) may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired enantiomer or diastereoisomer may be obtained from appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution; for example, with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst, all of which methods and processes may be performed under conditions known to the skilled person. Unless otherwise specified, all stereoisomers and mixtures thereof are included within the scope of the invention.

[0033] Unless otherwise specified, Ci-z alkyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and / or cyclic (so forming a Cs-z cycloalkyl group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic (so forming a C4-z partial cycloalkyl group). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclopentyl and cyclohexyl. Similarly, part cyclic alkyl groups (which may also be referred to as "part cycloalkyl" groups) that may be mentioned include cyclopropylmethyl. When there is a sufficient number of carbon atoms, such groups may also be multicyclic (e.g. bicyclic or tricyclic) and / or spirocyclic. For the avoidance of doubt, particular alkyl groups that may be mentioned include straight chain (i.e. not branched and / or cyclic) alkyl groups. References to "haloalkyl" groups are references to alkyl groups where one or more of the hydrogen atoms attached to the carbon skeleton is replaced by a halogen (e.g. F, Cl, Br or I). Where multiple halogen substitutions occur on the same alkyl group, the halogens present may be the same or different.

[0034] Unless otherwise specified, the term "Ci-z alkoxy" (where z is the upper limit of the range) refers to a -OCi-z alkyl group. By analogy with "haloalkyl", references to "haloalkoxyl" groups are references to alkoxyl groups in which one or more of the hydrogen atoms attached to the carbon skeleton is replaced by a halogen (e.g. F, Cl, Br or I).

[0035] For the avoidance of doubt, unless otherwise specified, groups referred to herein as "alkyl", "alkenyl" and / or "alkynyl" will be taken as referring to the highest degree of unsaturation in a bond present in such groups. For example, such a group having a carbon-carbon double bond and, in the same group, a carbon-carbon triple bond will be referred to as "alkynyl". Alternatively, it may be particularly specified that such groups will comprise only the degree of unsaturation specified (i.e. in one or more bond therein, as appropriate; e.g. in one bond therein). For the avoidance of doubt, alkyl groups as described herein may also act as linker groups (i.e. groups joining two or more parts of the compound as described), in which case such groups may be referred to as "alkylene" groups.

[0036] References to heteroatoms, as used herein, will take their normal meaning as understood by one skilled in the art. Particular heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen and sulfur (e.g. oxygen, nitrogen and sulfur, particularly oxygen and nitrogen).

[0037] As used herein, the term heterocyclyl may refer to non-aromatic monocyclic and polycyclic (e.g. bicyclic) heterocyclic groups (which groups may, where containing a sufficient number of atoms, also be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten, such as between three and eight; for example, forming a 5- or 6- membered heterocyclyl group). Further, such heterocyclyl groups may be saturated, forming a heterocycloalkyl, or unsaturated containing one or more carbon-carbon or, where possible, carbon-heteroatom or heteroatom-heteroatom double and / or triple bonds, forming for example a C2-Z (e.g. C4-z) heterocycloalkenyl (where z is the upper limit of the range) or a C?-z heterocycloalkynyl group. The term heterocyclyl may also refer to aromatic groups (i.e. heteroaryl groups) as discussed hereinafter.

[0038] For the avoidance of doubt, the skilled person will understand that heterocyclyl groups that may form part of compounds of the invention are those that are chemically obtainable, as known to those skilled in the art. Various non-aromatic heterocyclyl groups will be well-known to those skilled in the art, such as 7-azabicyclo- [2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8- azabicyclo[3.2.1]octanyl, aziridinyl, azepanyl, azetidinyl, diazocanyl,

[0039] 2.3-dihydroisothiazolyl, dihydropyranyl, dihydropyridinyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including

[0040] 1.3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, isothiazolidinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetra hydropyranyl, tetra hydrofuryl, 1, 3,4,6- tetrahydro-2H-2,6-methano[l,5]oxazocinyl, tetra hydropyridinyl (such as 1, 2,3,4- tetrahydropyridinyl and 1,2,3,6-tetrahydropyridinyl), thietanyl, thiiranyl, thiolanyl, tetra hydrothiopyranyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like.

[0041] Substituents on heterocyclyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocyclyl group, forming a spirocyclic compound. The point of attachment of heterocyclyl groups may be via any suitable atom in the ring system, including (where appropriate) a further heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocyclyl groups may also be in the N- or S- oxidised forms, as known to those skilled in the art (e.g. to form a 1,1-dioxidothiomorpholinyl group).

[0042] At each occurrence when mentioned herein, particular heterocyclyl groups that may be mentioned include 3- to 8-membered heterocyclyl groups (e.g. a 4- to 6- membered heterocyclyl group, such as a 5- or 6- membered heterocyclyl group).

[0043] For the avoidance of doubt, references to polycyclic (e.g. bicyclic or tricyclic) groups (for example when employed in the context of heterocyclyl or cycloalkyl groups (e.g. heterocyclyl)) will refer to ring systems wherein at least two scissions would be required to convert such rings into a non-cyclic (i.e. straight or branched) chain, with the minimum number of such scissions corresponding to the number of rings defined (e.g. the term bicyclic may indicate that a minimum of two scissions would be required to convert the rings into a straight chain). For the avoidance of doubt, the term bicyclic (e.g. when employed in the context of alkyl groups) may refer to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring, to groups in which two non-adjacent atoms are linked by an alkyl (which, when linking two moieties, may be referred to as alkylene) group (optionally containing one or more heteroatoms), which later groups may be referred to as bridged, or to groups in which the second ring is attached to a single atom, which latter groups may be referred to as spiro compounds.

[0044] Particular non-aromatic heterocyclyl groups that may be mentioned include octahydro- 1 H-isoindolyl (e.g. octahydro-lH-isoindol-2-yl), azetidinyl (e.g. azetidine-l-yl), oxetanyl (e.g. oxetan-3-yl), azepanyl (e.g. azepan-l-yl), imidazolidinyl (e.g. imidazolidine-2-yl), and pyrrolidinyl (e.g. pyrrolidine-lyl), and particularly diazocanyl (e.g. 1,5-diazocan-l-yl), piperidinyl (e.g. piperidin- 1-yl), morpholinyl (e.g. morpholin- 4-yl), thiomorpholinyl (e.g. thiomorpholin-4-yl), piperazinyl (e.g. piperazin-lyl or piperazin-4-yl) and l,3,4,6-tetrahydro-2H-2,6-methano[l,5]oxazocinyl).

[0045] As may be used herein, the term aryl may refer to Ce-14 (e.g. Ce-io) aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, be either wholly or partly aromatic. Ce-io aryl groups that may be mentioned include phenyl, naphthyl, 1, 2,3,4- tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyl, and the like). For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any suitable carbon atom of the ring system.

[0046] For the avoidance of doubt, the skilled person will understand that aryl groups that may form part of compounds of the invention are those that are chemically obtainable, as known to those skilled in the art. Particular aryl groups that may be mentioned include phenyl and naphthyl, such as phenyl.

[0047] As may be used herein, references to heteroaryl (which may also be referred to as heteroaromatic) groups may refer to 5- to 14- (e.g. 5- to 10-) membered heteroaromatic groups containing one or more heteroatoms (such as one or more heteroatoms selected from oxygen, nitrogen and / or sulfur). Such heteroaryl groups may comprise one, two, or three rings, of which at least one is aromatic. Substituents on heteroaryl / heteroaromatic groups may, where appropriate, be located on any suitable atom in the ring system, including a heteroatom (e.g. on a suitable N atom).

[0048] The point of attachment of heteroaryl / heteroaromatic groups may be via any atom in the ring system including (where appropriate) a heteroatom. Bicyclic heteroaryl / heteroaromatic groups may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which instances, the point of attachment of the polycyclic heteroaryl / heteroaromatic group may be via any ring including the benzene ring or the heteroaryl / heteroaromatic or heterocyclyl ring.

[0049] For the avoidance of doubt, the skilled person will understand that heteroaryl groups that may form part of compounds of the invention are those that are chemically obtainable, as known to those skilled in the art. Various heteroaryl groups will be well- known to those skilled in the art, such as pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thienothiophenyl, furopyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl and purinyl.

[0050] For the avoidance of doubt, the oxides of heteroaryl / heteroaromatic groups are also embraced within the scope of the invention (e.g. the / V-oxide).

[0051] As stated above, heteroaryl includes polycyclic (e.g. bicyclic) groups in which one ring is aromatic (and the other may or may not be aromatic). Hence, other heteroaryl groups that may be mentioned include groups such as benzo[l,3]dioxolyl, benzo[l,4]dioxinyl, dihydrobenzo[c / ]isothiazole, 3,4-dihydrobenz[l,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H, 7H-pyrrolo[l,2-b]pyrimidinyl, 1, 2,3,4- tetrahydroquinolinyl, thiochromanyl and the like.

[0052] Particular heteroaryl groups that may be mentioned include pyridinyl, quinolinyl and isoquinolinyl.

[0053] For the avoidance of doubt, where a ring is depicted having circle therein, its presence shall indicate that the relevant ring is aromatic. Alternatively, aromatic groups may be depicted as cyclic groups comprising therein a suitable number of double bonds to allow for aromaticity.

[0054] The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Hence, the compounds of the invention also include deuterated compounds, i.e. compounds of the invention in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

[0055] Particular deuterated compounds that may be mentioned in this respect include compounds in which R3is deuterium or a deuterated structural moiety, especially in compounds in which R2represents H. Alternatively, or additionally, one or more of the carbon atoms in the pyrazolidine ring skeleton may be deuterated.

[0056] For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which two or more "halogen" groups are present on different parts of the compound, those halogen groups may be the same or different.

[0057] Also for the avoidance of doubt, when a term such as "5- to 10-membered" is employed herein, this will be understood by the skilled person to mean 5-, 6-, 7-, 8-, 9- or 10- membered, inclusively. Unless otherwise stated, the same reasoning will apply to other such terms used herein.

[0058] Furthermore, when it is specified that a substituent is itself optionally substituted by one or more substituents (e.g. a 5- or 6-membered heterocyclyl group optionally substituted by one or more groups independently selected from the group consisting of halogen, Ci-4 alkyl and oxo), these substituents where possible may be positioned on the same or different atoms. Such optional substituents may be present in any suitable number thereof (e.g. the relevant group may be substituted with one or more such substituents, such as one such substituent).

[0059] Still further, where groups are referred to herein as being optionally substituted it is specifically contemplated that such optional substituents may be not present (i.e. references to such optional substituents may be removed), in which case the optionally substituted group may be referred to as being unsubstituted.

[0060] When the stereochemistry of a chiral centre is not explicitly defined herein (i.e. by the use of wedged / hashed bonds) it should be understood that the stereocentre may be present in the R- or S-configuration, or a mixture of both configurations.

[0061] For the avoidance of doubt, the skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are obtainable, i.e. those that may be prepared in a stable form. That is, compounds of the invention include those that are sufficiently robust to survive isolation, e.g. from a reaction mixture, to a useful degree of purity.

[0062] In particular embodiments (i.e. particular embodiments of the first aspect of the invention), the compound of formula I is such that R1represents phenyl or a 5- to 10- membered heteroaryl group (e.g. phenyl, pyridyl, quinolinyl or isoquinolinyl), each of which is optionally substituted as hereinbefore stated. In one embodiment, R1represents phenyl or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 alkoxy, -CN, benzyloxy, -C(O)O-R9, and -C(O)NH(R10).

[0063] In a further embodiment, R1represents phenyl, pyridyl, quinolinyl or isoquinolinyl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, methyl, methoxy, -CN, benzyloxy, -C(O)O-R9, and -C(O)NH(R10); R9represents H, methyl (optionally substituted by pyridyl) or benzyl (optionally substituted by one or more halogen or CF3 groups); and R10represents a C1-5 alkyl group).

[0064] It has also been found that the positioning of non-hydrogen substituents on the ring at R1(i.e, on the phenyl or heterocyclyl group) can improve the conformational bias of the molecule and thus its affinity for the binding site. For example, when R1is a 6- membered ring (e.g. phenyl or pyridyl), a favourable conformation of this part of the molecule is aided when one or more non-hydrogen substituents are present at the ortho and / or para positions. A similar improvement can be achieved with rings of other sizes (e.g. 5-membered rings) or bicyclic systems (such as naphthalene, quinoline or isoquinoline) in that the desired conformation can be aided by placing at least one nonhydrogen substituent on an alpha carbon of the R1ring (i.e. a carbon atom that is adjacent to the carbon atom bound to the mandatory pyrazolidine). Thus, in one embodiment, R1represents phenyl, pyridyl, quinolinyl or isoquinolinyl, each of which is substituted at an ortho or para position by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, -CN, benzyloxy, -C(O)O-R9, and -C(O)NH(R10).

[0065] In one embodiment of the invention, R9represents H, -CH3 or -CH2-R12. In the same or separate embodiments, R12represents phenyl or pyridyl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen and CF3.

[0066] In another embodiment, R10represents methyl, ethyl, propyl, isopropyl, straight chain or branched butyl, straight chain or branched pentyl, or straight chain or branched hexyl.

[0067] In a further embodiment, R2represents H, Ci-4 alkyl, pyridyl or phenyl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, Ci-4 alkyl, Ci-4 alkoxy, -O-C1-2 alkylene-R11and -aryl-CHi-2 alkylene- R13. For example, R2may represent H, pyridyl or phenyl, which latter two groups are optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 alkoxy and -O-C1-2 alkylene-R11. R2may still further represent H or phenyl optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkoxy, -O-C1-2 alkylene-R11and -aryl-CHi-2 alkylene-R13.

[0068] In a further embodiment, R2represents H, Ci-4 alkyl, heteroaryl, or aryl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, Ci-4 alkyl, Ci-4 alkoxy, and -O-C1-2 alkylene-R11.

[0069] In a yet further preferred embodiment, R2represents H, Ci-4 alkyl, pyridyl or phenyl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, Ci-4 alkyl, Ci-4 alkoxy, and -O-C1-2 alkylene-R11.

[0070] It has been surprisingly found that compounds of the invention in which R2represents phenyl, and the carbon atom to which R2is bound is in the S-configuration, exhibit particularly enhanced CypD inhibitory activity. In a particularly preferred embodiment of these compounds, R1represents phenyl substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 alkoxy, -CN, benzyloxy, -C(O)O-R9, and -C(O)NH(R10).

[0071] In another embodiment of the invention, R11represents a morpholinyl, thiomorpholinyl, piperazinyl or piperidinyl group, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl and oxo. R11may also represent a triphenylphosphonium moiety. Charged lipophilic moieties such as this are potentially useful in targeting mitochondria through nonmediated, membrane potential driven, accumulation of the compound of formula I within the mitochondrial matrix. The large triphenylphosphonium moiety may be bound to the R2group using an extended alkylene linker, i.e. a substituent on R2may also be a -O-Ci-s alkylene-triphenylphosphonium group.

[0072] In another embodiment of the invention, R13represents a thiomorpholinyl, piperazinyl, piperidinyl or, particularly, morpholinyl group. In compounds of the invention in which R2represents a group bearing an -aryl-CHi-2 alkylene-R13substituent, the -CH1-2 alkylene-R13is preferably bound to the aryl group in the para position.

[0073] In another embodiment, R3represents H, Ci-4 alkyl or a 5- or 6-membered heterocyclyl group, such as a heterocyclyl group selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, phenyl, pyridinyl, quinolinyl and isoquinolinyl. In particular compounds of the invention, R3represents H.

[0074] In compounds of formula I, X1to X6each independently represents C, CH, CH2, N, O or NH, and the ring containing X1to X6is aromatic or contains 0, 1 or 2 double bonds. That is, the ring containing X1to X6is a 6-membered carbocyclic or heterocyclic group which may be saturated, partially unsaturated or aromatic. Heteroatoms that may be present are N and O, and preferably only 0, 1 or 2 heteroatoms are present. The ring containing X1to X6may, therefore, be selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, cyclohexyl, tetrahydropyranyl, piperidinyl and piperazinyl. In particularly preferred compounds, the ring is phenyl.

[0075] In a further embodiment R4and R5each represent H, or R4and R5are linked together to form a 5- to 10-membered, fully or partially saturated heterocyclyl group which is optionally substituted as hereinbefore defined. Said heterocyclyl group may be monocyclic or polycyclic (including a bridged polycyclic group) 7- to 9-membered ring, containing from 1 to 3 heteroatoms (e.g. independently selected from O, N or S) in the ring skeleton, which is optionally substituted as hereinbefore defined. When R4and R5are so linked, it is preferred that the ring containing X1to X6is phenyl.

[0076] Particularly preferred groups which R4and R5may be linked together to form include those shown below: wherein Rxand Ryeach independently represents H or a Ci-4 alkyl group (e.g. wherein Rxis ethyl and Ryis H; or wherein both Rxand Ryare H). The monocyclic and polycyclic structures are fused to the mandatory X1to X6-containing ring (e.g. phenyl group) in formula I, and in the structures above, only the rings formed by R4and R5are shown together with the mandatory portion of the core structure included in those rings (i.e. -NH-C-C-). Also in the structures above, X4and X5both represent either C or CH depending on the degree of unsaturation in the X1to X6-containing ring.

[0077] For the avoidance of doubt, these structures may alternatively be drawn as follows: wherein each lower wavy line represents the point of attachment of R7and each upperright wavy line represents the point of attachment of the remainder of the compound of formula I.

[0078] In a particular embodiment, R4and R5are linked together to form:

[0079] Such structures formed by R4and R5are chiral, and the skilled person will appreciate that such groups may be represented by R4and R5as follows:

[0080] It has been surprisingly found that compounds of the invention in which R4and R5are linked together to form the heterocyclyl structure below (e.g. when the X1to X6- containing ring is phenyl) exhibit particularly enhanced CypD inhibitory activity, particularly when R7also represents H: The stereochemistry of this fragment may, in some embodiments, be that shown above (and also in Example 53) as this has been found to provide superior cyclophilin activity. Synthesis of this diastereomeric form may also be more facile than others. This portion of the molecule may, for example, be characterised using the following terminology: (2 / ?,3S,6 / ?)-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocinyl (which includes the adjacent phenyl ring); or O[C@@H]1CO[C@H]2C3=C(N[C@@H]1C2)C=CC(CN)=C3.

[0081] In another embodiment of the invention, R4and R5are linked together to form the heterocyclyl structure below (e.g. when the X1to X6-containing ring is phenyl), particularly when R7also represents H:

[0082] In one embodiment, R6represents H or Ci-4 alkyl optionally substituted by a morpholinyl, thiomorpholinyl, piperazinyl or piperidinyl group. In particular embodiments, R6represents Ci-4 alkyl or, most particularly, H.

[0083] In another embodiment, R7represents H or halogen.

[0084] Further compounds that may be mentioned include those in which the X1to X6- containing ring is phenyl, and R4, R5, R6and R7each represent H.

[0085] In one embodiment, R8arepresents H or Ci-4 alkyl optionally substituted by a morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolyl, imidazolyl, triazolyl, or tetrazolyl group, wherein each of said cyclic groups is optionally substituted by one or more Ci-4 alkyl substituents. In particular embodiments, R8arepresents Ci-4 alkyl or, most particularly, H.

[0086] In one embodiment, R8brepresents H or Ci-4 alkyl optionally substituted by a morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolyl, imidazolyl, triazolyl, or tetrazolyl group, wherein each of said cyclic groups is optionally substituted by one or more Ci-4 alkyl substituents. In particular embodiments, R8brepresents Ci-4 alkyl or, most particularly, H. In a further embodiment, both R8aand R8brepresent H.

[0087] Still further compounds that may be mentioned include those in which the X1to X6- containing ring is phenyl, and R3, R4, R5, R6, R7, R8aand R8beach represent H.

[0088] Particular compounds of the invention that may be mentioned include those compounds as described in the examples provided herein, and pharmaceutically acceptable salts thereof. For the avoidance of doubt, where such compounds of the invention include compounds in a particular salt form, compounds of the invention include those compounds in non-salt form and in the form of any pharmaceutically acceptable salt thereof (which may include the salt form present in such examples).

[0089] Thus, particular compounds of the invention that may be mentioned include: and pharmaceutically acceptable salts thereof.

[0090] In the case of a discrepancy between the names and structures of any of the compounds disclosed herein, the structures provided should prevail.

[0091] Medical uses

[0092] As indicated herein, the compounds of the invention, and therefore compositions and kits comprising the same, are useful as pharmaceuticals.

[0093] Thus, according to a second aspect of the invention there is provided a compound of the invention, as hereinbefore defined (i.e. a compound as defined in the first aspect of the invention, including all embodiments and particular features thereof), for use as a pharmaceutical (or for use in medicine).

[0094] For the avoidance of doubt, references to compounds as defined in the first aspect of the invention will include references to compounds of formula I (including all embodiments thereof) and pharmaceutically acceptable salts thereof.

[0095] As used herein, references to prodrugs will include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time, following enteral or parenteral administration (e.g. oral or parenteral administration). All prodrugs of the compounds of the invention are included within the scope of the invention.

[0096] Furthermore, certain compounds of the invention may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such. Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the active compounds of the invention to which they are metabolised), may also be described as "prodrugs".

[0097] For the avoidance of doubt, compounds of the invention are therefore useful because they possess pharmacological activity, and / or are metabolised in the body following oral or parenteral administration to form compounds that possess pharmacological activity. As described herein, compounds of the invention may be particularly useful in treating or preventing a disease or condition in which the inhibition of one or more cyclophilins is desired or required (e.g. any one of cyclophilins A, B, C and D).

[0098] Compounds of the invention may be particularly useful in treating or preventing a disease or condition in which the inhibition of cyclophilin D is desired or required. Particular diseases and conditions that may be mentioned in this respect include acute pancreatitis, myocardial infarction, acute ischaemic stroke, acute tubular necrosis, acute hepatic injury and failure, neurodegenerative diseases, and muscular dystrophy. Neurodegenerative diseases include, but are not limited to, Parkinson's disease, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Dementia, Multiple Sclerosis and Huntington's disease.

[0099] Diseases and conditions that may be mentioned in respect of cyclophilin A include viral infection, sepsis, chronic inflammatory disease, autoimmune disease, graft versus host disease, organ rejection, coronary and peripheral vascular disease, and cancer. Diseases and conditions that may be mentioned in respect of cyclophilin B include coronary and peripheral vascular disease, hypertension, diabetes mellitus, dyslipidaemia, metabolic syndrome, non-alcoholic fatty liver disease, fibrotic disease, and cancer. Diseases and conditions that may be mentioned in respect of cyclophilin C include coronary and peripheral vascular disease.

[0100] Thus, in a third aspect of the invention, there is provided a compound of the invention, as hereinbefore defined, for use in the treatment or prevention of a disease or condition selected from the group consisting of acute pancreatitis, myocardial infarction, acute ischaemic stroke, acute tubular necrosis, acute hepatic injury and failure, viral infection, sepsis, chronic inflammatory disease, autoimmune disease, graft versus host disease, organ rejection, coronary and peripheral vascular disease, hypertension, diabetes mellitus, dyslipidaemia, metabolic syndrome, non-alcoholic fatty liver disease, fibrotic disease, cancer, neurodegenerative diseases and muscular dystrophy. In one embodiment, the compound of the invention is for use in the treatment of acute pancreatitis.

[0101] In an alternative third aspect of the invention, there is provided a method of treating or preventing a disease or condition selected from the group consisting of acute pancreatitis, myocardial infarction, acute ischaemic stroke, acute tubular necrosis, acute hepatic injury and failure, neurodegenerative diseases and muscular dystrophy comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention, as hereinbefore defined.

[0102] In a further alternative third aspect of the invention, there is provided the use of a compound of the invention, as hereinbefore defined, for the manufacture of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of acute pancreatitis, myocardial infarction, acute ischaemic stroke, acute tubular necrosis, acute hepatic injury and failure, neurodegenerative diseases and muscular dystrophy.

[0103] The skilled person will understand that references to the treatment of a particular condition (or, similarly, to treating that condition) will take their normal meanings in the field of medicine. In particular, the terms may refer to achieving a reduction in the severity and / or frequency of occurrence of one or more clinical symptom associated with the condition, as adjudged by a physician attending a patient having or being susceptible to such symptoms. For example, in the case of acute pancreatitis said clinical symptom associated with the condition may include one or more of severe abdominal pain, gastrointestinal dysfunction, organ failure, pancreatic and / or peripancreatic necrosis with or without secondary infection, and prolonged debility.

[0104] As used herein, references to a patient (or to patients) will refer to a living subject being treated, including mammalian (e.g. human) patients. In particular, references to a patient will refer to human patients.

[0105] For the avoidance of doubt, the skilled person will understand that such treatment will be performed in a patient (or subject) in need thereof. The need of a patient (or subject) for such treatment may be assessed by those skilled the art using routine techniques.

[0106] As used herein, the terms disease and disorder (and, similarly, the terms condition, illness, medical problem, and the like) may be used interchangeably.

[0107] As used herein, the term effective amount will refer to an amount of a compound that confers a therapeutic effect on the treated patient. The effect may be observed in a manner that is objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and / or feels an effect). In particular, the effect may be observed (e.g. measured) in a manner that is objective, using appropriate tests as known to those skilled in the art. Pharmaceutical compositions

[0108] As described herein, compounds of the invention are useful as pharmaceuticals. Such compounds may be administered alone or may be administered by way of known pharmaceutical compositions / formulations.

[0109] In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as defined herein, in combination with a pharmaceutically-acceptable excipient.

[0110] As used herein, the term pharmaceutically-acceptable excipients includes references to vehicles, adjuvants, carriers, diluents, pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like. In particular, such excipients may include adjuvants, diluents or carriers.

[0111] For the avoidance of doubt, references herein to compounds of the invention being for particular uses (and, similarly, to uses and methods of use relating to compounds of the invention) may also apply to pharmaceutical compositions comprising compounds of the invention, as described herein.

[0112] Thus, in a fifth aspect of the invention, there is provided a pharmaceutical composition as defined in the fourth aspect of the invention for use in the treatment or prevention of a disease or condition in which the inhibition of cyclophilin D is desired or required (as defined herein, with reference to the third aspect of the invention and all embodiments thereof), for example in the treatment or prevention of a disease or condition selected from the group consisting of acute pancreatitis, myocardial infarction, acute ischaemic stroke, acute tubular necrosis, acute hepatic injury and failure, neurodegenerative diseases and muscular dystrophy. In one embodiment, the pharmaceutical composition is for use in the treatment of acute pancreatitis.

[0113] The skilled person will understand that compounds of the invention may act systemically and / or locally (i.e. at a particular site), and may therefore be administered accordingly using suitable techniques known to those skilled in the art.

[0114] The skilled person will understand that compounds and compositions as described herein will normally be administered orally, intravenously, intraperitoneally, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form. Compounds of the invention, and pharmaceutical compositions containing such compounds, are particularly suited for administration intravenously.

[0115] Pharmaceutical compositions as described herein will include compositions in the form, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. Alternatively, particularly where such compounds of the invention act locally, pharmaceutical compositions may be formulated for topical administration.

[0116] Thus, in particular embodiments, the pharmaceutical composition is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical administration. Pharmaceutical compositions that may be particularly mentioned are injectable formulations, including formulations that are prepackaged and sold in a syringe or other injector. For the avoidance of doubt, in such embodiments, compounds of the invention may be present as a solid (e.g. a solid dispersion), liquid (e.g. in solution) or in other forms, such as in the form of micelles.

[0117] For example, in the preparation of pharmaceutical compositions for oral administration, the compound may be mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or compressed into tablets.

[0118] Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Similarly, hard gelatin capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

[0119] Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

[0120] Solutions for parenteral administration may be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and / or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.

[0121] Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical compositions that may be mentioned include those in which the active ingredient is present in an amount that is at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.

[0122] The skilled person will understand that compounds of the invention may be administered (for example, as formulations as described hereinabove) at varying doses, with suitable doses being readily determined by one of skill in the art. Oral, pulmonary and topical dosages (and subcutaneous dosages, although these dosages may be relatively lower) may range from about 0.01 pg / kg of body weight per day (pg / kg / day) to about 30 mg / kg / day, e.g. from about 0.01 to about 200 pg / kg / day, preferably from about 0.01 to about 10 pg / kg / day, and more preferably from about 0.1 to about 5.0 pg / kg / day. For example, when administered orally, treatment with such compounds may comprise administration of a formulation typically containing between about 0.01 pg to about 2000 mg, for example between about 0.1 pg to about 500 mg, or between 1 pg to about 100 mg (e.g. about 20 pg to about 80 mg), of the active ingredient(s). When administered intravenously, the most preferred doses will range from about 0.001 to about 10 pg / kg / hour during constant rate infusion. Advantageously, treatment may comprise administration of such compounds and compositions in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily (e.g. twice daily with reference to the doses described herein, such as a dose of 25 mg, 50 mg, 100 mg or 200 mg twice daily).

[0123] When used herein in relation to a specific value (such as an amount), the term "about" (or similar terms, such as "approximately") will be understood as indicating that such values may vary by up to 10% (particularly, up to 5%, such as up to 1%) of the value defined. It is contemplated that, at each instance, such terms may be replaced with the notation "±10%", or the like (or by indicating a variance of a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted.

[0124] For the avoidance of doubt, the skilled person (e.g. the physician) will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. Although the above- mentioned dosages are exemplary of the average case, there can, of course, be individual instances where higher or lower dosage ranges are merited, and such doses are within the scope of the invention.

[0125] Preparation of compounds / compositions

[0126] Pharmaceutical compositions as described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0127] Thus, in a further aspect of the invention there is provided a process for the preparation of a pharmaceutical composition, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically-acceptable excipient. Compounds of the invention as described herein may be prepared in accordance with techniques that are well known to those skilled in the art, such as those described in the examples provided hereinafter. Moreover, by utilizing the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds that fall within the scope of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0128] According to a further aspect of the invention there is provided a process for the preparation of a compound of the invention as hereinbefore defined, comprising the step of:

[0129] (i) reaction of a corresponding compound of formula II, wherein R1, R2and R8bare as hereinbefore defined, and Xais a H or protecting group (such as butyloxycarbonyl, benzyl carbamate, trifluoroacetamide, 9-fluorenylmethyl carbamate), with a compound of formula III,

[0130] Wherein R3' R4, R5, R6, R7, R8aand X1to X6(as well as the ring containing X1to X6) is as hereinbefore defined and Xbrepresents a leaving group (e.g. imidazole, triazole, benzotriazole, tetrazole, thiazole, thiodiazole or oxadiazole), in the presence of a suitable catalyst (e.g. 4-dimethylaminopyridine (DMAP) or pyridine), together with a suitable base such as EtsN, ( / -Pr Net, NazCCh, K3PO4, CS2CO3, NaOH, KOH, K2CO3, CsF, t-BuONa or t-BuOK (or mixtures thereof) in a suitable solvent such as acetonitrile, dioxane, toluene, ethanol, dimethylformamide, ethylene glycol, dimethyl ether, water, dimethylsulfoxide (DMSO), dimethylacetamide, / V-methylpyrrolidinone (NMP), tetrahydrofuran, dimethoxyethane (DME) or mixtures thereof under standard conditions known to those skilled in the art (e.g. optionally in an inert atmosphere); or (ii) deprotection of a compound of formula I in which one or more hydroxyl groups is protected with an ether protecting group (such as silyl ether, a tert-butyl, benzyl, allyl, or methoxymethyl ether, preferably a tert-butyl ether), which deprotection may be performed under conditions known to a person skilled in the art, for example in the presence of tetra-n-butylammonium fluoride (as is commonly used for silyl ether deprotection, or an acid (such as trifluoroacetic acid, hydrochloric acid or p-toluenesulphonic acid) or a base (such as potassium carbonate), for example in the presence of a suitable organic solvent (e.g. dioxane, THF, MeCN, diethyl ether, EtOAc, DCM or DMF).

[0131] Compounds of formulae II are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia "Comprehensive Organic Synthesis" by B. M. Trost and I. Fleming, Pergamon Press, 1991. Further references that may be employed include "Heterocyclic Chemistry" by J. A. Joule, K. Mills and G. F. Smith, 3rdedition, published by Chapman & Hall, "Comprehensive Heterocyclic Chemistry II" by A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, 1996 and "Science of Synthesis", Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

[0132] In particular, compounds of formula II may be prepared by reaction of a compound of formula IV, wherein R1is as hereinbefore defined, with a compound of formula V,

[0133] Wherein R2and R8bis as hereinbefore defined, in the presence of a suitable coupling reagent (e.g. l,l'-carbonyldiimidazole, / V, / Vz-dicyclohexylcarbodiimide, 1-hydroxy- benzotriazole (HOBt), l-hydroxy-7-aza-benzotriazole (HOAt), (1- [Bis(dimethylamino)methylene-lH-l,2,3-triazolol[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), l,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide (T3P), or the like), or, alternatively the -C(O)OH group may first be activated to the corresponding acyl halide (e.g. -C(O)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), together with a suitable base such as ( / -Pr)2NEt, EtsN, Na2COs, K3PO4, Cs2CO3, NaOH, KOH, K2COs, CsF, t-BuONa or t-BuOK (or mixtures thereof) in a suitable solvent such as dimethylformamide (DMF), dioxane, toluene, ethanol, ethylene glycol, dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N- methylpyrrolidinone, tetra hydrofuran, di methoxyethane (DME) or mixtures thereof (preferably a polar aprotic solvent is employed, e.g. DMF) under standard conditions known to those skilled in the art (e.g. optionally in an inert atmosphere);

[0134] Compounds of formula IV may be prepared by reaction of a compound of formula VI,

[0135] Cbz with a compound of formula VII,

[0136] Xc— R1(vii) wherein R1is as hereinbefore defined and Xcrepresents a suitable leaving group, such as iodo, bromo, chloro or sulfonate group (e.g. -OS(O)2CFs, -OS(O)2CHs or -OS(O)2PhMe) (most preferably X2represents bromo or chloro), in the presence of a suitable base such as Na2COs, K3PO4, CS2CO3, NaH, NaOH, KOH, K2CO3, CsF, EtsN, (i- Pr)2NEt, t-BuONa or t-BuOK (or mixtures thereof), in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, dimethoxyethane (DME) or mixtures thereof (preferably a polar aprotic solvent is employed), This reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof such as Pd2(dba)3, PdCl2, Pd(OAc)2, Pd(Ph3P)2Cl2, or Pd(PhsP)4 (i.e. palladium tetrakistriphenylphosphine), and a ligand such as t-BusP, (CeHi sP, PF13P, AsPhs, P(o- Tol)3, 2-dicyclohexylphosphino-2'-(N,Ndimethylamino)biphenyl, 1,2- bis(diphenylphosphino)-ethane, 2,2'-bis(di-tent-butylphosphino)-l,l'-biphenyl, 2,2'- bis(diphenyl-phosphino)-l,l'-bi-naphfihyl, l,l'-bis(diphenylphosphino-ferrocene), l,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof, under suitable conditions know to the person skilled in the art, e.g. for a Buchwald-Hartwig Cross Coupling Reaction.

[0137] Furthermore, compounds of formula IV may also be prepared by reaction of a compound of formula VIII,

[0138] BocHNHN — R1(vni) wherein R1is as hereinbefore defined, with a compound of formula IX, wherein Xdand Xeboth represent a suitable leaving group, such as iodo, bromo, chloro, or sulfonate group (e.g. -OS(O)2CF3, -OS(O)2CH3 or -OS(O)2PhMe) (most preferably X2represents bromo or chloro), in the presence of a suitable organic base such as n-butyl lithium (n-BuLi), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), EtsN, 2, 2,6,6- tetramethylpiperidine (TMP), (i-Pr)2NEt, t-BuONa or t-BuOK or mixtures thereof, in a suitable solvent such as tetra hydrofuran (THF), dichloromethane (DCM), ethyl acetate, acetonitrile, chloroform, diethyl ether, dioxane, dimethyl formamide, toluene or mixtures thereof (preferably a polar aprotic solvent is employed) under standard conditions known to those skilled in the art (e.g . optionally in an inert atmosphere).

[0139] A compound of formula VI may be prepared by reaction of a compound of formula X,

[0140] BocHN— NHCbz (X) with a compound of formula IX in the presence of a suitable base such as sodium hydride, an organolithium reagent (e.g. n-butyllithium, tert-butyllithium, methyllithium), EtsN, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2, 2,6,6- tetramethylpiperidine (TMP), (i-Pr)2Net, t-BuONa or t-BuOK or mixtures thereof in a suitable solvent such as tetra hydrofuran (THF), dichloromethane (DCM), ethyl acetate, acetonitrile, chloroform, diethyl ether, dioxane, dimethyl formamide, toluene or mixtures thereof (preferably a polar aprotic solvent is employed) under standard conditions known to those skilled in the art (e.g . optionally in an inert atmosphere). Similarly, compounds of formulae III are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions.

[0141] In particular, compounds of formula III, in which R4and R5both represent H, may be prepared by reaction of compounds of formula XI, wherein R3, R5, R6, R7, R8aand X1to X6(as well as the ring containing X1to X6) is as hereinbefore defined, with a suitable reagent, such as carbonyldiimidazole (CDI), in the presence of a suitable catalyst (e.g. 4-dimethylaminopyridine (DMAP) or pyridine), in a suitable solvent such as tetra hydrofuran (THF), dichloromethane (DCM), ethyl acetate, acetonitrile, chloroform, diethyl ether, dioxane, dimethyl formamide, toluene or mixtures thereof (preferably a polar aprotic solvent is employed) under standard conditions known to those skilled in the art (e.g. optionally in an inert atmosphere).

[0142] Compounds of formula III in which R4and R5are linked to form a 5- to 10- membered heterocyclic bicyclic ring optionally substituted by one or more substituents may be prepared by reaction of a compound of formula XI with a compound of formula XII, in the presence of montmorillonite in a suitable solvent, such as dimethylformamide (DMF), dioxane, toluene, ethanol, ethylene glycol, dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, di methoxyethane (DME) or mixtures thereof (preferably a polar aprotic solvent is employed). The skilled person will understand that the substituents as defined herein, and substituents thereon, may be modified one or more times, after or during the processes described above for the preparation of compounds of the invention by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, dehydrogenations, alkylations, dealkylations, acylations, hydrolyses, esterifications, etherifications, halogenations, and nitrations. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. The skilled person may also refer to "Comprehensive Organic Functional Group Transformations" by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995 and / or "Comprehensive Organic Transformations" by R. C. Larock, Wiley-VCH, 1999.

[0143] Compounds of the invention may be isolated from their reaction mixtures and, if necessary, purified using conventional techniques as known to those skilled in the art. Thus, processes for preparation of compounds of the invention as described herein may include, as a final step, isolation and optionally purification of the compound of the invention.

[0144] It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups. The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.

[0145] Protecting groups may be applied and removed in accordance with techniques that are well-known to those skilled in the art and as described hereinafter. For example, protected compounds / intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.

[0146] Without wishing to be bound by theory, it is believed that compounds of the invention function as cyclophilin D (CypD) inhibitors through which they inhibit MPTP opening and cell necrosis and thereby are useful in treating acute pancreatitis and other MPTP- related diseases. Furthermore, it is believed that the use of a chiral pyrazolidine (Pz) moiety in the core structure provides a conformational cis bias at the pyrazolidine ring (i.e. there is conformational pre-organisation of the pyrazolidine ring), and this preorganisation increases binding affinity for CypD on entropic grounds, thus enhancing the inhibition of CypD-mediated MPTP opening.

[0147] Compounds of the invention may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and / or have a better pharmacokinetic profile (e.g. higher oral bioavailability and / or lower clearance) than, and / or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise. In particular, compounds of the invention may have the advantage that they are more efficacious and / or exhibit advantageous properties in vivo.

[0148] Figures

[0149] Figure 1 shows mitochondrial Ca2+Retention Capacity screening of example compounds, showing number of calcium pulses sustained by mitochondria before collapse of mitochondrial membrane potential in presence of 10 pM cyclosporine A (CsA) or example compounds (DMSO is negative control).

[0150] Figure 2 shows specificity of inhibitors for CypD, as shown by testing mitochondrial Ca2+retention capacity (CRC) using mitochondria from constitutive CypD knockout mice, demonstrating equal Ca2+retention with negative control (DMSO), positive control (cyclosporine, CsA) or example compounds 2, 17, 53 and 59, with no further increase in Ca2+retention capacity, indicating an absence of effect through other mechanisms.

[0151] Figure 3 shows inhibition of necrosis induced by taurolithocholate acid sulphate in murine pancreatic acinar cells as a result of protection by cyclosporine (CsA) or compounds 53, 56 or 59 at either 0.1, 1.0 or 10 pM.

[0152] Figure 4 shows the concentration-dependence for mitochondrial Ca2+retention capacity of the Compound 59.

[0153] Figure 5 shows the half-maximal effective concentrations of cyclosporine (Figure 5A), Compound 53 (Figure 5B) and Compound 59 (Figure 5C). Figure 6 shows the mean plasma concentration-time profiles of compound 59 and compound 65 after single dose administration in male CD1 mice.

[0154] Figure 7 shows effects of CypD inhibition on ameliorating acute pancreatitis in mice.

[0155] Figure 8 shows the mitochondrial Ca2+retention capacity of various compounds.

[0156] Figure 9 shows the concentration-dependence for mitochondrial Ca2+retention capacity of the Compound 65.

[0157] Figure 10 shows the effect of selected compounds on mitochondrial CRC at concentrations below 10 pM.

[0158] For the avoidance of doubt, the numbering used in figure legends refers to the numbering of compounds of the examples as provided herein.

[0159] Examples

[0160] The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention.

[0161] In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context).

[0162] Experimental procedures

[0163] Starting materials and intermediates used in the synthesis of compounds described herein are commercially available or can be prepared by the methods described herein or by methods known in the art.

[0164] All reactions that employed moisture sensitive reagents were performed in dry solvent under an atmosphere of nitrogen in oven dried glassware. All reagents were purchased from Sigma-Aldrich, Fluorochem, Apollo or Alfa Aesar and were used without purification. Thin layer chromatography (TLC) was carried out on Merck silica gel 60 F- 254 plates. Flash column chromatography was performed on Aldrich silica gel (technical grade, pore size 60 A, 230-400 mesh particle size, 40-63 particle size), eluting with various solvent mixtures and using an air line to apply pressure.XH and13C NMR spectra were recorded on Bruker (400 or 500 MHz) NMR spectrometers. Data analyses are reported as follows: chemical shift relative to TMS (6, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), coupling constant (J, Hz), integration.

[0165] High resolution mass spectrometry (HRMS) was recorded on an Agilent QToF 7200 mass spectrometer using ESI. Melting point was determined on Griffin Melting Point Apparatus / Gallenkamp Melting Point Apparatus.

[0166] Purity determination was performed by HPLC analysis using an Agilent 1200 solvent delivery system. The HPLC methods used the following conditions: Agilent Poroshell 120 EC-C18 (4.6 x 100 mm 4 pm) at 25 °C with 1.0 mL / min flow rate. Solvents - A) water containing 0.1% formic acid and B) acetonitrile containing 0.1% formic acid; run time: 18 min, gradient: 2% B hold to 1 min, 2-98% B in 11 min, then hold at 98% B to 15 min, at 15.01 back to 2%B until run ends.

[0167] Where applicable, compound names indicated in respect of the following examples have been generated using the structure naming function of ChemDraw Professional, Version 20.0.

[0168] General Procedures

[0169] General Chemical Syntheses:

[0170] Route 1 was used to synthesise Compounds 11-13, 28-31, 33-43, and 46-48.

[0171] The conditions for each synthetic step outlined in Route 1 are as below:

[0172] (i) DMF, 0°C, NaH, Ih then RT, CH2BrCH2CH2Br

[0173] (ii) EtOAc, Pd / C, H2, RT then Toluene, CsCO3, tBuXPhos, Rl-LG, Pd2(dba)3, RT

[0174] (iii) DCM, TFA, RT then Dry DMF, boc-glycine, DIPEA, HATU, RT

[0175] (iv) DCM, 0°C, CDI, DMAP, RT

[0176] (v) DCM, TFA, RT then MeCN, Et3N, DMAP, RT

[0177] Route 2 was used to synthesise Compounds 1-10, 14-20 and 27.

[0178] The conditions for each synthetic step outlined in Route 2 are as below:

[0179] (i) THF, Boc Anhydride Et3N, RT

[0180] (ii) THF, -78°C, n-BuLi, 0°C, BrCH2CH2CH2Br, 0°C, RT

[0181] (iii) DCM, TFA, RT then Dry DMF, boc-glycine, DIPEA, HATU, RT

[0182] (iv) DCM, 0°C, CDI, DMAP, RT

[0183] (v) DCM, TFA, RT then MeCN, Et3N, DMAP, RT

[0184] Route 3 was used to synthesise Compounds 52-63 and 65, and Reference compound 64.

[0185] The conditions for each synthetic step outlined in Route 3 are as below:

[0186] (i) THF, Boc Anhydride, Et3N, RT

[0187] (ii) MeCN, 2-deoxy-d-ribose (1), montmorillonite, RT

[0188] (iii) DCM, pyridine, 0°C, TBDMS triflate, RT

[0189] (iv) DCM, TFA, RT then DCM, DMAP, 0°C, CDI, RT

[0190] (v) DCM, TFA, RT then Dry MeCN, 2, Et3N, DMAP, RT

[0191] (vi) THF, TBAF, RT

[0192] Route 4 was used to synthesise Compounds 21-26.

[0193]

[0194] The conditions for each synthetic step outlined in Route 4 are as below:

[0195] (i) MeOH, 0°C, Thionyl Chloride

[0196] (ii) MeOH, NaOH, di-tert-butyl decarbonate

[0197] (iii) Acetone, K3CO3, allyl bromide, KI

[0198] (iv) DCM, MEOH, -78°C, ozone

[0199] (v) MeCN, morpholine, acetic acid.

[0200] (vi) MeOH, NaOH

[0201] (vii) DCM, TFA then Dry DMF, 3, DIPEA

[0202] (viii) DCM, TFA then MeCN, 4, Et3N, DMAP

[0203] Route 5 was used to synthesise Reference compounds 49-51.

[0204] X = F or OMe

[0205] The conditions for each synthetic step outlined in Route 5 are as below:

[0206] (i) Dry DMF, boc-glycine, DIPEA, HATU

[0207] (ii) DCM, TFA then Dry MeCN, DMAP, Et3N

[0208] Synthesis of intermediates

[0209] Intermediate 1

[0210] 1-benzyl 2- (tert- butyl) pyrazolidine-l,2-dicarboxylate BocNs

[0211] N Cbz

[0212] A solution of 1-benzyl 2-(tert-butyl) hydrazine-1, 2-dicarboxylate (1.03 g, 3.88 mmol, 1 eq) in DMF (7.8 mL) was cooled to 0°C, sodium hydride (0.31 g, 7.76 mmol, 2 eq) was added. The reaction mixture was left to stir for 1 hour then warm to room temperature for 2 hours before addition of 1,3-dibromopropane (0.40 ml, 3.88 mmol, 1 eq). The reaction mixture was allowed to stir at room temperature overnight before addition of EtOAc (50 ml) to the reaction mixture which was then washed with sat. NaHCCh (3 x 100 mL) followed by distilled water (50 mL) and brine (50 mL). The organic phases were dried over MgSC and purified by FCC (SiC ; 50:50 EtOAc: Hexane) to yield an orange / brown oil (0.53 g, 45%).XH NMR (400 MHz; CDCI3; ppm) 6 7.41-7.26 (m, 5H), 5.19 (s, 2H), 3.99-3.85 (unresolved, 2H), 3.35-3.15 (m, 2H), 2.07-1.98 (m, 2H), 1.42 (s, 9H).13C NMR (101 MHz; CDCI3) 6 156.1, 141.1, 128.9 (2C), 128.5 (2C), 127.7, 125.2, 81.0, 65.2, 46.3, 31.6, 28.2 (3C). HRMS (ES+) 329.1368 [M+Na]+Ci6H22N2O4Na requires 329.1477 (Diff -2.8 ppm).

[0213] Intermediate 2 tert- Butyl py razol id i ne- 1 -ca rboxy late

[0214] BocN„

[0215] N H

[0216] To a solution of 1-Benzyl 2- (tert- butyl) pyrazolidine-1, 2-dicarboxylate (1 g, 3.26 mmol, 1 eq) in ethyl acetate (16 ml) was added 10 wt.% Pd / C (0.98 g) under N2, after which the reaction was allowed to stir at room temperature under an H2 atmosphere for 16 hrs. The reaction was monitored by TLC. Upon completion, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the titled compound as a colourless oil (0.55 g, 98%), no further purification was required.XH NMR (400 MHz; CDCI3; ppm) 3.92 (s, 1H), 3.46 (t, J = 7.3 Hz, 2H), 3.06 (t, J = 7.3 Hz, 2H), 2.10-1.98 (m, 2H), 1.49 (s, 9H).13C NMR (101 MHz, CDCI3) 6 156.1, 81.0, 46.3, 31.6, 28.2 (3C). LRMS (CI) 71.1 [M-Boc]+requires C3H7N2 71.1.

[0217] Intermediate 3

[0218] 2-Bromo-l-chloro-4-methoxybenzene

[0219] To a solution of 3-bromo-4-chlorophenol (0.40 g, 1.93 mmol, 1 eq) and potassium carbonate (0.43 g, 3.09 mmol, 1.6 eq) in acetone (0.2 M, 7.7 mL), iodomethane (0.18 mL, 2.89 mmol, 1.5 eq) was added dropwise and reaction mixture was allowed to stir at room temperature overnight. EtOAc (10 ml) was added to the reaction mixture and washed with sat. aq. NaHCCh (3 x 10 mL), distilled water (10 mL) and brine (10 ml) then dried over MgSC . The crude product was purified by FCC (SiC ; 20:80 EtOAc: Hexane) to afford the titled compound as a clear yellow oil (0.23 g, 53%).XH NMR (400 MHz; CDCI3; ppm) 6 7.33 (d, J = 9.0 Hz, 1H) 7.16 (d, J = 3.0 Hz, 1H), 6.80 (dd, J = 9.0, 3.0 Hz, 1H), 3.79 (s, 3H).13C NMR (101 MHz; CDCI3) 6 158.6, 130.5,

[0220] 122.9, 122.6, 118.8, 114.8, 55.8. LRMS (CI) 220.9 [M + H]+C7H679BrO35CIH requires

[0221] 220.9.

[0222] Intermediate 4 tert-Butyl 2-(2-chloro-5-methoxyphenyl)pyrazolidine-l-carboxylate

[0223] To a solution of tert-Butyl pyrazolidine-l-carboxylate (0.22 g, 1.24 mmol, 1.1 eq) in toluene (10 mL), was added CS2CO3 (1.29 g, 3.39 mmol, 3.5 eq), tBuXPhos (48 mg, 0.11 mmol, 0.1 eq) and 2-Bromo-l-chloro-4-methoxybenzene (0.25 g, 1.13 mmol, 1 eq). The reaction mixture was evacuated and flushed with N2 twice before Pd2(dba)3 (52 mg, 0.056 mmol, 0.05 eq) was added and the reaction mixture was allowed to reflux overnight. After this time, the reaction mixture was cooled to room temperature and extracted with EtOAc (x 2), washed with brine, dried over MgS04, filtered and concentrated in vacuo to yield the crude product. The crude product was purified was purified by FCC (SiO2; 20:80 EtOAc:Hexane) to afford the titled compound as a yellow oil (0.10 g, 28%).XH NMR (400 MHz; CDCI3; ppm) 6 7.16 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 2.8 Hz, 1H), 6.45 (dd, J = 8.2, 2.8 Hz, 1H), 3.68 (s, 3H), 3.66 (t, J = 7.0 Hz, 2H), 3.47 (t, J = 7.0 Hz, 2H), 2.01-1.93 (m, 2H), 1.34 (s, 9H).13C NMR (101 MHz; CDCI3) 6 158.8, 149.6, 131.1, 120.0, 116.6, 109.1, 105.5, 80.8, 55.5, 55.0, 46.0, 30.9, 28.3 (3C). LRMS (ES+) 335.1 [M+Na]+C15H21O3N2CIH requires 335.1.

[0224] Intermediate 5 tert-Butyl 2-(2-chloro-5-methoxyphenyl)pyrazolidine-l-carboxylate tert-Butyl 2-(2-chloro-5-methoxyphenyl)pyrazolidine-l-carboxylate (0.24 g, 0.76 mmol, 1 eq) was dissolved in a mixture of DCM :TFA (5: 1, 7.5 mL, ~ lOmL / mmol) and the reaction mixture was allowed to stir at room temperature until TLC showed disappearance of starting material. The reaction mixture was concentrated in vacuo to afford the free amine as a trifluoroacetate salt and was used directly without further purification.

[0225] To a solution of the trifluoroacetate salt of the amine (0.25 g, 0.76 mmol, 1 eq) in anhydrous DMF (7.5 mL), was added boc-glycine (0.16 g, 0.92 mmol, 1.2 eq), DIPEA (0.33 mL, 1.91 mmol, 2.5 eq) and HATU (0.38 g, 0.99 mmol, 1.3 eq). The reaction mixture was allowed to stir at room temperature overnight under N2 (followed by TLC). Upon completion, the solution was diluted with EtOAc and washed with sat. aq. NaHCCh (x 3), water and brine. The organic layer was dried over MgSC and concentrated in vacuo. The crude product was purified by FCC (SiC ; 20:80 EtOAc: Hexane) to afford the titled compound as an orange / brown oil (0.24 g, 84%).XH NMR (400 MHz; CDCI3; ppm) 6 7.16 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 2.8 Hz, 1H), 6.45 (dd, J = 8.4, 2.8 Hz, 1H), 5.16 (s, INH), 3.68 (s, 3H) 3.66 (t, J = 7.0 Hz, 2H), 3.47 (t, J = 7.0 Hz, 2H), 3.42 (s, 1H), 4.4-3.2 (m, 6H), 2.01-1.93 (unresolved m, 2H), 1.35 (s, 9H).13C NMR (101 MHz; CDCI3) 6 170.8, 159.0, 155.8, 147.9, 131.6, 116.9, 109.8, 105.5, 79.5, 60.4, 55.6, 55.4, 45.0, 42.5, 28.4 (3C). HRMS (ES+) 392.1345 [M + Na]+Ci7H24N3O4Na requires 392.1353 (Diff -2.1 ppm).

[0226] Intermediate 6

[0227] / V-(4-Aminobenzyl)-l / - / -imidazole-l-carboxamide

[0228] 4-Aminobenzylamine (0.46 ml, 4.09 mmol, 1 eq) was dissolved in DCM (41 mL) and the reaction mixture was allowed to cool to 0 °C. CDI (730 mg, 4.50 mmol, 1.1 eq) and DMAP (50 mg, 0.41 mmol, 0.1 eq) were added and the reaction mixture was allowed to stir at r.t. overnight. After this time, the reaction mixture was diluted with EtOAc (10 mL) and washed with water (30 mL). The organic layer was dried over MgS04, filtered and concentrated in vacuo to yield a yellow solid that required no further purification (849 mg, 3.93 mmol, 96%).XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 8.21 (1H, s), 7.57 (1H, s), 7.07 (2H, d, J = 8.3), 6.99 (1H, s), 6.65 (2H, d, J = 8.3), 4.34 (2H, s);13C NMR (100 MHz; CD3OD; Me4Si) 6 149.2, 148.4, 136.4, 130.0, 129.0, 125.7, 117.0, 114.2, 43.8. Intermediate 7 tert-Butyl 2-(3-cyanophenyl)pyrazolidine-l-carboxylate tert-Butyl pyrazolidine-l-carboxylate (230 mg, 1.34 mmol) and methyl 3- bromobenzonitrile (244 mg, 1.34 mmol) were employed. The crude product was purified by flash column chromatography eluting with 10% EtOAc in hexane to 20% EtOAc in hexane to yield a yellow solid (296 mg, 1.08 mmol, 81%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.53 (1H, t, J = 8.0), 7.19 - 7.15 (2H, m), 7.11 (1H, ddd, J = 8.0, 2.5, 0.9), 3.61 (2H, br s), 3.56 (2H, t, J = 6.7), 2.05 (2H, ap: quintet, J = 6.7), 1.48 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 156.0, 151.5, 129.7, 124.3, 119.3, 119.2, 117.9, 112.7, 81.6, 53.2, 45.3, 28.3, 25.8; HRMS (ES+) m / z 296.1374 [M+Na]+CisHigNsC Na requires 296.1375 (Diff -0.3 ppm).

[0229] Intermediate 8 tert-Butyl (2-(2-(3-cyanophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(3-cyanophenyl)pyrazolidine-l-carboxylate (266 mg, 0.97 mmol) was employed. The reaction yielded a green oil that was taken directly to the next step.

[0230] The TFA salt of the amine (278 mg, 0.97 mmol) was employed. The crude product was purified by flash column chromatography eluting with 50% EtOAc in hexane to yield a pale yellow oil (278 mg, 0.84 mmol, 87%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.39 (1H, ap: t, J = 7.8), 7.30 (1H, d, J = 7.8), 7.22 (1H, s), 7.18 (1H, d, J = 7.8), 5.25 (1H, s), 4.31 (1H, br s), 4.27 (1H, br s), 3.71 (1H, br s), 3.67 (1H, br s), 3.38 (2H, t, J = 7.9), 2.12 (1H, br s), 1.98 (1H, br s), 1.43 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 171.9, 155.8, 150.8, 130.4, 126.4, 120.3, 118.9, 118.5, 113.5, 79.7, 55.0, 43.0, 42.4, 28.3, 24.4; HRMS (ES+) m / z 353.1588 [M + Na]+Ci7H22N4O3Na requires 353.1590 (Diff -0.5 ppm). Intermediate 9 l-(benzyloxy)-3-bromobenzene

[0231] To a solution of 3-bromophenol (1.00 g, 5.78 mmol, 1.00 eq) and K2CO3 (1.28 g, 9.25 mmol, 1.60 eq) in acetone (29 ml) benzyl bromide (1.03 ml, 8.67 mmol, 1.50 eq) was added dropwise. The reaction mixture was allowed to stir at room temperature overnight before EtOAc (50 ml) was added. The reaction mixture was then washed with sat. NaHCO3 (3 x 100 ml) followed by distilled water (50 ml) and brine (50 ml). The organic phases were dried over MgSO4 and concentrated in vacuo. No further purification was required to afford a white solid (1.52 g, 100%).XH NMR (400 MHz; CDCI3; ppm) 6 7.38-7.25 (m, 5H), 7.13-7.10 (m, 1H), 7.07-7.03 (m, 2H), 6.87-6.84 (m, 1H), 4.93 (s, 2H).13C NMR (101 MHz; CDCI3) 6 159.7, 136.5, 129.2, 128.9 (2C), 128.3, 127.7 (2C), 124.2, 123.0, 118.3, 114.0, 70.3. LRMS (CI) 263.0 [M + H]+Ci3Hn79BrONa requires 263.0.

[0232] Intermediate 10 l-(benzyloxy)-3-bromobenzene

[0233] To a solution of 3-bromophenol (1.00 g, 5.78 mmol, 1.00 eq) and K2CO3 (1.28 g, 9.25 mmol, 1.60 eq) in acetone (29 ml) benzyl bromide (1.03 ml, 8.67 mmol, 1.50 eq) was added dropwise. The reaction mixture was allowed to stir at room temperature overnight before EtOAc (50 ml) was added. The reaction mixture was then washed with sat. NaHCO3 (3 x 100 ml) followed by distilled water (50 ml) and brine (50 ml). The organic phases were dried over MgSO4 and concentrated in vacuo. No further purification was required to afford a white solid (1.52 g, 100%).XH NMR (400 MHz; CDCI3; ppm) 6 7.38-7.25 (m, 5H), 7.13-7.10 (m, 1H), 7.07-7.03 (m, 2H), 6.87-6.84 (m, 1H), 4.93 (s, 2H).13C NMR (101 MHz; CDCI3) 6 159.7, 136.5, 129.2, 128.9 (2C), 128.3, 127.7 (2C), 124.2, 123.0, 118.3, 114.0, 70.3. LRMS (CI) 263.0 [M + H]+Ci3Hn79BrONa requires 263.0.

[0234] Intermediate 11 tert-butyl 2-(3-(benzyloxy)phenyl)azapyrrolidine-l-carboxylate l-(benzyloxy)-3-bromobenzene (0.20 g, 0.74 mmol) was employed. The crude product was purified by FCC (SiC ; 20:80 EtOAc: Hexane) to afford the titled compound as a yellow oil (0.10 g, 39%).XH NMR (400 MHz; CDCI3; ppm) 6 7.46-7.36 (m, 5H), 7.33-7.29 (m, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.60 (m, 1H), 6.55 (dd, J = 8.0, 2.4 Hz, 1H), 5.03 (s, 2H), 3.58 (unresolved t, 2H), 3.52 (t, J = 6.8 Hz, 2H), 1.98 (br s, 2H), 1.47 (s, 9H).13C NMR (101 MHz; CDCI3) 6 159.6, 155.7, 152.7, 137.1, 129.6, 128.6 (2C), 127.9, 127.6 (2C), 108.6, 107.3, 102.9, 80.8, 70.0, 60.5, 54.2, 44.9, 28.4 (3C).

[0235] Intermediate 12 tert-butyl (2-(2-(3-(benzyloxy)phenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(3-(benzyloxy)phenyl)azapyrrolidine-l-carboxylate (0.10 g, 0.29 mmol) was employed. The crude product was purified by FCC (SiCh; 20:80 EtOAc:Hexane) to afford the titled compound as a yellow oil (0.049 g, 42%).XH NMR (400 MHz; CDCI3; ppm) 6 7.40-7.30 (m, 5H), 7.19-7.15 (m, 1H), 6.64-6.61 (m, 1H), 6.56-6.52 (m, 2H), 5.25 (s, NH), 5.04 (s, 2H), 4.40 (br s, 2H), 3.95 (br s, 2H), 3.75-3.55 (m, 2H), 3.45- 3.15 (m, 2H), 2.08-1.95 (br s, 2H), 1.42 (s, 9H).13C NMR (101 MHz; CDCI3) 6 171.2, 159.8, 155.7, 151.4, 136.8, 130.3, 128.6 (2C), 128.0, 127.5 (2C), 108.9, 108.8, 103.4, 79.5, 70.1, 55.2, 43.0, 42.4, 28.4 (3C). HRMS (ES+) 434.5059 [M + Na]+C23H29N3O4Na requires 434.2056 (Diff 0.7 ppm).

[0236] Intermediate 13 tert-Butyl 2-(isoquinolin-4-yl)pyrazolidine-l-carboxylate tert-Butyl pyrazolidine-l-carboxylate (197 mg, 1.14 mmo) and 4-bromoisoquinoline (237 mg, 1.14 mmol) were employed. The crude product was purified by flash column chromatography eluting with 30% EtOAc in hexane to 40% EtOAc in hexane to yield a yellow oil (262 mg, 0.88 mmol, 77%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.97 (1H, s), 8.28 (1H, d, J = 8.1), 8.21 (1H, s), 7.95 (1H, d, J = 8.1), 7.71 (1H, ddd, J = 8.1, 7.0, 1.2), 7.60 (1H, ddd, J = 8.1, 7.0, 1.2), 3.84 (2H, t, J = 7.3), 3.58 (2H, t, J = 6.6), 2.12 (2H, ap: quintet, J = 7.3, 6.6), 1.42 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 154.3, 148.3, 141.7, 131.5, 129.7, 129.6, 129.1, 127.6, 127.2, 122.9, 80.8, 55.6, 45.9, 28.3, 24.6; HRMS (ES+) m / z 300.1713 [M + H]+C17H22N3O2 requires 300.1712 (Diff 0.3 ppm).

[0237] Intermediate 14 tert-Butyl (2-(2-(isoquinolin-4-yl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(isoquinolin-4-yl)pyrazolidine-l-carboxylate (262 mg, 0.88 mmol, 1 eq) was employed. The reaction yielded a yellow oil that was taken directly to the next step.

[0238] The TFA salt of the amine (175 mg, 0.88 mmol) was employed. The crude product was purified by flash column chromatography eluting with 70% EtOAc in hexane to yield a white solid (213 mg, 0.60 mmol, 68%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 9.03 (1H, s), 8.21 (1H, d, J = 8.2), 8.16 (1H, s), 8.00 (1H, d, J = 8.2), 7.78 (1H, ap: t, J = 7.5), 7.67 (1H, ap: t, J = 7.5), 5.40 (1H, t, J = 4.5), 4.48 (1H, br s), 4.04 (1H, br s), 3.93 (1H, br s), 3.63 (1H, br s), 3.56 (2H, t, J = 6.6), 2.16 (2H, ap: quintet, J = 6.6), 1.40 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 170.2, 155.8, 149.5, 140.3, 131.1, 130.6, 129.3, 129.0, 127.9, 127.8, 122.2, 79.4, 56.1, 44.8, 42.4, 28.3, 23.3; HRMS (ES+) m / z 379.1751 [M + Na]+Ci9H24N4O3Na requires 379.1746 (Diff 1.3 ppm).

[0239] Intermediate 15 benzyl 2-(quinolin-5-yl)pyrazolidine-l-carboxylate Benzyl pyrazolidine-l-carboxylate (327 mg, 1.59 mmol) and 5-bromoquinoline (397 mg, 1.91 mmol) were employed. The crude product was purified by flash column chromatography eluting with 30% EtOAc in hexane to 50% EtOAc in hexane to yield a brown oil (426 mg, 1.28 mmol, 80%). 1H NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.92 (1H, dd, J = 4.2, 1.7), 8.66 (1H, d, J = 8.5), 7.83 (1H, d, J = 8.5), 7.56 (1H, ap: t, J = 8.5), 7.42, 7.40 (1H, ABq, J = 8.5, 4.2), 7.23 (3H, br s), 7.18 (2H, br s), 7.13 (1H, d, J = 7.6), 5.14 (2H, s), 3.90 (2H, t, J = 7.4), 3.55 (2H, t, J = 6.6), 2.11 (2H, ap: quintet, J = 7.4, 6.6); 13C NMR (100 MHz; CDCI3; Me4Si) 6 155.3, 150.3, 149.3, 147.7, 136.5, 132.4, 128.9, 128.3, 127.8, 127.4, 125.3, 122.3, 120.4, 113.7, 67.2, 56.5, 46.1, 24.3; HRMS (CI+) m / z 334.1550 [M + H]+ C20H20N3O2 requires 334.1561 (Diff -3.2 ppm).

[0240] Intermediate 16 l-(4-aminobenzyl)-3-(2-oxo-2-(2-(quinolin-5-yl)pyrazolidin-l-yl)ethyl)urea

[0241] 5-(Pyrazolidin-l-yl)quinoline

[0242] Benzyl 2-(quinolin-5-yl)pyrazolidine-l-carboxylate (426 mg, 1.28 mmol) and 10% Pd / C (68 mg, 0.064 mmol, 5 mol%) were dissolved in EtOH (13 mL) and allowed to stir under a H2 atmosphere at r.t. overnight. After this time, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The reaction yielded a yellow oil that required no further purification (221 mg, 1.11 mmol, 87%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.87 (1H, dd, J = 4.2, 1.7), 8.62 (1H, dd, J = 8.5, 0.8), 7.72 (1H, d, J = 8.5), 7.57 (1H, ap: t, J = 8.5), 7.39 (1H, d, J = 7.7), 7.36, 7.34 (1H, ABq, J = 8.5, 4.2), 3.46 (2H, t, J = 7.3), 3.22 (2H, t, J = 7.3), 2.09 (2H, ap: quintet, J = 7.3);13C NMR (100 MHz; CDCI3; Me4Si) 6 149.9, 144.2, 133.3, 130.5, 129.3, 123.5, 119.5, 119.1, 112.5, 56.2, 46.4, 27.7; MS (ES+) m / z 200 [M + H]+C12H N3 requires 200.

[0243] Intermediate 17 tert-butyl (2-oxo-2-(2-(quinolin-5-yl)pyrazolidin-l-yl)ethyl)carbamate

[0244] 5-(Pyrazolidin-l-yl)quinoline (221 mg, 1.11 mmol) was employed. The crude product was purified by flash column chromatography eluting with 50% EtOAc in hexane to 100% EtOAc to yield a cream solid (338 mg, 0.95 mmol, 86%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.95 (1H, dd, J = 4.1, 1.4), 8.58 (1H, d, J = 8.5), 8.02 (1H, s), 7.88 (1H, d, J = 8.5), 7.57 (1H, ap: t, J = 8.5), 7.47, 7.44 (1H, ABq, J = 8.5, 4.1), 7.08 (1H, d, J = 7.5), 5.27 (1H, br s), 4.43 (1H, br s), 3.96 (2H, br s), 3.52 (2H, m), 2.12 (2H, m), 1.39 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 170.1, 162.5, 155.8, 150.7, 149.3, 146.3, 131.6, 128.8, 126.3, 122.0, 113.6, 79.5, 56.7, 44.8, 42.5, 28.3, 23.2; HRMS (ES+) m / z 379.1747 [M + Na]+Ci9H24N4O3Na requires 379.1746 (Diff 0.2 ppm).

[0245] Intermediate 18 methyl 4-bromo-3-iodobenzoate

[0246] 3-Iodo-4-bromobenzoic acid (500 mg, 1.53 mmol, 1 eq) was dissolved in MeOH (3.1 ml, 0.5 M) and catalytic cone. H2SO4(3-4 drops) was added and the reaction mixture was allowed to reflux overnight. After this time, the reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (25 ml) and water (25 ml) and basified to pH 14 with 2M NaOH. The organic layer was separated before the aqueous layer was washed with EtOAc (2 x 25 ml). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo. The reaction yielded a yellow solid that required no further purification (513 mg, 1.51 mmol, 99%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.50 (1H, d, J = 2.0), 7.85 (1H, dd, J = 8.3, 2.0), 7.70 (1H, d, J = 8.3), 3.92 (3H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 165.0, 141.2, 135.3, 132.7, 130.3, 130.2, 101.0, 52.6; MS (ES+) m / z 363 [M + H+Na]+CsH BrIOzNa requires 363. Intermediate 19 tert-butyl 2-(2-bromo-5-(methoxycarbonyl)phenyl)pyrazolidine-l-carboxylate tert-Butyl pyrazolidine-l-carboxylate (161 mg, 0.94 mmol) and methyl 4-bromo-3- iodobenzoate (319 mg, 0.94 mmol) were employed. The crude product was purified by flash column chromatography eluting with 100% hexane to 10% EtOAc in hexane to yield a pale yellow solid (171 mg, 0.45 mmol, 47%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.70 (1H, d, J = 1.9), 7.60 (1H, d, J = 8.3), 7.56 (1H, dd, J = 8.3, 1.9), 3.90 (3H, s), 3.81 (2H, t, J = 7.2), 3.53 (2H, t, J = 6.7), 2.06 (2H, ap: quintet, J = 6.7), 1.38 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 174.2, 166.4, 150.4, 133.9, 129.8, 125.7, 120.8, 120.5, 80.8, 55.4, 52.3, 46.3, 28.3, 24.5; MS (ES+) m / z 407 [M+Na]+Ci6H2i79BrN2O4Na requires 407 (99%), m / z 409 [M+Na]+Ci6H2i81BrN2O4Na requires 409 (100%).

[0247] Intermediate 20 methyl 4-bromo-3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate tert-Butyl 2-(2-bromo-5-(methoxycarbonyl)phenyl)pyrazolidine-lcarboxylate (171 mg, 0.45 mmol) was employed. The reaction yielded a yellow oil that was taken directly to the next step.

[0248] The TFA salt of the amine (185 mg, 0.48 mmol) was employed. The crude product was purified by triturating with diethyl ether to yield a cream solid (106 mg, 0.24 mmol, 50%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.67 - 7.63 (2H, m), 7.60 (1H, s), 5.22 (1H, s), 4.37 (1H, br s), 4.04 (1H, br s), 3.90 (3H, s), 3.85 (1H, br s), 3.47 (3H, br s), 2.10 (2H, br s), 1.42 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 171.1, 165.9, 155.8, 148.7, 134.5, 130.3, 126.9, 121.2, 120.0, 79.5, 55.9, 52.5, 45.5, 42.6, 28.4, 23.3; HRMS (ES+) m / z 464.0787 [M + Na]+Ci8H2479BrN3O5Na requires 464.0797 (100%) (Diff -2.2 ppm), m / z 466.0775 [M + Na]+Ci8H2481BrN3O5Na requires 466.0777 (98%) (Diff -0.3 ppm).

[0249] Intermediate 21 benzyl 4-bromo-3-iodobenzoate

[0250] To a solution of 4-bromo-3-iodobenzoic acid (652 mg, 2 mmol) in acetone (20 mL) was added potassium carbonate (0.55 g, 4 mmol, 2 eq). The mixture was stirred at room temperature for 15 min. Benzyl bromide (0.36 ml, 3 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temperature for 16 h (followed by TLC). The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (x 2). The combined organic layers were dried over MgSC , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (SiC ; gradient elution, hexane to 1% EtOAc in hexane) to yield the title compound a colourless oil (782 mg, 94%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.47 (1H, d, J = 2.0), 7.84 (1H, dd, J = 8.5, 2.0), 7.65 (1H, d, J = 8.5), 7.29 - 7.24 (5H, m), 5.48 (2H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 168.3, 140.8, 137.2, 134.9, 132.8, 130.1, 129.8, 128.4, 128.2, 128.1, 101.5, 67.2; HRMS (ES+) m / z 438.8811 [M+Na]+Ci4HioBrINa02 requires 438.8807 (100%) (Diff 0.68 ppm).

[0251] Intermediate 22 tert-butyl 2-(2-bromo-5-(benzyloxycarbonyl)phenyl)pyrazolidine-l-carboxylate

[0252] Benzyl 4-bromo-3-iodobenzoate (712 mg, 1.71 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; gradient elution, hexane to 5% EtOAc in hexane) to yield the title compound as a pale yellow oil (567 mg, 72%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.54 (1H, d, J = 8.5), 7.42 (1H, dd, J = 8.5, 2.0), 1. 7 - 7.21 (5H, m), 7.09 (1H, d, J = 2.0), 5.43 (2H, s), 3.69 - 3.65 (2H, m), 3.50 (2H, br s), 2.17 (2H, quintet, J = 6.5), 1.43 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 166.8, 165.1, 149.4, 136.9, 134.2, 130.2, 128.6, 128.2, 122.0, 120.6, 114.9, 80.9, 67.1, 52.9, 46.5, 28.4, 24.7. (2 x ArH overlapping); HRMS (ES+) m / z 483.0893 [M+Na]+C22H2sBrN2NaO4 requires 483.0895 (100%) (Diff -0.41 ppm).

[0253] Intermediate 23 benzyl 4-bromo-3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate tert-Butyl 2-(2-bromo-5-(benzyloxycarbonyl)phenyl)pyrazolidine-l-carboxylate (552 mg, 1.20 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane: EtOAc; 1: 1) to yield the title compound as a yellow oil (397 mg, 64%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.53 (1H, d, J = 8.0), 7.45 - 7.39 (2H, m), 7.30 - 7.23 (5H, m), 5.89 (1H, br. s), 5.44 (2H, s), 4.16 (1H, br. s), 3.93 (1H, br. s), 3.59 - 3.55 (2H, m), 3.27 (1H, br s), 3.22 (1H, br. s), 2.07 (1H, br. s), 2.00 (1H, br. s), 1.36 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 170.8, 166.2, 157.4, 147.8, 137.0, 135.7, 129.6, 128.5, 128.2, 128.1, 121.9, 120.5, 115.7, 80.2, 67.7, 55.6, 43.8, 43.1, 28.4, 24.5; HRMS (ES+) m / z 540.1115 [M + Na]+C24H28BrN3NaOs requires 540.1110 (100%) (Diff 0.93 ppm).

[0254] Intermediate 24 benzyl 4-bromo-3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate tert-Butyl 2-(2-bromo-5-(benzyloxycarbonyl)phenyl)pyrazolidine-l-carboxylate (552 mg, 1.20 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane: EtOAc; 1: 1) to yield the title compound as a yellow oil (397 mg, 64%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.53 (1H, d, J = 8.0), 7.45 - 7.39 (2H, m), 7.30 - 7.23 (5H, m), 5.89 (1H, br. s), 5.44 (2H, s), 4.16 (1H, br. s), 3.93 (1H, br. s), 3.59 - 3.55 (2H, m), 3.27 (1H, br s), 3.22 (1H, br. s), 2.07 (1H, br. s), 2.00 (1H, br. s), 1.36 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 170.8, 166.2, 157.4, 147.8, 137.0, 135.7, 129.6, 128.5, 128.2, 128.1, 121.9, 120.5, 115.7, 80.2, 67.7, 55.6, 43.8, 43.1, 28.4, 24.5; HRMS (ES+) m / z 540.1115 [M + Na]+C24H28BrN3NaOs requires 540.1110 (100%) (Diff 0.93 ppm). Intermediate 25 benzyl 3-bromobenzoate

[0255] The title compound was obtained following similar procedures as described for benzyl 4-bromo-3-iodobenzoate starting from 3-Bromobenzoic acid (500 mg, 2.50 mmol) and benzyl bromide (0.45 ml, 3.75 mmol). The crude product was purified by flash column chromatography (SiC ; gradient elution, hexane to 1% EtOAc in hexane) to yield the title compound a colourless oil (689 mg, 95%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.14 (1H, t, J = 1.5), 7.85 (1H, dt, J = 7.5, 1.5), 7.62 - 7.59 (1H, m), 7.29 - 7.20 (6H, m), 5.42 (2H, s);13C NMR (101 MHz; CDCI3; Me4Si) 6 166.8, 138.3, 134.2, 133.1, 132.1, 130.3, 128.6, 128.3, 127.9, 127.4, 123.5, 67.1; HRMS (ES+) m / z 312.9838 [M+Na]+Ci4HnBrNaO2 requires 312.9840 (100%) (Diff -0.63 ppm).

[0256] Intermediate 26 tert-Butyl 2-(3-((benzyloxy)carbonyl)phenyl)pyrazolidine-l-carboxylate

[0257] Benzyl-3-bromobenzoate (655 mg, 2.26 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane:EtOAc; 7:3) to yield the title compound as a pale yellow oil (768 mg, 89%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.55 (1H, dd, J = 8.0, 2.0), 7.28 - 7.21 (7H, m), 7.07 (1H, dd, J = 8.0, 2.0), 5.46 (2H, s), 3.71 (2H, br. s), 3.63 (2H, t, J = 6.5), 2.05 (2H, quintet, J = 6.5), 1.45 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 167.6, 154.4, 148.9, 136.7, 131.1, 129.4, 128.4, 128.2, 128.0, 121.8, 120.3, 115.4, 81.0, 67.1, 53.7, 44.8, 28.4, 25.7; HRMS (ES+) m / z 383.1977 [M + H]+C22H27N2O4 requires 383.1976 (Diff 0.20 ppm).

[0258] Intermediate 27 benzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate tert-Butyl 2-(3-((benzyloxy)carbonyl)phenyl)pyrazolidine-l-carboxylate (680 mg, 1.78 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane:EtOAc; 7:3) to yield the title compound as a colourless yellow oil (563 mg, 72%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.61 (1H, br. d, J = 8.0), 7.42 (1H, s), 7.29 - 7.22 (6H, m), 7.08 (1H, dd, J = 8.0, 1.5), 5.48 (2H, s), 5.15 (1H, br. t, J = 4.5), 4.35 - 4.32 (1H, m), 4.12 - 4.07 (1H, m), 3.73 - 3.70 (2H, m), 3.43 (1H, br. s), 3.39 - 3.34 (1H, m), 2.04 - 1.98 (2H, m), 1.44 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 169.9, 167.2, 157.0, 148.6, 137.4, 131.3, 130.4, 128.4, 128.2, 128.0, 122.1, 120.7, 115.7, 79.8, 67.3, 52.8, 44.5, 43.4, 28.3, 24.9; HRMS (ES+) m / z 462.2013 [M + Na]+C24H29N30sNa requires 462.2010 (Diff 0.54 ppm).

[0259] Intermediate 28

[0260] 4-(trifluoromethyl)benzyl 3-bromobenzoate

[0261] The title compound was obtained following similar procedures as described for benzyl 4-bromo-3-iodobenzoate starting from 3-Bromobenzoic acid (500 mg, 2.50 mmol) and 4-trifluoromethylbenzyl bromide (0.58 mL, 3.75 mmol) were employed. The crude product was purified by flash column chromatography (SiCh; gradient elution, hexane to 1.5% EtOAc in hexane) to yield the title compound a yellow oil (814 mg, 91%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.16 (1H, t, J = 1.5), 7.89 (1H, dt, J = 7.5, 1.5), 7.65 (1H, dt, J = 7.5, 1.5), 7.52 (2H, d, J = 8.0), 7.27 (1H, t, J = 7.5), 7.21 (2H, d, J = 8.0), 5.45 (2H, s);13C NMR (101 MHz; CDCI3; Me4Si) 6 166.8, 143.5, 135.7, 132.9, 132.6 (d, J = 25.5), 131.6, 130.3, 129.4 (q, J = 5.0), 127.0, 125.1 (q, J = 7.5), 124.5 (q, J = 264), 123.6, 67.3;19F NMR (376 MHz CDCI3; Me4Si) 6 -63.4; HRMS (ES+) m / z 380.9717 [M+Na]+Ci5HioBrF3Na02 requires 380.9714 (100%) (Diff 0.73 ppm).

[0262] Intermediate 29 tert-butyl 2-(3-((4-(trifluoromethyl)benzyloxy)carbonyl)phenyl)pyrazolidine-l- carboxylate

[0263] 4-(Trifluoromethyl)benzyl 3-bromobenzoate (782 mg, 2.18 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane: EtOAc; 5: 1) to yield the title compound as an orange oil (806 mg, 82%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.55 (2H, d, J = 8.0), 7.52 - 7.49 (2H, m), 7.32 (1H, t, J = 8.0), 7.21 (2H, d, J = 8.0), 7.10 (1H, dt, J = 8.0, 1.5), 5.48 (2H, s), 3.63 (2H, br. s), 3.59 (2H, t, J = 6.5), 2.02 (2H, quintet, J = 6.5), 1.46 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 167.3, 156.0, 149.3, 142.8, 132.7 (d, J = 25.0), 131.5, 129.9, 129.1 (q, J = 5.0), 125.1 (q, J = 7.0), 124.2 (q, J = 262), 122.1, 119.5, 115.8,80.9, 67.2, 53.7, 45.0, 28.6, 25.5;19F NMR (376 MHz CDCI3; Me4Si) 6 -63.3; HRMS (ES+) m / z 473.1660 [M+Na]+C22H2sF3N2NaO4requires 473.1659 (Diff 0.30 ppm).

[0264] Intermediate 30

[0265] 4-(trifluoromethyl)benzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate tert-Butyl 2-(3-((4-(trifluoromethyl)benzyloxy)carbonyl)phenyl)pyrazolidine-l- carboxylate (765 mg, 1.70 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane:EtOAc; 5: 1) to yield the title compound as a pale yellow oil (577 mg, 67%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.59 (2H, d, J = 8.0), 7.55 - 7.50 (2H, m), 7.34 (1H, t, J = 8.0), 7.23 (2H, d, J = 7.5), 7.12 (1H, dt, J = 7.5, 1.5), 5.48 (2H, s), 5.20 (1H, t, J = 4.5), 4.33 - 4.30 (1H, m), 4.09 - 4.03 (1H, m), 3.62 - 3.58 (2H, m), 3.43 - 3.40 (1H, m), 3.35 - 3.31 (1H, m), 2.03 - 1.96 (2H, m), 1.41 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 171.2, 166.9, 156.0, 150.1, 141.9, 132.4 (d, J = 25.5), 131.6, 129.5, 129.0 (q, J = 5.0), 124.9 (q, J = 7.0), 124.3 (q, J = 265), 123.7, 120.2, 116.9, 81.0, 67.3, 55.2, 43.1, 42.6, 28.3, 24.5;19F NMR (376 MHz CDCI3; Me4Si) 6 -63.4; HRMS (ES+) m / z 530.1876 [M + Na]+C2sH2sF3N3Na Os requires 530.1873 (Diff 0.44 ppm).

[0266] Intermediate 31 tert-butyl 2-(3-(methoxycarbonyl)phenyl)pyrazolidine-l-carboxylate tert-Butyl pyrazolidine-l-carboxylate (143 mg, 0.83 mmol) and methyl-3- bromobenzoate (178 mg, 0.83 mmol) were employed. The crude product was purified by flash column chromatography eluting with 30% EtOAc in hexane to 40% EtOAc in hexane to yield a yellow oil (189 mg, 0.62 mmol, 74%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.61 - 7.58 (2H, m), 7.31 (1H, ap: t, J = 8.1), 7.12 (1H, dd, J = 8.1, 2.4), 3.90 (3H, s), 3.64 (2H, br s), 3.60 (2H, t, J = 6.7), 2.02 (2H, ap: quintet, J = 6.7), 1.47 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 167.2, 155.9, 151.2, 130.8, 128.9, 122.3, 119.7, 116.2, 81.1, 53.9, 52.1, 45.0, 28.3, 25.5; HRMS (ES+) m / z 329.1475 [M+Na]+Ci6H22N2O4Na requires 329.1477 (Diff -0.7 ppm).

[0267] Intermediate 32 methyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate tert-Butyl 2-(3-(methoxycarbonyl)phenyl)pyrazolidine-l-carboxylate (189 mg, 0.62 mmol) was employed. The reaction yielded a brown oil that was taken directly to the next step.

[0268] The TFA salt of the amine (205 mg, 0.64 mmol) was employed. The crude product was purified by flash column chromatography eluting with 40% EtOAc in hexane to 50% EtOAc in hexane to yield a pale yellow oil (159 mg, 0.44 mmol, 69%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.69 (1H, d, J = 7.9), 7.60 (1H, s), 7.36 (1H, ap: t, J = 7.9), 7.14 (1H, dd, J = 7.9, 1.7), 5.27 (1H, t, J = 4.4), 4.37 - 4.31 (1H, m), 4.10 - 4.04 (1H, m), 3.91 (3H, s), 3.74 - 3.67 (2H, m), 3.48 - 3.41 (1H, m), 3.37 - 3.30 (1H, m), 2.09 (1H, br s), 2.00 - 1.92 (1H, m), 1.42 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 171.6, 166.7, 155.8, 150.2, 131.4, 129.5, 124.1, 120.5, 116.8, 79.5, 55.3, 52.3, 43.1, 42.4, 28.3, 24.2; HRMS (ES+) m / z 386.1686 [M + Na]+CisHzsNsOsNa requires 386.1692 (Diff -1.5 ppm).

[0269] Intermediate 33 methyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate tert-Butyl 2-(3-(methoxycarbonyl)phenyl)pyrazolidine-l-carboxylate (189 mg, 0.62 mmol) was employed. The reaction yielded a brown oil that was taken directly to the next step.

[0270] The TFA salt of the amine (205 mg, 0.64 mmol) was employed. The crude product was purified by flash column chromatography eluting with 40% EtOAc in hexane to 50% EtOAc in hexane to yield a pale yellow oil (159 mg, 0.44 mmol, 69%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.69 (1H, d, J = 7.9), 7.60 (1H, s), 7.36 (1H, ap: t, J = 7.9), 7.14 (1H, dd, J = 7.9, 1.7), 5.27 (1H, t, J = 4.4), 4.37 - 4.31 (1H, m), 4.10 - 4.04 (1H, m), 3.91 (3H, s), 3.74 - 3.67 (2H, m), 3.48 - 3.41 (1H, m), 3.37 - 3.30 (1H, m), 2.09 (1H, br s), 2.00 - 1.92 (1H, m), 1.42 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 171.6, 166.7, 155.8, 150.2, 131.4, 129.5, 124.1, 120.5, 116.8, 79.5, 55.3, 52.3, 43.1, 42.4, 28.3, 24.2; HRMS (ES+) m / z 386.1686 [M + Na]+CisHzsNsOsNa requires 386.1692 (Diff -1.5 ppm).

[0271] Intermediate 34

[0272] 4-chlorobenzyl 5-bromo-2-fluorobenzoate

[0273] The title compound was obtained following similar procedures as described for benzyl 4-bromo-3-iodobenzoate starting from 5-Bromo-2-fluorobenzoic acid (500 mg, 2.28 mmol) and 4-chlorobenzyl bromide (516 mg, 2.51 mmol) were employed. The crude product was purified by flash column chromatography (SiCh; 100% hexane to 1% EtOAc in hexane) to yield a pale yellow oil (702 mg, 2.03 mmol, 90%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.11 (1H, dd, J = 6.0, 2.5), 7.61 (1H, ddd, J = 9.0, 4.5, 2.5), 7.30 (2H, d, J = 7.5), 7.24 (2H, d, J = 7.5), 7.01 (1H, dd, J = 10.0, 9.0), 5.42 (2H, s);13C NMR (101 MHz; CDCI3; Me4Si) 6 161.8 (d, J = 4.5), 160.6 (d, J = 263.5), 137.4 (d, J = 8.5), 135.5, 134.4 (d, J = 1.0), 134.0, 129.1, 128.8, 121.0 (d, J = 12.0), 118.9 (d, J = 25.5), 116.6 (d, J = 4.0), 66.9;19F NMR (376 MHz CDCI3; Me4Si; ppm) 6 -109.3; HRMS (ES+) m / z 364.9359 [M + Na]+Ci4H9BrCIFNaO2requires 364.9356 (100%) (Diff 0.66 ppm).

[0274] Intermediate 35 tert-butyl 2-(3-((4-chlorobenzyloxy)carbonyl)-4-fluorophenyl)pyrazolidine-l- carboxylate

[0275] 4-Chlorobenzyl 5-bromo-2-fluorobenzoate (648 mg, 1.89 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane: EtOAc; 5: 1) to yield a yellow oil (535 mg, 65%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.33 - 7.30 (1H, m), 7.28 (2H, d, J = 7.5), 7.17 (2H, d, J = 7.5), 7.06 - 7.01 (2H, m), 5.44 (2H, s), 3.63 (2H, br. s), 3.56 (2H, t, J = 6.8), 1.99 (2H, quintet, J = 7.0), 1.48 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 164.7 (d, J = 4.0), 154.0, 152.5 (d, J = 262.5), 143.9 (d, J = 8.5), 134.8, 134.1, 129.2, 128.8, 121.7 (d, J = 13.0), 119.1 (d, J = 26.5), 118.5 (d, J = 8.0), 116.8 (d, J = 4.0), 80.7, 66.9, 54.5, 44.8, 28.4, 25.6;19F NMR (376 MHz CDCI3; Me4Si; ppm) 6 -108.7; HRMS (ES+) m / z 457.1305 [M + Na]+C22H24CIFN2NaO4requires 457.1301 (Diff 0.94 ppm).

[0276] Intermediate 36

[0277] 4-chlorobenzyl 5-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)-2-fluorobenzoate tert-Butyl 2-(3-((4-chlorobenzyloxy)carbonyl)-4-fluorophenyl)pyrazolidine-l- carboxylate (492 mg, 1.13 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane: EtOAc; 3: 1) to yield a colourless oil (401 mg, 72%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.39 - 7.37 (1H, m), 7.33 (2H, d, J = 7.5), 7.26 (2H, d, J = 7.5), 7.03 - 6.98 (2H, m), 5.43 (2H, s), 5.10 (1H, br. s), 4.29 - 4.25 (1H, m), 4.03 - 3.97 (1H, m), 3.62 - 3.59 (2H, m), 3.48 - 3.44 (1H, m), 3.35 - 3.32 (1H, m), 2.00 - 1.93 (2H, m), 1.40 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 171.1, 164.6 (d, J = 4.5), 155.0, 152.8 (d, J = 264.0), 144.2 (d, J = 8.0), 135.4, 134.7, 129.1, 128.7, 122.3 (d, J = 15.0), 119.6 (d, J = 26.0), 118.7 (d, J = 7.5), 115.9 (d, J = 4.0), 80.3, 66.9, 54.7, 43.4, 42.6, 28.4, 24.7;19F NMR (376 MHz CDCI3; Me4Si; ppm) 6 -109.0; HRMS (ES+) m / z 514.1518 [M + Na]+C24H28FN3O5Na requires 514.1515 (Diff 0.49 ppm).

[0278] Intermediate 37

[0279] 4-chlorobenzyl 3-bromobenzoate

[0280] The title compound was obtained following similar procedures as described for benzyl 4-bromo-3-iodobenzoate starting from 3-Bromobenzoic acid (500 mg, 2.50 mmol) and 4-chlorobenzyl bromide (771 mg, 3.75 mmol) were employed. The crude product was purified by flash column chromatography (SiCh; gradient elution, hexane to 1% EtOAc in hexane) to yield the title compound a colourless oil (778 mg, 96%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.21 (1H, s), 7.90 (1H, t, J = 7.5), 7.63 (1H, t, J = 7.5), 7.34 (2H, d, J = 7.5), 7.27 (1H, t, J = 7.5), 7.21 (2H, d, J = 7.5), 5.43 (2H, s);13C NMR (101 MHz; CDCI3; Me4Si) 6 166.9, 136.4, 134.8, 133.7, 133.1, 132.3, 130.6, 129.3, 129.0, 127.2, 123.5, 67.5; HRMS (ES+) m / z 346.9451 [M + Na]+Ci4HioBrCINa02 requires 346.9450 (100%) (Diff 0.23 ppm).

[0281] Intermediate 38 tert-butyl 2-(3-((4-chlorobenzyloxy)carbonyl)phenyl)pyrazolidine-l-carboxylate

[0282] 4-Chlorobenzyl-3-bromobenzoate (742 mg, 2.29 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane: EtOAc; 4: 1) to yield the title compound as a yellow oil (724 mg, 76%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.56 (1H, d, J = 8.0), 7.36 (1H, s), 7.33 (2H, d, J = 7.5), 7.27 (1H, t, J = 8.0), 7.22 (2H, d, J = 7.5), 7.05 (1H, d, J = 8.0), 5.48 (2H, s), 3.66 (2H, br. s), 3.63 (2H, t, J = 6.5), 2.06 (2H, quintet, J = 6.5), 1.45 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 167.2, 154.7, 148.0, 135.1, 134.6, 131.3, 130.7, 129.3, 128.5, 121.9, 119.9, 115.8, 80.9, 67.1, 54.4, 45.3, 28.4, 25.7; HRMS (ES+) m / z 439.1408 [M + Na]+C22H25CIN2NaO4requires 439.1406 (Diff 0.37 ppm).

[0283] Intermediate 39

[0284] 4-chlorobenzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate tert-Butyl 2-(3-((4-chlorobenzyloxy)carbonyl)phenyl)pyrazolidine-l-carboxylate (698 mg, 1.68 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane: EtOAc; 4: 1) to yield the title compound as a pale yellow oil (587 mg, 74%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.53 (1H, d, J = 8.0), 7.48 (1H, s), 7.36 (2H, d, J = 7.5), 7.31 (1H, t, J = 8.0), 7.24 (2H, d, J = 7.5), 7.01 (1H, d, J = 8.0), 5.44 (2H, s), 5.06 (1H, br. t, J = 4.5), 4.32 - 4.29 (1H, m), 4.11 - 4.05 (1H, m), 3.73 - 3.68 (2H, m), 3.47 - 3.45 (1H, m), 3.35 - 3.33 (1H, m), 2.06 - 2.00 (2H, m), 1.42 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 169.8, 166.9, 157.4, 148.5, 135.2, 134.5, 131.4, 130.8, 129.1, 128.5, 122.4, 119.7, 115.9, 80.3, 66.9, 54.6, 43.5, 43.1, 28.3, 25.0; HRMS (ES+) m / z 496.1624 [M + Na]+C24H28CIN3O5Na requires 496.1621 (Diff 0.55 ppm).

[0285] Intermediate 40

[0286] 3-chlorobenzyl 3-bromobenzoate

[0287] The title compound was obtained following similar procedures as described for benzyl 4-bromo-3-iodobenzoate starting from 3-Bromobenzoic acid (500 mg, 2.50 mmol) and 3-chlorobenzyl bromide (0.49 ml, 3.75 mmol) were employed. The crude product was purified by flash column chromatography (SiCh; gradient elution, hexane to 1% EtOAc in hexane) to yield the title compound a colourless oil (737 mg, 91%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.15 (1H, t, J = 1.5), 7.87 (1H, dt, J = 8.0, 1.5), 7.61 (1H, ~d, J = 8.0), 7.37 (1H, s), 7.30 (1H, t, J = 8.0), 7.24 - 7.19 (3H, m), 5.46 (2H, s);13C NMR (101 MHz; CDCI3; Me4Si) 6 167.0, 139.8, 136.7, 133.5, 133.0, 132.2, 130.7, 128.7, 128.5, 127.8, 127.0, 126.5, 123.3, 67.2; HRMS (ES+) m / z 346.9452 [M + Na]+Ci4HioBrCINa02 requires 346.9450 (100%) (Diff 0.47 ppm).

[0288] Intermediate 41 tert-butyl 2-(3-((3-chlorobenzyloxy)carbonyl)phenyl)pyrazolidine-l-carboxylate

[0289] 3-Chlorobenzyl-3-bromobenzoate (720 mg, 2.22 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane: EtOAc; 4: 1) to yield the title compound as a pale yellow oil (749 mg, 81%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.52 (1H, br. d, J = 8.0), 7.38 (1H, s), 7.36 - 7.32 (2H, m), 7.17 - 7.22 (3H, m), 7.00 (1H, br. d, J = 8.0), 5.47 (2H, s), 3.67 (2H, br. s), 3.68 (2H, t, J = 6.5), 2.09 (2H, quintet, J = 6.5), 1.42 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 167.4, 153.1, 148.4, 139.9, 133.5, 131.2, 130.8, 128.8, 128.5, 128.1, 126.9, 122.0, 119.8, 115.2, 81.1, 66.9, 54.0, 45.3, 28.4, 25.6; HRMS (ES+) m / z 439.1407 [M + Na]+C22H25CIN2NaO4requires 439.1406 (Diff 0.26 ppm).

[0290] Intermediate 42

[0291] 3-chlorobenzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate tert-Butyl 2-(3-((3-chlorobenzyloxy)carbonyl)phenyl)pyrazolidine-l-carboxylate (704 mg, 1.69 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane:EtOAc; 4: 1) to yield the title compound as a colourless oil (640 mg, 80%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.59 (1H, s), 7.51 (1H, dt, J = 7.5, 1.5), 7.44 (1H, br. s), 7.33 - 7.31 (1H, m), 7.24 - 7.20 (3H, m), 6.95 (1H, br. d, J = 8.0), 5.46 (2H, s), 5.12 (1H, br. t, J = 4.0), 4.35 - 4.33 (1H, m), 4.10 - 4.06 (1H, m), 3.75 - 3.73 (2H, m), 3.46 - 3.44 (1H, m), 3.35 - 3.32 (1H, m), 2.08 - 2.04 (2H, m), 1.43 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 169.6, 167.0, 157.7, 148.2, 139.8, 133.1, 131.4, 129.9, 128.9, 128.5, 128.2, 127.1, 121.9, 120.3, 115.4, 80.2, 67.3, 53.8, 44.3, 43.6, 28.4, 25.1; HRMS (ES+) m / z 496.1623 [M + Na]+C24H28CIN3O5Na requires 496.1621 (Diff 0.50 ppm).

[0292] Intermediate 43

[0293] 3,4-dichlorobenzyl 3-bromobenzoate

[0294] The title compound was obtained following similar procedures as described for benzyl 4-bromo-3-iodobenzoate starting from 3-Bromobenzoic acid (500 mg, 2.50 mmol) and

[0295] 3,4-dichlorobenzyl bromide (0.55 mL, 3.75 mmol) were employed. The crude product was purified by flash column chromatography (SiCh; gradient elution, hexane to 1% EtOAc in hexane) to yield the title compound a pale yellow oil (877 mg, 98%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.19 (1H, s), 7.92 (1H, t, J = 8.0), 7.62 (1H, t, J = 8.0), 7.38 (1H, s), 7.29 - 7.25 (2H, m), 7.13 (1H, dd, J = 7.5, 1.5), 5.43 (2H, s);13C NMR (101 MHz; CDCI3; Me4Si) 6 167.1, 137.9, 136.2, 133.6, 132.1, 131.9, 131.6, 130.7, 130.5, 129.2, 127.4, 127.3, 123.8, 66.9; HRMS (ES+) m / z 380.9064 [M + Na]+Ci4H9BrCl2NaO2 requires 380.9061 (100%) (Diff 0.84 ppm).

[0296] Intermediate 44 tert-butyl 2-(3-((3,4-dichlorobenzyloxy)carbonyl)phenyl)pyrazolidine-l-carboxylate

[0297] 3,4-Dichlorobenzyl-3-bromobenzoate (824 mg, 2.30 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane: EtOAc; 5: 1) to yield the title compound as a yellow oil (715 mg, 69%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.59 (1H, d, J = 8.0), 7.38 (1H, d, J = 1.5), 7.33 (1H, t, J = 8.0), 7.27 (1H, t, J = 8.0), 7.21 (1H, d, J = 2.0), 7.08 (1H, dd, J = 7.5, 1.5), 7.01 (1H, dd, J = 8.0, 2.0), 5.46 (2H, s), 3.64 (2H, br. s), 3.61 (2H, t, J = 6.5), 2.04 (2H, quintet, J = 6.5), 1.47 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 167.0, 153.9, 148.6, 137.5, 133.4, 132.6, 131.1, 130.3, 129.6, 129.1, 127.4, 122.1, 119.7, 116.0, 81.2, 66.8, 53.8, 45.1, 28.4, 25.6; HRMS (ES+) m / z 473.1008 [M + Na]+C22H24Cl2N2NaO4requires 473.1005 (Diff 0.51 ppm). Intermediate 45

[0298] 3,4-dichlorobenzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate tert-Butyl 2-(3-((3,4-dichlorobenzyloxy)carbonyl)phenyl)pyrazolidine-l-carboxylate

[0299] (652 mg, 1.45 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane:EtOAc; 5: 1) to yield the title compound as a colourless oil (433 mg, 59%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.64 (1H, d, J = 8.0), 7.43 (1H, d, J = 1.5), 7.32 (1H, t, J = 8.0), 7.26 (1H, t, J = 8.0), 7.19 (1H, d, J = 2.0), 7.11 (1H, dd, J = 7.5, 1.5), 7.07 (1H, dd, J = 8.0, 2.0), 5.46 (2H, s), 5.13 (1H, t, J = 4.5), 4.30 - 4.27 (1H, m), 4.06 - 3.98 (1H, m), 3.57 - 3.51 (2H, m), 3.42 - 3.39 (1H, m), 3.32 - 3.27 (1H, m), 1.99 - 1.87 (2H, m), 1.38 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 171.5, 166.8, 155.9, 149.1, 137.6, 133.1, 132.3, 131.7, 131.2, 130.3, 129.4, 127.5, 122.0, 119.6, 117.2, 80.2, 66.8, 55.5, 43.2, 42.4, 28.4, 24.1;

[0300] HRMS (ES+) m / z 530.1223 [M + Na]+Cz^zChNsOsNa requires 530.1220 (Diff 0.52 ppm).

[0301] Intermediate 46 benzyl 5-bromo-2-fluorobenzoate

[0302] Benzyl bromide (0.30 ml, 2.51 mmol, 1.1 eq) and DIPEA (0.79 ml, 4.56 mmol, 2 eq) were added to 5-bromo-2-fluorobenzoic acid (500 mg, 2.28 mmol, 1 eq) and allowed to reflux for 2 hrs. After this time, the reaction mixture was concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 100% hexane to 1% EtOAc in hexane to yield a colourless oil (625 mg, 2.03 mmol, 89%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.07 (1H, dd, J = 6.3, 2.6), 7.62 (1H, ddd, J = 8.8, 4.3, 2.6), 7.46 - 7.43 (2H, m), 7.42 - 7.33 (3H, m), 7.04 (1H, dd, J = 10.1, 8.8), 5.38 (2H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 162.9 (d, J = 3.8), 161.1 (d, J = 261.2), 137.3 (d, J = 8.9), 135.4, 134.7 (d, J = 0.7), 128.7, 128.5, 128.3, 120.4 (d, J = 11.0), 118.9 (d, J = 24.0), 116.4 (d, J = 3.9), 67.4; HRMS (ES+) m / z 308.9927 [M + H]+Ci4Hn79BrFO2requires 308.9921 (100%) (Diff -2.1 ppm), m / z 310.9902 [M+H]+Ci4Hn81BrFO2 requires 310.9901 (99%) (Diff -0.3 ppm).

[0303] Intermediate 47 tert-butyl 2-(3-((benzyloxy)carbonyl)-4-fluorophenyl)pyrazolidine-l-carboxylate tert-Butyl pyrazolidine-l-carboxylate (150 mg, 0.87 mmol) and benzyl 5-bromo-2- fluorobenzoate (268 mg, 0.87 mmol) were employed. The crude product was purified by flash column chromatography eluting with 10% EtOAc in hexane to 20% EtOAc in hexane to yield a yellow oil (165 mg, 0.41 mmol, 47%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.48 - 7.44 (3H, m), 7.40 - 7.36 (2H, m), 7.34 - 7.30 (1H, m), 7.09 - 7.00 (2H, m), 5.37 (2H, s), 3.61 (2H, br s), 3.53 (2H, ap: t, J = 6.8), 2.01 (2H, ap: quintet, J = 6.8), 1.45 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 165.1 (d, J = 4.0), 164.4 (d, J = 4.0), 158.2, 157.0 (d, J = 262.5), 147.1 (d, J = 2.7), 135.8, 128.6, 128.2, 128.0, 121.3 (d, J = 8.3), 118.4 (d, J = 11.2), 117.3 (d, J = 24.1), 81.2, 66.9, 54.4, 45.1, 28.3, 25.4; HRMS (ES+) m / z 423.1690 [M + Na]+C22H25FN2O4Na requires 423.1696 (Diff -1.4 ppm).

[0304] Intermediate 48 benzyl 5-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)-2-fluorobenzoate tert-Butyl 2-(3-((benzyloxy)carbonyl)-4-fluorophenyl)pyrazolidinel-carboxylate (165 mg, 0.41 mmol) was employed. The reaction yielded a yellow oil that was taken directly to the next step. The TFA salt of the amine (170 mg, 0.41 mmol) was employed. The crude product was purified by flash column chromatography eluting with 50% EtOAc in hexane to yield a pale yellow oil (101 mg, 0.22 mmol, 54%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.42 (1H, dd, J = 5.5, 2.5), 7.38 (2H, d, J = 7.8), 7.33 - 7.29 (2H, m), 7.28 - 7.24 (1H, m), 7.04 - 6.96 (2H, m), 5.31 (2H, s), 5.19 (1H, br s), 4.21 (1H, br s), 3.95 (1H, br s), 3.57 (2H, br s), 3.36 (1H, br s), 3.24 (1H, br s), 2.00 (1H, br s), 1.88 (1H, br s), 1.34 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 171.6, 164.0 (d, J = 3.9), 157.9 (d, J = 256.3), 155.8, 146.0 (d, J = 2.8), 135.6, 128.6, 128.3, 128.1, 122.0 (d, J = 8.1), 119.2, 119.0 (d, J = 20.3), 117.9 (d, J = 24.2), 79.6, 67.2, 55.8, 43.2, 42.5, 28.3, 24.0; HRMS (ES+) m / z 480.1905 [M + Na]+Cz^sFNsOsNa requires 480.1911 (Diff -1.2 ppm).

[0305] Intermediate 49

[0306] 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoic acid

[0307] To solution of benzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate (0.11 g, 0.25 mmol, 1 eq) 10 wt.% Pd / C (0.28 eq) dissolved in ethyl aceatate (5 mL) was allowed to stir under H2 atmosphere at room temperature overnight before the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to yield the crude product. The crude mixture required no further purification to yield a colourless oil (0.074 g, 85%).XH NMR (400 MHz, CDCI3) 6 7.67 (d, J = 7.6 Hz, 1H), 7.59 (unresolved d, 1H), 7.30 (app t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.30 (s, 2H), 3.95-3.80 (m, 2H), 3.65 (br s, 2H), 3.25-3.15 (m, 2H), 2.04-1.95 (m, 2H), 1.48 (s, 9H).13C NMR (101 MHz, CDCI3) 6 171.7, 169.8, 155.9, 150.2, 131.1, 129.5, 124.6, 120.7, 117.4, 79.7, 63.5, 55.3, 47.8, 43.1, 28.3 (3C). HRMS (ES+) 348.1574 Da [M-H]+C17H22N3O5 requires 348.1565 (Diff -2.62 ppm).

[0308] Intermediate 50 pyridin-2-ylmethyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate To a solution of 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoic acid (0.072 g, 0.21 mmol, 1 eq) dissolved in DCM (5 mL) followed by addition of EDC (1.09 eq) and DMAP (0.01 eq), the reaction mixture was allowed to stir at room temperature overnight. Upon completion, solvent was removed in vacuo. The mixture was taken up with EtOAc and washed with sat. aq. NaHCC (x 3), water and brine. The organic phase was dried over MgS04and concentrated in vacuo to afford the crude product. The crude product was purified by FCC (SiC ; 50: 50 EtOAc: Hexane) to afford the titled compound a yellow solid (0.015 g, 15%).XH NMR (400 MHz, CDCI3) 6 8.63-6.60 (m, 1H), 7.78- 7.71 (m, 2H), 7.69-7.66 (m, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.27-7.21 (m, 1H), 7.16 (dd, J = 8.0, 1.6 Hz, 1H), 5.48 (d, J = 6.8 Hz, 2H), 5.29 (s, 1H), 4.36-4.03 (m, 2H), 3.75 (br s, 2H) 3.48-3.25 (br s, 2H), 2.04-1.95 (br s, 2H), 1.42 (s, 9H).13C NMR (101 MHz, CDCI3) 6 171.6, 165.9, 155.9, 150.3, 149.5, 148.5, 136.9, 131.2, 129.6, 124.3, 122.9, 121.7, 120.5, 117.2, 79.5, 67.4, 64.2, 60.4, 55.3, 43.1, 28.3 (3C). HRMS (ES+) 441.2145 Da [M + H]+C23H29N4O5 requires 441.2132 (Diff -2.78 ppm).

[0309] Intermediate 51 pyridin-3-ylmethyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate

[0310] The title compound was obtained following a similar procedure as described for pyridin- 2-ylmethyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate from 3-(2- ((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoic acid (200 mg, 0.57 mmol). The crude product was purified by FCC (SiCh; EtOAc to 70:30 EtOAc: Hexane) to afford the titled compound as a white solid (102.9 mg, 49 %).XH NMR (500 MHz; CDCI3; ppm) 6 8.69 (d, J = 1.5 Hz, 1H), 8.57 (dd, J = 5.5, 1.0 Hz, 1H), 7.76 (ddd, J = 8.0, 2.0, 2.0 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.60 (s, 1H), 7.35-7.29 (m, 2H), 7.13 (dd, J = 8.0, 1.5 Hz, 1H), 5.35 (br s, 2H), 5.30 (s, 1H), 4.38-3.94 (m, 2H), 3.68 (s, 2H), 3.35 (s, 2H), 2.1 -1.79 (m, 2H), 1.38 (s, 9H).13C NMR (126 MHz; CDCI3) 6 171.6, 165.8, 155.7, 150.3, 149.7, 136.1, 131.5, 131.0, 129.6, 124.1, 123.5, 120.6, 117.0, 79.5, 77.3, 64.3, 55.3, 43.0, 42.4, 28.3. LRMS (ES+) 463.2 [M + Na]+C23H28N4O5Na requires 463.2.

[0311] Intermediate 52 pyridin-4-ylmethyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate

[0312] The title compound was obtained following a similar procedure as described for pyridin- 2-ylmethyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate from 3-(2- ((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoic acid (200mg, 0.57 mmol, 1.14eq). The crude product was purified by FCC (SiC ; EtOAc to 75:25 EtOAc:Hexane) to afford the titled compound as a white solid (90.7 mg, 36 %).XH NMR (500 MHz; CDCI3; ppm) 6 8.59 (d, J = 4.5 Hz, 2H), 7.71 (d, J = 7.5 Hz,XH), 7.63 (s,1H), 7.35 (dd, J = 8.0, 8.0 Hz, 1H), 7.30 (d, J = 5.0 Hz, 2H), 7.15 (d, J = 8.0 Hz,XH), 5.35 (s, br, 2H), 5.32 (s,1H), 4.45-3.90 (m, 2H), 3.69 (s, 2H), 3.43-3.29 (m, 2H), 2.09-1.92 (m, 2H), 1.38 (s, 9H).13C NMR (126 MHz; CDCI3) 6 171.6, 165.7, 155.7, 150.4, 150.0, 144.9, 130.8, 129.7, 124.1, 121.8, 120.7, 117.0, 79.5, 77.4, 64.8, 55.3, 43.0, 42.4, 28.3. HRMS (ES+) 463.1950 [M + Na]+C23H28N4O5Na requires 463.1917.

[0313] Intermediate 53 tert-butyl 2-phenylpyrazolidine-l-carboxylate tert-Butyl 2-phenylhydrazine-l-carboxylate (2.62 g, 12.6 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane: EtOAc; 2: 1) to yield the title compound as an orange oil (1.62 g, 52%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.22 (2H, t, J = 7.5), 6.87 (1H, ~t, J = 7.5), 6.55 (2H, dd, J = 7.5, 1.5), 3.72 (2H, t, J = 7.0), 3.55 (2H, t, J = 7.0), 2.10 (2H, quintet, J = 7.0), 1.40 (9H, s);13C NMR (101 MHz; CDCI3; Me4Si; ppm) 6 153.6, 146.1, 130.0, 120.9, 118.1, 81.4, 53.9, 45.1, 28.5, 24.0; HRMS (ES+) m / z 271.1420 [M + Na]+Ci4H2oN202Na requires 271.1417 (100%) (Diff 1.05 ppm).

[0314] Intermediate 54 tert-butyl (2-oxo-2-(2-phenylpyrazolidin-l-yl)ethyl)carbamate tert-Butyl 2-phenylpyrazolidine-l-carboxylate (1.51 g, 6.09 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane: EtOAc; 2: 1) to yield the title compound as a yellow oil (1.17 g, 63%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.18 (2H, t, J = 8.0), 6.92 (1H, t, J = 7.5), 6.62 - 6.60 (2H, m), 5.34 (1H, br. s), 4.37 (1H, br. s), 4.02 (1H, br. s), 3.74 - 3.69 (2H, m), 3.60 (2H, t, J = 6.5), 2.02 (2H, quintet, J = 6.5), 1.43 (9H, s);13C NMR (101 MHz CDCI3; Me4Si; ppm) 6 170.0, 158.1, 146.7, 130.0, 121.6, 117.8, 81.3, 53.9, 44.6, 43.2, 28.5, 24.1; HRMS (ES+) m / z 328.1636 [M+Na]+Ci6H23N3O3Na requires 328.1632 (100%) (Diff 1.24 ppm).

[0315] Intermediate 55 tert-Butyl 2-(2-bromophenyl)hydrazinecarboxylate

[0316] 2-Bromophenylhydrazine hydrochloride (1.75 g, 7.83 mmol, 1 eq) was dissolved in THF (7.8 mL). Boc anhydride (1.71 g, 7.83 mmol, 1 eq) and NEt3 (1.31 ml, 9.40 mmol, 1.2 eq) were added and the reaction mixture was allowed to stir at r.t. overnight. After this time, the reaction mixture was concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 100% hexane to 2% EtOAc in hexane to yield an orange solid (2.41 g, 8.43 mmol, Quantitative).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.43 (1H, dd, J = 7.9, 1.3), 7.22 (1H, ap: t, J = 7.9), 6.93 (1H, d, J = 7.9), 6.75 (1H, ap: td, J = 7.9, 1.3), 6.39 (1H, br s), 6.20 (1H, s), 1.47 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 155.7, 145.1, 132.6, 128.4, 121.5, 113.4, 108.4, 81.6, 28.2; MS (CI+) m / z 287 [M + H]+CiiHi679BrN2O2 requires 287, m / z 289 [M+H]+CiiHi681BrN2O2 requires 289.

[0317] Intermediate 56 tert-Butyl 2-(2-bromophenyl)pyrazolidine-l-carboxylate A flame-dried flask was charged with tert-butyl 2-(2- bromophenyl)hydrazinecarboxylate (2.21 g, 7.73 mmol, 1 eq) and THF (30 mL). The reaction mixture was purged with argon and cooled to -78 °C. n-BuLi (1.6 M in hexanes) (9.66 mL, 15.46 mmol, 2 eq) was added dropwise and the reaction mixture was allowed to stir for 15 mins at -78 °C before being allowed to warm to 0 °C and allowed to stir for a further 15 mins. After this time, 1,3-diiodopropane (0.89 mL, 7.73 mmol, 1 eq) was added and the reaction mixture was allowed to stir for 1 hr at -78 °C before warming to r.t. and allowed to stir overnight. After this time, the reaction mixture was quenched with NH4CI (60 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 5% EtOAc in hexane to yield an orange solid (1.66 g, 5.09 mmol, 66%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.54 (1H, dd, J = 7.9, 1.3), 7.21 (1H, ap: td, J = 7.9, 1.3), 7.04 (1H, dd, J = 7.9, 1.3), 6.92 (1H, ap: td, J = 7.9, 1.3), 3.76 (2H, t, J = 7.4), 3.52 (2H, t, J = 6.6), 2.05 (2H, ap: quintet, J = 7.4, 6.6), 1.37 (9H, s);13C NMR (100 MHz; CDCI3; Me4Si) 6 147.2, 143.1, 126.8, 120.6, 117.9, 112.6, 108.5, 73.6, 48.5, 39.2, 21.3, 17.3; HRMS (ES+) m / z 349.0524 [M + Na]+Ci4Hi979BrN2O2Na requires 349.0528 (100%), m / z 351.0500 [M+Na]+Ci4Hi981BrN2O2Na requires 351.0507 (96%).

[0318] Intermediate 57 tert-Butyl (2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(2-bromophenyl)pyrazolidine-l-carboxylate (1.56 g, 4.78 mmol, 1 eq) was dissolved in a mixture of DCM:TFA (5: 1, 48 mL, ~ lOmL / mmol) and the reaction mixture was allowed to stir at room temperature until TLC showed disappearance of starting material. The reaction mixture was concentrated in vacuo to afford the free amine as a trifluoroacetate salt and was used directly without further purification.

[0319] To a solution of the trifluoroacetate salt of the amine (105 mg, 0.31 mmol) in anhydrous DMF (5 mL), was added boc-glycine (65 mg, 0.92 mmol, 1.2 eq), DIPEA (0.13 mL, 0.77 mmol, 2.5 eq) and HATU (0.15 g, 0.40 mmol, 1.3 eq). The reaction mixture was allowed to stir at room temperature overnight under N2 (followed by TLC). Upon completion, the solution was diluted with EtOAc and washed with sat. aq. NaHCCh (x 3), water and brine. The organic layer was dried over MgSC and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 35% EtOAc in hexane to 45% EtOAc in hexane to yield a yellow oil (125 mg, 0.33 mmol, Quantitative).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.57 (1H, d, J = 7.6), 7.22 (1H, ap: t, J = 7.6), 7.00 - 6.95 (2H, m), 5.22 (1H, s), 4.36 (1H, br s), 3.87 (2H, br s), 3.48 (3H, br s), 2.07 (2H, br s), 1.42 (9H, m);13C NMR (100 MHz; CDCI3; Me4Si) 6 170.7, 155.8, 148.3, 134.3, 128.1, 126.0, 119.2, 115.8, 79.4, 55.9, 45.4, 42.6, 28.4, 23.2; HRMS (ES+) m / z 406.0739 [M + Na]+Ci6H2279BrN3O3Na requires 406.0742 (100%), m / z 408.0726 [M+Na]+

[0320] Ci6H2281BrN3O3Na requires 408.0722 (98%).

[0321] Intermediate 58

[0322] (2-bromo-3-chlorophenyl)hydrazine

[0323] A solution of l-fluoro-2-bromo-3-chlorobenzene (2.50 g, 0.012 mol, 1 eq) and hydrazine monohydrate (2.30 ml, 0.047 mol, 3.97 eq) in DMSO (4.38 mL) was allowed to stir at reflux. After 48 hours, additional hydrazine monohydrate (2.30 ml, 0.047 mol, 3.97 eq) was added. After an additional 24 hours, the reaction mixture was left to cool to room temperature and washed with distilled water (50 mL) then filtered to afford the titled compound as a pale-yellow precipitate (1.73 g, 66%).XH NMR (400 MHz; CDCI3; ppm) 6 7.18 (app t, J = 8.4 Hz, 1H), 7.01 (dd, J = 8.2, 1.4 Hz, 1H) 6.9 (dd, J = 8.2, 1.4 Hz, 1H), 5.88 (s, 1H), 3.65 (s, 2H).13C NMR (101 MHz; CDCI3; ppm) 6 149.3, 134.5, 128.5, 119.7, 110.0, 108.0. LRMS (CI) 220.9 [M + H]+C6H6N235CI79BrNa requires 220.9 8r 222.9 [M + H]+CeH6N235CI79BrNa requires 222.9.

[0324] Intermediate 59 tert-butyl 2-(2-bromo-3-chlorophenyl)hydrazine-l-carboxylate

[0325] (2-bromo-3-chlorophenyl)hydrazine (1.00 g, 4.55 mmol) was employed. The crude product was purified by FCC (SiC ; 50: 50 EtOAc: Hexane) to afford the titled compound as a yellow / orange solid (1.14 g, 78%).XH NMR (400 MHz; CDCI3; ppm) 6 7.15 (app t, J = 8.0 Hz, 1H), 6.99 (dd, J = 8.0, 1.4 Hz, 1H), 6.82 (dd, J = 8.0, 1.4 Hz, 1H), 6.43 (br s, 1H), 6.33 (s, 1H), 1.46 (s, 9H).13C NMR (101 MHz; CDCI3) 6 155.4, 147.2, 135.0, 128.5, 121.7, 111.1 108.5, 81.8, 28.2 (3C).

[0326] Intermediate 60 tert-butyl 2-(2-bromo-3-chlorophenyl)pyrazolidine-l-carboxylate

[0327] The crude product was purified by FCC (SiO220:80 EtOAc: Hexane) to afford the desired compound as a clear orange oil (0.50 g, 39%).XH NMR (400 MHz; CDCI3; ppm) 6 7. 17 (d, J = 1.8 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.95 (dd, J = 8.0, 1.8 Hz, 1H), 3.78 (t, J = 7.2 Hz, 2H), 2.53 (t, J = 3.5, 6.8 Hz, 2H), 2.08-2.01 (m, 2H), 1.38 (s, 9H).13C NMR (101 MHz; CDCI3) 6 152.5, 150.6, 136.0, 129.3, 127.8, 125.3, 117.6, 116.1, 80.7, 55.5, 46.3, 44.6, 28.3 (3C). LRMS (ES+) 383.0 [M + Na]+Ci4Hi8N2O235CI79BrNa requires 383.0 & 385.0 [M+Na]+Ci4Hi8N2O235CI79BrNa requires 385.0.

[0328] Intermediate 61 tert-butyl (2-(2-(2-bromo-3-chlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(2-bromo-3-chlorophenyl)pyrazolidine-l-carboxylate (0.45 g, 1.25 mmol) was employed. The crude product was purified by FCC (SiCh; 20:80 EtOAc: Hexane) to afford the titled compound as an orange / brown oil (0.40 g, 83%).XH NMR (400 MHz; CDCI3; ppm) 6 7.29-7.16 (m, 2H), 6.94-6.65 (m, 1H), 4.35 (br s, 1H) 3.88-3.65 (unresolved m, 4H), 3.47-3.34 (unresolved m, 2H), 2.11-1.88 (unresolved m, 2H), 1.28 (s, 9H).13C NMR (101 MHz; CDCI3) 6 170.9, 150.6, 136.7, 128.2, 126.5, 117.3, 116.6, 112.9, 79.6, 56.0, 45.5, 42.5, 42.4, 28.3 (3C). HRMS (ES+) 440.0351 [M + Na]+Ci6H2iN3O335CI79BrNa requires 440.0353 (Diff -0.3 ppm) &. 442.0324 [M + Na]+Ci6H2iN3O335CI81BrNa requires 442.0332 (Diff -1.8 ppm).

[0329] Intermediate 62 tert-butyl 2-(2-bromo-4-chlorophenyl)pyrazolidine-l-carboxylate tert-Butyl 2-(2-bromo-4-chlorophenyl)hydrazine-l-carboxylate (2.50 g, 7.81 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane:EtOAc; 2: 1) to yield the title compound as a yellow oil (1.74 g, 62%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.38 (1H, d, J = 1.5), 7.21 (1H, dd, J = 8.0, 1.5), 6.63 (1H, d, J = 8.0), 3.69 (2H, t, J = 6.5), 3.52 (2H, t, J = 6.5), 2.08 (2H, quintet, J = 6.5), 1.38 (9H, s);13C NMR (101 MHz; CDCI3; Me4Si; ppm) 6 153.0, 143.5, 133.7, 130.3, 125.2, 118.4, 112.9, 81.0, 54.2, 44.8, 28.3, 23.6; HRMS (ES+) m / z 383.0141 [M+Na]+Ci4Hi8BrCIN2O2Na requires 383.0138 (100%) (Diff 0.77 ppm).

[0330] Intermediate 63 tert-butyl (2-(2-(2-bromo-4-chlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(2-bromo-4-chlorophenyl)pyrazolidine-l-carboxylate (1.70 g, 4.72 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane: EtOAc; 3: 1) to yield the title compound as a pale yellow oil (1.16 g, 59%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.40 (1H, d, J = 1.5), 7.16 (1H, dd, J = 8.0, 1.5), 6.65 (1H, d, J = 8.0), 5.19 (1H, br. s), 4.35 (1H, br. s), 4.04 (1H, br. s), 3.79 - 3.73 (2H, m), 3.52 - 3.46 (1H, m), 3.40 - 3.33 (1H, m), 2.02 (2H, br. s), 1.41 (9H, s);13C NMR (101 MHz CDCI3; Me4Si; ppm) 6 170.3, 154.9, 144.1, 133.4, 129.8, 125.0, 118.5, 114.8, 80.8, 54.0, 44.9, 43.1, 28.4, 24.0; HRMS (ES+) m / z 440.0359 [M + Na]+CieHziBrCINsChNa requires 440.0353 (100%) (Diff 1.50 ppm).

[0331] Intermediate 64

[0332] (2-bromo-5-chlorophenyl)hydrazine The title compound was obtained following a similar procedure as described for (2- bromo-3-chlorophenyl)hydrazine starting from l-fluoro-2-bromo-5-chlorobenzene (2.50 g, 11.90 mmol), the reaction mixture was left to cool to room temperature and washed with distilled water then filtered to afford the titled compound as a pale-yellow precipitate (1.98 g, 75%).XH NMR (400 MHz; CDCI3; ppm) 6 7.30 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.4 Hz, 1H), 5.25 (s, 1H), 3.63 (s, 2H).13C NMR (101 MHz; CDCI3; ppm) 6 148.3, 134.5, 133.0, 119.2, 112.4, 105.1. LRMS (CI) 220.9 [M + H]+C6H7N235CI79Br requires 220.9 & 222.9 [M + H]+C6H7N235CI79Br requires 222.9.(0. Rene and B. P. Fauber, Tetrahedron Lett., 2014, 55, 830-833.)

[0333] Intermediate 65 tert-butyl 2-(2-bromo-5-chlorophenyl)hydrazine-l-carboxylate

[0334] (2-bromo-5-chlorophenyl)hydrazine (1.50 g, 6.82 mmol) was employed. The crude product was purified by FCC (SiO2; 20:80 EtOAc: Hexane) to afford the titled compound as a pale-yellow powder (1.70 g, 78%).XH NMR (400 MHz; CDCI3; ppm) 6 7.34 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 8.4, 2.4 Hz, 1H), 6.39 (br s, 1H), 6.19 (s, 1H), 1.44 (s, 9H).13C NMR (101 MHz; CDCI3) 6 155.6, 146.2, 134.4, 133.3, 121.3, 113.5, 106.0, 82.0, 28.2. LRMS (ES+) 343.0 [M + Na]+CnHi5N2O235CI79Br requires 343.0 & 345.0 [M+H]+CnHi5N2O235CI79Br requires 345.0.

[0335] Intermediate 66 tert-butyl 2-(2-bromo-5-chlorophenyl)pyrazolidine-l-carboxylate

[0336] The crude product was purified by FCC (SiCh; 20:80 EtOAc: Hexane) to afford the titled compound as a brown solid (0.82 g, 45%). ^ NMR (400 MHz; CDCI3; ppm) 6 7.44 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.4, 2.4 Hz, 1H), 3.76 (t, J = 7.2 Hz, 2H), 3.53 (t, J = 7.2 Hz, 2H), 2.10-2.02 (m, 2H), 1.40 (s, 9H).13C NMR (101 MHz; CDCI3) 6 152.5, 136.0, 129.3, 127.8, 125.3, 117.6, 116.1, 80.7, 55.5, 46.3, 41.5, 28.3. LRMS (ES+) 383.0 [M+Na]+Ci4Hi8N2O235CI79BrNa requires 383.0 & 385.0 [M+Na]+Ci4Hi8N2O235CI79BrNa requires 385.0. Intermediate 67 tert-butyl (2-(2-(2-bromo-5-chlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(2-bromo-5-chlorophenyl)pyrazolidine-l-carboxylate (0.45 g, 1.25 mmol) was employed. The crude product was purified by FCC (SiCh; 20:80 EtOAc:Hexane) to afford the titled compound as an orange / brown oil (0.40 g, 83%).XH NMR (400 MHz; CDCI3; ppm) 6 7.51-7.47 (m, 1H), 7.04-6.86 (m, 2H), 4.01 (s, 2H), 3.85-3.70 (m, 2H), 3.62-3.42 (m, 2H), 2.15-2.02 (m, 2H), 1.42 (s, 9H).13C NMR (101 MHz; CDCI3) 6 155.8, 149.6, 135.1, 134.1, 126.0, 119.5, 113.5, 79.6, 60.4, 55.8, 45.3, 42.5, 28.4 (3C). LRMS (ES+) 440.0 [M + Na]+Ci6H2iN3O335CI79BrNa requires 440.0 & 442.0 [M+Na]+Ci6H2iN3O335CI81BrNa requires 442.0.

[0337] Intermediate 68 tert-butyl 2-(2-bromo-4-methoxyphenyl)pyrazolidine-l-carboxylate tert-butyl 2-(2-bromo-4-methoxyphenyl)hydrazine-l-carboxylate (2.14 g, 6.77 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane:EtOAc; 2: 1) to yield the title compound as an orange oil (1.59 g, 66%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.10 (1H, br. s), 6.61 (1H, ~d, J = 7.5), 6.56 (1H, d, J = 7.5), 3.81 (3H, s), 3.70 (2H, t, J = 6.5), 3.49 (2H, t, J = 6.5), 2.01 (2H, quintet, J = 6.5), 1.39 (9H, s);13C NMR (101 MHz; CDCI3; Me4Si; ppm) 6 153.8, 152.3, 136.8, 121.3, 120.2, 119.3, 114.5, 81.3, 56.0, 54.9, 45.8, 28.4, 25.94; HRMS (ES+) m / z 379.0636 [M+Na]+CisHziBrNzC Na requires 379.0633 (100%) (Diff 0.63 ppm).

[0338] Intermediate 69 tert-butyl (2-(2-(2-bromo-4-methoxyphenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(2-bromo-4-methoxyphenyl)pyrazolidine-l-carboxylate (1.43 g, 4.02 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane:EtOAc; 3: 1) to yield the title compound as an orange oil (945 g, 57%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.11 (1H, s), 6.67 - 6.65 (1H, m), 6.58 - 6.55 (1H, m), 3.81 (3H, s), 5.03 (1H, br. s), 4.36 (1H, br. s), 4.02 (1H, br. s), 3.92 - 3.86 (2H, m), 3.53 - 3.49 (2H, m), 2.08 - 2.02 (2H, m), 1.39 (9H, s);13C NMR (101 MHz CDCI3; Me4Si; ppm) 6 170.0, 155.4, 152.5, 136.5, 120.8, 120.1, 119.5, 115.0, 80.9, 56.2, 54.7, 45.6, 43.5, 28.1, 24.7; HRMS (ES+) m / z 436.0849 [M + Na]+Ci?H24BrN3O4Na requires 436.0848 (100%) (Diff 0.21 ppm).

[0339] Intermediate 70 tert-butyl 2-(2-bromo-4-methylphenyl)pyrazolidine-l-carboxylate tert-Butyl 2-(2-bromo-4-methylphenyl)hydrazine-l-carboxylate (1.86 g, 6.20 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane:EtOAc; 3: 1) to yield the title compound as a light brown oil (1.01 g, 48%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.30 (1H, br. s), 7.02 (1H, ~t, J = 8.0), 6.58 (1H, ~t, J = 8.0), 3.68 (2H, t, J = 7.5), 3.51 (2H, t, J = 7.5), 2.34 (3H, s), 2.04 (2H, quintet, J = 7.5), 1.43 (9H, s);13C NMR (101 MHz; CDCI3; Me4Si; ppm) 6 155.0, 144.5, 132.7, 131.5, 130.1, 120.2, 109.8, 80.9, 53.7, 44.6, 28.5, 24.5, 21.4; HRMS (ES+) m / z 363.0688 [M+Na]+CisHziBrNzC Na requires 363.0684 (100%) (Diff 1.01 ppm).

[0340] Intermediate 71 tert-butyl (2-(2-(2-bromo-4-methylphenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(2-bromo-4-methylphenyl)pyrazolidine-l-carboxylate (906 mg, 2.66 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane:EtOAc; 2: 1) to yield the title compound as a yellow oil (761 mg, 72%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.28 (1H, br. s), 7.00 (1H, ~t, J = 8.0), 6.59 (1H, ~t, J = 8.0), 5.13 (1H, br. s), 4.36 (1H, br. s), 3.99 (1H, br. s), 3.68 (2H, t, J = 7.0), 3.57 (2H, t, J = 7.0), 2.32 (3H, s), 1.98 (2H, quintet, J = 7.0), 1.41 (9H, s);13C NMR (101 MHz CDCI3; Me4Si; ppm) 6 170.6, 157.9, 144.3, 133.0, 131.4, 129.9, 119.9, 110.1, 80.8, 54.1, 44.5, 43.3, 28.6, 24.2, 21.5; HRMS (ES+) m / z 420.0903 [M + Na]+Ci7H24BrNsO3Na requires 420.0899 (100%) (Diff 0.92ppm).

[0341] Intermediate 72 tert-butyl 2-(2,4-dichlorophenyl)pyrazolidine-l-carboxylate tert-Butyl 2-(2,4-dichlorophenyl)hydrazine-l-carboxylate (1.85 g, 6.70 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; hexane:EtOAc; 2: 1) to yield the title compound as a yellow oil (1.08 g, 51%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.44 (1H, d, J = 1.5), 7.17 (1H, dd, J = 7.5, 1.5), 6.62 (1H, d, J = 7.5), 3.73 (2H, t, J = 7.0), 3.54 (2H, t, J = 7.0), 2.04 (2H, quintet, J = 7.0), 1.40 (9H, s);13C NMR (101 MHz; CDCI3; Me4Si; ppm) 6 153.5, 144.9, 132.8, 128.5, 125.7, 124.3, 119.9, 81.2, 55.3, 46.1, 28.2, 24.5; HRMS (ES+) m / z 339.0639 [M+Na]+Ci4Hi8Cl2N2O2Na requires 339.0638 (100%) (Diff 0.32 ppm).

[0342] Intermediate 73 tert-butyl (2-(2-(2,4-dichlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(2,4-dichlorophenyl)pyrazolidine-l-carboxylate (1.01 g, 3.19 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; hexane:EtOAc; 3: 1) to yield the title compound as a yellow oil (811 g, 68%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.34 (1H, d, J = 1.5), 7.14 (1H, dd, J = 8.0, 1.5), 6.61 (1H, d, J = 8.0), 5.37 (1H, br. t, J = 4.5), 4.40 (1H, br. s), 4.05 (1H, br. s), 3.96 (1H, br. s), 3.65 (1H, br. s), 3.50 - 3.43 (2H, m), 2.02 (2H, br. s), 1.42 (9H, s);13C NMR (101 MHz CDCI3; Me4Si; ppm) 6 169.9, 155.2, 144.6, 132.8, 128.3, 125.5, 124.6, 120.0, 80.8, 53.9, 45.8, 43.3, 28.1, 24.3; HRMS (ES+) m / z 396.0855 [M + Na]+CieHziCIzNsOsNa requires 396.0852 (100%) (Diff 0.64 ppm).

[0343] Intermediate 74 tert-butyl 2-(2,5-dichlorophenyl)hydrazine-l-carboxylate

[0344] 2,5-Dichlorophenyl)hydrazine (1.00 g, 5.67 mmol) was employed. The crude product was purified by FCC (SiC ; 20:80 EtOAc: Hexane) to afford the titled compound as a yellow solid (1.50 g, 95%).XH NMR (400 MHz; CDCI3; ppm) 6 7.18 (d, J = 8.4 Hz, 1H), 6.95 (unresolved d, 1H), 6.79 (dd, J = 8.4, 2.4 Hz, 1H), 1.49 (s, 9H).13C NMR (101 MHz; CDCI3) 6 155.7, 145.3, 133.6, 130.2, 120.7, 116.9, 113.9, 82.0, 28.2 (3C). HRMS (ES+) 299.0322 [M+Na]+CiiHi4N2O235Cl2Na requires 299.0330 (Diff -2.7 ppm).

[0345] Intermediate 75 tert-butyl 2-(2,5-dichlorophenyl)pyrazolidine-l-carboxylate

[0346] The crude product was purified by FCC (SiCh; 20:80 EtOAc: Hexane) to afford the titled compound as an orange / red solid (0.33 g, 29%).XH NMR (400 MHz; CDCI3; ppm) 6 7.25 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.4, 2.4 Hz, 1H), 3.74 (t, J = 7.2 Hz, 2H), 3.54 (t, J = 7.2 Hz, 2H), 2.09-2.02 (m, 2H), 1.41 (s, 9H).13C NMR (101 MHz; CDCI3) 6 151.5, 149.8, 131.5, 124.0, 123.2, 119.2, 108.2, 81.0, 54.9, 45.0, 31.5, 28.3 (3C). HRMS (ES+) 339.0636 [M+Na]+Ci4Hi8N2O235Cl2Na requires 339.0643 (Diff -2.1 ppm).

[0347] Intermediate 76 tert-butyl (2-(2-(2,5-dichlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(2,5-dichlorophenyl)pyrazolidine-l-carboxylate (0.33 g, 1.05 mmol) was employed. The crude product was purified by FCC (SiCh; 20:80 EtOAc:Hexane) to afford the titled compound as an orange / brown oil (0.24 g, 59%).XH NMR (400 MHz; CDCI3; ppm) 6 7.30 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 8.4, 2.4 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 4.03 (s, 2H), 3.8-3.3 (m, 4H), 2.09 (m, 2H), 1.42 (s, 9H).13C NMR (101 MHz; CDCI3) 6 171.1, 155.8, 148.2, 133.3, 132.0, 125.4, 123.8, 119.0, 79.6, 55.4, 45.0, 42.5, 28.3 (3C). HRMS (ES+) 396.0849 [M + Na]+Ci6H2iN3O335Cl2Na requires 396.0858 (Diff -2.2 ppm).

[0348] Intermediate 77 tert-butyl ( / ?)-(2-oxo-l-phenyl-2-(2-phenylpyrazolidin-l-yl)ethyl)carbamate

[0349] ( / ?)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (0.062 g, 0.25 mmol) was employed. The crude product was purified by FCC (SiCh; hexane to 20:80 EtOAc: Hexane) to afford the titled compounds as a yellow oil (0.056 g, 59%). With the yield consisting of a mixture of rotamers in ratio 1.2 / 1.XH NMR (400 MHz; CDCI3; ppm) 6 7.40-7.20 (m, 5H), 7.16-6.90 (m, 5H), 6.35 (major, s, 1H), 5.91 (major, NH), 5.81 (minor, NH), 5.36 (minor, s, 1H), 4.15-4.06 (minor, m, 2H), 3.98-3.87 (major, m, 2H), 3.40-3.28 (major & minor, m, 4H), 2.16-2.10 (minor, m, 2H), 1.90-1.75 (major, m, 2H), 1.39 (minor, s, 9H), 1.36 (major, s, 9H).13C NMR (101 MHz; CDCI3) 6 172.5, 172.6, 154.6, 154.5, 150.1, 150.0, 149.6, 149.4, 138.7, 138.5, 137.1, 137.0, 129.5 (4C), 128.4 (4C), 128.3 (2C), 128.1 (2C), 116.2, 116.1, 115.6 (2C), 115.5 (2C), 79.5, 79.4, 60.7, 60.4, 56.0, 55.9, 55.5, 53.6, 43.5, 43.3, 28.4, 28.3 (3C). HRMS (ES+) 404.1946 [M+Na]+C22H27N3O3Na requires 404.1950 (Diff -1.0 ppm).

[0350] Intermediate 78

[0351] (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid

[0352] To a solution of (S)-Phenylglycine (2.00 g, 13.20 mmol, 1 eq) acid (1.00 eq) and di- tert-butyl-dicarbonate (1.60 eq) dissolved in ‘BuOH (1.6M) followed by dropwise addition of 2M NaOH. The reaction mixture was allowed to stir at room temperature until consumption of the starting material. Reaction mixture was concentrated in vacuo and acidified to pH of ~3 and extracted in EtOAc (x 3), dried over MgSC and concentrated in vacuo to afford a crude solid. No further purification was required to afford a white solid (2.66 g, 80%). The product was present as a mixture of rotamers in ratio 2 / 1.XH NMR (400 MHz; CDCI3; ppm) 6 7.95 (major, s, 1H), 7.45-7.28 (major & minor, m, 6H), 5.53 (minor, s, NH), 5.33 (major, s, NH), 5.13 (s, 1H), 1.43 (minor, s, 9H), 1.21 (major, s, 9H).13C NMR (101 MHz; CDCI3) 6: 174.9, 156.8, 138.3, 128.9 (2C), 127.2 (2C), 81.6, 58.9, 28.3 (3C). HRMS (ES+) 274.1056 [M + Na]+Ci3Hi7NO4Na requires 274.105 (Diff -1.7 ppm).

[0353] Intermediate 79 tert-butyl (S)-(2-oxo-l-phenyl-2-(2-phenylpyrazolidin-l-yl)ethyl)carbamate

[0354] (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (62 mg, 0.25 mmol) was employed. The crude product was purified by FCC (SiC ; 20:80 to 50:50 EtOAc: Hexane) to afford the titled compound as a yellow oil (0.06 g, 63%). With the yield consisting of a mixture of rotamers in ratio 1.5 / 1.XH NMR (400 MHz; CDCI3; ppm) 6 7.40-7.20 (m, 5H), 7.05-6.80 (m, 5H), 6.36 (major, s, 1H), 5.91-5.69 (major & minor, m, NH), 5.30 (major, s, 1H), 4.08-3.97 (minor, m, 2H), 3.90-3.82 (major, m, 2H), 3.63-3.56 (minor, m, 2H), 3.33-3.17 (major, unresolved m, 2H), 2.08-1.95 (minor, m, 2H), 1.82-1.67 (major, m, 2H), 1.32 (minor, s, 9H), 1.29 (major, s, 9H).13C NMR (101 MHz; CDCI3) 6 172.4, 172.3, 154.9, 154.6, 149.6, 149.4, 138.4, 137.1, 129.5 (2C), 128.4 (2C), 128.1 (2C), 127.8 (2C), 127.6 (2C), 127.3 (2C), 122.6, 122.1, 116.2 (2C), 115.6 (2C), 79.7, 79.5, 56.6, 56.5, 55.6, 53.5, 43.4, 43.3, 43.0, 42.9, 28.4 (3C), 28.3 (3C). HRMS (ES+) 404.1949 [M + Na]+C22H27N3O3Na requires 404.1950 (Diff -0.3 ppm).

[0355] Intermediate 80 tert-butyl ( / ?)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)ca rbamate tert-Butyl 2-(2-bromophenyl)pyrazolidine-l-carboxylate (0.70 g, 1.82 mmol) was employed. The crude product was purified by FCC (SiCh; hexane to 20:80 EtOAc: Hexane) to afford the titled compound as a yellow oil (0.78 g, 93%). With the yield consisting of a mixture of rotamers in ratio 1 / 0.4.XH NMR (400 MHz; CDCI3; ppm) 6 7.62-7.44 (m, 1H), 7.41-7.18 (m, 2H), 7.14-6.79 (m, 5H), 6.74-6.60 (m, 1H), 6.19 (major, s, 1H), 5.89 (major, NH), 5.77 (minor, NH), 5.40 (minor, s, 1H), 3.96-3.84 (minor, m, 2H), 3.74-3.64 (minor, m, 2H), 3.65-3.64 (major, m, 2H), 3.47-3.36 (major, m, 2H), 2.11-2.03 (minor, m, 2H), 1.94-1.80 (minor, m, 2H), 1.39 (major, s, 9H), 1.35 (minor, s, 9H).13C NMR (101 MHz; CDCI3) 6 172.7, 171.1, 154.8, 154.6, 148.4, 147.5, 137.9, 137.1, 134.5, 1334, 128.4 (2C), 128.0 (2C), 127.7 (2C), 127.2 (2C), 125.6, 124.9, 119.1, 118.9, 115.2, 115.1, 79.4, 77.4, 60.4, 60.3, 56.5, 56.3, 56.1, 55.0, 45.7, 45.4, 28.4 (3C), 28.2 (3C). HRMS (ES+) 482.1065 [M + Na]+C22H26N3O379BrNa requires 482.1050 (Diff -3.07 ppm).

[0356] Intermediate 81 tert-Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)ca rbamate tert-Butyl 2-(2-bromophenyl)pyrazolidine-l-carboxylate (0.58 g, 1.77 mmol, 1 eq) was dissolved in a mixture of DCM:TFA (5: 1, 18 mL, ~ lOmL / mmol) and the reaction mixture was allowed to stir at room temperature until TLC showed disappearance of starting material. The reaction mixture was concentrated in vacuo to afford the free amine as a trifluoroacetate salt and was used directly without further purification.

[0357] To a solution of the trifluoroacetate salt of l-(2-bromophenyl)pyrazolidine (0.60 mg, 1.76 mmol) in anhydrous DMF (20 mL), was added Boc-Phg-OH (0.53 mg, 2.11 mmol, 1.2 eq), DIPEA (0.77 mL, 4.40 mmol, 2.5 eq) and HATU (0.87 g, 2.29 mmol, 1.3 eq). The reaction mixture was allowed to stir at room temperature overnight under N2 (followed by TLC). Upon completion, the solution was diluted with EtOAc and washed with sat. aq. NaHCC (x 3), water and brine. The organic layer was dried over MgSC and concentrated in vacuo. The crude product was purified by FCC (SiC ; 20:80 to 50:50 EtOAc:Hexane) to afford the titled compound as a yellow oil (0.65 g, 80%). With the yield consisting of a mixture of rotamers in ratio 2 / 1.XH NMR (400 MHz; CDCI3; ppm) 6 7.56-7.35 (m, 1H), 7.35-7.07 (m, 3H), 7.07-6.69 (m, 4H), 6.69-6.48 (m, 1H), 6.12 (major, s, 1H), 5.81 (major, s, NH), 5.74 (minor, s, NH), 5.33 (minor, s, 1H), 4.05-3.98 (minor, m, 2H), 3.86-3.74 (minor, m, 2H), 3.56-3.44 (major, m, 2H), 3.36- 3.26 (major, m, 2H), 1.99-1.90 (minor, m, 2H), 1.84-70 (major, m, 2H), 1.30 (major, s, 9H), 1.25 (minor, s, 9H).13C NMR (101 MHz; CDCI3) 6 172.6, 171.8, 154.7, 154.5, 148.2, 147.5, 137.8, 137.0, 134.5, 133.4, 128.3 (2C), 128.1 (2C), 127.7 (2C), 127.2 (2C), 125.9, 124.9, 119.1, 118.9, 115.0, 114.3, 79.5, 79.3, 56.2, 56.1, 55.1, 54.9, 45.7, 45.4, 36.9, 35.9, 28.4 (3C), 28.0 (3C). HRMS (ES+) 482.1063 [M + Na]+C22H26N3O379BrNa requires 482.1050 (Diff -2.67 ppm).

[0358] Intermediate 82

[0359] (S)-2-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acetic acid

[0360] (S)-4-Chlorophenylglye (2.50 g, 13.50 mmol) was employed. The crude product was purified by FCC (SiC ; 20:80 EtOAc:Hexane) to afford the titled compound as a white solid (2.20 g, 57%).XH NMR (500 MHz; CDCI3; ppm) 6 8.20 (d, J = 5.2 Hz, NH), 7.41 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 5.14 (d, J = 5.2 Hz, 1H), 1.25 (s, 9H).13C NMR (126 MHz; CDCI3) 6 173.0, 157.0, 136.9, 133.9, 128.6 (2C), 128.5 (2C), 82.1, 58.2, 29.0 (3C). HRMS (ES+) 308.0667 [M+Na]+Ci3Hi6NO4CINa requires 308.6660 (Diff -2.40 ppm).

[0361] Intermediate 83 tert-butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-chlorophenyl)-2- oxoethyl)ca rba mate

[0362] (S)-2-((tert--butoxycarbonyl)amino)-2-(4-chlorophenyl)acetic acid (0.25 g, 0.77 mmol) was employed. The crude product was purified by FCC (SiCh; 30:70 EtOAc: Hexane) to afford the titled compound as a yellow solid (0.20 g, 58%).XH NMR (500 MHz; CDCI3; ppm) 6 7.58 (app t, J = 7.0 Hz, 1H), 7.36 (d, J = 7.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.80-6.72 (unresolved m, 1H), 6.64 (t, J = 7.0, 1H), 6.11 (d, J = 7.5 Hz, NH), 6.01 (d, J = 7.5 Hz, 1H), 3.65-3.58 (m, 2H), 3.45-3.38 (m, 2H), 1.95-1.85 (m, 2H), 1.39 (s, 9H).13C NMR (126 MHz; CDCI3) 6

[0363] 171.7, 154.7, 147.1, 141.0, 133.5, 128.2 (4C), 127.7, 125.3, 124.9, 118.7, 115.1,

[0364] 79.7, 56.1, 56.0, 45.6, 31.6, 28.3 (3C). HRMS (ES+) 516.0662 [M + Na]+C22H2sN3O3CI79BrNa requires 516.0660 (Diff -0.3 ppm).

[0365] Intermediate 84

[0366] Methyl (S)-2-((tert--Butoxycarbonyl)amino)-2-(4-methoxyphenyl)acetate

[0367] To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4- hydroxyphenyl)acetate (0.50 g, 1.78 mmol, 1 eq) in acetone (9 mL) was added K2CO3 (0.32 g, 2.31 mmol, 1.3 eq), followed by methyl iodide (0.12 mL, 1.98 mmol, 1.1 eq) and KI (0.03 g, 10 mol%). The reaction mixture was heated to reflux overnight and concentrated in vacuo then taken up in EtOAc (50 mL), and washed with distilled water (3 x 50 ml), dried over MgS04 and concentrated in vacuo to afford a yellow solid (0.53 g, 100%). No further purification was required.XH NMR (500 MHz; CDCI3; ppm) 6 7.24 (br s, 2H), 6.83 (br s, 2H), 6.03 (br s, 1H), 5.67 (s, 1H), 5.23 (s, NH), 3.73 (s, 3H), 3.66 (s, 3H), 1.39 (s, 9H).13C NMR (126 MHz; CDCI3) 6 171.8, 159.6, 154.8, 128.9, 128.4 (2C), 114.2 (2C), 79.9, 57.0, 55.2, 52.5, 28.2 (3C). HRMS (ES+) 318.1320 [M+Na]+Ci5H2iNOsNa requires 318.1312 (Diff -2.5 ppm). Intermediate 85

[0368] (S)-2-((tert-butoxycarbonyl)amino)-2-(4-methoxyphenyl)acetic acid

[0369] Methyl (S)-2-((tert-Butoxycarbonyl)amino)-2-(4-methoxyphenyl)acetate (0.55 g, 1.87 mmol). The crude product was purified by FCC (SiCh; 20:80 EtOAc: Hexane) to afford the titled compound as a yellow solid (0.24 g, 26%).XH NMR (400 MHz; CDCI3; ppm) 6 7.43-7.32 (m, 2H), 7.22-7.15 (m, 1H), 7.01-6.94 (d, J = 7.5 Hz, 2H), 6.83- 6.78 (m, 1H), 6.67 (br s, 2H), 6.34 (d, J = 8.0 Hz, 1H), 6.17 (s, NH), 3.60-3.51 (m, 5H), 3.44-3.34 (m, 2H), 1.88-1.78 (m, 2H), 1.36 (s, 9H).13C NMR (126 MHz; CDCI3) 6 172.8, 171.0, 158.6, 147.7, 133.3, 128.9 (2C), 127.2, 124.8, 119.1, 115.1, 113.6, 113.4 (2C), 79.2, 60.3, 56.0, 55.6, 55.1, 45.3, 28.4 (3C). HRMS (ES+) 512.1158 [M+Na]+C23H2sN3O4Na requires 512.1155 (Diff -0.41 ppm).

[0370] Intermediate 86 tert-butyl (S)-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)ca rbamate tert-Butyl 2-(2-chloro-5-fluorophenyl)pyrazolidine-l-carboxylate (2.23 g, 7.7 mmol) was employed. The crude product was purified by FCC (SiO2; 20:80 EtOAc: Hexane) to afford the titled compound as a yellow oil (0.21 g, 6%).XH NMR (400 MHz; CDCI3; ppm) 6 8.55-8.20 (m, 1H), 7.80 (br s, 2H), 6.81-6.62 (m, 4H), 6.03 (m, 2H), 3.93 (s,2H), 3.85 (br s, 2H), 1.93-1.81 (m, 9H).13C NMR (101 MHz; CDCI3) 6 172.9, 164.6, 154.8, 136.9, 129.1, 127.9, 127.7, 111.6, 106.3, 78.5, 60.4, 56.4, 55.7, 45.2, 31.6, 29.17, 23.5. HRMS (ES+) 456.1461 [M + Na]+C22H25N3O3CIFNa requires 456.1463 (Diff -0.45 ppm).

[0371] Intermediate 87 tert-Butyl 2-(pyridin-2-yl)pyrazolidine-l-carboxylate BocNxN 6

[0372] 2-Bromopyridine (1.0 mL, 10.5 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution hexane:EtOAc; 3: 1 to 1 :2) to yield the title compound as a brown foam (994 mg, 38%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.18 (1H, d, J = 8.0), 7.61 (1H, t, J = 8.0), 7.00 (1H, t, J = 8.0), 6.75 (1H, d, J = 8.0), 3.71 (2H, t, J = 7.5), 3.55 (2H, t, J = 7.0), 2.09 - 2.03 (2H, m), 1.45 (9H, s);13C NMR (101 MHz; CDCI3; Me4Si; ppm) 6 155.2, 153.7, 149.0, 140.3, 119.4, 113.2, 81.3, 53.9, 45.3, 28.6, 24.9; HRMS (ES+) m / z 272.1373 [M + Na]+CisHigNsCkNa requires 272.1369 (100%) (Diff 1.15 ppm).

[0373] Intermediate 88 tert-butyl (2-oxo-2-(2-(pyridin-2-yl)pyrazolidin-l-yl)ethyl)carbamate tert-Butyl 2-(pyridin-2-yl)pyrazolidine-l-carboxylate (912 mg, 3.66 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; gradient elution hexane:EtOAc; 2: 1 to 1 :3) to yield the title compound as a pale brown oil (549 mg, 49%).XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 8.14 (1H, d, J = 8.0), 7.55 (1H, t, J = 8.0), 6.96 (1H, t, J = 8.0), 6.73 (1H, d, J = 8.0), 5.65 (1H, br. t, J = 4.0), 4.32 (1H, br. s), 4.08 (1H, br. s), 3.70 - 3.66 (2H, m), 3.55 (2H, t, J = 7.0), 2.06 (2H, quintet, J = 7.0), 1.43 (9H, s);13C NMR (101 MHz CDCI3; Me4Si; ppm) 6 171.0, 154.9, 153.6, 148.7, 139.9, 120.2, 109.4, 81.2, 53.9, 45.5, 43.4, 28.4, 24.6; HRMS (ES+) m / z 329.1585 [M+Na]+Ci5H22N4O3Na requires 329.1584 (100%) (Diff 0.36 ppm).

[0374] Intermediate 89 tert-butyl (((2S,3S,6S)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate

[0375] (((2S,3S,6S)-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-

[0376] 8-yl)methyl)carbamate (0.30 g, 0.94 mmol) was employed. The crude product was purified by FCC (SiO2; 50: 50 EtOAc: Hexane) to afford the titled compound as a yellow solid (0.31 g, 38%).XH NMR (500 MHz; CDCI3; ppm) 6 7.04 (d, J = 8.3 Hz, 1H), 6.96 (s, 1H), 6.58 (d, J = 8.3 Hz, 1H), 4.89 (s, NH), 4.64 (s, 1H), 4.58 (s, 1H), 4.16 (d, J = 5.0 Hz, 2H), 3.88-3.80 (m, 1H), 3.55-3.51 (m, 1H), 3.42 (br s, NH), 2.99 (t, J = 11.0 Hz, 1H), 2.16-2.10 (m, 1H), 1.96-1.90 (m, 1H), 1.46 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H).13C NMR (126 MHz; CDCI3) 6 155.8, 145.8, 129.6, 129.3, 127.4,

[0377] 119.8, 113.7, 79.1, 70.8, 67.4, 62.4, 49.7, 44.3, 28.5 (3C), 25.8 (3C), 18.9, -4.5, - 4.7. HRMS (ES+) 435.2672 [M + H]+C23H39N2O4Si requires 435.2674 (Diff 0.46 ppm).

[0378] Intermediate 90

[0379] / V-(((2S,3S,6S)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-lH-imidazole-l-ca rboxamide tert- butyl (((2S,3S,6S)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate (0.15 g, 0.35 mmol) was employed. The crude product was purified by FCC (SiCh; 50: 50 to 70:30 EtOAc: Hexane) to afford the titled compound as a yellow solid (0.084 g, 59%).XH NMR (500 MHz; CDCI3; ppm) 6 8.12 (s, 1H), 7.97 (br s, 1H), 7.49 (br s, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.01 (s, 1H), 6.60 (d, J = 7.8 Hz, 1H), 4.69 (s, NH), 4.58 (s, 1H), 4.58 (s, 1H), 4.50-4.30 (m, 2H), 3.85-3.78 (m, 1H), 3.56-3.51 (m, 1H), 3.47 (br s, NH), 2.99 (t, J = 11.0 Hz, 1H), 2.16-2.10 (m, 1H), 1.96-1.90 (m, 1H), 0.89 (s, 9H), 0.09 (s, 3H), 0.04 (s, 3H).13C NMR (126 MHz; CDCI3) 6 149.1, 146.2, 130.2, 129.8, 129.6,

[0380] 125.8, 119.6, 116.6, 114.1, 113.8, 82.7, 77.4, 77.1, 76.9, 70.6, 67.4, 62.4, 49.6, 44.5, 25.8 (3C), 18.0, -4.5, -4.7. HRMS (ES+) 429.2307 [M + H]+C22H33N4O3Si requires 429.2316 (Diff 2.08 ppm).

[0381] Intermediate 91 tert-Butyl (4-aminobenzyl)carbamate

[0382] To a solution of 4-(aminomethyl)aniline (4.70 g, 38.50 mmol, 1 eq) in THF (IM) followed by addition of BOC2O (9.20 g, 42.40 mmol, 1.1 eq) and dropwise addition of NEts (16 mL, 115.50 mmol, 3 eq). The reaction mixture was allowed to stir overnight. EtOAc (100 mL) was added to the reaction mixture and washed with IM HCI (50 mL), distilled water (100 mL), brine (100 mL). The organic phases were then combined, dried over MgS04and concentrated in vacuo to afford a crude product. The crude product was purified by FCC (SiC ; 20:80 EtOAc: Hexane) to afford the titled compound as a yellow solid (4.30 g, 50%).XH NMR (500 MHz; CDCI3; ppm) 6 7.10 (d, J = 7.8 Hz, 2H), 6.63 (d, J = 7.8 Hz, 2H), 4.89 (br s, NH), 4.17 (s, 2H), 3.70 (br s, 2NH), 1.45 (s, 9H).13C NMR (126 MHz; CDCI3) 6 155.9, 145.7, 128.9, 128.8 (2C), 115.2 (2C), 80.5, 44.4, 28.4 (3C). HRMS (ES+) 245.1263 [M + Na]+CizHisNzOzNa requires 245.126 (Diff -0.98 ppm).

[0383] Intermediate 92 tert-Butyl (((2S,3S,6S)-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate and tert-butyl (((2 / ?,3S,6 / ?)-3- hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c] [l,5]oxazocin-8- yl)methyl)carbamate44

[0384] A mixture of 2-deoxy-D-ribose (2 g, 14.90 mmol, 1 eq), tert-Butyl (4- aminobenzyl)carbamate (4.97 g, 22.4 mmol, 1.5 eq) and montmorillonite (14.5 g) in MeCN (150 mL) was stirred at room temperature for 5 days. The reaction mixture was filtered through celite and concentrated in vacuo. The crude product was purified by FCC (SiC ; 20:80 to 40:60 Acetone: Hexane) to afford the titled diastereoisomers.

[0385] First eluting: tert-butyl (((2S,3S,6S)-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate as a yellow solid (1.06 g, 44%).XH NMR (500 MHz; CDCI3; ppm) 6 6.99 (d, J = 7.8 Hz, 1H), 6.92 (s, 1H), 6.50 (d, J = 7.8 Hz, 1H), 5.19 (s, OH), 4.86 (s, NH), 4.56 (br s, 1H), 4.11 (br s, 2H), 3.72- 3.66 (m, 1H), 3.60-3.52 (m, 2H), 3.39 (br s, NH), 4.73 (brs, 1H), 4.67 (brs, 1H), 4.26- 4.09 (m, 2H), 3.81-3.75 (m, 1H), 3.75-3.68 (m, 1H), 3.67-3.63 (m, 1H), 2.86 (t, J = 11.0 Hz, 1H), 2.06-2.01 (m, 1H), 1.79 (m, 1H), 1.43 (s, 9H).13C NMR (126 MHz; CDCI3) 6 156.1, 145.3, 129.7, 129.2, 127.0, 119.3, 113.6, 79.4, 77.4, 69.2, 67.5, 62.4, 48.7, 44.2, 28.5 (3C). HRMS (ES+) 343.1629 [M + Na]+Ci7H24N2O4Na requires 343.1628 (Diff -0.26 ppm). [O]20D = 15.0 (c 1.0, CH3OH). Rf = 0.46 (50:50 Acetone: Hexane).

[0386] Second eluting: tert-butyl (((2 / ?,3S,6 / ?)-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate as a yellow solid (0.96 g, 38%).XH NMR (500 MHz; CDCI3; ppm) 6 7.04 (d, J = 8.0 Hz, 1H), 7.00 (br s, 1H), 6.51 (d, J = 8.0 Hz, 1H), 5.00 (br s, NH), 4.69 (br s, NH), 4.65 (s, 1H), 4.19-4.12 (m, 2H), 3.63-3.50 (m, 2H), 3.48-3.39 (m, 2H), 2.57 (d, J = 12.5 Hz, 1H), 1.44 (s, 9H).13C NMR (126 MHz; CDCI3) 6 156.0, 144.2, 130.0, 129.4, 126.7, 118.3, 113.1, 79.4, 77A, 69.8, 68.8, 63.4, 47.7, 44.2, 28.5 (3C). HRMS (ES+) 343.1630 [M + Na]+Ci7H24N2O4Na requires 343.1628 (Diff -0.46 ppm). [O]20D = 5 (c 1.0, CH3OH). Rf = 0.34 (50:50 Acetone: Hexane).

[0387] Intermediate 93 tert-Butyl (((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate

[0388] A solution of tert-butyl (((2 / ?,3S,6 / ?)-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate (0.95 g, 2.98 mmol, 1 eq) and pyridine (0.72 ml, 8.90 mmol, 3 eq) in DCM (20 mL) was cooled to 0°C followed by the dropwise addition of tert-butyldimethylsilyl trifluoromethanesulfonate (1.02 mL, 4.45 mmol, 1.5 eq). The reaction mixture was stirred at room temperature until TLC showed disappearance of starting material. The reaction mixture was diluted with DCM (20 mL) and washed with IM HCI (10 mL). The organic and aqueous phases were separated, and the aqueous phase was neutralised and extracted with DCM (2 x 20 mL). The organic phases were then combined, dried over MgS04and concentrated in vacuo. The crude product was purified by FCC (SiCh; 30:70 EtOAc: Hexane) to afford the titled compound as a yellow solid (0.72 g, 56%).XH NMR (500 MHz; CDCI3; ppm) 6 7.07- 6.98 (m, 2H), 6.48 (d, J = 8.0 Hz, 1H), 5.07 (br s, NH), 4.89 (br s, NH), 4.65 (s, 1H), 4.60 (s, 1H), 4.19-4.13 (m, 2H), 3.50-3.43 (m, 3H), 3.36-3.33 (m, 1H), 2.65 (d, J = 12.5 Hz, 1H), 1.45 (s, 9H), 0.93 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H).13C NMR (126 MHz; CDCI3) 6 155.9, 144.0, 130.0, 129.4, 126.7, 118.9, 113.0, 112.9, 79.1, 70.7, 68.5, 63.9, 48.6, 44.3, 28.5 (3C), 25.9 (3C), 18.2, -4.7, -4.8. HRMS (ES+) 457.2488 [M+Na]+C23H38N2O4SiNa requires 457.2493 (Diff 1.16 ppm).

[0389] Intermediate 94

[0390] / V-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-lH-imidazole-l-ca rboxamide tert-Butyl (((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate (0.15 g, 0.35 mmol, 1.00 eq) was dissolved in a mixture of DCM:TFA (5: 1, 5 mL) and the reaction mixture was allowed to stir at room temperature. The reaction was monitored by TLC. Upon completion, the reaction mixture diluted with DCM (10 ml) and neutralised with sat. NaHCCh (10 ml) and brine (10 ml) and extracted with DCM (3 x 20 ml) then dried over MgS04 and concentrated in vacuo to afford the free amine as a white solid (0.10 g, 94%) and it was used directly without further purification.

[0391] A solution of the free amine (0.10 g, 0.30 mmol, 1 eq) and DMAP (3.7 mg, 0.03 mmol, 0.1 eq) in DCM (2.5 mL) was cooled to 0°C, followed by slow addition of CDI (54 mg, 0.33 mmol. 1.1 eq). The reaction mixture was allowed to stir at room temperature overnight (followed by TLC). The reaction mixture was concentrated in vacuo and redissolved in EtOAc (20 mL) and washed with distilled water (15 mL), brine (10 mL) then dried over MgS04and concentrated in vacuo. The crude product was purified by FCC (SiC ; 50: 50 to 70:30 EtOAc: Hexane) to afford the titled compound as a yellow solid (0.06 g, 47%).XH NMR (500 MHz; CDCI3; ppm) 6 8.13 (s, 1H), 7.43 (br s, 1H), 7.18 (dd, J = 8.5 Hz, 1H), 7.11 (s, 1H), 7.06-7.03 (m, 1H), 6.54 (d, J = 8.0 Hz, 1H), 4.69 (br s, NH), 4.57-4.51 (m, 1H) 4.46-4.35 (m, 1H), 3.53 (br s, NH), 3.50 (s, 2H), 3.42-3.38 (m, 1H), 2.73-2.68 (m, 1H), 1.50-1.45 (m, 1H), 1.29-1.27 (m, 1H), 0.95 (s, 9H), 0.11 (br s, 6H).13C NMR (126 MHz; CDCI3) 6 154.8, 148.8, 144.5, 130.8, 130.1, 130.0, 125.2, 119.1, 116.2, 113.2, 70.5, 68.5, 63.9, 48.6, 44.6, 25.8 (3C), 23.4, 18.2, -4.7, -4.8. HRMS (ES+) 429.2319 [M + H]+C22H33N4O3Si requires 429.2316 (Diff -0.64 ppm).

[0392] Intermediate 95 tert-Butyl 2-(2-chloro-5-fluorophenyl)pyrazolidine-l-carboxylate

[0393] The title compound was obtained following similar procedures as described for tert- Butyl 2-(2-bromophenyl)pyrazolidine-l-carboxylate starting from tert-butyl 2-(2- chloro-5-fluorophenyl) hydrazine-1 -carboxylate (2.5 g, 9.6 mmol). The crude product was purified by FCC (SiC ; 20:80 EtOAc: Hexane) to afford the titled compound as a red solid (1.4 g, 48%).XH NMR (400 MHz; CDCI3; ppm) 6 7.30-7.26 (m, 1H), 6.82 (dd, J = 10.4, 2.8 Hz, 1H), 6.71-6.66 (m, 1H), 3.73 (t, J = 6.9 Hz, 2H), 3.55 (t, J = 6.9 Hz, 2H), 2.08-2.01 (m, 2H), 1.41 (s, 9H).13C NMR (101 MHz; CDCI3) 6 161.8 (d, J = 246.1 Hz), 154.4, 150.5 (d, J = 7.5 Hz), 131.5 (d, J = 9.3 Hz), 119.7 (d, J = 3.3 Hz), 110.9 (d, J = 24.2 Hz), 106.6 (d, J = 26.9 Hz), 81.0, 54.9, 46.0, 31.6, 28.7 (3C). HRMS (ES+) 323.0920 [M+Na]+Ci4Hi8N2O235CIFNa requires 323.0939 (Diff -2.6 ppm). Intermediate 96 tert-Butyl (2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate

[0394] The title compound was obtained following a similar procedure as described for tert- Butyl (2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate starting from tert-Butyl 2-(2-chloro-5-fluorophenyl)pyrazolidine-l-carboxylate (0.094 g, 0.31 mmol, 1.00 eq). The crude product was carried through to the next step. The crude product was purified by FCC (SiC ; 20:50 EtOAc: Hexane) to afford the titled compound as an orange solid (64.3 mg, 57%).XH NMR (400 MHz; CDCI3; ppm) 6 7.33 (dd, J = 8.4, 6.0 Hz, 1H), 6.80-6.74 (m, 2H), 4.02 (s, 2H), 4.0-3.4 (unresolved m, 4H), 2.15-2.00 (unresolved m, 2H), 1.42 (s, 9H).13C NMR (101 MHz; CDCI3) 6 171.1, 161.8 (d, J = 248.8 Hz), 160.5, 155.8, 148.7 (d, J = 8.2 Hz), 132.1 (d, J = 9.2 Hz), 118.9 (d, J = 1.5 Hz), 112.3 (d, J = 23.2 Hz), 106.4 (d, J = 27.1 Hz), 79.5, 55.3, 45.0, 31.6, 28.3 (3C). HRMS (ES+) 380.1150 [M+Na]+Ci6H2iN3O335CIFNa requires 380.1153 (Diff -0.8 ppm).

[0395] Intermediate 97 l-(((2 / ?,3S,6 / ?)-3-((tert--butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo [c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-5- fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea tert-Butyl (2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate

[0396] (120 mg, 0.33 mmol, 1 eq) was dissolved in a mixture of DCM:TFA (5: 1, 5 mL) and the reaction mixture was allowed to stir at room temperature until TLC showed disappearance of starting material. The reaction mixture was concentrated in vacuo to afford the free amine as a trifluoroacetate salt and was used directly without further purification.

[0397] To a solution of the trifluoroacetate salt in anhydrous acetonitrile (3 mL), was added / V-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-lH-imidazole-l-carboxamide (141 mg, 0.33 mmol, 1 eq), triethylamine (0.045 mL, 1.32 mmol, 4 eq) (0.20 mL, 1.41 mmol, 2.2 eq) and DMAP (4 mg, 0.03 mmol, 0.1 eq) and was allowed to stir at room temperature overnight under N2 (followed by TLC). Upon completion, the solution was extracted with ethyl acetate, washed with distilled water and brine, dried over MgSC and concentrated in vacuo. Purification by column chromatography (DCM: MeOH= 20: 1) gave the title compound (152 mg, 73%) as yellow solid. Rf = 0.60, 10% ethyl acetate in hexane. The crude product was purified by FCC (SiCh; 95:5 DCM:MeOH) to give the title compound as a yellow solid (285 mg, 55%).XH NMR (400 MHz; CDCI3) 6 7.31 (dt, J =12.3, 6.2 Hz, 1H), 7.11-7.01(m, 2H), 6.80-6.63(m, 2H) 6.47 (d, J =15.0 Hz, 1H), 5.34 (t, J =4.4 Hz, 1H), 5.05 (t, J =5.4 Hz, 1H), 4.66 (s, 1H), 4.32 (d, J =3.4 Hz, 1H), 4.22 (d, J =5.4 Hz, 2H), 3.54-3.40 (m, 10H), 3.34 (dd, J =12.9,1.6, 1H), 2.65 (d, J =12.9 Hz, 1H), 2.11-1.99 (m, 2H), 1.42 (d, J =12.6 Hz, 1H), 0.92(s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).13C NMR (101 MHz; CDCI3) 6 172.1 , 161.8 (d, J =247.6 Hz) 157.9, 148.8, 143.9, 132.3 (d, J =9.0 Hz), 130.2, 129.5, 127.6, 120.5, 119.1, 112.3 (d, J = 23.1 Hz), 106.5 (d, J = 26.4 Hz), 77.5, 70.9, 68.6, 64.0, 55.4, 48.8, 45.1, 44.2, 42.5, 26.0 (3C), 23.7, 23.6, 18.3, -4.6, -4.7. HRMS (ES+) C3oH42CIFN504Na [M+Na]+requires 640.2493, found 640.2484.

[0398] Intermediate 98 tert-butyl (S)-(2-(2-(2-chloro-5-fluorophenyl) pyrazolidin-l-yl)-2-oxo-l-phenylethyl) carbamate

[0399] The title compound was obtained following a similar procedure as described for tert- Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)carbamate starting from tert-Butyl 2-(2-chloro-5-fluorophenyl)pyrazolidine-l-carboxylate (700 mg, 2.33 mmol). The crude product was purified by FCC (SiCh; 1 :3 EtOAc:Hexane) to give the title compound as a yellow solid (500 mg, 51%). The product was present as a mixture of rotamers in ratio 2 / 1.XH NMR (400 MHz; CDCI3) 6 7.45-7.28 (m, 3H), 7.12- 7.08 (m, 2H), 6.91 (s, 2H), 6.82-6.76 (m, 1H), 6.47-6.44 (m, major, 1H), 5.89- 5.87 (m, major, 1H), 5.84-5.78 (m, minor, 1H), 5.39-5.37(m, minor 1H), 4.15-4.08 (m, minor, 2H), 3.95-3.92 (m, minor, 2H), 3.62-3.51 (m, major, 2H), 3.46-3.35 (m, major, 2H) 2.08-2.04 (m, minor, 2H), 1.89-1.80 (m, major, 2H), 1.39 (s, major, 9H), 1.35 (s, minor, 9H).13C NMR (101 MHz; CDCI3) 6 173.1, 172.4, 161.2 (d, J = 244 Hz), 160.8 (d, J = 244 Hz), 160.7, 160.4, 155.0, 154.8, 148.9, 148.2, 131.2, 131.2, 128.5,

[0400] 128.5, 128.5, 128.5, 128.3, 128.2, 123.0, 127.9, 127.9, 127.6, 119.8, 119.5, 112.2,

[0401] 111.5, 106.5, 106.3, 79.7, 79.4, 56.7, 56.5, 55.6, 54.4, 45.5, 45.1, 31.1, 28.5 (3C), 24.0 (3C), 23.4. HRMS (ES+) C22H25CIFN3O3Na [M + Na]+requires 456.1461, found 456.1464.

[0402] Intermediate 99 tert-butyl (((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-10-chloro-l,3,4,6-tetrahydro- 2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate

[0403] To a solution of / V-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro- 2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)-lH-imidazole-l-carboxamide (1 g, 2.30 mol) in DMF (20 mL) was added / V-chlorosuccinimide (1.69 g, 12.7 mol, 5 eq), the reaction mixture was allowed to stir at room temperature for 16h. The reaction mixture was extracted with EtOAc, the organic layers was washed with distilled water and brine, dried over MgS04, filtered and concentrated in vacuo to afford the crude product. The crude product was purified by FCC (SiCh; 5: 1 EtOAc: Hexane) to afford the titled compound as a yellow solid (600 mg, 56%).XH NMR (400 MHz; CDCI3) 6 7.18 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 4.83(d, J = 4.3 Hz, 1H), 4.78 (s, 1H), 4.68 (s, 1H), 4.16 (d, J = 4.8 Hz, 2H), 3.62 (s, 1H), 3.49 (d, J = 5.5 Hz, 2H), 3.29 (dd, J = 12.7, 1.5 Hz, 1H), 2.69 (d, J = 12.8 Hz, 1H), 1.46-1.44 (m, 10H), 0.93 (s, 9H), 0.09 (s, 6H).13C NMR (101 MHz; CDCI3) 6 155.9, 140.0, 128.8, 128.6, 127.4, 120.7, 117.1, 79.6, 70.4, 68.4, 64.0, 53.5, 48.7, 44.0, 28.5 (3C), 26.0 (3C), 18.3, - 4.6, -4.7. HRMS (ES+) C23H37CIN2O4SiNa [M+Na]+requires 491.2103, found 491.2103.

[0404] Intermediate 1OO

[0405] (4-amino-3-fluorophenyl)methanaminium chloride

[0406] To solution of 4-amino-3-fluorobenzonitrile (2 g, 14.7 mmol) in methanol (100 mL) was added 10 wt.% Pd / C (1 g, 9.39 mmol, 0.64 eq) and concentrated HCI (10 mL, the reaction mixture was allowed to stir at room temperature under a H2 atmosphere for 16h. After the complete consumption of starting material, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the titled compound as a yellow solid (2.4 g, 95%). No further purification was required.XH NMR (400MHz; MeOD; ppm) 6 7.61 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 10.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 4.21 (s, 2H).13C NMR (101 MHz; MeOD) 6 157.1 (d, J = 249.3 Hz), 127.2 (d, J = 3.4 Hz), 125.8, 118.2 (d, J = 18.2 Hz), 116.9 (d, J = 14.0 Hz), 116.9 (d, J = 19.2 Hz), 43.2.

[0407] Intermediate 101 tert-butyl (4-amino-3-fluorobenzyl)carbamate

[0408] To a solution of (4-amino-3-fluorophenyl)methanaminium chloride (1 g, 5.68 mmol) in THF (58 mL) was added di-tert-butyl dicarbonate (1.37 g, 6.27 mmol, 1.1 eq) and triethylamine (3.16 mL, 22.72 mmol, 4 eq), the reaction was allowed to stir at room temperature for 8h (followed by TLC). The reaction mixture was extracted with ethyl acetate, the organic layers was washed with distilled water and brine, dried over MgS04, filtered and concentrated in vacuo to afford the crude product. The crude product was purified by FCC (SiCh; 1 :3 EtOAc: Hexane) to afford the titled compound as a white solid (1.30 g, 95%).XH NMR (400 MHz; MeOD) 6 6.89-6.76 (m, 3H), 4.08(s, 2H), 1.45 (s, 9H).13C NMR (101 MHz; MeOD) 6 158.5, 153.1 (d, J = 237.7 Hz), 135.5 (d, J = 13.1 Hz), 131.1, 124.4, 118.2 (d, J = 3.8 Hz), 115.0 (d, J = 19.3 Hz), 80.1, 44.1, 28.8 (3C). HRMS (ES+) CizHi FNzOzNa [M + Na]+requires 263.1166, found 263.1171. Anal. Cal. (mass %) for C12H17FN2O2: C, 59.99; H, 7.13; N, 11.66. Found: C, 59.92; H, 7.13; N, 11.64.

[0409] Intermediate 102 tert-butyl (((2 / ?,3S,6 / ?)-10-fluoro-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c] [l,5]oxazocin-8-yl)methyl)carbamate tert-Butyl (4-amino-3-fluorobenzyl)carbamate (1 g, 4.15 mmol) was employed. The crude product was purified by FCC (SiC ; 2: 1 EtOAc: Hexane) to afford the titled compound as a yellow solid (80 mg, 11%).XH NMR (400 MHz; CDCI3) 6 6.91 (d, J = 10.7 Hz, 1H), 6.85 (s, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 4.54 (s, 1H), 4.16 (s, 2H), 3.72 (s, 1H), 3.56 (d, J= 13.6, 1H), 3.52 (s, 1H), 3.44 (d, J=12.9, 1H), 2.70 (s, 1H), 2.59 (d, J= 13.3, 1H), 1.51 (d, J= 13.3, 1H) 1.45(s, 9H).13C NMR (101 MHz; CDCI3) 6 156.0, 149.8 (d, J= 240.0 Hz), 143.0, 132.5 (d, J= 12.4 Hz), 124.8 (d, J= 2.7 Hz), 120.7 (d, J= 3.6 Hz), 114.6 (d, J= 18.3 Hz), 79.7, 69.9, 68.2 (d, J= 2.6 Hz), 63.9, 47.2, 44.1, 28.6 (3C), 23.7. HRMS (ES+) Ci7H23FN2O4Na [M + Na]+requires 361.1534, found 361.1538.

[0410] Intermediate 103 tert-butyl (((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-10-fluoro-l,3,4,6-tetrahydro-

[0411] 2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate tert-Butyl (((2 / ?,3S,6 / ?)-10-fluoro-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c] [l,5]oxazocin-8-yl)methyl)carbamate (150 mg, 1.6 mmol). The crude product was purified by FCC (SiO2; 1:3 EtOAc: Hexane) to afford the titled compound as a yellow oil (300 mg, 75%).XH NMR (400 MHz; CDCI3) 6 6.91 (d, J = 11.7, 1H), 6.85 (S, 1H), 4.77 (s, 1H), 4.70 (s, 1H), 4.47 (s, 1H), 4.17 (d, J = 5.1, 2H), 3.58 (s, 2H), 3.49 (s, 1H), 3.47 (s, 1H), 3.34 (d, J = 11.5 Hz, 1H), 2.70 (d, J = 13.0, 1H), 1.45 (s, 9H), 0.93 (s, 9H), 0.09 (s, 6H).13C NMR (101 MHz; CDCI3) 6 155.9, 149.8 (d, J = 239.6 Hz), 132.4 (d, J = 12.3 Hz), 126.8, 124.8, 121.4 (d, J = 3.4 Hz), 114.3 (d, J = 18.3), 79.6, 70.6, 67.9 (d, J = 12.3 Hz), 64.1, 48.1, 44.1, 28.5 (3C), 26.0 (3C), 23.5, 18.3, -4.6, -4.7. HRMS (ES+) C23H37FN2O4SiNa [M + Na]+requires 475.2399, found 475.2403. Anal. Cal. (mass %) for C23H37FN2O4Si: C, 61.03; H, 8.24; N, 6.19. Found: C, 59.65; H, 8.28; N, 5.20.

[0412] Intermediate 104 tert-butyl (S)-(2-(2-(2-chloro-5-methoxyphenyl) pyrazolidin-l-yl)-2-oxo-l- phenylethyl)Carbamate

[0413] The title compound was obtained following a similar procedure as described for tert-

[0414] Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)carbamate starting from tert-Butyl 2-(2-chloro-5-methoxyphenyl)pyrazolidine-l-carboxylate (450 mg, 1.44 mmol). The crude product was purified by FCC (SiCh; 50: 50 EtOAc: Hexane) to give the title compound as an orange oil (0.38 g, 60%). The product was present as a mixture of rotamers in ratio 3 / 1.XH NMR (400 MHz; CDCI3) 6 7.46-7.45 (m, 1H), 7.42-7.40 (m, 1H), 7.36-7.34 (m, 1H), 7.32-7.28 (m, 1H), 7.13-7.06 (m, 2H), 6.92- 6.88 (m, 2H), 6.59 (major, s, 1H), 6.30 (major, s, 1H), 5.84 (minor, s, 1H), 5.66 (minor, s, 1H), 4.07-4.05 (minor, m, 2H), 3.94-3.83 (minor, s, 2H), 3.76 (major, s, 2H), 3.62-3.52 (major, m, 2H), 3.44 (s, 3H), 2.07 (minor, s, 2H), 1.87 (major, br s, 2H), 1.44 (minor, s, 9H), 1.42 (major, s, 9H).13C NMR (101 MHz; CDCI3) 6 172.6, 172.0, 170.0, 159.0, 158.2, 155.0, 154.7, 154.5, 147.8, 147.1, 137.9, 137.7, 137.1, 131.63, 130.6, 128.9, 128.2, 128.1, 127.9, 127.7, 127.7, 127.1, 116.1, 115.8, 110.3, 110.0, 105.3, 104.6, 79.5, 79.3, 56.5, 56.2, 55.5, 55.1, 54.3, 45.4, 45.0, 35.9, 28.3 (3C), 23.6, 23.1 (3C), 22.6. HRMS (ES+) C23H28CIN3O4Na [M+ Na]+requires 468.1661, found 468.1670.

[0415] Intermediate 105 tert-butyl (2-(2-(2-chloro-4-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate tert-Butyl 2-(2-chloro-4-fluorophenyl) pyrazolidine-l-carboxylate (430 mg, 1.43 mmol) was employed. The crude product was purified by FCC (SiC ; 95: 5 DCM : MeOH) to give the title compound as an orange oil (0.4 g, 78%).XH NMR (400 MHz; CDCI3) 6 7.09 (dd, J = 8.0, 2.6 Hz, 1H), 6.96-6.78 (m, 2H), 5.20 (s, 1H), 3.97-3.29 (m, 6H), 2.01-1.98 (br s, 2H), 1.36 (s, 9H).13C NMR (101 MHz; CDCI3) 6 170.8, 159.2 (d, J = 246.8 Hz), 155.8, 143.5, 126.5, 119.8, 118.4, 114.4, 79.5, 55.6, 45.3, 42.5, 28.3 (3C), 23.2. HRMS (ES+) Ci6H2iCIFN3O3Na [M+Na]+requires 380.1148, found 380.1154.

[0416] Intermediate 106 tert-butyl 2-(2-chloro-4-fluorophenyl) hydrazine-l-carboxylate To a solution of (2-chloro-4-fluorophenyl) hydrazine (5 g, 30.15 mmol) in THF (60 mL) was added di-tert-butyl dicarbonate (7.24 g, 33.17 mmol, 1.1 eq) and triethylamine (5.90 mL, 42.3 mmol, 1.4 eq). The reaction mixture was allowed to stir at room temperature for 8h (followed by TLC), then the reaction mixture was extracted with EtOAc, washed with distilled water and brine, dried over MgSCX then concentrated in vacuo to afford the crude product. The crude product was purified by FCC (SiC ; 20:80 EtOAc: Hexane) to give the title compound as a yellow solid (5 g, 64%).XH NMR (400 MHz; CDCI3) 6 7.05 (dt, J = 8.1, 1.6 Hz, 1H), 6.92 (d, J = 1.3 Hz, 1H), 6.91(d, J =1.7 Hz, 1H), 6.37 (s, 1H), 6.10 (s, 1H), 1.46 (s, 9H).13C NMR (101 MHz; CDCI3) 6 156.9 (d, J = 203.9 Hz), 155.5, 141.0, 119.3, 116.8, 114.8, 114.2, 81.9, 28.3 (3C). HRMS (ES+) CiiHi4CIFN2O2Na [M+Na]+requires 283.0620, found 283.0618

[0417] Intermediate 107 tert-butyl 2-(2-chloro-4-fluorophenyl) pyrazolidine-l-carboxylate

[0418] The title compound was obtained following a similar procedure as described for tert- Butyl 2-(2-bromophenyl)pyrazolidine-l-carboxylate starting from tert-butyl 2-(2- chloro-4-fluorophenyl) hydrazine-1 -carboxylate (1 g, 3.85 mmol). The crude product was purified by FCC (SiCh; 20:80 EtOAc:Hexane) to give the title compound as a yellow oil (450 mg, 81%).XH NMR (400 MHz; CDCI3) 6 7.09 (dd, J = 8.2, 2.7 Hz, 1H), 7.01 (dd, J = 9.0, 5.5 Hz, 1H), 6.92-6.82 (m, 1H), 3.72 (t, J =7.3 Hz, 2H), 3.46 (t, J =6.6 Hz, 2H), 2.03 (t, J =7.0 Hz, 2H), 1.38 (s, 9H).13C NMR (101 MHz; CDCI3) 6 158.7 (d, J = 244.8 Hz), 154.4, 145.3, 126.0, 120.1, 117.9, 114.0, 80.8, 55.3, 46.3, 28.4 (3C), 24.5. HRMS (ES+) Ci4Hi8CIFN2O2Na [M+Na]+requires 323.0933, found 323.0939.

[0419] Intermediate 108 tert-butyl (S)-(2-(2-(2-chloro-4-fluorophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)ca rbamate

[0420] The title compound was obtained following a similar procedure as described for tert- Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)carbamate starting from tert-butyl 2-(2-chloro-4-fluorophenyl) pyrazolidine-l-carboxylate (0.5 g, 1.67 mmol). The crude product was purified by FCC (SiCh; 50:50 EtOAc: Hexane) to give the title compound as an orange oil (0.5 g, 69%). The product was present as a mixture of rotamers in ratio 2 / 1.XH NMR (400 MHz; CDCI3) 6 7.50-7.27 (m, 4H), 7.12- 6.90 (m, 4H), 6.31 (s, minor, 1H), 6.12-6.04 (m, minor, 1H), 5.83-5.70 (m, major, 1H), 5.55-5.26 (m, minor 1H), 4.05-3.86 (m, minor, 2H), 3.63-3.53 (m, minor, 2H), 3.51-3.45 (m, major, 2H), 3.45-3.24 (m, major, 2H) 2.05-2.02 (m, minor, 2H), 1.86- 1.84 (m, major, 2H), 1.40 (s, major, 9H), 1.37 (s, minor, 9H).13C NMR (101 MHz; CDCI3) 6 172.9, 170.3, 168.2, 159.6 (d, J = 237 Hz), 158.2 (d, J = 237 Hz), 155.2, 154.9, 152.1, 142.8, 137.9, 137.1, 132.9, 129.8, 129.4, 129.1, 128.9, 128.3, 128.2, 127.8, 127.5, 127.3, 126.5, 126.5, 125.7, 119.5, 117.5, 114.5, 113.5, 79.8, 79.7, 56.4, 55.8, 55.2, 54.6, 45.8, 45.4, 37.0, 36.1, 31.7 (3C), 28.4 (3C). HRMS (ES+) C22H25CIFN3O3Na [M+ Na]+requires 456.1461, found 456.1462.

[0421] Intermediate 109 tert-butyl (S)-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-l-(4-(2- morpholinoethoxy)phenyl)-2-oxoethyl)carbamate

[0422] The title compound was obtained following a similar procedure as described for tertbutyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-morpholinoethoxy)phenyl)- 2-oxoethyl)carbamate starting from methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4- (2-morpholinoethoxy)phenyl)acetate and tert-butyl 2-(2-chloro-5- fluorophenyl)pyrazolidine-l-carboxylate.XH NMR (400MHz; CDCI3) 6 7.35-7.33 (m, 1H), 7.24 (s, 1H), 7.12-7.10 (m, 1H), 6.97 (d, J = 8.1 Hz, 2H), 6.88-6.81 (m, 1H), 6.41 (d, J = 8.5 Hz, 1H), 5.89-5.86 (m, 1H), 5.75 (s, 1H), 3.92-3.87 (m, 2H), 3.73- 3.69 (m, 8H), 2.78 (s, 2H), 2.56-2.53 (m, 6H), 1.37 (s, 9H).13C NMR (101 MHz; MeOD) 6 172.0, 161.1 (d, J = 247 Hz), 158.9, 158.0, 154.9, 148.3, 131.2, 129.4, 129.1, 128.5, 119.8, 115.0, 114.5, 114.3, 79.6, 67.0, 67.0, 65.9, 57.7, 57.5, 54.2, 54.0, 52.7, 45.0, 38.7, 28.5 (3C). HRMS (ES+) C28H37CIFN4O5 [M+ H]+requires 563.2431, found 563.2436

[0423] Intermediate 110

[0424] / V-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-10-fluoro-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-lH-imidazole-l-ca rboxamide

[0425] The crude product was purified by FCC (SiCh; 95:5 DCM:MeOH) to afford the titled compound as a yellow solid (70 mg, 52%).XH NMR (400 MHz; CDCI3) 6 8.10 (s, 1H), 7.42 (s, 1H), 7.02 (dd, J = 11.6, 1.8Hz, 1H), 7.00(s, 1H), 6.89 (s, 1H) , 4.68 (s, 1H), 4.58-4.47 (m, 3H), 4.31 (dd, J = 14.4, 5.0 Hz, 1H), 3.6 (s, 1H), 3.50 (s, 2H), 3.38- 3.31 (m, 1H), 2.72 (d, J = 12.9, 1H), 1.49-1.38 (m, 1H), 0.93 (s, 9H), 0.09 (s, 6H).13C NMR (101 MHz; CDCI3) 6 150.0 (d, J = 183.7 Hz), 148.5, 133.0 (d, J = 12 Hz), 130.1, 125.6, 125.0, 125.0, 121.3, 121.3, 115.1 (d, J = 18.1 Hz), 70.4, 67.9, 64.1, 48.0, 44.4, 25.9 (3C), 23.3, 18.3, -4.6, -4.7. HRMS (ES+) C22H32FN4O3Si [M + H]+requires 446.2149, found 447.2225.

[0426] Intermediate 111 tert-butyl (R)-(2-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)-2-oxoethyl)carbamate

[0427] To a solution of (R)-2-(2-chloro-5-fluorophenyl)pyrrolidine hydrochloride (0.25 g, 1.06 mmol) in anhydrous DMF (7.5 mL) was added boc-glycine (0.22 g, 1.27 mmol, 1.2 eq), DIPEA (0.55 mL, 3.18 mmol, 3 eq) and HATU (0.48 g, 1.27 mmol, 1.2 eq). The reaction mixture was allowed to stir at room temperature overnight under N2 (followed by TLC).

[0428] Upon completion, the solution was diluted with EtOAc and washed with sat. aq. NaHCOs, water and brine. The organic layer was dried over MgS04and concentrated in vacuo. The crude product was purified by FCC (SiO2; 30:70 EtOAc:Hexane) to afford the titled compound as a white foam (0.33 g, 87%). With the yield consisting of a mixture of rotamers in ratio 1.1 / 1.

[0429] XH NMR (400 MHz, CDCI3) 6 7.35 (dd, J = 8.6, 5.1 Hz, 1H, minor), 7.31 (dd, J = 8.7, 5.1 Hz, 1H, major), 6.98 - 6.92 (m, 1H, minor), 6.91 - 6.85 (m, 1H, major), 6.78 (d, J = 9.1 Hz, 1H, minor), 6.68 (dd, J = 9.1, 3.0 Hz, 1H, major), 5.39 (m, 2H), 5.19 (dd, J = 7.8, 1.2 Hz, 1H), 4.03 - 4.00 (m, 1H, minor), 3.95 (dd, J = 10.9, 6.3 Hz, 1H, major), 3.87 - 3.74 (m, 1H, minor), 3.79 - 3.71 (m, 2H, major), 3.63 - 3.54 (m, 1H), 3.34 - 3.26 (m, 1H), 2.50 - 2.25 (m, 3H, minor), 1.97 (m, 3H, major), 1.45 - 1.38 (s, 9H). HRMS (ES+) Ci7H22N2O3FCINa [M+Na]+requires 379.1195, found 379.1200.

[0430] Intermediate 112 methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate

[0431] To a suspension of 4-hydroxyl-S-phenylglycine (7.70 g, 46 mmol, 1 eq) in methanol (90 mL), was cooled to 0°C followed by dropwise addition of thionyl chloride (9.4 mL, 129 mmol, 2.8 eq). The reaction mixture was heated to reflux overnight, cooled and concentrated in vacuo to afford a crude methyl ester salt. The salt, NaOH (1.94 g, 48.3 mmol, 1.05 eq) and di- tert- butyl dicarbonate (15.04 g, 69 mmol, 1.6 eq), in methanol (90 mL) was allowed to stir overnight and concentrated in vacuo. The residue was taken up in distilled water (200 ml) and extracted with EtOAc (3 x 150 mL), dried over MgS04 and concentrated in vacuo to afford a crude solid. The crude product was purified by FCC (SiC ; 50:50 EtOAc: Hexane) to afford the titled compound as a white solid (12.92 g, 52%).XH NMR (500 MHz; CDCI3; ppm) 6 7.18 (d, J = 7.9 Hz, 2H), 6.75 (d, J = 7.9 Hz, 2H), 5.65 (d, J = 6.8 Hz, 1H), 5.24 (d, J = 6.8 Hz, INH), 3.74 (s, 3H), 1.46 (s, 9H).13C NMR (126 MHz; CDCI3) 6 172.0, 156.3, 155.1, 128.4 (2C), 128.2, 115.8 (2C), 80.5, 57.1, 52.7, 28.3 (3C). HRMS (ES+) 304.1159 [M + Na]+Ci4Hi9NO5Na requires 304.1155 (Diff -1.22 ppm).

[0432] Intermediate 113 methyl (S)-2-(4-(allyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)acetate

[0433] To a solution of methyl (S) -2- ((tert- butoxy ca rbonyl)amino)-2-(4- hydroxyphenyl)acetate (2.67 g, 9.48 mmol 1 eq) in acetone (340 mL) was added K2CO3 (1.70 g, 12.32 mmol, 1.30 eq), followed by allyl bromide (1.22 ml, 10.42 mmol, 1.1 eq) and KI (0.16 g, 10mol%). The reaction mixture was heated to reflux overnight and concentrated in vacuo and taken up in EtOAc (200 mL) and washed with distilled water (3 x 150 mL) then dried over MgSC and concentrated in vacuo to afford a crude solid. The crude product was purified by FCC (SiCh; 40:60 EtOAc:Hexane) to afford the titled compound as a white solid (1.13 g, 100%).XH NMR (500 MHz; CDCI3; ppm) 6 7.17 (d, J = 7.3 Hz, 2H), 6.89 (d, J = 7.3 Hz, 2H), 6.07-5.99 (m, 1H), 5.54 (d, J = 6.6 Hz, 1H), 5.42-5.38 (m, 1H), 5.29-5.26(m, 1H), 5.25 (br s, INH), 4.52 (dt, J = 5.5, 1.0 Hz, 2H), 3.71 (s, 3H), 1.43 (s, 9H).13C NMR (126 MHz; CDCI3) 6 171.9, 158.7, 154.8, 133.1, 129.1, 128.4 (2C), 117.7, 115.1 (2C), 80.0, 68.8, 57.0, 52.6, 28.3 (3C). HRMS (ES+) 344.1473 [M + Na]+Ci7H23NO5Na requires 344.1468 (Diff -1.28 ppm).

[0434] Intermediate 114 methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2-oxoethoxy)phenyl)acetate

[0435] A solution of methyl (S)-2-(4-(allyloxy)phenyl)-2-((tert- butoxycarbonyl)amino)acetate (2.87 g, 8.94 mmol, 1 eq) in DCM (180 mL) with methanol (4.5 mL) was cooled to -78°C then ozone was bubbled through the reaction mixture until completion. Ozone was produced with an ozone generator (0.5 L / min O2, 150 V). Dimethyl sulfide (13.22 mL, 0.18 mol, 20 eq) was added to quench the reaction. The reaction mixture was concentrated in vacuo and taken up in EtOAc (150 mL) and washed with sat. NaHCOs (100 mL), distilled water (100 mL) and brine (50 mL) then dried over MgS04 and concentrated in vacuo to afford a crude solid. The crude product was purified by FCC (SiO2; 20:80 to 50:50 EtOAc:Hexane) to afford the titled compound as a colourless oil (1.53 g, 55%).XH NMR (400 MHz; CDCI3; ppm) 6

[0436] 9.84 (s, 1H), 7.31 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.54 (d, J = 6.1 Hz, 1H), 5.27 (d, J = 6.1 Hz, NH), 4.57 (s, 2H), 3.72 (s, 3H), 1.43 (s, 9H).13C NMR (101 MHz; CDCI3) 6 198.9, 171.7, 157.7, 154.8, 130.6, 128.7 (2C), 128.5, 115.0 (2C), 80.2, 72.7, 56.9, 52.7, 52.7, 28.3 (3C). HRMS (ES+) 346.1266 [M + Na]+CieHziNOeNa requires 346.1261 (Diff -1.44 ppm).

[0437] Intermediate 115 methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2- morpholinoethoxy)phenyl)acetate

[0438] A solution of morpholine (0.28 ml, 2.66 mmol, 3.5 eq) and methyl (S)-2-((tert- butoxycarbonyl)amino)-2-(4-(2-oxoethoxy)phenyl)acetate (0.30 g, 0.76 mmol, 1 eq) in MeCN (10 mL) was allowed to stir for an hour before sodium triacetoxyborohydride (NaH(OAc)3) (1.6 eq) was added followed by acetic acid (4 eq). The reaction was monitored by TLC until consumption of the starting material before being diluted with EtOAc then washed with sat. aq. NazCC , distilled water, brine then dried over MgS04 and concentrated in vacuo to afford the crude product. The crude product was purified by FCC (SiC ; 20:80 EtOAc: Hexane) to afford the titled compound as a colourless oil (0.26 g, 70%).XH NMR (500 MHz; CDCI3; ppm) 6 7.24 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H), 5.63 (d, J = 6.3 Hz, 1H), 5.22 (d, J = 6.3 Hz, NH), 4.06 (t, J = 6.0 Hz, 2H), 3.70-3.65 (m, 7H), 2.75 (t, J = 6.0 Hz, 2H), 2.52 (br s, 4H), 1.39 (s, 9H).13C NMR (126 MHz; CDCI3) 6 171.8, 158.8, 154.8, 129.1, 128.4 (2C), 114.9 (2C), 80.0, 66.8 (2C), 65.8, 57.5, 57.0, 54.0 (2C), 52.5, 28.9 (3C). HRMS (ES+) 395.2181 [M+Na]+CzoHsiNzOeNa requires 395.2177 (Diff -0.99 ppm).

[0439] Intermediate 116 tert-butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2- morpholinoethoxy)phenyl)-2-oxoethyl)carbamate

[0440]

[0441] To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2- morpholinoethoxy)phenyl)acetate (0.42 g, 1.07 mmol, 1 eq) in methanol (10 mL) followed by dropwise addition of NaOH (1.20 eq) in distilled water (0.24 M) was allowed to stir and monitored by TLC until consumption of the starting material and concentrated in vacuo. The residue was taken up in distilled water and neutralised with 4N HCI in dioxane then concentrated in vacuo to afford the crude (S)-2-((tert- butoxycarbonyl)amino)-2-(4-(2-morpholinoethoxy)phenyl)acetic acid. The crude acid was carried through to the next step without characterisation. tert-Butyl 2-(2-bromophenyl)pyrazolidine-l-carboxylate (0.50 g, 1.53 mmol, 1 eq) was dissolved in a mixture of DCM:TFA (5: 1, 6 mL) and the reaction mixture was allowed to stir at room temperature until completion. The reaction was monitored by TLC. Upon completion, the solvent was removed in vacuo to afford the product as a trifluoroacetate salt and was carried through to the next step.

[0442] To a solution of tert-butyl 2-(2-bromophenyl)pyrazolidine 2,2,2-trifluoroacetate (0.52 g, 1.53 mmol, 1 eq) in anhydrous DMF (15 mL), was added (S)-2-((tert- butoxycarbonyl)amino)-2-(4-(2-morpholinoethoxy)phenyl)acetic acid (0.41 g, 1.07 mmol, 1 eq), DIPEA (2.5 eq) and HATU (1.3 eq). The reaction mixture was allowed to stir at room temperature overnight under N2 (followed by tic). Upon completion, the solution was diluted with EtOAc and washed with sat. aq. NaHCCh (x 3), distilled water and brine before being dried over MgSC and concentrated in vacuo to afford the crude product. The crude product was purified by FCC (SiCh; EtOAc to 10:90 MeOH:EtOAc) to afford the titled compound as a yellow solid (0.63 g, 49%).XH NMR (500 MHz; CDCI3; ppm) 6 7.52-7.47 (m, 1H), 7.38-7.28 (m, 1H), 6.92 (d, J = 6.8 Hz, 2H), 6.80 (br s, 1H), 6.30 (d, J = 6.8 Hz, 2H), 6.15 (br s, 1H), 5.77 (br s, 1H), 5.27 (br s, INH), 4.05-3.99 (m, 2H), 3.64 (br s, 4H), 3.50 (m, 2H), 2.72 (br s, 2H), 2.62 (br s, 2H), 2.51-2.43 (m, 4H), 1.98-1.78 (m, 2H), 1.31 (s, 9H).13C NMR (126 MHz; CDCI3) 6 172.7, 162.5, 157.7, 154.7, 154.4, 147.7, 133.3, 128.9 (2C), 127.1, 124.7, 119.1, 115.1, 114.0 (2C), 79.2, 66.8 (2C), 65.6, 57.4, 56.0, 55.5, 54.0 (2C), 45.3, 38.6, 28.4 (3C). HRMS (ES+) 589.2032 [M + H]+C29H4oN40579Br requires 589.2032 (Diff -2.08 ppm).

[0443] Intermediate 117 methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2- thiomorpholinoethoxy)phenyl)acetate

[0444] Methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2-oxoethoxy)phenyl)acetate (0.70 g, 2.17 mmol, 1 eq) and thiomorpholine (0.76 ml, 7.58 mmol, 3.5 eq) were employed. The crude product was purified by FCC (SiCh; 80:20 EtOAc:Hexane) to afford the titled compound as a colourless oil (0.62 g, 70%).XH NMR (500 MHz; CDCI3; ppm) 6 7.23 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.58 (d, J = 6.5 Hz, 1H), 5.21 (d, J = 6.5 Hz, NH), 4.03 (t, J = 5.5 Hz, 2H), 3.67 (s, 3H), 2.82-2.77 (m, 6H), 2.65-2.62 (m, 4H), 1.39 (s, 9H).13C NMR (126 MHz; CDCI3) 6 171.8, 158.8, 154.8, 129.1, 128.4 (2C), 114.9 (2C), 80.0, 65.8, 57.8, 57.0, 55.3 (2C), 52.6, 28.3 (2C), 27.9 (3C). HRMS (ES+) 411.1948 [M + H]+C20H31N2O5S requires 411.1948 (Diff 0.01 ppm).

[0445] Intermediate 118 tert-butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-(4-(2- thiomorpholinoethoxy)phenyl)ethyl)carbamate

[0446] The crude product was purified by FCC (SiCh; 50:50 EtOAc: Hexane to EtOAc) to afford the titled compound as a yellow solid (0.48 g, 52%).XH NMR (500 MHz; CDCI3; ppm) 6 7.50-7.45 (m, 1H), 7.36-7.28 (m, 1H), 6.93-6.89 (m, 2H), 6.88-6.75 (m, 2H), 6.66-

[0447] 6.62 (m, 2H), 5.76 (m, 1H), 5.27 (br s, NH), 4.05-3.97 (m, 2H), 3.85-3.76 (m, 2H), 3.65-3.48 (m, 2H), 2.79-2.70 (m, 6H), 2.61-2.57 (m, 4H), 1.85-1.74 (m, 2H), 1.31 (s, 9H).13C NMR (126 MHz; CDCI3) 6 172.7, 157.7, 154.7, 147.7, 133.3, 129.3, 128.9 (2C), 127.1, 124.7, 115.1, 114.3, 114.0 (2C), 79.2, 65.5, 60.3, 57.7, 56.0, 55.5, 55.2 (2C), 55.1, 38.6, 28.4 (2C), 27.8 (3C). HRMS (ES+) 605.1787 [M + H]+C2sH38N4O4S79Br requires 605.1792 (Diff 0.83 ppm).

[0448] Intermediate 119 methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2-(4-methylpiperazin-l- yl)ethoxy)phenyl)acetate

[0449] The crude product was purified by FCC (SiCh; EtOAc to 95: 5 MeOH: DCM) to afford the titled compound as a white solid (48-70%).XH NMR (400 MHz; CDCI3; ppm) 6 7.26 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 5.51 (d, J = 7.6 Hz, 1H), 5.24 (d, J = 7.6 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.71 (s, 3H), 2.82 (t, J = 6.2 Hz, 2H), 2.73-2.45 (m, 8H), 2.34 (s, 3H), 1.40 (s, 9H).13C NMR (101 MHz; CDCI3) 6 171.6, 158.7, 154.3, 129.1, 128.5, 127.5, 114.9, 80.1, 65.9, 57.0, 54.9, 53.2, 52.6, 50.7, 45.7, 28.3. HRMS (ES+) 408.2494 [M + H]+C21H33N3O4 requires 408.511.

[0450] Intermediate 120 tert-butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(4-methylpiperazin-l- yl)ethoxy)phenyl)-2-oxoethyl)carbamate

[0451]

[0452] The crude product was purified by FCC (SiCh; 10:90 MeOH:DCM) to afford the titled compound as a yellow oil (42 %). With the yield consisting of a mixture of rotamers in ratio 2 / 1.XH NMR (400 MHz; CDCI3; ppm) 6 7.59-7.34 (m, 2H), 7.07-6.65 (m, 4H), 6.44-6.17 (m, 2H), 5.98-5.69 (m, 1H), 5.38-5.31 (m, 1H), 4.19-3.51 (m, 8H), 2.86- 2.42 (m, 8H), 2.35 (major, s, 3H), 2.17 (minor, s, 3H), 2.09-1.79 (m, 2H), 1.39 (major, s, 9H), 1.34 (minor, s, 9H).13C NMR (101 MHz; CDCI3) 6 177.9, 157.8, 147.8, 134.5, 133.3, 129.3, 128.9, 127.2, 124.8, 119.1, 114.4, 114.2, 114.1, 79.3, 65.9, 56.0, 54.9, 53.2, 45.8, 45.4, 30.9, 29.3, 28.4, 27.7. HRMS (ES+) 624.2146 [M + Na]+C29H4oNs04BrNa requires 625.5638.

[0453] Intermediate 121 methyl (S)-2- tert- butoxy ca rbonyl)amino)-2-(4-(2-(( / ?)-3- methylmorpholino)ethoxy)phenyl)acetate

[0454] Methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2-oxoethoxy)phenyl)acetate (0.70 g, 2.17 mmol, 1 eq) and ( / ?)-3-morpholine (0.86 ml, 7.58 mmol, 3.5 eq) were employed. The crude product was purified by FCC (SiCh; 50:50 EtOAc: Hexane) to afford the titled compound as a colourless oil (0.53 g, 60%).XH NMR (500 MHz; CDCI3; ppm) 6 7.25 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.57 (d, J = 6.4 Hz, 1H), 5.24 (d, J = 6.4 Hz, INH), 4.05 (t, J = 6.0 Hz, 2H), 3.77 (dt, J = 11.0, 2.5 Hz, 1H), 3.69 (s, 3H), 3.68-3.59 (m, 2H), 3.23 (dd, J = 11.0, 9.0 Hz, 1H), 3.13-3.07 (m, 1H), 2.82 (dt, J = 11.0, 2.5 Hz, 1H), 2.70 (dt, J = 13.5, 6.0 Hz, 1H), 2.55-2.49 (unresolved m, 2H), 1.41 (s, 9H), 1.00 (d, J = 6.4 Hz, 3H).13C NMR (126 MHz; CDCI3) 6 171.8, 158.8, 154.8, 129.1, 128.4 (2C), 114.8 (2C), 80.0, 73.0, 67.3, 65.9, 57.0, 55.2, 52.6, 52.6, 52.3, 30.9, 28.3 (3C), 14.3. HRMS (ES+) 409.2346 [M + H]+C29H4oN40579Br requires 409.2346 (Diff -3.17 ppm).

[0455] Intermediate 122 tert-butyl ((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(( / ?)-3- methylmorpholino)ethoxy)phenyl)-2-oxoethyl)carbamate

[0456] The crude product was purified by FCC (SiO2; EtOAc to 10:90 MeOH:EtOAc) to afford the titled compound as a yellow solid (0.33 g, 42%).XH NMR (500 MHz; CDCI3; ppm) 6 7.62-7.53 (m, 1H), 7.53-7.45 (m, 1H), 7.03-6.98 (m, 2H), 6.88-6.83 (m, 1H), 6.77- 6.65 (m, 3H), 5.84 (d, J = 6.7 Hz, 1H), 5.77 (br s, NH), 4.09-4.05 (m, 2H), 3.73-3.63 (m, 4H), 3.46-3.37 (m, 2H), 3.26 (t, J = 9.7 Hz, 2H), 3.16-3.08 (m, 1H), 3.07-2.99 (m, 1H), 2.60-2.48 (m, 3H), 1.94-1.82 (m, 2H), 1.39 (s, 9H), 1.05-0.99 (m, 3H).13C NMR (126 MHz; CDCI3) 6 171.1, 169.3, 157.8, 142.2, 133.4, 129.4, 128.9 (2C), 124.7, 119.1, 114.3 (2C), 114.0, 113.9, 79.4, 73.0, 67.3, 60.4, 56.1, 55.6, 55.2, 52.5, 45.4, 38.6, 30.9, 28.4 (3C), 14.4. HRMS (ES+) 603.2187 [M + H]+C29H40N4O579Br requires 603.2177 (Diff -1.79 ppm).

[0457] Intermediate 123 methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2-(l,l- dioxidothiomorpholino)ethoxy)phenyl)acetate

[0458]

[0459] Methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2-oxoethoxy)phenyl)acetate (0.70 g, 2.17 mmol, 1 eq) and thiomorpholine 1,1-dioxide (1.02 g, 7.58 mmol, 3.5 eq) were employed. The crude product was purified by FCC (SiCh; 80:20 EtOAc:Hexane to EtOAc) to afford the titled compound as a white solid (0.71 g, 74%).XH NMR (500 MHz; CDCI3; ppm) 6 7.23 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 5.64 (d, J = 6.5 Hz, 1H), 5.20 (d, J = 6.5 Hz, NH), 4.02 (t, J = 5.0 Hz, 2H), 3.64 (s, 3H), 3.10- 3.07 (m, 4H), 3.03-2.98 (m, 4H), 2.92 (t, J = 5.0 Hz, 2H), 1.37 (s, 9H).13C NMR (126 MHz; CDCI3) 6 171.7, 158.5, 154.8, 129.4, 128.5 (2C), 114.8 (2C), 80.0, 66.1, 60.3, 57.0, 55.5, 52.6, 51.3 (2C), 51.1 (2C), 28.3 (3C). HRMS (ES+) 465.1682 [M + Na]+C20H30N2O7S requires 465.1666 (Diff -3.4 ppm).

[0460] Intermediate 124 tert-butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(l,l- dioxidothiomorpholino)ethoxy)phenyl)-2-oxoethyl)carbamate

[0461] The crude product was purified by FCC (SiCh; 80:20 EtOAc: Hexane to EtOAc) to afford the titled compound as a yellow solid (0.48 g, 52%).XH NMR (500 MHz; CDCI3; ppm) 6 7.50-7.47 (m, 1H), 7.42-7.33 (m, 1H), 7.00-6.94 (m, 2H), 6.82-6.79 (m, 1H), 6.70- 6.65 (m, 2H), 6.34-6.32 (m, 1H), 5.79 (br s, 1H), 5.30 (d, J = 6.0 Hz, NH), 4.05-4.01 (m, 2H), 3.60-3.49 (m, 2H), 3.40-3.35 (m, 2H), 3.14-3.06 (m, 4H), 3.04-2.90 (m, 4H), 2.97-2.90 (m, 2H), 1.34 (s, 9H).13C NMR (126 MHz; CDCI3) 6 172.7, 171.1, 157.4, 147.7, 133.4, 129.0 (2C), 127.1, 124.7, 119.1, 114.2 (2C), 113.9, 79.3, 65.9, 60.3, 56.1, 55.5, 51.3 (2C), 51.0 (2C), 45.4, 38.6, 28.4 (3C). HRMS (ES+) 659.1507 [M+Na]+C28H37N4OeS79Br requires 659.1509 (Diff 0.33 ppm).

[0462] Intermediate 125 methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2-(4-fluoropiperidin-l- yl)ethoxy)phenyl)acetate

[0463] Methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2-oxoethoxy)phenyl)acetate (0.50 g, 1.55 mmol, 1 eq) and 4-fluoropiperidine (0.76 g, 5.41 mmol, 3.5 eq) were employed. The crude product was purified by FCC (SiCh; 80:20 EtOAc:Hexane to EtOAc) to afford the titled compound as a yield a white solid (0.17 g, 26%).XH NMR (500 MHz; CDCI3; ppm) 6 7.28 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.49 (br s, 1H), 5.20 (br s, NH), 4.75-4.20 (m, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.72 (s, 3H), 2.81 (t, J = 6.0 Hz, 2H), 2.78-2.69 (m, 2H), 2.54-2.48 (m, 2H), 1.99-1.85 (m, 4H), 1.44 (s, 9H).13C NMR (126 MHz; CDCI3) 6 171.8, 154.7, 158.9, 129.3, 128.3 (2C), 115.0 (2C), 88.2 (d, J = 19.7 Hz), 80.1, 66.3, 58.0, 57.0, 52.5, 50.0 (d, J = 5.4 Hz, 2C), 31.5 (d, J = 171.5 Hz, 2C), 28.3 (3C). HRMS (ES+) 411.2300 [M + H]+C21H32N2O5F requires 411.2217 (Diff -2.55 ppm).

[0464] Intermediate 126 tert-butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(4-fluoropiperidin-l- yl)ethoxy)phenyl)-2-oxoethyl)carbamate

[0465]

[0466] The crude product was purified by FCC (SiCh; 50:50 EtOAc: Hexane to EtOAc) to afford the titled compound as a yellow solid (0.16 g, 44%).XH NMR (500 MHz; CDCI3; ppm) 6 7.60-7.50 (m, 1H), 7.43-7.35 (m, 2H), 7.04-6.84 (m, 3H), 6.72-6.68 (m, 1H), 6.39- 6.35 (m, 1H), 5.82 (s, 1H), 5.35 (s, NH), 4.77-4.62 (m, 1H), 4.15-4.05 (m, 2H), 3.94- 3.84 (m, 2H), 3.65-3.54 (m, 2H), 2.85-2.79 (m, 2H), 2.76-2.66 (m, 4H), 2.58-2.45 (m, 4H), 1.96-1.85 (m, 2H), 1.39 (s, 9H).13C NMR (126 MHz; CDCI3) 6 172.8, 157.7, 147.7, 133.4, 129.4, 128.9 (2C), 127.2, 124.7, 119.1, 114.4, 114.1 (2C), 88.1 (d, J = 171.4 Hz), 79.3, 65.7, 56.9, 56.0, 55.6, 49.8 (d, J = 16.8 Hz, 2C), 45.4, 31.3 (d, J = 20.7 Hz, 2C), 30.8, 28.4 (3C). HRMS (ES+) 605.2144 [M + H]+C29H39N4O4F79Br requires 605.2133 (Diff -1.84 ppm).

[0467] Intermediate 127 tert-butyl (R)-(2-(2-(2,5-dichlorophenyl)pyrrolidin-l-yl)-2-oxoethyl)carbamate

[0468] ( / ?)-2-(2,5-dichlorophenyl)pyrrolidin-l-ium chloride (0.10 g, 0.40 mmol, 1 eq) and Boc-Gly-OH (83.00 mg, 0.48 mmol, 1.20 eq) were employed. The crude product was purified by FCC (SiO2; 20:80 EtOAc:hexane) to yield a brown foam (0.13 g, 85%) with the yield consisting of a mixture of rotamers in ratio 1.2 / 1.XH NMR (400MHz; CDCI3; Me4Si; ppm) 6 7.33 (minor, dd, J = 8.8 Hz, 1H), 7.22 (minor, dd, J = 8.8 Hz, 1H), 7.15 (major, dd, J = 8.8 Hz, 1H),7.14 (major, dd, J = 8.8 Hz, 1H), 7.03 (minor, d, J = 1.6 Hz, 1H), 6.93 (major, d, J = 2.8 Hz, 1H), 5.40 (major, m, 1H), 5.20 (minor, m, 1H), 4.03 (major, s, 2H), 4.02 (minor, s, 2H), 3.99-3.29 (major &. minor, m, 2H), 2.50- 2.27 (major, m, 2H), 2.1-1.8 (minor, m, 4H), 1.44 (major, s, 9H), 1.41 (minor, s, 9H).13C NMR (100 MHz; CDCI3; Me4Si) 6 167.1, 141.5, 131.1, 129.1, 128.3, 126.0, 58.9, 58.2, 50.9, 47.6, 46.8, 43.2, 34.3, 34.1, 32.0, 28.4. HRMS (ES+) 395.0892 [M + Na]+Ci?H22N2O335Cl2Na requires 395.0905 (Diff -3.3 ppm). Intermediate 128 tert- butyl ( / ?)-(2-(2-(2-chloro-5-methoxyphenyl)pyrrolidin-l-yl)-2- oxoethyl)ca rba mate

[0469] ( / ?)-2-(2-chloro-5-methoxyphenyl)pyrrolidin-l-ium chloride (0.10 g, 0.40 mmol) and Boc-Gly-OH (85.00 mg, 0.48 mmol, 1.2 eq) were employed. The crude product was purified by FCC (SiCh; 20:80 EtOAc: hexane) to yield a white foam (0.13 g, 90%) with the yield consisting of a mixture of rotamers in ratio 1.6 / 1.XH NMR (400MHz; CDCI3; Me4Si; ppm) 6 7.32-7.23 (major & minor, m, 2H), 6.75 (major, m, 1H), 6.70 (minor, m, 1H), 6.58 (major, m, 1H), 6.50 (minor, m, 1H), 5.18 (minor, m, 1H), 5.41 (major, m, 1H), 3.85-3.78 (major & minor, m, 10H), 3.57 (minor, m, 2H), 3.33 (major, m, 2H), 2.48-2.25 (minor, m, 2H), 2.08-1.75 (major & minor, m, 6H), 1.44 (minor, s, 9H), 1.41 (major, s, 9H).13C NMR (100 MHz; CDCI3; Me4Si) 6 158.3, 152.5, 140.7, 131.0, 130.6, 113.4, 112.5, 79.9, 59.1, 55.5, 48.0, 32.0, 28.3, 23.5. HRMS (ES+) 391.1393 [M+Na]+CisHzsNzO^CINa requires 391.1401 (Diff -1.9 ppm).

[0470] Intermediate 129 l-((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3-(((2S, 3S, 6S)- 3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea tert-Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)carbamate (0.05 g, 0.11 mmol eq) and / V-(((2S,3S,6S)-3-((tert- butyldimethylsilyl)oxy)- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c][ l,5]oxazocin-8- yl)methyl)-lH-imidazole-l-carboxamide (0.05 g, 0.12 mmol, 1.10 eq) were employed. The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as a yellow solid (0.17 g, 50%).XH NMR (500 MHz; CDCI3; ppm) 6 7.60-7.53 (m, 1H), 7.42-7.38 (m, 1H), 7.35-7.23 (m, 2H), 7.13-7.04 (m, 2H), 7.03-6.94 (m, 2H), 6.93- 6.83 (m, 2H), 6.75-6.62 (m, 1H), 6.58-6.56 (m, 1H), 6.21 (s, NH), 6.21 (s, NH), 5.43 (s, 1H), 4.58 (br s, 1H), 4.25 (s, 2H), 3.84-3.76 (m, 1H), 3.55-3.48 (m, 1H), 3.45- 3.36 (m, 2H), 3.34-3.25 (m, 2H), 2.96 (m, 1H), 2.15-2.09 (m, 1H), 2.00-1.86 (m, 2H), 1.83-1.73 (m, 1H), 0.87 (s, 9H), 0.07 (s, 3H), 0.01 (s, 3H).13C NMR (126 MHz; CDCI3) 6 171.2, 157.1, 145.7, 133.4, 130.0, 129.8 (2C), 129.7, 129.5, 129.4, 129.0, 128.2, 128.1, 127.9, 127.8 (2C), 127.1, 125.0, 119.7, 119.0, 113.7, 70.6, 67.3, 62.4, 60.4, 56.0, 49.6, 45.4, 44.1, 28.2, 25.8 (3C), 18.0, 14.2, -4.6, -4.7. HRMS (ES+) 720.2567 [M + H]+C36H47N5O479BrSi requires 720.2575 (Diff 1.08 ppm).

[0471] Intermediate 130 l-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo [c][l,5]oxazocin-8-yl)methyl)-3-((S)-2-(2-(2-chloro-5- fluorophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)urea tert-Butyl (S)-(2-(2-(2-chloro-5-fluorophenyl) pyrazolidin-l-yl)-2-oxo-l-phenylethyl) carbamate (390 mg, 0.89 mmol) was employed. The crude product was purified by FCC (SiC ; 95:5 DCM: MeOH) to give the title compound as a yellow solid (340 mg, 55%).XH NMR (400 MHz; CDCI3) 6 7.46-7.45 (m, 1H), 7.37-7.29 (m, 1H), 7.12- 6.92(m, 6H), 6.49-6.41 (m, 2H), 6.09-6.07 (m, 1H), 5.95-5.88 (m, 1H), 5.07 (s, 1H), 4.60 (s, 1H), 4.31 (s, 1H), 4.25-4.17 (m, 2H), 3.94-3.30 (m, 9H), 2.64-2.61 (d, J = 12.7 Hz 1H), 1.79-1.62 (m, 2H), 1.47-1.40 (d, J = 12.1 Hz 1H), 0.92 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).13C NMR (101 MHz; CDCI3) 6 174.0, 166.6 (d, J = 247.0 Hz), 157.1, 143.9, 137.5, 131.2, 131.1, 130.4, 130.4, 129.6, 128.6, 128.3, 128.2, 127.9, 127.6, 127.4, 127.4, 119.1, 113.1, 106.7, 70.9, 68.5, 64.0, 56.1, 55.5, 53.6, 48.8, 45.1, 44.2, 26.0 (3C), 23.6, 18.3, -4.5, -4.7. HRMS (ES+) C36H45CIFN5O4Na [M + Na]+requires 716.2806, found 716.2797.

[0472] Intermediate 131 l-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2 / ?,3S,6 / ?)-3-((tert- butyldimethylsilyl)oxy)- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c][ l,5]oxazocin-8- yl)methyl)urea tert-Butyl (2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (0.05 g, 0.12 mmol, 1 eq) and / V-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6- tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)-lH-imidazole-l- carboxamide (0.056 g, 2.0 mmol, 1.1 eq). The crude product was purified by FCC (SiC ; EtOAc) to afford the titled compound as a yellow solid (26 mg, 31%).XH NMR (400 MHz; CDCI3; ppm) 6 7.56 (app d, J = 7.5 Hz, 1H), 7.20 (app t, J = 7.5 Hz, 1H), 7.07-7.03 (m, 3H), 6.99-6.96 (m, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.65 (s, 1H), 4.57 (s, 1H), 4.37-4.30 (m, 2H), 4.23 (m, 1H), 3.82-3.70 (unresolved m, 2H), 3.52-3.44 (m, 5H), 3.40-3.36 (m, 1H), 2.70-2.62 (m, 1H), 2.02 (br s, 2H), 1.49-1.42 (m, 1H), 1.32- 1.25 (m, 1H), 0.94 (s, 9H), 0.1 (s, 3H), 0.09 (s, 3H).13C NMR (101 MHz; CDCI3) 6 166.8, 163.5, 158.0, 144.5, 135.4, 130.0, 129.9, 128.7, 126.0, 124.6, 119.5, 115.8, 113.3, 113.0, 82.7, 70.6, 68.4, 63.9, 48.6, 47.2, 45.4, 44.0, 25.9 (3C), 23.4, 20.0, 18.2, -4.7, -4.8. HRMS (ES+) 666.2071 [M + Na]+C3oH42N504BrNaSi requires 666.2082 (Diff 1.58 ppm).

[0473] Intermediate 132 l-((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3-(((2 / ?, 3S, 6 / ?)- 3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea tert-Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)carbamate (0.054 g, 0.12 mmol) and N-(((2R,3S,6R)-3-((tert- butyldimethylsilyl)oxy)- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c][ l,5]oxazocin-8- yl)methyl)-lH-imidazole-l-carboxamide (0.056 g, 2.0 mmol, 1.10 eq) were employed. The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as a yellow solid (0.03 g, 31%).XH NMR (500 MHz; CDCI3; ppm) 6 7.60-7.50 (m, 1H), 7.41-7.36 (m, 1H), 7.13-6.99 (m, 4H), 6.90-6.84 (m, 2H), 6.73-6.64 (m, 1H), 6.45- 6.40 (m, 1H), 6.20-6.12 (m, 2H), 5.31 (s, 1H), 4.64-4.60 (m, 1H), 4.40-4.34 (m, 1H), 4.30-4.15 (m, 2H), 3.55-3.48 (m, 6H), 3.35-3.30 (m, 1H), 2.66-2.60 (m, 1H), 1.85- 1.75 (m, 2H), 1.43-1.36 (m, 1H), 1.29-1.26 (m, 1H), 0.93 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H).13C NMR (126 MHz; CDCI3) 6 157.1, 143.8, 130.3, 129.6 (2C), 128.3, 128.0, 127.8 (2C), 127.4, 127.2, 125.0, 124.9, 119.1, 118.9, 112.9, 70.7, 68.4, 63.8, 56.0, 55.6, 48.6, 45.3, 44.0, 25.9 (3C), 23.5, 18.2, -4.7, -4.8. HRMS (ES+) 720.2572 [M + H]+C36H47NsO479BrSi requires 720.2575 (Diff 0.45 ppm).

[0474] Intermediate 133 l-(((2R,3S,6R)-10-chloro-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-5- fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea tert-Butyl (((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-10-chloro-l,3,4,6- tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)carbamate (308 mg, 0.88 mmol) was employed. The crude product was purified by FCC (SiC ; 95:5 DCM:MeOH) to give the title compound as a white solid (400 mg, 69%).^ NMR (400 MHz; CDCI3) 6 7.33 (dd, J =8.7, 5.6 Hz, 1H), 7.20 (d, J =1.8 Hz, 1H), 6.99 (d, J =1.6 Hz, 1H), 6.79-6.73 (m, 1H), 6.70 (dd, J= 9.7, 2.8 Hz, 1H), 5.21 (t, J = 4.4 Hz, 1H), 4.91 (t, J = 5.5 Hz, 1H), 4.80 (d, J = 4.5 Hz, 1H), 4.69 (s, 1H), 4.22 (d, J =5.7 Hz, 2H), 3.77-3.35 (m, 9H), 3.29 (dd, J =12.8, 1.4 Hz, 1H), 2.68 (d, J =12.8 Hz, 1H), 2.06 (br s, 2H), 1.40 (d, J =12.8 Hz, 1H), 0.93 (s, 9H), 0.09 (s, 3H), 0.09 (s, 3H).13C NMR (101 MHz; CDCI3) 6 171.2, 161.8 (d, J =247.5 Hz), 157.8, 148.8, 139.9, 132.3, 128.7 (d, J =28.3 Hz), 128.0, 120.7, 120.5, 120.5, 117.1, 112.4 (d, J =23.1 Hz), 106.5 (d, J =26.2 Hz), 70.5, 68.4, 64.0, 55.5, 48.7, 45.1, 43.7, 42.5, 26.0 (3C), 23.6, 23.3, 18.3, -4.6, -4.7.

[0475] Intermediate 134 l-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-10-fluoro-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-5-fluorophenyl) pyrazolidin-l-yl)-2-oxoethyl) urea / V-(((2 / ?,3S,6 / ?)-3-((tert-Butyldimethylsilyl)oxy)-10-fluoro-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-lH-imidazole-l-carboxamide (392 mg, 0.85 mmol). The crude product was purified by FCC (SiCh; 95:5 EtOAc:MeOH) to give the title compound as a white solid (350 mg, 50%).XH NMR (400 MHz; CDCI3) 6 7.33 (dd, J =8.7, 5.5 Hz, 1H), 6.93 (d, J =11.8 Hz, 1H), 6.86 (s, 1H), 6.78-6.73 (m, 1H), 6.70 (dd, J= 9.7, 2.8 Hz, 1H), 5.24 (s, 1H), 4.95 (br s, 1H),4.69 (s, 1H),4.42 (s, 1H), 4.23 (d, J =5.6 Hz, 2H), 3.66-3.35 (m, 9H), 3.33 (dd, J =12.8, 1.7 Hz, 1H), 2.68(d, J = 12.8 Hz, 1H), 2.04 (br s, 2H), 1.43 (d, J =12.8 Hz, 1H), 0.93 (s, 9H), 0.09 (s, 3H), 0.09 (s, 3H).13C NMR (101 MHz; CDCI3) 6171.9, 163.8, 163.2 (d, J =264.0 Hz), 157.8, 151.3, 132.3, 127.3, 124.8, 114.5, 114.3, 112.5, 106.7, 106.4, 106.3, 70.6, 67.9, 64.1, 55.5, 48.1, 45.1, 43.8, 42.5, 26.0 (3C), 23.6, 23.5, 18.3, -4.6, -4.7. HRMS (ES+) C3oH4oCIF2N504Si Na [M + Na]+requires 658.2398, found 658.2399.

[0476] Intermediate 135 l-(((2R,3S,6R)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-5- methoxyphenyl)pyrazolidin-l-yl)-2-oxoethyl)urea tert-Butyl 2-(2-chloro-5-methoxyphenyl)pyrazolidine-l-carboxylate (0.5 g, 1.35 mmol) was employed. The crude product was purified by FCC (SiCh; 95:5 DCM:MeOH) to give the title compound as a white solid (0.6 g, 67%).XH NMR (400 MHz; CDCI3) 6 7.26 (d, J = 8.7 Hz, 1H), 7.07(dd, J = 8.2, 2.0 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H) 6.56 (dd, J = 8.7, 2.9 Hz, 1H), 6.50 (d, J = 2.9 Hz, 1H), 6.48 (d, J = 8.2 Hz, 1H), 5.13 (t, J =4.4 Hz, 1H), 4.76 (t, J = 4.5 Hz, 1H), 4.67 (s, 1H), 4.31 (s, 1H,), 4.22 (d, J = 5.5 Hz, 2H), 3.74 (s, 3H), 3.73-3.41 (m, 9H), 3.36 (dd, J = 13,1.6 Hz, 1H), 2.68-2.62 (m, 1H), 2.06-2.03 (br s, 2H), 1.44 (d, J = 13.5 Hz, 1H), 0.92 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).13C NMR (101 MHz; CDCI3) 6 171.6, 159.1, 157.0, 148.0, 144.0, 131.8, 130.2, 129.4, 127.4, 119.2, 117.1, 113.1, 109.9, 105.7, 79.9, 70.8, 68.6, 64.0, 55.7, 55.5, 48.8, 45.2, 44.4, 42.5, 26.0 (3C), 23.66, 23.50, 18.33, -4.54, -4.69. HRMS (ES+) C3iH44CIN5O5Si [M+H]+requires 630.2838, found 630.2873. Intermediate 136 l-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-((S)-2-(2-(2-chloro-5- methoxyphenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)urea tert-butyl (S)-(2-(2-(2-chloro-5-methoxyphenyl) pyrazolidin-l-yl)-2-oxo-l- phenylethyl)Carbamate (0.3 g, 0.67 mmol) was employed. The crude product was purified by FCC (SiC ; 95:5 DCM:MeOH) to give the title compound as a white solid (0.3 g, 64%).XH NMR (400 MHz; CDCI3) 6 7.46 (s, 1H), 7.41-7.28 (m, 2H), 7.16-6.94 (m, 4H), 6.94-6.83 (m, 1H), 6.57-6.53 (m, 1H), 6.45-6.42 (m, 1H), 6.29 (d, J = 7.7 Hz, 1H), 6.07 (s, 1H), 5.64-5.59 (m, 1H), 5.03 (s, 1H), 4.61 (s, 1H), 4.31 (s, 1H), 4.25-4.19 (m, 2H), 3.77 (d, J = 6.2 Hz, 1H), 3.50-3.26 (m, 10H), 2.62 (d, J = 12.7 Hz, 1H), 1.76 (s, 2H), 1.43-1.33 (m, 1H), 0.92 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).13C NMR (101 MHz; CDCI3) 6 171.5, 156.9, 143.9, 130.4, 129.6, 129.3, 129.1, 128.4, 128.3, 128.2, 128.2, 128.0, 128.0, 127.5, 127.2, 127.1, 125.2, 119.1, 113.1, 110.0,

[0477] 70.9, 68.5, 64.0, 56.0, 55.6, 55.4, 48.8, 45.1, 44.2, 26.0 (3C), 23.7, 23.2, 18.3, -4.5, -4.6. HRMS (ES+) C37H48CIN5O5SiNa [M+ Na]+requires 728.3005, found 728.3008.

[0478] Intermediate 137 l-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6 methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-4- fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea tert-Butyl (2-(2-(2-chloro-4-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (350 mg, 0.98 mmol) was employed. The crude product was purified by FCC (SiCh; 95:5 DCM:MeOH) to give the title compound as a white solid (430 mg, 71%).XH NMR (400 MHz; CDCI3) 6 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 7.07 (dd, J = 8.2, 2.0 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.91-6.87 (m, 2H), 6.47 (d, J = 8.1 Hz, 1H), 5.18 (s, 1H), 4.85 (s, 1H), 4.66 (s, 1H), 4.31 (s, 1H), 4.22 (d, J = 5.5 Hz, 2H), 3.88-3.39 (m, 9H), 3.35 (dd, J = 12.9, 1.6 Hz, 1H), 2.70-2.60 (m, 1H), 2.03 (s, 2H), 1.43 (d, J = 12.3 Hz, 1H), 0.92 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).13C NMR (101 MHz; CDCI3) 6 171.7, 159.4 (d, J = 246.9 Hz), 157.9, 144.0, 143.5, 130.2, 129.5, 127.5, 126.7 (d, J = 10.4 Hz), 119.8, 119.7, 118.5 (d, J = 25.7 Hz), 114.4 (d, J = 22.1 Hz), 113.1, 70.9, 68.6, 64.0, 55.7, 48.8, 45.4, 44.3, 42.5, 26.0 (3C), 23.7, 23.3, 18.3, -4.6, -4.7. HRMS (ES+) C3oH42CIFN504Si [M+H]+requires 618.2673, found 618.2685

[0479] Intermediate 138 l-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-((S)-2-(2-(2-chloro-4- fluorophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)urea tert-Butyl (S)-(2-(2-(2-chloro-4-fluorophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)carbamate (0.5 g, 1.40 mmol) was employed. The crude product was purified by FCC (SiC ; 95: 5 DCM : MeOH) to give the title compound as a white solid (300 mg, 31%).XH NMR (400 MHz; CDCI3) 6 7.53-7.27 (m, 2H), 7.19-6.80 (m, 6H), 6.43 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 6.11 (s, 1H), 5.86 (s, 1H), 4.96 (s, 1H), 4.61 (s, 1H), 4.30 (s, 1H), 4.22 (d, J = 5.3 Hz, 2H), 3.96-3.20 (m, 9H), 2.63 (d, J = 12.7 Hz, 1H), 2.01-1.75 (m, 2H), 1.40 (d, J = 13.9 Hz, 1H), 0.92 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).13C NMR (101 MHz; CDCI3) 6 175.9, 161.7 (d, J = 238.0 Hz), 157.9, 143.9,

[0480] 130.3, 129.6, 129.2, 129.1, 128.3, 127.9, 127.4, 125.7, 122.3, 119.8, 119.6, 119.1,

[0481] 117.4, 115.1, 113.8, 113.1, 70.9, 68.5, 64.0, 56.0, 55.9, 48.8, 44.3, 44.2, 31.7, 26.0 (3C), 23.7, 18.3, -4.6, -4.7. HRMS (ES+) C36H46CIFN5O4Si [M + H]+requires 694.2986, found 694.2978.

[0482] Intermediate 139 l-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-((S)-2-(2-(2-chloro-5- fluorophenyl)pyrazolidin-l-yl)-l-(4-(2-morpholinoethoxy)phenyl)-2-oxoethyl)urea

[0483] tert-butyl (S)-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-l-(4-(2- morpholinoethoxy)phenyl)-2-oxoethyl)carbamate (0.5 g, 0.85 mmol) was employed. The crude product was purified by FCC (SiCh; 95:5 DCM:MeOH) to give the title compound as a white solid (0.35 g, 50%).XH NMR (400 MHz; CDCI3; ppm) 6 7.36-7.34 (m, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.13-7.11 (m, 1H), 7.02-6.96 (m, 3H), 6.83 (d, J = 7.2 Hz, 1H), 6.42 (d, J = 7.9 Hz, 2H), 5.97-5.72 (m, 1H), 5.42-5.40 (m, 1H), 5.15 (s, 1H), 5.08-5.01 (m, 1H), 4.59 (s, 1H), 4.41 (br s, 1H), 4.18-4.05 (m, 3H), 3.91 (br s, 1H), 3.74-3.70 (m, 4H), 3.63 (s, 1H), 3.50-3.28 (m, 5H), 2.79-2.76 (m, 1H), 2.74 (d, J = 13.8 Hz, 1H), 2.62-2.55 (m, 5H), 2.00-1.96 (m, 1H), 1.77 (s, 1H), 1.44-1.42 (m, 2H), 1.39 (d, J = 13.8 Hz, 1H), 0.91 (s, 9H), 0.06 (s, 6H).13C NMR (101 MHz; CDCI3) 6172.8, 170.3, 158.8, 158.0, 157.3, 144.0, 143.9, 135.2, 130.2, 130.1, 129.8, 129.5, 129.1, 128.6, 121.9, 119.0, 115.0, 114.6, 114.4, 113.1, 70.8, 68.6, 67.0, 67.0, 65.8, 65.7, 63.9, 57.7, 57.5, 54.1, 54.0, 52.7, 48.7, 45.0, 44.07, 26.0 (3C), 23.6, 18.3, - 4.6, -4.7.

[0484] HRMS (ES+) C42H57CIFN6O6Si [M + H]+requires 823.3776, found 823.3778.

[0485] Intermediate 140 l-(((2R,3S,6R)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-((R)-2-(2-chloro-5- fluorophenyl)pyrrolidin-l-yl)-2-oxoethyl)urea

[0486] To a solution of tert-butyl (R)-(2-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)-2- oxoethyl)carbamate (75 mg, 0.21 mmol) in dichloromethane (3 mL) was add trifluoroacetic acid (0.5 mL). The reaction mixture was allowed to stir at room temperature until disappearance of starting material (2 h, followed by TLC). Upon completion, the solvent was removed in vacuo to give the free amine as TFA salt which was used directly without further purification.

[0487] The TFA salt of the free amine was redissolved in anhydrous acetonitrile (15 mL), N- (((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-lH-imidazole-l-carboxamide (100 mg, 0.23 mmol, 1.1 eq), triethylamine (0.06 mL, 0.46 mmol, 2.2 eq) and DMAP (3 mg, 0.02 mmol, 0.1 eq) were added. The reaction mixture was allowed to stir at room temperature overnight (followed by TLC). Upon completion, the reaction was diluted with dichloromethane, washed with water, followed by brine, dried over MgSC , filtered and concentrated in vacuo to a light brown oil. The crude product was purified by FCC (SiC ; 4:96 MeOH:DCM) to afford the titled compound as a white solid (90 mg, 69%). With the yield consisting of a mixture of rotamers in ratio 1 / 1.12.

[0488] XH NMR (400 MHz, CDCI3) 6 7.35 (dd, J = 8.8, 5.0 Hz, 1H, minor), 7.30 (dd, J = 8.8, 5.1 Hz, 1H, major), 7.09 - 7.00 (m, 2H), 6.98 - 6.91 (m, 1H, minor), 6.90 - 6.84 (m, 1H, majorj), 6.75 (dd, J = 9.0, 3.0 Hz, 1H, minor), 6.67 (dd, J = 9.2, 2.9 Hz, 1H, major), 6.47 (d, J = 8.2 Hz, 1H), 5.38 (dd, J = 8.1, 2.0 Hz, 1H, major), 5.33 (br s, 1H), 5.22 (d, J = 7.2 Hz, 1H, minor), 4.79 (t, J = 5.6 Hz, 1H, minor), 4.71 (t, J = 5.2 Hz, 1H, major), 4.67 (s, 1H), 4.31 (s, 1H), 4.23 (d, J = 5.5 Hz, 1H), 4.19 (d, J = 5.5 Hz, 1H), 4.12 (d, J = 4.0 Hz, 1H), 4.09 (d, J = 4.9 Hz, 1H, minor), 3.83 - 3.56 (m, 3H), 3.47 (d, J = 11.8 Hz, 3H), 3.41 - 3.30 (m, 2H), 2.66 (d, J = 12.5 Hz, 1H), 2.47 - 2.26 (m, 2H), 2.06 - 1.93 (m, 2H), 1.93 - 1.72 (m, 2H), 1.56 (d, J = 12.1 Hz, 1H), 1.44 (d, J = 14.6 Hz, 1H), 0.93 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H).

[0489] Intermediate 141 l-((S)-l-(4-bromophenyl)-2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2- oxoethyl)-3-(((2R,3S,6R)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea tert-butyl (S)-(l-(4-bromophenyl)-2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2- oxoethyl)carbamate (1 g, 1.95 mmol, 1 eq) and N-(((2R,3S,6R)-3-((tert- butyldimethylsilyl)oxy)- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c][ l,5]oxazocin-8- yl)methyl)-lH-imidazole-l-carboxamide (0.056 g, 2.0 mmol, 1.10 eq) were employed. The crude product was purified by FCC (SiCh; 20: 1 DCM : MeOH) to give the title compound as a yellow solid (1.02 g, 68%). Rf = 0.50, 10% MeOH in DCM.XH NMR (400 MHz; MeOD) 6 7.40 (s, 1H), 7.29 (s, 1H), 7.19-7.16 (m, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.93-6.81 (m, 3H), 6.58 (t, J = 7.1 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 5.96 (d, J = 9.6 Hz, 1H), 4.52 (s, 1H), 4.10-3.90 (m, 3H), 3.73-3.24 (m, 8H), 2.52 (d, J = 12.6 Hz, 1H), 2.02-1.79 (m, 2H), 1.30 (d, J = 12.2 Hz, 1H), 0.88 (s, 9H), 0.04 (s, 6H).13C NMR (101 MHz; MeOD) 6 174.49, 159.88, 159.81, 149.73, 146.00, 137.52, 132.65, 132.38, 130.89, 130.66, 130.62, 130.23, 130.20, 127.89, 122.58, 121.21, 119.20, 114.03, 112.55 (d, J = 23.3 Hz), 107.94 (d, J = 27.3 Hz), 71.93, 70.38, 64.97, 56.88, 56.63, 46.49, 46.34, 44.41, 26.32 (3C), 24.52, 23.97, 18.97, -4.69, -4.76. HRMS (ESI+) C36H4479Br35CIFN5O4SiNa [M+ Na]+requires 796.1916, found 796.1890.

[0490] Intermediate 142 l-((S)-2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-l-(4'-(morpholinomethyl)- [l,l'-biphenyl]-4-yl)-2-oxoethyl)-3-(((2R,3S,6R)-3-hydroxy-l,3,4,6-tetrahydro-2H- 2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea

[0491] To a solution of l-((S)-l-(4-bromophenyl)-2-(2-(2-chloro-5-fluorophenyl)pyrazolidin- l-yl)-2-oxoethyl)-3-(((2R, 3S, 6R)-3-((tert-butyldimethylsilyl)oxy)- 1,3,4, 6-tetrahydro- 2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea (200 mg, 0.26 mmol, 1 eq) in anhydrous dioxane (4 ml) and H2O (0.6 ml) was added [4-(Morpholinomethyl) phenyl] boronic acid (129.3 mg, 0.58 mmol, 2 eq), [1, l'-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) (20 mg, 0.026 mmol, 0.1 eq), K2CO3 (107.6 mg, 0.78 mmol, 3 eq) under N2, the reaction was heated to reflux for 24h. The mixture was filtrated through Celite and extracted with DCM, washed with distilled water and brine, dried over MgS04 then concentrated in vacuo to afford crude product. Purification by column chromatography (DCM: MeOH= 30: 1) gave the title compound (300 mg, 88%) as a white solid. Rf= 0.6, 10% MeOH in DCM.XH NMR (400 MHz; MeOD) 6 7.51 (s, 1H), 7.36 (s, 1H), 7.30 (s, 4H), 7.16-7.12 (m, 1H), 7.11-7.06 (m, 3H), 6.94 (d, J = 8.0 Hz, 1H), 6.88-6.80 (m, 1H), 6.46-6.39 (m, 1H), 5.97-5.92 (m, 1H), 4.52 (s, 1H), 4.13-3.93 (m, 2H), 3.63-3.61 (m, 4H), 3.59 (s, 2H), 3.55-3.47 (m, 4H), 3.42 (br s, 2H), 3.36 (br s, 1H), 3.27 (s, 1H), 3.25 (s, 1H), 2.51 (d, J = 12.5 Hz, 1H), 2.41 (s, 4H), 2.04-1.79 (m, 2H), 1.29 (d, J = 12.6 Hz, 1H), 0.88 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H).13C NMR (101 MHz; MeOD) 6 174.98, 162.40 (d, J = 247.5 Hz), 159.95, 149.86, 149.82, 145.98, 141.52, 141.04, 137.42, 137.15, 132.48, 132.40, 131.06, 130.62, 130.21, 129.63, 129.49, 127.91, 127.85 (2C), 121.21, 121.17, 119.20, 114.04, 112.38 (d, J = 20.5 Hz), 107.98 (d, J = 27.3 Hz), 71.92, 70.36, 68.11, 67.73 (2C), 64.95, 63.97, 57.23, 56.64, 54.64 (2C), 46.27, 44.44, 26.34 (3C), 24.50, 23.99, 18.97, -4.67, -4.75. HRMS (ESI+) C47H5935CIFN6O5Si [M+ H]+requires 869.3989, found 869.3979.

[0492] Example compounds

[0493] Example compounds as described below were prepared in accordance with the general procedures indicated.

[0494] Example 1 l-(4-aminobenzyl)-3-(2-oxo-2-(2-phenylpyrazolidin-l-yl)ethyl)urea tert-Butyl (2-oxo-2-(2-phenylpyrazolidin-l-yl)ethyl)carbamate (210 mg, 0.69 mmol) was employed. The crude product was purified by flash column chromatography (SiCh; gradient elution, EtOAc to 3% MeOH in EtOAc) to yield the title compound as a colourless foam (170 mg, 70%). IR vmax / cm-13328 (br. m), 1619 (s), 1501 (s), 1395 (m), 1258 (s), 1113 (m);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.10 (2H, d, J = 8.5), 7.03 (1H, t, J = 7.5), 6.82 - 6.79 (1H, m), 6.68 (2H, d, J = 8.5), 6.64 (1H, ~t, J = 8.0), 4.28 (1H, br. s), 4.15 (2H, s), 3.92 (1H, br. s), 3.79 (1H, br. s), 3.74 (1H, br. s), 3.40 (2H, br. s), 2.07 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 169.8, 158.7, 147.0, 146.5, 129.5, 128.1, 124.5, 121.2, 118.1, 116.0, 54.8, 48.2, 43.1, 42.2, 23.1; HRMS (ES+) m / z 376.1751 [M + Na]+Ci9H23N5O2Na requires 376.1749 (100%) (Diff 0.38 ppm). Example 2 l-(4-Aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea tert-Butyl (2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (0.25 g, 0.65 mmol, 1 eq) was dissolved in a mixture of DCM:TFA (5: 1, 8 mL) and the reaction mixture was allowed to stir at room temperature until TLC showed disappearance of starting material. The reaction mixture was concentrated in vacuo to afford the free amine as a trifluoroacetate salt and was used directly without further purification.

[0495] To a solution of the trifluoroacetate salt (0.25 g, 0.63 mmol, 1 eq) in acetonitrile (8 mL), was added / V-(4-Aminobenzyl)-l / - / -imidazole-l-carboxamide (0.15 g, 0.69 mmol, 1.1 eq), triethylamine (0.19 mL, 1.38 mmol, 2.2 eq) and DMAP (7.7 mg, 0.06 mmol, 0.1 eq) and was allowed to stir at room temperature overnight under N2 (followed by TLC). Upon completion, the solution was diluted with DCM and washed with distilled water. The organic phase was dried over MgS04and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 100% EtOAc to 2% MeOH in EtOAc to yield a yellow foam (207 mg, 0.48 mmol, 76%). M.p: 132 - 135 °C; IR Vmax (cm-1) 753 (C-Br), 1517 (N-H), 1542 (N-H), 1621 (amide C=O), 3388 (N-H);XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.56 (1H, dd, J = 8.0, 1.3), 7.19 (1H, ap: td, J = 8.0, 1.3), 7.09 (2H, s), 7.06 (2H, d, J = 8.4), 6.97 (1H, ap: td, J = 8.0, 1.3), 6.85 (1H, dd, J = 8.0, 1.3), 6.61 (2H, d, J = 8.4) 5.57 (1H, t, J = 4.4), 5.36 (1H, t, J = 5.1), 5.25 (2H, br s), 4.23 (2H, d, J = 5.1), 3.64 (2H, br s), 3.42 (2H, br s), 1.98 (2H, m);13C NMR (100 MHz; CDCI3; Me4Si) 6 171.3, 158.1, 148.1, 145.6, 135.1, 134.3, 128.9, 128.1, 126.1, 121.9, 119.1, 115.1, 55.8, 45.3, 44.1, 42.4, 23.0; HRMS (ES+) m / z 454.0851 [M + Na]+Ci9H2279BrN5O2Na requires 454.0855 (99%), m / z 456.0837 [M+Na]+Ci9H2281BrN5O2Na requires 456.0834 (100%).

[0496] Example 3 l-(4-aminobenzyl)-3-(2-(2-(2-bromo-3-chlorophenyl)pyrazolidin-l-yl)-2- oxoethyl)urea tert-Butyl (2-(2-(2-bromo-3-chlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (0.30 g, 0.95 mmol) was employed. The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as a pale white solid (0.21 g, 48%).XH NMR (400 MHz; CDCI3; ppm) 6 7.42-7.30 (m, 2H), 7.08 (app d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 8.4 Hz, 2H), 4.91 (s, 2H), 3.95 (s, 2H), 3.77 (unresolved t, 2H), 3.4 (unresolved t, 2H), 2.5 (m, 2H).13C NMR (101 MHz; CDCI3) 6 171.5, 158.2, 147.8, 135.3, 129.6, 128.5 (2C), 127.9, 126.5, 119.1, 116.2, 114.1 (2C), 56.1, 45.5, 43.1, 41.9, 40.4. HRMS (ES+) 488.0463 [M + Na]+Ci9H2iN5O235CI79BrNa requires 488.0465 (Diff -0.4 ppm) & 490.0439 [M + Na]+Ci9H2iN5O235CI81BrNa requires 490.0444 (Diff - 1.1 ppm). M.p. 164-166°C.

[0497] Example 4 l-(4-aminobenzyl)-3-(2-(2-(2-bromo-4-chlorophenyl)pyrazolidin-l-yl)-2- oxoethyl)urea tert-Butyl (2-(2-(2-bromo-4-chlorophenyl)pyrazolidin-l-yl)-2-oxoethyl) carbamate (195 mg, 0.47 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 3% MeOH in EtOAc) to yield the title compound as a pale yellow foam (137 mg, 63%). IR vmax I cm-13302 (br. w), 1624 (s), 1543 (m), 1462 (m), 1218 (m), 1012 (s);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.15 - 7.12 (3H, m), 6.65 (2H, d, J = 8.5), 6.61 (1H, d, J = 8.0) 4.30 (1H, br. s), 4.17 (2H, s), 3.98 (1H, br. s), 3.74 (2H, br s), 3.41 (2H, br. s), 2.12 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 170.2, 159.0, 146.9, 144.7, 133.3, 129.4, 128.2, 125.1, 124.5, 120.2, 117.8, 115.8, 55.1, 48.3, 42.7, 41.8, 23.0; HRMS (ES+) m / z 465.0563 [M+Na]+CigHziBrCINsOzNa requires 465.0567 (100%) (Diff -0.94 ppm).

[0498] Example 5 l-(4-aminobenzyl)-3-(2-(2-(2-bromo-5-chlorophenyl)pyrazolidin-l-yl)-2- oxoethyl)urea tert-butyl (2-(2-(2-bromo-5-chlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (0.67 g, 1.61 mmol) was employed. The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as a pale white solid (0.063 g, 45%).XH NMR (400 MHz; CDCI3; ppm) 6 7.47 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 5.89 (br s, NH), 5.72 (br s, NH), 4.22 (br s, 2H), 3.65-3.55 (unresolved m, 2H), 3.43 (s, 2H), 3.40-3.30 (unresolved m, 2H), 2.00-1.83 (unresolved m, 2H).13C NMR (101 MHz; CDCI3) 6 135.3, 129.2 (2C), 128.5, 127.9, 126.5, 119.1, 115.1 (2C), 113.7, 56.1, 45.1, 44.1, 42.4. LRMS (ES+) 488.0 [M + Na]+Ci9H2iN5O235CI79BrNa requires 488.0 & 490.0 [M+Na]+Ci9H2iN5O235CI81BrNa requires 490.0. IR vmax (cm'1) 3362 (N-H), 1621 (urea C=O), 1517 (N-H), 823 (C-CI), 572 (C-Br). M.p. decomposed.

[0499] Example 6 l-(4-aminobenzyl)-3-(2-(2-(2-bromo-4-methoxyphenyl)pyrazolidin-l-yl)-2- oxoethyl)urea tert-Butyl (2-(2-(2-bromo-4-methoxyphenyl)pyrazolidin-l-yl)-2-oxoethyl) carbamate (210 mg, 0.51 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 2% MeOH in EtOAc) to yield the title compound as a beige foam (169 mg, 72%). IR vmax I cm-13300 (br. m), 1620 (s), 1586 (s), 1304 (m), 1235 (m), 1096 (s);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.12 (2H, d, J = 8.5), 7.05 (1H, s), 6.75 (1H, dd, J = 8.0, 1.5), 6.66 (2H, d, J = 8.5), 6.59 (1H, d, J = 8.0) 4.35 (1H, br. s), 4.18 (2H, s), 4.09 (1H, br. s), 3.79 (3H, s), 3.75 (2H, br s), 3.43 (2H, br. s), 2.12 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 169.8, 159.2, 151.7, 135.6, 145.8, 128.2, 124.3, 122.0, 121.1, 118.9, 118.5, 115.4, 56.2, 55.4, 47.2, 43.2, 41.8, 23.0; HRMS (ES+) m / z 484.0962 [M + Na]+C2oH24BrNs03Na requires 484.0960 (100%) (Diff 0.43 ppm). Example 7 l-(4-aminobenzyl)-3-(2-(2-(2-bromo-4-methylphenyl)pyrazolidin-l-yl)-2- oxoethyl)urea tert-Butyl (2-(2-(2-bromo-4-methylphenyl)pyrazolidin-l-yl)-2-oxoethyl) carbamate (190 mg, 0.49 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 2% MeOH in EtOAc) to yield the title compound as an orange foam (155 mg, 73%). IR vmax I cm'13332 (br. w), 1620 (s), 1523 (s), 1452 (m), 1364 (s), 1212 (m), 1023 (s);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.32 (1H, d, J = 1.5), 7.08 (2H, d, J = 8.5), 6.99 (1H, ~d, J = 8.0), 6.67 (2H, d, J = 8.0), 6.55 (1H, d, J = 8.5), 4.27 (1H, br. s), 4.20 (2H, s), 3.99 (1H, br. s), 3.82 (1H, br. s), 3.73 (1H, br. s), 3.40 (2H, br. s), 2.34 (3H, s), 2.12 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 170.1, 159.2, 145.9, 143.2, 132.9, 131.5, 129.7, 128.0, 124.3, 120.0, 118.3, 112.9, 55.0, 47.9, 42.8, 41.7, 23.2, 21.6; HRMS (ES+) m / z 468.1014 [M+Na]+C2oH24BrN502Na requires 468.1011 (100%) (Diff 0.59 ppm).

[0500] Example 8 l-(4-aminobenzyl)-3-(2-(2-(2,4-dichlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea tert-Butyl (2-(2-(2,4-dichlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (175 mg, 0.47 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 3% MeOH in EtOAc) to yield the title compound as a colourless foam (111 mg, 56%). IR vmax I cm'13322 (br. m), 1619 (s), 1550 (m), 1386 (m), 1117 (m), 1001 (s), 908 (m);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.30 (1H, s), 7.16 (1H, dd, J = 7.5, 1.5), 7.09 (2H, d, J = 8.5), 6.62 - 6.65 (3H, m), 4.31 (1H, br. s), 4.20 (2H, s), 4.01 (1H, br. s), 3.78 (2H, br s), 3.45 (2H, br. s), 2.06 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 170.8, 158.5, 146.5, 145.3, 133.1, 128.0, 127.9, 125.9, 124.8, 124.1, 120.0, 115.4, 55.6, 46.5, 43.6, 42.0, 23.1; HRMS (ES+) m / z 444.0971 [M + Na]+CigHziCIzNsOzNa requires 444.0975 (100%) (Diff -1.02 ppm). Example 9 l-(4-aminobenzyl)-3-(2-(2-(2,5-dichlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea tert-Butyl (2-(2-(2,5-dichlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (0.22 g, 0.59 mmol) was employed. The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as a pale white powder (92.70 mg, 37%).XH NMR (400 MHz; CDCI3; ppm) 6 7.30 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.01 (dd, J = 8.5, 2.4 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 2H), 5.70 (s, NH), 5.47 (s, NH), 4.47 (s, 2H), 4.23 (s, 2H), 3.75-3.55 (unresolved m, 2H), 3.48-3.30 (unresolved m, 2H), 2.01-1.90 (unresolved m, 2H).13C NMR (101 MHz; CDCI3) 6 172.0, 158.0, 148.1, 145.7, 133.2, 132.1, 129.2, 129.1 (2C), 125.4, 124.0, 118.9, 115.1 (2C), 54.3, 44.9, 44.2, 42.3, 23.3. HRMS (ES+) 444.0965 [M + Na]+Ci9H2iN5O235Cl2Na requires 444.0970 (Diff -1.1 ppm). IR vmax (cm'1) 3354 (N-H), 1603 (urea C=O), 809 (C-CI). M.p. 182.0-188.0°C.

[0501] Example 10 l-(4-Aminobenzyl)-3-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2- oxoethyl) urea tert-Butyl (2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (0.11 g, 0.31 mmol) was employed. The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as an orange solid (25.4 mg, 20%).XH NMR (400 MHz; CDCI3; ppm) 6 7.30-7.18 (m, 1H), 7.04-6.96 (m, 2H), 6.75-6.64 (m, 1H), 6.60- 6.52 (unresolved m, 3H), 5.49 (br s, NH), 5.23 (br s, NH), 4.16 (br s, 2H), 3.57 (s, 2H), 3.50-3.10 (unresolved m, 4H), 1.95-1.65 (unresolved m, 2H).13C NMR (101 MHz; CDCI3) 6 170.9, 160.6 (d, J = 245.4 Hz), 156.9, 147.6 (d, J = 7.7 Hz), 144.9, 131.1 (d, J = 8.9 Hz), 128.2, 128.0 (2C), 119.4 (d, J = 2.2 Hz), 114.1 (2C), 111.2 (d, J = 21.6 Hz), 105.4 (d, J = 26.1 Hz), 54.3, 43.8, 43.2, 41.3, 22.3. HRMS (ES+) 428.1255 [M+Na]+Ci9H2iN5O235CIFNa requires 428.1266 (Diff -2.5 ppm). M.p. 123.5-125.0°C.

[0502] Example 11 l-(4-Aminobenzyl)-3-(2-(2-(2-chloro-5-methoxyphenyl)pyrazolidin-l-yl)-2- oxoethyl) urea tert-Butyl 2-(2-chloro-5-methoxyphenyl)pyrazolidine-l-carboxylate (0.11 g, 0.30 mmol, 1 eq) was dissolved in a mixture of DCM:TFA (5: 1, 3 mL) and the reaction mixture was allowed to stir at room temperature until TLC showed disappearance of starting material. The reaction mixture was concentrated in vacuo to afford the free amine as a trifluoroacetate salt and was used directly without further purification.

[0503] To a solution of the trifluoroacetate salt (0.11 g, 0.29 mmol, 1 eq) in acetonitrile (6 mL), was added / V-(4-Aminobenzyl)-l / - / -imidazole-l-carboxamide (68 mg, 0.32 mmol, 1.1 eq), triethylamine (88 pL, 0.63 mmol, 2.2 eq) and DMAP (3.5 mg, 0.03 mmol, 0.1 eq) and was allowed to stir at room temperature overnight under N2 (followed by TLC). Upon completion, the solution was diluted with DCM and washed with distilled water. The organic phase was dried over MgSC and concentrated in vacuo. The crude product was purified by FCC (SiC ; EtOAc) to afford the titled compound as a pale white solid (0.12 g, 96%).^ NMR (400 MHz; CDCI3; ppm) 6 7.27 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H), 6.57 (dd, J = 8.6, 2.8 Hz, 1H), 6.49 (d, J =

[0504] 2.8 Hz, 1H), 5.20 (br s, NH), 4.82 (br s, NH), 4.24 (s, 1H), 4.22 (s, 1H), 3.80-3.60 (unresolved m, 2H), 3.78 (s, 3H), 3.55-3.42 (unresolved m, 2H), 2.06-1.99 (unresolved m, 2H).13C NMR (101 MHz; CDCI3) 6 171.5, 159.2, 157.8, 147.8, 145.2, 131.6, 130.2, 128.9 (2C), 127.2, 115.2 (2C), 109.7, 105.5, 55.6, 55.4, 45.2, 45.0, 44.3, 32.0. HRMS (ES+) 440.1457 [M + Na]+C2oH24CIN503Na requires 440.1465 (Diff -

[0505] 1.9 ppm). IR Vmax (cm-1) 3350 (N-H), 1630 (urea C=O), 1568 (N-H), 824 (C-CI). M.p. 194.0-196.0°C.

[0506] Example 12 l-(4-Aminobenzyl)-3-(2-(2-(3-cyanophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea tert-Butyl (2-(2-(3-cyanophenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (278 mg, 0.84 mmol) was employed. The reaction yielded a yellow oil that was taken directly to the next step.

[0507] The TFA salt of the amine (289 mg, 0.84 mmol) and N-(4-aminobenzyl)-lH-imidazole- 1-carboxamide (199 mg, 0.92 mmol) were employed. The crude product was purified by flash column chromatography eluting with 100% EtOAc to yield a cream solid (216 mg, 0.57 mmol, 68%). M.p: 145 - 147 °C; IR vmax (cm’1) 1514 (N-H), 1564 (N-H), 1657 (amide C=O), 2226 (ON), 3355 (N-H);XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.37 (1H, ap: t, J = 7.6), 7.28 (1H, d, J = 7.6), 7.14 (1H, s), 7.13 (1H, d, J = 7.6), 7.05 (2H, d, J = 8.3), 6.59 (2H, d, J = 8.3), 5.86 (1H, t, J = 4.5), 5.69 (1H, t, J = 5.5), 4.42 - 4.35 (1H, m), 4.21 (2H, t, J = 4.5), 3.72 (1H, br s), 3.63 (2H, br s), 3.26 (1H, br s), 3.08 (1H, br s), 1.97 (1H, br s), 1.84 (1H, br s);13C NMR (100 MHz; CDCI3; Me4Si) 6 172.9, 158.2, 150.6, 145.7, 135.2, 130.4, 128.9, 126.5, 120.6, 118.8, 118.6, 115.1, 113.3, 55.0, 44.1, 42.9, 42.2, 24.1; HRMS (ES+) m / z 401.1698 [M + Na] + CzoHzzNeOzNa requires 401.1702 (Diff -1.0 ppm); Anal. Calcd. for C20H22N6O2: C, 63.48; H, 5.86; N, 22.21. Found C, 62.68; H, 5.96; N, 22.17.

[0508] Example 13 l-(4-aminobenzyl)-3-(2-(2-(3-(benzyloxy)phenyl)pyrazolidin-l-yl)-2-oxoethyl)urea tert-butyl (2-(2-(3-(benzyloxy)phenyl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (0.050 g, 0.12 mmol) was employed. The crude product was purified by FCC (SiCh; 20:80 EtOAc: Hexane) to afford the titled compound as a yellow solid (0.030 g, 54%).XH NMR (400 MHz; CD3OD; ppm) 6 7.33-7.23 (m, 5H), 7.22-7.15 (m, 1H), 7.13-7.05 (m, 1H), 6.98-6.90 (m, 2H), 6.61-6.53 (m, 2H), 6.51-6.42 (m, 1H), 4.97 (m, 2H), 4.12 (br s, 2H), 4.04 (s, 1H), 3.21 (br s, 2H), 1.93 (br s, 2H).13C NMR (101 MHz; CD3OD) 6 172.1, 159.8, 151.5, 137.3, 130.0, 128.1 (2C), 128.0 (2C), 127.5, 127.1 (2C), 118.8, 115.3 (2C), 109.1, 108.5, 102.8, 69.6, 54.7, 43.2, 42.9, 42.8, 41.3. HRMS (ES+) 482.2163 [M+Na]+CzeHzgNsOsNa requires 482.2168 (Diff -1.1 ppm). Example 14

[0509] ( / ?)-l-(4-aminobenzyl)-3-(2-oxo-l-phenyl-2-(2-phenylpyrazolidin-l-yl)ethyl)urea tert-Butyl ( / ?)-(2-oxo-l-phenyl-2-(2-phenylpyrazolidin-l-yl)ethyl)carbamate (0.044 g, 0.12 mmol, 1.00 eq). The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as a yellow solid (0.03 mg, 60%).XH NMR (400 MHz; CDCI3; ppm) 6 7.40-7.20 (m, 5H), 7.15-6.85 (m, 7H), 6.56 (d,J = 7.8 Hz, 2H), 5.58 (s, 1H), 5.04 (broad s, NH), 4.20 (s, 2H), 3.70-3.50 (unresolved m, 2H), 3.40-3.00 (unresolved m, 2H), 1.70-1.67 (unresolved m, 2H).13C NMR (101 MHz; CDCI3) 6 149.4, 145.5, 129.5, 129.2 (4C), 129.1 (2C), 128.4 (2C), 128.1, 127.9, 122.8, 122.1, 116.2, 115.8 (2C), 115.1 (2C), 61.9, 58.5, 53.6, 44.1, 32.0. HRMS (ES+) 452.2045 [M + Na]+CzsHz NsOzNa requires 452.2062 (Diff -3.9 ppm). [O]20D = 2.5 (c 1.0, CH3OH). IR vmax (cm-1) 3342 (N-H), 1621 (urea C=O), 1516 (N-H). M.p. 90-92 °C.

[0510] Example 15

[0511] (S)-l-(4-aminobenzyl)-3-(2-oxo-l-phenyl-2-(2-phenylpyrazolidinasapyrrolidin-l- yl)ethyl)urea tert-Butyl (S)-(2-oxo-l-phenyl-2-(2-phenylpyrazolidin-l-yl)ethyl)carbamate (0.044 g, 0.12 mmol) was employed. The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compounds as a yellow oil (0.03 g, 60%). With the yield consisting of a mixture of rotamers in ratio 1.31 / 1.XH NMR (400 MHz; CDCI3; ppm) 6 7.38-6.25 (major and minor, m, 14H), 6.08 (minor, s, 1H), 5.55 (major, s, 1H), 5.39-5.18 (unresolved m, 2NH), 4.12 (s, 2H), 3.77-3.37 (major &. minor, m, 4H), 3.36-3.26 (minor, m, 2H), 3.20-3.05 (major, unresolved m, 2H), 1.88-1.53 (major & minor, m, 4H).13C NMR (101 MHz; CDCI3) 6 149.4, 145.5, 129.5, 129.2 (2C), 129.1 (4C), 128.4 (2C), 128.1, 127.9, 122.8, 122.1, 116.2, 115.8 (2C), 115.1 (2C), 61.9, 58.5, 53.6, 44.1, 32.0. HRMS (ES+) 452.2045 [M + Na]+CzsHzzNsOzNa requires 452.2062 (Diff - 3.9 ppm). [Q]20D = 2.5 (c 1.0, CH3OH). IR Vmax (erm1) 3345 (N-H), 1620 (urea C=O), 1515 (N-H). M.p. 91-94 °C.

[0512] Example 16

[0513] ( / ?)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazoldin-l-yl)-2-oxo-l- phenylethyl)urea tert-Butyl ( / ?)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)carbamate (0.78 g, 1.70 mmol, 1.00 eq). The crude product was purified by FCC (SiC ; EtOAc) to afford the titled compound as a yellow solid (0.20 g, 23%).XH NMR (400 MHz; DMSO; ppm) 6 7.71-7.61 (m, 1H), 7.55-7.21 (m, 5H), 7.20-7.02 (m, 2H), 6.96-6.76 (m, 8H), 6.60-6.52 (m, 4H), 6.42-6.32 (m, 2H), 5.98-5.92 (m, 2 NH), 5.48 (d, J = 8.82 Hz, 1H), 3.95-3.85 (br s, 2H), 4.75-3.58 (m, 2H), 3.50-2.20 (m, 2H), 2.10-2.00 (m, 2H).13C NMR (101 MHz; DMSO) 6 173.4, 172.2, 157.3, 148.4, 145.6, 134.4, 133.5, 129.4, 128.7 (2C), 128.5 (2C), 128.1 (2C), 127.8, 127.3, 125.7, 120.1, 115.3 (2C), 56.8, 55.4, 45.9, 45.7 43.0. HRMS (ES+) 530.1159 C25H26N5O279BrNa requires 530.1168 (Diff -1.6 ppm) & 532.1151 [M+Na]+C25H26N5O281BrNa requires 532.1147 (Diff 0.7 ppm). [O]20D = -10.0 (c 1.0, CH3OH). IR Vmax (cm-1) 3357 (N-H), 1620 (urea C=O), 1515 (N-H), 697 (C-Br). M.p. 103-105 °C.

[0514] Example 17

[0515] (S)-l-(4-Aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)urea tert-Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)carbamate (0.30 g, 0.65 mmol, 1.00 eq) was dissolved in a mixture of DCM:TFA (5: 1, 8 mL) and the reaction mixture was allowed to stir at room temperature until TLC showed disappearance of starting material. The reaction mixture was concentrated in vacuo to afford the free amine as a trifluoroacetate salt and was used directly without further purification.

[0516] To a solution of the trifluoroacetate salt (0.31 g, 0.65 mmol, 1 eq) in acetonitrile (8 mL), was added / V-(4-Aminobenzyl)-l / - / -imidazole-l-carboxamide (0.15 g, 0.70 mmol,

[0517] 1.1 eq), triethylamine (0.20 mL, 1.41 mmol, 2.2 eq) and DMAP (7.9 mg, 0.06 mmol, 0.1 eq) and was allowed to stir at room temperature overnight under N2 (followed by TLC). Upon completion, the solution was diluted with DCM and washed with distilled water. The organic phase was dried over MgSC and concentrated in vacuo. The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as a yellow solid (0.17 g, 50%).XH NMR (400 MHz; DMSO; ppm) 6 7.75-7.68 (m, 1H), 7.57-7.30 (m, 5H), 7.23-7.10 (m, 2H), 7.03-6.83 (m, 8H), 6.65-6.37 (m, 6H), 6.00 (d, J = 6.21 Hz, 1H), 5.55 (unresolved d, 1H), 4.96 (s, 2H), 4.05-3.93 (m, 2H), 3.82-3.75 (m, 2H), 2.15-2.07 (m, 2H).13C NMR (101 MHz; DMSO) 6 173.4, 157.2, 147.9, 134.4, 133.5, 129.0, 128.7, 128.5 (2C), 128.1 (2C), 127.8 (2C), 127.3, 126.4, 125.7, 120.5, 120.2,

[0518] 114.1 (2C), 56.3, 55.4, 49.1, 45.6, 43.1. HRMS (ES+) 530.1156 [M + Na]+C25H26N5O279BrNa requires 530.1168 (Diff -2.2 ppm) & 532.1151 [M+Na]+C25H26N5O281BrNa requires 532.1147 (Diff 0.7 ppm). [O]20D = 10.0 (c 1.0, CH3OH). IR Vmax (cm-1) 3336 (N-H), 1619 (urea C=O), 1515 (N-H), 696 (C-Br). M.p. 103-104 °C.

[0519] Example 18

[0520] (S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4- chlorophenyl)-2-oxoethyl)urea tert-Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-chlorophenyl)-2- oxoethyl)carbamate (0.80 g, 1.62 mmol) was employed. The crude product was purified by FCC (SiO2; 30:50 to 50:50 EtOAc: Hexane) to afford the titled compound as a yellow solid (0.18 g, 20%).XH NMR (500 MHz; CDCI3; ppm) 6 7.50-7.35 (m, 2H), 7.30-7.20 (m, 1H), 7.08-6.95 (unresolved m, 4H), 6.82-6.72 (unresolved m, 4H), 6.54 (d, J = 7.0, 1H), 6.15 (s, NH), 6.0 (s, NH), 5.80 (m, 1H), 4.20 (m, 2H), 3.65-3.45 (unresolved m, 2H), 3.39-3.28 (unresolved m, 2H), 1.90-1.70 (m, 2H).13C NMR (126 MHz; CDCI3) 6 173.0, 157.2, 147.3, 145.8, 136.6, 133.5, 132.9, 129.3, 129.2, 127.4 (4C), 125.2, 119.7, 119.1, 115.2, 114.9 (2C), 60.4, 56.0, 55.0, 45.3, 44.1, 41.2. HRMS (ES+) 542.0953 [M + H]+C25H26N5O3CI79Br requires 542.0953 (Diff 0.03 ppm). IR Vmax (cm-1) 3341 (N-H), 1619 (urea C=O), 1516 (N-H), 756 (C-CI), 599 (C-Br). M.p. 91-94°C.

[0521] Example 19

[0522] (S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4- methoxyphenyl)-2-oxoethyl)urea

[0523] (S)-2-((tert--Butoxycarbonyl)amino)-2-(4-methoxyphenyl)acetic acid (0.27 g, 0.54 mmol, 1.00 eq). The crude product was purified by FCC (SiCh; 50: 50 to 100:0 EtOAc: Hexane) to afford the titled compound as an orange solid (0.07 g, 24%).XH NMR (500 MHz; CDCI3; ppm) 6 7.5-7.35 (m, 2H), 7.25-7.14 (m, 1H), 7.08-6.95 (m, 3H), 6.85-6.80 (m, 1H), 6.74-6.66 (m, 1H), 6.55 (br s, 1H), 6.48-6.35 (unresolved m, 2H), 6.15-6.05 (m, 1H), 5.5 (s, 1H), 4.22 (s, 2H), 3.85-3.65 (unresolved m, 2H), 3.61 (s, 3H), 3.40-3.20 (unresolved m, 2H), 1.96-1.72 (unresolved m, 2H).13C NMR (126 MHz; CDCI3) 6 171.2, 158.6, 157.3, 145.6, 133.4, 130.1, 129.5, 129.2 (2C), 129.0 (2C), 127.2, 124.9, 119.7, 119.2, 115.2, 115.0 (2C), 113.5 (2C), 60.4, 56.0, 55.2, 45.2, 44.1, 30.9. HRMS (ES+) 538.1451 [M + H]+C26H29N5O379Br requires 538.1448 (Diff -0.5 ppm). IR vmax (cm-1) 3345 (N-H), 1612 (urea C=O), 1509 (N-H), 611 (C-Br). M.p. 195-198°C.

[0524] Example 20

[0525] (S)-l-(4-aminobenzyl)-3-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxo- lphenylethyl)urea tert-Butyl (S)-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)carbamate (0.19 g, 0.4 mmol, 1.0 eq). The crude product was purified by FCC (SiC ; EtOAc) to afford the titled compound as a white solid (0.11 g, 53%). With the yield consisting of a mixture of rotamers in ratio 1.03 / 1.XH NMR (400 MHz; DMSO; ppm) 6 7.44 (unresolved d, 1H), 7.17-6.64 (m, 1H), 6.62-6.41 (m, 1H), 6.13 (unresolved d, 1H), 5.56-5.33 (m, 1H), 4.88 (s, NH), 4.02 (unresolved dd, 1H), 3.31 (s, 2H), 2.51 (s, 3H), 2.09 (s, 7H), 1.92-1.65 (m, 1H), 1.56-1.32 (m, 1H), 1.33-1.13 (m, 1H), 1.11-0.92 (m, 1H).13C NMR (101 MHz; DMSO) 6 209.2, 203.5, 130.97, 126.1, 115.7, 111.9, 102.9, 96.08, 40.6, 40.2, 39.7, 39.6, 31.2. HRMS (ES+) 482.1754 [M + Na]+CzsHzsNsOzCIFNa requires 482.1753 (Diff 0.18ppm). M.p 125.5- 127.5°C.

[0526] Example 21

[0527] (S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2- morpholinoethoxy)phenyl)-2-oxoethyl)urea tert-butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2- morpholinoethoxy)phenyl)-2-oxoethyl)carbamate (0.31 g, 0.52 mmol, 1 eq) was dissolved in a mixture of DCM:TFA (5: 1, 5 mL) and the reaction mixture was allowed to stir at room temperature until TLC showed disappearance of starting material. The reaction mixture was concentrated in vacuo to afford the free amine as a trifluoroacetate salt and was used directly without further purification.

[0528] To a solution of the trifluoroacetate salt (1 eq) in acetonitrile (10 mL / mmol), was added / V-(4-Aminobenzyl)-l / - / -imidazole-l-carboxamide (1.1 eq), triethylamine (2.2 eq) and DMAP (0.1 eq) and was allowed to stir at room temperature overnight under N2 (followed by TLC). Upon completion, the solution was diluted with DCM and washed with distilled water. The organic phase was dried over MgSC and concentrated in vacuo. The crude product was purified by FCC (SiC ; EtOAc) to afford the titled compound as a yellow solid (0.20 g, 23%).XH NMR (500 MHz; CDCI3; ppm) 67.48- 7.36 (m, 1H), 7.24-7.15 (m, 1H), 7.02-6.95 (m, 4H), 6.90-6.78 (m, 1H), 6.70-6.67 (m, 2H), 6.56-6.49 (m, 2H), 6.38-6.32 (m, 1H), 6.14-6.02 (m, 1H), 5.70 (s, 1H), 4.25- 4.03 (m, 4H), 3.75-3.70 (m, 4H), 3.62-3.43 (m, 2H), 3.37-3.28 (m, 2H), 2.75-2.68 (m, 2H), 2.60-2.53 (m, 4H), 1.90-1.65 (m, 2H).13C NMR (126 MHz; CDCI3) 6 173.7, 157.6, 157.3, 147.7, 145.6, 134.5, 133.4, 130.5, 129.5, 129.2 (2C), 129.1 (2C), 129.0, 127.1, 124.8, 119.2, 115.0 (2C), 114.3 (2C), 66.9 (2C), 65.6, 57.5, 56.0, 55.0, 54.0 (2C), 45.2, 44.1. HRMS (ES+) 659.5790 [M + Na]+C3iH37BrN6O4Na requires 659.1956 (Diff -0.59 ppm). IR vmax cmr1) 3332 (N-H), 1615 (urea C=O), 1512 (N-H), 1233 (C-O), 613 (C-Br). M.p. 94-95°C.

[0529] Example 22

[0530] (S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-(4-(2- thiomorpholinoethoxy)phenyl)ethyl)urea tert-Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-(4-(2- thiomorpholinoethoxy)phenyl)ethyl)carbamate (0.48 g, 0.79 mmol, 1 eq) was employed. The crude product was purified by FCC (SiC ; EtOAc to 20:80 MeOH:EtOAc) to afford the titled compound as a yellow solid (66 mg, 19%).XH NMR (500 MHz; CDCI3; ppm) 6 7.60-7.53 (m, 1H), 7.50-7.36 (m, 1H), 7.25-7.15 (m, 1H), 7.07-6.97 (m, 4H), 6.73-6.43 (m, 1H), 6.60-6.43 (m, 3H), 6.15-6.04 (m, 1H), 5.67-5.50 (m, 1H), 4.45-4.05 (m, 4H), 3.93-3.85 (m, 2H), 3.40-3.33 (m, 2H), 2.93-2.73 (m, 6H), 2.72-2.67 (m, 4H), 1.80-1.76 (m, 2H).13C NMR (126 MHz; CDCI3) 6 173.7, 172.9, 157.6, 157.3, 145.6, 133.4, 130.4, 129.5, 129.2 (2C), 129.1 (2C), 129.0, 127.1, 124.9, 119.2, 115.0 (2C), 114.1 (2C), 65.6, 57.9, 57.7, 56.0, 55.2 (2C), 55.0, 45.2, 44.1, 27.9 (2C). HRMS (ES+) 675.1725 [M + Na]+C3iH37N6O3S79Br requires 675.1723 (Diff -0.22 ppm). Anal. Cal. (mass %) for C3iH37BrNeO4: C, 58.40; H, 5.85; N, 13.18. Found: C, 58.91; H, 5.64; N, 12.08. IR vmax (crn-1) 3340 (N-H), 1618 (urea C=O), 1509 (N-H), 1230 (C-O), 612 (C-Br). M.p. 89-91°C.

[0531] Example 23

[0532] (S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(4- methylpiperazin-l-yl)ethoxy)phenyl)-2-oxoethyl)urea

[0533] Tert-butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(4-methylpiperazin-l- yl)ethoxy)phenyl)-2-oxoethyl)carbamate was employed. The crude product was purified by flash column chromatography (0 - 10 % MeOH in DCM) and then further purified by preparative TLC to afford the title compound as an off-white solid (11 %) and as a rotameric mixture in ratio 1: 1.XH NMR (500 MHz, CDCI3) 6: 7.59-7.33 (1H, m), 7.07-6.00 (12H, m), 5.58 (NH, s), 5.36 (1H, m), 4.31-3.66 (6H, m), 3.56-3.21 (3H, m), 2.90-2.41 (9H, m), 2.34 (3H, s, minor), 2.18 (3H, s, major), 2.12-1.69 (2H, m).13C NMR (125 MHz, CDCI3) 6: 173.7, 157.7, 157.2, 145.6, 133.4, 129.5, 129.1, 128.9, 128.2, 127.1, 124.8, 119.2, 115.0, 114.4, 114.1, 98.3, 80.9, 69.5, 65.8, 56.9, 56.0, 54.9, 53.9, 53.3, 45.8, 45.3, 44.1, 31.8, 30.9, 29.7, 29.3. HRMS (ES+) 652.2442 [M + H]+C32H4i81BrN7O3 requires 651.2434. mp 80-84 °C.

[0534] Example 24 l-(4-aminobenzyl)-3-((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(( / ?)-3- methylmorpholino)ethoxy)phenyl)-2-oxoethyl)urea tert-butyl ((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(( / ?)-3- methylmorpholino)ethoxy)phenyl)-2-oxoethyl)carbamate (0.33 g, 0.54 mmol) was employed. The crude product was purified by FCC (SiC ; EtOAc to 20:80 MeOH:EtOAc) to afford the titled compound as a yellow solid (0.066 g, 19%).XH NMR (400 MHz; CDCI3; ppm) 6 7.41-7.29 (m, 2H), 6.97-6.89 (m, 3H), 6.79-6.74 (m, 1H), 6.69-6.60 (m, 1H), 6.49-6.48 (m, 2H), 6.33-6.23 (m, 2H), 6.06-5.98 (m, 1H), 5.51 (br s, 1H), 5.29 (br s, 2NH), 4.14 (br s, 2H), 3.84-3.70 (m, 2H), 3.65-3.55 (m, 3H), 3.48-3.41 (m, 1H), 3.66-3.31 (m, 2H), 3.19 (t, J = 10.1 Hz, 2H), 3.10-2.90 (m, 2H), 2.80-2.66 (m, 2H), 2.50-2.40 (m, 2H), 1.88-1.60 (m, 2H), 0.95 (d, J = 5.5 Hz, 3H).13C NMR (101 MHz; CDCI3) 6 157.2, 147.7, 145.6, 133.4, 130.9, 130.3, 129.1 (2C), 129.0 (2C), 124.8, 119.2, 115.0 (2C), 114.1 (2C), 73.0, 67.3, 65.6, 565.0, 55.2, 52.5, 52.3, 45.2, 44.1, 30.9, 29.3, 14.3. HRMS (ES+) 651.2296 [M + H]+C32H4oN60479Br requires 651.2289 (Diff -1.09 ppm). IR vmax (crn-1) 3345 (N-H), 1620 (urea C=O), 1509 (N-H), 1231 (C-O), 659 (C-Br). M.p. 88-90°C.

[0535] Example 25

[0536] (S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(l,l- dioxidothiomorpholino)ethoxy)phenyl)-2-oxoethyl)urea tert-Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(l,l- dioxidothiomorpholino)ethoxy)phenyl)-2-oxoethyl)carbamate (0.36 g, 0.56 mmol) was employed. The crude product was purified by FCC (SiCh; EtOAc to 10:90 MeOH:EtOAc) to afford the titled compound as a yellow solid (0.10 g, 26%).XH NMR (500 MHz; CDCI3; ppm) 6 7.55-7.40 (m, 1H), 7.05-6.80 (m, 5H), 6.75-6.68 (m, 1H), 6.58-6.53 (m, 2H), 6.37-6.32 (m, 2H), 6.13-6.06 (m, 1H), 5.42 (s, 1H), 4.40-4.08 (m, 4H), 3.95-3.70 (m, 2H), 3.43-3.35 (m, 2H), 3.17-3.11 (m, 4H), 3.09-3.05 (m, 4H), 2.94-2.90 (unresolved t, 2H), 1.76 (m, 2H).13C NMR (126 MHz; CDCI3) 6 157.3, 157.2, 147.8, 145.7, 140.0, 134.5, 133.4, 129.6, 129.1 (2C), 129.0 (2C), 127.1, 124.8, 119.2, 115.0 (2C), 114.3 (2C), 114.1, 69.5, 65.9, 55.6, 53.8 , 51.4 (2C), 51.0 (2C), 44.1. HRMS (ES+) 685.1806 [M + H]+C3iH37N6O5S79Br requires 684.1730 (Diff - 0.51 ppm). IR Vmax (cm-1) 3360 (N-H), 1617 (urea C=O), 1510 (N-H), 1329 (S=O), 1233 (C-O), 607 (C-Br). M.p. 101-104°C. Example 26

[0537] (S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(4- fluoropiperidin-l-yl)ethoxy)phenyl)-2-oxoethyl)urea tert-Butyl (S)-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(4-fluoropiperidin-l- yl)ethoxy)phenyl)-2-oxoethyl)carbamate (0.11 g, 0.18 mmol) was employed. The crude product was purified by FCC (SiCh; EtOAc to 10:90 MeOH:EtOAc) to afford the titled compound as a yellow solid (0.06 g, 50%).XH NMR (500 MHz; CDCI3; ppm) 6 7.44-7.36 (m, 1H), 7.27-7.18 (m, 1H), 7.06-6.93 (m, 3H), 6.88-6.81 (m, 1H), 6.74- 6.67 (m, 1H), 6.60-6.55 (m, 2H), 6.40-6.35 (m, 2H), 6.15-6.09 (m, 1H), 5.59 (s, 1H), 5.34 (s, NH), 4.79-4.65 (m, 1H), 4.25-4.08 (m, 4H), 3.93-3.76 (m, 2H), 3.55-3.28 (m, 4H), 2.86-2.81 (m, 2H), 2.78-2.50 (m, 4H), 2.00-1.89 (m, 4H), 1.83-1.75 (m, 2H).13C NMR (126 MHz; CDCI3) 6 173.7, 169.6, 157.7, 147.6, 133.4, 129.1 (2C), 129.0 (2C), 127.3, 127.2, 124.9, 119.8, 119.2, 119.1, 115.0 (2C), 114.3 (2C), 114.2, 88.1 (d, J = 171.3 Hz), 65.7, 56.9, 56.0, 55.1, 49.8 (d, J = 18.7 Hz, 2C), 45.3, 44.1, 31.3 (d, J = 18.5 Hz, 2C), 30.9. HRMS (ES+) 653.2257 [M + H]+C32H39N6O3F79Br requires 653.2246 (Diff -1.75 ppm). M.p. 90-92°C.

[0538] Example 27 l-(4-aminobenzyl)-3-(2-oxo-2-(2-(pyridin-2-yl)pyrazolidin-l-yl)ethyl)urea tert-Butyl (2-oxo-2-(2-(pyridin-2-yl)pyrazolidin-l-yl)ethyl)carbamate (176 mg, 0.58 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, 1% MeOH in EtOAc to 6% MeOH in EtOAc) to yield the title compound as a yellow foam (106 mg, 52%). IR vmax I cm'13329 (br. w), 1615 (s), 1486 (m), 1433 (w), 1266 (m), 1124 (m), 908 (s);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 8.08 (1H, dd, J = 7.5, 1.5), 7.40 (1H, td, J = 7.5, 1.5), 7.08 (2H, d, J = 8.5), 6.63 (2H, d, J = 8.5), 6.55 - 6.40 (2H, m), 4.28 (1H, br. s), 4.19 (2H, s), 4.03 (1H, br. s), 3.85 (1H, br. s), 3.78 (1H, br. s), 3.42 (2H, br. s), 2.11 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 170.4, 159.4, 157.6, 147.1, 146.2, 137.6, 128.3, 124.1, 115.4, 111.2, 106.1, 54.8, 48.3, 43.3, 41.4, 23.2; HRMS (ES+) m / z 425.1263 [M+H]+C18H23N6O2 requires 425.1265 (100%) (Diff -0.43 ppm).

[0539] Example 28 l-(4-Aminobenzyl)-3-(2-(2-(isoquinolin-4-yl)pyrazolidin-l-yl)-2-oxoethyl)urea tert-Butyl (2-(2-(isoquinolin-4-yl)pyrazolidin-l-yl)-2-oxoethyl)carbamate (213 mg, 0.60 mmol) was employed. The reaction yielded a yellow oil that was taken directly to the next step.

[0540] The TFA salt (222 mg, 0.60 mol) and (4-aminobenzyl)-l / - / -imidazole-l-carboxamide (143 mg, 0.66 mmol) were employed. The crude product was purified by flash column chromatography eluting with 80% EtOAc in hexane to 10% MeOH in EtOAc to yield a brown solid (36 mg, 0.089 mmol, 15%). M.p: 190 - 192 °C; IR vmax (cm-1) 1448 (C=N), 1518 (N-H), 1538 (N-H), 1622 (amide C=O), 3341 (N-H);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 9.05 (1H, s), 8.37 (1H, d, J = 8.5), 8.16 (1H, d, J = 8.0), 8.11 (1H, s), 7.93 (1H, ap: t, J = 7.9), 7.79 (1H, ap: t, J = 7.9), 7.04 (2H, d, J = 8.3), 6.71 (2H, d, J = 8.3), 4.48 (2H, br s), 4.14 (2H, s), 3.97 (2H, br s), 3.64 (2H, br s), 2.18 (2H, s);13C NMR (100 MHz; CD3OD; Me4Si) 6 159.6, 148.6, 145.1, 141.6, 141.4, 131.6, 131.0, 129.9, 129.6, 129.2, 128.5, 128.0, 127.9, 122.2, 115.7, 55.8, 44.7, 43.1, 41.5, 22.8; HRMS (ES+) m / z 427.1848 [M + Na]+C22H24N6O2Na requires 427.1858 (Diff -2.4 ppm); Anal. Calcd. for C22H24N6O2: C, 65.33; H, 5.98; N, 20.78. Found C, 62.23; H, 5.75; N, 19.51.

[0541] Example 29 l-(4-Aminobenzyl)-3-(2-oxo-2-(2-(quinolin-5-yl)pyrazolidin-l-yl)ethyl)urea tert-Butyl (2-oxo-2-(2-(quinolin-5-yl)pyrazolidin-lyl)ethyl)carbamate (338 mg, 0.95 mmol) was employed. The reaction yielded an orange oil that was taken directly to the next step.

[0542] The TFA salt of the amine (136 mg, 0.37 mmol) and N-(4-aminobenzyl)-lH-imidazole- 1-carboxamide (89 mg, 0.41 mmol) were employed. The crude product was purified by flash column chromatography eluting with 100% EtOAc to 10% MeOH in EtOAc to yield a yellow foam (172 mg, 0.43 mmol, Quantitative). M.p: 128 - 130 °C; IR vmax (cm-1) 1448 (C=N), 1517 (N-H), 1561 (N-H), 1663 (amide C=O), 1688 (amide C=O), 3350 (N-H);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 8.90 (1H, d, J = 4.0), 8.84 (1H, d, J = 8.5), 7.82 (1H, d, J = 8.5), 7.69 (1H, ap: t, J = 8.5), 7.65, 7.63 (1H, ABq, J = 8.5, 4.0), 7.23 (1H, d, J = 7.5), 7.01 (2H, d, J = 8.1), 6.67 (2H, d, J = 8.1), 4.12 (2H, s), 3.95 (3H, br s), 3.59 (3H, br s), 2.14 (2H, m);13C NMR (100 MHz; CD3OD; Me4Si) 6 172.8, 151.6, 149.9, 148.3, 147.7, 134.3, 130.8, 130.5, 129.4, 125.8, 123.6, 122.4, 122.2, 116.8, 115.6, 57.9, 46.1, 44.6, 43.0, 24.1; HRMS (ES+) m / z 427.1852 [M+Na]+C22H24N6O2Na requires 427.1858 (Diff -1.5 ppm).

[0543] Example 30 methyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-4-bromobenzoate

[0544] Methyl 4-bromo-3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-lyl)benzoate (106 mg, 0.24 mmol) was employed. The reaction yielded a yellow oil that was taken directly to the next step.

[0545] The TFA salt of the amine (115 mg, 0.25 mmol) and N-(4-aminobenzyl)-lH-imidazole- 1-carboxamide (61 mg, 0.28 mmol) were employed. The crude product was purified by flash column chromatography eluting with 100% EtOAc to 3% MeOH in EtOAc in hexane to yield a white solid (30 mg, 0.061 mmol, 25%). IR Vmax (cm-1) 761 (C-Br), 1273 (ester C-O), 1508 (N-H), 1564 (N-H), 1631 (amide C=O), 1724 (ester C=O), 3326 (N-H);XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.67 - 7.62 (2H, m), 7.54 (1H, d, J = 1.4), 7.08 (2H, d, J = 8.3), 6.62 (2H, d, J = 8.3), 5.38 (1H, t, J = 4.4), 5.09 (1H, t, J = 5.2), 4.23 (2H, d, J = 5.2), 3.90 (3H, s), 3.67 (4H, br s), 3.45 (2H, br s), 2.01 (2H, br s);13C NMR (100 MHz; CDCI3; Me4Si) 6 171.9, 166.0, 157.8, 148.6, 145.7, 134.5, 130.2, 129.1, 129.0, 126.9, 121.4, 119.9, 115.2, 55.8, 52.5, 45.4, 44.2, 42.4, 23.2; HRMS (ES+) m / z 512.0900 [M + Na]+C2iH2479BrN5O4Na requires 512.0909 (100%) (Diff -1.8 ppm), m / z 514.0895 [M+Na]+C2iH2481BrNsO4Na requires 514.0889 (99%) (Diff 1.2 ppm).

[0546] Example 31

[0547] 3-(2-(((4-Aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-4-bromobenzoic acid

[0548] Methyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-4-bromobenzoate (15 mg, 0.031 mmol, 1 eq) was dissolved in MeOH:water (0.16 ml, 1 : 1, 0.2 M). IM NaOH (62 pl, 0.062 mmol, 2 eq) was added and the reaction mixture was allowed to stir at r.t. overnight. After this time, the reaction mixture was concentrated in vacuo. The reaction yielded a pale yellow solid that required no further purification (15 mg, 0.032 mmol, Quantitative). M.p: 249 °C (decomposed); IR vmax (cm ) 763 (C-Br), 1231 (acid C-O), 1510 (N-H), 1565 (N-H), 1632 (amide C=O), 1694 (acid C=O), 2847 (O-H), 3304 (N-H);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.79 (1H, d, J = 8.1), 7.72 - 7.68 (2H, m), 7.47 (2H, d, J = 8.4), 7.35 (2H, d, J = 8.4), 4.35 (2H, s), 3.92 (3H, br s), 3.55 (3H, br s), 2.15 (2H, br s);13C NMR (100 MHz; CD3OD; Me4Si) 6 172.0, 171.6, 159.7, 148.9, 141.6, 134.2, 131.0, 129.1, 128.4, 126.8, 122.7, 120.7, 120.2, 55.6, 45.3, 42.5, 41.6, 22.6; LRMS (ES+) m / z 498 [M + Na]+C2oH2279BrN504Na requires 498 (100%), m / z 500 [M+Na]+C2oH2281BrNs04Na requires 500 (98%).

[0549] Example 32

[0550] 3-(2-(((4-Aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-4-bromo-N- methylbenzamide Methyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-4-bromobenzoate (12 mg, 0.025 mmol, 1 eq) was dissolved in methylamine (33% in ethanol) (1.38 ml, 4.17 mmol, 170 eq) and allowed to stir at r.t. overnight in a sealed tube. After this time, the reaction mixture was concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 100% EtOAc to 10% MeOH in EtOAc to yield a cream solid (9 mg, 0.019 mmol, 76%). M.p: 214 °C (decomposed); IR vmax (cm-1) 757 (C-Br), 1518 (N-H), 1565 (NH), 1619 (amide C=O), 1676 (amide C=O), 3360 (N-H);XH NMR (400 MHz; (CD3)2SO; Me4Si; ppm) 6 7.76 (1H, d, J = 8.2), 7.50 (1H, dd, J = 8.2, 1.7), 7.45 (1H, d, J = 1.7), 6.86 (2H, d, J = 8.3), 6.47 (2H, d, J = 8.3), 5.90 (1H, t, J = 4.9), 5.32 (1H, t, J = 4.7), 4.91 (2H, s), 3.95 (2H, d, J = 4.9), 3.80 (2H, br s), 3.43 - 3.39 (2H, m), 2.76 (3H, s), 1.99 (2H, br s);13C NMR (100 MHz; (CD3)2SO; Me4Si) 6 177.1, 175.7, 163.4, 148.0, 143.9, 136.2, 134.2, 129.2, 128.5, 126.5, 121.5, 114.1, 108.4, 54.1, 53.6, 45.0, 42.3, 28.9, 22.6; HRMS (ES+) m / z 511.1064 [M+Na]+C2iH2579BrN6O3Na requires 511.1069 (100%) (Diff -1.0 ppm), m / z 513.1043 [M+Na]+C2iH2581BrN6O3Na requires 513.1049 (98%) (Diff -1.1 ppm).

[0551] Example 33 benzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-4-bromobenzoate

[0552] Benzyl 4-bromo-3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate (150 mg, 0.29 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 1% MeOH in EtOAc) to yield the title compound as a pale yellow oil (113 mg, 70%). IR vmax / cm’13260 (br. m), 1728 (s), 1559 (s), 1510 (m), 1188 (s), 925 (m);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.52 (1H, br. s), 7.38 - 7.26 (7H, m), 7.11 (2H, d, J = 8.5), 6.69 (2H, d, J = 8.5), 5.40 (2H, s), 4.32 (1H, br. s), 4.21 (2H, s), 3.95 (1H, br. s), 3.77 (2H, br s), 3.47 (2H, br. s), 2.13 (1H, br. s), 1.98 (1H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 172.2, 169.0, 159.3, 147.9, 145.8, 136.9, 136.2, 131.3, 128.4, 128.1, 128.2, 124.4, 120.5, 119.8, 118.6, 113.0, 66.9, 54.8, 47.7, 44.8, 41.4, 23.2 (2 x ArH overlapping); HRMS (ES+) m / z 588.1223 [M+Na]+C27H28BrN5O4Na requires 588.1222 (100%) (Diff 0.17 ppm).

[0553] Example 34 benzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)benzoate

[0554] Benzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate (202 mg, 0.46 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 2% MeOH in EtOAc) to yield the title compound as a pale yellow oil (182 mg, 81%). IR vmax I cm'13193 (br. m), 1723 (s), 1564 (s), 1480 (m), 1367 (w), 1212 (s);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.59 (1H, br. s), 7.42 - 7.48 (1H, m) 7.19 - 7.28 (6H, m) 7.12 (2H, d, J = 8.5), 6.74 (1H, br. s), 6.67 (2H, d, J = 8.5), 5.42 (2H, s), 4.31 (1H, br. s), 4.15 (2H, s), 3.96 (1H, br. s), 3.76 (2H, br s), 3.45 (2H, br. s), 2.09 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 171.9, 168.5, 159.2, 147.5, 145.9, 137.1, 132.5, 131.5, 129.0, 128.8, 128.5, 128.0 124.4, 120.4, 118.5, 118.0, 106.8, 66.9, 55.2, 47.7, 43.0, 41.6, 23.2; HRMS (ES+) m / z 510.2121 [M+Na]+C27H29N5O4Na requires 510.2123 (100%) (Diff -0.36 ppm).

[0555] Example 35

[0556] 4-(trifluoromethyl)benzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l- yl)benzoate

[0557] 4-Trifluoromethylbenzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl) benzoate (250 mg, 0.49 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 2% MeOH in EtOAc) to yield the title compound as a pale yellow oil (189 mg, 69%). IR vmax / cm-13310 (br. m), 1724 (s), 1565 (s), 1424 (w), 1286 (s), 1006 (m);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.64 - 7.62 (2H, m), 7.48 - 7.47 (1H, m), 7.28 - 7.21 (4H, m), 7.07 (2H, d, J = 8.5), 6.93 (1H, br. s), 6.66 (2H, d, J = 8.5), 5.43 (2H, s), 4.29 (1H, br. s), 4.20 (2H, s), 3.96 (1H, br. s), 3.80 (1H, br. s), 3.74 (1H, br. s), 3.50 (2H, br. s), 2.10 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 171.7, 169.1, 158.6, 148.2, 146.7, 142.5, 133.2 (q, J = 25.0), 131.4, 130.7, 129.3 (q, J = 5.0), 127.9, 124.8 (q, J = 7.0), 124.7, 124.5 (q, J = 264), 118.7, 118.2, 117.6, 105.7, 66.9, 55.3, 47.9, 42.8, 41.6, 23.1;19F NMR (376 MHz CD3OD; Me4Si; ppm) 6 -63.2; HRMS (ES+) m / z 578.1999 [M + Na]+C28H28F3N5O4Na requires 578.1997 (100%) (Diff 0.38 ppm).

[0558] Example 36 methyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)benzoate

[0559] Methyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate (159 mg, 0.44 mmol) was employed. The reaction yielded an orange oil that was taken directly to the next step.

[0560] The TFA salt of the amine (171 mg, 0.45 mmol) and N-(4-aminobenzyl)-lH-imidazole- 1-carboxamide (108 mg, 0.50 mmol) were employed. The crude product was purified by flash column chromatography eluting with 100% EtOAc to 2% MeOH in EtOAc in hexane to yield a yellow oil (124 mg, 0.30 mmol, 67%). IR vmax (cm-1) 1260 (ester C- O), 1293 (ester C-O), 1516 (N-H), 1556 (N-H), 1627 (amide C=O), 1727 (ester C=O), 3350 (N-H);XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.67 (1H, d, J = 7.8), 7.55 (1H, ap: t, J = 1.7), 7.34 (1H, ap: t, J = 7.8), 7.09 - 7.07 (1H, m), 7.07 (2H, d, J = 8.2), 6.59 (2H, d, J = 8.2), 5.85 (1H, t, J = 4.4), 5.62 (1H, t, J = 5.2), 4.22 (2H, d, J = 4.4), 3.91 (3H, s), 3.74 - 3.72 (2H, m), 3.66 (2H, br s), 3.24 (1H, br s), 3.13 (1H, br s), 1.92 (1H, br s), 1.83 (1H, m);13C NMR (100 MHz; CDCI3; Me4Si) 6 172.5, 166.7, 158.1, 150.0, 145.7, 131.3, 129.5, 129.1, 129.0, 124.1, 120.6, 116.8, 115.1, 55.3, 52.3, 44.1, 42.9, 42.3, 24.0; HRMS (ES+) m / z 434.1797 [M + Na]+C2iH25N5O4Na requires 434.1804 (Diff -1.7 ppm).

[0561] Example 37

[0562] 3-(2-(((4-Aminobenzyl)carbamoyl)glycyl)pyrazolidin- 1-yl) benzoic acid Methyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)benzoate (124 mg, 0.30 mmol, 1 eq) was dissolved in MeOH:water (1.5 ml, 1 : 1, 0.2 M). IM NaOH (0.60 ml, 0.60 mmol, 2 eq) was added and the reaction mixture was allowed to stir at r.t. overnight. After this time, the reaction mixture was concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 100% EtOAc to 20% MeOH in EtOAc and 1% AcOH to yield a yellow solid (11 mg, 0.028 mmol, 9%). M.p: 281 °C (decomposed); IR Vmax

[0563] (cm’1) 1263 (acid C-O), 1517 (N-H), 1556 (N-H), 1625 (amide C=O), 1686 (acid C=O), 2928 (O-H), 3333 (N-H);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.65 (2H, s), 7.36 (1H, ap: t, J = 8.1), 7.17 (1H, d, J = 8.1), 7.03 (2H, d, J = 8.3), 6.68 (2H, d, J = 8.3), 4.28 (1H, br s), 4.15 (2H, s), 3.96 (1H, br s), 3.83 (1H, br s), 3.75 (1H, br s), 3.43 (2H, br s), 2.10 (2H, br s);13C NMR (100 MHz; CD3OD; Me4Si) 6 175.0, 170.0, 162.9, 159.8, 146.3, 140.1, 133.1, 128.8, 128.0, 119.1, 116.5, 115.3, 112.3, 54.7, 47.9, 42.8, 41.5, 23.4; HRMS (ES+) m / z 420.1649 [M + Na]+C2oH23N504Na requires 420.1648 (Diff 0.3 ppm).

[0564] Example 38

[0565] 4-chlorobenzyl 5-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-2- fluorobenzoate

[0566] 4-Chlorobenzyl 5-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)-2-fluoro benzoate (180 mg, 0.37 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 1% MeOH in EtOAc) to yield the title compound as a yellow oil (123 mg, 62%). IR vmax I cm-13340 (br. m), 1723 (s), 1569 (s), 1502 (w), 1365 (s), 1162 (m);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.37 (2H, d, J = 8.0), 7.24 - 7.21 (3H, m), 7.11 - 7.02 (4H, m), 6.62 (2H, d, J = 8.5), 5.42 (2H, s), 4.35 (1H, br. s), 4.20 (2H, s), 3.91 (1H, br. s), 3.77 (2H, br s), 3.48 (2H, br. s), 2.05 (1H, br. s), 1.89 (1H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 169.3, 165.0 (d, J = 4.0), 158.8, 157.9 (d, J = 254.0), 146.6 (d, J = 2.5), 146.3, 136.3, 134.7, 129.4, 128.6 128.1, 124.7, 122.4 (d, J = 8.5), 119.3 (d, J = 6.0), 119.0 (d, J = 9.0), 118.0 (d, J = 23.5), 115.2, 67.1, 55.6, 47.3, 43.2, 42.3, 23.6;19F NMR (376 MHz CD3OD; Me4Si; ppm) 6 -110.4; HRMS (ES+) m / z 562.1637 [M + Na]+C27H27CIFN5NaO4requires 562.1639 (100%) (Diff -0.23 ppm). Example 39

[0567] 4-chlorobenzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)benzoate

[0568] 4-Chlorobenzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate (250 mg, 0.53 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 1% MeOH in EtOAc) to yield the title compound as a colourless oil (207 mg, 75%). IR vmax I cm’13280 (br. s), 1724 (s), 1565 (s), 1502 (m), 1375 (s), 1205 (m), 1015 (s);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.48 - 7.45 (2H, m), 7.38 (2H, d, J = 7.5), 7.29 (1H, t, J = 8.0), 7.25 - 7.16 (3H, m), 7.11 (2H, d, J = 8.5), 6.98 (1H, br. s), 6.72 (2H, d, J = 8.5), 5.45 (2H, s) 4.31 (1H, br. s), 4.18 (2H, s), 4.01 (1H, br. s), 3.79 (2H, br s), 3.51 (2H, br. s), 2.10 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 171.8, 159.8, 159.1, 147.8, 146.3, 136.8, 135.2, 133.4, 130.7, 129.6, 129.3, 128.1, 123.9, 118.5, 118.6, 118.2, 105.5, 70.1, 55.2, 48.0, 42.8, 41.4, 23.1; HRMS (ES+) m / z 544.1730 [M + Na]+C27H28CIN5O4Na requires 544.1733 (100%) (Diff -0.55 ppm).

[0569] Example 40

[0570] 3-chlorobenzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)benzoate

[0571] 3-Chlorobenzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)benzoate (250 mg, 0.53 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 1% MeOH in EtOAc) to yield the title compound as a colourless oil (215 mg, 78%). IR vmax I cm'13300 (br. w), 1725 (s), 1562 (s), 1472 (m), 1401 (s), 1210 (s), 999 (m);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.51 - 7.48 (1H, m), 7.42 (1H, s), 7.29 - 7.32 (2H, m), 7.18 - 7.22 (3H, m), 7.08 (2H, d, J = 8.0), 6.91 (1H, br. s), 6.62 (2H, d, J = 8.0), 5.46 (2H, s), 4.30 (1H, br. s), 4.20 (2H, s), 3.95 (1H, br. s), 3.80 (1H, br s), 3.75 (1H, br. s), 3.47 (2H, br. s), 2.08 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 172.1, 169.2, 158.9, 148.1, 146.3, 139.5, 132.4, 132.0, 130.4, 128.9, 128.4, 128.1, 127.9, 125.9, 124.1, 118.6, 118.4, 117.5, 106.0, 67.4, 55.3, 48.0, 43.0, 41.5, 23.2; HRMS (ES+) m / z

[0572] 544.1729 [M + Na]+C27H28CIN5O4Na requires 544.1733 (100%) (Diff -0.73 ppm).

[0573] Example 41

[0574] 3,4-dichlorobenzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin- 1-yl) benzoate

[0575] 3,4-Dichlorobenzyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl) benzoate (250 mg, 0.49 mmol) was employed. The crude product was purified by flash column chromatography (SiC ; gradient elution, EtOAc to 1% MeOH in EtOAc) to yield the title compound as a yellow oil (219 mg, 80%). IR vmax I cm-13245 (br. m), 1723 (s), 1568 (s), 1372 (w), 1313 (w), 1106 (s);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.50 - 7.47 (1H, br. s), 7.36 (1H, d, J = 8.0), 7.28 - 7.22 (2H, m), 7.14 - 7.10 (3H, m), 6.65 (2H, d, J = 8.0), 5.50 (2H, s), 4.28 (1H, br. s), 4.20 (2H, s), 3.97 (1H, br. s), 3.82 (1H, br. s), 3.76 (1H, br. s), 3.46 (2H, br. s), 2.12 (2H, br. s);13C NMR (101 MHz CD3OD; Me4Si; ppm) 6 172.1, 169.1, 159.0, 146.9, 145.9, 138.6, 133.0, 132.8, 131.7, 130.8, 130.5, 128.9, 128.1, 127.8, 124.4, 118.6, 118.3, 117.8, 106.3, 67.2, 55.3, 47.7, 42.8, 41.6, 23.5; HRMS (ES+) m / z 578.1343 [M + Na]+C27H27Cl2N5O4Na requires 578.1343 (100%) (Diff 0.02 ppm).

[0576] Example 42 benzyl 5-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-2-fluorobenzoate

[0577] Benzyl 5-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin-l-yl)-2-fluorobenzoate (101 mg, 0.22 mmol) was employed. The reaction yielded a yellow oil that was taken directly to the next step.

[0578] The TFA salt of the amine (104 mg, 0.22 mmol) and N-(4aminobenzyl)-lH-imidazole- 1-carboxamide (52 mg, 0.24 mmol) were employed. The crude product was purified by flash column chromatography eluting with 100% EtOAc to 2% MeOH in EtOAc to yield a yellow oil (87 mg, 0.17 mmol, 78%). IR vmax (cm-1) 1071 (C-F), 1244 (ester C-0), 1517 (N-H), 1553 (N-H), 1626 (amide C=0), 1723 (ester C=0), 3350 (NH);XH NMR (400 MHz; CDCI3; Me4Si; ppm) 6 7.47 - 7.40 (3H, m), 7.38 - 7.31 (2H, m), 7.09 - 7.00 (5H, m), 6.58 (2H, d, J = 8.3), 5.78 (1H, t, J = 4.4), 5.54 (1H, t, J = 5.1), 5.38 (2H, s), 4.41 (1H, br s), 4.21 (2H, s), 3.73 (1H, br s), 3.64 (1H, br s), 3.55 (2H, br s), 3.18 (1H, br s), 1.92 (1H, br s), 1.85 (1H, br s);13C NMR (100 MHz; CDCI3; Me4Si) 6 172.6, 164.1 (d, J = 4.0), 158.2, 157.9 (d, J = 256.2), 145.9 (d, J = 2.8), 145.7, 135.6, 129.1, 129.0, 128.6, 128.3, 128.1, 122.2 (d, J = 8.6), 119.2 (d, J = 5.8), 119.0 (d, J = 8.7), 118.0 (d, J = 24.1), 115.1, 67.2, 55.8, 44.1, 43.1, 42.4, 23.8; HRMS (ES+) m / z 528.2014 [M + Na]+C27H2sFN5O4Na requires 528.2023 (Diff -1.7 ppm).

[0579] Example 43

[0580] 5-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-2-fluorobenzoic acid

[0581] To a solution of benzyl 5-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-2- fluorobenzoate (44 mg, 0.087 mmol) in ethanol was added 10% Pd / C (5 mg). The reaction mixture was allowed to stir at r.t. under H2 environment overnight (followed by TLC). Upon completion, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 100% EtOAc to 20% MeOH in EtOAc and 1% AcOH to yield a yellow solid (4.7 mg, 0.011 mmol, 13%). M.p: 151 - 154 °C; IR vmax (cm-1) 1020 (C-F), 1226 (acid C-O), 1518 (N-H), 1557 (N-H), 1614 (amide C=O), 1697 (acid C=O), 2965 (O-H), 3316 (N-H);XH NMR (400 MHz; CD3OD; Me4Si; ppm) 6 7.50 (1H, br s), 7.23 (2H, br s), 7.09 (2H, d, J = 8.3), 6.66 (2H, d, J = 8.3), 4.30 (1H, br s), 4.18 (2H, s), 3.96 (1H, br s), 3.75 (2H, br s), 3.47 (2H, br s), 2.12 (1H, br s), 1.95 (1H, br s);13C NMR (100 MHz; CD3OD; Me4Si) 6 172.6, 169.0, 167.9 (d, J = 235.1), 167.5 (d, J = 3.9), 160.4 (d, J = 22.3), 148.9, 142.3, 136.7, 128.0, 124.2, 121.5, 118.6, 113.4, 55.1, 43.2, 42.9, 41.5, 23.3; HRMS (ES+) m / z 438.1556 [M + Na]+C2oH22FNs04Na requires 438.1554 (Diff -0.5 ppm).

[0582] Example 44

[0583] 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-N-isobutylbenzamide (44)

[0584] To a solution of 3-(2-(((4-Aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)benzoic acid (40.8 mg, 0.10 mmol, 1 eq) in DMF (5ml) was added / sobutylamine (9mg, 0.12 mmol, 1.2 eq), HATU (50.6mg, 0.13 mmol, 1.3 eq) and DIPEA (33.1mg, 0.26 mmol, 2.5 eq)). The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as a yellow solid (21 mg, 45%).XH NMR (500 MHz; MeOD; ppm) 6 7.49 (br s, 1H), 7.47 (s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.22 (dd, J = 7.5, 2.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 7.8 Hz, 1H), 4.19 (s, 1H), 3.93 - 3.79 (m, 2H), 3.50 - 3.37 (m, 2H), 3.34 - 3.32 (m, 4H), 2.15 - 2.13 (m, 1H), 1.94 (tt, J = 13.5, 7.0 Hz, 2H), 0.96 (d, J = 7.0 Hz, 6H).13C NMR (101 MHz; CDCI3) 6 172.6, 150.4, 145.4, 135.8, 129.3, 128.4, 128.0, 127.9, 121.2, 118.8, 115.6, 115.6, 114.4, 54.5, 48.2, 46.5, 42.8, 42.4, 28.4, 23.6, 19.2. IR Vmax (cm-1) 3300 (br, NH), 2919 (CH), 1673 and 1633 (CO), and 1132 (C-N). HRMS (ES+) 475.2417 [M + Na]+Cz^NeOsNa requires 475.5488. M.p. 63.5 °C.

[0585] Example 45

[0586] 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-N-isopentylbenzamide

[0587] The title compound was obtained following a similar procedure as described for example 35 starting from 3-(2-(((4-Aminobenzyl)carbamoyl)glycyl)pyrazolidin-l- yl)benzoic acid (81.6 mg, 0.21 mmol, 1 eq) and / sopentylamine (21.4 mg, 0.25 mmol, 1.2 eq). The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as a yellow solid (lOmg, 10 %).XH NMR (500 MHz; CDCI3; ppm) 6 7.89- 6.87 (m, 8H), 6.64 (d, J = 8.0 Hz, 1H), 6.56 (s, 1H), 6.35 (s, 1H), 5.20 (s, 2H), 4.04- 3.97 (m, 2H), 3.85-3.73 (m, 2H), 3.73-3.60 (m, 2H), 3.53-3.32 (m, 4H), 2.37-2.29 (m, 3H), 1.85-1.75 (m, 2H), 0.91 (d, J = 7.5 Hz, 6H).13C NMR (126 MHz; CDCI3) 6 182.5, 171.5, 167.8, 162.6, 140.6, 138.3, 135.6, 135.4, 129.9, 128.6, 121.8, 119.1,

[0588] 117.6, 111.4, 65.5, 62.1, 57.6, 31.9, 31.4, 29.7, 28.2, 22.7, 22.5. HRMS (ES+) 489.2582 [M + Na]+CzsK^NeChNa requires 489.5757. Example 46 pyridin-2-ylmethyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin- 1-yl) benzoate

[0589] Pyridin-2-ylmethyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate (0.015 g, 0.30 mmol) was employed. The crude product was purified by FCC (SiO2; EtOAc to 20:80 MeOH:EtOAc) to afford the titled compound as a yellow solid (0.010 g, 61%).XH NMR (400 MHz; CDCI3; ppm) 6 8.68-8.58 (m, 1H), 8.26-8.18 (m, 1H), 7.8- 7.6 (m, 3H), 7.45-7.40 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.28-7.24 (m, 2H), 7.16 (unresolved dd, 1H), 5.48 (s, 2H), 4.15-4.0 (m, 2H), 3.75-3.61 (br s, 2H), 3.49-3.20 (br s, 2H), 2.04-1.95 (br s, 2H).13C NMR (101 MHz; CDCI3) 6 177.6, 175.8, 166.0, 155.8, 150.6, 149.5, 149.3, 137.3, 136.8, 131.2, 129.5 (2C), 128.9, 124.0, 123.0, 121.8, 120.4, 117.2 (2C), 67.4, 55.2, 43.4, 43.0, 39.1, 30.9. HRMS (ES+) 511.2051 [M+Na]+C26H28N6O4Na requires 511.2064 (Diff 2.62 ppm).

[0590] Example 47 pyridin-3-ylmethyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin- 1-yl) benzoate

[0591] Pyridin-3-ylmethyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate (103.2mg, 0.23 mmol) was employed. The crude product was purified by FCC (SiCh; EtOAc) to afford the titled compound as a yellow solid (42.9 mg, 38.7 %)XH NMR (400 MHz; CDCI3; ppm) 6 8.71 (s, 1H), 8.60 (d, J = 4.0 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.39-7.31 (m, 2H), 7.10 (dd, J = 8.0, 2.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H), 6.60 (d, J = 8.0 Hz, 2H), 5.68 (s, 2H), 5.44-5.34 (m, 3H), 4.47-4.40 (m, 1H), 4.22 (s, 2H), 3.82-3.63 (m, 4H), 3.30-3.17 (m, 2H), 2.01- 1.83 (m, 2H).13C APT NMR (101 MHz; CDCI3) 6 172.51, 165.93, 158.00, 150.21, 149.68, 149.65, 145.65, 136.20, 131.62, 130.94, 129.61, 129.09, 129.00, 124.20, 123.62, 120.74, 117.12, 115.11, 64.34, 55.33, 44.18, 42.98, 42.34, 24.03. IR vmax (cm’1) 3300 (br, NH), 2924 (CH), 1715 and 1628 (CO), and 1246 (C-O). HRMS (ES+) 511.2056 [M+Na]+C23H28N4O5Na requires 511.5378. M.p 60.8 (°C). Example 48 pyridin-4-ylmethyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin- 1-yl) benzoate

[0592] Pyridin-4-ylmethyl 3-(2-((tert-butoxycarbonyl)glycyl)pyrazolidin- 1-yl) benzoate (81.9mg, 0.19 mmol) was employed. The crude product was purified by FCC (SiCh; EtOAc to 10:90 MeOH:EtOAc) to afford the titled compound as a dark yellow solid (22.1mg, 24.3 %).XH NMR (400 MHz; CDCI3; ppm) 6 8.56 (d, J = 5.0 Hz, 2H), 7.66 (d, J = 7.5 Hz, 1H), 7.55 (s, 1H), 7.30 (dd, J = 8.0, 8.0 Hz, 1H), 7.26 (d, J = 5.5 Hz, 2H), 7.06 (dd, J = 8.0, 1.5 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 8.5 Hz, 2H), 5.51 (s, 2H), 5.31 (d, J = 3.5 Hz, 2H), 5.25-4.31 (m, 2H), 4.15 (s, 2H), 3.73 (s, br, 2H), 3.62 (br s, 2H), 3.31-3.09 (m, 2H), 1.95-1.76 (m, 2H).13C NMR (101 MHz; CDCI3) 6 172.5, 165.8, 157.9, 150.3, 150.1, 145.7, 144.9, 130.8, 129.7, 129.0, 124.2, 121.9, 120.8, 117.2, 115.1, 64.8, 55.3, 44.2, 43.0, 42.4, 24.1. IR vmax (cnT1) 3350 (br, NH), 2925 (CH), 1717 and 1634 (CO), and 1247 (C-O). HRMS (ES+) 511.2056 [M+Na]+C23H28N4O5Na requires 511.5378. M.p. 106.1 (°C).

[0593] Reference Example 49

[0594] (R)-l-(4-aminobenzyl)-3-(2-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)-2- oxoethyl)urea

[0595] To a solution of tert-butyl (R)-(2-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)-2- oxoethyl)carbamate (0.12, 0.35 mmol) in dichloromethane (3 mL) was add trifluoroacetic acid (0.5 mL). The reaction mixture was allowed to stir at room temperature until disappearance of starting material (2 h, followed by TLC). Upon completion, the solvent was removed in vacuo to give the free amine as TFA salt which was used directly without further purification.

[0596] The TFA salt of the free amine (0.13 g, 0.35 mmol) was redissolved in anhydrous acetonitrile (10 mL), N-(4-aminobenzyl)-lH-imizole-l-carboxamide (82.50 mg, 0.38 mmol, 1.10 eq) , triethylamine (0.11 mL, 0.77 mmol, 2.2 eq) and DMAP (4 mg, 0.04 mmol, 0.1 eq) were added. The reaction mixture was allowed to stir at room temperature overnight (followed by TLC). Upon completion, the reaction was diluted with dichloromethane, washed with water, followed by brine, dried over MgS04, filtered and concentrated in vacuo. The crude product was purified by FCC (SiO2; EtOAc) to yield a white foam (59.4 mg, 42%) with the yield consisting of a mixture of rotamers in ratio 1.03 / 1.XH NMR (400MHz; CDCI3; Me4Si; ppm) 6 7.25 (major, m, 1H), 7.15 (minor, m, 1H), 6.98- 6.88 (major & minor, m, 4H), 6.53-6.45 (major & minor, m, 4H), 5.99 (major, s, NH), 5.87 (minor, s, NH), 5.69 (major, s, NH), 5.57 (minor, s, NH), 5.21 (minor, board d, J = 8.0 Hz, 1H), 5.09 (major, board d, J = 8.0 Hz, 1H), 4.15-3.95 (major & minor, m, 8H), 3.35-3.10 (major & minor, m, 4H), 2.30-2.13 (major &. minor, m, 2H), 1.93-1.50 (major &. minor, m, 6H);13C NMR (100 MHz; CDCI3; Me4Si) 6 169.6, 168.9, 162.8, 160.3, 160.2, 158.3, 158.1, 145.6, 145.5, 142.0, 141.9, 141.4, 141.3, 131.7, 131.6, 131.2, 131.1, 129.5, 129.3, 128.7, 126.7, 116.1, 115.8, 115.2, 115.1, 115.0, 113.4, 113.3, 113.2, 113.0, 58.9, 58.4, 47.3, 46.9, 43.8. 43.1, 41.9, 33.8, 31.9; HRMS (ES+) 427.1301 [M + Na]+C2oH22N40235CIFNa requires 427.1313 (Diff -2.8 ppm). Anal. Cal. (mass %) for C2oH22N402CIF: C, 59.33; H, 5.48; N, 13.84. Found: C, 56.09; H, 5.28; N, 12.38. m.p. 76-82°C.

[0597] Reference Example 50

[0598] (R)-l-(4-aminobenzyl)-3-(2-(2-(2,5-dichlorophenyl)pyrrolidin-l-yl)-2-oxoethyl)urea tert-Butyl (R)-(2-(2-(2,5-dichlorophenyl)pyrrolidin-l-yl)-2- oxoethyl)carbamate (0.13 g, 0.33 mmol, 1 eq) was employed. The crude product was purified by FCC (SiO2; EtOAc) to yield a pale brown foam (70 mg, 50%) with the yield consisting of a mixture of rotamers in ratio 1.04 / 1.XH NMR (400MHz; CDCI3; Me4Si; ppm) 6 7.30 (m, 1H), 7.19 (major, dd, J = 6.0 Hz, 1H), 7.08 (minor, dd, J = 6.0 Hz, 1H), 7.04 (m, 2H), 6.90 (m, 1H), 6.58 (m, 2H), 6.03 (major, s, NH), 5.88 (minor, s, NH), 5.70 (major, s, NH), 5.53 (minor, s, NH), 5.29 (major, d, J = 6.8 Hz, 1H), 5.17 (minor, d, J = 6.8 Hz, 1H), 4.3-4.05 (major & minor, m, 8H), 3.8-3.5 (major & minor, m, 4H), 2.4-2.2 (major, m, 2H), 2.0-1.6 (major & minor, m, 6H).13C NMR (100MHz; CDCI3; Me4Si) 6 169.6, 168.6, 158.2, 158.1, 145.6, 145.5, 141.5, 140.9, 133.3, 132.8, 131.4, 131.1, 130.2, 130.1, 129.4, 129.2, 129.0, 128.8, 128.3, 126.0, 125.9, 115.1, 115.0, 60.4, 58.8, 58.3, 47.7, 47.0, 44.0, 43.8, 43.1, 42.7, 33.9, 32.0, 23.4, 21.1. HRMS (ES+) 421.1185 [M+H]+C2oH23N40235Cl2 requires 421.1198 (Diff -1.3 ppm). Anal. Cal. (mass %) for C2oH22Cl2N402: C, 57.02; H, 5.26; N, 13.30. Found: C, 56.45; H, 5.41; N, 12.48. m.p. 80-84°C. Reference Example 51

[0599] ( / ?)-l-(4-aminobenzyl)-3-(2-(2-(2-chloro-5-methoxyphenyl)pyrrolidin-l-yl)-2- oxoethyl)urea tert-Butyl ( / ?)-(2-(2-(2-chloro-5-methoxyphenyl)pyrrolidin-l-yl)- 2-oxoethyl)carb- amate (0.18 g, 0.50 mmol) was employed. The crude product was purified by FCC (SiC ; EtOAc) to yield a brown foam (50.5 mg, 25%) with the yield consisting of a mixture of rotamers in ratio 1.1 / 1.

[0600] XH NMR (400MHz; CDCI3; Me4Si; ppm) 6 7.30-7.21 (major &. minor, m, 2H), 7.05 (m, 2H), 6.74 (major, dd, J = 8.8 Hz, 1H), 6.67 (minor, dd, J = 8.8 Hz, 1H), 6.61 (major & minor, m, 2H), 6.49 (m, 2H), 5.68 (major, s, NH), 5.64 (minor, s, NH), 5.36 (major, m, 1H), 5.24 (major, s, NH), 5.18 (minor, m, 1H), 5.08 (minor, s, NH), 4.25-4.05 (major & minor, m, 8H), 3.76 (major, m, 1H), 3.72 (minor, m, 1H), 3.63-3.35 (major & minor, m, 4H), 2.45-2.23 (minor, m, 4H), 2.02-1.70 (major & minor, m, 6H).13C NMR (100 MHz; CDCI3; Me4Si) 6 169.2, 158.7, 158.3, 145.5, 140.1, 131.0, 130.6, 128.8, 123.1, 115.1, 113.1, 112.8, 58.5, 55.5, 47.4, 44.0, 43.1, 34.0, 23.4. HRMS (ES+) 439.1499 [M+Na]+C2iH25N4O335CINa requires 439.1513 (Diff -3.2 ppm). Anal. Cal. (mass %) for C2iH25N4O3CI: C, 60.50; H, 6.04; N, 13.44. Found: C, 59.73; H, 6.14; N, 13.70. m.p.76-80°C.

[0601] Example 52 l-((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3-(((2S,3S,6S)-

[0602] 3-hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c] [l,5]oxazocin-8- yl)methyl)urea l-((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3-(((2S, 3S, 6S)- 3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea (0.04 g, 0.05 mmol, 1.00 eq) was employed. The crude product was purified by FCC (SiCh; 95:5 EtOAc:MeOH) to afford the titled compound as a yellow solid (0.02 g, 52%).XH NMR (500 MHz; CDCI3; ppm) 6 7.60-7.53 (m, 1H), 7.42-7.38 (m, 1H), 7.35-7.23 (m, 2H), 7.13-7.04 (m, 2H), 7.03- 6.94 (m, 2H), 6.93-6.83 (m, 2H), 6.75-6.62 (m, 1H), 6.58-6.56 (m, 1H), 6.21 (s, NH), 6.21 (s, NH), 5.43 (s, 1H), 4.58 (br s, 1H), 4.25 (s, 2H), 3.84-3.76 (m, 1H), 3.55-3.48 (m, 1H), 3.45-3.36 (m, 2H), 3.34-3.25 (m, 2H), 2.96 (m, 1H), 2.15-2.09 (m, 1H), 2.00-1.86 (m, 2H), 1.83-1.73 (m, 1H).13C NMR (126 MHz; CDCI3) 6 157.3, 147.5, 145.0, 137.2, 134.5, 133.4, 129.9 (2C), 129.4, 128.1, 127.8 (2C), 127.7, 127.3, 127.2, 125.0, 119.5, 119.0, 115.3, 113.7, 69.1, 67.4, 62.6, 56.0, 55.8, 48.7, 45.5, 43.9, 30.9, 27.9. HRMS (ES+) 606.1700 [M + H]+C3oH33N50479Br requires 606.1710 (Diff 1.69 ppm). IR Vmax (cm-1) 3339 (N-H), 1620 (urea C=O), 1509 (N-H), 610 (C-Br). M.p. 135-139 °C.

[0603] Example 53 l-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2 / ?,3S,6 / ?)-3- hydroxy-l,3,4,6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea

[0604] To a solution of l-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro- 2H-2,6-methanobenzo [c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-5- fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea (500 mg, 0.81 mmol) in anhydrous THF (8 mL) was add tetra-n-butylammonium fluoride in IM THF (1.62 mL, 1.62 mmol, 2 eq) was added dropwise. The reaction mixture was allowed to stir at room temperature overnight (followed by TLC). Upon completion, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with distilled water (10 mL), followed by brine (10 mL), dried over MgSC and concentrated in vacuo. The crude product was purified by FCC (SiCh; 95:5 EtOAc:MeOH) to give the title compound as a yellow solid (346 mg, 85%).XH NMR (400 MHz; CDCI3) 6 7.32 (dd, J =8.7, 5.7 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.76-6.69 (m, 2H), 6.46 (d, J =8.1 Hz, 1H), 5.55 (s, 1H), 5.41 (br s, 1H), 4.60 (s, 1H), 4.54-4.28 (m, 1H), 4.19 (s, 2H), 3.88-3.34 (m, 10H), 2.52 (d, J = 12.4 Hz, 1H), 2.04 (br s, 3H), 1.43 (d, J = 12.3 Hz, 1H).13C NMR (101 MHz; CDCI3) 6 172.3, 161.8 (d, J = 247.6 Hz), 158.3, 148.7, 144.1, 132.1, 130.1, 129.6, 127.6, 120.5, 118.3, 113.3, 112.4 (d, J = 23.2 Hz), 106.6 (d, J = 26.3 Hz), 70.0, 68.9, 63.7, 55.5, 47.8, 45.1, 44.1, 42.4, 23.9, 23.5. HRMS (ES+) C24H27CIFN5O4Na [M+Na]+requires 526.1628, found 526.1623. Anal. Cal. (mass %) for C24H27CIFN5O4: C, 57.20; H, 5.40; N, 13.90. Found: C, 55.86; H, 5.66; N, 12.53. Mp: 145-146°C. Example 54 l-((S)-2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3- (((2 / ?,3S,6 / ?)-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin- 8-yl)methyl)urea l-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo [c][l,5]oxazocin-8-yl)methyl)-3-((S)-2-(2-(2-chloro-5- fluorophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)urea (500 mg, 0.72 mmol) was employed. The crude product was purified by FCC (SiCh; 98:2 EtOAc: MeOH) to give the title compound as a yellow solid (312 mg, 75%).XH NMR (400 MHz; CDCI3) 6 7.45 (br s, 1H), 7.31 (br s, 1H), 7.09-6.75 (m, 6H), 6.44 (d, J = 8.1 Hz, 1H), 6.17-5.86 (m, 2H), 5.23 (br s, 1H), 4.57 (s, 1H), 4.45 (s, 1H), 4.28-3.79 (m, 3H), 3.58-3.32 (m, 7H), 2.98 (br s, 1H), 2.52 (d, J = 13.2 Hz, 1H), 2.02 (br s, 1H), 1.81-1.76 (m, 3H), 1.43 (d, J = 12.5 Hz, 1H).13C NMR (101 MHz; CDCI3) 6 174.1, 159.9, 157.3, 144.1, 137.4, 131.3, 131.2, 130.2, 129.8, 128.4, 128.4, 127.9, 127.6, 127.5, 119.9. 118.2, 113.3, 111.5, 111.3, 106.6, 70.0, 68.9, 63.7, 58.3, 56.1, 47.8, 45.1, 44.0, 23.8, 23.3. HRMS (ES+) C3oH3iCIFN504Na [M+Na]+requires 602.1941, found 602.1941. Anal. Cal. (mass %) for C30H31CIFN5O4: C, 62.12; H, 5.39; N, 12.07. Found : C, 62.91; H, 6.26; N, 9.71. Mp: 138-139°C.

[0605] Example 55 l-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2 / ?,3S,6 / ?)-3-hydroxy- l,3,4,6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea l-(2-(2-(2-Bromophenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2 / ?,3S,6 / ?)-3-((tert- butyldimethylsilyl)oxy)- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c][ l,5]oxazocin-8- yl)methyl)urea (0.03 g, 0.05 mmol) was employed. The crude product was purified by FCC (SiC ; 95: 5 EtOAc: MeOH) to afford the titled compound as a yellow solid (0.02 g, 79%).XH NMR (400 MHz; CDCI3; ppm) 6 7.62-7.55 (m, 1H), 7.20 (br s, 1H), 7.11- 7.03 (m, 3H), 7.0-6.93 (m, 1H), 6.60-6.56 (m, 1H), 4.65 (s, 1H), 4.57 (s, 1H), 4.37- 4.30 (m, 2H), 4.23 (m, 1H), 3.82-3.70 (unresolved m, 2H), 3.52-3.44 (m, 5H), 3.40- 3.36 (m, 1H), 2.70-2.62 (m, 1H), 2.02 (br s, 2H), 1.49-1.42 (m, 1H), 1.32-1.25 (m, 1H).13C NMR (101 MHz; CDCI3) 6 171.5, 166.8, 148.3, 144.5, 134.3, 129.8, 128.9,

[0606] 128.1, 126.0, 124.8, 119.2, 118.3, 115.8, 113.5, 82.8, 69.9, 68.8, 63.8, 55.9, 47.8,

[0607] 47.1, 45.5, 44.1, 42.4, 30.9. HRMS (ES+) 606.1707 [M + H]+C3oH33N50479Br requires 606.1710 (Diff 1.69 ppm). IR vmax(cmr1) 3322 (Broad O-H), 1632 (urea C=O), 578 (C- Br). Mp. 119-121 °C.

[0608] Example 56 l-((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3-(((2 / ?,3S,6 / ?)- 3-hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c] [l,5]oxazocin-8- yl)methyl)urea l-((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3-(((2 / ?, 3S, 6 / ?)- 3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea (0.02 g, 0.03 mmol) was employed. The crude product was purified by FCC (SiC ; 95:5 EtOAc:MeOH) to afford the titled compound as a yellow solid (0.015 g, 79%).XH NMR (500 MHz; CDCI3; ppm) 6 7.60- 7.50 (m, 1H), 7.41-7.36 (m, 1H), 7.13-6.99 (m, 4H), 6.90-6.84 (m, 2H), 6.73-6.64 (m, 1H), 6.45-6.40 (m, 1H), 6.20-6.12 (m, 2H), 5.31 (s, 1H), 4.64-4.60 (m, 1H), 4.40- 4.34 (m, 1H), 4.30-4.15 (m, 2H), 3.55-3.48 (m, 6H), 3.35-3.30 (m, 1H), 2.66-2.60 (m, 1H), 1.85-1.75 (m, 2H), 1.43-1.36 (m, 1H), 1.29-1.26 (m, 1H).13C NMR (126 MHz; CDCI3) 6 157.2, 144.0, 137.3, 133.4, 130.1, 129.7 (2C), 128.4, 128.3, 128.1, 127.8 (2C), 127.4, 127.3, 125.0, 119.2, 119.1, 118.1, 115.2, 113.1, 69.9, 68.8, 63.5, 56.0, 55.8, 47.7, 45.5, 43.9, 29.7. HRMS (ES+) 606.1707 [M + H]+C3oH33N50479Br requires 606.1710 (Diff 1.69 ppm). IR vmax (cm'1) 3332 (N-H), 1618 (urea C=O), 1508 (N-H), 610 (C-Br). [O]20D = 2.5 (c 1.0, CH3OH). M.p. 132-136 °C.

[0609] Example 57 l-(((2 / ?,3S,6 / ?)-10-chloro-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-5- fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea l-(((2R,3S,6R)-10-Chloro-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-5- fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea (400 mg, 0.61 mmol). The crude product was purified by FCC (SiC ; 96:4 EtOAc: MeOH) to give the title compound as a white solid (256 mg, 78%).XH NMR (400 MHz; CDCI3) 6 7.33 (dd, J = 8.7, 5.6 Hz, 1H), 7.21 (d, J = 1.9 Hz, 1H), 6.99 (d, J = 1.7 Hz, 1H), 6.76 (ddd, J =8.7, 7.6, 2.9 Hz, 1H), 6.71 (dd, J = 9.8, 2.8 Hz, 1H), 6.74-6.69 (m, 1H), 5.30 (s, 1H), 5.01 (br s, 1H), 4.71 (s, 1H), 4.46 (, 1H), 4.2 (s, 2H), 3.77-3.38 (m, 10H), 2.63-2.51 (m, 1H), 2.06 (br s, 1H), 1.76 (br s, 2H), 1.49 (d, J = 13.1 Hz, 1H).13C NMR (101 MHz; CDCI3) 6 172.1, 161.8 (d, J =247.7 Hz), 157.9, 148.7, 140.0, 132.3 (d, J =9.0 Hz), 129.1, 128.5, 128.2, 120.5, 119.9, 117.3, 112.4 (d, J =22.5 Hz), 106.5 (d, J =26.4 Hz), 69.7, 68.8, 63.8, 55.5, 47.8, 45.2, 43.7, 42.5, 23.6, 23.6. HRMS (ES+) Cz^eChFNsC Na [M + Na]+requires 560.1238, found 560.1242. Anal. Cal. (mass %) for C24H26CI2FN5O4: C, 53.54; H, 4.87; N, 13.01. Found : C, 52.03; H, 4.93; N, 12.22. Mp: 134-136°C.

[0610] Example 58 l-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2 / ?,3S,6 / ?)-10- fluoro-3-hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c][ l,5]oxazocin-8- yl)methyl)urea l-(((2 / ?,3S,6 / ?)-3-((tert-Butyldimethylsilyl)oxy)-10-fluoro-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-5-fluorophenyl) pyrazolidin-l-yl)-2-oxoethyl) urea (400 mg, 0.61 mmol). The crude product was purified by FCC (SiCh; 95: 5 EtOAc: MeOH) to give the title compound as a yellow solid (256 mg, 78%).XH NMR (400 MHz; CDCI3) 6 7.33 (dd, J = 8.7, 5.6 Hz, 1H), 6.94 (d, J = 11.8 Hz, 1H), 6.84 (s, 1H), 6.76 (t, J = 8.1Hz, 1H), 6.73-6.68 (m, 1H), 5.35 (s, 1H), 5.13 (br s, 1H), 4.70 (s, 1H), 4.50 (s, 1H), 4.22 (t, J = 5.0 Hz, 2H), , 3.72-3.34 (m, 10H) , 2.59 (d, J = 13.3 Hz, 1H), 2.06 (br s, 2H), 1.68 (br s, 1H), 1.43 (d, J = 13.3 Hz, 1H).13C NMR (101 MHz; CDCI3) 6172.2, 160.6, 168.0, 149.9 (d, J =223.1 Hz), 132.5, 132.3, 132.3, 127.6, 124.7, 120.6, 114.7, 114.5, 112.4 (d, J =22.9 Hz), 106.5 (d, J =26.5 Hz), 69.8, 68.2, 63.8, 55.5, 47.2, 45.1, 43.8, 42.4, 23.7, 23.8. HRMS (ES+) C24H26CIF2N5O4Na [M + Na]+requires 544.1534, found 544.1523. Mp: 122-124°C.

[0611] Example 59 l-(2-(2-(2-chloro-5-methoxyphenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2 / ?,3S,6 / ?)-3- hydroxy-l,3,4,6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea l-(((2R,3S,6R)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-5- methoxyphenyl)pyrazolidin-l-yl)-2-oxoethyl)urea (0.5 g, 0.80 mmol). The crude product was purified by FCC (SiC ; 96:4 DCM : MeOH) to give the title compound as a yellow solid (0.3 g, 75%).XH NMR (400 MHz; MeOD) 6 7.33 (d, J = 8.8 Hz, 1H), 7.03 (dd, J = 8.3, 2.1 Hz, 1H), 6.98 (d, J = 1.9 Hz, 1H), 6.69 (dd, J = 8.8, 2.8 Hz, 1H), 6.59 (d, J = 2.8 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 4.63 (s, 1H), 4.14 (d, J = 4.3 Hz, 2H), 3.84 (br s, 2H), 3.76 (s, 3H), 3.57-3.35 (m, 8H), 2.67-2.53 (m, 1H), 2.08 (br s, 2H), 1.43 (d, J = 14.6 Hz, 1H).13C NMR (100 MHz; DMSO-de) 6 172.0, 159.7, 158.7, 149.2, 145.5, 132.2, 130.2, 129.4, 127.5, 118.7, 116.6, 113.1, 111.1, 106.5, 69.8, 68.8, 64.0, 56.4, 56.0, 48.0, 45.6, 43.5, 42.4, 24.2, 24.0. HRMS (ES+) C25H3oCIN505Na [M+Na]+requires 538.1828, found 538.1827. Anal. Cal. (mass %) for C25H30CIN5O5: C, 58.19; H, 5.86; N, 13.57. Found : C, 57.58; H, 6.00; N,12.88. MP: 153-154°C.

[0612] Example 60 l-((S)-2-(2-(2-chloro-5-methoxyphenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3-

[0613] (((2R,3S,6R)-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-

[0614] 8-yl)methyl)urea l-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-((S)-2-(2-(2-chloro-5- methoxyphenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)urea (230 mg, 0.32 mmol) was employed. The crude product was purified by FCC (SiCh; 95:5 DCM:MeOH) to give the title compound as a yellow solid (150 mg, 79%).XH NMR (400 MHz; CDCI3) 6 7.47 (s, 1H), 7.29 (s, 1H), 7.08-7.00 (m, 4H), 6.98-6.89 (m, 2H), 6.56 (br s, 1H), 6.45 (d, J = 8.1 Hz, 1H), 6.30 (d, J = 8.1 Hz, 1H), 6.08 (s, 1H), 5.97 (s, 1H), 5.66-5.58 (m, 1H), 5.06-4.98 (m, 1H), 4.60 (s, 1H), 4.23-4.11 (m, 2H), 3.76 (s, 2H), 3.60-3.37 (m, 10H), 2.53 (dd, J = 13.1, 2.9 Hz, 1H), 1.81 (s, 2H), 1.47 (d, J = 12.8 Hz, 1H).13C NMR (101 MHz; CDCI3) 6 173.7, 158.3, 157.3, 144.1, 137.6, 130.8, 130.2, 129.8, 129.7, 128.5, 128.3, 128.2, 128.0, 127.4, 127.3, 118.3, 116.5, 113.2, 110.1, 104.9, 70.0, 68.9, 63.6, 56.0, 55.7, 55.6, 55.4, 47.8, 45.2, 23.8, 23.2. HRMS (ES+) C3iH34CIN5O5Na [M + Na]+requires 614.2141, found 614.2143. Anal. Cal. (mass %) for C31H34CIN5O5: C, 62.89; H, 5.79; N, 11.83. Found: C, 61.30; H, 6.29; N, 11.91. MP: 68-69°C.

[0615] Example 61 l-(2-(2-(2-chloro-4-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2 / ?,3S,6 / ?)-3- hydroxy-l,3,4,6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea l-(((2 / ?,3S,6 / ?)-3-((tert-Butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6 methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-4- fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea (200 mg, 0.32 mmol) was employed. The crude product was purified by FCC (SiCh; 96:3 DCM:MeOH) to give the title compound as a yellow solid (150 mg, 93%).XH NMR (400 MHz; CDCI3) 6 7.14 (dd, J = 8.1, 1.8 Hz, 1H), 7.10-7.03 (m, 1H), 6.99 (d, J = 1.9 Hz, 1H), 6.91-6.86 (m, 2H), 6.48 (d, J = 8.2 Hz, 1H), 5.42 (t, J = 4.7 Hz, 1H), 5.22 (t, J = 5.5 Hz, 1H), 4.63 (s, 1H), 4.48 (s, 1H), 4.20 (d, J = 5.5 Hz, 2H), 3.90-3.33 (m, 9H), 2.98-2.70 (m, 1H), 2.80 (br s, 1H), 2.60-2.47 (m, 1H), 2.04 (s, 2H), 1.48 (d, J = 12.2 Hz, 1H).13C NMR (101 MHz; CDCI3) 6 171.9, 159.3 (d, J =262.0 Hz), 158.1, 144.1, 143.5, 129.9 (d, J =43.2 Hz), 127.6, 119.8, 119.7, 118.6, 118.4, 118.3, 114.4 (d, J = 22.2 Hz), 113.3, 70.0, 67.0, 63.7, 55.7, 47.9, 45.4, 44.1, 42.5, 23.9, 23.2. HRMS (ES+) C24H28CIFN5O4 [M + H]+requires 504.1808, found 504.1811. Anal. Cal. (mass %) for C24H27CIFN5O4: C, 57.20;

[0616] H, 5.40; N, 13.90. Found: C, 55.54; H, 5.52; N, 13.81. MP: 123-124°C. Example 62 l-((S)-2-(2-(2-chloro-4-fluorophenyl) pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3-

[0617] (((2 / ?,3S,6 / ?)-3-hydroxy-l, 3, 4, 6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin- 8-yl)Methyl)Urea l-(((2 / ?,3S,6 / ?)-3-((tert--butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-((S)-2-(2-(2-chloro-4- fluorophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)urea (0.3 g, 0.43 mmol) was employed. The crude product was purified by FCC (SiCh; 92:8 DCM:MeOH) to give the title compound as a yellow solid (200 mg, 80%).XH NMR (400 MHz; CDCI3) 6 7.67- 7.44 (m, 1H), 7.35-7.28 (m, 1H), 7.05-6.86 (m, 6H), 6.40 (d, J = 8.1 Hz, 1H), 6.16 (s, 1H), 6.09 (s, 1H), 5.52 (br s, 1H), 4.48 (s, 1H), 4.18 (s, 1H), 4.10 (s, 1H), 3.85- 3.65 (m, 2H), 3.52-3.22 (m, 9H), 2.47 (d, J = 12.8 Hz, 1H), 1.96 (s, 1H), 1.79 (s, 2H), 1.34 (d, J = 12.0 Hz, 1H).13C NMR (101 MHz; CDCI3) 6 176.2, 161.1, 157.4,

[0618] 144.1, 130.1, 129.7, 128.7, 128.3, 128.3, 128.0, 127.9, 127.3, 126.1, 118.3, 118.2,

[0619] 118.2, 113.2, 113.2, 69.8, 68.8, 63.5, 56.0, 47.7, 45.6, 45.5, 43.9, 25.2, 23.7. HRMS (ES+) C3oH3iCIFNs04Na [M+ Na]+requires 602.1941, found 602.1945. Anal. Cal. (mass %) for C30H31CIFN5O4: C, 62.12; H, 5.39; N, 12.07. Found: C, 61.55; H, 5.71; N, 11.29. MP: 140-141°C.

[0620] Example 63 l-((S)-2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-l-(4-(2- morpholinoethoxy)phenyl)-2-oxoethyl)-3-(((2 / ?,3S,6 / ?)-3-hydroxy-l,3,4,6- tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea

[0621] l-(((2 / ?,3S,6 / ?)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-((S)-2-(2-(2-chloro-5- fluorophenyl)pyrazolidin-l-yl)-l-(4-(2-morpholinoethoxy)phenyl)-2-oxoethyl)urea (0.35 g, 0.42 mmol) was employed. The crude product was purified by FCC (SiC ; 90: 10 EtOAc:MeOH) to give the title compound as a white solid (0.2 g, 67%).XH NMR (400 MHz; CDCI3; ppm) 6 7.44-7.23 (m, 2H), 7.01-6.91 (m, 4H), 6.60 (d, J = 7.4 Hz, 1H), 6.53-6.50 (m, 2H), 6.02 (d, J = 9.8 Hz, 1H), 4.60 (s, 1H), 4.20-3.95 (m, 5H), 3.73-3.22 (m, 14H), 2.82-2.56 (m, 8H), 2.10 (br s, 1H), 1.91-1.86 (m, 1H), 1.69-1.62 (m, 1H), 1.43 (d, J = 14.0 Hz, 1H).13C NMR (101 MHz; CDCI3) 6 175.4, 160.0, 159.4, 150.0, 146.1, 132.5, 130.6, 130.5, 130.3, 130.2, 128.0, 121.2, 120.0, 115.5, 115.4,

[0622] 114.1, 112.6, 112.4, 108.1, 107.8, 70.9, 70.4, 67.5, 66.2, 64.4, 58.4, 56.8, 56.6,

[0623] 55.1, 54.9, 46.2, 44.4, 24.8, 24.6, 24.0, 13.9. HRMS (ES+) C36H43CIFN6O6 [M + H]+requires 709.2911, found 709.2916. Mp: 112-113°C. Anal. Cal. (mass %) for C30H31CIFN5O4: C, 60.97; H, 5.97; N, 11.85. Found: C, 59.49; H, 6.30; N, 10.63.

[0624] Reference Example 64 l-(2-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)-2-oxoethyl)-3-(((2R,3S,6R)-3- hydroxy- 1,3, 4, 6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea

[0625] To a solution of l-(((2R,3S,6R)-3-((tert-butyldimethylsilyl)oxy)-l,3,4,6-tetrahydro- 2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-((R)-2-(2-chloro-5- fluorophenyl)pyrrolidin-l-yl)-2-oxoethyl)urea (80 mg, 0.13 mmol) in anhydrous THF (5 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 0.26 mL, 0.26 mmol, 2 eq) dropwise. The reaction mixture was allowed to stir at room temperature for 16 h (followed by TLC). Upon completion, the reaction was diluted with ethyl acetate, washed with water and brine, dried over MgSC , filtered and concentrated in vacuo to a white solid. The crude product was purified by FCC (SiC ; 5:95 MeOH:DCM) to afford the titled compound as a white solid (48 mg, 73 %). Purity 98%, Rt = 7.672 min, with the yield consisting of a mixture of rotamers in ratio 1 / 1.18.XH NMR (400 MHz, CDCI3) 6 7.36 (dd, J = 8.8, 5.0 Hz, 1H, minor), 7.30 (dd, J = 8.7, 5.1 Hz, 1H, major), 7.09 - 7.04 (m, 1H), 7.01 (dd, J = 11.3, 1.9 Hz, 1H), 6.98 - 6.92 (m, 1H, minor), 6.91 - 6.84 (m, 1H, major), 6.75 (dd, J = 9.0, 3.0 Hz, 1H, minor), 6.69 (dd, J = 9.2, 3.0 Hz, 1H, major), 6.49 (d, J = 8.2 Hz, 1H), 5.49 (dd, J = 8.4, 4.3 Hz, 1H), 5.42 - 5.35 (m, 1H, major), 5.24 (d, J = 7.2 Hz, 1H, minor), 5.07 - 5.01 (m, 1H, minor), 5.00 - 4.92 (m, 1H, major), 4.67 (s, 1H), 4.38 (d, J = 3.5 Hz, 1H), 4.25 - 4.21 (m, 1H), 4.18 (dd, J = 8.9, 5.6 Hz, 1H), 4.14 (d, J = 4.6 Hz, 1H, major), 4.10 (d, J = 4.1 Hz, 1H, minor), 4.09 (d, J = 3.5 Hz, 1H, major), 4.06 (d, J = 4.2 Hz, 1H, minor), 3.85 - 3.70 (m, 1H), 3.67 - 3.55 (m, 2H), 3.55 - 3.39 (m, 3H), 3.36 (d, J = 3.4 Hz, 1H, major), 3.32 (d, J = 3.2 Hz, 1H, minor), 2.59 - 2.49 (m, 2H), 2.47 - 2.37 (m, 1H,), 2.37 - 2.26 (m, 1H), 2.05 - 1.94 (m, 1H), 1.94 - 1.86 (m, 1H), 1.80 (m, 1H), 1.51 (d, J = 13.2 Hz, 1H). HRMS (ES+) C25H29N4O4FCI [M+H]+requires 503.1856, found 503.1852. HPLC purity 98.7%, t = 7.613 min.

[0626] Example 65 l-((S)-2-(2-(2-chloro-5-methoxyphenyl)pyrazolidin-l-yl)-l-(4'-(morpholinomethyl)- [l,l'-biphenyl]-4-yl)-2-oxoethyl)-3-(((2R,3S,6R)-3-hydroxy-2,3,4,6-tetrahydro-lH- 2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea

[0627] The title compound was obtained following a similar procedure to Example 55 starting from l-((S)-2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-l-(4'- (morpholinomethyl)-[l,l'-biphenyl]-4-yl)-2-oxoethyl)-3-(((2R,3S,6R)-3-hydroxy- l,3,4,6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea (300 mg, 0.34 mmol, 1 eq). The crude product was purified by column chromatography (DCM: MeOH= 15: 1) gave the title compound (150 mg, 57.7%) as a white solid. Rt = 0.5, 10% MeOH in DCM. m.p. deco...

Claims

Claims1. A compound of formula I,wherein,R1represents phenyl or a 5 to 10-membered heterocyclyl group, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, -CN, benzyloxy, -C(O)O-R9, and -C(O)NH(R10);R2represents H, Ci-4 alkyl, heteroaryl, or aryl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, Ci-4 alkyl, Ci-4 alkoxy, -O-C1-2 alkylene-R11and -aryl-CHi-2 alkylene-R13;R3represents H, Ci-4 alkyl or a heterocyclic group;R4and R5each represent H, or R4and R5are linked to form a 5- to 10-membered heterocyclic mono- or polycyclic ring optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, oxo and Ci-4 alkyl;R6represents H or Ci-4 alkyl optionally substituted by a heterocyclic group;R7represents H, halogen, or hydroxy;R8aand R8beach independently represents H or Ci-4 alkyl optionally substituted by a heterocyclic group, which heterocyclic group is optionally substituted by one or more Ci-4 alkyl substituents;R9represents H or C1-2 alkyl optionally substituted by R12;R10represents H or C1-6 alkyl;R11and R13independently represent a 5- or 6-membered heterocyclyl group optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl and oxo;R12represents a 6-membered heterocyclyl or phenyl group, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, CH3 and CF3;X1to X6each independently represents C, CH, CH2, N, O or NH, and the ring containing X1to X6is aromatic or contains 0, 1 or 2 double bonds; or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1, wherein R1represents phenyl or a 5- to 10-membered heteroaryl group, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 alkoxy, -CN, benzyloxy, -C(O)O-R9, and -C(O)NH(R10).

3. The compound according to Claim 1 or Claim 2, wherein R2represents H, Ci-4 alkyl, pyridyl or phenyl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, Ci-4 alkyl, Ci-4 alkoxy, -O-C1-2 alkylene-R11and -aryl-CHi-2 alkylene-R13.

4. The compound according to Claim 3, wherein:R1represents phenyl substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 alkoxy, -CN, benzyloxy, -C(O)O-R9, and -C(O)NH(R10);R2represents phenyl; and the carbon atom to which R2is bound is in the S-configuration.

5. The compound according to any one of the preceding claims, wherein R3represents H.

6. The compound according to any one of the preceding claims, wherein R4and R5each represent H, or R4and R5are linked together to form:wherein Rxand Ryeach independently represents H or a Ci-4 alkyl group; optionally wherein R7is H and R4and R5are linked together to form:

7. The compound according to any one of the preceding claims, wherein R7represents H or halogen.

8. The compound according to any one of the preceding claims, wherein:(i) R9represents H, -CH3 or -CH2-R12; and / or(ii) R12represents phenyl or pyridyl, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen and CF3.

9. The compound according to any one of the preceding claims, wherein R10represents methyl, ethyl, propyl, isopropyl, straight chain or branched butyl, straight chain or branched pentyl, or straight chain or branched hexyl.

10. The compound according to any one of the preceding claims, wherein R11represents a morpholinyl, thiomorpholinyl, piperazinyl or piperidinyl group, each of which is optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-4 alkyl and oxo.

11. The compound according to Claim 1, wherein the compound is selected from the group consisting of: l-(4-aminobenzyl)-3-(2-oxo-2-(2-phenylpyrazolidin-l-yl)ethyl)urea; l-(4-Aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea; l-(4-aminobenzyl)-3-(2-(2-(2-bromo-3-chlorophenyl)pyrazolidin-l-yl)-2- oxoethyl)urea;l-(4-aminobenzyl)-3-(2-(2-(2-bromo-4-chlorophenyl)pyrazolidin-l-yl)-2- oxoethyl)urea; l-(4-aminobenzyl)-3-(2-(2-(2-bromo-5-chlorophenyl)pyrazolidin-l-yl)-2- oxoethyl)urea; l-(4-aminobenzyl)-3-(2-(2-(2-bromo-4-methoxyphenyl)pyrazolidin-l-yl)-2- oxoethyl)urea; l-(4-aminobenzyl)-3-(2-(2-(2-bromo-4-methylphenyl)pyrazolidin-l-yl)-2- oxoethyl) urea; l-(4-aminobenzyl)-3-(2-(2-(2,4-dichlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea; l-(4-aminobenzyl)-3-(2-(2-(2,5-dichlorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea; l-(4-Aminobenzyl)-3-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2- oxoethyl)urea; l-(4-Aminobenzyl)-3-(2-(2-(2-chloro-5-methoxyphenyl)pyrazolidin-l-yl)-2- oxoethyl)urea; l-(4-Aminobenzyl)-3-(2-(2-(3-cyanophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea; l-(4-aminobenzyl)-3-(2-(2-(3-(benzyloxy)phenyl)pyrazolidin-l-yl)-2-oxoethyl)urea;(R)-l-(4-aminobenzyl)-3-(2-oxo-l-phenyl-2-(2-phenylpyrazolidin-l-yl)ethyl)urea;(S)-l-(4-aminobenzyl)-3-(2-oxo-l-phenyl-2-(2-phenylpyrazolidinasapyrrolidin-l- yl)ethyl)urea;(R)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazoldin-l-yl)-2-oxo-l- phenylethyl)urea;(S)-l-(4-Aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l- phenylethyl)urea;(S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4- chlorophenyl)-2-oxoethyl)urea;(S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4- methoxyphenyl)-2-oxoethyl)urea;(S)-l-(4-aminobenzyl)-3-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxo- lphenylethyl)urea;(S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2- morpholinoethoxy)phenyl)-2-oxoethyl)urea;(S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-(4-(2- thiomorpholinoethoxy)phenyl)ethyl)urea;(S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(4- methylpiperazin-l-yl)ethoxy)phenyl)-2-oxoethyl)urea; l-(4-aminobenzyl)-3-((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-((R)-3- methylmorpholino)ethoxy)phenyl)-2-oxoethyl)urea;(S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(l,l- dioxidothiomorpholino)ethoxy)phenyl)-2-oxoethyl)urea;(S)-l-(4-aminobenzyl)-3-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-l-(4-(2-(4- fluoropiperidin-l-yl)ethoxy)phenyl)-2-oxoethyl)urea; l-(4-aminobenzyl)-3-(2-oxo-2-(2-(pyridin-2-yl)pyrazolidin-l-yl)ethyl)urea; l-(4-Aminobenzyl)-3-(2-(2-(isoquinolin-4-yl)pyrazolidin-l-yl)-2-oxoethyl)urea; l-(4-Aminobenzyl)-3-(2-oxo-2-(2-(quinolin-5-yl)pyrazolidin-l-yl)ethyl)urea; methyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-4-bromobenzoate;3-(2-(((4-Aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-4-bromobenzoic acid;3-(2-(((4-Aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-4-bromo-N- methylbenzamide; benzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-4-bromobenzoate; benzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)benzoate;4-(trifluoromethyl)benzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l- yl)benzoate; methyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)benzoate;3-(2-(((4-Aminobenzyl)carbamoyl)glycyl)pyrazolidin- 1-yl) benzoic acid;4-chlorobenzyl 5-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-2- fluorobenzoate;4-chlorobenzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)benzoate;3-chlorobenzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)benzoate;3,4-dichlorobenzyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l- yl)benzoate; benzyl 5-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-2-fluorobenzoate;5-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-2-fluorobenzoic acid;3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-N-isobutyl benzamide;3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l-yl)-N-isopentylbenzamide; pyridin-2-ylmethyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l- yl)benzoate; pyridin-3-ylmethyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l- yl)benzoate; pyridin-4-ylmethyl 3-(2-(((4-aminobenzyl)carbamoyl)glycyl)pyrazolidin-l- yl)benzoate; l-((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3-(((2S,3S,6S)-3-hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c] [l,5]oxazocin-8- yl)methyl)urea;l-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2R,3S,6R)-3- hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c] [l,5]oxazocin-8- yl)methyl)urea; l-((S)-2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3- (((2R,3S,6R)-3-hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c][ l,5]oxazocin- 8-yl)methyl)urea; l-(2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2R,3S,6R)-3-hydroxy-1.3.4.6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea; l-((S)-2-(2-(2-bromophenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3-(((2R,3S,6R)- 3-hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c] [l,5]oxazocin-8- yl)methyl)urea; l-(((2R,3S,6R)-10-chloro-3-hydroxy-l,3,4,6-tetrahydro-2H-2,6- methanobenzo[c][l,5]oxazocin-8-yl)methyl)-3-(2-(2-(2-chloro-5- fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)urea; l-(2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2R,3S,6R)-10- fluoro-3-hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c][ l,5]oxazocin-8- yl)methyl)urea; l-(2-(2-(2-chloro-5-methoxyphenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2R,3S,6R)-3- hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c] [l,5]oxazocin-8- yl)methyl)urea; l-((S)-2-(2-(2-chloro-5-methoxyphenyl)pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3- (((2R,3S,6R)-3-hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c][ l,5]oxazocin- 8-yl)methyl)urea; l-(2-(2-(2-chloro-4-fluorophenyl)pyrazolidin-l-yl)-2-oxoethyl)-3-(((2R,3S,6R)-3- hydroxy- 1,3,4, 6-tetrahydro-2H-2, 6-methanobenzo[c] [l,5]oxazocin-8- yl)methyl)urea; l-((S)-2-(2-(2-chloro-4-fluorophenyl) pyrazolidin-l-yl)-2-oxo-l-phenylethyl)-3- (((2R,3S,6R)-3-hydroxy-l, 3, 4, 6-tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin- 8-yl)methyl)urea; l-((S)-2-(2-(2-chloro-5-fluorophenyl)pyrazolidin-l-yl)-l-(4-(2- morpholinoethoxy)phenyl)-2-oxoethyl)-3-(((2R,3S,6R)-3-hydroxy-l,3,4,6- tetrahydro-2H-2,6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea; and l-((S)-2-(2-(2-chloro-5-methoxyphenyl)pyrazolidin-l-yl)-l-(4'-(morpholinomethyl)- [l,l'-biphenyl]-4-yl)-2-oxoethyl)-3-(((2R,3S,6R)-3-hydroxy-2,3,4,6-tetrahydro-lH-2.6-methanobenzo[c][l,5]oxazocin-8-yl)methyl)urea; and pharmaceutically acceptable salts thereof.

12. A pharmaceutical composition comprising a compound as defined in any one of the preceding claims in combination with a pharmaceutically acceptable excipient.

13. A compound as defined in any one of Claims 1 to 11, or a pharmaceutical composition as defined in Claim 12, for use in medicine.

14. A compound as defined in any one of Claims 1 to 11, or a pharmaceutical composition as defined in Claim 12, for use in treating or preventing a disease or condition in which the inhibition of one or more of cyclophilins A to D is desired or required, optionally wherein the use is in treating or preventing a disease or condition in which the inhibition of cyclophilin D is desired or required.

15. A compound for use or pharmaceutical composition for use according to Claim 14, wherein the disease or condition is selected from the group consisting of acute pancreatitis, myocardial infarction, acute ischaemic stroke, acute tubular necrosis, acute hepatic injury and failure, viral infection, sepsis, chronic inflammatory disease, autoimmune disease, graft versus host disease, organ rejection, coronary and peripheral vascular disease, hypertension, diabetes mellitus, dyslipidaemia, metabolic syndrome, non-alcoholic fatty liver disease, fibrotic disease, cancer, neurodegenerative diseases, and muscular dystrophy.

16. A process for the preparation of a compound of formula I as defined in Claim 1, which process comprises:(i) reaction of a corresponding compound of formula II,wherein R1, R2and R8bare as defined in Claim 1, and Xais H or a protected derivative thereof, with a compound of formula III,wherein R3, R4, R5, R6, R7, R8a, X1to X6and the ring containing X1to X6are as defined in Claim 1, and Xbrepresents a leaving group; or(ii) deprotection of a compound of formula I in which one or more hydroxyl groups is protected with an ether protecting group.

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