WO2018109496A2

WO2018109496A2 - Unnatural amino acids

Info

Publication number: WO2018109496A2
Application number: PCT/GB2017/053768
Authority: WO
Inventors: Daniel Jamie LEONARD; John William WARD; Jonathan Paul CLAYDEN
Original assignee: The University Of Bristol
Priority date: 2016-12-16
Filing date: 2017-12-15
Publication date: 2018-06-21
Also published as: GB201621512D0; GB2557931A; WO2018109496A3

Abstract

The present invention relates to a process for the preparation compounds of Formula (I): Formula (I) wherein X, Z, Q, Ar, R¹, R^2, R³ and R⁴ are each as defined herein. The present invention also relates to processes for the preparation of the compounds of quaternary amino acids and hydantions, to compound of Formula(I), to intermediate compounds of Formula (II), to quaternary amino acid compounds of Formula (III) and to hydantoin compounds of Formula (IV).

Description

UNNATURAL AMINO ACIDS

INTRODUCTION

[0001] The present invention relates to a process for preparing certain compounds comprising quaternary centres, in particular quaternary unnatural amino acids and/or hydantoins. The present invention also relates to the products of this process, to the quaternary unnatural amino acids and hydantoins directly obtainable therefrom and to the novel starting materials used in the process.

BACKGROUND OF THE INVENTION

[0002] a-Amino acids are the most fundamental building blocks of life, and their structural features dictate every aspect of the function of proteins, peptide hormones, and many signalling molecules. Many single amino acids (glutamate, thyroxine) have key biological function. The ability to modify the chemical structure of amino acids synthetically is thus central to our ability to enhance, modify or mimic biological function, or to correct disease states. Modified peptides are resistant to metabolism, avoiding the problem of short in vivo half life of potential peptide therapeutics. Synthetic peptides thus offer the potential to make ideal antibiotics, and modified enzymes can be used to harness powerful biological activity to catalyse valuable non-biological reactions.

[0003] For this reason, there is a globally important market in the biotech, pharmaceutical, agrochemical and fine chemical sectors for enantiopure modified amino acids. Fine chemical companies sell a range of structures, and sales of modified amino acids provide a significant income stream for specialist suppliers.

[0004] To date, access to enantiopure modified amino acids has been restricted by the limited availability of chemical reactions that are capable of producing amino acids with high stereocontrol. Indeed, no general method for the synthesis of enantiopure a-arylated quaternary amino acids currently exists.

[0005] In addition, the hydantoin derivatives of quaternary amino acids are also valuable compounds due to their broad range of biological activities.

[0006] Accordingly, there exists a need for new and improved chemical reactions capable of yielding enantiopure α-arylated quaternary amino acids and their hydantoin derivatives in an effective and scalable manner.

[0007] The present invention was devised with the foregoing in mind. SUMMARY OF THE INVENTION

[0008] According to a first aspect of the present invention, there is provided a process for the preparation of a compound of Formula (I), as defined herein. [0009] According to a second aspect of the present invention, there is provided a compound of Formula (I), as defined herein, or a salt, hydrate or solvate thereof.

[0010] According to a third aspect of the present invention, there is provided a compound of Formula (II), as defined herein, or a salt, hydrate or solvate thereof.

[0011] According to a fourth aspect of the present invention, there is provided a compound of Formula (lll-1 a), as defined herein, or a salt, hydrate or solvate thereof.

[0012] According to a fifth aspect of the present invention, there is provided a compound of Formula (IV), as defined herein, or a salt, hydrate or solvate thereof.

[0013] According to a sixth aspect of the present invention, there is provided a compound of Formula (I), obtainable by, obtained by or directly obtained by the process of aspect one.

[0014] According to a seventh aspect of the present invention, there is provided a process for preparing a compound of Formula (II), or a salt, hydrate or solvate thereof, as defined herein.

[0015] According to an eighth aspect of the present invention, there is provided a process for preparing a compound of Formula (III), or a salt, hydrate or solvate thereof, as defined herein.

[0016] According to a ninth aspect of the present invention, there is provided a process for preparing a compound of Formula (IV), or a salt, hydrate or solvate thereof, as defined herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0017] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0018] In this specification the term "alkyl" includes both straight and branched chain alkyl groups and analogues thereof. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as "isopropyl" are specific for the branched chain version only. For example, "(1- 6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl and f-butyl. A similar convention applies to other radicals, for example "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

[0019] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0020] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups. Thus, "(1- 6C)alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like. [0021] "(2-6C)alkenylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, for example, as in ethenylene, 2,4-pentadienylene, and the like.

[0022] "(2-6C)alkynylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, for example, as in ethynylene, propynylene, and butynylene and the like.

[0023] "(3-8C)cycloalkyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

[0024] "(3-8C)cycloalkenyl" means a hydrocarbon ring containing at least one double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, such as 3- cyclohexen-1-yl, or cyclooctenyl.

[0025] "(3-8C)cycloalkyl-(1-6C)alkylene" means a (3-8C)cycloalkyl group covalently attached to a (1-6C)alkylene group, both of which are defined herein.

[0026] The term "halo" or "halogeno" refers to fluoro, chloro, bromo and iodo.

[0027] The term "heterocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). The term heterocyclyl includes both monovalent species and divalent species. Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocycles contain from about 7 to about 17 ring atoms, suitably from 7 to 12 ring atoms. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 ,3-dithiol, tetrahydro-2 - -thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 , 1 -dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 ,1-dioxide, thiomorpholinyl, thiomorpholinyl 1 ,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1- yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0028] By "bridged ring systems" it is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4^th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.

[0029] "Heterocyclyl(1-6C)alkyl" means a heterocyclyl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein.

[0030] The term "heteroaryl" or "heteroaromatic" means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0031] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 H-pyrazolo[4,3-d]-oxazolyl,

4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1 ,2-b][1 ,2,4]triazinyl. "Heteroaryl" also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo- 1 ,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro- benzo[1 ,4]dioxinyl, benzo[1 ,3]dioxolyl, 2,2-dioxo-1 ,3-dihydro-2-benzothienyl, 4,5,6,7- tetrahydrobenzofuranyl, indolinyl, 1 ,2,3,4-tetrahydro-1 ,8-naphthyridinyl,

1 ,2,3,4-tetrahydropyrido[2,3-0]pyrazinyl and 3,4-dihydro-2/-/-pyrido[3,2-£>][1 ,4]oxazinyl.

[0032] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0033] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0034] A bicyclic heteroaryl group may be, for example, a group selected from:

a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;

a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;

a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

a pyrrole ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;

a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;

a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms.

[0035] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.

[0036] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0037] "Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently attached to a (1- 6C)alkylene group, both of which are defined herein. Examples of heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0038] The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.

[0039] The term "aryl(1-6C)alkyl" means an aryl group covalently attached to a (1-6C)alkylene group, both of which are defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.

[0040] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example heterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted by heterocyclyl.

[0041] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term "wherein a/any CH, CH₂, CH₃ group or heteroatom (i.e. NH) within a R¹ group is optionally substituted" suitably means that (any) one of the hydrogen radicals of the R¹ group is substituted by a relevant stipulated group.

[0042] Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0043] The phrase "compound of the invention" means those compounds which are disclosed herein, both generically and specifically. Processes of the invention

Process for the preparation of a compound of Formula (I)

Process 1

[0044] In one aspect, the present invention relates to a process for the preparation of a compound of Formula (I), as sh

(I)

wherein:

X is selected from CR⁵R⁶, C=S or C=0;

Z is selected from O, S or NR⁷;

Q is selected from S, NR⁸ or O, wherein R⁸ is selected from H, (1-4C)alkyl or aryl;

Ar is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, (1-4C)alkoxy, azido, carboxy, carbamoyl, sulphamoyl, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^aR^b, OR^a, C(0)R^a, C(0)OR^a, OC(0)R^a, C(0)N(R )R^a, N(R^b)C(0)R^a, S(0)_yR^a (where y is 0, 1 or 2), S0₂N(R^b)R^a, N(R )S0₂R^a or (CH₂)_zNR^bR^a (where z is 1 , 2 or 3), wherein R^a and R^b are independently selected from H or (1-4C)alkyl;

R¹ is selected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1- 2C)alkyl or oxo;

Y¹ is absent or selected from O, N(R^C), S, SO, S0₂, Se, C(O), C(0)0, OC(O), C(0)N(R^c), N(R^d)C(0), N(R^d)C(0)N(R^c), N(R^d)C(NH)N(R^c), S(0)₂N(R^c), or N(R^d)S0₂, wherein R^cand R^d are each independently selected from H or (1-4C)alkyl; and

W¹ is selected from H, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, SiR^a1R^a2R^a3 (wherein R^a1, R^a2 and R^a3 are independently selected from H, (1-4C)alkyl or aryl), (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or heteroaryl; each of which, other than H, cyano or SiR^a1 R^a2R^a3, is optionally substituted with one or more substituents selected from nitro, cyano, halo, (1 -4C)haloalkyl, (1 -4C)halalkoxy, amino, hydroxy, azido, carboxy, carbamoyl, sulphamoyl, aryl, aryl-(1-2C)alkyl, heteroaryl, (1-4C)alkyl, OR⁹, NR^eR^f, C(0)R⁹, C(0)OR⁹, OC(0)R⁹, C(0)N(R^h)R⁹, N(R^h)C(0)R⁹, S(0)_yR⁹ (where y is 0, 1 or 2), S0₂N(R^h)R⁹, N(R^h)S0₂R⁹ or

(CH₂)wNR^hR⁹ (where w is 1 , 2 or 3), wherein R⁹ and R^h are each independently selected from H, (1 -4C)alkyl, aryl, aryl-(1 - 2C)alkyl, heteroaryl or heteroaryl-(1 -2C)-alkyl; and wherein R^e and R^f are independently selected from H, (1-4C)alkyl or a group of the formula:

-L²-Y²-W²

wherein:

L² is absent or (1 -2C)alkylene optionally substituted by (1-2C)alkyl;

Y² is absent or selected from SiR^a4R^a5, S0₂, C(O), C(0)0 or Ο(Ο)Ν^), wherein R', R^a4 and R^a5 are each independently selected from H or (1 -4C)alkyl;

W² is selected from H, (1 -6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1 -2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1- 2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1 -4C)alkyl, halo, (1 -4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heteroatyl, heterocyclyl or NR^jR^k, wherein R^j and R^k are independently selected from H or (1 -6C)alkyl; or

R¹ and R^k are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl, which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, amino, hydroxy or cyano; or

R^c and W¹ are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl which is optionally substituted with one or more substituents selected from halo, hydroxy, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, aryl, heteroaryl, NR'R^m, C(0)R', C(0)OR', C(0)N(R^m)R' or N(R^m)C(0)R', wherein R' and R^m are each independently selected from H or (1- 4C)alkyl; or

R' and R^m are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl, which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, hydroxyl, amino, nitro or cyano;

R² is selected from (1-8C)alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, NRⁿR°, C(0)Rⁿ, C(0)ORⁿ, C(0)N(R°)Rⁿ or N(R°)C(0)Rⁿ, wherein Rⁿ and R° are each independently selected from H or (1-4C)alkyl; or Rⁿ and R° are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl, which is optionally substituted with one or more substituents selected from (1- 4C)alkyl, halo, amino, hydroxy or cyano; or

R² is an organometallic complex;

R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl or SiR^b1 R^b2R^b3 (wherein R ¹ , R^b2 and R ³ are independently selected from H or (1-4C)alkyl), each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heteroaryl, heterocyclyl, NR^pR^q, C(0)R^p, C(0)OR^p, C(0)N(R^q)R^p or N(R^q)C(0)R^p, wherein R^p and R^q are each independently selected from H or (1-4C)alkyl; or

R³ is linked with Ar such that, together with the nitrogen atom to which R³ is attached they form a 4- to 15-membered heterocyclyl or heteroaryl, which is optionally substituted with one or more substituents selected from halo, hydroxy, amino, nitro, cyano, (1-4)alkyl or (1-4C)alkoxy;

R⁴ is absent or H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1- 2C)alkyl, C(0)OR^r or C(0)N(R^r) or nitroso, wherein R^r is selected from H or (1-4C)alkyl, and wherein each (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl is optionally substituted with one or more substituents selected from (1-4C)alkyl, aryl, heteroaryl, halo, hydroxy, nitro or cyano; R⁵ and R⁶ are independently selected from H, (1-4C)alkyl, aryl or heteroaryl wherein each (1-4C)alkyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydroxy, halo, amino, (1-4C)alkyl, nitro or cyano;

R⁷ is selected from H or a group of the formula:

-L³-Y³-W³

wherein:

L³ is absent or (1-4C)alkylene optionally substituted by (1-2C)alkyl;

Y³ is absent or selected from SiR^a6R^a7, S0₂, C(O), C(0)0 or

C(0)N(R^s), wherein R^s, R^aS and R^a7 are each independently selected from H or (1-4C)alkyl;

W³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano or NR'R^U wherein R' and R^u are independently selected from H or (1-4C)alkyl;

with the proviso that:

(i) when R⁴ is absent, the compound of Formula (I) is anionic (i.e. carries a negative charge);

(ii) when R¹ is a carbonyl moiety (i.e. a group selected from C(0)-W¹, C(0)0-Wi , C(0)N(R^c)-W¹), X is CR⁵R⁶; and

(iii) when R¹ is not a carbonyl moiety (i.e. it is a group other than C(0)-W¹, C(0)0-W\ C(0)N(R^c)-W¹), X is C=0 or C=S.

the process comprising the steps of:

i) reacting a compound of Formula (II), as shown below, with a base in the presence of an aprotic solvent:

wherein X, Z , Q , Ar, R¹ , R², R³ and all substituent groups associated therewith, have the same meaning as defined for the compounds of Formula (I); and

ii) optionally, thereafter:

a) converting the compound Formula I into another compound of Formula I ;

and/or

b) forming a salt or solvate thereof.

[0045] The inventors have surprisingly discovered that the process of the present invention advantageously allows for the synthesis of compounds of Formula (I) in good yields and with excellent regio- and/or stereocontrol. Following hydrolysis of the compounds of Formula (I), this process allows simple access into a number of unnatural quaternary amino acids and hydantoins, which are otherwise challenging to synthesise.

[0046] Furthermore, the high level of regio- and/or stereocontrol displayed by the process of the present invention, coupled with the high yields displayed, allows scalable access into a number of enantioenriched unnatural quaternary amino acids and hydantoins.

[0047] In an embodiment, the process of the present invention is enantiocontrolled (i.e. the the enantiomeric excess of the compounds of Formula (II) is substantially maintained throughout the process to yield enantiopure compounds of Formula (I)).

[0048] It will be understood that the process of the present invention allows for stereocontrol at the quaternary carbon to which both R¹ and Ar are attached. Suitably, the process of the present invention provides compounds of the Formula (I) with an enantiomeric excess of equal to or greater than 60%. More suitably, the process of the present invention provides compounds of the Formula (I) with an enantiomeric excess of equal to or greater than 70%. Yet more suitably, the process of the present invention provides compounds of the Formula (I) with an enantiomeric excess of equal to or greater than 75%. Even more suitably, the process of the present invention provides compounds of the Formula (I) with an enantiomeric excess of equal to or greater than 85%. Most suitably, the process of the present invention provides compounds of the Formula (I) with an enantiomeric excess of equal to or greater than 90%.

[0049] It will be appreciated that the enatiomeric purity of the compounds of Formula (I) may be expressed in terms of their enantiomeric ratio (er). Suitably, the process of the present invention provides compounds of the Formula (I) with an enantiomeric ratio of equal to or greater than 60:40. More suitably, the process of the present invention provides compounds of the Formula (I) with an enantiomeric ratio of equal to or greater than 70:30. Yet more suitably, the process of the present invention provides compounds of the Formula (I) with an enantiomeric ratio of equal to or greater than 80:20. Most suitably, the process of the present invention provides compounds of the Formula (I) with an enantiomeric ratio of equal to or greater than 90:10.

[0050] In certain embodiments, the compounds of Formula (I) provided by the process of the present invention may comprise more than one chiral centre. In such situations, the compounds of Formula (I) may exist as diastereomers. Suitably, the diastereomeric ratio for diastereomeric compounds of Formula (I) is equal to or greater than 60:40. More suitably, the diastereomeric ratio for diastereomeric compounds of Formula (I) is equal to or greater than 70:30. Yet more suitably, the diastereomeric ratio for diastereomeric compounds of Formula (I) is equal to or greater than 80:20. Most suitably, the diastereomeric ratio for diastereomeric compounds of Formula (I) is equal to or greater than 90: 10.

[0051] It will be understood that the present invention provides a process for the preparation of a compound of Formula (I), as defined hereinbefore or in any one of numbered paragraphs (1) to (55) hereinbelow. Moreover, it will be understood that the present invention also provides a process for the preparation of a compound of formula la to Ik (i.e. sub defintions of the compounds of Formula (I)).

Step (i)

[0052] Any suitable reaction conditions may be used in step (i) of the process defined hereinabove.

[0053] The reaction conditions used in step (i) of the process will vary according to the compound of Formula (II) used. A person skilled in the art will be able to select suitable reaction conditions (e.g. temperature, pressures, reaction times, concentration etc.) to use in step (i) of the process.

[0054] It is understood by one skilled in the art of organic synthesis that the functionality present at various positions of the compound of Formula (II) must be compatible with the reagents and reaction conditions utilised.

[0055] In an embodiment, step (i) of the process of the present invention is conducted at a temperature of between -100 °C and 200 °C. Suitably, step (i) of the process of the present invention is conducted at a temperature of between -80 °C and 150 °C. More suitably, step (i) of the process of the present invention is conducted at a temperature of between -80°C and 100 °C. Yet more suitably, step (i) of the process of the present invention is conducted at a temperature of between -80 °C and 50 °C.

[0056] In another embodiment, step (i) of the process of the present invention may be carried out in the presence of any suitable aprotic solvent. The aprotic solvent may be used to solubilise the compound of Formula (II) and base and facilitate a reaction therebetween. Accordingly, it will be understood that the aprotic solvent selected will depend on compound of Formula (II) and base selected. Suitable aprotic solvents may include, but are not limited to, tetrahydrofuran, benzene, toluene, xylene, chloroform, dichloromethane, 2- methyltetrahydrofuran, ethers (e.g. diethylether), Λ/,/V-dimethylformamide, acetonitrile, dimethyl sulfoxide and acetone. Suitably, the aprotic solvent is tetrahydrofuran, benzene, toluene, xylene, chloroform or dichloromethane. Most suitably, the aprotic solvent is tetrahydrofuran.

[0057] Furthermore, step (i) of the process of the present invention may be carried out in the presence of any suitable base. The base may be used to deprotonate the tertiary carbon bearing the R¹ substituent, in order to facilitate the rearrangement of the compounds of Formula (II) to compounds of Formula (I). Accordingly, it will be understood that the base selected will depend on compound of Formula (II). The base may be any suitable organic or inorganic base. Suitably, the base is an organic base, such as, for example, lithium diethylamide, sodium, lithium or potassium bis(trimethylsilyl)amide, lithium 2,2,6,6- tetramethylpiperidide, sodium, lithium or potassium tert-butoxide, lithium diisopropylamide, n- butyllithium, sec-butyllithium or tert-butyllithium. Suitably, the base is an organic base selected from lithium diethylamide, sodium, lithium or potassium bis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidide or sodium, lithium or potassium tert-butoxide. Most suitably, the base is potassium bis(trimethylsilyl)amide or lithium diisopropylamide.

[0058] In a further embodiment, the base used in step (i) of the process of the present invention has a pK_a of 12 or greater. Suitably, the base used in step (i) of the process of the present invention has a pK_a of 15 or greater. More suitably, the base used in step (i) of the process of the present invention has a pK_a of 20 or greater. Most suitably, the base used in step (i) of the process of the present invention has a pKa of 25 or greater.

[0059] It will also be appreciated that during the synthesis of the compounds of Formula (I) in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0060] For examples of protecting groups see one of the many general texts on the subject, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0061] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. [0062] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyl oxycarbony I, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a te/ -butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0063] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0064] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a f-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0065] Resins may also be used as a protecting group.

Step (ii)

[0066] Once a compound of Formula (I) has been synthesised by the process defined herein, the process may then further comprise the additional steps of:

(i) removing any protecting groups present;

(ii) converting the compound Formula (I) into another compound of Formula (I); and/or

(iii) forming a salt, hydrate or solvate thereof. [0067] An example of (ii) above is when a compound of Formula (I) is synthesised and then one or more of the groups of X, Z, Q, Ar, R¹, R², R³ or R⁴, may be further reacted to change the nature of the group and provide an alternative compound of Formula (I). For example, the compound can be reacted to convert any 'R' group into a substituent group other than hydrogen.

[0068] The resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art.

Process 2

[0069] In another aspect, the present invention relates to a process for the preparation of a compound of Formula (I), as sh

(I)

wherein R R², R³, R⁴, Ar, Q, X and Z are as defined herein;

the process comprising the steps of:

A) preparing a compound of Formula (II), as shown below:

(ii)

wherein X, Z, Q, Ar, R\ R², R³ and all substituent groups associated therewith, have the same meaning as defined for the compounds of Formula (I)

B) reacting the compound of Formula (II), as shown above, with a base in the presence of an aprotic solvent: and

C) optionally, thereafter:

c) converting the compound Formula I into another compound of Formula I; and/or

d) forming a salt or solvate thereof. Step A

[0070] It will be understood by the person skilled in the art of organic chemistry that the compounds of the Formula (II) may be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0071] In an embodiment, the compounds of the Formula (II) may be prepared according to any one of the following methods:

Method 1

(a) reacting a compound of Formula

Formula (A)

(wherein R¹, R², X and Z are as defined herein)

with a compound of Formula (B):

Formula (B)

(wherein R³, Ar and Q are as defined herein and LG is a suitable leaving group (e.g.

a halo group)) in the presence of a suitable base (e.g. DMAP);

(b) optionally thereafter, and if necessary:

i) removing any protecting groups present;

ii) converting the compound Formula II into another compound of Formula II; and/or

forming a salt or solvate thereof.

Method 2

(a) reacting a compound of Formula (C):

Formula (C)

(wherein R¹ , R², X, Z and Q are as defined herein and LG is a suitable leaving group (e.g. a halo group))

with a compound of Formula (D):

Ar^ R³

Formula (D)

(wherein R³ and Ar are as defined herein)

in the presence of a suitable base and an iodide salt (e.g. potassium iodide);

(b) optionally thereafter, and if necessary:

i) removing any protecting groups present;

iii) forming a salt or solvate thereof.

[0072] In an embodiment, the compounds of Formula (II) are prepared by Method 1 as given above.

[0073] In another embodiment, the compounds of Formula (II) are prepared by Method 2 as given above.

[0074] It will be appreciated that suitable and preferred conditions for steps B and C of process 2 are identical to the suitable and preferred conditions for steps (i) and (ii) of process 1 described hereinabove.

[0075] In another aspect of the present invention there is provided a compound of Formula (I) obtainable by, obtained by or directly obtained by any one of the processes described hereinabove.

Process for the preparation of a compound of Formula (III)

Process 3

[0076] In another aspect, the present invention relates to a process for the preparation of a compound of Formula (III), as shown below:

(ill)

wherein:

Ar and R¹ are as defined hereinabove;

A is selected from OR^v SR^W or NR R^W, wherein R and R^w are independently selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl or heteroaryl-(1- 2C)alkyl; and

R^a1 and R^a2 are independently selected from H or a group of the formula:

-L-Y-W

wherein:

L is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl;

Y is absent or selected from SiR^a8R^a9, S0₂, C(O), C(0)0 or

C(0)N(R^z), wherein R^z, R^aS and R^a9 are independently selected from H or (1-4C)alkyl; and

W is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, aryl, heteroaryl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano or NR^aaR^ab, wherein R^aa and R^ab are independently selected from H or (1-4C)alkyl;

the process comprising the steps of:

) subjecting a compound of Formula (I), as shown below, with a base, an acid or a sequential combination thereof:

(I)

wherein R¹ , R², R³, R⁴, Ar, Q, X and Z are as defined hereinabove; 2) optionally, thereafter, and if necessary:

i) adding or removing any protecting groups;

ii) converting the compound Formula III into another compound of Formula III; and/or

iii) forming a salt or solvate thereof.

[0077] Suitably, the compounds of Formula (I) may be prepared according to any of the processes described hereinabove.

[0078] Step 1 of process 3 described hereinabove may be carried out in the presence of any suitable acid and/or base. Subjecting the compounds of Formula (I) to an acid, a base or a sequential combination thereof will be understood to result in the hydrolysis of the compounds of Formula (I).

[0079] It will be readily understood by the person skilled in the art that the acid and/or base used in Step 1 of the above process will vary according to the specific functional groups present in the compounds of Formula (I). Suitably, the acid is HCI or HBr and the base is NaOH, KOH or Ba(OH)₂.

[0080] Furthermore, any suitable reaction conditions may be used in step 1 of process 3 defined hereinabove.

[0081] The reaction conditions used in step 1 of process 3 will vary according to the compound of Formula (I) used. A person skilled in the art will be able to select suitable reaction conditions (e.g. temperature, pressures, reaction times, concentration etc.) to use in step 1 of the process.

[0082] In an embodiment, step 1 of process 3 of the present invention is conducted at a temperature of between 0 °C and 200 °C. Suitably, step 1 of process 3 of the present invention is conducted at a temperature of between 50 °C and 200 °C. More suitably, step 1 of process 3 of the present invention is conducted at a temperature of between 75°C and 175 °C. Yet more suitably, step 1 of process 3 of the present invention is conducted at a temperature of between 100 °C and 150 °C.

Process for the preparation of a compound of Formula (IV)

Process 4

[0083] In another aspect, the present invention relates to a process for the preparation of a compound of Formula (IV), as shown below:

(IV)

wherein:

Ar, R¹ and R³ are as defined hereinabove;

X¹ is S or O;

Q is selected from S, NR⁸ or O, wherein R⁸ is selected from H, (1-4C)alkyl or aryl; and

R⁹ is selected from H or a group of the formula:

-L^x-Y^x-W^x

wherein:

L^x is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl;

Y^x is absent or selected from SiR^a10R^a1\ S0₂, C(O), C(0)0 or C(0)N(R^z1), wherein R^z1 , R^a1° and R^a11 are independently selected from H or (1-4C)alkyl; and

W^x is selected from (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which is optionally substituted with one or more substituents selected from (1- 4C)alkyl, aryl, heteroaryl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro or cyano;

the process comprising the steps of:

) subjecting a compound of Formula (I), as shown below, with an acid:

(I)

i) adding or removing any protecting groups;

iii) forming a salt or solvate thereof.

[0084] Suitably, the compounds of Formula (I) may be prepared according to any of the processes described hereinabove.

[0085] It will be appreciated that suitable and preferred conditions for steps 1 of process 4 are identical to the suitable and preferred conditions for steps 1 of process 3 described hereinabove.

Compounds of the invention

Rearrangement products

[0086] In another aspect, the present invention provides a compound of Formula (I), or a salt, hydrate or solvate thereof, as defined hereinabove. The compounds of Formula (I) may synomously be referred to herein as the "rearrangement products", in reference to the rearrangement step defined in processes 1 and/or 2 of the present invention defined hereinabove.

[0087] Particular compounds of the invention include, for example, compounds of Formula I, or salts and/or solvates thereof, wherein, unless otherwise stated, each of X, Z, Q, Ar, R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (55) hereinafter: -

(1) X is selected from CR⁵R^S or C=0;

(2) X is selected from C=S or C=0;

(3) X is C=0;

(4) X is CR⁵R⁶;

(5) Z is selected from O or NR⁷;

(6) Z is selected from S or NR⁷;

(7) Z is NR⁷;

(8) Z is O;

(9) Q is selected from NR⁸ or O, wherein R⁸ is selected from H, (1-2C)alkyl or aryl;

(10) Q is selected from S, NR⁸ or O, wherein R⁸ is selected from H, methyl or phenyl;

(1 1) Q is selected from S or O;

(12) Q is O; (13) Ar is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, (1- 4C)alkoxy, azido, carboxy, carbamoyl, sulphamoyl, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^aR^b, OR^a, C(0)R^a, C(0)OR^a, C(0)N(R^b)R^a,

N(R^b)C(0)R^a, S(0)_yR^a (where y is 0, 1 or 2), S0₂N(R^b)R^a or N(R^b)S0₂R^a, wherein R^a and R^b are independently selected from H or (1-4C)alkyl;

(14) Ar is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, (1- 4C)alkoxy, azido, carboxy, carbamoyl, sulphamoyl, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^aR^b, OR^a, C(0)R^a, C(0)OR^a or C(0)N(R^b)R^a, wherein R^a and R^b are independently selected from H or (1-4C)alkyl;

(15) Ar is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, (1- 4C)alkoxy, carboxy, carbamoyl, sulphamoyl, hydroxy, cyano, aryl, heteroaryl, NR^aR^b, OR^a, C(0)R^a, C(0)OR^a or C(0)N(R^b)R^a, wherein R^a and R^b are independently selected from H or (1-4C)alkyl;

(16) Ar is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, (1- 4C)alkoxy, carboxy, carbamoyl, sulphamoyl, hydroxy, cyano, NR^aR^b or OR^a, wherein R^a and R^b are independently selected from H or (1-4C)alkyl;

(17) Ar is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, (1- 4C)alkoxy, cyano, NR^aR^b or OR^a, wherein R^a and R are independently selected from H or (1-4C)alkyl;

(18) R¹ is selected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1- 2C)alkyl or oxo;

W¹ is selected from H, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, SiR^a1R^a2R^a3 (wherein R^a1, R^a2 and R^a3 are independently selected from H, (1-4C)alkyl or aryl), (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or heteroaryl; each of which, other than H, cyano or SiR^a1R^a2R^a3, is optionally substituted with one or more substituents selected from nitro, cyano, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, amino, hydroxy, azido, carboxy, carbamoyl, sulphamoyl, aryl, aryl-(1-2C)alkyl, heteroaryl, (1-4C)alkyl, OR⁹, NR^eR^f, C(0)R⁹, C(0)OR⁹, OC(0)R⁹, C(0)N(R^h)R⁹, N(R^h)C(0)R⁹, S(0)_yR⁹ (where y is 0, 1 or 2), S0₂N(R^h)R⁹, N(R^h)S0₂R⁹ or

(CH₂)wNR^hR⁹ (where w is 1 , 2 or 3), wherein R⁹ and R^h are each independently selected from H, (1-4C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl or heteroaryl-(1-2C)-alkyl; and wherein R^e and R^f are independently selected from H, (1-4C)alkyl or a group of the formula:

-L²-Y²-W²

wherein:

L² is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl;

Y² is absent or selected from SiR^a4R^a5, S0₂, C(O), C(0)0 or CiO R¹), wherein R', R^a4 and R^a5 are each independently selected from H or (1-4C)alkyl;

W² is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1- 2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heterocyclyl or NR^jR^k, wherein R^j and R^k are independently selected from H or (1-6C)alkyl; or R^j and R^k are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl, which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, amino, hydroxy or cyano; or R^c and W¹ are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl which is optionally substituted with one or more substituents selected from halo, hydroxyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy or NR'R^m, wherein R' and R^m are each independently selected from H or (1-4C)alkyl;

elected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1- 2C)alkyl or oxo;

W¹ is selected from H, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, SiR^{a1 a2}R^a3 (wherein R^a1, R^a2 and R^a3 are independently selected from H, (1-4C)alkyl or aryl), (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or heteroaryl; each of which, other than H, cyano or SiR^a1R^a2R^a3, is optionally substituted with one or more substituents selected from nitro, cyano, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, amino, hydroxy, azido, carboxy, carbamoyl, sulphamoyl, aryl, aryl-(1-2C)alkyl, heteroaryl, (1-4C)alkyl, OR⁹, NR^eR^f, C(0)R⁹, C(0)OR⁹, OC(0)R⁹, C(0)N(R^h)R⁹, N(R^h)C(0)R⁹, S(0)_yR⁹ (where y is 0, 1 or 2), S0₂N(R^h)R⁹, N(R^h)S0₂R⁹ or (CH₂)_wNR^hR⁹ (where w is 1 , 2 or 3), wherein R⁹ and R^h are each independently selected from H, (1-4C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl or heteroaryl-(1-2C)-alkyl; and wherein R^e and R^f are independently selected from H, (1-4C)alkyl or a group of the formula:

-L²-Y²-W²

wherein:

L² is absent or (1-2C)alkylene; Y² is absent or selected from SiR^a4R^a5, C(O), C(0)0 or Ο(Ο)Ν^), wherein R', R^a4 and R^a5 are each

independently selected from H or (1-2C)alkyl;

W² is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1- 2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heterocyclyl or NR^jR^k, wherein R^j and R^k are independently selected from H or (1-2C)alkyl; or R^c and W¹ are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl which is optionally substituted with one or more substituents selected from halo, hydroxyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy or NR'R^m, wherein R' and R^m are each independently selected from H or (1-4C)alkyl;

elected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1- 2C)alkyl or oxo;

W¹ is selected from H, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, SiR^{a1 a2}R^a3 (wherein R^a1, R^a2 and R^a3 are independently selected from H, (1-4C)alkyl or aryl), (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or heteroaryl; each of which, other than H, cyano or SiR^a1R^a2R^a3, is optionally substituted with one or more substituents selected from nitro, cyano, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, amino, hydroxy, azido, carboxy, carbamoyl, sulphamoyl, aryl, aryl-(1-2C)alkyl, heteroaryl, (1-4C)alkyl, OR⁹, NR^eR^f, C(0)R⁹, C(0)OR⁹, OC(0)R⁹, C(0)N(R^h)R⁹, N(R^h)C(0)R⁹, S(0)_yR⁹ (where y is 0, 1 or 2), S0₂N(R^h)R⁹, N(R^h)S0₂R⁹ or

(CH₂)_wNR^hR⁹ (where w is 1 , 2 or 3), wherein R⁹ and R^h are each independently selected from H, (1-4C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl or heteroaryl-(1-2C)-alkyl; and wherein R^e and R^f are independently selected from H, (1-4C)alkyl or a group of the formula:

-Y²-W²

wherein:

Y² is absent or selected from SiR^a4R^a5, C(O), C(0)0 or C(0)N(R'), wherein R', R^a4 and R^a5 are each

independently selected from H or (1-2C)alkyl;

W² is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1- 2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano or NR^jR^k, wherein R^j and R^k are independently selected from H or (1-2C)alkyl; or

R^c and W¹ are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl which is optionally substituted with one or more substituents selected from halo, hydroxyl, amino, cyano, (1- 4C)alkyl, (1-4C)alkoxy or NR'R^m, wherein R' and R^m are each independently selected from H or (1-2C)alkyl;

(21) R¹ is selected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1- 2C)alkyl or oxo;

Y¹ is absent or selected from O, N(R^C), S, SO, S0₂, Se, C(O), C(0)0, OC(O), C(0)N(R^c), N(R^d)C(0), N(R^d)C(0)N(R^c), N(R^d)C(NH)N(R^c), S(0)₂N(R^c), or N(R^d)S0₂, wherein R^cand R^d are each independently selected from H or (1-4C)alkyl; and W¹ is selected from H, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, SiR^a1R^a2R^a3 (wherein R^a1, R^a2 and R^a3 are independently selected from H, (1-4C)alkyl or aryl), (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or heteroaryl; each of which, other than H, cyano or SiR^a1R^a2R^a3, is optionally substituted with one or more substituents selected from nitro, cyano, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, amino, hydroxy, azido, carboxy, carbamoyl, sulphamoyl, aryl, aryl-(1-2C)alkyl, heteroaryl, (1-4C)alkyl, OR⁹, NR^eR^f, C(0)R⁹, C(0)OR⁹, OC(0)R⁹, C(0)N(R^h)R⁹, N(R^h)C(0)R⁹, S(0)_yR⁹ (where y is 0, 1 or 2), S0₂N(R^h)R⁹, N(R^h)S0₂R⁹ or (CH₂)_wNR^hR⁹ (where w is 1 , 2 or 3), wherein R^s and R^h are each independently selected from H, (1-4C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl or heteroaryl-(1-2C)-alkyl; and wherein R^e and R^f are independently selected from H or (1-4C)alkyl: or R^c and W¹ are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl which is optionally substituted with one or more substituents selected from halo, hydroxyl, amino, cyano, (1-4C)alkyl, (1-4C)alkoxy or NR'R^m, wherein R' and R^m are each independently selected from H or (1- 2C)alkyl;

elected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1- 2C)alkyl or oxo;

W¹ is selected from H, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, SiR^a1R^a2R^a3 (wherein R^a1, R^a2 and R^a3 are independently selected from H, (1-4C)alkyl or aryl), (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or

heteroaryl; each of which, other than H, cyano or SiR^a1R^a2R^a3, is optionally substituted with one or more substituents selected from nitro, cyano, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, amino, hydroxy, azido, carboxy, carbamoyl, sulphamoyl, aryl, aryl-(1-2C)alkyl, heteroaryl, (1-4C)alkyl, OR⁹, NR^eR^f, C(0)R⁹, C(0)OR⁹, OC(0)R⁹, C(0)N(R^h)R⁹, N(R^h)C(0)R⁹, S(0)_yR⁹ (where y is 0, 1 or 2), S0₂N(R^h)R⁹, N(R^h)S0₂R⁹ or

(CH₂)wNR^hR⁹ (where w is 1 , 2 or 3), wherein R⁹ and R^h are each independently selected from H, (1-4C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl or heteroaryl-(1-2C)-alkyl; and wherein R^e and R^f are independently selected from H or (1-4C)alkyl; (23) R¹ is selected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1- 2C)alkyl or oxo;

Y¹ is absent or selected from O, N(R^C), S, SO, S0₂, Se, C(O), C(0)0, OC(O) or C(0)N(R^c), wherein R^c is selected from H or (1-2C)alkyl; and

(CH₂)_wNR^hR⁹ (where w is 1 , 2 or 3), wherein R⁹ and R^h are each independently selected from H, (1-4C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl or heteroaryl-(1-2C)-alkyl; and wherein R^e and R^f are independently selected from H or (1-4C)alkyl; (24) R¹ is selected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene;

Y¹ is absent or selected from O, N(R^C), Se, C(O), C(0)0 or C(0)N(R^c), wherein R^c is selected from H or (1-2C)alkyl; and W¹ is selected from H, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, SiR^a1R^a2R^a3 (wherein R^a1, R^a2 and R^a3 are independently selected from H, (1-4C)alkyl or aryl), (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or heteroaryl; each of which, other than H, cyano or SiR^a1R^a2R^a3, is optionally substituted with one or more substituents selected from nitro, cyano, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, amino, hydroxy, azido, carboxy, carbamoyl, sulphamoyl, aryl, aryl-(1-2C)alkyl, heteroaryl, (1-4C)alkyl, OR⁹, NR^eR^f, C(0)R⁹, C(0)OR⁹, OC(0)R⁹, C(0)N(R^h)R⁹, N(R^h)C(0)R⁹, S(0)_yR⁹ (where y is 0, 1 or 2), S0₂N(R^h)R⁹, N(R^h)S0₂R⁹ or

(CH₂)_wNR^hR⁹ (where w is 1 , 2 or 3), wherein R⁹ and R^h are each independently selected from H, (1-4C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl or heteroaryl-(1-2C)-alkyl; and wherein R^e and R^f are independently selected from H or (1-4C)alkyl;

(25) R¹ is selected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene;

Y¹ is absent or selected from C(0)0 or C(0)N(R^c), wherein R^c is selected from H or (1-2C)alkyl; and

W¹ is selected from H, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, SiR^a1R^a2R^a3 (wherein R^a1, R^a2 and R^a3 are independently selected from H, (1-4C)alkyl or aryl), (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or heteroaryl; each of which, other than H, cyano or SiR^a1R^a2R^a3, is optionally substituted with one or more substituents selected from nitro, cyano, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, amino, hydroxy, carboxy, carbamoyl, sulphamoyl, aryl, aryl-(1- 2C)alkyl, heteroaryl, (1-4C)alkyl, OR⁹, NR^eR^f, C(0)R⁹,

C(0)OR⁹, OC(0)R⁹, C(0)N(R^h)R⁹, N(R^h)C(0)R⁹, S(0)_yR⁹ (where y is 0, 1 or 2), S0₂N(R^h)R⁹, N(R^h)S0₂R⁹ or

(CH₂)_wNR^hR⁹ (where w is 1 , 2 or 3), wherein R⁹ and R^h are each independently selected from H, (1-4C)alkyl, aryl, aryl-(1- 2C)alkyl or heteroaryl; and wherein R^e and R^f are

independently selected from H or (1-4C)alkyl;

(26) R² is selected from H, (1-8C)alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, NRⁿR°, C(0)Rⁿ, C(0)ORⁿ, C(0)N(R°)Rⁿ or N(R°)C(0)Rⁿ, wherein Rⁿ and R° are each independently selected from H or (1-4C)alkyl; or Rⁿ and R° are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl;

(27) R² is selected from H, (1-8C)alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, NRⁿR°, C(0)Rⁿ, C(0)ORⁿ, C(0)N(R°)Rⁿ or N(R°)C(0)Rⁿ, wherein Rⁿ and R° are each independently selected from H or (1-4C)alkyl;

(28) R² is selected from H, (1-8C)alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano or N ⁿR°, wherein Rⁿ and R° are each independently selected from H or (1-4C)alkyl;

(29) R² is selected from H, (1-8C)alkyl, aryl, 5- or 6-membered heteroaryl, (3-8C)cycloalkyl or heterocyclyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano or NRⁿR°, wherein Rⁿ and R° are each independently selected from H or (1-4C)alkyl;

(30) R² is selected from H, (1-8C)alkyl, phenyl, 5- or 6-membered heteroaryl or (3- 8C)cycloalkyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano or NRⁿR°, wherein Rⁿ and R° are each independently selected from H or (1-4C)alkyl;

(31) R² is selected from H, (1-8C)alkyl, phenyl, 5- or 6-membered heteroaryl or (3- 8C)cycloalkyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano or NRⁿR°, wherein Rⁿ and R° are each independently selected from H or (1-4C)alkyl;

(32) R² is selected from H, (1-8C)alkyl, phenyl, 5- or 6-membered heteroaryl or (3- 8C)cycloalkyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, hydroxy, nitro, cyano or NRⁿR°, wherein Rⁿ and R° are each independently selected from H or (1-2C)alkyl;

(33) R² is selected from H, (1-8C)alkyl, phenyl, 5- or 6-membered heteroaryl or (3- 8C)cycloalkyl;

(34) R² is (1-8C)alkyl;

(35) R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1- 2C)alkyl, cycloalkyl, cycloalkenyl or heterocyclyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano, aryl, heterocyclyl or NR^pR^q, wherein R^p and R^q are each independently selected from H or (1-4C)alkyl;

(36) R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1- 2C)alkyl, cycloalkyl, cycloalkenyl or heterocyclyl;

(37) R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl or heteroaryl, each of which, other than H, is optionally substituted with one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano or NR^pR^q, wherein R^p and R^q are each independently selected from H or (1-4C)alkyl;

(38) R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl or heteroaryl;

(39) R³ is H or (1-6C)alkyl;

(40) R⁴ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl or heteroaryl-(1- 2C)alkyl, and wherein each (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1- 2C)alkyl is optionally substituted with one or more substituents selected from (1- 4C)alkyl, halo, hydroxy, nitro or cyano;

(41) R⁴ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl or heteroaryl-(1- 2C)alkyl;

(42) R⁴ is selected from H, (1-6C)alkyl, aryl or aryl-(1-2C)alkyl;

(43) R⁴ is H;

(44) R⁵ and R⁵ are independently selected from H, (1-4C)alkyl, aryl or heteroaryl;

(45) R⁵ and R^s are independently selected from H or (1-4C)alkyl;

(46) R⁵ and R^s are H;

(47) R⁷ is selected from H or a group of the formula: -L³-Y³-W³

wherein:

L³ is absent or (1-4C)alkylene;

Y³ is absent or selected from SiR^a6R^a7, C(O), C(0)0 or C(0)N(R^s), wherein R^s, R^a6 and R^a7 are each independently selected from H or (1- 2C)alkyl;

W³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyi, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano or NR'R^U, wherein R¹ and R^u are independently selected from H or (1-4C)alkyl;

(48) R⁷ is selected from a group of the formula:

-L³-Y³-W³

wherein:

L³ is absent or (1-4C)alkylene;

W³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyi, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano or NR'R^U, wherein R' and R^u are independently selected from H or (1-4C)alkyl;

with the proviso that R⁷ is not H;

(49) R⁷ is selected from H or a group of the formula:

-Y³-W³

wherein:

W³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano or NR'R^U, wherein R' and R^u are independently selected from H or (1-4C)alkyl;

(50) R⁷ is selected from a group of the formula:

-Y³-W³

wherein:

Y³ is absent or selected from C(0)0 or C(0)N(R^s), wherein R^s is selected from H or (1-2C)alkyl;

with the proviso that R⁷ is not H;

(51) R⁷ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1- 2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano or NR'R^U, wherein R' and R^u are independently selected from H or (1- 4C)alkyl;

(52) R⁷ is selected from (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1- 2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano or NR'R^U, wherein R' and R^u are independently selected from H or (1- 4C)alkyl;

(53) R⁷ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1- 2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1-2C)alkyl or cycloalkenyl;

(54) R⁷ is selected from H, (1-6C)alkyl, aryl or aryl-(1-2C)alkyl;

(55) R⁷ is (1-6C)alkyl. [0088] The term "organometallic complex" will be readily understood by the person skilled in the art to mean a chemical compound comprising at least one bond between a carbon atom of an organic compound and a metal. An example of a related structure containing an organometallic complex is described in W09612726A1.

[0089] In an embodiment, the organometallic complex is a ferrocenyl based complex, suitably ferrocenyl.

[0090] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.

[0091] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0092] Suitably, a heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, a heterocyclyl group is a 5-, 6- or 7-membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. morpholinyl (e.g. 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl or pyrrolidinonyl].

[0093] Suitably an aryl group is phenyl.

[0094] Suitably, X is as defined in any one of paragraphs (1) to (4). Most suitably, X is as defined in paragraph (4).

[0095] Suitably, Z is as defined in any one of paragraphs (5) to (8). Most suitably, Z is as defined in paragraph (8).

[0096] Suitably, Q is as defined in any one of paragraphs (9) to (12). Most suitably, Q is as defined in paragraph (12).

[0097] Suitably, Ar is as defined in any one of paragraphs (13) to (17). Most suitably, Ar is as defined in paragraph (17).

[0098] Suitably, R¹ is as defined in any one of paragraphs (18) to (25). More suitably, R¹ is as defined in any one of paragraphs (22) to (25). Most suitably, R¹ is as defined in paragraph (25).

[0099] Suitably, R² is as defined in any one of paragraphs (26) to (34). More suitably, R² is as defined in any one of paragraphs (29) to (34). Most suitably, R² is as defined in paragraph (34).

[00100] Suitably, R³ is as defined in any one of paragraphs (35) to (39). Most suitably, R³ is as defined in paragraph (39).

[00101] Suitably, R⁴ is as defined in any one of paragraphs (40) to (43). Most suitably, R⁴ is as defined in paragraph (43). [00102] Suitably, R⁵ and R⁶ are as defined in any one of paragraphs (44) to (46). Most suitably, R⁵ and R^s are as defined in paragraph (46).

[00103] Suitably, R⁷ is as defined in any one of paragraphs (47) to (55). More suitably, R⁷ is as defined in any one of paragraphs (47), (51) or (53) to (55). Most suitably, R⁷ is as defined in paragraph (55).

[00104] In a particular group of compounds of the invention, the compounds are enantioenriched and thus have the structural formula la or lb (sub-definitions of Formula (I)) shown below or a salt, hydrate and/or solvate thereof:

la lb wherein each of X, Z, Q, Ar, R¹ , R², R³ and R⁴ are as defined herein.

[00105] In an embodiment of the compounds of Formulae la and lb:

X is as defined in any one of paragraphs (1) to (4) above;

Z is as defined in any one of paragraphs (5) to (8) above;

Q is as defined in any one of paragraphs (9) to (12) above;

Ar is as defined in any one of paragraphs (13) to (17) above;

R¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above; and

R⁴ is as defined in any one of paragraphs (40) to (43) above.

[00106] In another embodiment of the compounds of Formulae la and lb:

X is as defined in paragraph (4) above;

Z is as defined in paragraph (8) above;

Q is as defined in paragraph (12) above;

Ar is as defined in paragraph (17) above;

R¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above;

R³ is as defined in paragraph (39) above; and

R⁴ is as defined in paragraph (43) above. [00107] In another group of compounds of the invention, Q is oxygen i.e. the compounds have the structural Formula Ic (a sub-definition of Formula (I)) shown below, or an acceptable salt, hydrate and/or solvate thereof:

Ic

wherein each of X, Z, Ar, R¹ , R², R³ and R⁴ are as defined herein.

[00108] In an embodiment of the compounds of Formula Ic:

X is as defined in any one of paragraphs (1) to (4) above;

Z is as defined in any one of paragraphs (5) to (8) above;

Ar is as defined in any one of paragraphs (13) to (17) above;

R¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above; and

R⁴ is as defined in any one of paragraphs (40) to (43) above.

[00109] In another embodiment of the compounds of Formula Ic:

X is as defined in paragraph (4) above;

Z is as defined in paragraph (8) above;

Ar is as defined in paragraph (17) above;

R¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above;

R³ is as defined in paragraph (39) above;

R⁴ is as defined in paragraph (43) above.

[00110] In another group of compounds of the invention, Q is oxygen and R⁴ is H, i.e. the compounds have the structural Formula Id (a sub-definition of Formula (I)) shown below, or an acceptable salt, hydrate and/o

Id wherein each of X, Z, Ar, R¹ , R² and R³ are as defined herein.

[00111] In an embodiment of the compounds of Formula Id:

X is as defined in any one of paragraphs (1) to (4) above;

Z is as defined in any one of paragraphs (5) to (8) above;

Ar is as defined in any one of paragraphs (13) to (17) above;

R¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above.

[00112] In another embodiment of the compounds of Formula Id:

X is as defined in paragraph (4) above;

Z is as defined in paragraph (8) above;

Ar is as defined in paragraph (17) above;

R¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above; and

R³ is as defined in paragraph (39) above.

[00113] In another group of compounds of the invention, Q is oxygen, R⁴ is H, X is C=0 and Z is NR⁷, i.e. the compounds have the structural Formula le (a sub-definition of Formula (I)) shown below, or an accepta thereof:

le

wherein each of Ar, R¹, R², R³ and R⁷ are as defined herein.

[00114] In an embodiment of the compounds of Formula le:

Ar is as defined in any one of paragraphs (13) to (17) above;

R¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above; and

R⁷ is as defined in any one of paragraphs (47) to (55) above.

[00115] In another embodiment of the compounds of Formula le:

Ar is as defined in paragraph (17) above;

R¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above; R³ is as defined in paragraph (39) above; and

R⁷ is as defined in paragraph (55) above.

[00116] In another group of compounds of the invention, Q is oxygen, R⁴ is H, X is C=0, Z is NR⁷and the compounds are enantioenriched, i.e. the compounds have the structural Formula If or Ig (sub-definitions of Formula (I)) shown below, or an acceptable salt, hydrate and/or solvat

If

wherein each of Ar, R\ R², R³ and R⁷ are as defined herein.

[00117] In an embodiment of the compounds of Formulae If and Ig:

Ar is as defined in any one of paragraphs (13) to (17) above;

R¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above; and

R⁷ is as defined in any one of paragraphs (47) to (55) above.

[00118] In another embodiment of the compounds of Formulae If and Ig:

Ar is as defined in paragraph (17) above;

R¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above;

R³ is as defined in paragraph (39) above; and

R⁷ is as defined in paragraph (55) above

[00119] In another group of compounds of the invention, Q is oxygen, R⁴ is H, X is CR⁵R⁶, Z is O and R¹ is of the formula C(0)OW¹, i.e. the compounds have the structural Formula Ih (a sub-definition of Formula (I)) shown below, or an acceptable salt, hydrate and/or solvate thereof:

Ih

wherein each of Ar, R², R³, R⁵, R⁶ and W¹ are as defined herein.

[00120] In an embodiment of the compounds of Formula Ih:

Ar is as defined in any one of paragraphs (13) to (17) above;

W¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above; and

R⁵ and R⁶ are as defined in any one of paragraphs (44) to (46) above.

[00121] In another embodiment of the compounds of Formula Ih:

Ar is as defined in paragraph (17) above;

W¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above;

R³ is as defined in paragraph (39) above; and

R⁵ and R⁶ are as defined in paragraph (46) above.

[00122] In another group of compounds of the invention, Q is oxygen, R⁴ is H, X is CR⁵R⁶, Z is O, R¹ is of the formula C(0)OW¹ and the compounds are enantioenriched, i.e. the compounds have the structural Formula Ij or Ik (sub-definitions of Formula (I)) shown below, or an acceptable salt, hydrate and/or solvate thereof:

wherein each of Ar, R², R³, R⁵, R⁶ and W¹ are as defined herein.

[00123] In an embodiment of the compounds of Formulae Ij and Ik:

Ar is as defined in any one of paragraphs (13) to (17) above;

W¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above; and

R⁵ and R⁶ are as defined in any one of paragraphs (44) to (46) above.

[00124] In another embodiment of the compounds of Formula Ij and Ik:

Ar is as defined in paragraph (17) above;

W¹ is as defined in paragraph (25) above;

R⁵ and R⁶ are as defined in paragraph (46) above.

[00125] Particular compounds of Formula (I) (i.e. the present invention) include any of the compounds exemplified in the present application, or a salt or solvate thereof, and, in pa

[00126] Further particular compounds of Formula (I) (i.e. the present invention) include any of the compounds exemplified in the present application, or a salt or solvate thereof, and, in particular, any of the following:

Precursor compounds

[00127] In another aspect, the present invention provides a compound of Formula (II), or a salt, hydrate or solvate thereof, as defined herein. The compounds of Formula (II) may synomously be referred to herein as the precursor compounds, in reference to them being the precursors for the rearrangement step defined in processes 1 and/or 2 of the present invention hereinabove.

[00128] Thus, the present invention provides a compound of Formula (II) as shown below, or a salt or solvate thereof:

(ID

wherein:

X is selected from CR⁵R⁶, C=S or C=0;

Z is selected from O, S or NR⁷;

Ar is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, (1-4C)alkoxy, azido, carboxy, carbamoyl, sulphamoyl, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^aR^b, OR^a, C(0)R^a, C(0)OR^a, OC(0)R^a, C(0)N(R )R^a, N(R )C(0)R^a, S(0)_yR^a (where y is 0, 1 or 2), S0₂N(R^b)R^a, N(R )S0₂R^a or (CH₂)_zNR^bR^a (where z is 1 , 2 or 3), wherein R^a and R^b are independently selected from H or (1-4C)alkyl;

R¹ is selected from H, cyano, nitro, halo, hydroxyl, or a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1- 2C)alkyl or oxo;

W¹ is selected from H, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, SiR^a1R^a2R^a3 (wherein R^a1, R^a2 and R^a3 are independently selected from H or (1-4C)alkyl), (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or heteroaryl; each of which, other than H and SiR^a1R^a2R^a3, is optionally substituted with one or more substituents selected from nitro, cyano, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, amino, hydroxy, azido, carboxy, carbamoyl, sulphamoyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, (1-4C)alkyl, OR⁹, NR^eR^f, C(0)R⁹, C(0)OR⁹, OC(0)R⁹, C(0)N(R^h)R⁹, N(R^h)C(0)R⁹, S(0)_yR⁹ (where y is 0, 1 or 2), S0₂N(R^h)R⁹, N(R^h)S0₂R⁹ or (CH₂)wNR^hR⁹ (where w is 1 , 2 or 3), wherein R⁹ and R^h are each independently selected from H, (1-4C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl or heteroaryl-(1-2C)-alkyl; and wherein R^e and R^f are independently selected from H, (1-4C)alkyl or a group of the formula:

-L²-Y²-W²

wherein:

L² is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl;

Y² is absent or selected from SiR^a4R^a5, S0₂, C(O), C(0)0 or Ο(Ο)Ν^), wherein R', R^a4 and R^a5 are each independently selected from H or (1-4C)alkyl; W² is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyi, cycloalkyl-(1- 2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heterocyclyl or NR^jR^k, wherein R^j and R^k are independently selected from H or (1-6C)alkyl;or

R^j and R^k are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl, which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, amino, hydroxy or cyano; or

R^c and W¹ are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl which is optionally substituted with one or more substituents selected from halo, hydroxyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, aryl, heteroaryl, NR'R^m, C(0)R', C(0)OR', C(0)N(R^m)R' or

N(R^m)C(0)R', wherein R' and R^m are each independently selected from H or (1-4C)alkyl;

or R' and R^m are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl, which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, hydroxyl, amino, nitro or cyano;

R² is selected from H, (1-8C)alkyl, aryl, heteroaryl, cycloalkyi, cycloalkenyl or heterocyclyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano, NRⁿR°, C(0)Rⁿ, C(0)ORⁿ,

C(0)N(R°)Rⁿ or N(R°)C(0)Rⁿ, wherein Rⁿ and R° are each independently selected from H or (1-4C)alkyl;

or Rⁿ and R° are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl, which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, amino, hydroxy or cyano; or R² is an organometallic complex;

R³ is selected from H, (1-6C)alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl or SiR^b1 R^b2R^b3 (wherein R ¹ , R^b2 and R^b3 are independently selected from H or (1-4C)alkyl), each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heterocyclyl, NR^PR", C(0)R^p, C(0)OR^p, C(0)N(R^q)R^p or N(R^q)C(0)R^p, wherein R^p and R^q are each independently selected from H or (1-4C)alkyl; or

R³ is linked with Ar such that, together with the nitrogen atom to which R³ is attached they form a 4- to 15-membered heterocyclyl or heteroaryl, which is optionally substituted with one or more substituents halo, hydroxy, amino, nitro, cyano, (1-4)alkyl or (1-4C)alkoxy;

R⁵ and R⁶ are independently selected from H, (1-4C)alkyl, halo or (1- 4C)alkoxy;

R⁷ is selected from H or a group of the formula:

-L³-Y³-W³

wherein:

L³ is absent or (1-4C)alkylene optionally substituted by (1-2C)alkyl;

Y³ is absent or selected from SiR^a6R^a7, S0₂, C(O), C(0)0 or

C(0)N(R^s), wherein R^s, R^aS and R^a7 are independently selected from H or (1-4C)alkyl;

W₃ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano or NR^lR^u, wherein R^l and R^u are independently selected from H or (1-4C)alkyl;

with the proviso that:

(ii) when R¹ is a carbonyl moiety (i.e. a group selected from C(0)-W¹, C(0)0-W\ C(0)N(R^c)-W¹), X is CR⁵R⁶; and

(iii) when R¹ is not a carbonyl moiety, X is C=0 or C=S. [00129] Particular precursor compounds, include, for example, compounds of Formula (II), or salts and/or solvates thereof, wherein, unless otherwise stated, each of X, Z, Q, Ar, R¹ , R², R³ and any associated substituent groups has any of the meanings defined in any of paragraphs (1) to (55) hereinbefore.

[00130] Suitable X, Z, Q, Ar, R\ R² and R³ groups of the compounds of Formula (II) are identical to the suitable X, Z, Q, Ar, R¹ , R² and R³ groups of the compounds of Formula (I), as defined hereinabove.

[00131] In a particular group of compounds of Formula (II), the compounds are enantioenriched and thus have the structural formula lla or lib (sub-definitions of Formula (II)) shown below,

(lla) (lib)

[00132] In an embodiment of the compounds of Formulae lla and lib:

X is as defined in any one of paragraphs (1) to (4) above;

Z is as defined in any one of paragraphs (5) to (8) above;

Q is as defined in any one of paragraphs (9) to (12) above;

Ar is as defined in any one of paragraphs (13) to (17) above;

R¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above; and

R³ is as defined in any one of paragraphs (35) to (39) above.

[00133] In another embodiment of the compounds of Formulae lla and lb:

X is as defined in paragraph (4) above;

Z is as defined in paragraph (8) above;

Q is as defined in paragraph (12) above;

Ar is as defined in paragraph (17) above;

R¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above; and

R³ is as defined in paragraph (39) above. [00134] In another group of compounds of Formula (II), Q is oxygen i.e. the compounds have the structural formula lie (a sub-definition of Formula (II)) shown below, or an acceptable salt, hydrate and/or solvate thereof:

lie

wherein each of X, Z, Ar, R¹ , R² and R³ are as defined herein.

[00135] In an embodiment of the compounds of Formula lie:

X is as defined in any one of paragraphs (1) to (4) above;

Z is as defined in any one of paragraphs (5) to (8) above;

Ar is as defined in any one of paragraphs (13) to (17) above;

R¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above; and

R³ is as defined in any one of paragraphs (35) to (39) above.

[00136] In another embodiment of the compounds of Formula lie:

X is as defined in paragraph (4) above;

Z is as defined in paragraph (8) above;

Ar is as defined in paragraph (17) above;

R¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above; and

R³ is as defined in paragraph (39) above.

[00137] In a further group of compounds of Formula (II), Q is oxygen, X is C=0 and Z is NR⁷, i.e. the compounds have the structural formula lid (a sub-definition of Formula (II)) shown below, or an acceptable reof:

lid

wherein each of Ar, R¹, R², R³ and R⁷ are as defined herein.

[00138] In an embodiment of the compounds of Formula lid: Ar is as defined in any one of paragraphs (13) to (17) above;

R¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above; and

R⁷ is as defined in any one of paragraphs (47) to (55) above.

[00139] In another embodiment of the compounds of Formula lid:

Ar is as defined in paragraph (17) above;

R¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above;

R³ is as defined in paragraph (39) above; and

R⁷ is as defined in paragraph (55) above.

[00140] In yet another group of compounds of Formula (II), Q is oxygen, X is C=0, Z is NR⁷ and the compounds are enantioenriched, i.e. the compounds have the structural formula lie or I If (sub-definitions of Formula (II)) shown below, or an acceptable salt, hydrate and/or solvate

[00141] In an embodiment of the compounds of Formulae lie and llf:

Ar is as defined in any one of paragraphs (13) to (17) above;

R¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above; and

R⁷ is as defined in any one of paragraphs (47) to (55) above.

[00142] In another embodiment of the compounds of Formulae lie and llf:

Ar is as defined in paragraph (17) above;

R¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above;

R³ is as defined in paragraph (39) above; and

R⁷ is as defined in paragraph (55) above. [00143] In yet a further group of compounds of Formula (II), Q is oxygen, X is CR⁵R⁶, Z is O and R¹ is of the formula C(0)OW¹, i.e. the compounds have the structural formula llg (a sub- definition of Formula (II)) shown below, or an acceptable salt, hydrate and/or solvate thereof:

wherein each of Ar, R², R⁴, R⁵, R⁶ and W¹ are as defined herein.

[00144] In an embodiment of the compounds of Formula llg:

Ar is as defined in any one of paragraphs (13) to (17) above;

W¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above; and

R⁵ and R⁶ are as defined in any one of paragraphs (44) to (46) above.

[00145] In another embodiment of the compounds of Formula llg:

Ar is as defined in paragraph (17) above;

W¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above;

R³ is as defined in paragraph (39) above; and

R⁵ and R⁶ are as defined in paragraph (46) above.

[00146] In another group of compounds of Formula (II), Q is oxygen, X is CR⁵R^S, Z is O, R¹ is of the formula C(0)OW¹ and the compounds are enantioenriched, i.e. the compounds have the structural formula llh or llj (sub-definitions of Formula (II)) shown below, or an acceptable salt, hydrate and/or solvate thereof:

llh llj wherein each of Ar, R², R⁴, R⁵, R⁶ and W¹ are as defined herein. [00147] In an embodiment of the compounds of Formulae llh and llj:

Ar is as defined in any one of paragraphs (13) to (17) above;

W¹ is as defined in any one of paragraphs (18) to (25) above;

R² is as defined in any one of paragraphs (26) to (34) above;

R³ is as defined in any one of paragraphs (35) to (39) above; and

R⁵ and R⁶ are as defined in any one of paragraphs (44) to (44) above.

[00148] In another embodiment of the compounds of Formula llh and llj:

Ar is as defined in paragraph (17) above;

W¹ is as defined in paragraph (25) above;

R² is as defined in paragraph (34) above;

R³ is as defined in paragraph (39) above; and

R⁵ and R⁶ are as defined in paragraph (46) above.

[00149] Particular compounds of Formula (II) (i.e. the present invention) include any of the compounds exemplified in the present application, or a salt or solvate thereof, and, in particular, any of the following:

[00150] In certain embodiments of the compounds of Formula (II), one or more of the following provisos may apply:

- the compou ompounds:

R¹ is not aminomethylene or benzyl;

- when Ar is pyrimidine, R¹ is not H;

- when X is CR⁵CR⁶, Z is not S; and/or

- when Z is S, R² is not isopropyl.

Amino acid compounds

[00151] In yet another aspect, the present invention provides a compound of Formula (lll-1a) as shown below, or a salt or solvate thereof:

(lll-1a)

wherein:

A is selected from OR^v SR^W or NR R^W, wherein R^v and R^w are independently selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl or heteroaryl-(1- 2C)alkyl;

Ar¹ and R¹¹ are independently selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^xR^y, C(0)R^x, C(0)OR^x, C(0)N(R^y)R^x, N(R*)C(0)R^x S(0)_yR^x (where y is 0, 1 or 2), S0₂N(R^)R^x, N(R^y)S0₂R^x or (CH₂)zNR^yR^x (where z is 1 , 2 or 3), wherein R^x and R^y are independently selected from H or (1-4C)alkyl; and

R^a1 and R^a2 are independently selected from H or a group of the formula:

-L-Y-W

wherein:

L is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl;

Y is absent or selected from SiR^a8R^a9, S0₂, C(O), C(0)0 or

C(0)N(R^z), wherein R^z, R^a8 and R^a9 are independently selected from H or (1-4C)alkyl; and

with the proviso that when Ar¹ and R¹¹ are both optionally substituted aryl groups, the compound of Formula (111-1 a) is not racemic and is not selected from one of the following:

[00152] In an embodiment of the compounds of Formula (lll-1 a), when Ar¹ and R¹¹ are both optionally substituted aryl groups, the compound of Formula (II 1-1 a) is not racemic and is not sele

[00153] In an embodiment of the compound of Formula (lll-1 a), at least one of Ar¹ and R¹¹ is a heteroaryl.

[00154] Particular compounds of the Formula (lll-1 a), include, for example, compounds of Formula lll-1 a or salts and/or solvates thereof, wherein, unless otherwise stated, each of R^a1 , R^a2, A, Ar, R¹ and any associated substituent groups have any of the meanings defined hereinbefore or in any of paragraphs (A1) to (A22) hereinafter: -

(A1) A is selected from OR^v SR^W or NR R^W, wherein R^v and R^w are independently selected from H, (1-6C)alkyl, aryl or heteroaryl;

(A2) A is selected from OR^v SR^W or NR^VR^W, wherein R^v and R^w are independently selected from H or (1-6C)alkyl;

(A3) A is selected from OR^v or NR^VR^W, wherein R^v and R^w are independently selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl or heteroaryl-(1-2C)alkyl;

(A4) A is selected from OR^v, wherein R^v is selected from H, (1-6C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl or heteroaryl-(1-2C)alkyl; (A5) A is selected from OR^v, wherein R^v is selected from H, (1-6C)alkyl, aryl or heteroaryl;

(A7) A is selected from OR^v, wherein R^v is selected from H, (1-6C)alkyl, phenyl or a 5- or 6-membered heteroaryl;

(A8) A is selected from OR , wherein R^v is selected from H or (1-6C)alkyl;

(A9) Ar¹ and R¹¹ are independently selected from aryl or heteroaryl, each of which is

optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^xR^y, C(0)R^x, C(0)OR^x, C(0)N(R^y)R^x, N(R^y)C(0)R^x or (CH₂)_zNR^yR^x (where z is 1 , 2 or 3), wherein R^x and R^y are independently selected from H or (1- 4C)alkyl;

(A10) Ar¹ and R¹¹ are independently selected from aryl or heteroaryl, each of which is

optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, mercapto, phenyl, a 5- or 6-membered heteroaryl, NR^xR^y, C(0)R^x, C(0)OR^x, C(0)N(R^y)R^x or N(R^y)C(0)R^x, wherein R^x and R^y are independently selected from H or (1-4C)alkyl;

(A11) Ar¹ and R are independently selected from aryl or heteroaryl, each of which is

optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano or mercapto;

(A12) Ar¹ and R¹¹ are independently selected from a heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^xR^y, C(0)R^x, C(0)OR^x, C(0)N(R^y)R^x, N(R^y)C(0)R^x or (CH₂)_zNR R^x (where z is 1 , 2 or 3), wherein R^x and R^y are independently selected from H or (1-4C)alkyl;

(A13) Ar¹ and R¹¹ are independently selected from a heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano, mercapto, phenyl, a 5- or 6-membered heteroaryl, NR^xR^y, C(0)R^x, C(0)OR^x, C(0)N(R^y)R^x or N(R )C(0)R^x, wherein R^x and R^y are independently selected from H or (1-4C)alkyl;

(A14) Ar¹ and R¹¹ are independently selected from a heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano or mercapto;

(A15) R^a1 and R^a2 are independently selected from H or a group of the formula:

-L-Y-W

wherein:

L is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl; Y is absent or selected from SiR^a8R^a9, S0₂, C(O), C(0)0 or

W is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl or cycloalkyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano or NR^aaR^a , wherein R^aa and R^a are independently selected from H or (1-4C)alkyl; (A16) R^a1 and R^a2 are independently selected from H or a group of the formula:

-L-Y-W

wherein:

L is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl;

Y is absent or selected from C(O), C(0)0 or C(0)N(R^z), wherein R^z is selected from H or (1-4C)alkyl; and

W is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl or cycloalkyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano or NR^aaR^a , wherein R^aa and R^a are independently selected from H or (1-4C)alkyl; (A17) R^a1 and R^a2 are independently selected from H or a group of the formula:

-L-Y-W

wherein:

L is absent or (1-2C)alkylene;

W is selected from H, (1-6C)alkyl, phenyl, phenyl-(1-2C)alkyl or a 5- or 6-member heteroaryl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano or NR^aaR^ab, wherein R^aa and R^a are independently selected from H or (1- 4C)alkyl;

(A18) R^a1 and R^a2 are independently selected from H or a group of the formula:

-Y-W wherein:

Y is absent or selected from C(O) or C(0)0; and

W is selected from H, (1-6C)alkyl, phenyl, phenyl-(1-2C)alkyl or a 5- or

6-member heteroaryl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano or

NR^aaR^ab, wherein R^aa and R^ab are independently selected from H or (1-

4C)alkyl;

(A19) R^a1 and R^a2 are independently selected from H or a group of the formula:

-Y-W

wherein:

Y is absent or selected from C(O) or C(0)0; and

W is selected from H, (1-6C)alkyl, phenyl, phenyl-(1-2C)alkyl or a 5- or 6-member heteroaryl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro or cyano;

(A20) R^a1 and R^a2 are independently selected from H or a group of the formula:

-Y-W

wherein:

Y is absent or selected from C(O) or C(0)0; and

W is selected from H, (1-6C)alkyl, phenyl, phenyl-(1-2C)alkyl or a 5- or

6-member heteroaryl;

(A21) R^a1 and R^a2 are independently selected from H or (1-6C)alkyl;

(A22) R^a1 and R^a2 are H.

[00155] In another group of compounds of Formula (lll-1 a), the compounds are enantioenriched and thus have the structural Formula lll-1ai or Nl-1a2 (sub-definitions of Formula (Ilia)) show

wherein each of R¹¹ , R^a1, R^a2, A and Ar¹ are as defined herein.

[00156] In an embodiment of the compounds of Formulae lll-1ai and III

A is as defined in any one of paragraphs (A1) to (A8) above; Ar¹ and R¹¹ are as defined in any one of paragraphs (A9) to (A14) above; and R^a1 and R^a2 are as defined in any one of paragraphs (A15) to (A22) above.

[00157] In another embodiment of the compounds of Formulae lll-1ai and lll-1a₂:

A is as defined in paragraph (A8) above;

Ar¹ and R¹¹ are as defined in paragraph (A14) above; and

R^a1 and R^a2 are as defined in paragraph (A22) above.

Hydantoins

[00158] In a further aspect, the present invention provides a compound of Formula (IV) shown below, or a salt or solvate thereof:

(IV)

wherein:

X¹ is S or O;

Ar¹ and R¹¹ are independently selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^xR^y, C(0)R^x, C(0)OR^x, C(0)N(R^y)R^x,

N(RS C(O)R^x, S(0)_yR^x (where y is 0, 1 or 2), S0₂N(R^y)R^x, N(R^y)S0₂R^x or (CH2)_zNR^yR^x (where z is 1 , 2 or 3), wherein R^x and R^y are independently selected from H or (1-4C)alkyl;

R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl or SiR ¹ R ²R^b3 (wherein R ¹ , R^b2 and R ³ are independently selected from H or (1-4C)alkyl), each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, aryl, heteroaryl, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, NR^pR^q, C(0)R^p, C(0)OR^p, C(0)N(R")R^P or N(R")C(0)R^p, wherein R and R^ are each independently selected from H or (1-4C)alkyl; or R³ is linked with Ar such that, together with the nitrogen atom to which R³ is attached they form a 4- to 10-membered heterocyclyl or heteroaryl, which is optionally substituted with one or more substituents halo, hydroxy, amino, nitro, cyano, (1-4)alkyl or (1-4C)alkoxy; and

R⁹ is selected from H or a group of the formula:

-L^x-Y^x-W^x

wherein:

L^x is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl;

with the proviso that:

when Ar¹ and R¹¹ are both optionally substituted aryl groups, R³ and R⁸ are not H and the compound of Formula (IV) is not racemic;

when R³ and R⁹ are H, Q and X¹ are O and one of Ar¹ or R¹¹ is phenyl, the other of Ar¹ or R¹¹ is not a phenyl or a substituted phenyl; and

the compound of Formula (IV) is not one of the following:

[00159] In an embodiment of the compounds of Formula (lll-1 a), least one of Ar¹ and R¹¹ is a heteroaryl.

[00160] Particular compounds of Formula (IV), include, for example, compounds of Formula (IV), or salts and/or solvates thereof, wherein, unless otherwise stated, each of X¹, Q, Ar¹ , R¹ , R⁹, R¹¹ and any associated substituent groups has any of the meanings defined in hereinbefore or in any of paragraphs (B1) to (B12) hereinafter: - (B1) X¹ is O;

(B2) Q is selected from NR⁸ or O, wherein R⁸ is selected from H, (1-4C)alkyl or aryl; (B3) Q is selected from S, NR⁸ or O, wherein R⁸ is selected from H, methyl or phenyl; (B4) Q is selected from S or O;

(B5) Q is O;

(B6) Ar¹ and R¹¹ are as defined in any one of paragraphs (A9) to (A14) hereinabove; (B7) R³ is as defined in any one of paragraphs (33) to (37) hereinabove;

(B8) R⁹ is selected from H or a group of the formula:

-L^x-Y^x-W^x

wherein:

L^x is absent or (1-2C)alkylene;

Y^x is absent or selected from SiR^a10R^al\ S0₂, C(O), C(0)0 or

C(0)N(R^z1), wherein R^z1 , R^a1° and R^a11 are independently selected from H or (1-4C)alkyl; and

W^x is selected from (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl or heteroaryl-(1-2C)alkyl, wherein each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, aryl, heteroaryl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro or cyano;

(B9) R⁹ is selected from H or a group of the formula:

-Y^x-W^x

wherein:

Y^x is absent or selected from SiR^a10R^a1\ S0₂, C(O), C(0)0 or

C(0)N(R^z1), wherein R^z1 , R^a1° and R^a11 are independently selected from H or (1-4C)alkyl; and W^x is selected from (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl or heteroaryl-(1-2C)alkyl, wherein each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, aryl, heteroaryl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro or cyano;

(B10) R⁹ is selected from H or a group of the formula:

-Y*-W^x

wherein:

Y^x is absent or selected from SiR^a10R^a1\ S0₂, C(O), C(0)0 or

W^x is selected from (1-6C)alkyl, aryl or aryl-(1-2C)alkyl, wherein each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro or cyano;

(B11) R⁹ is selected from H or a group of the formula:

-Y*-W^x

wherein:

Y^x is absent or selected from SiR^a10R^a1\ S0₂, C(O) or C(0)0, wherein, R^a1° and R^a11 are independently selected from H or (1-4C)alkyl; and W^x is selected from (1-6C)alkyl, aryl or aryl-(1-2C)alkyl.

(B12) R⁹ is selected from H or (1-6C)alkyl.

[00161] In a particular group of compounds of Formula (IV), the compounds are enantioenriched and thus have the structural Formula IVa or IVb (sub-definitions of Formula (IV)) shown below, nd/or solvate thereof:

(IVa) (IVb) wherein X¹ , Q, Ar\ R ¹ , R³ and R⁹ are as defined hereinabove.

[00162] In an embodiment of the compounds of Formulae IVa and IVb:

X¹ is as defined in paragraph (B1) above;

Q is as defined in any one of paragraphs (B2) to (B5) above;

Ar¹ and R¹¹ are as defined in any one of paragraphs (A9) to (A 14) above; R³ is as defined in any one of paragraphs (33) to (37) above; and

R⁹ is as defined in any one of paragraphs (B8) to (B12) above.

[00163] In another embodiment of the compounds of Formulae IVa and IVb:

X¹ is as defined in paragraph (B1) above;

Q is as defined in paragraph (B5) above;

Ar¹ and R¹¹ are as defined in paragraph (A14) above;

R³ is as defined in paragraph (37) above; and

R⁹ is as defined in paragraph (B12) above.

[00164] In a particular group of compounds of Formula (IV), X¹ is O, Q is O and the compounds are enantioenriched and thus have the structural Formula IVc or IVd (sub-definitions of Formula (IV)) sh

wherein Ar¹ , R¹¹, R³ and R⁹ are as defined hereinabove.

[00165] In an embodiment of the compounds of Formulae IVc and IVd:

Ar¹ and R¹¹ are as defined in any one of paragraphs (A9) to (A14) above;

R³ is as defined in any one of paragraphs (33) to (37) above; and

R⁹ is as defined in any one of paragraphs (B8) to (B12) above.

[00166] In another embodiment of the compounds of Formulae IVc and IVd:

Ar¹ and R¹¹ are as defined in paragraph (A14) above;

R³ is as defined in paragraph (37) above; and

R⁹ is as defined in paragraph (B12) above.

Further embodiments of the compounds of the present invention

[00167] A suitable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. [00168] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".

[00169] The compounds of this invention may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.

[00170] Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers).

[00171] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and180; and the like.

[00172] It is also to be understood that certain compounds of Formulae (I) to (IV) may exist in solvated as well as unsolvated forms such as, for example, hydrated forms.

[00173] Compounds of any one of the Formulae (I) to (IV) may exist in a number of different tautomeric forms and references to compounds of any one of the Formulae (I) to (IV) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by any of the Formulae (I) to (IV). Examples of tautomeric forms include keto-, enol- , and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.

keto enol enolate

[00174] Compounds of the Formulae (I) to (IV) containing an amine function may also form N- oxides. A reference herein to a compound of any one of the Formulae (I) to (IV) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen- containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m- chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[00175] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

Particular embodiments of the present invention

[00176] Particular embodiments of the present invention include:

1.1 The present invention provides a process for the preparation of a compound of Formula (la) or For

la lb

wherein each of X, Z, Q, Ar, R R², R³ and R⁴ are as defined herein,

with the proviso that:

(i) when R⁴ is absent, the compound of Formula (I) is anionic (i.e. carries a negative charge); (ii) when R¹ is a carbonyl moiety (i.e. a group selected from C(O)- W\ C(0)0-Wi, C(0)N(R^G)-W¹), X is CR⁵R⁶; and

(iii) when R¹ is not a carbonyl moiety (i.e. it is a group other than C(0)-W\ C(0)0-W\ C(0)N(R^c)-W¹), X is C=0 or C=S.

the process comprising the steps of:

i) reacting a compound of Formula (I la) or (Mb), as shown below, with a

(I la) (lib)

wherein X, Z , Q , Ar, R\ R², R³ and all substituent groups associated therewith, have the same meaning as defined for the compounds of Formula (la) or Formula (lb); and

ii) optionally, thereafter:

a) converting the compound Formula la or Formula lb into another compound of Formula la or Formula lb; and/or b) forming a salt or solvate thereof.

The present invention provides a process for the preparation of a compound of Formula (If) or Formula (Ig), as shown below:

ig

wherein each of Ar, R¹ , R², R³ and R⁷ are as defined herein,

the process comprising the steps of:

i) reacting a compound of Formula (Me) or (I If), as shown below, with a base in the presence of an aprotic solvent:

llf

wherein Ar, R¹ , R², R³, R⁷ and all substituent groups associated therewith, have the same meaning as defined for the compounds of Formula (I); and

ii) optionally, thereafter:

a) converting the compound Formula If or Formula Ig into another compound of Formula If or Formula Ig; and/or

b) forming a salt or solvate thereof.

The present invention provides a process for the preparation of a compound of Formula (Ij) or Formula (Ik), as shown below:

Ij Ik wherein each of Ar, W¹, R², R³, R⁵ and R⁶ are as defined herein,

the process comprising the steps of:

llf

wherein Ar, R¹ , R², R³, R⁷ and all substituent groups associated therewith, have the same meaning as defined for the compounds of Formula (I); and ii) optionally, thereafter:

a) converting the compound Formula Ij or Formula Ik into another compound of Formula Ij or Formula Ik; and/or

b) forming a salt or solvate thereof.

1.4 The present invention provides a process for the preparation of a compound of Formula (lll-1ai) or Fo

wherein each of R\ R^a1 , R^a2, A and Ar are as defined herein;

the process comprising the steps of:

1) subjecting a compound of Formula (If) or Formula (Ig), as shown below, with a base,

2) optionally, thereafter, and if necessary:

i) adding or removing any protecting groups;

ii) converting the compound Formula lll-1ai or Formula lll-1a₂ into another compound of Formula lll-1ai or Formula lll-1 a₂; and/or

iii) forming a salt or solvate thereof.

1.5 The present invention provides a process for the preparation of a compound of Formula (lll-1ai) or Fo

wherein each of R\ R^a1 , R^a2, A and Ar are as defined herein; the process comprising the steps of:

1 ) subjecting a compound of Formula (Ij) or Formula (Ik), as shown below, with a base, a

Ij Ik wherein each of Ar, W , R², R³, R⁵ and R⁶ are as defined herein;

2) optionally, thereafter, and if necessary:

i) adding or removing any protecting groups;

ii) converting the compound Formula ll l-1 ai or Formula I l l-1 a2 into another compound of Formula ll l-1 ai or Formula 111-1 a2; and/or iii) forming a salt or solvate thereof.

The present invention provides a process for the preparation of a compound of Formula (IVa) or Formula (IVb) , as shown below:

(IVa) (IVb) wherein each of R R³, R⁹, X¹ , Q and Ar are as defined herein;

the process comprising the steps of:

1 ) su d:

wherein each of Ar, R\ R², R³ and R⁷ are as defined herein;

2) optionally, thereafter, and if necessary: i) adding or removing any protecting groups;

ii) converting the compound Formula IVa or Formula IVb into another compound of Formula IVa or Formula IVb; and/or iii) forming a salt or solvate thereof.

1.7 The present invention provides a process for the preparation of a compound of Formula (IVa) or Formula (IVb), as shown below:

(IVa) (IVb)

wherein each of R¹, R³, R⁹, X¹, Q and Ar are as defined herein;

the process comprising the steps of:

1) s cid:

Ij Ik

wherein each of Ar, W¹, R², R³, R⁵ and R⁶ are as defined herein; 2) optionally, thereafter, and if necessary:

i) adding or removing any protecting groups;

[00177] It will be readily appreciated by the person skilled in the art that a compound prepared by any one of the processes described in paragraphs 1.1 to 1.7 above, is prepared by reacting the 'precursor' compound containing the same R¹ stereochemistry as the 'rearrangement' product, with a base (i.e. the stereochemistry at the R¹ position is maintained, and not inverted, during the present process). For example, in paragraph 1.1 above, it will be appreciated that compounds of Formula la are prepared by reacting compounds of Formula lla with a base, and, similarly, compounds of Formula lb are prepared by reacting compounds of Formula lib with a base. Suitably, compounds of Formula la may not be prepared by reacting compounds of Formula lib with a base.

EXAMPLES

Materials and apparatus

[00178] All reactions were performed under a nitrogen atmosphere in flame-dried apparatus, unless stated otherwise. All reagents and chemicals were obtained from chemical suppliers and used without further purification, with the exception of those listed below. THF was distilled from sodium wire under nitrogen using benzophenone as an indicator. DCM and DIPA were distilled from CaH₂ under nitrogen. Et₂0 and toluene were collected under argon from an Innovative Technologies PureSolve PS-MP-5 solvent purification system. TMSCI was distilled under reduced pressure from CaH₂. Et₃N was stored over KOH pellets and used directly. Commercial nBuLi solutions were titrated with /V-benzylbenzamide in anhydrous THF prior to use.¹ Pet.Ether refers to the fractions of petroleum ether boiling between 40 - 60 °C. Acetone/dry ice cooling baths were used to maintain -78 °C.

[00179] Thin-layer chromatography (TLC) was performed using commercially available pre- coated plates (Macherey-Nagel Polygram SIL G/UV254). Visualisation was achieved by way of UV light (at 254 nm), and either potassium permanganate or 'Seebach' stains (2.50 g phosphomolybdic acid hydrate, 1.00 g cerium (IV) sulphate tetrahydrate, 3.20 mL cone. H2SO4, 90.50 mL water). Flash column chromatography was carried out using chromatography grade silica (60 A pore size, 230 - 400 mesh) from Sigma-Aldrich, with compounds loaded as saturated solutions in DCM.

[00180] Nuclear Magnetic Resonance (NMR) spectra (¹H NMR and ¹³C NMR) were recorded on either Bruker Ultrashield 300 (DPX), 400 (Avance III or Avance III HD with CryoProbe Prodigy BBO) or 500 (DRX, Avance II+ or Avance III HD with CryoProbe Prodigy BBO) spectrometers. Chemical shifts (δ) are quoted in parts per million (ppm) downfield of trimethylsilane. Spectra were calibrated using the residual solvent peaks for CDCI3 (5H: 7.26 ppm; 5c: 77.16 ppm), CD₃OD (δ_Η: 3.31 ppm; 5_C: 49.00 ppm) and (CDs^SO (δ_Η: 2.50 ppm; 5_C: 39.52 ppm) as appropriate.² Coupling constants (J) are quoted in Hz and are rounded to the nearest 0.1 Hz. Splitting patterns are abbreviated to: singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin.), septet (sept.), multiplet (m), broad (br.) or some combination thereof. Major and minor rotameric peaks are denoted by the subscripts _(maj) and _(min).

[00181] Capillary melting points were determined on a Stuart SMP10 apparatus and are uncorrected. Infrared (IR) spectra were recorded on a Thermo Scientific Nicolet iS5 FT-IR spectrometer using an iD5 diamond ATR accessory, with samples applied as neat films. Absorption maxima (v_max) of interest are quoted in wavenumbers (cm^-1). High resolution mass spectra (HRMS) were recorded by staff at the University of Manchester on a Thermo Finnigan MAT95XP or Waters QTOF.

General Procedures

Procedure 1 : N-Methylamide formation from amino ester hydrochloride

[00182] To an amino ester hydrochloride (1.0 eq.) was added MeNhb (33% w/w solution in

EtOH, 7.0 eq.). The mixture was left to stir at room temperature for 48 h before being concentrated in vacuo, dissolved in CHCb and washed with K2CO3 (3.8 M, aq.). The organic layer was separated and the aqueous layer was extracted 3 times with CHCb. The combined organic layers were dried over MgSC , filtered and concentrated in vacuo.

Procedure 2: Imine formation from amino acid N-methylamide

[00183] To a solution of /V-methylamide (1.0 eq.) in anhydrous DCM (1.5 M) was added MgSC (1.0 eq.) and pivalaldehyde (1.5 eq.). The mixture was left to stir at room temperature for 16 h before being filtered and concentrated in vacuo.

Procedure 3a: Imidazolidinone carbamoyl chloride formation from N-methylamide (TFA)

[00184] To a solution of amino acid A/-methylamide (1.0 eq.) in anhydrous DCM (0.75 M) was added pivalaldehyde (1.5 eq.), followed by TFA (1.5 - 5.0 eq.). The reaction mixture was heated to reflux and allowed to stir overnight before being quenched by slow addition of NaHCC (sat. aq.) until pH > 9. The organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSCv, filtered and concentrated in vacuo. The crude product was dissolved in anhydrous DCM (2.0 M) and added dropwise to a solution of triphosgene (0.45 eq.) and 2,6-lutidine (1.2 eq.) in anhydrous DCM (1.0 M) at -78 °C. After 15 min, the reaction mixture was warmed to room temperature and allowed to stir overnight. The reaction was quenched by addition of HCI (1.0 M, aq.). The organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSC , filtered and concentrated in vacuo.

Procedure 3b: Imidazolidinone carbamoyl chloride formation from N-methylamide (PTSA)

[00185] To a solution of amino acid V-methylamide (1.0 eq.) in anhydrous toluene (0.65 M) was added molecular sieves (3 A), pivalaldehyde (1.1 eq.) and PTSA monohydrate (0.15 eq.). The reaction mixture was heated to reflux and allowed to stir overnight. The reaction mixture was filtered and quenched by slow addition of NaHCCb (sat. aq.) until pH > 9. The organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSC , filtered and concentrated in vacuo. The crude product was dissolved in anhydrous DCM (2.0 M) and added dropwise to a solution of triphosgene (0.45 eq.) and 2,6-lutidine (1.2 eq.) in anhydrous DCM (1.0 M) at -78 °C. After 15 min, the reaction mixture was warmed to room temperature and allowed to stir overnight. The reaction was quenched by addition of HCI (1.0 M, aq.). The organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSC , filtered and concentrated in vacuo.

Procedure 4: Ureic imidazolidinone formation from N-methylamide imine

[00186] /V-Methylamide imine (1.0 eq.), A/-alkyl-/V-arylcarbamoyl chloride³ (1.35 - 1.5 eq.) and

DMAP (0.05 eq.) were dissolved in anhydrous solvent (0.2 - 0.25 M). The reaction mixture was stirred at reflux (18 - 65 h) before being concentrated in vacuo.

Procedure 5: N-Aryl urea formation from imidazolidinone carbamoyl chloride

[00187] To a solution of carbamoyl chloride (1.0 eq.) in anhydrous solvent (0.2 - 1.0 M) was added tertiary amine base (2.0 eq.), /V-alkylaniline (5.0 eq.) and Kl (1.1 eq.). The reaction mixture was heated to reflux and left until TLC analysis showed the starting material had been completely consumed. The reaction mixture was cooled to room temperature and quenched with HCI (1.0 M, aq.), the organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSCv, filtered and concentrated in vacuo.

Procedure 6: Rearrangement of N-aryl urea

[00188] To a solution of A/-aryl urea (1.0 eq.) in anhydrous THF (0.1 M) at 0 °C was added dropwise KHMDS (1.0 M in THF, 1.5 eq.). After 15 min, the reaction mixture was warmed to room temperature and allowed to stir for 4 h. The reaction was quenched by dropwise addition of NH₄CI (sat. aq.) and stirred for 15 min. The organic layer was separated and the aqueous layer was extracted 3 times with EtOAc. The combined organic layers were dried over MgSCU, filtered and concentrated in vacuo.

Procedure 7: 'U rearrangement' of carbamoyl chloride (tandem urea formation / rearrangement)

[00189] To a solution of carbamoyl chloride (1.0 eq.) and /V-alkylaniline (1.1 eq.) in anhydrous THF (0.1 M) at -78 °C was added dropwise KHMDS (1.0 M in THF, 1.5 eq.) and left to stir for 2 h. The reaction mixture was allowed to warm to 0 °C where it was stirred for a further 30 min before additional KHMDS (1.0 M in THF, 1.5 eq.) was added dropwise. After 15 min, the reaction mixture was warmed to room temperature and allowed to stir overnight. The reaction was quenched by dropwise addition of NH₄CI (sat. aq.) and stirred for 15 min. The organic layer was separated and the aqueous layer was extracted 3 times with EtOAc. The combined organic layers were dried over MgSC , filtered and concentrated in vacuo.

Procedure 8: Hydrolysis of rearranged urea to a mixture of amino acid and hydantoin.

[00190] Rearranged urea (1.0 eq.) was suspended in HCI (6.0 , aq.) and refluxed at 135 °C in a sealed tube for 37 h. The cooled reaction mixture was purified by ion-exchange chromatography (Dowex^® 50W8-200, 100 - 200 mesh), washing sequentially with deionised water and dioxane before the product was eluted with NH3 (3.5% w/w, aq.). The ninhydrin- positive aqueous fractions were combined and concentrated in vacuo. The resulting solid was dissolved in MeOH, filtered and concentrated in vacuo. Extended drying under high vacuum afforded the amino acid. The dioxane wash was concentrated in vacuo and purified to give the hydantoin.

Procedure 9: Methylation and hydrolysis of rearranged urea to amino acid.

[00191] To a solution of rearranged urea (1.0 eq.) in anhydrous DMF (0.1 M) at 0 °C was added NaH (60% suspension in mineral oil, 1.2 eq.) and left to stir for 30 min before Mel (1.5 eq.) was added dropwise. The reaction mixture was warmed to room temperature and allowed to stir overnight. The reaction was quenched with HCI (1.0 M, aq.) before being extracted 3 times with ΕΪΣΟ. The combined organic layers were washed twice with brine, before being dried over MgSC , filtered and concentrated in vacuo. The crude product was suspended in HCI (6.0 , aq.) / EtOH (10:1 , 0.2 M) and heated in a microwave reactor at 160 °C for 3 h. The cooled reaction mixture was diluted with water and washed 3 times with DCM before being concentrated in vacuo. The resulting crude material was purified by ion-exchange chromatography (Dowex^® 50W8-200, 100 - 200 mesh), washing with deionised water before the product was eluted with NH₃ (3.5% w/w, aq.). The ninhydrin-positive aqueous fractions were combined and concentrated in vacuo. The resulting solid was dissolved in MeOH, filtered and concentrated in vacuo. Extended drying under high vacuum afforded the amino acid.

Synthesis of the W-Methylamides and Imines

(S)-2-Amino-/V-methylpropanamide (1)

[00192] Following general procedure 1 , ethanolic MeNH₂ (68.00 ml_, 547

mmol) was added to L-alanine ethyl ester hydrochloride (12.09 g, 78.70 mmol). The title compound (7.20 g, 70.49 mmol, 90%) was yielded as a pale yellow oil. 1 : R_f (4:1 DCM:MeOH): 0.16; ¹H NMR (500 MHz, CDCI₃): δ_Η = 7.26 (br. s, 1 H, NH), 3.48 (q, J = 7.0, 1 H, CHCH3), 2.80 (d, J = 5.0, 3H, NHCH₃), 1.45 (br. s, 2H, NW₂), 1.32 (d, J = 7.0, 3H, CHCH₃); ¹³C {¹H} NMR (125 MHz, CDCI3): 5_C = 176.4 (C=0), 50.9 (CHCH3), 25.9 (NHCH3), 21.9 (CHCH3); IR: Vmax = 3292, 3099 (N-H), 2971 , 2936, 2881 (C-H), 1645 (C=0); MS (ESI⁺, MeOH): m/z 103 (100%, [M+H]⁺). Data in agreement with reported values.⁴ of /V-methylamide 1 added MgS0₄ (625

mg, 5.19 mmol) and pivalaldehyde (0.85 ml_, 7.78 mmol). The title compound (861 mg, 5.06 mmol, 97%) was yielded as a pale yellow oil. 2: ¹H NMR (500 MHz, CDCI₃): δ_Η = 7.52 (s, 1 H, CHC(CH₃)₃), 6.92 (br. s, 1 H, NH), 3.68 (q, J = 7.0, 1 H, CHCH₃), 2.84 (d, J = 4.9, 3H, NHCH3), 1.31 (d, J = 7.0, 3H, CHCH3), 1.07 (s, 9H, C(CH₃)₃); MS (ESI⁺, DCM): m/z 193 (100%, [M+Na]⁺). Data in agreement with reported values.⁵ (S)-2-Amino-/V-methyl-3-phenylpropanamide (3)

[00194] Following general procedure 1 , ethanolic MeNH₂ (37.8 ml_, 304 mmol) was added to L-phenylalanine ethyl ester hydrochloride (9.97 g, 43.40

mmol). The title compound (7.60 g, 42.64 mmol, 98%) was yielded as a white solid. 3: mp 66-69 °C; R_f (4: 1 DCM:MeOH): 0.70; ¹H N R (400 M Hz, CDCb): δ_Η = 7.33 - 7.29 (m, 2H, PhH), 7.28 - 7.20 (m, 4H, PhH and NH), 3.60 (dd, J = 9.5, 4.0, 1 H, CHCH_AH_B), 3.28 (dd, J = 13.7, 4.0, 1 H, CHCH_AH_b), 2.81 (d, J = 5.0, 3H, N HCH₃), 2.66 (dd, J = 13.7, 9.5, 1 H, CHCHAWB), 1.34 (br. s, 2H, NH₂); ¹³C {¹H} NMR (100 MHz, CDCb): δ₀ = 175.0 (C=0), 138.1 (Cp_h), 129.4 (2xCHp_h), 128.8 (2xCH_Ph), 126.9 (CH_Ph), 56.6 (NHCH₃), 41.1 (CHCH₂), 25.9 (CHCH₂); IR: v_max = 3367, 3304 (N-H), 3072, 3053, 3001 , 2925 (C-H), 1657 (C=0); MS (ESI⁺, MeOH): m/z 179 (100%, [M+H]⁺). Data in agreement with reported values.⁴

(S)-2-((2,2-Dimethylpropylidene)amino)- V-methyl-3-phenylpropanamide (4)

95] Following general procedure 2, to a solution of /V-methylamide 3 m^g' ^{68 mmo1}) ^{in DCM} C - ^{2 mL}' ^{5 M}) ^{was added} gS0₄ (200

2.49 mmol) and pivalaldehyde (0.27 ml_, 2.52 mmol). The title compound (410 mg, 1.66 mmol, 99%) was yielded as a pale yellow oil. 4: ¹H NMR (400 MHz,

CDCb): δ_Η = 7.26 - 7.20 (m, 2H, PJnH), 7.18 - 7.13 (m, 1 H, PJnH) , 7.08 - 7.03 (m, 2H, P H),

6.90 (br. s, 1 H, NH), 6.80 (s, 1 H, CHC(CH₃)₃), 3.69 (dd, J = 10.6, 3.0, 1 H, CHCH_AH_B), 3.36

(dd, J = 13.4, 3.0, 1 H, CHCH„H_B), 2.86 (d, J = 5.0, 3H, NHCH₃), 2.73 (dd, J = 13.4, 10.7, 1 H,

CHCH_AWB), 0.86 (s, 9H, C(CH₃)₃); MS (ESI⁺, DCM): m/z 269 (100%, [M+Na]⁺). Data in agreement with reported values.⁵

(ft)-2-Amino-/V-methyl-2-phenylacetamide (5)

[00196] Following general procedure 1 , ethanolic MeNH₂ (51.90 ml_, 417 mmol) was added to D-phenylglycine methyl ester hydrochloride (12.09 g,

59.96 mmol). The title compound (9.30 g, 56.33 mmol, 94%) was yielded as a pale yellow oil. 5: Rf (4:1 DCM:MeOH): 0.68; ¹H NMR (400 MHz, CDCb): δ_Η = 7.39 - 7.37 (m, 2H, PJnH), 7.36 - 7.32 (m, 2H, PhH), 7.30 - 7.26 (m, 1 H, PhH), 7.08 (br. s, 1 H, NH), 4.51 (s, 1 H, CHPh), 2.81 (d, J = 5.0, 3H, NHCH₃), 1.80 (br. s, 2H, NH₂); ¹³C {¹H} NMR (100 M Hz, CDCb): δ₀ = 173.7 (C=0), 141.2 (C_Ph), 129.0 (2xCH_Ph), 128.1 (CH_Ph), 127.0 (2xCH_Ph), 60.0 (CHPh) 26.2 (NHCH₃); IR: v_max = 3295 (N-H), 3061 , 3030, 2940 (C-H), 1650 (C=0); MS (ESI⁺, MeOH): m/z 165 (100%, [M+H]⁺). Data in agreement with reported values.⁶

( R)-2-((2,2-Dimethylpropylidene)amino)-/V-methyl-2-phenylacetamide (6)

Ph [00197] Following general procedure 2, to a solution of /V-methylamide 5 H

iBu^N^[|^^N^ (^{250 m}9> ^{1 52} mmol) in DCM (1.01 ml_, 1.5 M) was added MgS0₄ (180

O mg, 1.50 mmol) and pivalaldehyde (0.25 imL, 2.28 mmol). The title compound (340 mg, 1.46 mmol, 96%) was yielded as a pale yellow oil. 6: ¹H NMR (500 MHz, CDCb): δ_Η = 7.59 (s, 1 H, CHC(CH₃)₃), 7.37 (d, J = 7.7, 2H, PhH), 7.31 (t, J = 7.4, 2H, PhH), 7.28 - 7.23 (m, 1 H, PhH), 7.00 (br. s, 1 H, NH), 4.73 (s, 1 H, CHPh), 2.85 (d, J = 4.9, 3H, NHCHs), 1.10 (s, 9H, C(CH₃)₃); MS (ESI⁺, DCM): m/z 233 (100%, [M+H]⁺). Data in agreement with reported values.⁵

(S)-2-Amino-/V,3-dimethylbutanamide (7)

[00198] Following general procedure 1 , ethanolic MeNH₂ (62.40 ml_, 501 mmol) was added to L-valine methyl ester hydrochloride (12.11 g, 72.24

mmol). The title compound (8.78 g, 67.44 mmol, 93%) was yielded as a pale yellow oil. 7: R, (4:1 DCM:MeOH): 0.63; ¹H NMR (500 MHz, CDCb): δ_Η = 7.26 (br. s, 1 H, NH), 3.23 (d, J = 3.7, 1 H, NH₂CHCH), 2.82 (d, J = 5.0, 3H, NHCH₃), 2.35 - 2.27 (1 H, m, CH(CH₃)₂) , 1.23 (br. s, 2H, NH₂), 0.98 (d, J = 7.0, 3H, CH(CH₃)A(CH₃)_b), 0.80 (d, J = 6.9, 3H, CH(CH₃)_A(CH₃)_b); ¹³C {¹H} NMR (125 MHz, CDCb): 5_C = 175.1 (C=0), 60.3 (N H₂CH), 30.9 (CH(CH₃)₂), 25.8 (NH CH₃), 19.9 (CHCH₃), 16.1 (CH CH₃); IR: v_max = 3305, 3089 (N-H), 2959, 2872 (C-H), 1649 (C=0); MS (ESI⁺, MeOH): m/z 131 (100%, [M+H]⁺). Data in agreement with reported values.⁷

(S)-2-Amino-/V,4-dimethylpentanamide (8)

[00199] Following general procedure 1 , ethanolic MeNH₂ (57.60 ml_, 462 mmol) was added to L-leucine methyl ester hydrochloride (12.05 g, 66.33 ¾ mmol). The title compound (9.15 g, 63.46 mmol, 96%) was yielded as a pale

yellow oil. 8: R, (4:1 DCM:MeOH): 0.52; ¹H NMR (400 MHz, CDCb): δ_Η = 7.26 (br. s, 1 H, NH), 3.37 (dd, J = 9.9, 3.3, 1 H, N H₂CHCH_AH_B) , 2.80 (d, J = 5.0, 3H, N HCH₃), 1.82 - 1.57 (m, 2H, CHCH„H_BCH and CH_AH_BCH(CH₃)₂), 1.36 (br. s, 2H, NH₂), 1.36 - 1.26 (m, 1 H, CHCHAHBCH), 0.94 (d, J = 6.2, 3H, CH(CH₃) (CH₃)_B), 0.92 (3H, d, J = 6.1 , CH(CH₃)A(CH₃)_B) ; ¹³C {¹H} NMR (100 MHz, CDCb): 5_C = 176.3 (C=0), 53.6 (NH₂CHCH₂), 44.2 (CH₂CH), 25.9 (NHCH₃), 25.0 (CH(CH₃)₂), 23.6 (CH(CH₃HCH₃)_B), 21.4 (CH(CH₃)_A(CH₃)_B); IR: v_max = 3295, 3090 (N-H), 2955, 2871 (C-H), 1651 (CO); MS (ESI⁺, MeOH): m/z 145 ([M+H]⁺) (100%).

(S)-2-((2,2-Dimethylpropylidene)amino)-A/,4-dimethylpentanamide (9)

[00200] Following general procedure 2, to a solution of /V-methylamide 8 (1000 mg, 6.93 mmol) in DCM (4.62 mL, 1.5 ) was added MgS0₄ (850 mg, 7.06 mmol) and pivalaldehyde (1.13 mL, 10.4 mmol). The title

compound (1442 mg, 6.79 mmol, 98%) was yielded as a pale yellow oil. 9: ¹H NMR (500 MHz, CDCb): δ_Η = 7.47 (s, 1 H, CHC(CH₃)₃), 6.67 (br. s, 1 H, NH), 3.63 (dd, J = 9.9, 3.9, 1 H, CHCHAHB), 2.82 (d, J = 5.0, 3H, N HCH₃), 1.65 (ddd, J = 13.6, 9.6, 3.9, 1 H, CHCHAHBCH), 1.58 (ddd, J = 13.8, 9.9, 4.4, 1 H, CHCHAHBCH), 1.47 - 1.37 (m, 1 H, CH₂CH(CH₃)₂), 1.08 (s, 9H, C(CH₃)₃), 0.89 (d, J = 6.7, 3H, CH(CH₃) CH₃)_B), 0.86 (d, J = 6.6, 3H, CH(CH₃)_A(CH₃)_e); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5_C = 174.7 (C=0), 173.5 (CHC(CH₃)₃), 71.7 (CHCH₂), 43.6 (CHCH₂), 36.6 (C(CH₃)₃), 27.0 (C(CH₃)₃), 26.0 (NHCH₃), 24.1 (CH(CH₃)₂), 23.6 (CH(CH₃) CH₃)B), 21.2 (CH(CH₃)_A(CH₃)_S); HRMS (ESI⁺): m/z calcd for Ci₂H₂₅ON₂ ([M+H]⁺) 213.1961 , found 213.1949.

(S)-2-Amino-/V-methyl-4-(methylt io)butanamide (10)

[00201] Following general procedure 1 , ethanolic MeNH₂ (52.40 ml_, 421 mmol) was added to L-methionine methyl ester hydrochloride (12.20 g, 61.09 mmol). The title compound (9.17 g, 56.58 mmol, 93%) was yielded as a pale

yellow oil. 10: R_f (4: 1 DCM:MeOH): 0.65; ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.24 (br. s, 1 H, NH), 3.49 (dd, J = 8.2, 4.5, 1 H, CWCH_AH_B), 2.82 (d, J = 5.0, 3H, NHCH₃), 2.60 (t, J = 7.3, 2H, CH_AH_BCrt₂SCH₃), 2.17 (dtd, J = 14.2, 7.7, 4.5, 1 H,

2.10 (s, 3H, SC - ₃), 1 .75 (ddt, J = 14.1 , 8.1 , 6.9, 1 H, CHCH_AH_B), 1.43 (br. s, 2H, NH₂); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 175.2 (C=0), 54.4 (CHCH₂), 34.2 (CHCH₂), 30.8 (CH₂SCH₃), 26.0 (CH₃NH), 15.4 (SCH₃); IR: v_max = 3303, 3090 (N-H), 2916 (C-H), 1646 (C=0); MS (ESI⁺, MeOH): m/z 163 (100%, [M+H]⁺). Data in agreement with reported values.⁸

(S)-2-((2,2-Dimethylpropylidene)amino)-A)-methyl-4-(methylthio)butanamide (1 1)

[00202] Following general procedure 2, to a solution of /V-methylamide 10 (1 100 mg, 6.78 mmol) in DCM (1.10 ml_, 1 .5 M) was added MgS0₄ (820 mg, 6.81 mmol) and pivalaldehyde (0.74 ml_, 10.17 mmol). The title

compound (1544 mg, 6.70 mmol, 99%) was yielded as a pale yellow oi 11 : ¹H NMR (500 MHz, CDCI3): δ_Η = 7.54 (s, 1 H, CHC(CH₃)₃) , 6.72 (br. s, 1 H , N - ), 3.73 (dd, J = 9.0, 3.9, 1 H, CHCHAHB), 2.84 (d, J = 5.0, 3H , N HC/- 3), 2.43 (ddd, J = 13.4, 9.1 , 4.7, 1 H , CHAHBOMHB SCHS), 2.32 (dt, J = 13.1 , 8.1 , 1 H, CHAHBCHA-WBSCHS), 2.19 - 2.12 (tdd, J = 9.3, 7.8, 4.5, 1 H, CHCA^H_BCH₂), 2.07 (s, 3H, SO/₃), 1.91 (dtd, J = 13.7, 8.9, 4.7, 1 H, CHCH_AA7BCH₂), 1 .09 (s, 9H, C(CH₃)₃); MS (ESI⁺, DCM): m/z 253 (100%, [M+Na]⁺). Data in agreement with reported values.⁵

fe/ -Butyl (S)-(3-(4-(benzyloxy)phenyl)-1-(methylamino)-1 -oxopropan-2-yl)carbamate (12)

[00203] Following a similar method to general procedure 1 , ethanolic MeNH₂ (1.07 ml_, 8.62 mmol, 2.0 eq.) was added to a suspension of L-Boc-Tyr(OBn)-OSu (2.02 g, 4.31 mmol, 1.0 eq.) in EtOH (43.1 mL, 0.1 M) and left to stir for 2 h. The

title compound (1 .63 g, 4.24 mmol, 98%) was yielded as a white solid without further purification. 12: ¹H NMR (400 MHz, CDCI3): δ_Η = 7.44 - 7.41 (m, 2H, PJnH), 7 AO - 7.36 (m, 2H, Ph ), 7.35 - 7.30 (m, 1 H, PhH), 7.1 1 (d, J = 8.4, 2H, ArH), 6.93 - 6.89 (m, 2H, ArH), 5.63 (br. s, 1 H, NH), 5.04 (s, 2H, OCH>Ph), 5.02 (br. s, 1 H, NH), 4.22 (br. dd, J = 13.5, 7.4, 1 H, CWCHAHB), 3.03 (dd, J = 13.4, 5.6, 1 H, CHCHAHB), 2.95 (dd, J = 13.6, 7.5, 1 H, CHCH/He), 2.72 (d, J = 4.5, 3H, NHCH , 1.41 (s, 9H, C(CH₃)₃) ; MS (ESI⁺, DCM): m/z 385 (100%, [M+H]⁺). Data in agreement with reported values.⁹

Benzyl 1-benzyl-/V_a-(fert-butoxycarbonyl)-L-tryptophanate (13)

[00204] Following the procedure of Wolfe et a/.,¹⁰ to a cooled (0 °C) solution of Λ/α-Boc-L-tryptophan (1.00 g, 3.29 mmol, 1.0 eq.) in DMF (3.30 ml_, 1.0 M) was added NaH (389 mg, 9.78 mmol, 60% suspension in mineral oil, 3.0 eq.). The solution was stirred

for 30 min at 0 °C before BnBr (1.4 ml_, 11.83 mmol, 3.6 eq.) was added dropwise. The reaction mixture was warmed to room temperature and allowed to stir for 18 h. The reaction was quenched with NH₄CI (sat. aq.) and diluted with EtOAc. The organic layer was separated and the aqueous layer was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SC>4, filtered and concentrated in vacuo. Purification by flash column chromatography (S1O₂, 9:1 Pet. Ether: EtOAc) gave the title compound (1.20 g, 2.48 mmol, 75%) as an off-white solid. 13: R_f (9: 1 Pet. Ether: EtOAc): 0.23; ¹H NMR (400 MHz, CDCI3) (major rotamer): δ_Η = 7.55 (d, J =

7.8, 1 H, ArH), 7.33 - 7.19 (m, 9H, ArH), 7.16 (t, J = 7.4, 1 H, ArH), 7.09 (t, J = 7.3, 1 H, ArH), 7.02 (d, J = 6.3, 2H, ArH), 6.64 (s, 1 H, C=CH), 5.18 (s, 2H, NCH₂Ph), 5.09 (d, J = 12.2, 1 H, OOMHBPI-I), 5.01 (d, J = 12.2, 1 H, OCH_AH_sPh), 4.69 (dt, J = 8.3, 5.2, 1 H, NHCHCH₂), 3.35 - 3.23 (m, 2H, CHCH₂), 1.42 (s, 9H, C(CH₃)₃); HRMS (ESI⁺): m/z calcd for C₃oH₃20₄N₂Na ([M+Na]⁺) 507.2260, found 507.2280. Data in agreement with reported values.¹⁰

fert-Butyl (S)-(3-(1-benzyl-1 H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl)carbamate (14)

[00205] Following a similar method to general procedure 1 , ethanolic MeNH₂ (0.94 ml_, 7.52 mmol, 7.0 eq.) was added to ester 13 (521 mg, 1.08 mmol, 1.0 eq.) and left to stir for 18 h. The title compound (408 mg, 1.00 mmol, 93%) was yielded as a

white solid without further purification. 14: ¹H NMR (400 MHz, CDC ): δ_Η = 7.66 (d, J = 7.8, 1 H, ArH), 7.32 - 7.24 (m, 4Η, ArH), 7.21 - 7.16 (m, 1 Η, ArH), 7.16 - 7.12 (m, 1 Η, ArH), 7.11 - 7.06 (m, 2Η, ArH), 6.98 (s, 1 Η, C=CH), 5.68 (br. s, 1 Η, NH), 5.30 - 5.20 (m, 2Η, NCH>Ph), 5.17 (br. s, 1 Η, NH), 4.39 (dd, J = 14.3, 7.3, 1 Η, NHCHCH₂), 3.31 (dd, J = 14.8, 5.3, 1 H, CHCH,H_B), 3.13 (dd, J = 14.5, 7.7, 1 H, CHCH_AH_B), 2.61 (d, J =

4.9, 3H, NHCHs), 1.42 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5_C = 172.3 (C=0), 155.6 (C=0), 137.6 (CAT), 136.7 (CAT), 128.9 (2xCH_Ar), 128.2 (CAT), 127.8 (CH_Ar), 127.3 (C=CH), 126.9 (2xCH_Ar), 122.2 (CH_Ar), 119.6 (CH_Ar), 119.3 (CH_Ar), 1 10.2 (C=CH), 109.9 (CH_Ar), 80.1 (C(CH₃)₃), 55.4 (CHCH₂), 50.0 (NCH₂Ph), 28.7 (CHCH₂), 28.4 (C(CH₃)₃), 26.2 (NHCH₃); HRMS (ESI⁺): m/z calcd for C₂₄H₂₉0₃N₃Na ([M+Na]⁺) 430.2107, found 430.2104.

(S)-2-Amino-3-(1-benzyl-1 /-/-indol-3-yl)-/V-methylpropanamide (15)

[00206] To a solution of /V-methylamide 14 (79 mg, 0.194 mmol, 1.0 eq.) in DCM (0.80 ml_, 0.24 M) was added TFA (75 μΙ_, 0.969 mmol, 5.0 eq.) dropwise and the reaction mixture was left to stir at room temperature for 18 h. The reaction mixture was concentrated in vacuo,

redissolved in DCM and washed with NaHC0₃ (sat. aq.). The organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSC , filtered and concentrated in vacuo to give the title compound (50 mg, 0.163 mmol, 84%) as a yellow solid without further purification. 15: ¹H N R (400 MHz, CDCI₃): δ_Η = 7.69 (d, J = 7.8, 1 H, ArH), 7.33 - 7.23 (m, 5H, ArH and NH), 7.22 - 7.17 (m, 1 H, ArH), 7.16 - 7.08 (m, 3H, ArH), 7.00 (s, 1 H, C=CH), 5.28 (s, 2H, NCH₂Ph), 3.75 - 3.67 (m, 1 H, NH₂CHCH₂), 3.39 (dd, J = 14.4, 4.0, 1 H, CHCH_AHB), 2.92 (dd, J = 14.4, 8.9, 1 H, CHCH_AHB), 2.79 (d, J = 5.0, 3H, NHCH₃), 1.46 (br. s, 2H, N - ₂); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5c = 175.4 (C=0), 137.5 {CM), 136.8 (CAT), 128.9 (2xCH_Ar), 128.3 (CAT), 127.8 (CH_Ar), 127.2 (C=CH), 126.9 (2xCH_Ar), 122.1 (CH_Ar), 119.5 (CH_Ar), 119.3 (CH_Ar), 11 1.1 (C=CH), 109.9 (CHAr), 55.8 (CHCH₂), 50.0 (NCH₂Ph), 30.8 (CHCH₂), 25.9 (NHCH₃); HRMS (ESI⁺): m/z calcd for Ci₉H₂iON₃Na ([M+Na]⁺) 330.1576, found 330.1579. Data in agreement with reported values.⁴

(S)-3-(1-Benzyl-1 -/-indol-3-yl)-2-((2,2-dimethylpropylidene)amino)-/V-methylpropanamide(16)

[00207] Following general procedure 2, to a solution of N- methylamide 15 (1000 mg, 3.25 mmol) in DCM (2.20 ml_, 1.5 M) was added MgSC (400 mg, 3.32 mmol) and pivalaldehyde (0.53 ml_, 4.88 mmol). The title compound (1208 mg, 3.22 mmol, 99%)

was yielded as a colourless oil. 16: ¹H NMR (400 MHz, CDCI₃): 5_H = 7.64 (ddd, J = 7.7, 1.3, 0.8, 1 H, ArH), 7.30 - 7.19 (m, 4H, ArH), 7.14 (ddd, J = 8.2, 7.0, 1.4, 1 H, ArH), 7.12 - 7.03 (m, 3H, ArH), 6.92 (br. q, J = 5.0, 1 H, NHCH₃), 6.82 (s, 1 H, C=CH), 6.81 (s, 1 H, CHC(CH₃)₃), 5.28 - 5.14 (m, 2H, NCH₂Ph), 3.77 (dd, J = 10.1 , 3.1 , 1 H, CHCH_AHB), 3.46 (ddd, J = 14.3, 3.1 , 0.9, 1 H, CHCH_AHB), 2.92 (dd, J = 14.3, 10.1 , 1 H, CHCH_AHB), 2.84 (d, J = 5.0, 3H, NHCH₃), 0.74 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 173.9 (C=0), 173.6 (CHC(CH₃)₃), 137.6 (C_Ar), 136.6 (C_Ar), 128.8 (2xCH_Ar), 128.5 (C_Ar), 127.7 (CH_Ar), 127.2 (C=CH), 126.9 (2xCH_Ar), 121.8 (CH_Ar), 119.8 (CH_Ar), 119.1 (CH_Ar), 111.2 (C=CH), 109.6 (CH_Ar), 73.7 (CHCH₂), 49.9 (NCH₂Ph), 36.2 (C(CH₃)₃), 30.6 (CHCH₂), 26.5 (C(CH₃)₃), 25.9 (NHCH₃); IR: v_max = 3397 (N-H), 3089, 3057, 3030, 2957, 2927, 2865 (C-H), 1667 (C=0); HRMS (ESI⁺): m/z calcd for C₂₄H₃₀ON₃ ([M+H]⁺) 376.2383, found 376.2386. Synthesis of Heterocyclic Carbamoyl Chlorides

(5S)-2-(ferf-Butyl)-3,5-dimethyl-4-oxoimidazolidine-1 -carbonyl chloride (17)

[°⁰²⁰⁸1 ^Followin9 general procedure 3a, /V-methylamide 1 (100 mg, 0.979 mmol), pivalaldehyde (0.12 mL, 1.08 mmol) and TFA (0.15 mL, 1.96 mmol,

2.0 eq.) were reacted to give a crude diastereomeric imidazolidinone (80:20 trans.cis) which was phosgenated with triphosgene (1 15 mg, 0.388 mmol) in the presence of 2,6-lutidine (0.12 mL, 1.03 mmol). Purification by flash column chromatography (S1O2, 99: 1 DCM: Acetone) gave isolated diastereomers:

[00209] trans-M (158 mg, 0.679 mmol, 69%) as a white solid: ¹H NMR (400 MHz, CDC ) (0.55:0.45 rotamers): δ_Η = 5.16 (br. s, 0.45H, CHC(CH3)3₍min)), 5.1 1 (br. s, 0.55H, CtfC(CH3)3₍ma_j)), 4.12 (br. s, 1 H, CHCH₃), 3.03 (br. s, 3H, NCHs), 1.73 (br. s, 1.35H, CHCH₃₍min)), 1.59 (br. s, 1.65H, CHCH₃₍maj)), 1.04 (br. s, 4.95H, C(CH₃)3₍maj)), 1.04 (br. s, 4.05H, C(Ctf₃)3(min)); ¹³C {¹H} NMR (100 MHz, CDCb): 5_C = 171.2

147.6

(C=0_(min)), 145.3 (C=0₍maj)), 83.8 (CHC(CH₃)3(maj)), 82.7 (CHC(CH₃)3(min)), 58.5 (CHCH₃₍maj)),

57.4 (CHCH₃₍min)), 41.4 (C(CH₃)₃(_min)), 41.2 (C(CH₃)₃(_maD), 32.3 (NCH₃), 26.8 (C(CH₃)_3(m¾), 26.4 (C(CH₃)3(min)), 19.8 (CHCH3(min)) , 15.9 (CHCH₃₍maj,); IR: Vmax = 2969, 2876 (C-H), 1746 (C=0), 1710 (C=0); HRMS (ESI⁺): /z calcd for C10H18O2N2CI ([M+H]⁺) 233.1051 , found 233.1049.

[00210] c/s-17 (40 mg, 0.170 mmol, 18%) as a pale yellow oil: ¹H NMR (400 MHz, CDCb): δ_Η = 5.07 (s, 1 H, CtfC(CH₃)3), 4.35 (q, J = 7.0, 1 H, CHCH₃), 2.98 (s, 3H, NCH₃), 1.58 (d, J = 7.0, 3H , CHCHs), 1 .01 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 M Hz, CDCI₃): 5_C = 170.3 (C=0), 150.3 (C=0), 83.8 (CHC(CH₃)₃), 58.6 (CHCH3), 38.1 (C(CH₃)₃), 31 .7 (NCH₃), 26.6 (C(CH₃)₃), 17.6 (CHCH₃); IR: Vmax = 2976, 2877 (C-H), 1746 (C=0), 1708 (C=0); HRMS (ESI⁺): m/z calcd for C₁0H₁8O₂N₂CI ([M+H]⁺) 233.1051 , found 233.1049.

(2f?,5S)-5-Benzyl-2-(te -butyl)-3-methyl-4-oxoimidazolidine-1-carbonyl chloride (18)

[00211] Following a similar method to general procedure 3b, /V-methylamide 3 (2.00 g, 1 1.22 mmol), pivalaldehyde (1 .34 mL, 12.34 mmol) and PTSA monohydrate (320 mg, 1.68 mmol) were reacted to give a crude

diastereomeric imidazolidinone (60:40 trans.cis) which was phosgenated with triphosgene (1350 mg, 4.55 mmol) in the presence of pyridine (0.98 mL, 12.13 mmol, 1.2 eq.). Purification by flash column chromatography (S1O2, 99: 1 DCM:Acetone) gave isolated diastereomers:

[00212] trans- β (1048 mg, 3.39 mmol, 30%) as a white solid: ¹H NMR (400 MHz, CDCb) (0.55:0.45 rotamers): δ_Η = 7.22 (br. s, 3H, Phtf), 7.17 - 7.15 (m, 2H, PhH), 4.72 (s, 0.55H, CWC(CH3)₃(maj)), 4.59 (s, 0.45H, CHC(CH3)₃₍min)), 4.45 (br. s, 0.55H, CHCH_AH_B(maj)), 4.42 (br. s, 0.45H, CHCH_AH_B(min)) , 3.87 (dd, J = 14.1 , 4.3, 0.45H,

3.72 (dd, J = 14.1 , 4.5, 0.55H,

3.34 (d, J = 14.1 , 0.45H, CHCH_AW_e(_min)), 3.26 (d, J = 14.2, 0.55H, CHCH_AH_S(maj)), 2.87 (s, 1 .65H, NCH₃(_maj)), 2.73 (s, 1.35H, NCH₃₍min)), 1.00 (s, 4.95H, C(CH₃)3(maj)), 0.92 (s, 4.05H, C(CH₃)_3(min)); ¹³C {¹H} N M R (100 MHz, CDCI₃): δ₀ = 169.9

(C=0(ma;)), 169.3 (C=0(min)), 147.3 (C=0(_min)), 146.2 (C=0(ma;)), 134.4 (Cph(maj)), 134.1 (Cph(min)),

130.2 (2x CH_Ph(ma_j)), 130.1 (2x CH_Ph(min)), 128.5 (2x CH_Ph(min)), 128.3 (2xCHp_h(ma_j)), 127.6

(CHph(min)), 127.3 (CHph(maj)), 83.5 (CHC(CH3)3(maj)), 82.9 (CHC(CH3)3(min)), 63.6 (CHCH₂(_maj)), 62.8 (CHCH₂(min)), 41.8 (C(CH₃)3(min)), 41 .7 (C(CH₃)3(maj)), 36.7 (CHCH₂(min)), 32.9 (CHCH₂(maj)),

32.1 (NCH₃), 26.8 (C(CH₃)3(maj)) , 26.5 (C(CH₃)3(min)); IR: v_max = 2968, 2936, 2874 (C-H), 1739 (C=0), 1708 (C=0); HRMS (ESI⁺): m/z calcd for CisH2i0₂N₂CINa ([M+Na]⁺) 331.1 189, found 331 .1 197.

[00213] c/s-18 (687 mg, 2.23 mmol, 20%) as a pale yellow oil: ¹H NMR (400 MHz, CDCI₃): 5_H = 7.38 (d, J = 7.2, 2H, PhH), 7.32 (t, J = 7.3, 2H, PhH), 7.28 - 7.24 (m, 1 H, PhH), 5.1 1 (s, 1 H, CWC(CH₃)₃), 4.52 (dd, J = 8.2, 4.7, 1 H, CWCH_AH_B), 3.24 (dd, J = 22.9, 13.9, 1 H,

and dd, J = 23.9, 13.9, 1 H, CHCH_AW_B), 3.02 (s, 3H, NCH₃), 1.08 (s, 9H, C(CW₃)₃); ¹³C {¹ H} NM R (100 MHz, CDCI₃): 5_C = 169.5 (C=0), 150.9 (C=0), 136.8 (C_Ph), 129.7 (2xCH_Ph), 128.7 (2xCHp_h), 127.2 (CHph), 83.9 (CHC(CH₃)₃), 63.7 (CHCH₂), 39.8, (CHCH₂), 38.1 (C(CH₃)₃), 31.7 (NCH₃), 26.9 (C(CH₃)3); IR: v_max = 3087, 3062, 3032, 2968 (C-H) , 1740 (C=0), 1711 (C=0); HRMS (ESI⁺): m/z calcd for Ci₆H₂i0₂N₂CINa ([M+Na]⁺) 331.1 189, found 331.1 187.

(5R)-2-(fert-Butyl)-3-methyl-4-oxo-5-phenylimidazolidine-1 -carbonyl chloride (19)

3b, /V-methylamide 5 (2.00 g, 12.18 3.40 mmol) and PTSA monohydrate

d to give a crude diastereomeric imidazolidinone (55:45 trans.cis) which was phosgenated with triphosgene (1 .51 g, 5.10 mmol) in the presence of 2,6-lutidine (1.58 ml_, 13.61 mmol). Purification by flash column chromatography (Si0₂, 4: 1 Pentane: EtOAc) gave isolated diastereomers:

[00215] ira 7S-19 (1.58 g, 5.37 mmol, 44%) as a white solid: ¹H NMR (400 MHz, CDCI₃) (0.82:0.18 rotamers): δ_Η = 7.40 - 7.32 (m, 3H, PhH), 7.20 (d, J = 6.9, 2H, PhH), 5.45 (s, 0.82H, CHC(CH₃)3(maj)), 5.38 (s, 0.18H, CHC(CH₃)3₍min)), 5.07 (s, 0.18H, CHPh_(min)), 5.03 (s, 0.82H, CHPh_(maj)), 3.14 (s, 0.54H, NCH₃₍min)), 3.08 (s, 2.46H, NCH₃₍maj)), 1 .15 (s, 1.62H, C(CH₃)3₍min)), 1.09 (s, 7.38H, C(CH₃)₃(maj)); ¹³C {¹ H} N M R (100 MHz, CDCI₃): 5_C = 169.8

169.2

(C=0(maj)), 148.8 (C=0(maj)), 145.0 (C=0(min)), 137.8 (Cph(maj)), 134.9 (C_Ph(min)), 129.6 - 128.8

(3xCH_Ph), 128.1 - 125.7 (2x CH_Ph), 83.8 (CHC(CH₃)_3(min)), 82.8 (CHC(CH₃)_3(mi0), 66.5 (CHPh_(min)), 66.1 (CHPh_(mai)), 41.6 (C(CH₃)₃), 32.5 (NCH₃), 26.8 (C(CH₃)_3(min)), 26.4 (C(CH₃)₃₍maj)); IR: v_max = 3066, 3032, 2966, 2924 (C-H), 1713 (C=0); HRMS (ESI⁺): m/z calcd for Ci5Hi₉0₂N₂CINa ([M+Na]⁺) 317.1033, found 317.1031. [00216] c/s-19 (1.50 g, 5.10 mmol, 42%) as a colourless oil: ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.69 (d, J = 7.5, 2H, PhW), 7.38 (t, J = 7.5, 2H, P H), 7.30 (t, J = 7.2, 1 H, PUH), 5.56 (s, 1 H, C«C(CH₃)₃), 5.24 (s, 1 H, CHPh), 3.02 (s, 3H, NCH₃), 0.90 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 167.7 (C=0), 151.7 (00), 133.8 (Cm), 128.4 (2xCH_Ph), 128.0 (CH_Ph), 125.8 (2xCHp_h), 84.1 (CHC(CH₃)₃), 63.8 (CHPh), 37.8 (C(CH₃)₃), 31.6 (NCH₃), 26.4 (C(CH₃)₃); IR: Vmax = 3064, 3034, 2970 (C-H), 1711 (C=0); HRMS (ESI⁺): m/z calcd for Ci5Hi90₂N₂CINa ([M+Na]⁺) 317.1033, found 317.1034.

(5S)-2-(ferf-Butyl)-5-isopropyl-3-methyl-4-oxoimidazolidine-1-carbonyl chloride (20)

[00217] Following general procedure 3b, /V-methylamide 7 (135 mg, 1.04 mmol) and pivalaldehyde (0.12 mL, 1.14 mmol) and PTSA monohydrate (30 mg, 0.156 mmol) were reacted to give a crude diastereomeric

imidazolidinone (60:40 trans.cis) which was phosgenated with triphosgene

(138 mg, 0.465 mmol) in the presence of 2,6-lutidine (0.14 mL, 1.24 mmol). Purification by flash column chromatography (Si0₂, 3:1 Pet. Ether: EtOAc) gave isolated diastereomers:

[00218] trans-20 (143 mg, 0.548 mmol, 53%) as a white solid: ¹H NMR (500 MHz, CDCI₃) (0.65:0.35 rotamers): 5_H = 5.14 (s, 1 H, CHC(CH₃)₃), 4.08 (br. s, 0.65H, CHCH(CH₃)_2(MAJ)), 4.02 (br. s, 0.35H, CHCH(CH₃)_2(MIN)), 3.06 - 2.90 (m, 4H, NCH₃ and CHCH(CH₃)₂), 1.23 (d, J = 7.0, 3H, CH(CH₃HCH₃)B), 1.05 (s, 5.85H, C(CH₃)_3(maj)), 0.99 (s, 3.15H, C(CH₃)_3(min)), 0.74 (d, J = 6.9, 3H, CH(CH₃)_A(CH₃)_b); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5_C = 169.5 (C=0_(maj)), 168.8

(C=0_(min)) , 147.7 (C=0_(min)) , 145.1 (C=0_(maj)), 83.5 (CHC(CH3)₃₍maj)), 82.8 (CHC(CH₃)3(min)) , 66.5

(CHCH(CH₃)_2(maj)), 65.7 (CHCH(CH₃)_2(min)) , 42.1 (C(CH₃)_3(min)), 41.7 (C(CH₃)_3(maj)), 31.8 (NCH₃), 31.4 (CH(CH₃)_2(mi„)), 26.8 (C(CH₃)_3(maj)), 26.6 (C(CH₃)_3(min)), 25.3 (CH(CH₃)_2(maj)), 18.4 (CH(CH₃)MCH₃)_B(min)) , 18.0 (CH(CH₃HCH₃)_B(m_aj)), 14.9 (CH(CH₃)_A(CH₃)_B); IR: v_max = 2964, 2936, 2878 (C-H), 1743 (C=0), 1706 (C=0); HRMS (ESI⁺): m/z calcd for Ci₂H₂₂0₂N₂CI ([M+H]⁺) 261.1364, found 261.1359.

[00219] c/s-20 (92 mg, 0.353 mmol, 34%) as a white solid: ¹H NMR (500 MHz, CDCI₃): δ_Η = 5.07 (s, 1 H, CWC(CH₃)₃), 4.05 (d, J = 10.8, 1 H, CHCH(CH₃)₂), 2.97 (s, 3H, NCH₃), 2.05 - 1.93 (m, 1 H, CHCrt(CH₃)₂), 1.28 (d, J = 6.5, 3H, CH(CH₃)4CH₃)_B), 1.14 (d, J = 6.9, 3H, CH(CH₃)_A(CH₃)B), 1.04 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5_C = 170.2 (C=0), 151.9 (C=0), 84.6 (CHC(CH₃)₃), 67.3 (CHCH(CH₃)₂), 37.5 (C(CH₃)₃), 32.1 (CH(CH₃)₂), 31.4 (NCH₃), 26.9 (C(CH₃)₃), 20.3 (CH(CH₃)4CH₃)_B), 20.1 (CH(CH₃)_A(CH₃)_B); IR: v_max = 2968, 2936, 2876 (C-H), 1734 (C=0), 1702 (C=0); HRMS (ESI⁺): m/z calcd for Ci₂H₂₂0₂N₂CI ([M+H]⁺) 261.1364, found 261.1361.

(5S)-5-(4-(benzyloxy)benzyl)-2-(ie/t-butyl)-3-methyl-4-oxoimidazolidine-1-carbonyl chloride (21) [00220] Following general procedure 3a, V-methylamide 12 (457 mg, 1.19 mmol, 1.0 eq.) and pivalaldehyde (0.19 mL, 1.78 mmol) and TFA (0.46 mL, 5.94 mmol, 5.0 eq.) were reacted to give a crude diastereomeric imidazolidinone (60:40 trans:cis) which was

phosgenated with triphosgene (159 mg, 0.535 mmol) in the presence of 2,6-lutidine (0.17 mL, 1.43 mmol). Purification by flash column chromatography (Si0₂, 99: 1 DCM: Acetone) gave:

[00221] trans-ΙΛ (208 mg, 0.501 mmol, 42%) as a white solid: R_f (99: 1 DCM: Acetone): 0.26; ¹H N R (400 MHz, CDCI₃) (0.55:0.45 rotamers): δ_Η = 7.42 (d, J = 7.3, 2H, PhH), 7.38 (t, J = 7.3, 2H, PhH), 7.35 - 7.29 (m, 1 H, PhH), 7.09 (d, J = 8.5, 2H, ArH), 6.86 (d, J = 8.4, 2H, ArH), 5.06 - 4.98 (m, 2H, OCH₂Ph), 4.74 (s, 0.55H, CWC(CH₃)3₍maj)) , 4.61 (s, 0.45H, CHC(CH₃)3₍min)) , 4.43 (d, J = 2.9, 0.55H, NCH_(maj)), 4.38 (d, J = 3.0, 0.45H, ΝΟ/_(πιίη)), 3.83 (dd, J = 14.4, 5.2, 0.45H, CHCHAHB(min)) , 3.69 (dd, J = 14.4, 4.8, 0.55H ,

3.29 (d, J = 14.3, 0.45H, CHCH_AW_S(_min)), 3.21 (d, J = 14.6, 0.55H, CHCH_Atf_S(maj)) , 2.87 (s, 1.65H,

2.73 (s, 1.35H, NCW₃₍min)), 1.01 (s, 4.95H, C(CHz)z_(mai)), 0.93 (s, 4.05H, C(CH₃)3(min)); ¹³C {¹H} NMR (100 MHz, CDCI3): δο = 170.0 (C=0₍maj)), 169.4 (C=0_(min)), 158.2 (C_ArO_(mi„)), 158.0 (C_AAmaj)), 147.4

(C=0(min)) , 146.2 (C=0_(maj)), 137.1 (Cph(maj)) , 137.0 (Cph(min)) , 131.3 (2xCH_Ar(maj)), 131.2

(2xCH_Ar(min)), 128.7 (2x CH_Ph), 128.1 (CH_Ph), 127.7 (2x CH_Ph), 126.6 (C _maj)), 126.2 (C_Ar(min)) , 1 14.9 (2xCH_Ar(min)), 1 14.7 (2xCH_Ar(maj)), 83.5 (CHC(CH₃)3₍maj)), 82.9 (CHC(CH₃)3₍min)) , 70.0 (OCH₂Ph), 63.8 (CHCH₂(maj)) , 62.9 (CHCH_2(min)) , 41.8 (C(CH₃)3(min)) , 41.7 (C(CH₃)_3(maj)), 35.9 (CHCH_2(min)), 32.2 (NCH₃), 32.0 (CHCH_2(maj)), 26.8 (C(CH₃)_3(maj)) , 26.6 (C(CH₃)_3(min)) ; IR: v_max = 3034, 2968, 2929, 2871 (C-H), 1736 (C=0), 1697 (C=0); HRMS (ESI⁺): m/z calcd for C₂₃H₂₇0₃N₂CIK ([M+K]⁺) 453.1347, found 453.1357.

[00222] c/s-21 (128 mg, 0.308 mmol, 26%) as a white solid: R_f (99: 1 DCM:Acetone): 0.21 ; ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.43 (d, J = 7.1 , 2H, PhH), 7.38 (t, J = 7.3, 2H, PhH), 7.35 - 7.30 (m, 1 H, PhH), 7.29 (d, J = 8.6, 2H, ArH), 6.93 (d, J = 8.6, 2H, ArH), 5.10 (s, 1 H, CHC(CH₃)3), 5.05 (s, 2H, OCH₂Ph), 4.46 (dd, J = 8.2, 4.7, 1 H, CA7CH_AH_B), 3.21 (dd, J = 14.0, 8.3, 1 H,

3.15 (dd, J = 14.0, 4.7, 1 H, CHCH_AH_B), 3.01 (s, 3H, NCH₃), 1.07 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): δ₀ = 169.6 (C=0), 158.0 (C_ARO) , 150.9 (C=0), 137.1 (C_PH), 130.8 (2x CH_Ar), 129.1 (CM), 128.7 (2xCH_Ph), 128.1 (CH_PH), 127.6 (2x CH_Ph), 115.0 (2xCH_Ar), 83.9 (CHC(CH₃)3), 70.0 (OCH₂Ph), 63.8 (CHCH₂), 39.0 (CH CH₂), 38.1 (C(CH₃)₃), 31 .7 (N CH₃), 26.8 (C(CH₃)₃); IR: v_max = 2967 (C-H), 1746 (C=0), 1613 (C=0); HRMS (ESI⁺): m/z calcd for C₂3H₂₇0₃N₂CIK ([M+K]⁺) 453.1347, found 453.1352. Methyl (2f?,4S)-2-(ferf-butyl)-3-(chlorocarbonyl)oxazolidine-4-carboxylate (22)

[00223] To a stirred suspension of L-serine methyl ester hydrochloride (375 mg, 2.41 mmol, 1.0 eq.) in pentane (8.00 ml_, 0.3 M) was added pivalaldehyde (0.39 ml_, 3.62 mmol, 1.5 eq.) and Et₃N (0.37 ml_, 2.65 mmol,

1.1 eq.). The stirred reaction mixture was refluxed overnight under Dean-

Stark conditions. The mixture was cooled to room temperature and diluted with EtOAc, before NaHCC>₃ (3.00 ml_, sat. aq.) was added. The aqueous layer was separated and the organic layer was washed a further 2 times with NaHCC>₃ (sat. aq.). The organic layer was dried over MgSC , filtered and concentrated in vacuo to give a crude diastereomeric oxazolidine (65:35 trans.cis). To a stirred solution of the crude oxazolidine (315 mg, 1.68 mmol, 1.0 eq.) in DCM (6.50 ml_, 0.26 M) at -15 °C, was added, dropwise, phosgene (1.80 ml_, 2.52 mmol, 1.5 eq., 1.4 in toluene) and Et₃N (0.30 ml_, 2.19 mmol, 1.3 eq.). The reaction was allowed to warm to room temperature and left to stir for 2 h. The reaction mixture was filtered and concentrated in vacuo before being redissolved in EtOAc and washed 3 times with water. The organic layer was separated, dried over MgS04, filtered and concentrated in vacuo to give the title compound (420 mg, 1.68 mmol, 70% over 2 steps, >95:5 dr) as a white solid without further purification. 22: ¹H NMR (500 MHz, CDC ) (major diastereomer): δ_Η = 5.18 (s, 1 H, CHC(CH₃)₃), 4.91 (dd, J = 8.0, 4.5, 1 H, CtfCH_AH_B), 4.41 (dd, J = 8.9, 4.5, 1 H,

4.22 (t, J = 8.5, 1 H, CHCHAHB), 3.82 (s, 3H, C 7₃), 0.97 (s, 9H, C(CH₃)₃). Data in agreement with reported values.¹¹

Synthesis of the Heterocyclic Ureas

(2S,5S)-2-(te/f-Butyl)-/V,3,5-trimethyl-4-oxo-A/-ph (23)

[00224] To a solution of trans-M (1.00 g, 4.30 mmol, 1.0 eq.) in anhydrous MeCN (4.30 ml_, 1.0 M) was added Et₃N (1.20 ml_, 8.59 mmol,

2.0 eq.) and /V-methylaniline (2.33 ml_, 21.49 mmol, 5.0 eq.). The reaction mixture was heated to reflux and left to stir for 18 h. The reaction mixture was cooled to room temperature and quenched with HCI (1.0 M, aq.), the organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSC , filtered and concentrated in vacuo. Purification by flash column chromatography (Si0₂, 2:1 Pet. Ether: EtOAc) gave the title compound (1.10 g, 3.63 mmol, 84%) as a pale yellow oil. 23: ¹H NMR (500 MHz, CDCb): δ_Η = 7.35 (t, J = 7.4, 2H, P H), 7.32 - 7.22 (m, 2H, P H), 7.18 (t, J = 7.1 , 1 H, PhH), 5.43 (s, 1 H, CHC(CH₃)₃), 3.32 (s, 3H, NCH₃), 2.96 (s, 3H, NCH₃), 2.87 (br. s, 1 H, CHCH₃), 1.24 (br. s, 3H, CHCH₃), 0.99 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCIs): 5_C = 173.1 (C=0), 158.9 (C=0), 144.0 (C_Ph), 129.4 (2xCH_Ph), 125.9 (CH_Ph), 127.2 (2xCHp_h), 81.6 (CHC(CH₃)₃), 55.8 (CHCH₃), 40.1 (C(CH₃)₃), 38.7 (NCH₃), 32.2 (NCH₃), 26.1 (C(CH₃)₃), 19.9 (CHCH₃); IR: v_max = 2961 , 2923, 2851 (C-H), 1707 (C=0), 1652 (C=0); HRMS (ESI⁺): m/z calcd for Ci₇H₂50₂N₃Na ([M+Na]⁺) 326.1844, found 326.1834.

(2R,5S)-2-(ie/t-Butyl)-/V,3,5-trimethyl-4-oxo-/V-phenylimidazolidine-1-carboxamide (24)

[00225] To a solution of c/s-17 (120 mg, 0.516 mmol, 1.0 eq.) in anhydrous DCM (1.00 ml_, 0.5 M) was added Et₃N (0.11 ml_, 0.774 mmol,

1.5 eq.) and /V-methylaniline (61 μΙ_, 0.567 mmol, 1.1 eq.). The reaction mixture was heated to reflux and left to stir for 18 h. The reaction mixture was cooled to room temperature and quenched with HCI (1.0 M, aq.), the organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSCU, filtered and concentrated in vacuo. Purification by flash column chromatography (Si0₂, 2:1 EtOAc: Pet. Ether) gave the title compound (152 mg, 0.501 mmol, 97%) as a pale yellow oil. 24: ¹H NMR (500 MHz, CDCb): δ_Η = 7.43 - 7.38 (m, 2H, PhH), 7.30 - 7.25 (m, 1 H, PhH), 7.20 - 7.15 (m, 2H, PhH), 5.60 (s, 1 H, CHC(CH₃)₃), 3.96 (q, J = 6.9, 1 H, CHCH₃), 3.19 (s, 3H, NCH₃), 2.94 (s, 3H, NCH₃), 0.98 (s, 9H, C(CH₃)₃), 0.33 (d, J = 6.9, 3H, CHCH₃); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5_C = 173.4 (C=0), 163.4 (C=0), 146.1 (C_Ph), 130.2 (2xCH_Pfl), 127.6 (2xCH_Ph), 127.1 (CH_Ph), 82.7 (CHC(CH₃)₃), 59.3 (CHCH₃), 41.5 (NCH₃), 36.7 (C(CH₃)₃), 31.6 (NCH₃), 26.9 (C(CH₃)₃), 17.4 (CHCH₃); IR: v_max = 2960, 2927, 2873 (C-H), 1703 (C=0), 1655 (C=0); HRMS (ESI⁺): m/z calcd for Ci₇H₂₅0₂N₃Na ([M+Na]⁺) 326.1844, found 326.1854. (2f?,5S)-2-(ferf-But l)-A/-(4-cyanophenyl)-/V,3,5 rimethyl-4-oxoimidazolid (25)

[00226] Following general procedure 5, c s-17 (85 mg, 0.365 mmol), 4-(methylamino)benzonitrile (241 mg, 1.83 mmol), 2,6- lutidine (85 μΙ_, 0.731 mmol) and Kl (67 mg, 0.402 mmol) were

reacted in toluene (1 .05 ml_, 0.35 M) at reflux for 72 h. Purification by flash column chromatography (S1O₂, 4: 1→6:1 EtOAc:Pentane) gave the title compound (87 mg, 0.265 mmol, 73%) as a yellow oil. 25: R_f (4: 1 EtOAc:Pentane): 0.21 ; ¹H NMR (500 MHz, CDCI3): δ_Η = 7.71 - 7.65 (m, 2H, ArH), 7.27 - 7.23 (m, 2H, ArH), 5.50 (s, 1 H, CWC(CH₃)₃), 3.98 (q, J = 6.9, 1 H, CWCH3), 3.21 (s, 3H, NCH₃), 2.95 (s, 3H, NCH₃), 0.99 (s, 9H, C(CH₃)₃), 0.59 (d, J = 6.9, 3H, CHCH ; ¹³C {¹H} NMR (125 MHz, CDCI₃): δ₀ = 172.5 (C=0), 162.8 (C=0), 150.3 (C_Ar), 134.0 (2* CH_Ar), 126.3 (2*CH_Ar), 118.2 (C≡N), 109.6 (CA_T), 82.8 (CHC(CH₃)₃), 58.9 (CHCH₃), 40.6 (NCH₃), 36.9 (C(CH₃)₃), 31.7 (NCH₃), 26.9 (C(CH₃)₃), 17.7 (CHCH₃); IR: v_max = 2973, 2938, 2874 (C-H), 2227 (C≡N), 1699 (C=0), 1659 (C=0); HRMS (ESI⁺): m/z calcd for Ci7H₂502N₃Na ([M+Na]⁺) 326.1844, found 326.1834.

(2f?,5S)-2-(ferf-Butyl)- V-(4-chlorophenyl)-/V,3,5-trimethyl-4-oxoimidazolidine-1-carboxamide (26)

[00227] Following general procedure 4, imine 2 (71 1 mg, 4.18 m^mo')' W-(4-chlorophenyl)-/V-methylcarbamoyl chloride (1150 m9> ^{5 64 mmol}> ^{35 ec}l ) ^and DMAP (26 mg, 0.209 mmol) were

dissolved in DCE (17.0 ml_, 0.25 M) and reacted for 88 h. Purification by flash column chromatography (S1O₂, 2: 1 EtOAc: Pet. Ether), followed by recrystallisation from hexane/EtOAc gave the title compound (718 mg, 2.13 mmol, 51 %) as a white solid. 26: R_f (2: 1 EtOAc: Pet. Ether): 0.19; ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.39 - 7.32 (m, 2H, ArH), 7.14 - 7.05 (m, 2Η, ArH), 5.56 (s, 1 Η, CHC(CH₃)₃), 3.92 (q, J = 6.9, 1 H, CWCH₃), 3.13 (s, 3H, NCW₃), 2.92 (s, 3H, NCrt₃), 0.96 (s, 9H, C(CW₃)₃), 0.44 (d, J = 6.9, 3H, CHCH₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 173.0 (C=0), 163.1 (C=0), 144.7 (C_Ar), 132.6 (C_Ar), 130.3 (2x CH_Ar), 128.6 (2x CH_Ar), 82.7 (CHC(CH₃)₃), 59.1 (CHCH₃), 41 .4 (NCH₃), 36.7 (C(CH₃)₃), 31 .5 (NCH₃), 26.9 (C(CH₃)₃), 17.7 (CHCH₃); IR: v_max = 2975, 2873 (C-H), 1699 (C=0), 1655 (C=0); HRMS (ESI⁺): m/z calcd for Ci₇H₂50₂N₃CI ([M+H]⁺) 338.1630, found 338.1632.

(2R,5S -2-(fert-Butyl)- V-(4-fluorophenyl)-/V,3,5-trimethyl-4-oxoimidazolidine-1-carboxamide (27)

[00228] Following general procedure 4, imine 2 (812 mg, 4.77 rnrnol), V-(4-fluorophenyl)- V-methylcarbamoyl chloride (1208 mg, 6.44 mmol, 1.35 eq.) and DMAP (29 mg, 0.238 mmol) were

dissolved in DCE (19.0 ml_, 0.25 M) and reacted for 88 h. Purification by flash column chromatography (S1O₂, 2: 1→5:2 EtOAc: Pet. Ether), followed by recrystallisation from hexane/EtOAc gave the title compound (701 mg, 2.18 mmol, 46%) as a white solid. 27: R, (2: 1 EtOAc: Pet. Ether): 0.18; ¹H NMR (500 MHz, CDCI₃): δ_Η = 7.16 - 7.06 (m, 4H, ArH), 5.59 (s, 1 H, CWC(CH₃)₃), 3.94 (q, J = 6.9, 1 H, CHCH₃), 3.14 (s, 3H, NCH₃), 2.93 (s, 3H, NCH₃), 0.97 (s, 9H, C(CW₃)₃), 0.41 (d, J = 6.9, 3H, CHCH₃); ¹³C {¹H} NMR (125 M Hz, CDCIs): 5c = 173.1 (C=0), 163.3 (C=0), 161 .3 (d, ¹ _C-F = 247.9, C_ArF), 142.2 (d, ⁴ _C-F = 3.4, CAT), 129.2 (d, ³J_C-_F = 8.3, 2xCH_Ar), 1 17.1 (d, ² _C-F = 22.6, 2xCH_Ar), 82.7 (CHC(CH₃)₃), 59.1 (CHCH₃), 41.7 (NCH₃), 36.7 (C(CH₃)₃), 31.5 (NCH₃), 26.9 (C(CH₃)₃), 17.7 (CHCH₃); IR: v_max = 2974, 2874 (C-H), 1702 (C=0), 1655 (C=0); HRMS (ESI⁺): m/z calcd for Ci₇H₂50₂N₃F ([M+H]⁺) 322.1925, found 322.1914.

(20.0 mL, 0.25 M) and reacted for 88 h. Purification by flash column chromatography (S1O₂, 99: 1 EtOAc:MeOH) gave the title compound (652 mg, 2.14 mmol, 42%) as a yellow oil. 28: R_f (99: 1 EtOAc:MeOH): 0.21 ; ¹H NMR (500 MHz, CDCI₃): δ_Η = 8.37 (ddd, J = 4.9, 1 .8, 0.6, 1 H , ArH), 7.65 (ddd, J = 8.1 , 7.6, 2.0, 1 H, ArH), 7.06 - 7.00 (m, 2H, ArH), 5.36 (s, 1 H, CHC(CH₃)₃), 4.15 (q, J = 7.0, 1 H, CWCH₃), 3.25 (s, 3H, NCH₃), 2.94 (s, 3H, NCH₃), 1.01 (s, 9H, C(CH₃)₃), 0.78 (d, J = 6.9, 3H, CHCH ; ¹³C {¹ H} NMR (125 MHz, CDCI₃): δ₀ = 172.8 (C=0), 163.0 (C=0),

158.1 (CAT), 149.1 (CH_Ar), 138.4 (CH_Ar), 1 19.9 (CH_Ar), 1 17.3 (CH_Ar), 82.6 (CHC(CH₃)₃), 58.5 (CHCH₃), 37.9 (N CH₃), 37.1 (C(CH₃)₃), 31.7 (NCH₃), 26.8 (C(CH₃)₃), 17.7 (CHCH₃); IR: v_max = 3053, 2961 , 2873 (C-H), 1700 (C=0), 1665 (C=0); HRMS (ESI⁺): m/z calcd for C16H25O2N4 ([M+H]⁺) 305.1972, found 305.1969.

(2R,5S)-5-Benzyl-2-(ferf-butyl)-/V,3-dimethyl-4-oxo-/V-phenylimidazolidine-1-carboxamide (29)

[00230] Following general procedure 4, imine 4 (50 mg, 0.203 mmol), N- phenyl-/V-methylcarbamoyl chloride (52 mg, 0.304 mmol, 1 .5 eq.) and DMAP (1 mg, 0.010 mmol) were dissolved in DCE (1.00 mL, 0.2 M) and

reacted for 68 h. Purification by flash column chromatography (S1O₂, 2: 1→3:2 Pet. Ether: EtOAc) gave the title compound (57 mg, 0.150 mmol, 74%) as a colourless oil. 29: R_f (3:2 Pet. Ether: EtOAc): 0.18; ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.31 (t, J = 7.8, 2H , PhH), 7.23 - 7.12 (m, 6H, PhH), 7.05 (d, J = 7.1 , 2H, PhH), 5.27 (s, 1 H, CWC(CH₃)₃), 4.25 (dd, J = 10.7, 3.2, 1 H, CWCHAHB), 3.18 (s, 3H, NCH₃), 2.86 (s, 3H, NCH₃), 2.61 (dd, J = 14.1 , 10.8, 1 H, CHCHAHB), 2.07 (dd, J = 14.1 , 2.6, 1 H, CHCH_AH_S) , 1.04 (s, 9H, C(CW₃)₃); ¹³C {¹ H} NMR (100 MHz, CDCI₃): δ₀ = 171 .7 (C=0), 163.2 (C=0), 146.0 (CAT), 137.7 (CAT), 130.2 (2xCH_Ar),

129.2 (2x CH_Ar), 128.1 (2x CH_Ar), 126.6 (CH_Ar), 126.3 (CH_Ar), 125.9 (2x CH_Ar), 82.3 (CHC(CH₃)₃), 63.1 (CHCH₂), 41.3 (NCH₃), 39.3 (CHCH₂), 37.0 (C(CH₃)₃), 31.6 (NCH₃), 27.1 (C(CH₃)₃); IR: v_max = 3062, 3029, 2960, 2931 , 2872 (C-H), 1704 (C=0), 1655 (C=0); HRMS (ESI⁺): m/z calcd for C23H₂902N₃Na ([M+Na]⁺) 402.2157, found 402.2149.

(2S,5S)-5-Benzyl-2-(feAf-butyl)-A/,3-dimethyl-4-oxo-/V^henylimidazolidine-1-carboxam (30)

[00231] Following general procedure 5, trans-Λ Ζ (50 mg, 0.162 mmol), N- methylaniline (87 uL, 0.810 mmol), 2,6-lutidine (38 uL, 0.324 mmol) and Kl (30 mg, 0.178 mmol) were reacted in DCM/toluene (0.50 ml_, 0.32 M,

4: 1) at 60 °C for 72 h. Purification by flash column chromatography (Si0₂,

2: 1 Pentane:EtOAc) gave the title compound (54 mg, 0.142 mmol, 88%) as a yellow oil. 30: ¹H NMR (400 MHz, CDC ) (major rotamer): δ_Η = 7.43 (t, J = 7.6, 2H, PJnH), 7.38 (d, J = 7.6, 2H, PJnH), 7.28 - 7.21 (m, 4H, PJnH), 7.07 (d, J = 6.9, 2H, PJnH), 4.92 (s, 1 H, CHC(CH₃)3), 3.44 (s, 3H, NC - 3), 3.21 - 3.17 (m, 2H, CHCH„H_B and CHCH_AH_B), 2.86 (d, J = 1 1.8, 1 H, CHCH_AH_e), 2.57 (s, 3H, NCrt₃), 0.94 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI3): 6_C = 171 .0 (C=0), 158.3 (C=0), 144.2 (CAT), 134.8 (CAT), 130.2 (2* CH_Ar), 129.8 (2xCH_Ar), 128.1 (2* CH_Ar), 127.1 (CH_Ar), 126.4 (CH_Ar), 125.7 (2x CH_Ar), 82.1 (CHC(CH₃)₃), 61.1 (CHCH₂), 40.4 (C(CH₃)₃), 39.4 (NCH3), 37.6 (CHCH₂), 31.8 (NCH₃), 26.4 (C(CH₃)₃); IR: v_max = 3062, 3031 , 2965, 2931 (C-H), 1703 (C=0), 1650 (C=0); HRMS (ESI⁺): m/z calcd for C23H30O2N3 ([M+H]⁺) 380.2338, found 380.2321.

(2R,5S)-5-Benzyl-2-(fe/f-butyl)- V-(4-cyanophenyl)-/V,3-dimethyl-4-oxoimidazolidine-1 - carboxamide (31 )

[00232] Following general procedure 4, imine 4 (58 mg, 0.235 mmol), /V-(4-cyanophenyl)-A/-methylcarbamoyl chloride (69 mg, 0.353 mmol, 1.5 eq.) and DMAP (1 mg, 0.011 mmol) were

dissolved in DCE (1.20 ml_, 0.2 M) and reacted for 68 h. Purification by flash column chromatography (Si0₂, 2: 1→1 : 1 Pet. Ether: EtOAc) gave the title compound (80 mg, 0.198 mmol, 84%) as a colourless oil. 31 : ¹H NMR (500 MHz, CDCI3): δ_Η = 7.50 (d, J = 8.5, 2H , ATH), 7.25 (t, J = 7.0, 2H, PJnH), 7.19 (t, J = 7.2, 1 H, PJnH), 7.07 (d, J = 7.4, 2H, PJnH), 6.96 (d, J = 8.4, 2H , ArH), 5.22 (s, 1 H, CHC(CH₃)3), 4.26 (dd, J = 8.9, 3.3, 1 H, CHCHAHB), 3.06 (s, 3H, NCH₃), 2.99 - 2.88 (m, 4H, NCH₃ and CHCHAHB), 2.47 (dd, J = 14.7, 3.1 , 1 H, CHCHAHB), 1.07 (s, 9H, 0(ΟΗ₃)₃); ¹³C {¹H} NMR (125 MHz, CDCI3): δ₀ = 171.3 (C=0), 162.1 (C=0), 149.6 (CA_T), 137.6 (C_Ph), 133.8 (2xCH_Ar), 128.8 (2x CH_Ph), 128.4 (2xCH_Ph), 126.7 (CHph), 123.0 (2xCH_Ar), 1 18.4 (C≡N), 108.1 (CAT), 82.7 (CHC(CH₃)₃), 62.5 (NCHCH₂), 40.0 (CHCH₂), 39.8 (NCH₃), 37.2 (C(CH₃)₃), 31.6 (NCH₃), 27.1 (C(CH₃)₃); IR: v_max = 3062, 3029, 2969 (C-H), 2225 (C≡N), 1704 (C=0), 1663 (C=0); HRMS (ESI⁺): m/z calcd for C24H29O2N4 ([M+H]⁺) 405.2285, found 405.2285. (2R,5S)-5-Benzyl-2-(ferf-butyl)-W-(4-chlorophenyl)-A/,3-dimethyl-4-oxoimi carboxamide (32)

[00233] Following general procedure 4, imine 4 (100 mg, 0.406 mmol), /V-(4-chlorophenyl)-/V-methylcarbamoyl chloride (124 mg,

0.609 mmol, 1.5 eq.) and DMAP (3 mg, 0.020 mmol) were

dissolved in DCE (2.00 ml_, 0.2 M) and reacted for 68 h.

Purification by flash column chromatography (S1O2, 2: 1→3:2 Pet. Ether: EtOAc) gave the title compound (135 mg, 0.326 mmol, 80%) as a colourless oil. 32: R_f (3:2 Pet. Ether: EtOAc): 0.24; ¹H N R (500 MHz, CDC ): δ_Η = 7.23 (t, J = 7.4, 2H, PhH), 7.19 - 7.14 (m, 3H, PhH and ArH), 7.06 (d, J = 7.5, 2H, PhH), 6.96 (d, J = 8.4, 2H, ArH), 5.35 (s, 1 H, CHC(CH₃)₃), 4.27 (dd, J = 10.0, 1.6, 1 H, CWCHAHB), 3.11 (s, 3H, NCHs), 2.91 (s, 3H, NCHs), 2.77 (dd, J = 14.8, 10.3, 1 H, CHCHAHB), 2.14 (d, J = 15.0, 1 H, CHCH_AH_B), 1 .04 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCIs): 5_C = 171.8 (C=0), 163.0 (C=0), 144.3 (CAT), 137.8 (C_Ph), 132.0 (CAT), 130.1 (2xCH_Ar), 128.8 (2xCHp_h), 128.0 (2xCH_Ph), 127.0 (2xCH_Ar), 126.3 (CH_Ph), 82.4 (CHC(CH₃)₃), 62.5 (CHCH₂), 41.3 (NCH₃), 39.8 (CHCH₂), 36.9 (C(CH₃)₃), 31.5 (NCH₃), 27.0 (C(CH₃)₃); IR: Vmax = 3062, 3029, 2965 (C-H), 1702 (C=0), 1656 (C=0); HRMS (ESI⁺): m/z calcd for C₂₃H290₂N₃CI ([M+H]⁺) 414.1943, found 414.1945.

(2R,5S)-5-Benzyl-2-(ferf-butyl)-/V-(4-fluorophenyl)-/V,3-dimethyl-4-oxoimidazolidine-1- carboxamide (33)

[00234] Following general procedure 4, imine 4 (613 mg, 2.49 mmol), /V-(4-fluorophenyl)- V-methylcarbamoyl chloride (700 mg,

3.73 mmol, 1.5 eq.) and DMAP (15 mg, 0.120 mmol) were

dissolved in DCE (2.00 ml_, 0.2 M) and reacted for 68 h. Purification by flash column chromatography (S1O2, 2: 1→3:2 Pet. Ether: EtOAc) gave the title compound (445 mg, 1.12 mmol, 45%) as a colourless oil. 33: ¹H NMR (500 MHz, CDCb): δ_Η = 7.24 - 7.19 (m, 2H, PhH), 7.18 - 7.13 (m, 1 H, PhH), 7.09 - 7.01 (m, 4H, PhH and ArH), 6.96 - 6.89 (m, 2H, ArH), 5.37 (s, 1 Η, CHC(CH₃)₃), 4.27 (dd, J = 10.5, 2.8, 1 H, CHCH_AH_B), 3.12 (s, 3H, NCH₃), 2.90 (s, 3H, NCH₃), 2.71 (dd, J = 14.7, 10.6, 1 Η, CHCH_AH_B), 2.04 (dd, J = 14.8, 2.8, 1 H, CHCH_/Hs), 1.04 (s, 9Η, C(CW₃)₃); ¹³C {¹H} NMR (125 M Hz, CDCb): δ₀ = 171.7 (C=0), 163.2 (C=0), 160.8 (d, ¹JC-F = 247.5, C_ArF), 141.8 (d, ⁴ C-F = 3.2, CA_T), 137.6 (C_Ph), 128.8 (2x CH_Ph), 128.0 (2x CH_Ph), 127.7 (d, ³J_C__F = 8.4, 2xCH_Ar), 126.3 (CH_Ph), 1 16.9 (d, ²J_C-_F = 22.8, 2xCH_Ar), 82.3 (CHC(CH₃)₃), 62.6 (CHCH₂), 41 .7 (NCH₃), 39.6 (CHCH₂), 36.8 (C(CH₃)₃), 31.5 (NCH₃), 27.0 (C(CH₃)₃); IR: v_max = 2964, 2248 (C-H), 1701 (C=0), 1651 (C=0); HRMS (ESI⁺): m/z calcd for C₂₃H₂80₂N₃F ([M+H]⁺) 420.2058, found 420.2042. (2R,5S)-5-Benzyl-2-(teAf-butyl)-A/,3-dimethyl-4-oxo-W-(p-tolyl)imidazolidine-1-carboxa (34)

[00235] Following general procedure 4, imine 4 (800 mg, 3.25 mmol), V-(p-tolyl)-/V-methylcarbamoyl chloride (895 mg, 4.87 mmol, 1.5 eq.) and DMAP (20 mg, 0.162 mmol) were dissolved in

DCE (2.00 ml_, 0.2 M) and reacted for 68 h. Purification by flash column chromatography (Si0₂, 2:1→3:2 Pet. Ether: EtOAc) gave the title compound (524 mg,

1.33 mmol, 41%) as a colourless oil.34: ¹H NMR (400 MHz, CDC ) δ_Η = 7.24-7.18 (m, 2H, PhH), 7.17-7.12 (m, 1H, PhH), 7.08-7.02 (m, 4H, PhWand ArH), 7.00-6.96 (m, 2H, ArH),

5.34 (s, 1H, CHC(CH₃)₃), 4.25 (dd, J= 10.7, 3.0, 1H, CWCH_AH_B), 3.14 (s, 3H, NCW₃), 2.88 (s, 3H, NCH5), 2.63 (dd, J= 14.5, 10.7, 1H, CHCH,H_B), 2.28 (s, 3H, CH₃), 2.06 (dd, J= 14.4, 3.0, 1H, CHCHAWB), 1.04 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 6_C = 171.9 (C=0), 163.3 (C=0), 143.2 (CAT), 137.9 (CPU), 136.5 (CAT), 130.7 (2xCH_Ar), 129.1 (2xCH_Ph), 127.9 (2xCHp_h), 126.2 (CHph), 125.9 (2xCH_Ar), 82.3 (CHC(CH₃)₃), 62.8 (CHCH₂), 41.5 (NCH₃), 39.4 (CHCH₂), 36.9 (C(CH₃)₃), 31.6 (NCH₃), 27.1 (C(CH₃)₃), 21.1 (CH₃); IR: v_max= 2960 (C-H), 1703 (C=0), 1652 (C=0); HRMS (ESI⁺): m/z calcd for C₂4H₃₂0₂N₃ ([M+H]⁺) 394.2489, found 394.2482.

(2R,5S)-5-Benzyl-2-(ferf-butyl)-V-(3-methoxyphenyl)-V,3-dimethyl-4-oxoimidazolidine-1- carboxamide (35)

[00236] Following general procedure 4, imine 4 (140 mg, 0.568 mmol), /V-(3-methoxyphenyl)-W-methylcarbamoyl chloride (170 mg, 0.852 mmol, 1.5 eq.) and DMAP (3 mg, 0.028 mmol) were

dissolved in toluene (2.85 ml_, 0.2 M) and reacted for 68 h.

Purification by flash column chromatography (Si0₂, 1:1 Pet. Ether: EtOAc) gave the title compound (123 mg, 0.300 mmol, 53%) as a white solid.35: R_f (1:1 Pet. Ether: EtOAc): 0.28; ¹H NMR(400 MHz, CDCI₃): δ_Η = 7.24-7.18 (m, 3H, PhH and ArH), 7.16-7.11 (m, 1H, PhH), 7.09-7.05 (m, 2Η, PhH), 6.71 (t, J= 1.9, 1Η, ArH), 6.69 (t, J=2.1, 1Η, ArH), 6.59 (t, J =2.2, 1Η, ArH), 5.31 (s, 1Η, CHC(CH₃)₃), 4.26 (dd, J= 10.7, 3.0, 1H, CHCH_AH_B), 3.62 (s, 3H, OCH₃), 3.15 (s, 3H, NCH₃), 2.88 (s, 3Η, NCH₃), 2.66 (dd, J= 14.3, 10.7, 1Η, ΟΗΟΗ_ΛΗ_Β), 2.13 (dd, J = 14.3, 2.3, 1Η, CHCHAHB), 1.04 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 171.6 (C=0), 163.0 (C=0), 160.8 (CAT), 147.0 (CAT), 137.7 (C_PH), 130.6 (CH_Ar), 129.0 (2xCH_Ph), 127.9 (2xCHp_h), 126.2 (CHph), 117.8 (CH_Ar), 112.2 (CH_Ar), 111.5 (CH_Ar), 82.2 (CHC(CH₃)₃), 62.8 (CHCH₂), 55.2 (OCH₃), 41.1 (NCH₃), 39.3 (CHCH₂), 36.9 (C(CH₃)₃), 31.5 (NCH₃), 27.0 (C(CH₃)₃); IR: v_max = 3062, 3029, 2960, 2873, 2836 (C-H), 1700 (C=0), 1653 (C=0); HRMS (ESI⁺): m/z calcd for C₂₄H₃₂0₃N₃ ([M+H]⁺) 410.2438, found 410.2434. (2R,5S)-5-Benzyl-2-(ferf-butyl)-W-(2-methoxyphenyl)-W,3-dimethyl-4-oxoimi carboxamide (36)

[00237] Following general procedure 4, imine 4 (140 mg, 0.568 mmol), /V-(2-methoxyphenyl)- /V-methylcarbamoyl chloride (170 mg, 0.852 mmol, 1.5 eq.) and DMAP (3 mg, 0.028 mmol) were dissolved in toluene (2.85 ml_, 0.2 M) and reacted for 68 h. Purification by flash column chromatography (Si0₂,

1 :1 Pet. Ether: EtOAc) gave the title compound (143 mg, 0.349 mmol,

61%) as a white solid. 36: Rf (1 :1 Pet. Ether: EtOAc): 0.26; ¹H NMR (400 MHz, CDCI3): δ_Η = 7.20 - 7.06 (m, 5H, Ph/- and Ar/- ), 7.04 (d, J = 7.1 , 2H, P H), 6.90 (td, J = 7.6, 1.0, 1 H, ArH), 6.58 (d, J = 8.3, 1 Η, ArH), 5.50 (s, 1 Η, CHC(CH₃)₃), 4.30 (dd, J = 11.0, 2.5, 1 H, CHCH_AH_B), 3.53 (s, 3H, OCH3), 3.05 (s, 3H, NCH₃), 2.89 (s, 3H, NCH₃), 2.61 (dd, J = 15.2, 11.1 , 1 Η,

1.74 (dd, J = 15.3, 2.1 , 1 H, CHCH_AH_S), 1.01 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 172.2 (C=0), 163.5 (C=0), 154.2 (CAT), 137.8 (C_Ph), 133.2 (CAT), 128.8 (2xCHp_h), 128.6 (CHAT), 128.5 (CH_Ar) 127.7 (2xCH_Ph), 125.8 (CH_Ph), 121.1 (CH_Ar), 112.5 (CH_Ar), 82.0 (CHC(CH₃)₃), 61.4 (CHCH₂), 55.0 (OCH₃), 39.4 (CHCH₂), 39.2 (NCH₃), 36.6 (C(CH₃)₃), 31.4 (NCH₃), 26.9 (C(CH₃)₃); IR: v_max = 3063, 3026, 2960, 2873, 2838 (C-H), 1698 (C=0), 1651 (C=0); HRMS (ESI⁺): m/z calcd for C₂₄H₃₂0₃N₃ ([ +H]⁺) 410.2438, found 410.2428.

(2R,5f?)-2-(feAf-Butyl)-/V-(4-cyanophenyl)-/V,3-dimethyl-4-oxo-5-phenylimidazolidine-1- carboxamide (37)

[00238] Following general procedure 4, imine 6 (52 mg, 0.224 mmol), /V-(4-cyanophenyl)-/V-methylcarbamoyl chloride (65 mg, 0.336 mmol, 1.5 eq.) and DMAP (1 mg, 0.011 mmol) were

dissolved in DCE (1.10 ml_, 0.2 M) and reacted for 68 h. Purification by flash column chromatography (Si0₂, 3:2→1 : 1 Pet. Ether: EtOAc) gave the title compound (76 mg, 0.195 mmol, 87%) as a pale yellow oil. 37: R_f (1 :1 Pet. Ether: EtOAc): 0.30; ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.36 - 7.29 (m, 2H, ArH), 7.21 - 7.07 (m, 5Η, PhH), 7.00 - 6.95 (m, 2Η, ArH), 5.46 (s, 1 Η, CHC(CH₃)₃), 5.15 (s, 1 H, CHPh), 3.09 (s, 3H, NCH₃), 2.94 (s, 3H, NCH₃), 1.00 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 M Hz, CDCI₃): 5_C = 169.0 (C=0), 163.4 (C=0), 148.8 (CAT), 135.5 (C_Ph), 133.6 (2xCH_Ar), 127.8 (2xCH_Ph), 127.2 (CH_Ph), 126.3 (2xCH_Ph), 125.6 (2xCH_Ar), 118.2 (C≡N), 109.4 (CAT), 82.7 (CHC(CH₃)₃), 65.5 (CHPh), 41.0 (NCH₃), 36.8 (C(CH₃)₃), 31.3 (NCH₃), 26.9 (C(CH₃)₃); IR: v_max = 3061 , 2969, 2932, 2874 (C- H), 2226 (C≡N), 1703 (C=0), 1668 (C=0); HRMS (ESI⁺): m/z calcd for C₂₃H₂₇0₂N₄ ([M+H]⁺) 391.2129, found 391.2124. (2R,5R)-2-(feAf-Butyl)-A/-(4-chlorophenyl)-/V,3-dimethyl-4-oxo-5^henylim

carboxamide (38)

[00239] Following general procedure 4, imine 6 (52 mg, 0.224 mmol), A/-(4-chlorophenyl)-/V-methylcarbamoyl chloride (69 mg, 0.336 mmol, 1.5 eq.) and DMAP (1 mg, 0.01 1 mmol) were

dissolved in DCE (1.10 ml_, 0.2 M) and reacted for 68 h.

Purification by flash column chromatography (S1O2, 3:2→1 : 1 Pet. Ether: EtOAc) gave the title compound (63 mg, 0.158 mmol, 70%) as a pale yellow oil. 38: R_f (3:2 Pet. Ether: EtOAc): 0.17; ¹H N R (500 MHz, CDC ): δ_Η = 7.13 - 7.08 (m, 3H, PhW), 7.04 (t, J = 7.4, 2H, PhW), 6.95 - 6.90 (m, 2H, ArW), 6.84 - 6.79 (m, 2H, ArH), 5.60 (s, 1 H, CHC(CH₃)₃), 5.14 (s, 1 H, CHPh), 3.05 (s, 3H, NC/-/3), 2.92 (s, 3H, NCW₃), 1.00 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NMR (500 MHz, CDCI₃): 5c = 169.4 (C=0), 164.1 (C=0), 143.2 (CA_T), 135.8 (C_Ph), 132.8 (CA_T), 129.8 (2xCH_Ar), 128.5 (2xCH_Ar), 127.5 (2xCHp_h), 126.6 (CH_Ph), 126.0 (2xCH_Ph), 82.6 (CHC(CH₃)₃), 65.9 (CHPh), 42.1 (NCH₃), 36.6 (C(CH₃)₃), 31.2 (NCH₃), 27.0 (C(CH₃)₃); IR: v_max = 3061 , 2970, 2931 , 2874 (C- H), 1702 (C=0), 1659 (C=0); HRMS (ESI⁺): m/z calcd for C22H₂70₂N₃CI ([M+H]⁺) 400.1786, found 400.1782.

(2S,5f?)-2-(ierf-Butyl)-/V-(4-fluorophenyl)-/V,3-dimethyl-4-oxo-5-phenylimidazolidine-1- carboxamide (39)

[00240] Following general procedure 4, imine 6 (800 mg, 3.44 mmol), /V-(4-fluorophenyl)-/V-methylcarbamoyl chloride (969 mg, 5.16 mmol, 1.5 eq.) and DMAP (21 mg, 0.172 mmol) were

dissolved in DCE (17 ml_, 0.2 M) and reacted for 63 h. Purification by flash column chromatography (S1O2, 3:2→1 : 1 Pet. Ether: EtOAc) gave the title compound (356 mg, 0.158 mmol, 27%) as a white solid. 39: ¹H NMR (500 MHz, CDCb): C_H = 7.14 - 7.1 1 (m, 2H, Phtf), 7.08 - 7.02 (m, 3H, PhH), 6.90 - 6.84 (m, 2H, ArH), 6.68 - 6.62 (m, 2H, ArH), 5.63 (s, 1 H, CWC(CH₃)₃), 5.17 (s, 1 H, CHPh), 3.06 (s, 3H, NCH₃), 2.93 (s, 3H, NCH₃), 1 .01 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (500 MHz, CDCb): 5_C = 169.5 (C=0), 164.3 (C=0), 161.3 (d, ¹J_C- F = 247.2, C_ArF), 140.7 (d, ⁴J_C-F = 3.0, CAT), 136.0 (C_Ph), 129.1 (d, ³J_C-F = 8.6, 2xCH_Ar), 127.5 (2xCH_Ph), 126.6 (CH_Ph), 126.0 (2xCH_Ph), 1 16.5 (d, ²J_C-_F = 22.9, 2xCH_Ar), 82.6 (CHC(CH₃)₃), 66.0 (CHPh), 42.4 (NCH₃), 36.6 (C(CH₃)₃), 31.2 (NCH₃), 27.0 (C(CH₃)₃); IR: v_max = 2972 (C- H), 1704 (C=0), 1658 (C=0); HRMS (ESI⁺): m/z calcd for C22H₂s0₂N₃FNa ([M+Na]⁺) 406.1901 , found 406.1894. (2S,5/?)-2-(fe/f-Butyl)-A/-(4-methoxyphe

carboxamide (40)

[00241] Following general procedure 4, imine 6 (52 mg, 0.224 mmol), /V-(4-methoxyphenyl)-/V-methylcarbamoyl chloride (67 mg, 0.336 mmol, 1 .5 eq.) and DMAP (1 mg, 0.011 mmol) were

dissolved in DCE (1 .10 ml_, 0.2 M) and reacted for 68 h.

Purification by flash column chromatography (S1O2, 2: 1→1 : 1 Pet. Ether: EtOAc) gave the title compound (48 mg, 0.121 mmol, 54%) as an off-white solid. 40: R_f (3:2 Pet. Ether: EtOAc): 0.18; ¹H N R (500 MHz, CDC ): δ_Η = 7.16 - 7.09 (m, 2H, PhW), 7.04 - 6.97 (m, 3H, PhH), 6.83 - 6.77 (m, 2H, ArW), 6.49 - 6.42 (m, 2H, ArH), 5.62 (s, 1 H, CHC(CH₃)₃), 5.16 (s, 1 H, CHPh), 3.62 (s, 3H, OCH3), 3.06 (s, 3H, NCH₃), 2.90 (s, 3H, NCH₃), 0.98 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (500 MHz, CDCI3): δ₀ = 169.7 (C=0), 164.2 (C=0), 158.3 (CAT), 137.2 (C_Ph), 136.2 (CAT), 128.6 (2x CH_Ar), 127.2 (2x CH_Ar), 126.2 (CH_Ph), 126.1 (2xCH_Ph), 1 14.8 (2x CH_Pfl), 82.5 (CHC(CH₃)₃), 65.9 (CHPh), 55.3 (OCH₃) 42.4 (NCH₃), 36.5 (C(CH₃)₃), 31 .2 (NCH₃), 26.9 (C(CH₃)₃); IR: v_max = 3060, 2964, 2934, 2836 (C-H), 1701 (C=0), 1652 (C=0); HRMS (ESI⁺): m/z calcd for C23H30O3N3 ([M+H]⁺) 396.2282, found 396.2279.

(2S,5R)-2-(tert-Butyl)-N-(4-chlorophenyl)-3-methyl-4-oxo-5-phenylimidazolidine-1 - carboxamide (41 )

[00242] Following general procedure 5, c/s-19 (200 mg, 0.679 mmol), 4-chloroaniline (433 mg, 3.39 mmol), Et₃N (0.19 ml_, 1.36 mmol) and Kl (124 mg, 0.746 mmol) were reacted in DCM (1.50

ml_, 0.45 M) at reflux for 18 h. Purification by flash column chromatography (S1O2, 3:1 Pentane: EtOAc) gave the title compound (188 mg, 0.487 mmol, 72%) as a yellow oil. 41 : Rf (2: 1 Pentane: EtOAc): 0.35; ¹H NMR (500 MHz, CDCI3): δ_Η = 7.83 - 7.75 (m, 2H, PhH), 7.49 (t, J = 7.7, 2H, PhH), 7.40 (t, J = 7.4, 1 H, Phtf), 7.23 - 7.18 (m, 2H, ATH), 7.18 - 7.13 (m, 2H, ArH), 6.34 (s, 1 H, NH), 5.51 (s, 1 H, CHC(CH₃)₃), 5.19 - 5.15 (m, 1 H, CrtPh), 3.06 (s, 3H, NCH₃), 1.01 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCb): 5_C = 168.3 (C=0), 156.6 (C=0), 136.6 (CAT), 135.0 (CAT), 129.3 (2x CH_Pfl), 129.1 (2xCH_Ph), 129.0 (CAT), 128.8 (CHph), 126.0 (2x CH_Ar), 121.4 (2xCH_Ar), 81.1 (CHC(CH₃)₃), 62.6 (CHPh), 37.9 (C(CH₃)₃), 31.8 (NCH₃), 26.6 (C(CH₃)₃); IR: v_max = 3338 (N-H) 3063, 3033, 2963, 2924, 2872 (C-H), 1690 (C=0); HRMS (ESI⁺): m/z calcd for C₂i H₂50₂N₃CI ([M+H]⁺) 386.1630, found 386.1625. (2R,5S)-2-(ferf-Butyl)-5-isopropyl-W,3-dime (42)

[00243] Following general procedure 5, c/s-20 (62 mg, 0.238 mmol), N- methylaniline (0.13 mL, 1.19 mmol), EtsN (66 pL, 0.476 mmol) and Kl (43 mg, 0.262 mmol) were reacted in DCM (0.50 mL, 0.48 M) at reflux for 18

h. Purification by flash column chromatography (Si0₂, 3:2 Pentane:EtOAc) gave the title compound (69 mg, 0.208 mmol, 88%) as a white solid. 42: ¹H N R (500 MHz, CDC ): δ_Η = 7.36 - 7.31 (m, 2H, PhH), 7.19 - 7.14 (m, 1 H, PhH), 6.90 - 6.86 (m, 2H, PhH), 4.41 (s, 1 H, CHC(CH₃)3), 3.69 (d, J = 9.8, 1 H, CHCH(CH₃)₂), 3.14 (s, 3H, NO/₃), 2.58 (s, 3H, NC/- 3), 1.85 (dsept., J = 10.0, 6.7, 1 H, CHCH(CH₃)₂), 1.18 (d, J = 6.5, 3H, CH(CH₃)A(CH₃)B), 1.15 (d, J = 6.9, 3H, CH(CH₃)A(CH₃)B), 0.94 (s, 9H, C{CH^)z); ¹³C {¹ H} NMR (125 MHz, CDCIs): 5c = 171.7 (C=0), 162.3 (C=0), 146.2 (C_Ph), 129.8 (2x CH_Ph), 125.0 (CH_PFL) , 122.1 (2xCHp_h), 82.2 (CHC(CH₃)3), 66.7 (CHCH(CH₃)₂), 40.2 (NCH₃), 36.8 (C(CH₃)₃), 32.5 (CH(CH₃)₂), 30.7 (NCH₃), 26.6 (C(CH₃)3), 20.8 (CH(CH₃)A(CH₃)B), 19.8 (CH(CH₃WCH₃)B); IR: Vmax = 2965, 2928, 2873 (C-H), 1699 (C=0), 1660 (C=0); HRMS (ESI⁺): m/z calcd for Ci₉H₂₉0₂N₃Na ([M+Na]⁺) 354.2152, found 354.2147.

(2R,5S)-2-(ie/t-Butyl)-/V-(4-cyanophenyl)-5-isobutyl-/V,3-dimethyl-4-oxoimidazolidine-1 - carboxamide (43)

[00244] Following general procedure 4, imine 9 (771 mg, 3.63 mmol), V-(4-cyanophenyl)-/V-methylcarbamoyl chloride (954 mg, 4.90 mmol, 1.35 eq.) and DMAP (22 mg, 0.182 mmol) were dissolved in DCE (18.0 mL, 0.2 M) and reacted for 88 h.

Purification by flash column chromatography (Si0₂, 3:2→5:4 Pet. Ether: EtOAc) gave the title compound (632 mg, 1.71 mmol, 47%) as a white solid. 43: R_f (1 : 1 Pet. Ether: EtOAc): 0.32; ¹H NMR (400 MHz, CDCI3): δ_Η = 7.66 - 7.60 (m, 2H, ArH), 7.13 - 7.07 (m, 2H, ArH), 5.14 (s, 1 H, CHC(CH₃)₃), 3.97 (dd, J = 10.7, 3.3, 1 H, NCHCH_AH_B), 3.20 (s, 3H, NCH₃), 2.89 (s, 3H, NCH3), 1.90 - 1.75 (m, 1 H, CH₂CH(CH₃)₂), 1.47 (ddd, J = 13.4, 10.8, 5.3, 1 H, CHC^H_BCH), 0.99 (s, 9H, C(CH₃)₃), 0.89 - 0.79 (m, 1 H, CHCH_AHBCH), 0.75 (d, J = 6.7, 3H, CH(CH₃)A(CH₃)B), 0.72 (d, J = 6.6, 3H , CH(CH₃)A(CH₃)B); ¹³C {¹H} NMR (100 MHz, CDCb): δ₀ = 171.8 (C=0), 162.2 (C=0), 150.0 (CAT), 133.8 (2x CH_Ar), 122.9 (2x CH_Ar), 1 18.5 (C≡N), 107.5 (C_Ar), 82.5 (CHC(CH₃)₃), 60.6 (N CHCH₂), 42.2 (NCHCH₂), 39.7 (N CH₃), 37.0 (C(CH₃)₃), 31.6 (N CH₃), 27.1 (C(CH₃)₃), 25.2 (CH(CH₃) ), 23.5 (CH(CH₃) CH₃)B), 21.6 (CH(CH₃)A(CH₃)B); IR: v_max = 2957, 2927, 2870 (C-H), 2225 (C≡N), 1699 (C=0), 1662 (C=0); HRMS (ESI⁺): m/z calcd for C₂i H₃i0₂N₄ ([M+H]⁺) 371.2442, found 371.2441. (2R,5S)-2-(ie/t-Butyl)-A/-(4-chlorophenyl)-5-isobutyl-A/,3-dimethyl-4-oxoimi carboxamide (44)

[00245] Following general procedure 4, imine 9 (690 mg, 3.25 mmol), V-(4-chlorophenyl)-/V-methylcarbamoyl chloride (895 mg, 4.39 mmol, 1.35 eq.) and DMAP (20 mg, 0.163 mmol) were

dissolved in DCE (16.0 ml_, 0.2 M) and reacted for 88 h.

Purification by flash column chromatography (S1O2, 2:1→1 : 1 Pet. Ether: EtOAc) gave the title compound (558 mg, 1.47 mmol, 45%) as a white solid. 44: R_F (2:1 Pet. Ether: EtOAc): 0.20; ¹ H N R (500 MHz, CDCI3): δ_Η = 7.28 - 7.25 (m, 2H, Arrt), 7.00 - 6.97 (m, 2H, ArH), 5.21 (s, 1 H, CWC(CH₃)₃), 3.83 (dd, J = 11.3, 3.6, 1 H, NCHCH_AH_B), 3.06 (s, 3H, NCH₃), 2.79 (s, 3H, NCH₃), 1.79 - 1.60 (m, 1 H, CH₂CW(CH₃)₂), 1.24 (ddd, J = 13.4, 1 1.3, 5.3, 1 H, CHC^H_BCH), 0.90 (s, 9H, C(CH₃)₃), 0.65 (d, J = 6.6, 3H, CH(CH₃)A(CH₃)_b), 0.62 (d, J = 6.7, 3H, CH(CH₃)_A(CH₃)_B) , 0.37 (ddd, J = 13.1 , 9.6, 3.4, 1 H, CHCH_AH_BCH); ¹³C {¹ H} N M R (125 MHz, CDCI3): 5_C = 171.9 (C=0), 162.9 (C=0), 144.5 (CA_T), 131.4 (CA_T), 129.8 (2*CH_Ar), 126.9 (2*CH_Ar), 82.1 (CHC(CH₃)₃), 60.9 (N CHCH2), 41.4 (NCHCH₂), 41.0 (NCH₃), 36.6 (C(CH₃)₃), 31.3 (NCH₃), 26.9 (C(CH₃)₃), 24.7 (CH(CH₃)₂), 23.5 (CH(CH₃)_A(CH₃)_B), 21.2 (CH(CH₃) CH₃)_B); IR: v_max = 2957, 2870 (C-H), 1699 (C=0), 1655 (C=0); HRMS (ESI⁺): m/z calcd for C₂oH₃₀0₂N₃CINa ([M+Na]⁺) 402.1919, found 420.1920.

(2R,5S)-2-(ie/t-Butyl)-/V-(4-fluorophenyl)-5-isobutyl-/V,3-dimethyl-4-oxoimidazolidine-1- carboxamide (45)

[00246] Following general procedure 4, imine 9 (822 mg, 3.87 mmol), /V-(4-fluorophenyl)-/V-methylcarbamoyl chloride (980 mg, 5.23 mmol, 1.35 eq.) and DMAP (24 mg, 0.194 mmol) were

dissolved in DCE (19.0 ml_, 0.2 M) and reacted for 88 h. Purification by flash column chromatography (S1O2, 2:1→5:4 Pet. Ether: EtOAc) gave the title compound (667 mg, 1.86 mmol, 48%) as a white solid. 45: R_F (3:2 Pet. Ether: EtOAc): 0.24; ¹ H NMR (400 MHz, CDCI₃): δ_Η = 7.13 - 7.04 (m, 4H, ArH), 5.31 (s, 1 H, CHC(CH₃)₃), 3.93 (dd, J = 11.4, 3.7, 1 H, NCHCHAHB), 3.14 (s, 3H, NCH₃), 2.87 (s, 3H, NCH₃), 1.89 - 1.74 (m, 1 H, CH₂CH(CH₃)₂), 1.31 (ddd, J = 13.3, 11.5, 5.1 , 1 H, CHCHAHBCH), 0.98 (s, 9H, C(CH₃)₃) , 0.75 (d, J = 6.6, 3H, CH(CH₃)A(CH₃)_B), 0.69 (d, J = 6.7, 3H, CH(CH₃)_A(CH₃)_B), 0.37 (ddd, J = 13.3, 9.7, 3.6, 1 H, CHCH_AHBCH); ¹³C {¹ H} NMR (100 MHz, CDCI₃): 5_C = 172.3 (C=0), 163.4 (C=0), 160.8 (d, ¹ JC-F = 246.9, C_ArF), 142.3 (d, ⁴J_C-F = 3.1 , CA_T), 127.8 (d, ³J_C-F = 8.2, 2xCH_Ar), 116.8 (d, ²J_C__F = 22.5, 2xCH_Ar), 82.3 (CHC(CH₃)₃), 61.2 (N CHCH₂), 41.7 (NCH₃), 41.6 (NCHCH₂), 36.7 (C(CH₃)₃), 31.5 (NCH₃), 27.2 (C(CH₃)₃), 24.8 (CH(CH₃)₂), 23.8 (CH(CH₃)_A(CH₃)_B), 21.3 (CH(CH₃) CH₃)_B); IR: v_max = 2957, 2871 (C-H), 1700 (C=0), 1656 (C=0); HRMS (ESI⁺): m/z calcd for C₂oH₃i0₂N₃F ([M+H]⁺) 364.2395, found 364.2393. (2R,5S)-2-(ferf-Butyl)-5-isobutyl-W,3-dim^ (46)

[00247] Following general procedure 4, imine 9 (877 mg, 4.13 mmol), /V-(p-tolyl)-/V-methylcarbamoyl chloride (1024 mg, 5.58 mmol, 1.35 eq.) and DMAP (25 mg, 0.207 mmol) were dissolved in DCE (21.0 ml_, 0.2 M) and reacted for 88 h. Purification by flash

column chromatography (S1O2, 2:1→3:2 Pet. Ether: EtOAc) gave the title compound (505 mg, 1.40 mmol, 34%) as a white solid. 46: R_f (2: 1 Pet. Ether: EtOAc): 0.19; ¹H N R (400 MHz, CDC ): δ_Η = 7.17 (d, J = 8.0, 2H, ArH), 7.00 (d, J = 8.3, 2H, ArH), 5.29 (s, 1 H, CWC(CH₃)₃), 3.91 (dd, J = 1 1.3, 3.7, 1 H, NCHCH_AH_B), 3.14 (s, 3H, NCH₃), 2.85 (s, 3H, NC/-/3), 2.34 (s, 3H, CH₃), 1.83 - 1.67 (m, 1 H, CH₂CH(CH₃)₂), 1 .24 (ddd, J = 13.3, 1 1.4, 5.3, 1 H,

0.97 (s, 9H, C(CHj)j), 0.72 (d, J = 6.6, 3H , CH(CW₃)MCH₃)B), 0.65 (d, J = 6.7, 3H, CH(CH₃)A(CH₃)B), 0.36 (ddd, J = 13.3, 9.6, 3.7, 1 H, CHCH_AH_BCH); ¹³C {¹ H} NMR (100 MHz, CDCb): 6_C = 172.5 (C=0), 163.4 (C=0), 143.5 (CAT), 136.2 (CAT), 130.5 (2x CH_Ar), 126.1 (2xCH_Ar), 82.2 (CHC(CH₃)₃), 61 .3 (NCHCH₂), 41 .4 (NCH₃ and NCHCH₂), 36.7 (C(CH₃)₃), 31.4 (NCH₃), 27.2 (C(CH₃)₃), 24.8 (CH(CH₃)₂), 23.7 (CH(CH₃)_A(CH₃)_B), 21.3 (CH(CH₃HCH₃)_B), 21.0 (CH₃); IR: v_max = 2955, 2869 (C-H), 1702 (C=0), 1652 (C=0); HRMS (ESI⁺): m/z calcd for C₂i H₃ 0₂N₃ ([M+H]⁺) 360.2646, found 360.2643.

(2R,5S)-2-(ierf-Butyl)-/V-(4-isocyanophenyl)- V,3-dimethyl-5-(2-(methylthio)ethyl)-4- oxoimidazolidine-1-carboxamide (47)

[00248] Following general procedure 4, imine 1 1 (777 mg, 3.37 mmol), /V-(4-cyanophenyl)-/V-methylcarbamoyl chloride (886 mg, 4.55 mmol, 1.35 eq.) and DMAP (21 mg, 0.169 mmol) were dissolved in DCE (17.0 ml_, 0.2 M) and reacted for 88 h.

Purification by flash column chromatography (S1O2, 1 : 1→2: 1

EtOAc: Pet. Ether) gave the title compound (585 mg, 1.51 mmol, 45%) as a pale yellow oil. 47: R_f (2: 1 EtOAc: Pet. Ether): 0.25; ¹H NMR (500 MHz, CDCb): δ_Η = 7.68 (d, J = 8.5, 2H, ArH), 7.20 (d, J = 8.4, 2Η, ArH), 5.29 (s, 1 Η, CWC(CH₃)₃), 3.89 (dd, J = 10.9, 2.0, 1 H, CHCH_AH_B), 3.19 (s, 3H, NCH₃), 2.90 (s, 3H, NCH5), 2.72 (ddd, J = 12.4, 1 1.5, 4.8, 1 H,

2.19 (ddd, J = 12.6, 10.7, 6.1 , 1 H, CHAHBCHA-HBSCHS), 1.94 (s, 3H, SCH₃), 1.67 (dtd, J = 13.6, 10.9, 4.8, 1 H, CHCH₄H_BCH₂), 0.97 (s, 9H, C(CH₃)₃), 0.84 (br. s, 1 H, CHCHAHBCH₂); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5_C = 171.6 (C=0), 162.4 (C=0), 149.9 (CAT), 134.0 (2x CH_Ar), 125.1 (2xCH_Ar), 1 18.2 (C≡N), 109.5 (CAT), 82.7 (CHC(CH₃)₃), 61.6 (NCHCH₂), 40.4 (NCH₃), 37.0 (C(CH₃)₃), 33.7 (NCHCH₂), 31.6 (NCH₃), 31 .2 (CH₂SCH₃), 26.9 (C(CH₃)₃), 15.8 (SCH₃); IR: v_max = 2967, 2918, 2873 (C-H), 2227 (C≡N), 1696 (C=0), 1662 (C=0); HRMS (ESI⁺): m/z calcd for C2oH₂80₂N SNa ([M+Na]⁺) 41 1.1825, found 41 1.1825. (2R,5S -2-(terf-Butyl)-W-(4-chloropheny^

oxoimidazolidine-1-carboxamide (48)

[00249] Following general procedure 4, imine 11 (766 mg, 3.33 mmol), A/-(4-chlorophenyl)-/V-methylcarbamoyl chloride (916 mg,

4.49 mmol, 1.35 eq.) and DMAP (20 mg, 0.166 mmol) were dissolved in DCE (16.0 ml_, 0.2 M) and reacted for 88 h.

Purification by flash column chromatography (Si0₂, 1 : 1→2: 1

EtOAc: Pet. Ether) gave the title compound (607 mg, 1.53 mmol, 46%) as an off-white solid. 48:

R_f (1 : 1 Pet. Ether: EtOAc): 0.20; ¹H NMR (500 MHz, CDC ): δ_Η = 7.29 - 7.22 (m, 2H, ArH),

7.04 - 6.98 (m, 2H, ArH), 5.34 (s, 1 H, CHC(CH₃)₃), 3.64 (dd, J = 1 1.4, 2.0, 1 H, CHCH_AH_B),

3.01 (s, 3H, NCH₃), 2.79 (s, 3H, NCH₃), 2.62 (td, J = 12.7, 4.4, 1 H, CH₂C^H_BSCH₃), 1.93 (td,

J = 12.0, 5.2, 1 H, CH₂CH_AH_SSCH₃), 1.79 (s, 3H, SCH₃), 1.38 (dtd, J = 12.7, 1 1.6, 4.4, 1 H,

CHCH^H_BCH₂), 0.84 (s, 9H, C(CH₃)₃), 0.42 (tdd, J = 12.8, 4.9, 1.7, 1 H, CHCH_AH_BCH₂); ¹³C

{¹H} NMR (125 MHz, CDCI3): δ₀ = 171.7 (C=0), 162.7 (C=0), 144.2 (CA_T), 132.5 (CA_T), 130.1

(2xCH_Ar), 127.7 (2xCH_Ar), 82.1 (CHC(CH₃)₃), 61.7 (NCHCH₂), 41.2 (NCH₃), 36.4 (C(CH₃)₃),

33.9 (NCHCH₂), 31 .1 (NCH₃), 30.7 (CH₂SCH₃), 26.6 (C(CH₃)₃), 15.3 (SCH₃); IR: v_max = 2973,

2918, 2873 (C-H), 1694 (C=0), 1656 (C=0); HRMS (ESI⁺): m/z calcd for Ci₉H₂₈0₂N₃CISNa

([M+Na]⁺) 420.1483, found 420.1483.

(2R,5S)-2-(ierf-Butyl)-/V,3-dimethyl-5-(2-(methylthio)ethyl)-4-oxo-/V-(pyridin-2- yl)imidazolidine-1-carboxamide (49)

[00250] Following general procedure 4, imine 11 (829 mg, 3.60 mmol), /V-(pyridin-2-yl)-/V-methylcarbamoyl chloride (829 mg, 4.86 mmol, 1.35 eq.) and DMAP (22 mg, 0.180 mmol) were dissolved in DCE (18.0 ml_, 0.2 M) and reacted for 44 h. Purification by flash column

chromatography (Si0₂, 98:2 EtOAc: MeOH) gave the title compound (546 mg, 1.50 mmol, 42%) as a pale yellow oil. 49: ¹H NMR (500 MHz, CDCb): δ_Η = 8.25 - 8.21 (m, 1 H, ArH), 7.62 - 7.55 (m, 1 H, ArH), 6.96 - 6.92 (m, 1 H, ArH), 6.85 (d, J = 8.2, 1 H , ArH), 4.99 (s, 1 H, CHC(CH₃)₃), 4.02 (dd, J = 9.9, 3.5, 1 H, CHCH_AH_B), 3.12 (s, 3H, NCH₃), 2.81 (s, 3H, NCH₃), 2.69 (ddd, J = 13.0, 1 1.2, 4.9, 1 H, CH_AH_BCH,THB'SCH₃), 2.34 (ddd, J = 13.0, 10.6, 6.1 , 1 H, CHAHBCHAHB'SCHS), 1 .89 (s, 3H, SCH₃), 1.73 (dtd, J = 14.8, 10.3, 4.9, 1 H, CHCH^H_BCH₂), 1 .16 (br. s, 1 H, CHCH_AH_SCH₂), 0.90 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCIs): δ₀ = 171.8 (C=0), 162.5 (C=0), 157.8 (CA_T), 148.8 (CH_Ar), 138.3 (CH_Ar), 1 19.3 (CHAr), 1 15.1 (CHAr), 82.5 (CHC(CH₃)₃), 60.8 (NCHCH₂), 37.3 (NCH₃), 37.0 (C(CH₃)₃), 33.4 (NCHCH₂), 31.3 (NCH₃), 31.0 (CH₂SCH₃), 26.6 (C(CH₃)₃), 15.4 (SCH₃); IR: v_max = 2960, 2916, 2873 (C-H), 1696 (C=0), 1667 (C=0); HRMS (ESI⁺): m/z calcd for Ci₈H₂₉0₂N₄S ([M+H]⁺) 365.2006, found 365.2003. (2R,5S)-2-(ierf-Butyl)-A/,3-dimethyl-5-(2-(methylt io)ethyl)-4-oxo-A/-(p-tol^ carboxamide (50)

[00251] Following general procedure 4, imine 11 (815 mg, 3.54 mmol), /V-(p-tolyl)-/V-methylcarbamoyl chloride (877 mg, 4.78 mmol, 1.35 eq.) and DMAP (22 mg, 0.177 mmol) were dissolved in DCE

(18.0 ml_, 0.2 M) and reacted for 88 h. Purification by flash column

chromatography (Si0₂, 1 : 1 Pet. Ether: EtOAc) gave the title compound (729 mg, 1.93 mmol, 55%) as a white solid. 50: R_f (1 : 1 Pet. Ether: EtOAc): 0.21 ; ¹H N R (400 MHz, CDCI3): δ_Η = 7.19 (d, J = 8.1 , 2H, ArH), 7.04 (d, J = 8.2, 2H, ArH), 5.50 (s, 1 H, CHC(CH₃)₃), 3.70 (dd, J = 1 1.5, 2.0, 1 H, CWCH_AH_B), 3.12 (s, 3H, NCW₃), 2.90 (s, 3H, NC/-/3), 2.69 (td, J = 12.8, 4.4, 1 H, CH₂C^H_BSCH₃), 2.35 (s, 3H, CW₃), 1.99 (td, J = 12.3, 4.8, 1 H, CH₂CHAHSSCH₃), 1.87 (s, 3H , SCW₃), 1.40 (dtd, J = 13.1 , 12.1 , 4.5, 1 H, CHCHAH_BCH₂) , 0.95 (s, 9H, C(CH₃)₃), 0.30 (tdd, J = 12.9, 4.6, 1.9, 1 H, CHCH_AHBCH₂); ¹³C {¹H} NMR (100 MHz, CDCI3): δο = 172.4 (C=0), 163.3 (C=0), 143.1 (C_Ar), 137.5 (CAT), 130.8 (2x CH_Ar), 126.8 (2xCH_Ar), 82.4 (CHC(CH₃)3), 62.3 (NCHCH₂), 41 .6 (NCH₃), 36.7 (C(CH₃)₃), 34.1 (NCHCH₂), 31.5 (NCH₃), 31.4 (CH₂SCH₃), 26.9 (C(CH₃)₃), 21.1 (CH₃), 15.3 (SCH₃); IR: v_max = 2958, 2918, 2873 (C-H), 1697 (C=0), 1655 (C=0); HRMS (ESI⁺): m/z calcd for C₂oH3₂0₂N₃S ([M+H]⁺) 378.2210, found 378.2208.

(2R,5S)-5-(4-(Benzyloxy)benzyl)-2-(tert-butyl)-/V,3-dimethyl-4-oxo-/V-phenylimidazolidine-1- carboxamide (51 )

[00252] Following general procedure 5, c/s-21 (320 mg, 0.771 mmol), /V-methylaniline (418 μΙ_, 3.86 mmol, 5.0 eq.), 2,6- lutidine (179 μΙ_, 1.54 mmol) and Kl (140 mg, 0.848 mmol) were reacted in DCM/toluene (2.2 ml_, 0.35 M, 4:1) at 60 °C for

18 h. Purification by flash column chromatography (Si0₂, 1 : 1 Pet. Ether: EtOAc) gave the title compound (318 mg, 0.655 mmol, 85%) as a white solid. 51 : ¹H NMR (500 MHz, CDCI3): δ_Η = 7.44 - 7.40 (m, 2H, PhH), 7.40 - 7.35 (m, 2H, P H), 7.35 - 7.29 (m, 3H, PhH), 7.20 - 7.15 (m, 1 H, PhH), 7.15 - 7.1 1 (m, 2H, PhH), 6.97 (d, J = 8.6, 2Η, ArH), 6.86 - 6.82 (m, 2Η, ArH), 5.27 (s, 1 Η, CWC(CH₃)₃), 5.02 (s, 2Η, OCH₂Ph), 4.19 (dd, J = 10.7, 3.2, 1 Η, CHCHAHB), 3.18 (s, 3H, NCH3), 2.87 (s, 3Η, NCHs), 2.57 (dd, J = 14.1 , 10.8, 1 Η,

2.02 (dd, J = 14.0, 1 .7, 1 H, CHCH_AH_S), 1.04 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NMR (125 MHz, CDCI3): δο = 171.7 (C=0), 163.1 (C=0), 157.3 (C_ArO), 146.0 (C_Ph), 137.3 (C_Ph), 130.2 (2xCH_Ar), 130.1 (2xCH_Ar), 130.0 (CAT), 128.6 (2xCH_Ph), 127.9 (CH_Ph), 127.6 (2xCH_Ph), 126.5 (CHph), 125.8 (2xCH_Ph), 1 14.4 (2x CH_Ar), 82.3 (CHC(CH₃)3), 70.0 (OCH₂Ph), 63.2 (CHCH₂) , 41.2 (NCH₃), 38.5 (CH CH₂), 36.9 (C(CH₃)₃), 31.6 (NCH₃), 27.1 (C(CH₃)₃); IR: v_max = 3062, 3033, 2959, 2930, 2871 (C-H), 1703 (C=0), 1654 (C=0); HRMS (ESI⁺): m/z calcd for C30H36O3N3 ([M+H]⁺) 486.2751 , found 486.2749. (2R,5S)-2-(fe/f-Butyl)-5-(4-hydroxybenzy^

carboxamide (52)

[00253] To a solution of 51 (150 mg, 0.309 mmol, 1.0 eq.) in anhydrous THF (3.0 ml_, 0.1 M) was added Pd/C (16 mg, 0.015 mmol, 10% w/w, 0.05 eq.). The suspension was stirred under a hydrogen atmosphere for 18 h. The reaction mixture was filtered

over Celite^®, washed through with DCM and concentrated in vacuo.

Purification by flash column chromatography (S1O₂, 2:1 EtOAc: Pet. Ether) gave the title compound (116 mg, 0.294 mmol, 95%) as a white solid. 52: ¹H NMR (400 MHz, CDC ): δ_Η = 7.35 (t, J = 7.7, 2H, PhH), 7.24 - 7.12 (m, 3H, PJnH), 6.76 (d, J = 7.9, 2H, ArH), 6.47 (d, J = 7.9, 2H, ArH), 5.38 (s, 1 H, CHC(CH₃)3), 4.22 (dd, J = 11.6, 3.6, 1 H, CHCH_AH_B), 3.21 (s, 3H, NC/-/3), 2.89 (s, 3H, NC - 3), 2.43 (t, J = 12.6, 1 H, CHCH„H_B), 1.84 (d, J = 13.4, 1 H, CHCH_AH_B), 1.05 (s, 9H, C(CH₃)₃); ¹³C {¹ H} N M R (100 M Hz, CDCb): δ₀ = 172.3 (C=0), 163.2 (C=0), 155.1 (C_ArO), 145.9 (Cph), 130.2 (2xCH_Ar), 130.0 (2xCH_Ar), 127.8 (C_Ar), 126.8 (CH_Ph), 126.3 (2xCHp_h), 115.3 (2xCH_Ar), 82.5 (CHC(CH₃)3), 63.7(CHCH₂), 41.5 (NCH₃), 38.3 (CHCH₂), 36.8 (C(CH₃)₃), 31.7 (NCH₃), 27.2 (C(CH₃)₃); IR: v_max = 3319 (O-H), 2967, 2247 (C-H), 1683 (C=0), 1653 (C=0); HRMS (ESI⁺): m/z calcd for C24H₂903N₃Na ([M+Na]⁺) 418.2101 , found 418.2081.

(2R,5S)-5-((1-Benzyl-1H-indol-3-yl)methyl)-2-(teAf-butyl)-A/,3-dimethyl-4-oxo-A/-(pyridin-2- yl)imidazolidine-1 -carboxamide (53)

[00254] Following general procedure 4, imine 16 (800 mg, 2.13 mmol), /V-(pyridin-2-yl)-/V-methylcarbamoyl chloride (543 mg, 3.19 mmol, 1.5 eq.) and DMAP (13 mg, 0.106 mmol, 0.05 eq.) were dissolved in DCE (11.0 ml_, 0.2 M) and reacted for 63 h.

Purification by flash column chromatography (S1O₂, 3:2→1 :1

Pet. Ether: EtOAc) gave the title compound (727 mg, 1.43 mmol, 67%) as a white solid. 53: ¹ H NM R (400 MHz, CDCI₃): δ_Η = 8.09 - 8.06 (m, 1 H, ArH), 7.44 (d, J = 7.9, 1 H, ArH), 7.39 (ddd, J = 8.5, 7.3, 2.0, 1 H, ArH), 7.29 - 7.18 (m, 4H, ArH), 7.13 - 7.08 (m, 3H, ArH), 7.07 (s, 1 H, C=CH), 7.02 - 6.96 (m, 1 H, ArH), 6.76 (dd, J = 7.2, 5.0, 1 H, ArH), 6.39 (d, J = 8.3, 1 H, ArH), 5.23 (s, 2H, NCH₂Ph), 5.03 (s, 1 H, CWC(CH₃)₃), 4.43 (dd, J = 8.0, 5.4, 1 H, CWCH_AH_B), 3.18 (dd, J = 14.9, 8.0, 1 H, CHC«*H_B), 2.97 (dd, J = 5.5, 14.9, 1 H, CHCH_AW_B), 2.94 (s, 3H, NCH₃), 2.69 (s, 3H, NCH₃), 1.08 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NM R (100 MHz, CDCb): δ₀ = 172.0 (C=0), 163.1 (C=0), 157.7 (CAT), 148.5 (CH_Ar), 138.1 (CH_Ar), 137.8 (C_Ar), 136.6 (CAT), 128.8 (2xCH_Ar), 128.3 (CAT), 127.7 (CH_Ar), 127.2 (C=CH), 127.0 (2xCH_Ar), 121.7 (CH_Ar), 119.5 (CH_Ar), 1 19.1 (CH_Ar), 117.8 (CH_Ar), 112.3 (CH_Ar), 111.4 (C=CH), 109.6 (CH_Ar), 83.0 (CHC(CH₃)3), 61.7 (CHCH₂), 50.1 (NCH2PI-1), 37.4 (C(CH₃)₃), 36.1 (NCH₃), 31.6 (NCH₃), 29.8 (CHCH₂), 27.2 (C(CH₃)₃); IR: v_max = 2961 , 2244 (C-H), 1697 (C=0), 1660 (C=0); HRMS (ESI+): m/z calcd for C3i H350₂N₅Na ([M+Na]⁺) 532.2683, found 532.2674. Methyl (2f?,4S)-2-(ferf-butyl)-3-(methyl(phenyl)carbamoyl)oxazolidine-4-carboxylate (54)

[00255] To a solution of 22 (366 mg, 1.47 mmol, 1.0 eq.) in anhydrous DCM (1 .80 ml_, 0.8 M) was added Et₃N (0.41 ml_, 2.93 mmol, 2.0 eq.) and /V-methylaniline (0.48 ml_, 4.40 mmol, 3.0 eq.). The reaction mixture was

heated to reflux and left to stir for 18 h. The reaction mixture was cooled to room temperature and quenched with HCI (1.0 M, aq.), the organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSC , filtered and concentrated in vacuo. Purification by flash column chromatography (Si0₂, 4:1 Pentane:EtOAc) gave the title compound (432 mg, 1.35 mmol, 92%) as a pale yellow oil. 54: R_f (4:1 Pentane:EtOAc): 0.18; ¹H NMR (500 MHz, CDCI3): δ_Η = 7.33 (t, J = 7.5, 2H, PhH), 7.20 (t, J = 7.4, 1 H, PUH), 7.15 (d, J = 7.9, 2H, PhH), 5.35 (s, 1 H, CHC(CH₃)₃), 4.29 (d, J = 6.9, 1 H, CHCHAHB), 4.00 (d, J = 8.9, 1 H,

3.83 (dd, J = 8.9, 6.9, 1 H, CHCH_AH_S), 3.21 (s, 3H, OCH3), 3.19 (s, 3H, NCH₃), 0.99 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NMR (125 MHz, CDCI3): 5c = 170.1 (C=0), 163.0 (C=0), 144.4 (C_Ph), 129.6 (2xCH_Ph), 128.1 (2xCH_Ph), 126.7 (CH_Ph), 98.4 (CHC(CH₃)₃), 70.2 (CH CH₂), 63.2 (CHCH₂), 51.6 (OCH₃), 40.3 (NCH₃), 36.0 (C(CH₃)₃), 26.3 (C(CH₃)₃); IR: v_max = 2972, 2954, 2904, 2870 (C-H), 1768 (C=0), 1661 (C=0); HRMS (ESI⁺): m/z calcd for Ci₇H₂404N₂Na ([M+Na]⁺) 343.1628, found 343.1620.

Methyl (2f?,4S)-2-(ferf-butyl)-3-((3-fluorophenyl)(methyl)carbamoyl)oxazolidine-4-carboxylate (55)

[00256] To a solution of 22 (200 mg, 0.801 mmol, 1.0 eq.) in anhydrous DCM (1.80 ml_, 0.8 M) was added Et₃N (0.41 ml_, 2.93 mmol, 1.5 eq.) and 3-fluoro- V-methylaniline (0.27 ml_, 2.403 mmol,

3.0 eq.). The reaction mixture was heated to reflux and left to stir for

18 h. The reaction mixture was cooled to room temperature and quenched with HCI (1.0 M, aq.), the organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over MgSC , filtered and concentrated in vacuo. Purification by flash column chromatography (Si0₂, 98:2→97:3 DCM: Acetone) gave the title compound (232 mg, 0.686 mmol, 86%) as a colourless oil. 55: R_f (98:2 DCM:Acetone): 0.26; ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.28 (td, J = 8.1 , 6.8, 1 H, ArH), 6.97 - 6.93 (m, 1 H, ArH), 6.93 - 6.85 (m, 2H, ArH), 5.33 (s, 1 H, CHC(CH₃)₃), 4.25 (d, J = 6.5, 1 H, CHCH_AH_B), 4.02 (d, J = 8.9, 1 H, 3.82 (dd, J = 8.9, 6.9, 1 H, CHCH_AH_B), 3.30 (s, 3H, OCH₃), 3.18 (s, 3H, NC - 3), 0.98 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NMR (100 MHz, CDCI₃): 5_C = 170.0 (C=0), 163.1 (d, ¹ Jc-F = 247.7, C_ArF), 162.6 (C=0), 145.9 (d, ³ _C-F = 9.7, C_Ar), 130.7 (d, ³J_C-F = 9.5, CH_AR), 123.4 (d, ⁴ C-F = 3.0, CH_AR), 1 15.2 (d, ²JC-F = 22.6, CH_AR), 1 13.5 (d, ² _C-F = 21.2, CH_AR), 98.4 (CHC(CH₃)₃), 70.1 (CH CH₂), 63.1 (CHCH₂), 51.6 (OCH₃), 40.0 (NCH₃), 36.0 (C(CH₃)₃), 26.3 (C(CH₃)₃); IR: v_max = 2956, 2904, 2871 (C-H), 1767 (C=0), 1661 (C=0); HRMS (ESI⁺): m/z calcd for Ci₇H₂30₄N₂FNa ([M+Na]⁺) 361.1534, found 361.1523.

Rearrangement of Heterocyclic Ureas

(2S,5S)-2-(fe/f-Butyl)-/V,3,5-trimethyl-4-oxo-5-phenylimidazolidine-1-carboxamide (56)

[00257] Following general procedure 6, KHM DS (2.47 mL, 2.47 mmol, 1.0 M in THF) was added to a solution of 23 (500 mg, 1 .65 mmol) in THF (16.5

mL). The title compound (490 mg, 1.62 mmol, 98%) was yielded as a white solid without further purification. 56: ¹H NMR (500 MHz, CDCI₃): δ_Η = 7.33 (t, J = 7.6, 2H, P H), 7.25 (t, J = 7.3, 1 H, PhH), 7.18 (d, J = 7.4, 2H, PhH), 5.61 (s, 1 H, CHC(CH₃)3), 3.86 (br. s, 1 H, NHCH₃), 3.04 (s, 3H, NCH₃), 2.28 (d, J = 4.8, 3H, NHCH₃), 1 .99 (s, 3H , CCH₃), 1.05 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NMR (125 MHz, CDCI3): 5_C = 172.9 (C=0), 158.6 (C=0), 141.8 (C_Ph), 129.2 (2xCHp_h), 128.3 (CHph), 125.2 (2xCH_Ph), 80.7 (CHC(CH₃)₃), 66.0 (CCH₃), 38.7 (C(CH₃)₃), 32.2 (NCH₃), 26.9 (NHCH3), 26.8 (C(CH₃)₃), 23.5 (CCH₃); IR: v_max = 3415 (N-H), 2960 (C-H), 1698 (C=0), 1656 (C=0); HRMS (ESI⁺): m/z calcd for C17H26O2N3 ([M+H]⁺) 304.2025, found 304.2029.

(2R,5R)-2-(ieAf-Butyl)-/V,3,5-trimethyl-4-oxo-5-phenylimidazolidine-1-carboxamide (57)

[00258] Following general procedure 6, KHMDS (0.27 mL, 0.272 mmol, 1.0 M in THF) was added to a solution of 24 (55 mg, 0.181 mmol) in THF (1.80

mL). The title compound (52 mg, 0.172 mmol, 95%) was yielded as a white solid without further purification. For full data see compound 56.

(2^,5 )-2-(te/if-Butyl)-5-(4-cyanophenyl)-/V,3,5-trimethyl-4-oxoimidazolidine-1 -carboxamide (58)

[00259] Following a similar method to general procedure 6, KHMDS (0.35 mL, 0.350 mmol, 1.0 M in THF, 2.5 eq.) was added to a solution of 25 (46 mg, 0.140 mmol) in THF (1.40 mL). The title compound (44 mg, 0.134 mmol, 96%) was yielded as a pale yellow oil without further purification. 58: Rf (1 : 1

Pet. Ether: EtOAc): 0.10; ¹H NMR (400 MHz, CDCI3): δ_Η = 7.66 - 7.60 (m, 2H, ArH), 7.34 - 7.28 (m, 2H, ArH), 5.61 (s, 1 H, CHC(CH₃)₃), 3.95 (br. s, 1 H, NHCH3), 3.04 (s, 3H, NCH₃), 2.36 (d, = 4.6, 3H , N HCH3), 2.03 (s, 3H, CCH₃), 1.04 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI3): 5_C = 171 .7 (C=0), 158.1 (C=0), 147.2 (CAT), 132.8 (2x CH_Ar), 126.2 (2xCH_Ar), 1 18.4 (C≡N), 1 12.2 (CAT), 80.7 (CHC(CH₃)3), 66.2 (CCH₃), 38.7 (C(CH₃)₃), 32.3 (NCH₃), 26.9 (NHCH3), 26.6 (C(CH₃)₃), 23.9 (CCH₃); IR: v_max = 3401 (N-H), 2962, 2930 (C- H), 2229 (C≡N), 1698 (C=0), 1660 (C=0); HRMS (ESI⁺): m/z calcd for C18H25O2N4 ([M+H]⁺) 329.1972, found 329.1968. (2f?,5 ?)-2-(terf-Butyl)-5-(4-c lorophenyl)-A/,3,5-trimethyl-4-oxoimidazolidin (59)

[00260] Following general procedure 6, KHM DS (3.19 ml_, 3.19 mmol, 1.0 M in THF) was added to a solution of 26 (718 mg, 2.13 mmol) in THF (21.0 ml_). Purification by flash column chromatography (S1O2, 3:2→1 : 1 Pet. Ether: EtOAc) gave the title compound (675 mg, 2.00 mmol, 94%) as a

white solid. 59: R_f (1 : 1 Pet.Ether: EtOAc): 0.21 ; ¹H NMR (500 MHz, CDCI₃): δ_Η = 7.33 - 7.28 (m, 2H, ArH), 7.15 - 7.10 (m, 2H, ArH), 5.60 (s, 1 H, CHC(CH₃)₃), 3.90 (br. s, 1 H, NHCH₃), 3.04 (s, 3H, NCH₃), 2.37 (d, J = 4.8, 3H, NHCH₃), 1.98 (s, 3H, CCH₃), 1.04 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCI₃): δ₀ = 172.4 (C=0), 158.4 (C=0), 140.5 (CA_T), 134.3 (CA_T), 129.3 (2xCH_Ar), 126.7 (2xCH_Ar), 80.6 (CHC(CH₃)₃), 65.7 (CCH₃), 38.7 (C(CH₃)₃), 32.3 (NCH₃), 27.0 (NHCH3), 26.7 (C(CH₃)₃), 23.8 (CCH₃); IR: v_max = 3426 (N-H), 2983, 2960, 2906, 2874 (C-H), 1705 (C=0), 1656 (C=0); HRMS (ESI⁺): m/z calcd for C17H25O2N3CI ([M+H]⁺) 338.1630, found 338.1629.

(2f?,5f?)-2-(tert-Butyl)-5-(4-fluorophenyl)-/V,3,5-trimethyl-4-oxoimidazolidine-1-carboxamide (60)

[00261] Following general procedure 6, KHM DS (3.11 ml_, 3.11 mmol, 1.0 M in THF) was added to a solution of 27 (667 mg, 2.08 mmol) in TH F (21.0 ml_). Purification by flash column chromatography (S1O2, 1 :1 Pet. Ether: EtOAc) gave the title compound (635 mg, 1.98 mmol, 95%) as a

white solid. 60: R_f (1 : 1 Pet. Ether: EtOAc): 0.23; ¹H NMR (500 MHz, CDCI₃): 5_H = 7.19 - 7.14 (m, 2H, ArH), 7.05 - 6.99 (m, 2H, ArH), 5.60 (s, 1 H, CHC(CH₃)₃), 3.88 (br. s, 1 H, NHCH₃), 3.05 (s, 3H, NCH₃), 2.36 (d, J = 4.8, 3H, NHCH₃), 1.99 (s, 3H, CCH₃), 1.05 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NMR (125 MHz, CDCI3): δ₀ = 172.6 (C=0), 162.5 (d, ¹ _C-F = 247.9, C_ArF), 159.5 (C=0), 137.7 (d, ⁴JC-F = 3.2, CAT), 127.1 (d, ³J_C-F = 8.3, 2xCH_Ar), 116.0 (d, ²J_C__F = 21.7, 2xCH_Ar), 80.6 (CHC(CH₃)₃), 65.7 (CCH₃), 38.7 (C(CH₃)₃), 32.3 (NCH₃), 27.0 (NHCH₃), 26.7 (C(CH₃)₃), 23.9 (CCH₃); IR: v_max = 3428 (N-H), 2962, 2903 (C-H), 1700 (C=0), 1655 (C=0); HRMS (ESI⁺): m/z calcd for Ci₇H₂50₂N₃F ([M+H]⁺) 322.1918, found 322.1925.

(2R,5R)-2-(feAf-Butyl)-A/,3,5-trimethyl-4-oxo-5-(pyridin-2-yl)imidazolidine-1-carboxamide (61)

[00262] Following general procedure 6, KHM DS (3.16 ml_, 3.16 mmol, 1.C M in THF) was added to a solution of 28 (641 mg, 2.1 1 mmol) in THF (21.0 mL)- Purification by flash column chromatography (S1O2, 97:3→95:5 DCM:MeOH) gave the title compound (622 mg, 2.04 mmol, 97%) as a white

solid. 61 : R_f (95:5 DCM:MeOH): 0.34; ¹H NMR (500 MHz, CDCI₃): δ_Η = 8.55 (ddd, J = 4.9, 1 .7, 0.9, 1 H, ArH), 7.68 - 7.62 (m, 1 H, ArH), 7.17 (ddd, J = 7.5, 4.9, 1.0, 1 H, ArH), 7.10 (d, J = 8.0, 1 H , ArH), 5.59 (s, 1 H , CHC(CH₃)₃), 4.07 (br. s, 1 H, NHCH₃), 3.09 (s, 3H, NCH₃), 2.27 (d, J = 4.7, 3H, NHCH₃), 2.05 (s, 3H, CCH₃), 1.05 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5c = 172.7 (C=0), 159.8 (C_Ar), 158.5 (C=0), 148.8 (C_Ar), 137.4 (CH_Ar), 122.9 (CH_Ar), 120.6 (CH_Ar), 80.6 (CHC(CH₃)3), 68.1 (CCH₃), 38.5 (C(CH₃)3), 32.2 (NCH₃), 26.8 (NHCH₃), 26.7 (C(CH₃)₃), 22.6 (CCH₃); IR: v_max = 3392 (N-H), 2960, 2909 (C-H), 1694 (C=0), 1656 (C=0); HRMS (ESI⁺): m/z calcd for C16H25O2N4 ([M+H]⁺) 305.1972, found 305.1964.

(2S,5S)-2-(te/f-Butyl)-/V,3,5-trime^ (62)

[00263] Following a similar method to general procedure 7, a solution of

6^mg' ^{0,262 mmo}') ^and 2-(methylamino)pyridine (30 pL, 0.288 mmol, 1.1 eq.) in THF (2.60 mL) was treated with 2 portions of KHMDS

(2x0.29 mL, 0.577 mmol, 1.0 M in THF, 2.2 eq.). Purification by flash column chromatography (S1O₂, 95:5 EtOAc:MeOH) gave the title compound (75 mg, 0.246 mmol, 94%) as a pale yellow oil. For full data see compound 61 .

(2S,5S)-2-(te/ -Butyl)-/V,3,5-trimethyl-4-oxo-5-(pyridin-3-yl)imidazolidine-1-carboxamide (63)

[00264] Following a similar method to general procedure 7, a solution of trans-M (70 mg, 0.301 mmol) and 3-(methylamino)pyridine (34 μΙ_, 0.331 mmol, 1.1 eq.) in THF (3.00 mL) was treated with 2 portions of KHMDS (2x0.33 mL, 0.662 mmol, 1.0 in THF, 2.2 eq.). Purification by flash

column chromatography (S1O2, 95:5 EtOAc:MeOH) gave the title compound (83 mg, 0.273 mmol, 91%) as a pale yellow oil. 63: R_F (95:5 DCM:MeOH): 0.26; ¹H NM R (400 MHz, CDCI3): δ_Η = 8.51 (d, J = 4.7, 2H, ArH), 7.43 (d, J = 6.7, 1 H, ArH), 7.25 (dd, J = 7.7, 4.5, 1 H, ArH), 5.61 (s, 1 H, CHC(CH₃)₃), 4.06 (br. s, 1 H, N/-/CH3), 3.03 (s, 3H, NCH₃), 2.34 (d, J = 3.0, 3H, NHCH₃), 2.02 (s, 3H, CCH₃), 1.02 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NM R (100 MHz, CDCI₃): δ₀ = 172.0 (C=0), 158.1 (C=0), 149.5 (CH_Ar), 146.9 (CH_Ar), 137.4 (CAT), 132.8 (CH_Ar), 123.7 (CH_Ar), 80.6 (CHC(CH₃)₃), 64.9 (CCH₃), 38.6 (C(CH₃)₃), 32.3 (NCH₃), 26.9 (NHCH3), 26.6 (C(CH₃)3), 23.5 (CCH₃); IR: Vmax = 3391 (N-H), 2961 , 2878 (C-H), 1695 (C=0), 1652 (C=0); HRMS (ESI⁺): m/z calcd for C15H25O2N4 ([M+H]⁺) 305.1972, found 305.1966.

(2S,5S)-2-(ie/ -Butyl)-/V,3,5-trimethyl-4-oxo-5-(pyridin-4-yl)imidazolidine-1-carboxamide (64)

[00265] Following a similar method to general procedure 7, a solution of trans-M (70 mg, 0.301 mmol) and 4-(methylamino)pyridine (36 mg, 0.331 mmol, 1.1 eq.) in THF (3.00 mL) was treated with 2 portions of KHMDS (2x0.33 mL, 0.662 mmol, 1.0 in THF, 2.2 eq.). Purification by flash column

chromatography (S1O2, 95:5 EtOAc:MeOH) gave the title compound (49 mg, 0.161 mmol, 54%) as a yellow oil. 64: R_F (95:5 DCM:MeOH): 0.24; ¹ H NMR (500 MHz, CDCI3): δ_Η = 8.52 (dd, J = 4.6, 1.6, 2H, ArH), 7.05 (dd, J = 4.6, 1.6, 2Η, ArH), 5.57 (s, 1 Η, CtfC(CH₃)₃), 3.90 (br. s, 1 H, N - CH3), 2.98 (s, 3H, NC 7₃), 2.30 (d, J = 4.6, 3H, NHCHs), 1.95 (s, 3Η, CCH₃), 0.98 (s, 9Η, C(CH₃)3); ¹³C {¹ H} NM R (125 M Hz, CDCI₃): 5_C = 171.5 (C=0), 158.1 (C=0), 150.9 (CAT), 150.5 (2xCH_Ar), 120.2 (2xCH_Ar), 80.7 (CHC(CH₃)₃), 65.7 (CCH₃), 38.6 (C(CH₃)₃), 32.3 (NCH₃), 26.8 (NHCHs), 26.6 (C(CH₃)₃), 23.3 (CCH₃); IR: v_max = 3391 (N-H), 2961 , 2878 (C- H), 1698 (C=0), 1658 (C=0); HRMS (ESI⁺): m/z calcd for C16H25O2N4 ([M+H]⁺) 305.1972, found 305.1966.

(2R,5R)-5-Benzyl-2-(tert-butyl)-A/,3-dimethyl-4-oxo-5^henylimidazolidine-1-carboxam (65)

[00266] Following general procedure 6, KHMDS (0.22 mL, 0.217 mmol, 1.0 M in THF) was added to a solution of 29 (55 mg, 0.145 mmol) in THF (1.50 mL). Purification by flash column chromatography (Si0₂, 2: 1→3:2

Pet. Ether: EtOAc) gave the title compound (54 mg, 0.142 mmol, 98%) as a white solid. 65: R, (1 : 1 Pet.Ether: EtOAc): 0.29; ¹H NMR (500 MHz, CDCI₃): δ_Η = 7.44 - 7.40 (m, 2H, Phtf), 7.38 - 7.33 (m, 2H, Phtf), 7.33 - 7.23 (m, 6H, Phtf), 5.58 (s, 1 H, CHC(CH₃)₃), 3.89 - 3.81 (m, 2H, CH_AH_BP and NHCH₃), 3.63 (d, J = 14.3, 1 H, CH_AH_BPh), 2.97 (s, 3H, NCH₃), 2.20 (d, J = 4.6, 3H, NHCH₃), 0.73 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5c = 171.4 (C=0), 159.5 (C=0), 141.5 (C_Ph), 135.6 (C_Ph), 131.6 (2xCH_Ph), 129.1 (2xCH_Pfl), 129.0 (2xCH_Ph), 128.2 (CH_Ph), 127.8 (CH_Ph), 125.6 (2xCH_Ph), 81.3 (CHC(CH₃)₃), 71.9 (CCH₂Ph), 40.9 (CH₂Ph), 37.7 (C(CH₃)₃), 31.9 (NCH₃), 27.1 (NHCH₃), 26.5 (C(CH₃)₃); IR: v_max = 3434 (N-H), 3062, 3031 , 2959, 2908 (C-H), 1695 (C=0), 1658 (C=0); HRMS (ESI⁺): m/z calcd for C₂₃H₂90₂N₃Na ([M+Na]⁺) 402.2152, found 402.2149.

(2S,5S)-5-Benzyl-2-(feAf-butyl)-/V,3-dimethyl-4-oxo-5-phenylimidazolidine-1-carboxamide (66)

[°°267] LDA (1.5 eq.) was prepared by dropwise addition of nBuLi (0.33 mL, 0.435 mmol, 1.5 eq.) to a solution of freshly distilled DIPA (60 μΙ_, 0.435

mmol, 1.5 eq.) in anhydrous THF (1.30 mL, 0.22 M) at 0 °C. After stirring for 15 min, this LDA (0.22 M in THF, 1.5 eq.) was added dropwise to a solution of 30 (110 mg, 0.290 mmol, 1.0 eq.) in anhydrous THF (1.60 mL, 0.18 M) at 0 °C. After 15 min, the reaction mixture was warmed to room temperature and allowed to stir for 4 h. The reaction was quenched by dropwise addition of NH₄CI (sat. aq.) and stirred for 15 min. The organic layer was separated and the aqueous layer was extracted 3 times with EtOAc, dried over MgSC , filtered and concentrated in vacuo to give the title compound (108 mg, 0.285 mmol, 98%) as a white solid without further purification. For full data see compound 65.

(2R,5 ^)-5-Benzyl-2-(te/ -butyl)-5-(4-cyanophenyl)-/V,3-dimethyl-4-oxoimidazolidine-1- carboxamide (67)

[00268] Following general procedure 6, KHM DS (2.28 mL, 2.28 mmol, 1.0

M in THF) was added to a solution of 31 (614 mg, 1.52 mmol) in THF (15.0 mL). Purification by flash column chromatography (Si0₂, 1 : 1→2:1 EtOAc: Pet. Ether) gave the title compound (522 mg, 1.29 mmol, 85%) as a

white solid. 67: ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.63 (d, J = 8.6, 2H, ArH), 7.43 (d, J = 8.6, 2H, ArH), 7.40 - 7.35 (m, 2H, Ph/7), 7.35 - 7.26 (m, 3H, PhH), 5.57 (s, 1 H , CHC(CH₃)₃), 3.85 (br. s, 1H, NHCH₃), 3.77 (d, J= 14.4, 1H, CH^HePh), 3.68 (d, J= 14.5, 1H, CH_AH_sPh), 2.96 (s, 3H, NCH₃), 2.20 (br. d, J = 4.6, 3H, NHCH₃), 0.75 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 170.4 (C=0), 158.7 (C=0), 146.5 (CA_T), 134.8 (C_PH), 132.6 (2xCH_Ar), 131.3 (2xCHp_h), 129.2 (2xCH_Pfl), 128.2 (CH_Ph), 126.6 (2xCH_Ar), 118.3 (C≡N), 112.0 (CA_T), 81.2 (CHC(CH₃)₃), 72.0 (CCH₂Ph), 40.8 (CH₂Ph), 37.7 (C(CH₃)₃), 31.9 (NCH₃), 27.0 (NHCH₃), 26.4 (C(CH₃)₃); IR: v_max= 3433 (N-H), 2959, 2930 (C-H), 2229 (C≡N), 1694 (C=0), 1664 (C=0); HRMS (ESI⁺): m/z calcd for C₂4H280₂N4Na ([M+Na]⁺) 427.2104, found 427.2087.

(2R,5ft)-5-Benzyl-2-(te/f-butyl)-5-(4-chlorophenyl)-/V,3-dim

carboxamide (68)

[00269] Following general procedure 6, KHMDS (2.61 ml_, 2.61 mmol, 1.0 M in THF) was added to a solution of 32 (719 mg, 1.74 mmol) in THF (17.0 m^L)- Purification by flash column chromatography (Si0₂, 1:1→2:1 EtOAc: Pet. Ether) gave the title compound (634 mg, 1.53 mmol, 88%) as a

^{white solid}- ^{68: H NMR} (^{400 MHz}> CDCI3): 5_H = 7.42 - 7.36 (m, 2H, PhH), 7.35-7.23 (m, 7H, PhHandArH), 5.56 (s, 1H, CHC(CH₃)₃), 3.82 (br. s, 1H, NHCH₃), 3.77 (d, j= 14.4, 1H, CH^HePh), 3.63 (d, J= 14.4, 1H, CH_AH_BPh), 2.96 (s, 3H, NCH₃), 2.23 (d, J =4.6, 3H, NHCH₃), 0.75 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 170.9 (C=0), 159.0 (C=0), 139.7 (CA_T), 135.1 (C_PH), 134.1 (C_Ar), 131.3 (2xCH_Ph), 129.0 (2xCH_Ar), 128.9 (2xCH_Pfl), 127.9 (CHp_h), 127.0 (2xCH_Ar), 81.0 (CHC(CH₃)₃), 71.5 (CCH₂Ph), 40.8 (CH₂Ph), 37.6 (C(CH₃)₃), 31.8 (NCH₃), 27.0 (NHCH₃), 26.4 (C(CH₃)₃); IR: v_max = 3435 (N-H), 2959, 1694 (C=0), 1667 (C=0); HRMS (ESI⁺): m/z calcd for C₂₃H₂₈0₂N₃CINa ([M+Na]⁺) 436.1762, found 436.1776.

(2R,5f?)-5-Benzyl-2-(fe/f-butyl)-5-(4-fluorophenyl)-/V,3-dimethyl-4-oxoimidazolidine-1- carboxamide (69)

[00270] Following general procedure 6, KHMDS (2.45 mL, 2.45 mmol, 1.0

^{M in THF}) ^was added to a solution of 33 (650 mg, 1.64 mmol) in THF (16.0 mL). Purification by flash column chromatography (S1O2, 1:1→2:1 EtOAc: Pet. Ether) gave the title compound (580 mg, 1.46 mmol, 89%) as a

white solid.69: ¹H NMR (400 MHz, CDCI3): 5_H = 7.42 - 7.36 (m, 2H, PhH), 7.33 - 7.24 (m, 5H, PhH and ArH), 7.08 - 6.97 (m, 2H, ArH), 5.55 (s, 1H, CHC(CH₃)₃), 3.88 (s, 1H, NHCH₃), 3.79 (d, J= 14.4, 1H, CH^H_BPh), 3.60 (d, J= 14.3, 1H, CH_AH_BPh), 2.96 (s, 3H, NCH₃), 2.23 (d, J = 4.7, 3H, NHCH₃), 0.72 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5c = 171.2 (C=0), 162.3 (d, ¹J_C__F = 248.1, C_ArF), 159.2 (C=0), 137.2 (d, ⁴ _C-F = 3.4, CAT), 135.3 (CPh), 131.5 (2xCH_Ph), 129.0 (2xCH_Ph), 127.9 (CH_Ph), 127.5 (d, ³JC-F = 8.2, 2xCH_Ar), 115.9 (d, ² C-F = 21.5, 2xCH_Ar), 81.1 (CHC(CH₃)₃), 71.5 (CCH₂Ph), 41.1 (CH₂Ph), 37.7 (C(CH₃)₃), 31.9 (NCH₃), 27.1 (NHCH₃), 26.4 (C(CH₃)₃); IR: v_max = 3432 (N-H), 2960, 1693 (C=0), 1658 (C=0); HRMS (ESI⁺): m/z calcd for CasHbsC^NsFNa ([M+Na]⁺) 420.2058, found 420.2037.

(2R,5 ?)-5-Benzyl-2-(feii-butyl)-/V,3-dimethyl-4-oxo-5-(p olyl)imidazolidine-1-car^ (70)

[00271] Following general procedure 6, KHM DS (1.91 ml_, 1.91 mmol, 1.0 M in THF) was added to a solution of 34 (500 mg, 1 .27 mmol) in THF (13.0 mL)- Purification by flash column chromatography (S1O2, 1 : 1→2: 1 EtOAc: Pet. Ether) gave the title compound (400 mg, 1.01 mmol, 80%) as a

white solid. 70: ¹H NMR (400 MHz, CDC ): δ_Η = 7.44 - 7.38 (m, 2H, PhH), 7.32 - 7.23 (m, 3H, PhH), 7.17 (d, J = 8.6, 2H, ArH), 7.14 (d, J = 8.6, 2H, ArH), 5.55 (s, 1 H , CHC(CH₃)₃), 3.87 (br. q, J = 4.7, 1 H, NHCH₃), 3.80 (d, J = 14.3, 1 H, C ^HePh), 3.61 (d, J = 14.3, 1 H, CH_AtfsPh), 2.95 (s, 3H, NCH₃), 2.30 (s, 3H, CH₃), 2.22 (d, J = 4.7, 3H, NHC - ₃), 0.72 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 171.5 (C=0), 159.5 (C=0), 138.4 (CAT), 137.9 (CAT), 135.7 (CPU), 131.5 (2xCH_Ph), 129.7 (2xCH_Ar), 128.9 (2xCH_Ph), 127.7 (CH_Ph), 125.4 (2xCH_Ar), 81 .2 (CHC(CH₃)₃), 71.7 (CCH₂Ph), 40.8 (CH₂Ph), 37.7 (C(CH₃)₃), 31.9 (NCH₃), 27.1 (NHCH₃), 26.5 (C(CH₃)₃), 21.1 (CH₃); IR: v_max = 3436 (N-H), 2959 (C-H), 1682 (C=0), 1660 (C=0); HRMS (ESI⁺): m/z calcd for C₂₄H₃₂0₂N₃Na ([M+Na]⁺) 416.2308, found 416.2302.

(2^,5 )-5-Benzyl-2-(te/ -butyl)-5-(3-methoxyphenyl)-/V,3-dimethyl-4-oxoimidazolidine-1 - carboxamide (71 )

[00272] Following general procedure 6, KHM DS (0.16 ml_, 0.161 mmol, 1.0 M in THF) was added to a solution of 35 (44 mg, 0.107 mmol) in TH F

(1 .10 ml_). Purification by flash column chromatography (S1O2, 1 : 1 Pet. Ether: EtOAc) gave the title compound (36 mg, 0.088 mmol, 82%) as a

white solid. 71 : R, (1 : 1 Pet. Ether: EtOAc): 0.24; ¹H NMR (400 MHz, CDCb): δ_Η = 7.44 - 7.39 (m, 2H, PhH), 7.33 - 7.23 (m, 4H, PhH and ArH), 6.88 - 6.83 (m, 2H, ArH), 6.82 - 6.78 (m, 1 H, ArH), 5.55 (s, 1 H, CHC(CH₃)₃), 3.91 (br. q, J = 4.9, 1 H, N/- CH₃), 3.83 (d, J = 14.3, 1 H, CH^H_BPh), 3.78 (s, 3H, OCH₃), 3.59 (d, J = 14.3, 1 H, CH_AH_ePh), 2.97 (s, 3H, NCH₃), 2.24 (d, J = 4.7, 3H, NHCH₃), 0.71 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCb): 5_C = 171.3 (C=0), 160.1 (CAT), 159.5 (C=0), 143.2 (CAT), 135.5 (C_Ph), 131.6 (2x CH_Ph), 130.1 (CH_Ar), 128.9 (2xCH_Ph), 127.8 (CHph), 1 17.8 (CH_Ar), 1 13.2 (CH_Ar), 1 12.1 (CHAT), 81.3 (CHC(CH₃)₃), 71.8 (CCH₂Ph), 55.4 (OCH3), 40.9 (CH₂Ph), 37.7 (C(CH₃)₃), 31.9 (NCH₃), 27.1 (NHCH₃), 26.5 (C(CH₃)₃); IR: v_max = 3435 (N-H), 3064, 3031 , 2958, 2922, 2852 (C-H), 1696 (C=0), 1657 (C=0); HRMS (ESI⁺): m/z calcd for 0₂₄Η₃₂Ο₃Ν₃ ([M+H]⁺) 410.2438, found 410.2429. (2R,5 )-5-Benzyl-2-(fe/f-butyl)-5-(2-methoxyphenyl)-A/,3-dimethyl-4-oxoimid carboxamide (72)

[00273] Following general procedure 6, KHM DS (0.17 ml_, 0.165 mmol, 1.0 M in THF) was added to a solution of 36 (45 mg, 0.110 mmol) in TH F (1.10 ml_). Purification by flash column chromatography (S1O2, 2:1

EtOAc: Pet. Ether) gave the title compound (38 mg, 0.093 mmol, 84%) as a white solid. 72: R_f (2: 1 EtOAc: Pet. Ether): 0.24; ¹H NMR (400 M Hz, CDC ): δ_Η = 7.70 (d, J = 7.6, 1 H, ArH), 7.55 (d, J = 7.3, 2H, PhH), 7.31 (t, J = 7.3, 2H, PhH), 7.28 - 7.19 (m, 2H, PhH and ArH), 6.92 (td, J = 7.7, 0.9, 1 H, ArH), 6.82 (d, J = 8.1 , 1 H, ArH), 5.33 (s, 1 Η, CHC(CH₃)₃) , 3.72 (s, 3H, OCH3), 3.67 (br. q, J = 4.6, 1 H, NHCH₃), 3.65 (s, 2H, CH>Ph), 3.03 (s, 3Η, NCH>), 2.07 (d, J = 4.6, 3Η, NHCH , 0.88 (s, 9Η, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI3): δ₀ = 172.8 (C=0), 159.3 (C=0), 156.8 (CAT), 136.1 (C_PH), 131.7 (2xCH_Ph), 129.8 (CH_Ar), 128.8 (2xCHp_h), 128.7 (CHAT), 128.2 (CAT), 127.6 (CH_PH), 120.5 (CH_Ar), 1 1 1 .7 (CH_Ar), 82.6 (CHC(CH₃)₃) , 69.5 (CCH2PI-1), 56.5 (OCH₃), 42.6 (CH₂Ph) , 37.1 (C(CH₃)₃), 32.2 (NCH₃), 27.1 (C(CH₃)₃), 26.8 (NHCH₃); IR: v_max = 3435 (N-H), 3064, 3030, 2958, 2922 (C-H), 1692 (C=0), 1660 (C=0); HRMS (ESI⁺): m/z calcd for C₂4H₃₂03N3 ([M+H]⁺) 410.2438, found 410.2438.

(2S,5S)-2-(fe/f-Butyl)-5-(4-cyanophenyl)-/V,3-dimethyl-4-oxo-5-phenylimidazolidine-1- carboxamide (73)

[00274] Following general procedure 6, KHMDS (1.97 ml_, 1.97 mmol, 1.0 M in THF) was added to a solution of 37 (512 mg, 1.31 mmol) in THF (13.0 ml_). Purification by flash column chromatography (S1O2, 1 : 1→2:1 EtOAc: Pet. Ether) gave the title compound (404 mg, 1.03 mmol, 79%) as a

white solid. 73: ¹H NMR (400 M Hz, CDCI3): δ_Η = 7.94 - 7.89 (m , 2H, PhH), 7.60 - 7.54 (m, 2Η, ArH), 7.54 - 7.48 (m, 2Η, PhH), 7.48 - 7.42 (m, 1 Η, PhH), 7.15 - 7.09 (m, 2Η, ArH), 5.80 (s, 1 Η, CHC(CH₃)3), 3.99 (q, J = 4.8, 1 H, N/-/CH3), 3.13 (s, 3H, NCH₃), 2.23 (d, J = 4.7, 3H, NHCH3), 0.93 (s, 9Η, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI3): 5_C = 170.7 (C=0), 157.8 (C=0), 147.8 (CAT) , 136.0 (C_Ph), 132.6 (2xCH_Ar), 129.0 (CH_Ph), 128.9 (2xCH_Pfl), 128.3 (2xCH_Ph), 127.8 (2xCH_Ar), 118.2 (C≡N), 1 12.3 (CAT), 80.5 (CHC(CH₃)₃), 72.5 (NCPh), 38.3 (C(CH₃)₃), 32.1 (NCH₃), 26.9 (NHCH₃), 26.5 (C(CH₃)₃); IR: v_max = 3428 (N-H), 2969 (C- H), 2228 (C≡N), 1705 (C=0), 1666 (C=0); HRMS (ESI⁺): m/z calcd for C23H26O2N4 ([M+H]⁺) 413.1948, found 413.1952. (2S,5S)-2-(te/f-Butyl)-5-(4-chlorophenyl)-A/,3-dimethy^

carboxamide (74)

[00275] Following general procedure 6, KHMDS (1.73 ml_, 1.73 mmol, 1.0 M in THF) was added to a solution of 38 (460 mg, 1.15 mmol) in THF (12.0 ml_). Purification by flash column chromatography (S1O2, 1 : 1→2:1 EtOAc: Pet. Ether) gave the title compound (404 mg, 1.01 mmol, 88%) as a

white solid. 74: ¹H NMR (400 MHz, CDC ): δ_Η = 7.97 - 7.89 (m, 2H, PhH),

7.51 - 7.45 (m, 2H, PhH), 7.45 - 7.39 (m, 1 H, PhW), 7.29 - 7.20 (m, 2H, ArH), 6.93 - 6.88 (m, 2H, ArW), 5.80 (s, 1 H, CHC(CH₃)₃), 3.97 (q, J = 4.7, 1 H, N - CH3), 3.13 (s, 3H, NCH₃), 2.26 (d, J = 4.7, 3H, NHCH₃), 0.92 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI3): 5_C= 171.3 (C=0), 158.3 (C=0), 141.2 (C_Ar), 136.8 (C_Ph), 134.4 (C_Ar), 129.1 (2xCH_Ar), 128.7 (3xCH_Ph), 128.4 (2xCH_Ar), 128.3 (2xCHp_h), 80.3 (CHC(CH₃)3), 72.3 (NCPh), 38.4 (C(CH₃)₃), 32.1 (NCH₃), 27.1 (NHCH3), 26.6 (C(CH₃)3); IR: v_max = 3424 (N-H), 2967 (C-H), 1701 (C=0), 1666 (C=0); HRMS (ESI⁺): m/z calcd for C22H260₂N₃CINa ([M+Na]⁺) 422.1606, found 422.1620.

(2S,5S)-2-(fe/f-Butyl)-5-(4-fluorophenyl)-/V,3-dimethyl-4-oxo-5-phenylimidazolidine-1- carboxamide (75)

[00276] Following general procedure 6, KHMDS (1.56 ml_, 1.56 mmol, 1.0 M in THF) was added to a solution of 39 (400 mg, 1.04 mmol) in THF (10.0 ml_). Purification by flash column chromatography (S1O2, 1 : 1→2:1 EtOAc: Pet. Ether) gave the title compound (339 mg, 0.88 mmol, 85%) as a

white solid. 75: ¹H NMR (400 MHz, CDCI3): 5_H = 7.97 - 7.89 (m, 2H, PhH),

7.51 - 7.45 (m, 2H, PhH), 7.44 - 7.38 (m, 1 H, PhH), 7.00 - 6.90 (m, 4H, ArH), 5.80 (s, 1 H, CWC(CH₃)₃), 3.96 (q, J = 4.8, 1 H, N - CH3), 3.13 (s, 3H, NCH₃), 2.25 (d, J = 4.7, 3H, NHC - 3), 0.92 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCb): 5_C = 171.5 (C=0), 162.3 (d, ¹J_C-F = 249.0, C_ArF), 158.3 (C=0), 138.4 (d, ⁴ _C-F = 3.4, CAT), 137.1 (C_Ph), 128.9 (d, ³ _C-F = 8.3, 2xCH_Ar), 128.6 (3xCHp_h), 128.3 (2xCH_Ph), 115.9 (d, ² _C-F = 21.8, 2xCH_Ar), 80.3 (CHC(CH₃)3) , 72.3 (NCPh), 38.4 (C(CH₃)₃), 32.1 (NCH₃), 27.1 (NHCH₃), 26.6 (C(CH₃)₃); IR: v_max = 3464 (N- H), 2922 (C-H), 1703 (C=0), 1664 (C=0); HRMS (ESI⁺): m/z calcd for C₂₂H₂₆0₂N₃FNa ([M+Na]⁺) 406.1901 , found 406.1905.

(2S,5S)-2-(fe/f-Butyl)-5-(4-methoxyphenyl)-/V,3-dimethyl-4-oxo-5-phenylimidazolidine-1- carboxamide (76)

[00277] Following general procedure 6, KHMDS (0.13 ml_, 0.125 mmol, 1.0 M in THF) was added to a solution of 40 (33 mg, 0.083 mmol) in THF (0.85 ml_). Purification by flash column chromatography (Si0₂, 1 :1 Pet. Ether: EtOAc) gave the title compound (31 mg, 0.078 mmol, 94%) as a

white solid. 76: R, (1 : 1 Pet. Ether: EtOAc): 0.24; ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.94 (d, J = 7.1 , 2H, PhH), 7.46 (t, J = 7.3, 2H, PhH), 7.40 (t, J = 7.2, 1 H, PhH), 6.87 (d, J = 8.9, 2H, ArH), 6.79 (d, J = 8.9, 2H, ArH), 5.79 (s, 1 H, CHC(CH₃)₃), 3.98 (q, J = 4.8, 1 H, NHCH₃), 3.74 (s, 3H, OCH₃), 3.13 (s, 3H, NCH₃), 2.26 (d, J = 4.7, 3H, NHCH₃), 0.91 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 171.9 (C=0), 159.4 (CA_T), 158.7 (C=0), 137.6 (Cp_h), 134.5 (CAT), 128.4 (2xCH_Ph), 128.3 (3xCH_Pfl and 2xCH_Ar), 114.3 (2xCH_Ar), 80.2 (CHC(CH₃)₃), 72.4 (NCPh), 55.4 (OCH₃), 38.4 (C(CH₃)₃), 32.1 (NCH₃), 27.2 (NHCH₃), 26.6 (C(CH₃)₃); IR: v_max = 3452 (N-H), 3062, 2957, 2923, 2853 (C-H), 1703 (C=0), 1666 (C=0); HRMS (ESI⁺): m/z calcd for C₂₃H₂90₃N₃Na ([M+Na]⁺) 418.2101 , found 418.2107.

(2S,5S)-2-(fe/f-Butyl)-5-(4-chlorophenyl)-3-methyl-4-oxo-5-phenylimidazolidine-1- carboxamide (77)

[00278] LDA (2.5 eq.) was prepared by dropwise addition of nBuLi (0.13 mL, 0.194 mmol, 2.5 eq., 1.5 M in hexanes) to a solution of freshly distilled DIPA (27 pL, 0.194 mmol, 2.5 eq.) in anhydrous THF (0.40 mL, 0.49 M) at 0 °C. After stirring for 15 min, the solution was cooled to -78 °C before

TMSCI (10 pL, 0.078 mmol, 1.0 eq.) was added. After 5 min, a solution of 41 (30 mg, 0.078 mmol, 1.0 eq.) in anhydrous THF (0.60 mL, 0.13 M) was added dropwise to the cooled LDA/TMSCI mixture - an intense yellow colouration was observed. The reaction mixture was left to stir for 30 min at -78 °C, before it was allowed to warm to room temperature and stirred for a further 15 h. The reaction was quenched by dropwise addition of NH₄CI (sat. aq.) and stirred for 15 min. The organic layer was separated and the aqueous layer was extracted 3 times with EtOAc, dried over MgSC , filtered and concentrated in vacuo. Purification by flash column chromatography (S1O2, 2:1 Pentane:EtOAc) gave the title compound (16 mg, 0.041 mmol, 53%) as a yellow oil. 77: ¹H NMR (500 MHz, CDCI₃): δ_Η = 7.99 - 7.95 (m, 2H, PhH), 7.51 - 7.46 (m, 2H, PhH), 7.45 - 7.41 (m, 1 H, PhH), 7.28 - 7.25 (m, 2H, ArH), 6.97 - 6.93 (m, 2H, ArH), 5.76 (s, 1 H, CHC(CH₃)₃), 4.29 (s, 2H, NH₂), 3.15 (s, 3H, NCH₃), 0.93 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5_C = 171.3 (C=0), 157.7 (C=0), 140.8 (CAT), 136.4 (C_Ph), 134.9 (CAT), 129.4 (2xCH_Ar), 128.8 (CH_Pfl and 2xCH_Ar), 128.7 (2xCH_Ph), 128.3 (2xCH_Ar), 80.5 (CHC(CH₃)₃), 72.0 (NCPh), 38.7 (C(CH₃)₃), 32.2 (NCH₃), 26.7 (C(CH₃)₃); IR: v_max = 3491 , 3341 , 3210 (N-H), 3066, 3027, 2959, 2924, 2872, 2853 (C-H), 1702 (C=0); HRMS (ESI⁺): m/z calcd for C21 H25O2N3CI ([M+H]⁺) 386.1630, found 386.1627.

(2R,5f?)-2-(te/f-Butyl)-5-isopropyl-/V,3-dimethyl-4-oxo-5-phenylimidazolidine-1-carboxamide (78)

[00279] LDEA (1.5 eq.) was prepared by dropwise addition of nBuLi (0.12 mL, 0.181 mmol, 1.5 eq., 1.5 M in hexanes) to a solution of freshly distilled DEA (19 pL, 0.181 mmol, 1.5 eq.) in anhydrous THF (0.50 mL, 0.36 M) at 0

°C. After stirring for 15 min, this LDEA (0.36 M in THF, 1.5 eq.) was added dropwise to a solution of 42 (40 mg, 0.121 mmol, 1.0 eq.) in anhydrous THF (0.70 mL, 0.17 M) at 0 °C. After 15 min, the reaction mixture was warmed to room temperature and allowed to stir for 4 h. The reaction was quenched by dropwise addition of NH₄CI (sat. aq.) and stirred for 15 min. The organic layer was separated and the aqueous layer was extracted 3 times with EtOAc, dried over MgSCv, filtered and concentrated in vacuo to give the title compound (39 mg, 0.1 18 mmol, 98%, 91 :9 dr) as a pale yellow oil without further purification. 78: ¹H NMR (500 MHz, CDC ) (major diastereomer): δ_Η = 7.29 (t, J = 7.7, 2H, PhH), 7.22 (t, J = 7.3, 1 H, PhH), 7.1 1 (d, J = 7.8, 2H, PhH), 5.43 (s, 1 H, CHC(CH₃)3), 4.42 (br. q, J = 4.4, 1 H, NHCH₃), 3.08 (s, 3H, NCH₃), 2.93 - 2.82 (m, 1 H, CH(CH₃)₂), 2.32 (d, J = 4.8, 3H, NHC - 3), 1.34 (d, J = 7.1 , 3H, CH(CH₃)A(CH₃)B), 1.31 (d, J = 6.9, 3H, CH(CH₃)A(CH₃)B), 1.08 (s, 9H, C(CHz ); ¹³C {¹H} NMR (125 MHz, CDCb) (major diastereomer): 5_C = 172.3 (C=0), 160.1 (C=0), 139.1 (Cph), 128.7 (2xCHp_h), 128.0 (CH_Ph), 126.9 (2*CH_Ph), 80.5 (CHC(CH₃)₃), 73.8 (CCH(CH₃)₂), 37.6 (C(CH₃)₃), 33.8 (CH(CH₃)₂), 31.5 (NCH₃), 27.5 (C(CH₃)₃), 19.9 (CH(CH₃)A(CH₃)S), 19.5 (CH(CH₃)A(CH₃)B); I : v_max = 3391 (N-H), 2962, 2936, 2876 (C-H) 1690 (C=0); HRMS (ESI⁺): m/z calcd for

([M+Na]⁺) 354.2152, found 354.2150.

(2^,5/^)-2-(ie/f-Butyl)-5-(4-cyanophenyl)-5-isobutyl-/V,3-dimethyl-4-oxoimidazolidine-1- carboxamide (79)

[00280] Following general procedure 6, KHMDS (2.60 ml_, 2.57 mmol, 1.0 M in THF) was added to a solution of 43 (634 mg, 1.71 mmol) in THF (17.0 ml_). Purification by flash column chromatography (Si0₂, 3:2 Pet. Ether: EtOAc) gave the title compound (549 mg, 1.48 mmol, 87%) as a

^{white solid}- ^79: Rf (3:2 Pet. Ether: EtOAc): 0.21 ; ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.63 - 7.58 (m, 2H, ArH), 7.28 - 7.23 (m, 2H, ArH), 5.61 (s, 1 H , CHC(CH₃)3), 4.12 (br. q, J = 4.6, 1 H, N - CH3), 3.05 (s, 3H, NCH₃), 2.47 (dd, J = 14.7, 5.2, 1 H, CH_.H_BCH), 2.36 (d, J = 4.7, 3H, NHCH3), 2.16 (dd, J = 14.8, 5.3, 1 H, CH_AH_SCH), 2.16 - 2.04 (m, 1 H, CH₂CH(CH₃)₂), 1.14 (d, J = 6.4, 3H, CH(CH₃MCH₃)B), 1.10 (d, J = 6.5, 3H, CH(CH₃)A(CH₃)B), 1.08 (s, 9H, C(CH₃)3); ¹³C {¹H} NMR (100 MHz, CDCI3): 5_C = 171.1 (C=0), 158.9 (C=0), 147.4 (CAT), 132.7 (2xCH_Ar), 126.5 (2xCH_Ar), 1 18.4 (C≡N), 1 12.0 (CAT), 81.3 (CHC(CH₃)3), 69.9 (NCCH₂), 45.2 (NCCH₂), 38.2 (C(CH₃)₃), 32.1 (NCH₃), 27.1 (C(CH₃)₃), 27.0 (NHCH3), 25.1 (CH(CH₃WCH₃)B) , 24.4 (CH(CH₃)A(CH₃)B), 24.2 (CH(CH₃)₂); IR: v_max = 3432 (N-H), 2958, 2871 (C-H), 2229 (C≡N), 1697 (C=0); HRMS (ESI⁺): m/z calcd for C₂i H₃i0₂N₄ ([M+H]⁺) 371.2442, found 371.2441. (2R,5 )-2-(feAf-Butyl)-5-(4-c lorophenyl)-5-isobutyl-A/,3-dimethyl-4-oxoimidaz carboxamide (80)

[00281] Following general procedure 6, KHM DS (2.14 ml_, 2.14 mmol, 1.0

M in THF) was added to a solution of 44 (543 mg, 1 .43 mmol) in THF (14.3 ml_). Purification by flash column chromatography (Si0₂, 2: 1 Pet. Ether: EtOAc) gave the title compound (474 mg, 1.25 mmol, 87%) as a

white solid. 80: Rf (2: 1 Pet.Ether: EtOAc): 0.24; ¹H NMR (500 MHz, CDCI3): δ_Η = 7.31 - 7.26 (m, 2H, ArH), 7.10 - 7.05 (m, 2H, ArH), 5.60 (s, 1 H , CHC(CH₃)₃), 4.08 (br. q, J = 4.5, 1 H, N - CH3), 3.05 (s, 3H, NCH₃), 2.41 (dd, J = 14.8, 5.4, 1 H, C^H_BCH), 2.37 (d, J = 4.7, 3H, NHCH₃), 2.16 (dd, J = 14.9, 5.2, 1 H, CH_AW_BCH), 2.15 - 2.05 (m, 1 H, CH₂CH(CH₃)₂), 1.13 (d, J = 6.4, 3H, CH(CH₃)A(CH₃)_B), 1.10 (d, J = 6.6, 3H, CH(CH₃)_A(CH₃)_B), 1.08 (s, 9H, C(CW₃)₃); ¹³C {¹H} NMR (125 M Hz, CDCI3): 5_C = 171.9 (C=0), 159.2 (C=0), 140.6 (CA_T), 134.1 (CAT), 129.2 (2x CH_Ar), 127.1 (2x CH_Ar), 81 .2 (CHC(CH₃)3) , 69.6 (NCCH₂), 46.3 (NCCH₂), 38.2 (C(CH₃)₃), 32.1 (NCH₃), 27.2 (C(CH₃)₃), 27.1 (NHCH₃), 25.2 (CH(CH₃KCH₃)_B), 24.4 (CH(CH₃)A(CH₃)S), 24.3 (CH(CH₃)₂); IR: v_max = 3431 (N-H), 2958, 2871 (C-H), 1697 (C=0), 1663 (C=0); HRMS (ESI⁺): m/z calcd for C₂₀H₃iO₂N₃CI ([M+H]⁺) 380.2091 , found 380.2099.

(2R,5f?)-2-(feAf-Butyl)-5-(4-fluorophenyl)-5-isobutyl- V,3-dimethyl-4-oxoimidazolidine-1- carboxamide (81 )

[00282] Following general procedure 6, KHMDS (2.62 ml_, 2.62 mmol, 1.0 M in THF) was added to a solution of 45 (635 mg, 1 .75 mmol) in THF (14.3 ml_). Purification by flash column chromatography (Si0₂, 3: 1 Pet. Ether: EtOAc) gave the title compound (530 mg, 1.46 mmol, 83%) as a

white solid. 81 : Rf (2: 1 Pet. Ether: EtOAc): 0.33; ¹H NMR (500 MHz, CDCI3): 5_H = 7.13 - 7.06 (m, 2H, ArH), 7.02 - 6.95 (m, 2H, ArH), 5.59 (s, 1 H , CHC(CH₃)₃), 4.08 (br. q, J = 4.4, 1 H, NHCH₃), 3.04 (s, 3H, NCH₃), 2.39 (dd, J = 14.9, 5.5, 1 H,

2.34 (d, J = 4.7, 3H, N HCH3), 2.16 (dd, J = 14.9, 5.2, 1 H, CH_AHsCH), 2.14 - 2.05 (m, 1 H, CH₂CH(CH₃)₂), 1.11 (d, J = 6.4, 3H, CH(CH₃)A(CH₃)B), 1.08 (d, J = 6.7, 3H, CH(CH₃)A(CH₃)B), 1.07 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NMR (125 MHz, CDCI₃): 6_C = 172.0 (C=0), 162.2 (d, ¹ J_C-F = 247.9, C_ArF), 159.2 (C=0), 137.7 (d, ⁴J_C-F = 3.1 , CAT), 127.5 (d, ³J_C-F = 8.2, 2*CH_Ar), 1 15.9 (d, ²J_C-F = 21 .6, 2x CH_Ar), 81.1 (CHC(CH₃)₃), 69.4 (NCCH₂), 45.2 (NCCH₂), 38.1 (C(CH₃)₃), 32.0 (NCH₃), 27.1 (C(CH₃)₃), 27.0 (NHCH₃), 25.1 (CH(CH₃)A(CH₃)_B) , 24.4 (CH(CH₃)_A(CH₃)_B), 24.3 (CH(CH₃)₂); |R: vmax = 3427 (N-H), 2958, 2871 (C-H), 1696 (C=0), 1662 (C=0); HRMS (ESI⁺): m/z calcd for C₂₀H₃iO₂N₃F ([M+H]⁺) 364.2395, found 364.2386. (2R,5ft)-2-(terf-Butyl)-5-isobutyl-W,3-dimethyl-4-o^ (82)

[00283] Following general procedure 6, KHM DS (2.07 ml_, 2.07 mmol, 1.0 M in THF) was added to a solution of 636 (496 mg, 1.38 mmol) in THF (14.0 ml_). Purification by flash column chromatography (S1O2, 3: 1→2:1 Pet. Ether: EtOAc) gave the title compound (402 mg, 1.12 mmol, 81 %) as a

white solid. 82: Rf (2:1 Pet. Ether: EtOAc): 0.21 ; ¹H NMR (500 MHz, CDCI₃): δ_Η = 7.11 (d, J = 8.1 , 2H, ArH), 7.01 (d, J = 8.4, 2H, ArH), 5.61 (s, 1 H, CHC(CH₃)₃), 4.04 (br. q, J = 4.6, 1 H, N/-/CH3), 3.04 (s, 3H, NCH₃), 2.37 (dd, J = 15.0, 5.8, 1 H, CH_AH_BC ), 2.32 (d, J = 4.8, 3H, NHC/-/3), 2.28 (s, 3H, CHj), 2.21 (dd, J = 15.0, 5.1 , 1 H, CH_AH_BCH), 2.17 - 2.06 (m, 1 H, CH₂CH(CH₃)₂), 1.12 (d, J = 6.5, 3H, CH(CH₃)A(CH₃)B), 1.10 (d, J = 6.6, 3H, CH(CH₃)A(CH₃)B), 1.09 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCI3): 5_C = 172.5 (C=0), 159.4 (C=0), 138.7 (CAT), 137.9 (CAT), 129.8 (2xCH_Ar), 125.5 (2xCH_Ar), 81.2 (CHC(CH₃)3), 69.7 (NCCH₂), 45.0 (NCCH₂), 38.2 (C(CH₃)₃), 32.1 (NCH₃), 27.2 (C(CH₃)₃), 27.1 (NHCH₃), 25.2 (CH(CH₃)„(CH₃)_B), 24.4 (CH(CH₃)A(CH₃)_b and CH(CH₃)₂), 21.1 (CH₃); IR: v_max = 3432 (N-H), 2957, 2870 (C-H), 1697 (C=0), 1661 (C=0); HRMS (EST): m/z calcd for C21 H34O2N3 ([M+H]⁺) 360.2646, found 360.2647.

(2R,5f?)-2-(feAf-Butyl)-5-(4-cyanophenyl)-/V,3-dimethyl-5-(2-(methylthio)ethyl)-4- oxoimidazolidine-1-carboxamide (83)

[00284] Following general procedure 6, KHM DS (2.23 ml_, 2.23 mmol, 1.0 M in THF) was added to a solution of 47 (578 mg, 1.49 mmol) in THF (14.9 mL). Purification by flash column chromatography (S1O2, 5:1 DCM : EtOAc) gave the title compound (497 mg, 1.28 mmol, 86%) as a

pale yellow solid. 83: R_f (5: 1 DCM : EtOAc): 0.27; ¹H NMR (500 MHz,

CDC ): δ_Η = 7.65 - 7.61 (m, 2H, ArH), 7.31 - 7.27 (m, 2H, ArH), 5.58 (s, 1 H, CHC(CH₃)₃),

4.44 (br. q, J = 4.6, 1 H, NHCH₃), 3.06 (s, 3H, NCH₃), 2.88 - 2.72 (m, 3H, CH₂CH₂SCH₃ and

CHXHBCH₂SCH₃), 2.62 - 2.54 (m, 1 H, CH_AH_BCH₂SCH₃), 2.37 (d, J = 4.7, 3H, N HCH₃), 2.19

(s, 3H, SCHz), 1.07 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCb): 5_C = 170.8 (C=0),

158.7 (C=0), 145.8 (CAT), 132.7 (2xCH_Ar), 126.7 (2xCH_Ar), 118.3 (C≡N), 112.3 (CAT), 81.0

(CHC(CH₃)₃), 38.2 (C(CH₃)₃), 36.8 (NCCH₂), 32.0 (NCH₃), 30.1 (CH₂SCH₃), 27.1 (NHCH₃),

27.0 (C(CH₃)₃), 16.1 (SCH₃); IR: v_max = 3401 (N-H), 2963, 2917 (C-H), 2229 (C≡N), 1695

(C=0); HRMS (ESI⁺): m/z calcd for C20H29O2N4S ([M+H]⁺) 389.2006, found 389.2006. (2R,5R)-2-(feAf-Butyl)-5-(4-c lorophenyl)-W,3-dimethyl-5-(2-(methylt io)ethyl)-4- oxoimidazolidine-1-carboxamide (84)

[00285] Following general procedure 6, KHMDS (2.01 ml_, 2.01 mmol,

1.0 M in THF) was added to a solution of 48 (533 mg, 1.34 mmol) in THF

(13.4 ml_). Purification by flash column chromatography (Si0₂, 3:2 Pet. Ether: EtOAc) gave the title compound (460 mg, 1.16 mmol, 86%) as

a white solid. 84: R_f (3:2 Pet. Ether: EtOAc): 0.21 ; ¹H N R (400 MHz,

CDC ): δ_Η = 7.33 - 7.28 (m, 2H, ArH), 7.12 - 7.07 (m, 2H, ArH), 5.58 (s, 1 H, CWC(CH₃)₃),

4.30 (br. q, J = 4.6, 1 H, N - CH3), 3.05 (s, 3H, NCHj), 2.88 - 2.68 (m, 3H, CH₂CH>SCH₃ and

C^H_BCH₂SCH₃), 2.62 - 2.52 (m, 1 H, CH/H_BCH₂SCH₃), 2.37 (d, J = 4.7, 3H, NHCH₃), 2.18

(s, 3H, SCHz), 1.06 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCb): 5_C = 171.4 (C=0),

158.9 (C=0), 138.8 (CAT), 134.4 (CAT), 129.2 (2xCH_Ar), 127.2 (2xCH_Ar), 80.8 (CHC(CH₃)₃), 69.1

(NCCH₂), 38.1 (C(CH₃)₃), 36.9 (NCCH₂), 32.0 (NCH₃), 30.1 (CH₂SCH₃), 27.1 (NHCH₃), 27.0

(C(CH₃)₃), 16.0 (SCH₃); IR: v_max = 3400 (N-H), 2962, 2916 (C-H), 1694 (C=0); HRMS (ESI⁺): m/z calcd for Ci₉H₂₉0₂N₃CIS ([M+H]⁺) 398.1664, found 398.1666.

(2R,5f?)-2-(feAf-Butyl)-/V,3-dimethyl-5-(2-(methylthio)ethyl)-4-oxo-5-(pyridin-2- yl)imidazolidine-1-carboxamide (85)

[00286] Following general procedure 6, KHMDS (2.06 ml_, 2.06 mmol, 1.0 M in THF) was added to a solution of 49 (501 mg, 1.37 mmol) in THF

(13.7 ml_). Purification by flash column chromatography (Si0₂, 99: 1→97:3 EtOAc: MeOH) gave the title compound (450 mg, 1 .23 mmol,

90%) as a white solid. 85: ¹H NMR (500 MHz, CDCb): δ_Η = 8.55 (ddd, J = 4.8, 1 .6, 0.8, 1 H , ArH), 7.65 (td, J = 7.8, 1.8, 1 H, ArH), 7.18 (ddd, J = 7.5, 4.9, 0.8, 1 H , ArH), 7.02 (d, J = 8.0, 1 H , ArH), 5.58 (s, 1 H, CHC(CH₃)₃), 4.42 (br. q, J = 4.5, 1 H , NHCH₃), 3.1 1 (s, 3H , NCH₃), 3.00 - 2.83 (m, 3H , CH₂CH₂SCH₃ and CH_AH_BCH₂SCH₃), 2.70 - 2.62 (m, 1 H , CH_AH_BCH₂SCH₃), 2.26 (d, J = 4.7, 3H, NHCH₃), 2.19 (s, 3H , SCH₃), 1 .07 (s, 9H , C(CW₃)₃); ¹³C {¹H} NMR (125 MHz, CDCb): 5_C = 171 .7 (C=0), 158.6 (C=0), 158.5 (CAT), 148.5 (CH_AR), 137.5 (CH_AR), 123.1 (CH_AR), 121 .6 (CH_AR), 80.7 (CHC(CH₃)₃), 70.7 (N CCH₂), 38.1 (C(CH₃)₃), 36.6 (NCCH₂), 32.0 (NCH₃), 29.9 (CH₂SCH₃), 27.0 (C(CH₃)₃), 26.9 (N H CH₃) , 15.8 (SCH₃); IR: v_max = 3399 (N-H), 2960, 2916 (C-H), 1698 (C=0), 1668 (C=0); HRMS (ESI⁺): m/z calcd for Ci₈H₂₉0₂N₄S ([M+H]⁺) 365.2006, found 365.1998. (2R,5ft)-2-(ferf-Butyl)-A/ dimethyl-5-(2^

carboxamide (86)

[00287] Following general procedure 6, KHM DS (2.86 ml_, 2.86 mmol, 1 .0 M in THF) was added to a solution of 50 (720 mg, 1.91 mmol) in THF (19.1 mL). Purification by flash column chromatography (S1O2, 3:2→1 :1 Pet. Ether: EtOAc) gave the title compound (527 mg, 1.40 mmol, 73%) as

a white solid. 86: R_f (1 : 1 Pet. Ether: EtOAc): 0.26; ¹H N R (500 MHz,

CDC ): 5_H = 7.14 (d, J = 7.7, 2H, ArH), 7.04 (d, J = 7.6, 2H, ArH), 5.60 (s, 1 H, CWC(CH₃)₃), 4.13 (br. q, J = 4.1 , 1 H, N - CH3), 3.06 (s, 3H , NCH₃), 2.90 - 2.66 (m, 3H, CH₂CH₂SCH₃ and C^H_BCH₂SCH₃), 2.66 - 2.55 (m, 1 H, CH_AW_BCH₂SCH₃), 2.33 (d, J = 4.3, 3H, NHCH₃), 2.29 (s, 3H, CHz), 2.19 (s, 3H, SCW₃), 1 .07 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NMR (125 MHz, CDCb): 5_C = 172.0 (C=0), 159.1 (C=0), 138.4 (CAT), 137.0 (CAT), 129.9 (2xCH_Ar), 125.6 (2x CH_Ar), 80.9 (CHC(CH₃)₃), 69.1 (NCCH₂), 38.2 (C(CH₃)₃), 36.8 (NCCH₂), 32.0 (NCH₃), 30.2 (CH₂SCH₃), 27.1 (C(CH₃)₃ and NHCHs), 21 .1 (CH₃), 16.0 (SCH₃); IR: v_max = 3400 (N-H), 2960, 2916, 2875 (C-H), 1694 (C=0), 1658 (C=0); HRMS (ESI⁺): m/z calcd for C₂₀H₃₂O₂N₃S ([M+H]⁺) 378.2210, found 378.2202.

(2R,5f?)-5-(4-(Benzyloxy)benzyl)-2-(ieAf-butyl)-/V,3-dimethyl-4-oxo-5-phenylimidazolidine-1- carboxamide (87)

[00288] Following a similar method to general procedure 6, KHMDS (1 .03 mL, 1.03 mmol, 1.0 M in THF, 2.5 eq.) was added to a solution of 51 (200 mg, 0.412 mmol, 1.0 eq.) in THF (4.00 mL, 0.1 M). Purification by flash column chromatography (Si0₂, 2: 1 EtOAc: Pet. Ether) gave the title compound (190 mg, 0.391 mmol, 95%) as a white solid. 87: ¹H

NMR (400 MHz, CDCI₃): δ_Η = 7.44 - 7.22 (m, 12H, PhH and ArH), 6.91 (d, J = 8.2, 2H, ArH), 5.58 (s, 1 H , CHC(CH₃)₃), 5.06 (s, 2H, OCH₂Ph), 3.86 (br. q, J = 4.4, 1 H, NMCH₃), 3.77 (d, J = 14.5, 1 H,

3.59 (d, J = 14.6, 1 H, NCCH_AH_E), 2.97 (s, 3H, NCH₃), 2.18 (d, J = 4.7, 3H, NHCH₃), 0.76 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCb): 5c = 171.5 (C=0), 159.4 (C=0), 158.5 (C_ArO), 141.4 (C_Ph), 137.0 (C_Pfl), 132.6 (2x CH_Ar), 129.0 (2xCHp_h), 128.7 (2x CHp_h), 128.2 (CH_PFL), 128.1 (CH_PH), 127.7 (C_Ar), 127.4 (2xCH_Ph), 125.6 (2xCH_Ph), 1 15.5 (2x CH_Ar), 81 .2 (CHC(CH₃)₃), 71.9 (NCCH₂), 70.1 (OCH₂Ph), 39.9 (NCCH₂), 37.8 (C(CH₃)₃), 31.9 (NCH₃), 27.0 (NHCH3), 26.6 (C(CH₃)₃); IR: v_max = 3432 (N-H), 2958, 2243 (C-H), 1694 (C=0), 1660 (C=0); HRMS (ESI⁺): m/z calcd for C₃₀H₃₅O₃N₃Na ([M+Na]⁺) 508.2570, found 508.2555. (2R,5ft)-2-(feAf-Butyl)-5-(4-hydroxybenz^

carboxamide (88)

[00289] Following a similar method to general procedure 6, KHMDS (1.26 mL, 1.26 mmol, 1.0 M in THF, 5.0 eq.) was added to a solution of 52 (100 mg, 0.253 mmol, 1.0 eq.) in THF (2.50 mL, 0.1 M). Purification by flash column chromatography (Si0₂, 3:1 EtOAc: Pet. Ether) gave the title compound (90 mg, 0.227 mmol, 90%) as a white solid. 88: ¹H NMR (500

MHz, CDC ): δ_Η = 7.38 - 7.33 (m, 2H, PhH), 7.32 - 7.28 (m, 3H, PhH), 7.28 - 7.25 (m, 2H, ArH), 6.77 - 6.73 (m, 2H, ArH), 6.70 (br. s, 1 H, OH), 5.61 (s, 1 H, CWC(CH₃)₃), 3.83 (br. q, J = 4.0, 1 H, NHCH₃), 3.69 (d, J = 14.7, 1 H, NCCH_AH_B), 3.64 (d, J = 14.7, 1 H, NCCH_AHB), 2.99 (s, 3H, NCH₃), 2.15 (d, J = 4.7, 3H, N HCH₃), 0.83 (s, 9H, C(CH₃)₃) ; ¹³C {¹H} NMR (125 MHz, CDCI₃): δ₀ = 171.8 (C=0), 159.6 (C=0), 156.3 (C_ArO), 141.0 (C_Ph), 132.6 (2xCH_Ar), 129.1 (2xCH_Pfl), 128.3 (CH_Ph), 126.6 (CAT), 125.7 (2xCH_Ph), 116.0 (2xCH_Ar), 81.5 (CHC(CH₃)₃), 72.2 (NCCH₂), 39.8 (NCCH₂), 37.9 (C(CH₃)₃), 32.1 (NCH₃), 27.1 (NHCH₃), 26.7 (C(CH₃)₃); IR: v_max = 3279 (O-H), 2960, 2540 (C-H), 1692 (C=0), 1644 (C=0); HRMS (ESI⁺): m/z calcd for C₂₃H₂₉0₃N₃Na ([M+Na]⁺) 418.2101 , found 418.2109.

(2R,5 )-5-((1-Benzyl-1H-indol-3-yl)methyl)-2-(ferf-butyl)-A/,3-dimethyl-4-oxo-5-(pyridin-2- yl)imidazolidine-1 -carboxamide (89)

[00290] Following a similar method to general procedure 6,

KHMDS (1.72 mL, 1.72 mmol, 1.0 M in THF, 2.5 eq.) was added to a solution of 53 (350 mg, 0.687 mmol, 1.0 eq.) in THF (7.00 mL, 0.1 M). Purification by flash column chromatography (Si0₂,

3:1 EtOAc: Pet. Ether) gave the title compound (315 mg, 0.618 mmol, 90%) as a white solid. 89: ¹H NMR (400 MHz, CDCb): δ_Η = 8.69 - 8.62 (m, 1 H, ArH),

8.07 - 7.97 (m, 1 H, ArH), 7.62 (td, J = 7.8, 1.9, 1 H, ArH), 7.39 (s, 1 Η, C=CH), 7.32 - 7.24 (m,

4Η, ArH), 7.21 - 7.10 (m, 6Η, ArH), 5.69 (s, 1 Η, CHC(CH₃)₃), 5.27 (s, 2H, NCH>Ph), 4.49 (d,

J = 15.1 , 1 Η,

4.06 (q, J = 4.8, 1 H, NHCH₃), 3.58 (d, J = 15.1 , 1 H, NCCH_AH_B), 3.07

(s, 3H, NCH₃), 1.74 (d, J = 4.6, 3H, N HCHj), 1.01 (s, 9Η, C(CH₃)₃); ¹³C {¹H} NMR (100 M Hz,

CDCb): δ₀ = 172.0 (C=0), 159.1 (C=0 and C_Ar), 148.5 (CH_Ar), 137.2 (C_Ar), 136.9 (CH_Ar), 136.2

(CAT), 129.9 (C=CH), 129.1 (CAT), 128.9 (2xCH_Ar), 127.9 (CH_Ar), 127.1 (2xCH_Ar), 122.6 (CH_Ar),

122.2 (CH_Ar), 120.8 (CH_Ar), 120.4 (CH_Ar), 119.8 (CH_Ar), 109.7 (CH_Ar), 109.1 (C=CH), 81.0

(CHC(CH₃)₃), 74.0 (NCCH₂), 50.3 (NCH₂Ph), 37.9 (C(CH₃)₃), 32.0 (NCH₃), 30.4 (NCCH₂), 26.7

(C(CH₃)₃), 26.3 (NHCH₃); IR: v_max = 3379 (N-H), 2957, 2930 (C-H), 1696 (C=0), 1667 (C=0);

HRMS (ESI⁺): m/z calcd for C₃i H₃₅0₂N₅Na ([M+Na]⁺) 532.2683, found 532.2684. Rearrangement to a-Phenylated Serine-Derived Acid and Hvdantoin

[00291] Following a similar method to general procedure 6, KHMDS (94 μΙ_, 0.094 mmol, 1.0 in THF) was added to a solution of 54 (20 mg, 0.062 mmol) in THF (0.60 mL) at -78 °C. The reaction was slowly allowed to warm to room temperature over 2 h and then stirred for a further 3 h. The crude product mixture was triturated with CHCb, leaving behind solid 90. The triturate liquor was concentrated in vacuo to give 91.

(2R,4S)-2-(ie/t-Butyl)-3-(methylcarbamoyl)-4-phenyloxazolidine-4-carboxylic acid (90)

[00292] The title compound (10 mg, 0.033 mmol, 52%) was yielded as a white solid without further purification. 90: ¹H NMR (400 MHz, CD₃OD): 5_H = 7.34 (d, J = 7.4, 2H, PhH), 7.28 (t, J = 7.3, 2H, PhH), 7.26 - 7.21 (m, 1 H,

PhH), 5.68 (s, 1 H, CHC(CH₃)₃), 4.89 (d, J = 9.0, 1 H, OCH_AH_B), 3.97 (d, J =

9.0, 1 H, OCH_AH_S), 2.23 (s, 3H, NHCH₃), 0.97 (s, 9H, C(CH₃)₃); ¹³C {¹H} N R (100 MHz, CD3OD): 5c = 179.7 (C=0), 161.7 (C=0), 144.7 (C_Ph), 129.3 (2xCH_Ph), 128.4 (CH_Ph), 127.0 (2xCHp_h), 99.4 (CHC(CH₃)₃), 80.8 (CH₂), 77.0 (CCH₂), 39.7 (C(CH₃)₃), 26.4 (C(CH₃)₃), 26.1 (NHCH₃); IR: v_max = 3361 (N-H and O-H), 3062, 3033, 2957, 2872 (C-H), 1592 (C=0); HR S (ESI⁺): m/z calcd for Ci6H220₄N₂Na ([M+Na]⁺) 329.1472, found 329.1470.

(3R,7aS)-3-(teAf-Butyl)-6-methyl-7a-phenyldihydro-3/-/,5H-imidazo[1 ,5-c]oxazole-5,7(6H)- dione (91)

[00293] The title compound (7 mg, 0.024 mmol, 39%) was yielded as colourless oil without further purification. 91 : ¹H NMR (400 MHz, CDCI3): δ_Η = 7.54 - 7.49 (m, 2H, PhH), 7.45 - 7.40 (m, 2H, PhH), 7.39 - 7.34 (m, 1 H, PhH),

4.52 (d, J = 8.6, 1 H, OCH„H_B), 4.25 (s, 1 H, CHC(CH₃)₃), 4.01 (d, J = 8.6, 1 H,

OCH_AH_B), 2.98 (s, 3H, NCH₃), 1.25 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCI₃): 5_C = 173.3 (C=0), 157.7 (C=0), 137.3 (C_Ph), 129.3 (2xCH_Ph), 129.0 (CH_Ph), 125.4 (2xCH_Ph), 98.9 (CHC(CH₃)₃), 73.5 (CCH₂), 73.4 (CH₂), 33.6 (C(CH₃)₃), 26.0 (C(CH₃)₃), 25.7 (NCH₃); IR: v_max = 2959, 2926, 2879 (C-H), 1784 (C=0), 1719 (C=0); HRMS (ESI⁺): m/z calcd for Ci6H₂i0₃N₂ ([M+H]⁺) 289.1547, found 289.1544.

Rearrangement to o-Fluorophenylated Serine-Derived Acid and Hvdantoin

Following a similar method to general procedure 6, KHMDS (0.25 mL, 0.247 mmol, 1.0 M in THF) was added to a solution of 55 (55 mg, 0.164 mmol) in THF (1.65 mL) at -78 °C. The reaction was slowly allowed to warm to room temperature over 2 h and then stirred for a further 3 h. The crude product mixture was triturated with CHCI3, leaving behind solid 92. The triturate liquor was concentrated in vacuo to give 93. (2R,4S)-2-(terf-Butyl)-4-(3-fluorophenyl)-3-(methylcarbamoyl)oxazolidine-4-carboxylic acid (92)

[00294] The title compound (29 mg, 0.089 mmol, 54%) was yielded as a white solid without further purification. 92: ¹H NMR (400 MHz, CD₃OD): δ_Η = 7.29 (td, J = 8.0, 6.2, 1 H, ArH), 7.16 (d, J = 8.0, 1 H, ArH), 7.09 (dt, J = 10.6, 1.9, 1 H, ArH), 6.98 (td, J = 8.3, 2.1 , 1 H, ArH), 5.68 (s, 1 Η,

CWC(CH₃)₃), 4.88 (d, J = 9.2, 1 H, OCH_AH_B), 3.97 (d, J = 9.2, 1 H, OCH_AH_B), 2.29 (s, 3H, NHCH , 0.96 (s, 9Η, C(CHj)₃); ¹³C {¹H} NMR (100 MHz, CD₃OD): 5_C = 178.9 (C=0), 164.1 (d, ¹JC-F = 244.5, C_ArF), 161.5 (C=0), 147.8 (d, ³J_C-F = 6.3, CAT), 131.0 (d, ³ _C-F = 8.4, CH_Ar), 122.8 (d, ⁴JC-F = 2.5, CH_Ar), 115.1 (d, ² _C-F = 21.4, CH_Ar), 1 14.0 (d, ²JC-F = 22.9, CH_Ar), 99.5 (CHC(CH₃)₃), 80.7 (CH₂), 76.6 (CCH₂), 39.7 (C(CH₃)₃), 26.4 (C(CH₃)₃), 26.2 (NHCH₃); IR: v_max = 3347 (N-H and O-H), 2957, 2872 (C-H), 1588 (C=0); HRMS (ESI⁺): m/z calcd for C16H22O4N2F ([M+H]⁺) 325.1558, found 325.1548.

(3R,7aS)-3-(teAf-Butyl)-7a-(3-fluorophenyl)-6-methyldihydro-3H5Himidazo[1 ,5-c]oxazole- 5,7(6H)-dione (93)

[00295] Purification by flash column chromatography (S1O2, DCM) gave the title compound (15 mg, 0.049 mmol, 30%) as a colourless oil. 93: R_f (DCM): 0.38; ¹H NMR (400 MHz, CDCI₃): δ_Η = 7.40 (td, J = 8.0, 5.8, 1 H,

ArH), 7.31 (dt, J = 8.0, 1.3, 1 Η, ArH), 7 '.27 - 7 '.22 (m, 1 Η, ArH), 7.06 (tdd, J = 8.3, 2.5, 0.8, 1 Η, ArH), 4.51 (d, J = 8.7, 1 Η, OCH_AH_B), 4.23 (s, 1 Η, CHC(CH₃)₃), 3.96 (d, J = 8.7, 1 H, OCH/Hs), 2.98 (s, 3Η, NCH₃), 1.25 (s, 9Η, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCIs): 5c = 172.8 (C=0), 163.2 (d, ¹J_C-F = 247.8, C_ArF), 157.6 (C=0), 139.8 (d, ³ _C-F = 7.6, CA_T), 131.0 (d, ³JC-F = 8.1 , CH_Ar), 121.2 (d, ⁴J_C-F = 2.9, CH_Ar), 116.0 (d, ²JC-F = 20.9, CH_Ar), 112.7 (d, ²Jc-_F = 23.5, CH_Ar), 99.3 (CHC(CH₃)₃), 73.4 (CCH₂), 73.2 (d, ⁴ _C-_F = 1.7, CH₂), 33.7 (C(CH₃)₃), 26.1 (C(CH₃)₃), 25.8 (NHCH₃); IR: v_max = 2961 , 2925, 2878 (C-H), 1787 (C=0), 1720 (C=0); HRMS (El): m/z calcd for Ci₂Hi₀O₃N₂F ([M-C₄H₉]⁺) 249.0670, found 249.0661.

Hydrolysis to Amino Acids and Hydantoins

(S)-2-Amino-2-phenylpropanoic acid (94)

Ph [00296] Urea 56 (48 mg, 0.158 mmol) was suspended in HCI (1.00 ml_, 6.0 M, H₂N C0₂H aq.) and refluxed at 130 °C in a sealed tube for 18 h. The cooled reaction mixture was concentrated in vacuo and NaOH (2.0 M, aq.) was added until pH = 14, before being refluxed at 130 °C in a sealed tube for 42 h. The cooled reaction mixture was reduced in vacuo and HCI (6.0 M, aq.) was added until pH < 3. The crude product was purified according to general procedure 8 to afford the title compound (20 mg, 0.121 mmol, 77%) as a white solid. 94: ¹H NMR (400 MHz, CD₃OD): δ_Η = 7.58 (d, J = 7.4, 2H, PhH), 7.43 (t, J = 7.3, 2Η, PhH), 7.40 - 7.34 (m, 1 Η, PhH), 1.89 (s, 3Η, CHj) ; ¹³C {¹H} NMR (100 MHz, CD₃OD): δ₀ = 175.3 (C=0), 140.1 (Cp_h), 129.9 (2xCH_Pfl), 129.7 (CH_Ph), 127.0 (2xCH_Ph), 63.8 (CCH₃), 22.6 (CCH₃); IR: Vmax = 3062, 2978 (NH₃ ⁺ and C-H), 1593 (COO^" asym.), 1389 (COO^" sym.); HRMS (ESI⁺): m/z calcd for C₉Hi₂0₂N ([M+H]⁺) 166.0868, found 166.0869. Data in agreement with reported values.¹²

Hydrolysis of a-Chlorophenyl Alanine-Derived Urea

[00297] Following general procedure 8, urea 59 (619 mg, 1.83 mmol) was suspended in HCI (10.0 ml_, 6.0 M, aq.) and hydrolysed to give:

(ft)-2-Amino-2-(4-chlorophenyl)propanoic acid (95)

[00298] 95 (306 mg, 1.53 mmol, 84%) as a white solid: ¹H NMR (400 MHz,

CD₃OD): δ_Η = 7.57 - 7.53 (m, 2H, ArH), 7.44 - 7.39 (m, 2H, ArH), 1.86 (s, 3H, CH₃); ¹³C {¹H} NMR (125 MHz, CD₃OD): 5_C = 175.1 (C=0), 139.4 (CAT),

135.5 (C_Ar), 129.8 (2xCH_Ar), 128.9 (2xCH_Ar), 63.6 (CCH₃), 22.8 (CCH₃); IR: Vmax = 3012, 2979 (NH₃ ⁺ and C-H), 1596 (COO^" asym.), 1390 (COO^" sym.); HRMS (ESI⁺): m/z calcd for C9H11O2N2CI ([M+H]⁺) 200.0473, found 200.0467.

(f?)-5-(4-Chlorophenyl)-3,5-dimethylimidazolidine-2,4-dione (96)

[00299] 96 (51 mg, 0.214 mmol, 12%) as a white solid, purified by flash column chromatography (Si0₂, 1 :1 Pet. Ether: EtOAc): R_f (1 :1 Pet. Ether: EtOAc): 0.31 ; ¹H NMR (500 MHz, CDCI₃): δ_Η = 7.49 - 7.43 (m, 2H, ArH), 7.39 - 7.33 (m, 2H, ArH), 6.40 (br. s, 1 H, NH), 3.02 (s, 3H, NCH₃), 1.81

(s, 3H, CCH₃); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5_C = 175.1 (C=0), 157.0

(C=0), 137.3 (C_Ar), 134.8 (C_Ar), 129.2 (2xCH_Ar), 126.9 (2xCH_Ar), 63.6 (CCH₃), 26.0 (CCH₃), 25.1 (NCH₃); IR: v_max = 3274 (N-H), 2923, 2850 (C-H), 1763 (C=0), 1703 (C=0); HRMS (ESr): m/z calcd for C11 H10O2N2CI ([M-H]^") 237.0436, found 237.0427.

Hydrolysis of a-Chlorophenyl Phenylalanine-Derived Urea

[00300] Following general procedure 8, 68 (480 mg, 1.16 mmol) was suspended in aqueous HCI (10.0 ml_, 6 M) and hydrolysed to give:

( ?)-2-Amino-2-(4-chlorophenyl)-3-phenylpropanoic acid (97)

id: H NMR (500 MHz, 8.5, 2H, ArH), 7.31 - 3.44 (d, J = 14.1 , 1 H,

= 169.1 (C=0), 139.1 (CAT), 135.6 (C_PH), 131.8 (CAT), 130.7 (2xCH_Ph), 128.3 (2xCH_Ar), 128.0 (2xCH_Pfl), 127.6 (2xCH_Ar), 126.7 (CHph), 66.0 (NCCH₂), 43.2 (NCCH₂); HRMS (ESI⁺): m/z calcd for Ci₅Hi₅0₂N ([M+H]⁺) 276.0786, found 276.0780. ( ?)-5-Benzyl-5-(4-chlorophenyl)-3-met ylimidazolidine-2,4-dione (98)

.356 mmol, 31 %) as a white solid: ¹H NMR (400 M Hz, = 8.7, 2H, ArH), 7.40 - 7.33 (m, 3H, ArH and NH), 7.29 7.09 - 7.00 (m, 2H, P H), 3.45 (d, J = 13.7, 1 H, = 13.6, 1 H, CH_AH_ePh), 2.82 (s, 3H, NCH₃); ¹³C {¹ H}

₃): δ₀ = 174.2 (C=0), 157.2 (C=0), 136.2 (CA_T), 134.7 (CA_T), 133.7 (C_PH), 130.2 (2xCH_Ph), 129.0 (2xCH_Ar), 128.5 (2xCH_Ph), 127.8 (CH_Ph), 127.3 (2xCH_Ar), 67.7 (NCCH₂), 45.7 (NCCH₂), 24.7 (NCH₃); IR: v_max = 3262 (N-H), 2917 (C-H), 1770 (C=0), 1697 (C=0); HRMS (ESI⁺): m/z calcd for Ci7Hi50₂N₂CINa [M+Na]⁺ 337.0714; found 337.0709.

Hydrolysis of a-Fluorophenyl Phenylalanine-Derived Urea

[00303] Following general procedure 8, 69 (350 mg, 0.881 mmol) was suspended in aqueous HCI (10.0 ml_, 6 M) and hydrolysed to give:

( R)-2-Amino-2-(4-fluorophenyl)-3-phenylpropanoic acid (99)

[00304] 99 (98 mg, 0.378 mmol, 43%) as a white solid: ¹H NM R (500 MHz,

CD3OD): δ_Η = 7.74 - 7.69 (m, 2H, ArH), 7.33 - 7.27 (m, 5H, PhH), 7.20 - 7.14 (_m_ 2H, ArH), 3.71 (d, J = 14.1 , 1 H, CH_AH_BPh), 3.49 (d, J = 14.0, 1 H,

CH_AH_BPh); ¹³C {¹H} NMR (125 MHz, CD3OD): 5_C = 173.7 (C=0), 164.0 (d, ¹ C-F = 246.6, C_ArF), 135.9 (d, ⁴ _C-F = 3.1 , CAT) , 135.7 (C_PH) , 131.7 (2xCH_Pfl), 129.8 (2xCH_Pfl), 129.8 (d, ³JC-F = 8.1 , 2xCH_Ar), 128.7 (CH_Ph), 1 16.4 (d, ²J_C-F = 21.8, 2xCH_Ar), 68.2 (NCCH2), 43.3 (NCCH2); HRMS (ESF): m/z calcd for C15H13O2N ([M-H]-) 258.0936, found 258.0940.

(f?)-5-Benzyl-5-(4-fluorophenyl)-3-methylimidazolidine-2,4-dione (100)

,

, 133.8 (CPh), 133.5 (d, ⁴J_C-_F = 3.1 , CAT), 130.2 (2xCH_Ph), 128.5 (2xCH_Pfl), 127.8 (CH_Ph), 127.7 (d, ³JC-F = 8.3, 2xCH_Ar), 115.7 (d, ²JC-F = 21.6, 2xCH_Ar), 67.6 (NCCH₂), 45.8 (NCCH₂), 24.7 (NCH₃); IR: Vmax = 3274 (N-H), 2922 (C-H), 1770 (C=0), 1694 (C=0); HRMS (ESI⁺): m/z calcd for Ci₇Hi₅0₂N₂Na ([M+Na]⁺) 321.1010, found 321.1011.

Hydrolysis of a-Tolyl Phenylalanine-Derived Urea

[00306] Following general procedure 8, 70 (422 mg, 1.07 mmol) was suspended in aqueous HCI (10.0 ml_, 6 M) and hydrolysed to give: (f?)-2-Amino-3-phenyl-2-(p-tolyl)propanoic acid (101)

a white solid: ¹H NMR (500 MHz, 29 (s, 5H, PhH), 7.25 (d, J = 8.0, 3.46 (d, J = 14.2, 1 H, CH_AH_ePh),

CD₃OD): 5_C = 174.0 (C=0), 139.6 (CAT), 136.9 (CAT), 135.9 (C_PH), 131.7 (2xCH_Ph), 130.3 (2xCH_Ar), 129.7 (2xCH_Ph), 128.6(CH_Ph), 127.3 (2xCH_Ar), 68.5 (NCCH₂), 43.2 (NCCH₂), 21.0 (CH₃); HRMS (ESI-): m/z calcd for Ci₆Hi₆0₂N ([M-H]-) 254.1187, found 254.1188.

(R)-5-Benzyl-3-methyl-5-(p-tolyl)imidazolidine-2,4-dione (102)

[00308] 102 (89 mg, 0.302 mmol, 28%) as a white solid: ¹H NMR (400 MHz, CDC ): δ_Η = 7.49 (d, J = 8.3, 2H, ArH), 7.26 - 7.22 (m, 3H, PhH), 7.20 (d, J =

8.2, 2H, ArH), 7.09 - 7.05 (m, 2H, PhH), 7.01 (s, 1 H, NAT), 3.48 (d, J = 13.6, 1 H, CWxH_BPh), 3.27 (d, J = 13.6, 1 H, CH_AH_BPh), 2.80 (s, 3H, NCH₃), 2.36 (s,

3H, O/3); ¹³C {¹H} NMR (100 MHz, CDCI3): 5_C = 174.6 (C=0), 157.1 (C=0), 138.4 (CAT), 134.7 (CAT), 134.1 (C_PH), 130.3 (2xCH_Ph), 129.5 (2xCH_Ar), 128.4 (2xCH_Ph), 127.6 (CHph), 125.6 (2xCH_Ar), 67.9 (NCCH₂), 45.3 (NCCH₂), 24.6 (NCH₃), 21.2 (CH₃); IR: v_max = 3285 (N-H), 2923, 2852 (C-H), 1766 (C=0), 1693 (C=0); HRMS (ESI⁺): m/z calcd for Ci₈Hi802N₂Na ([M+Na]⁺) 317.1260, found 317.1261.

(ft)-4-(1-Amino-1-carboxy-3-methylbutyl)benzoic acid (103)

Following general procedure 8, urea 79 (515 mg, 1.39 mmol) was suspended in HCI (10.0 ml_, 6.0 M, aq.) and hydrolysed to give the title compound (174 mg, 0.692 mmol, 50%) as a white solid. 103: ¹H NMR

(400 MHz, CD₃OD): δ_Η = 7.98 - 7.94 (m, 2H, ArH), 7.61 - 7.56 (m, 2Η, ArH), 2.28 (dd, J = 14.7, 6.8, 1 Η,

2.22 (dd, J = 14.7, 5.4, 1 Η, CH_AH_SCH), 1.90 - 1.73 (m, 1 H, CH₂CH(CH₃)₂), 1.02 (d, J = 6.6, 3H, CH(CH₃HCH₃)B), 0.93 (d, J = 6.6, 3H, CH(CH₃)A(CH₃)S); ¹³C {¹H} NMR (100 MHz, CD₃OD): 5_C = 174.6 (C=0), 174.3 (C=0), 143.0 (CAT), 138.5 (CAT), 130.5 (2xCH_Ar), 126.6 (2xCH_Ar), 67.8 (NCCH₂), 46.1 (NCCH₂), 25.5 (CH(CH₃)₂), 25.0 (CH(CH₃)A(CH3)B), 23.8

IR: v_max = 2956, 2932, 2869 (N H₃ ⁺ and C-H), 1596 (COO^" asym.), 1380 (COO^" sym.); HRMS (ESI⁺): m/z calcd for C₁₃H₁₈0₄N ([M+H]⁺) 252.1230, found 252.1226.

Hydrolysis of a-Chlorophenyl Leucine-Derived Urea

[00309] Following general procedure 8, urea 80 (429 mg, 1.13 mmol) was suspended in HCI (10.0 ml_, 6.0 M, aq.) and hydrolysed to give: (f?)-2-Amino-2-(4-chlorophenyl)-4-methylpentanoic acid (104)

[00310] 104 (1 13 mg, 0.467 mmol, 41%) as a white solid: ¹H NMR (400 MHz, CD₃0D): δ_Η = 7.59 - 7.52 (m, 2H, ArW), 7.42 - 7.35 (m, 2H, ArH), 2.25 (dd, J = ^{4 7} _> ^{6 9} _> ^{1 H} _> CHAHBCH), 2.17 (dd, J = 14.7, 5.3, 1 H, CH_AH_ECH), 1.89 -

1.74 (m, 1 H, CH₂CH(CH₃)₂) , 1.02 (d, J = 6.6, 3H, CH(CH₃)MCH₃)B), 0.94 (d, J = 6.6, 3H, CH(CH₃)A(CW₃)B); ¹³C {¹H} NMR (100 MHz, CD₃OD): 5_C = 174.2 (C=0), 139.7 (CAT), 135.2 (CAT), 129.6 (2xCH_Ar), 129.0 (2xCH_Ar), 67.3 (N CCH₂), 46.0 (NCCH₂), 25.5 (CH(CH₃)₂), 25.0 (CH(CH₃)_A(CH₃)e), 23.8 (CH(CH₃WCH₃)_B); IR: v_max = 2960, 2929, 2872 (N H₃ ⁺ and C-H) , 1606 (COO^" asym.), 1376 (COO^" sym.); HRMS (ESI⁺): m/z calcd for Ci₂Hi₇0₂NCI ([M+H]⁺) 242.0942, found 242.0932.

(f?)-5-(4-Chlorophenyl)-5-isobutyl-3-methylimidazolidine-2,4-dione (105)

10 mmol, 36%) as an off-white solid, purified by graphy (Si0₂, 3:1 Pet. Ether: EtOAc): R_f (3:1 NMR (500 MHz, CDCI₃): δ_Η = 7.57 - 7.48 (m, 3H, 1 (m, 2H, ArH), 3.00 (s, 3H, NCtf₃), 2.10 (dd, J =

2.03 (dd, J = 14.5, 7.3, 1 H, CH_AH_BCH), 1.71 - 1.59 (m, 1 H, CH₂CH(CH₃)₂), 0.88 (d, J = 6.6, 3H, CH(CH₃HCH₃)_B), 0.85 (d, J = 6.7, 3H, CH(CH₃)_A(CH₃)e); ¹³C {¹H} NMR (125 MHz, CDCI₃): 5_C = 175.1 (C=0), 157.7 (C=0), 137.2 (CAT), 134.5 (CAT), 129.0 (2xCH_Ar), 127.0 (2xCH_Ar), 67.1 (NCCH₂), 47.6 (NCCH₂), 25.0 (N CH₃), 24.8 (CH(CH₃)₂), 24.2 (CH(CH₃)_A(CH₃)_B), 23.2 (CH(CH₃)^(CH₃)_B); IR: v_max = 3280 (N-H), 2957, 2872 (C-H), 1773 (C=0), 1707 (C=0); HRMS (ESI⁺): m/z calcd for Ci₄Hi₈0₂N₂CI ([M+H]⁺) 281.1051 , found 281.1049.

Hydrolysis of a-Fluorophenyl Leucine-Derived Urea

[00312] Following general procedure 8, urea 81 (436 mg, 1.20 mmol) was suspended in HCI (10.0 ml_, 6.0 M, aq.) and hydrolysed to give:

(f?)-2-amino-2-(4-fluorophenyl)-4-methylpentanoic acid (106)

[00313] 106 (89 mg, 0.395 mmol, 33%) as a white solid: ¹H NMR (400 MHz, CD₃OD): 5H = 7.63 - 7.56 (m, 2H, ArH), 7.15 - 7.07 (m, 2H, ArH), 2.26 (dd, J

= 14.7, 6.9, 1 H, CH_/,HBCH), 2.18 (dd, J = 14.7, 5.2, 1 H, CH_AH_BCH), 1.90 -

5 _(rri] H, CH₂CH(CH₃)₂), 1.02 (d, J = 6.6, 3H, CH(CH₃MCH₃)_B), 0.95 (d, J = 6.6, 3H, CH(CH₃)_A(CH₃)_B); ¹³C {¹H} NMR (100 M Hz, CD₃OD): 5_C = 174.5 (C=0), 163.9 (d, ¹ JC-F = 246.4, C_ARF), 137.0 (d, ⁴J_C-F = 3.1 , CAT), 129.5 (d, ³J_C-F = 8.3, 2xCH_Ar), 116.2 (d, ²J_C-F = 21.7, 2xCH_Ar), 67.3 (N CCH₂), 46.0 (NCCH₂), 25.5 (CH(CH₃)₂), 25.0 (CH(CH₃)_A(CH₃)_B, 23.8 (CH(CH₃)4CH₃)_B); IR: v_max = 2960, 2932, 2872 (N H₃ ⁺ and C-H), 1630 (COO^" asym.), 1366 (COO^" sym.); HRMS (ESI⁺): m/z calcd for Ci₂Hi₇0₂N F ([M+H]⁺) 226.1238, found 226.1230. ( ?)-5-(4-Fluorophenyl)-5-isobutyl-3-methylimidazolidine-2,4-dione (107)

flash (3: 1 , 2H, 2.03

1.64

- 1.52 (m, 1 H, CH₂CH(CH₃)₂), 0.82 (d, J = 6.6, 3H, CH(CH₃)A(CH₃)_b), 0.78 (d, J = 6.7, 3H, CH(CH₃)A(CH₃)_b); ¹³C {¹H} NMR (125 MHz, CDCb): 5_C = 175.3 (C=0), 162.7 (d, ¹ _C-F = 247.9, C_ArF), 157.7 (C=0), 134.5 (d, ⁴JC-F = 2.9, CAT), 127.3 (d, ³J_C-F = 8.2, 2xCH_Ar), 115.7 (d, ²J_C__F = 21.4, 2x CH_Ar), 67.0 (NCCH₂), 47.7 (NCCH₂), 24.9 (NCH₃), 24.8 (CH(CH₃)₂), 24.2 (CH(CH₃)_A(CH₃)S), 23.2 (CH(CH₃^(CH₃)_B); IR: v_max = 3280 (N-H), 2958, 2872 (C-H), 1773 (C=0), 1704 (C=0); HRMS (ESI^"): m/z calcd for Ci₄Hi₆0₂N₂F ([M-H]^") 263.1 190, found 263.1 193.

Hydrolysis of a-Tolyl Leucine-Derived Urea

[00315] Following general procedure 8, urea 82 (320 mg, 0.890 mmol) was suspended in HCI (10.0 ml_, 6.0 M, aq.) and hydrolysed to give:

(ft)-2-Amino-4-methyl-2-(p-tolyl)pentanoic acid (108)

b [00316] 108 (37 mg, 0.167 mmol, 19%) as a white solid: ¹H NMR (500 MHz,

/ CDaOD): δ_Η = 7.47 - 7.42 (m, 2H, ArH), 7.19 (d, J = 8.1 , 2H, ArH), 2.32 (s, 3H, j/ \ CH₃), 2.25 (dd, J = 14.7, 6.8, 1 H, CH,H_BCH), 2.20 (dd, J = 14.7, 5.3, 1 H, H₂N C0₂H Q_{HAHSCH)] 1 88} _ ₁ 75 ^ _{1 H ]} CH₂CH(CH₃)₂), 1.02 (d, J = 6.6, 3H,

CH(CH₃) ,(CH₃)_B), 0.93 (d, J = 6.6, 3H , CH(CH₃)_a(CH₃)B); ¹³C {¹ H} NMR (100 MHz, CD₃OD): 5c = 174.9 (C=0), 139.2 (C_AR), 137.9 (CM), 130.2 (2 <CH_Ar), 127.1 (2xCH_Ar), 67.6 (NCCH₂), 45.8 (NCCH₂), 25.5 (CH(CH₃)₂), 25.1 (CH(CH₃)_A(CH₃)_B), 23.8 (CH(CH₃) ,(CH₃)_B), 21.0 (CH₃); IR: Vmax = 2956, 2926, 2869 (NH₃ ⁺ and C-H), 1602 (COO^" asym.), 1377 (COO- sym.); HRMS (ESI⁺): m/z calcd for Ci₃H₂₀O₂N ([M+H]⁺) 222.1489, found 222.1482.

(R)-5-lsobutyl-3-methyl-5-(p-tolyl)imidazolidine-2,4-dione (109)

[00317] 109 (140 mg, 0.538 mmol, 60%) as an off-white solid, purified by flash column chromatography (Si0₂, 3: 1 Pet. Ether: EtOAc): R_f (3: 1 Pet. Ether: EtOAc): 0.26; ¹H NMR (500 MHz, CDCb): δ_Η = 7.45 (d, J = 8.3, 2H, ArH), 7.41 (br. s, 1 Η, NH), 7.17 (d, J = 8.2, 2Η, ArH), 2.98 (s, 3Η, NCH₃), 2.33 (s, 3Η, CH>), 2.12

(dd, J = 14.5, 5.5, 1 Η, CH_AH_BCH), 2.05 (dd, J = 14.5, 7.3, 1 Η, CH_AH_BCH), 1.74

- 1.61 (m, 1 H, CH₂CH(CH₃)₂), 0.89 (d, J = 6.6, 3H, CH(CH₃)A(CH₃)_b), 0.86 (d, J = 6.7, 3H, CH(CH₃)_a(CH₃)B); ¹³C {¹ H} NMR (125 MHz, CDCb): δ₀ = 175.5 (C=0), 157.8 (C=0), 138.1 (CA_T), 135.7 (C_AR), 129.5 (2xCH_Ar), 125.3 (2x CH_Ar), 67.3 (NCCH₂) , 47.3 (NCCH₂), 24.8 (NCH₃ and CH(CH₃)₂), 24.2 (CH(CH₃)_A(CH₃)_S), 23.2 (CH(CH₃)„(CH₃)_B), 21 .1 (CH₃); IR: v_max = 3270 (N-H), 2956, 2871 (C-H), 1772 (C=0), 1704 (C=0); HRMS (ESI⁺): m/z calcd for Ci5H₂o0₂N₂Na ([M+Na]⁺) 283.1417, found 283.1414.

(f?)-4-(1-Amino-1-carboxy-3-(methylthio)propyl)benzoic acid (110)

[00318] Following general procedure 8, urea 83 (277 mg, 0.713 mmol) was suspended in HCI (10.0 ml_, 6.0 M, aq.) and hydrolysed to give the title compound (64 mg, 0.238 mmol, 33%) as a white solid. 110: ¹ H NMR

(400 MHz, CD₃OD): 5_H = 7.98 (d, J = 8.5, 2H, ArH), 7.57 (d, J = 8.5, 2H, ArH), 2.62 - 2.50 (m, 4H, CH>CH₂SCH₃), 2.13 (s, 3H, SCHs); ¹³C {¹H} NMR (100 MHz, CD3OD): 5c = 174.1 (C=0), 173.8 (C=0), 141.9 (CAT), 138.6 (CAT), 130.7 (2xCH_Ar), 126.8 (2xCH_Ar), 67.8 (NCCH₂), 37.7 (NCCH₂), 29.3 (CH₂SCH₃), 15.2 (SCH₃); IR: v_max = 2969, 2916 (NH₃ ⁺ and C-H), 1589 (COO^" asym.), 1376 (COO^" sym.); HRMS (ESI⁺): m/z calcd for Ci₂Hi₆0₄NS ([M+H]⁺) 270.0795, found 270.0787.

Hydrolysis of a-Chlorophenyl Methionine-Derived Urea

[00319] Following general procedure 8, urea 84 (373 mg, 0.937 mmol) was suspended in HCI (10.0 ml_, 6.0 M, aq.) and hydrolysed to give:

(R)-2-Amino-2-(4-chlorophenyl)-4-(methylthio)butanoic acid (111)

[00320] 11 1 (133 mg, 0.512 mmol, 55%) as a white solid: ¹H NMR (400 MHz, CD₃OD): δ_Η = 7.57 - 7.51 (m, 2H, ArH), 7.42 (d, J = 8.6, 2H, ArH), 2.61 - 2.47 (m, 4Η, CH>CH?SCH₃), 2.13 (s, 3H, SCH₃); ¹³C {¹ H} N MR (100

MHz, CD₃OD): 5_C = 173.4 (C=0), 138.5 (CAT), 135.5 (CAT), 129.9 (2xCH_Ar),

129.1 (2xCH_Ar), 67.4 (NCCH₂), 37.6 (NCCH₂), 29.3 (CH₂SCH₃), 15.3 (SCH₃); IR: v_max = 3048,

2965, 2917 (NH₃ ⁺ and C-H), 1601 (COO^" asym.), 1373 (COO^" sym.); HRMS (ESI⁺): m/z calcd for Cii Hi₅0₂NCIS ([M+H]⁺) 260.0507, found 260.0500.

(f?)-5-(4-Chlorophenyl)-3-methyl-5-(2-(methylthio)ethyl)imidazolidine-2,4-dione (112)

[00321 ] 112 (63 mg, 0.211 mmol, 22%) as an off-white solid, purified by f^lasn column chromatography (Si0₂, 3:1→2: 1 Pet. Ether: EtOAc): R_F (3:1 Pet. Ether: EtOAc): 0.29; ¹H NMR (500 MHz, CDCI₃): δ_Η = 7.73 (br. s, 1 H, NH), 7.57 - 7.46 (m, 2Η, ArH), 7.41 - 7.30 (m, 2Η, ArH), 3.00 (s, 3Η,

NCtf₃), 2.50 - 2.31 (m, 4Η, CH₂CH₂SCH₃), 2.06 (s, 3H, SCH₃); ¹³C {¹ H}

NM R (125 MHz, CDCI₃): 5_C = 174.3 (C=0), 157.5 (C=0), 135.8 (CAT), 134.8 (CAT), 129.2 (2xCH_Ar), 127.0 (2xCH_Ar), 66.8 (NCCH₂), 37.9 (NCCH₂), 28.7 (CH₂SCH₃), 25.1 (NCH₃), 15.5 (SCH₃); IR: v_max = 3280 (N-H), 2917, 2852 (C-H), 1775 (C=0), 1703 (C=0); HRMS (ESI⁺): m/z calcd for Ci₃Hi₅0₂N₂CISNa ([M+Na]⁺) 321.0435, found 321.0434. Additional examples

(2S,5 )-5-Benzyl-5-(3-bromophenyl)-2-(teAf-butyl)-A/,3-dimethyl-4-oxoimidazolidin carboxamide (113)

[00322] Following general procedure 7, a solution of frans-18 (535 mg, 1-73 mmol) and 3-bromo-V-methylaniline (0.26 ml_, 2.08 mmol) in THF (17.0 mL) was treated with 2 portions of KHMDS (2x2.60 mL, 5.19 mmol,

1.0 M in THF). Purification by flash column chromatography (S1O2, 2:1→9:1 Et₂0: Pet. Ether) gave the title compound (644 mg, 1.40 mmol, 81%) as a white solid. 113: ¹H NMR (400 MHz, CDC ): δ_Η = 7.56 (t, J= 1.9, 1H, ArH), 7.42 (ddd, J= 7.9, 1.9, 1.1, 1H, ArH), 7.44-7.37 (m, 2H, PhH), 7.35-7.27 (m, 3H, Ph ), 7.23 (t, J =7.9, 1H, Ar^/), 7.16 (ddd, J= 8.0, 2.0, 1.1, 1H, ArH), 5.57 (s, 1H, C 7C(CH₃)₃), 3.84 (br. s, 1H, NHCH3), 3.80 (d, J = 14.3, 1 H, C^HsPh), 3.60 (d, J = 14.4, 1 H, CH_AH_BPh), 2.99 (s, 3H, NCH₃), 2.26 (d, J = 4.7, 3H, NHC/-/3), 0.74 (s, 9H, C(C 7₃)₃); ¹³C {¹H} NMR (125 MHz, CDCb): 5_C= 170.8 (C=0), 159.1 (C=0), 143.7 (C_Ar), 135.1 (CA_T), 131.5 (2xCH_Ar), 131.4 (CH_Ar), 130.5 (CH_Ar), 129.1 (2xCH_Ar), 128.0 (CH_Ar), 124.2 (CH_Ar), 123.2 (C_ArBr), 81.2 (CHC(CH₃)₃), 71.6 (CCH₂Ph), 41.0 (CH₂Ph), 37.7 (C(CH₃)₃), 31.9 (NCH₃), 27.1 (NHCH₃), 26.5 (C(CH₃)₃); HRMS (ESI⁺): m/z calcd for C₂₃H290₂N₃Br ([M+H]⁺) 458.1438, found 458.1431.

(2S,5 )-5-Benzyl-5-(3,5-dichlorophenyl)-2-(te/-butyl)-A/,3-dimethyl-4-oxoimidazolidine-1- carboxamide (114)

[00323] Following general procedure 7, a solution of trans- Ζ (535 mg, 1.73 mmol) and 3,5-dichloro-/V-methylaniline (366 mg, 2.08 mmol) in THF (17.00 mL) was treated with 2 portions of KHMDS (2x2.60 mL, 5.20 mmol, 1.0 M in THF). Purification by flash column chromatography (S1O2,

1:1→8:1 Et₂0: Pet. Ether) gave the title compound (653 mg, 1.46 mmol, 84%) as a white solid.114: ¹H NMR (400 MHz, CDCI3): δ_Η = 7.38-7.34 (m, 2H, ArH), 7.33- 7.26 (m,4H, ArH), 7.18 (d, = 1.8.2H, ArH), 5.54 (s, 1H, CHC(CH₃)₃), 3.97 (br. s, 1H, NWCH₃), 3.74 (d, J= 14.3, 1H, CH_{A B}Ph), 3.59 (d, J= 14.4, 1H, CH_Att_sPh), 2.97 (s, 3H, NCH₃), 2.30 (d, J = 4.4, 3H, NHC-3), 0.71 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (100 MHz, CDCb): 5_C= 170.3 (C=0), 158.7 (C=0), 144.8 (CAT), 135.6 (2xC_Ar), 134.8 (C_Ph), 131.4 (2xCH_Ar), 129.1 (2xCH_Ar), 128.5 (CH_Ar), 128.1 (CH_Ar), 124.5 (2xCH_Ar), 81.1 (CHC(CH₃)₃), 71.5 (CCH₂Ph), 41.0 (CH₂Ph), 37.7 (C(CH₃)₃), 31.9 (NCH₃), 27.1 (NHCH₃), 26.4 (C(CH₃)₃); HRMS (ESI⁺): m/z calcd for C2₃H₂80₂N₃Cl2 ([M+H]⁺) 448.1553, found 448.1548. (2R,5ft)-2-(feAf-Butyl)-A/,3-dimeth^

carboxamide (1 15)

[00324] Following a similar method to general procedure 7, a solution of frans-19 (40 mg, 0.136 mmol) and W-methylbenzen-cfs-amine (32 mg, 0.271 mmol, 2.0 eq.) in THF (1.4 mL) was treated with 2 portions of KHMDS (2x0.27 mL, 0.271 mmol, 1.0 M in THF, 4.0 eq.). Purification by

flash column chromatography (S1O₂, 9:1→1 :9 Pet. Ether: EtOAc) gave the title compound (40 mg, 0.109 mmol, 80%) as awhite solid. 115: ¹ H NMR (400 MHz, CDCI3): δ_Η = 8.00 - 7.90 (m, 2H, PhH), 7.52 - 7.44 (m, 2H, PhH), 7.44 - 7.39 (m, 1 H, PhH), 5.82 (s, 1 H, CHC(CH₃)₃), 3.93 (q, J = 4.7, 1 H, NHCH3), 3.14 (s, 3H, NCH₃), 2.18 (d, J = 4.8, 3H, NHCH3), 0.93 (s, 9H, C(CH₃)₃); ¹³C {¹ H} NMR (100 MHz, CDCI3): 5_C = 171.7 (C=0), 158.6 (C=0), 142.4 (CAT), 137.2 (C_Ph), 128.9 - 127.6 (m, 4xCH_Ar and 5xCH_Pri), 126.5 (t, ¹ _C__D = 24.0, ΟΗΑΓ), 80.4 (CHC(CH₃)3), 72.8 (NCPh), 38.4 (C(CH₃)3), 32.1 (NCH₃), 27.0 (NHCH3), 26.6 (C(CH₃)3); HRMS (ESI⁺): m/z calcd for C22H22D₅02N₃Na ([M+Na]⁺) 393.2309, found 393.2309.

(2S,5 ?)-5-(4-(Benzyloxy)benzyl)-2-(te/f-butyl)-/V-ethyl-3-methyl-5-(naphthalen-1-yl)-4- oxoimidazolidine-1 -carboxamide (116)

[00325] Following general procedure 7, a solution of trans-ΐλ (150 mg, 0.362 mmol) and A/-ethyl-1-naphthylamine (74 mg, 0.432 mmol) in THF (3.60 mL) was treated with 2 portions of

KHMDS (2x0.54 mL, 1.08 mmol, 1.0 M in THF). Purification by

flash column chromatography gave the title compound (123 mg,

0.224 mmol, 62%) as a white solid. 116: ¹ H NM R (500 MHz, CDCI₃): δ_Η = 8.14 (d, J = 7.4, 1 H,

ArH), 7.79 - 7.74 (m, 2H, ArH), 7.72 (d, J = 8.4, 2H, ArH), 7.49 - 7.44 (m, 1 H, ArH), 7.44 -

7.35 (m, 6H, ArH), 7.34 - 7.31 (m, 1 H, ArH), 7.29 (t, J = 7.4, 1 H, ArH), 6.98 (d, J = 8.8, 2H,

ArH), 5.93 (s, 1 H, CHC(CH₃)₃), 5.11 - 5.03 (m, 2H, OCH₂Ph), 3.97 (d, J = 15.6, 1 H, NCCH ,H_B),

3.62 (d, J = 15.6, 1 H, NCCH_AH_B), 3.48 (t, J = 5.6, 1 H, NHCH₂), 3.22 (s, 3H, NCH₃), 2.30 - 2.15

(m, 2H, NHCH2CH3), 1.28 (s, 9H, C(CH₃)₃), -0.27 (t, J = 7.2, 3H, NHCH2CH3); ¹³C {¹ H} NM R

(125 MHz, CDC ): δ₀ = 173.3 (C=0), 158.2 (C_ArO), 157.2 (C=0), 136.9 (C_Ar), 134.9 (C_Ar),

134.8 (C_Ar), 132.6 (2xCH_Ar), 131.3 (C_Ar), 130.1 (CH_Ar), 129.5 (CH_Ar), 128.7 (2xCH_Ar), 128.2

(CAT), 128.1 (2xCH_Ar), 127.5 (2xCH_Ar), 127.0 (CH_Ar), 125.9 (CH_Ar), 124.5 (CH_Ar), 122.5 (CH_Ar),

115.2 (2xCH_Ar), 82.1 (CHC(CH₃)3), 70.8 (NCCH₂), 70.1 (OCH₂Ph), 42.6 (NCCH₂), 38.4

(C(CH₃)3) , 34.6 (N HCH2CH3), 32.2 (NCH₃), 27.9 (C(CH₃)₃), 13.5 (NHCH2CH3); HRMS (ESI⁺): m/z calcd for CssHsgOsNsNa ([M+Na]⁺) 572.2884, found 572.2880. (2S,5ft)-5-(4-(Benzyloxy)benzyl)-2-(terf-butyl)-5-(2-methoxyphen

oxoimidazolidine-1-carboxamide (117)

[00326] Following general procedure 7, a solution of frans-21 (^{200 mg}' ^{0482 mmo1}) ^and 2-methoxy-/V-methylaniline (79 mg,

0.576 mmol) in THF (4.80 mL) was treated with 2 portions of KHMDS (2x0.72 mL, 1.45 mmol, 1.0 M in THF). Purification by

flash column chromatography gave the title compound (149 mg,

0.289 mmol, 60%) as a white solid.117: ¹H N R (500 MHz, CDCb): δ_Η = 7.70 (d, J = 7.8, 1H, ArH), 7.47 (d, J = 8.2, 2H, ArH), 7.41 (d, J =7.0, 2H, ArH), 7.37 (t, J =7.5, 2H, ArH), 7.31 (t, J = 7.0, 1H, ArH), 7.22 (t, J= 7.8, 1H, ArH), 6.96-6.89 (m, 3H, ArH), 6.82 (d, J= 8.2, 1H, ArH), 5.34 (s, 1H, CHC(CH₃)3), 5.06 (s, 2H, OCH₂Ph), 3.72 (s, 3H, OCH₃), 3.67 (br. s, 1H, NHCH₃), 3.64 - 3.55 (m, 2H, NCCH₂), 3.03 (s, 3H, NCH₃), 2.06 (d, J = 4.7, 3H, NHCH₃), 0.91 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCb): δ₀ = 172.9, 159.3, 158.3, 156.9, 137.0, 132.7, 129.7, 128.7, 128.7, 128.1, 128.0, 127.5, 120.5, 115.2, 111.7, 82.6, 70.1, 69.5, 56.5, 41.7, 37.2, 32.2, 27.2, 26.8; HRMS (ESI⁺): m/z calcd for C₃iH₃₈0₄N₃ ([M+H]⁺) 516.2857, found 516.2857.

(2S,5f?)-5-(4-(Benzyloxy)benzyl)-5-(4-bromo-3-fluorophenyl)-2-(iert-butyl)-/V,3-dimethyl-4- oxoimidazolidine-1-carboxamide (118)

[00327] Following general procedure 7, a solution of trans-ΐλ (150 mg, 0.362 mmol) and 4-bromo-3-fluoro-/V-methylaniline (89 mg, 0.436 mmol) in THF (3.60 mL) was treated with 2 portions of

KHMDS (2x0.54 mL, 1.08 mmol, 1.0 M in THF). Purification by

flash column chromatography gave the title compound (194 mg,

0.333 mmol, 92%) as a white solid.118: ¹H NMR (500 MHz, CDCb): δ_Η = 7.50 (dd, J = 8.5,

7.1, 1H, ArH), 7.41 -7.33 (m, 4H, ArH), 7.33-7.27 (m, 3H, ArH), 7.14 (dd, J= 10.1,2.3, 1H,

ArH), 6.96-6.90 (m, 3H, ArH), 5.57 (s, 1H, CHC(CH₃)₃), 5.06 (s, 2H, OCH₂Ph), 3.89 (br. s,

1H, NHCH₃), 3.66 (d, J= 14.6, 1H,

3.56 (d, J= 14.8, 1H, NCCH_AH_E), 2.96 (s, 3H,

NCH₃), 2.24 (br. s, 3H, NHCH₃), 0.77 (s, 9H, C(CH₃)₃); ¹³C {¹H} NMR (125 MHz, CDCb): 5_C =

170.5 (C=0), 159.1 (d, ¹ _C-F = 248.4, C_ArF), 158.7 (C=0), 158.5 (C_ArO), 143.1 (CA_T), 136.7

(CAT), 133.7 (CH_Ar), 132.3 (2xCH_Ar), 128.6 (2xCH_Ar), 128.0 (CH_Ar), 127.3 (2xCH_Ar), 126.9 (CAT),

122.5 (d, ⁴ C-F = 3.5, CH_Ar), 115.5 (2xCH_Ar), 114.4 (d, ²J_C-F = 24.3, CH_Ar), 108.8 (d, ²JC-F =

20.9, C_ArBr), 81.0 (CHC(CH₃)₃), 71.5 (NCCH₂), 69.9 (OCH₂Ph), 39.9 (NCCH₂), 37.7 (C(CH₃)₃),

31.8 (NCH₃), 27.0 (NHCH₃), 26.4 (C(CH₃)₃); HRMS (ESI⁺): m/z calcd for C₃₀H₃₃O₃N₃BrFNa

([M+Na]⁺) 604.1582, found 604.1568. (f?)-2-Amino-2-(4-fluorophenyl)propanoic acid (1 19)

[00328] Following general procedure 9, NaH (56 mg, 1.40 mmol, 60% suspension) and Mel (0.11 ml_, 1.75 mmol) were added to 60 (375 mg, 1.17 mmol) in DMF (1 1.70 ml_). The resulting methylated urea was suspended in

HCI/EtOH (5.85 ml_, 10:1) and hydrolysed to give the title compound (175 mg, 0.955 mmol, 82%) as a white solid. 1 19: ¹ H NMR (400 MHz, CD₃OD): δ_Η = 7.62 - 7.56 (m, 2H, ArH), 7.17 - 7.10 (m, 2H, ArH), 1.87 (s, 3H, CH₃) ¹³C {¹ H} NMR (100 MHz, CD₃OD): 5_C = 175.3 (C=0), 164.1 (d, ¹ Jc-F = 246.4, C_ArF), 136.7 (d, ⁴J_C-F = 3.4, CAT), 129.4 (d, ³J_C-F = 8.3, 2xCH_Ar), 1 16.4 (d, ² C-F = 21.9, 2x CH_Ar), 63.6 (NCCH₃), 22.9 (CH₃); HRMS (ESI^"): m/z calcd for C9H9O₂NF ([M-H]-) 182.0623, found 182.0623.

(f?)-2-amino-2-(3-bromophenyl)-3-phenylpropanoic acid (120)

[00329] Following general procedure 9, NaH (51 mg, 1.27 mmol, 60% suspension) and Mel (0.10 ml_, 1.59 mmol) were added to 1 13 (485 mg,

1.06 mmol) in DMF (10.60 mL). The resulting methylated urea was suspended in HCI/EtOH (5.30 mL, 10: 1 ) and hydrolysed to give the title compound (281 mg, 0.878 mmol, 83%) as a white solid. 120: ¹ H N MR (400 MHz, CD₃OD): δ_Η = 7.88 (t, J = 1.9, 1 H, ATH), 7.64 (dd, J = 8.0, 2.0, 1 H, ArH), 7.54 (dd, J = 7.9, 1.8, 1 H, ArH), 7.34 (t, J = 8.0, 1 H, ATH), 7.31 - 7.20 (m, 5H, ArH), 3.70 (d, J = 14.1 , 1 H, OMH_BPh), 3.44 (d, J = 14.1 , 1 H, CH_AH_BPh); ¹³C {¹ H} N M R (100 MHz, CD₃OD): 5_C = 171 .7 (C=0), 140.9 (C_Ar), 134.1 (C_Ar), 131.1 (CH_Ar), 130.3 (2xCH_Ar), 130.0 (CH_Ar), 129.2 (CH_Ar), 128.4 (2x CH_Ar), 127.3 (CH_Ar), 124.8 (CH_Ar), 122.2 {C_Ar), 66.8 (NCCH₂), 42.2 (NCCH₂); HRMS (ESI⁺): m/z calcd for Ci₅Hi₅0₂NBr ([M+H]⁺) 320.0281 , found 320.0281 .

(S)-2-amino-2-(4-chlorophenyl)-/V-methyl-2-phenylacetamide (121 )

[00330] Following general procedure 9, NaH (12 mg, 0.309 mmol, 60% suspension) and Mel (24 μΙ_, 0.386 mmol) were added to 74 (103 mg, 0.258 mmol) in DMF (2.60 mL). The resulting methylated urea was suspended in HCI/EtOH (1 .30 mL, 10: 1) and hydrolysed to give the title compound (25 mg,

0.091 mmol, 35%) as a white solid. 121 : ¹ H N M R (400 MHz, CD₃OD): δ_Η = 7.50 - 7.30 (m, 9H, ArH), 2.79 (s, 3H, NCH₃); MS (ESI⁺): mlz 275.0936 ([M+H]⁺).

[00331 ] While specific embodiments of the invention have been described for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims. REFERENCES

(1) Burchat, A. F.; Chong, J. M.; Nielsen, N. J. Organomet. Chem. 1997, 542, 281.

(2) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512.

(3) Atkinson, R. C; Leonard, D. J.; Maury, J.; Castagnolo, D.; Volz, N.; Clayden, J. Chem.

Commun. 2013, 49, 9734.

(4) Samulis, L; Tomkinson, N. C. O. Tetrahedron 2011 , 67, 4263.

(5) Naef, R.; Seebach, D. Helv. Chim. Acta 1985, 68, 135.

(6) Reichard, G. A.; Stengone, C; Paliwal, S.; Mergelsberg, I.; Majmundar, S.; Wang, C;

Tiberi, R.; McPhail, A. T.; Piwinski, J. J.; Shih, N.-Y. Org. Lett. 2003, 5, 4249.

(7) Rowley, J. H.; Yau, S. C; Kariuki, B. M.; Kennedy, A. R.; Tomkinson, N. C. O. Org.

Biomol. Chem. 2013, 11, 2198.

(8) Balaev, A. N.; Osipov, V. N.; Okhmanovich, K. A.; Fedorov, V. E. Pharm. Chem. J.

2015, 49, 334.

(9) Kortylewicz, Z. P.; Galardy, R. E. J. Med. Chem. 1990, 33, 263.

(10) Leathen, M. L; Rosen, B. R.; Wolfe, J. P. J. Org. Chem. 2009, 74, 5107.

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Claims

1. A process for the preparation of a compound of Formula (I), as shown below:

(I)

wherein:

X is selected from CR⁵R⁶, C=S or C=0;

Z is selected from O, S or NR⁷;

Ar is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)halalkoxy, (1-4C)alkoxy, azido, carboxy, carbamoyl, sulphamoyl, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^aR , OR^a, C(0)R^a, C(0)OR^a, OC(0)R^a, C(0)N(R )R^a, N(R )C(0)R^a, S(0)_yR^a (where y is 0, 1 or 2), S0₂N(R^b)R^a, N(R )S0₂R^a or (CH₂)zNR R^a (where z is 1 , 2 or 3), wherein R^a and R^b are independently selected from H or (1-4C)alkyl;

R¹ is selected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1- 2C)alkyl or oxo;

-L²-Y²-W²

wherein:

L² is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl;

Y² is absent or selected from SiR^a4R^a5, S0₂, C(O), C(0)0 or Ο(Ο)Ν^), wherein R', R^a4 and R^a5 are each independently selected from H or (1-4C)alkyl;

W² is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1- 2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heteroatyl, heterocyclyl or NR^jR^k, wherein R^j and R^k are independently selected from H or (1-6C)alkyl; or

N(R^m)C(0)R', wherein R' and R^m are each independently selected from H or (1-4C)alkyl; or

R² is an organometallic complex;

R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl or SiR^b1 R^b2R^b3 (wherein R ¹ , R^b2 and R ³ are independently selected from H or (1-4C)alkyl), each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heteroaryl, heterocyclyl, NR^pR^q, C(0)R^p, C(0)OR^p, CCC NKR^R^P or Ν^)0(0^^ρ, wherein R^p and R^ are each independently selected from H or (1-4C)alkyl; or

R⁷ is selected from H or a group of the formula:

-L³-Y³-W³

wherein:

L³ is absent or (1-4C)alkylene optionally substituted by (1-2C)alkyl;

Y³ is absent or selected from SiR^a6R^a7, S0₂, C(O), C(0)0 or

with the proviso that:

(iii) when R¹ is not a carbonyl moiety (i.e. it is a group other than C(0)-W, C(0)0-W\ C(0)N(R^c)-W¹), X is C=0 or C=S.

the process comprising the steps of:

1) reacting a compound of Formula (II), as shown below, with a base in the

presence of an aprotic solvent:

wherein X, Z, Q, Ar, R R², R³ and all substituent groups associated therewith, have the same meaning as defined for the compounds of Formula (I); and

2) optionally, thereafter:

a) converting the compound Formula I into another compound of Formula I; and/or

b) forming a salt or solvate thereof.

2. A compound of Formula or solvate thereof:

(I)

wherein:

X is selected from CR⁵R⁶, C=S or C=0;

Z is selected from O, S or NR⁷;

Q is selected from S, NR⁸ or O, wherein R⁸ is selected from H, (1 -4C)alkyl or aryl;

Ar is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1 -4C)halalkoxy, (1 -4C)alkoxy, azido, carboxy, carbamoyl, sulphamoyl, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^aR^b, OR^a, C(0)R^a, C(0)OR^a, OC(0)R^a, C(0)N(R )R^a, N(R^b)C(0)R^a, S(0)_yR^a (where y is 0, 1 or 2), S0₂N(R^b)R^a, N(R )S0₂R^a or (CH₂)zNR^bR^a (where z is 1 , 2 or 3), wherein R^a and R^b are independently selected from H or (1-4C)alkyl;

R¹ is selected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1 - 2C)alkyl or oxo; Y¹ is absent or selected from O, N(R^C), S, SO, S0₂, Se, C(O), C(0)0, OC(O), C(0)N(R^c), N(R^d)C(0), N(R^d)C(0)N(R^c), N(R^d)C(NH)N(R^c), S(0)₂N(R^c), or N(R^d)S0₂, wherein R^cand R^d are each independently selected from H or (1-4C)alkyl; and

-L²-Y²-W²

wherein:

L² is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl;

W² is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1- 2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heterocyclyl or NR^jR^k, wherein R^j and R^k are independently selected from H or (1-6C)alkyl; or

C(0)N(R°)Rⁿ or N(R°)C(0)Rⁿ, wherein Rⁿ and R° are each independently selected from H or (1-4C)alkyl; or Rⁿ and R° are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8- membered heterocyclyl, which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, amino, hydroxy or cyano; or

R² is an organometallic complex;

R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, cycloalkyi, cycloalkenyl, heterocyclyl or SiR^b1 R^b2R^b3 (wherein R^b1 , R^b2 and R ³ are independently selected from H or (1-4C)alkyl), each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heterocyclyl, NR^pR^q, C(0)R^p, C(0)OR^p, C(0)N(R")R^P or N(R")C(0)R^p, wherein RP and R^ are each independently selected from H or (1-4C)alkyl; or

R⁴ is absent or H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1- 2C)alkyl, C(0)OR^r or C(0)N(R^r) or nitroso, wherein R^r is selected from H or (1-4C)alkyl, and wherein each (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, hydroxy, nitro or cyano;

R⁵ and R⁶ are independently selected from H, (1-4C)alkyl, aryl or heteroaryl wherein each (1-4C)alkyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydroxy, halo, amino, (1-4C)alkyl, nitro or cyano;

R⁷ is selected from H or a group of the formula:

-L³-Y³-W³

wherein:

L³ is absent or (1-4C)alkylene optionally substituted by (1-2C)alkyl;

Y³ is absent or selected from SiR^a6R^a7, S0₂, C(O), C(0)0 or

C(0)N(R^s), wherein R^s, R^a5 and R^a7 are each independently selected from H or (1-4C)alkyl;

W³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano or NR'R^J, wherein R' and R^L are independently selected from H or (1-4C)alkyl;

with the proviso that:

(ii) when R¹ is a carbonyl moiety (i.e. a group selected from C(0)-W¹, C(0)0-W\ C(0)N(R^c)-W¹), X is CR⁵R⁶; and (iii) when R¹ is not a carbonyl moiety (i.e. it is a group other than C(0)-W¹, C(0)0-W\ C(0)N(R^c)-W¹), X is C=0 or C=S.

3. A compound of the Formula or solvate thereof:

wherein:

X is selected from CR⁵R⁶, C=S or C=0;

Z is selected from O, S or NR⁷;

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene optionally substituted by (1- 2C)alkyl or oxo;

Y¹ is absent or selected from O, N(R^C), S, SO, S0₂, Se, C(O), C(0)0, OC(O), C(0)N(R^c), N(R^d)C(0), N(R^d)C(0)N(R^c), N(R^d)C(NH)N(R^c), S(0)₂N(R^c), or N(R^d)S0₂, wherein R^cand R^d are each independently selected from H or (1-4C)alkyl; and W¹ is selected from H, (1-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, SiR^a1 R^a2R^a3 (wherein R^a1 , R^a2 and R^a3 are independently selected from H or (1-4C)alkyl), (3- 8C)cycloalkyl, (3-8C)cycloalkenyl, aryl, heterocyclyl or heteroaryl; each of which, other than H and SiR^a1 R^a2R^a3, is optionally substituted with one or more substituents selected from nitro, cyano, halo, (1 -4C)haloalkyl, (1 -4C)halalkoxy, amino, hydroxy, azido, carboxy, carbamoyl, sulphamoyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, (1-4C)alkyl, OR⁹, NR^eR^f, C(0)R⁹, C(0)OR⁹, OC(0)R⁹, C(0)N(R^h)R⁹, N(R^h)C(0)R⁹, S(0)_yR⁹ (where y is 0, 1 or 2), S0₂N(R^h)R⁹, N(R^h)S0₂R⁹ or

-L²-Y²-W²

wherein:

L² is absent or (1 -2C)alkylene optionally substituted by (1-2C)alkyl;

Y² is absent or selected from SiR^a4R^a5, S0₂, C(O), C(0)0 or C(0)N(R , wherein R', R^a4 and R^a5 are each independently selected from H or (1 -4C)alkyl;

W² is selected from H, (1 -6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1 -2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1- 2C)alkyl or cycloalkenyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1 -4C)alkyl, halo, (1 -4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heterocyclyl or NR^jR^k, wherein R^j and R^k are independently selected from H or (1 -6C)alkyl;or

R) and R^k are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl, which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, amino, hydroxy or cyano; or

or Rⁿ and R° are linked such that, together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclyl, which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, amino, hydroxy or cyano; or

R² is an organometallic complex;

R³ is selected from H, (1-6C)alkyl, aryl, heteroaryl, cycloalkyi, cycloalkenyl, heterocyclyl or SiR ¹ R ²R^b3 (wherein R ¹ , R^b2 and R^b3 are independently selected from H or (1-4C)alkyl), each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, aryl, heterocyclyl, NR^PR«, C(0)R^p, C(0)OR^p, 0(0)1^^ or Ν^)0(Ο)Ρ^ρ, wherein RP and R^ are each independently selected from H or (1-4C)alkyl; or

R³ is linked with Ar such that, together with the nitrogen atom to which R³ is attached they form a 4- to 15-membered heterocyclyl or heteroaryl, which is optionally substituted with one or more substituents halo, hydroxy, amino, nitro, cyano, (1-4)alkyl or (1-4C)alkoxy; R⁵ and R⁶ are independently selected from H, (1-4C)alkyl, halo or (1- 4C)alkoxy;

R⁷ is selected from H or a group of the formula:

-L³-Y³-W³

wherein:

L³ is absent or (1-4C)alkylene optionally substituted by (1-2C)alkyl;

Y³ is absent or selected from SiR^a6R^a7, S0₂, C(O), C(0)0 or

with the proviso that:

(i) when R¹ is a carbonyl moiety (i.e. a group selected from C(0)-W¹, C(0)0-W\ C(0)N(R^c)-W¹), X is CR⁵R⁶;

(ii) when R¹ is not a carbonyl moiety, X is C=0 or C=S; and

(iii) the compound of Formula (II) is not selected from one of the following

4. A process according to claim 1 or a compound according to claim 2, wherein the compound of Formula (I) is enantioenriched and has the structure (la) or (lb) shown below:

la lb

wherein Ar, Q, X, Z, R¹ , R², R³ and R⁴ are as defined in claim 1.

5. A proess according to claim 1 or a compound according to claim 3, wherein the

compound of Formula (II) is enantioenriched and has the structure (I la) or (lib) shown below:

(I la) (lib)

wherein Ar, Q, X, Z, R¹ , R² and R³ are as defined in claim 1.

6. A process according to any one of claims 1 , 4 or 5, or a compound according to any one of claims 2 to 5, wherein X is selected from CR⁵R⁶ or C=0.

7. A process according to any one of claims 1 or 4 to 6, or a compound according to any one of claims 2 to 6, wherein Z is selected from O or NR⁷.

8. A process according to any one of claims 1 or 4 to 7, or a compound according to any one of claims 2 to 7, wherein Q is O.

9. A process according to any one of claims 1 or 4 to 8, or a compound according to any one of claims 2 to 8, wherein Ar is selected from aryl or heteroaryl optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)halalkoxy, (1-4C)alkoxy, carboxy, carbamoyl, sulphamoyl, hydroxy, cyano, NR^aR or OR³, wherein R^a and R are independently selected from H or (1-4C)alkyl.

10. A process according to any one of claims 1 or 4 to 9, or a compound according to any one of claims 2 to 9, wherein R¹ is selected from a group of the formula:

-L¹-Y¹-W¹

wherein:

L¹ is absent or (1-6C)alkylene;

Y¹ is absent or selected from O, N(R^C), Se, C(O), C(0)0 or C(0)N(R^c), wherein R^c is selected from H or (1-2C)alkyl; and

(CH₂)_wNR^hR⁹ (where w is 1 , 2 or 3), wherein R⁹ and R^h are each independently selected from H, (1-4C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl or heteroaryl-(1-2C)-alkyl; and wherein R^e and R^f are independently selected from H or (1-4C)alkyl.

11. A process according to any one of claims 1 or 4 to 10, or a compound according to any one of claims 2 to 10, wherein R² is selected from H, (1-8C)alkyl, phenyl, 5- or 6- membered heteroaryl or (3-8C)cycloalkyl, each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1- 4C)haloalkyl, (1-4C)alkoxy, hydroxy, nitro, cyano or NRⁿR°, wherein Rⁿ and R° are each independently selected from H or (1-4C)alkyl.

12. A process according to any one of claims 1 or 4 to 11 , or a compound according to any one of claims 2 to 11 , wherein R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1- 2C)alkyl or heteroaryl.

13. A process according to any one of claims 1 or 4 to 12, or a compound according to any one of claims 2 to 12, wherein R⁷ is selected from H, (1-6C)alkyl, aryl, aryl-(1- 2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyl, cycloalkyl-(1-2C)alkyl or cycloalkenyl.

14. A compound selected from:

143

144

16. A compound of Formula (lll-1a) as shown below, or a salt or solvate thereof:

(lll-1a)

wherein:

A is selected from OR^v SR^W or NR^VR^W, wherein R^v and R^w are independently selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl or heteroaryl-(1-

2C)alkyl;

Ar¹ and R¹¹ are independently selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^xR^y, C(0)R^x, C(0)OR^x, C(0)N(R^y)R^x, N(R> C(O)R^x S(0)_yR^x (where y is 0, 1 or 2), S0₂N(R^)R^x, N(R^y)S0₂R^x or (CH₂)zNR^yR^x (where z is 1 , 2 or 3), wherein R^x and R^y are independently selected from H or (1-4C)alkyl; and

R^a1 and R^a2 are independently selected from H or a group of the formula:

-L-Y-W

wherein:

L is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl;

Y is absent or selected from SiR^a8R^a9, S0₂, C(O), C(0)0 or

with the proviso that when Ar¹ and R¹¹ are both optionally substituted aryl groups, the compounds of Formula (111-1 a) are not racemic and are not selected from one of the following:

17. A compound according to claim 16, wherein said compound is enantioenriched and has the s

wherein each of R¹¹, R^a1 , R^a2, A and Ar¹ are as defined in claim 16.

18. A compound according to claim 16 or 17, wherein A is selected from OR^v, wherein R^v is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl or heteroaryl-(1- 2C)alkyl.

19. A compound according to any one of claims 16 to 18, wherein Ar¹ and R¹¹ are

independently selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1- 4C)alkoxy, hydroxy, amino, nitro, cyano or mercapto.

20. A compound according to any one of claims 16 to 19, wherein R^a1 and R^a2 are

independently selected from H or a group of the formula:

-Y-W

wherein:

Y is absent or selected from C(O) or C(0)0; and

W is selected from H, (1-6C)alkyl, phenyl, phenyl-(1-2C)alkyl or a 5- or 6- member heteroaryl.

21. A compound of Formula (IV) as shown below, or a salt or solvate thereof:

(IV)

wherein:

X¹ is S or O;

Ar¹ and R¹¹ are independently selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1- 4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, mercapto, aryl, heteroaryl, NR^xR^y, C(0)R^x, C(0)OR^x, C(0)N(R^y)R^x, N(R*)C(0)R^x S(0)_yR^x (where y is 0, 1 or 2), S0₂N(R^)R^x, N(R^y)S0₂R^x or (CH₂)zNR^yR^x (where z is 1 , 2 or 3), wherein R^x and R^y are independently selected from H or (1-4C)alkyl;

R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl or SiR ¹ R ²R^b3 (wherein R ¹ , R^b2 and R ³ are independently selected from H or (1-4C)alkyl), each of which, other than H, is optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, aryl, heteroaryl, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, NR^pR^q, C(0)R^p, C(0)OR^p, C(0)N(R^q)R^p or N(R^q)C(0)R^p, wherein R^p and R^q are each independently selected from H or (1-4C)alkyl; or

R³ is linked with Ar such that, together with the nitrogen atom to which R³ is attached they form a 4- to 10-membered heterocyclyl or heteroaryl, which is optionally substituted with one or more substituents halo, hydroxy, amino, nitro, cyano, (1-4)alkyl or (1-4C)alkoxy; and

R⁹ is selected from H or a group of the formula:

-L^x-Y^x-W^x

wherein:

L^x is absent or (1-2C)alkylene optionally substituted by (1-2C)alkyl; Y^x is absent or selected from SiR^a10R^a1\ S0₂, C(O), C(0)0 or C(0)N(R^z1), wherein R^z1 , R^a1° and R^a11 are independently selected from H or (1-4C)alkyl; and

W^x is selected from (1-6C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, cycloalkyi, cycloalkyl-(1-2C)alkyl or cycloalkenyl, each of which is optionally substituted with one or more substituents selected from (1- 4C)alkyl, aryl, heteroaryl, halo, (1-4C)haloalkyl, (1-4C)alkoxy, hydroxy, amino, nitro or cyano;

with the proviso that:

i) when Ar¹ and R¹¹ are both optionally substituted aryl groups, R³ and R⁸ are not H and the compound of Formula (IV) is not racemic;

ii) when R³ and R⁹ are H, Q and X¹ are O and one of Ar¹ or R¹¹ is phenyl, the other of Ar¹ or R¹¹ is not a phenyl or a substituted phenyl; and

iii) the compound of Formula (IV) is not one of the following:

22. A compound according to claim 21 , wherein said compound is enatioenriched and has the structural formula (IVa) or (IVb):

(IVa) (IVb) wherein X¹ , Q, Ar , R , R³ and R⁹ are as defined in claim 22.

23. A compound according to claim 21 or 22, wherein X¹ is O.

24. A compound according to any one of claims 21 to 23, wherein Q is O.

25. A compound according to any one of claims 21 to 24, wherein Ar¹ and R¹¹ are

26. A compound according to any one of claims 21 to 25, wherein R³ is selected from H, (1-6C)alkyl, aryl, aryl-(1-2C)alkyl or heteroaryl.

27. A compound according to any one of claims 21 to 26, wherein R⁹ is selected from H or (1-6C)alkyl.