SULFUR COMPOUNDS AND PROCESSES AND INTERMEDIATES USEFUL IN THE

PREPARATION THEREOF

INTRODUCTION

[001] The present application provides novel sulfondiimidamide compounds, mild and versatile processes for the preparation of sulfondiimidamide compounds and intermediates useful in said processes.

BACKGROUND OF THE INVENTION

[002] Sulfur(VI) compounds have played a substantial role in the development of medicines. Sulfones and sulfonamides in particular are key components of numerous drugs as well as agrochemicals ¹ . Replacing one of the oxygen atoms in these molecules with a nitrogen atom gives sulfoximines ² and sulfonimidamides ³ respectively.

[003] Sulfoximines and sulfonimidamides have recently gained traction in medicinal chemistry, first as isosteric replacements for their oxygenated analogues ⁴ , and more recently due to increasing recognition of their potent mix of physicochemical properties. Being inherently chiral at sulfur, polar, and three-dimensional, with good aqueous solubility and high chemical and metabolic stability ⁵ , sulfoximines and sulfonimidamides represent an invaluable addition to the medicinal chemist’s toolbox ⁶ .

[004] Considerable advances have been made in recent years in the synthesis of sulfoximines and sulfonimidamides by the Bolm and Bull groups, as well as others, which have simplified the imination of thioethers ⁷ , sulfoxides ⁸ , and sulfenamides ⁹ .

[005] However, to date there have been no reports of a mild and versatile route to obtain sulfondiimidamides which are obtained when the oxygen atom in a sulfonimidamides is replaced with a nitrogen atom.

[006] It is envisaged that a mild and verstaile route to sulfondiimidamide compounds would provide access to sulfondiimidamide compound libraries useful for screening against biological targets and/or provide a means of accessing compounds potentially bio-isosteric to sulfonimidamides with known biological activity which may enable further optimisation of potency, physiochemical and pharmacokinetic properties.

[007] There is a need for further diversity in a chemist’s toolbox. The present invention provides novel sulfondiimidamide compounds, mild and versatile processes for the preparation of sulfondiimidamide compounds and intermediates useful in said processes. SUMMARY OF THE INVENTION

[008] In one aspect, the present invention provides a process for preparing a compound of formula I, or a salt thereof:

(I), comprising:

(i) reacting a compound of formula la:

(la), with a reactant suitable for introducing group R ³ to give a compound of formula lb:

(lb); and/or

(ii) deprotecting a compound of formula lb to yield a compound of formula lc: (lc), and/or

(iii) reacting a compound of formula lc with a reactant suitable for introducing group R ⁴ to give a compound of formula I; and

(iv) optionally preparing a salt of formula I; wherein R, R ¹ , R ² , R ³ , R ⁴ and P ³ are defined herein.

[009] In another aspect, the present invention provides a compound of Formula I, or a salt thereof: as defined herein.

[0010] In another aspect, the present invention provides a compound of Formula la, or a salt thereof:

(la), as defined herein.

[0011] In another aspect, the present invention provides a process for preparing a compound of formula la

(la), comprising reacting a compound of formula (III):

(HI), with a compound of formula (IV):

H-NR ¹ R ² (IV); wherein R, R ¹ , R ² and P ³ are defined herein.

[0012] In another aspect, the present invention provides a compound of formula III, or a salt thereof:

(III), as defined herein [0013] In another aspect, the present invention provides a process for preparing a compound of formula III:

(III), comprising reacting a compound of formula V:

(V), with a compound of formula VI:

P ³ -X ⁵ (VI). wherein R, P ³ and X ⁵ are defined herein.

[0014] In another aspect, the present invention provides a compound of formula V, or a salt thereof:

(V), as defined herein.

[0015] In another aspect, the present invention provides a process for preparing a compound of formula V:

(V), comprising reacting a compound of formula VII: with a compound of formula VIII:

R-M (VIII); wherein R, P ¹ , P ² and M are defined herein.

[0016] In another aspect, the present invention provides a compound of formula lb, or a salt thereof:

(lb), as defined herein.

[0017] In another aspect, the present invention provides a compound of formula lc, or a salt thereof:

(lc), as defined herein.

[0018] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0019] The compounds and intermediates described herein may be named according to either the lUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems.

[0020] The various hydrocarbon-containing moieties provided herein may be described using a prefix designating the minimum and maximum number of carbon atoms in the moiety, e.g. “(C _a-b )” or “C _a -C _b ” or “(a-b)C”. For example, (C _a-b )alkyl indicates an alkyl moiety having the integer “a” to the integer “b” number of carbon atoms, inclusive. Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure. For example, the terms “a to b membered ring” or “having between a to b members” refer to a moiety having the integer “a” to the integer “b” number of atoms, inclusive.

[0021] "About" when used herein in conjunction with a measurable value such as, for example, an amount or a period of time or temperature and the like, is meant to encompass reasonable variations of the value, for instance, to allow for experimental error in the measurement of said value.

[0022] As used herein by themselves or in conjunction with another term or terms, "alkyl" and “alkyl group” refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkyl groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc.

[0023] As used herein by themselves or in conjunction with another term or terms, “alkylene” and “alkylene group” refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkylene groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, methylene (-CH2-), the ethylene isomers (-CH(CH3)- and - CH2CH2-), the propylene isomers (-CH(CH ₃ )CH ₂ - -CH(CH ₂ CH ₃ )-, -C(CH ₃ ) ₃ -, and - CH2CH2CH2-), etc.

[0024] As used herein by themselves or in conjunction with another term or terms, “alkenyl” and “alkenyl group” refer to a branched or unbranched hydrocarbon chain containing at least one double bond. Unless specified otherwise, alkenyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl.

[0025] As used herein by themselves or in conjunction with another term or terms, “alkynyl” and “alkynyl group” refer to a branched or unbranched hydrocarbon chain containing at least one triple bond. Unless specified otherwise, alkynyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.

[0026] As used herein by itself or in conjunction with another term or terms, “aromatic” refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer. Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”). An aromatic ring system can be substituted or unsubstituted.

[0027] As used herein by itself or in conjunction with another term or terms, “non-aromatic” refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system. As used herein, non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S. A non-aromatic ring system can be substituted or unsubstituted.

[0028] As used herein by themselves or in conjunction with another term or terms, “aryl” and “aryl group” refer to phenyl or polycyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic. Aryl groups can be substituted or unsubstituted. Unless specified otherwise, an aryl group may contain 6 ring atoms (i.e., phenyl) or a ring system containing 9 to 15 atoms, such as 9 to 11 ring atoms, or 9 or 10 ring atoms. Representative examples include, but are not limited to, naphthyl, indenyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl. Suitably an aryl group is phenyl or naphthyl, suitably phenyl.

[0029] As used herein by themselves or in conjunction with another term or terms, “arylene” and “arylene group” refer to a phenylene (-C6H4-) or to 7 to 15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic. Arylene groups can be substituted or unsubstituted. In some embodiments, an arylene group may contain 6 (i.e. , phenylene) ring atoms or be a ring system containing 9 to 15 atoms; such as 9 to 11 ring atoms; or 9 or 10 ring atoms. Arylene groups can be substituted or unsubstituted.

[0030] As used herein by themselves or in conjunction with another term or terms, “arylalkyl” and “arylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by an aryl group, wherein alkyl group and aryl group are as previously defined, such as, for example, benzyl (C6H5CH2-). Arylalkyl groups can be substituted or unsubstituted.

[0031] As used herein by themselves or in conjunction with another term or terms, “carbocyclic group” and “carbocycle” refer to monocyclic and polycyclic ring systems that contain only carbon atoms in the ring(s), i.e., hydrocarbon ring systems, without regard or reference to aromaticity or degree of unsaturation. Thus, carbocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a cyclohexyl group), ring systems that are aromatic (such as, for example, a phenyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, cyclohexenyl, 2,3-dihydro-indenyl, and 1,2,3,4-tetrahydro- naphthalenyl). The terms carbocyclic and carbocycle further include bridged, fused, and spirocyclic ring systems.

[0032] As used herein by themselves or in conjunction with another term or terms, “cycloalkyl” and “cycloalkyl group” refer to a non-aromatic carbocyclic ring system, that may be monocyclic, bicyclic, or tricyclic, saturated or unsaturated, and may be bridged, spiro, and/or fused. A cycloalkyl group may be substituted or unsubstituted. Unless specified otherwise, a cycloalkyl group typically contains from 3 to 12 ring atoms. In some instances a cycloalkyl group may contain 4 to 10 ring atoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, etc.). Representative examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[3.3.2]decane. Suitably, cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

[0033] As used herein by themselves or in conjunction with another term or terms, “cycloalkylalkyl” and “cycloalkylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a cycloalkyl group, wherein alkyl group and cycloalkyl group are as previously defined, such as, for example, cyclohexylmethyl (C ₆ HnCH ₂ -). Cycloalkylalkyl groups can be substituted or unsubstituted.

[0034] As used herein by themselves or in conjunction with another term or terms, “haloalkyl” and “haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes both saturated alkyl groups as well as unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, -CF3, - CHF ₂ , -CH ₂ F, -CF ₂ CF ₃ , -CHFCF _S , -CH ₂ CF ₃ , -CF ₂ CH ₃ , -CHFCH _S , -CF ₂ CF ₂ CF ₃ , - CF ₂ CH ₂ CH ₃ , -CF=CF ₂ , -CCI=CH ₂ , -CBr=CH ₂ , -CI=CH ₂ , -CºC-CF ₃ , -CHFCH ₂ CH ₃ and - CHFCH ₂ CF ₃ . Haloalkyl groups can be substituted or unsubstituted. Suitably, a haloalkyl group is selected from CHF ₂ and CF ₃ , suitably CF ₃ .

[0035] As used herein by themselves or in conjunction with another term or terms, “haloalkoxy” and “haloalkoxy group” refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkoxy includes both saturated alkoxy groups as well as unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCF ₂ CF ₃ , -OCHFCFs, -OCH ₂ CF ₃ , -OCF ₂ CH ₃ , -OCHFCH _S , -OCF ₂ CF ₂ CF ₃ , -OCF ₂ CH ₂ CH ₃ , -OCF=CF ₂ , -OCCI=CH ₂ , - OCBr=CH ₂ , -OCHFCH ₂ CH ₃ and -OCHFCH ₂ CF ₃ . Haloalkoxy groups can be substituted or unsubstituted. Suitably, a haloalkyoxy group is selected from -OCHF ₂ and -OCF ₃ , suitably -

OCF ₃ .

[0036] As used herein by themselves or in conjunction with another term or terms, “halo” and “halogen” include fluorine, chlorine, bromine and iodine atoms and substituents.

[0037] As used herein by themselves or in conjunction with another term or terms, “heteroaryl” and “heteroaryl group” refer to (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7 to15 membered bicyclicand tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic. In some instances, a heteroaryl group can contain two or more heteroatoms, which may be the same or different. Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and/or fused. In some instances, a heteroaryl group may contain 5, 6, or 8 to 15 ring atoms. In other instances, a heteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms. Representative examples include, but are not limited to, 2,3-dihydrobenzofuranyl, 1,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl, 2-thienyl, 3- thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin- 2-yl, pyridazin-4-yl, pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indolizinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl, quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl, 10-aza-tricyclo[6.3.1.0 ² ' ⁷ ]dodeca-2(7),3,5-trienyl, 12- oxa-10-aza-tricyclo[6.3.1.0 ² ' ⁷ ]dodeca-2(7),3,5-trienyl, 12-aza-tricyclo[7.2.1.0 ² ' ⁷ ]dodeca- 2(7),3,5-trienyl, 10-aza-tricyclo[6.3.2.0 ² ' ⁷ ]trideca-2(7),3,5-trienyl, 2,3,4,5-tetrahydro-1 H- benzo[d]azepinyl, 1 ,3,4,5-tetrahydro-benzo[d]azepin-2-onyl, 1 ,3,4,5-tetrahydro- benzo[b]azepin-2-onyl, 2,3,4,5-tetrahydro-benzo[c]azepin-1-onyl, 1,2,3,4-tetrahydro- benzo[e][1 ,4]diazepin-5-onyl, 2,3,4,5-tetrahydro-1 H-benzo[e][1 ,4]diazepinyl, 5, 6,8,9- tetrahydro-7-oxa-benzocycloheptenyl, 2,3,4,5-tetrahydro-1 H-benzo[b]azepinyl, 1 ,2,4,5- tetrahydro-benzo[e][1 ,3]diazepin-3-onyl, 3,4-dihydro-2H-benzo[b][1 ,4]dioxepinyl, 3,4-dihydro- 2H-benzo[f][1 ,4]oxazepin-5-onyl, 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, 5,5- dioxo-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, and 2,3,4,5-tetrahydro- benzo[f][1,4]oxazepinyl. Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0038] As used herein by themselves or in conjunction with another term or terms, “heteroarylalkyl” and “heteroarylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a heteroaryl group, wherein alkyl group and heteroaryl group are as previously defined. Heteroarylalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. heteroaryl(C _n-m )alkyl, the range refers to the alkyl group. Suitably, the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.

[0039] As used herein by themselves or in conjunction with another term or terms, “heterocyclic group” and “heterocycle” refer to monocyclic and polycyclic ring systems that contain carbon atoms and at least one heteroatom selected from nitrogen, oxygen, sulfur or phosphorus in the ring(s), without regard or reference to aromaticity or degree of unsaturation. Thus, a heterocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a piperidinyl group), ring systems that are aromatic (such as, for example, a pyrindinyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, 1, 2,3,6- tetrahydropyridinyl and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrizinyl). The terms heterocyclic and heterocycle further include bridged, fused, and spirocyclic ring systems.

[0040] As used herein by themselves or in conjunction with another term or terms, “heterocycloalkyl” and “heterocycloalkyl group” refer to 3to15 membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkyl groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused ring systems. In some instances a heterocycloalkyl group may contain at least two or heteroatoms, which may be the same or different. Heterocycloalkyl groups can be substituted or unsubstituted. In some instances a heterocycloalkyl group may contain from 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Representative examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-5-oxide, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 3,8-diaza- bicyclo[3.2.1]octanyl, 2,5-diaza-bicyclo[2.2.1]heptanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3,9- diaza-bicyclo[4.2.1]nonanyl, 2,6-diaza-bicyclo[3.2.2]nonanyl, [1,4]oxaphosphinanyl- 4-oxide, [1,4]azaphosphinanyl- 4-oxide, [1,2]oxaphospholanyl- 2-oxide, phosphinanyl-1 -oxide, [1,3]azaphospholidinynl- 3-oxide, [1,3]oxaphospholanyl- 3-oxide, 7-oxabicyclo[2.2.1]heptanyl,

6.8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl,

6.8-dihydro-5H-imidazo[1 ,2-a]pyrazin-7-yl, 5,6,8,9-tetrahydro-[1 ,2,4]triazolo[4,3- d][1,4]diazepin-7-yl and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl. Suitably, a heterocyclylalkyl group as defined herein is a monocyclic, bicyclic or spiro heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.

[0041] As used herein by themselves or in conjunction with another term or terms, “heterocycloalkylene” and “heterocycloalkylene group” refer to 3 to15 membered monocyclic, bicyclic, or tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkylene groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused. Heterocycloalkylene groups can be substituted or unsubstituted. In some instances, a heterocycloalkylene group may contain from 3 to 10 ring atoms; such as from 3 to 7 ring atoms. In other instances a heterocycloalkylene group may contain from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.

[0042] As used herein by themselves or in conjunction with another term or terms, “heterocycloalkylalkyl” and “heterocycloalkylalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a heterocycloalkyl group, wherein alkyl group and heterocycloalkyl group are as previously defined, such as, for example, pyrrolidinylmethyl (C4H8NCH2-). Heteroycloalkylalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. heterocycloalkyl(C _n-m )alkyl, the range refers to the alkyl group. Suitably, the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.

[0043] As used herein by themselves or in conjunction with another term or terms, “stable” and “chemically stable” refer to a compound that is sufficiently robust to be isolated from a reaction mixture with a useful degree of purity. The present application is directed solely to the preparation of stable compounds. When lists of alternative substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group. For example, when considering the degree of optional substitution of a particular moiety, it should be understood that the number of substituents does not exceed the valency appropriate for that moiety. For example, if R ¹ is a methyl group (-CH3), it can be optionally substituted by 1 to 3 groups.

[0044] As used herein by itself or in conjunction with another term or terms, “substituted” indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent.” It should be understood that the terms “substituent”, “substituents”, “moiety”, “moieties”, “group”, or “groups” refer to substituent(s).

[0045] As used herein “protecting group” refers to a functional group that facilitates chemoselectivity in a subsequent chemical reaction. Protecting groups are described, for example, in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2nd ed. New York; John Wiley & Sons, Inc., 1991. For a particular compound and/or a particular chemical reaction, a person skilled in the art knows how to select and implement appropriate protecting groups and synthetic methods. Examples of nitrogen protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC), and silyl groups, such as [2- (trimethylsilyl)ethoxy]methyl (SEM). Examples of carboxyl protecting groups include (1 - 6C)alkyl groups, such as methyl, ethyl and t-butyl. Examples of alcohol protecting groups include benzyl, trityl, silyl ethers, and the like.

[0046] As used herein “leaving group” refers to a molecule or a molecular fragment (e.g., an anion) that is displaced in a chemical reaction as stable species taking with it the bonding electrons. Examples of leaving groups include arylsulfonyloxy group or an alkylsulfonyloxy group, such as a mesylate or a tosylate group. Common anionic leaving groups also include halides such as Cl , Br, and I .

Compounds of Formula I

[0047] In one aspect the present invention relates to a compound of formula I, ora salt thereof:

(I), wherein,

R ¹ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a1 , C2-ioalkenyl optionally substituted by one or more R ^a1 , C^alkynyl optionally substituted by one or more R ^a1 , Ce-isaryl optionally substituted by one or more R ^a1 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a1 , C3-11 cycloalkyl optionally substituted by one or more R ^a1 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a1 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a1 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , 4-15 membered heteroaryl optionally substituted by one or more R ^a1 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)OR ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a1 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl;

R ² is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a2 , C ₂ -ioalkenyl optionally substituted by one or more R ^a2 , C _2-6 alkynyl optionally substituted by one or more R ^a2 , Ce-isaryl optionally substituted by one or more R ^a2 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a2 , C3-11 cycloalkyl optionally substituted by one or more R ^a2 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a2 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , 4-15 membered heteroaryl optionally substituted by one or more R ^a2 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a2 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- 6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-ehaloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; or

R ¹ is absent and R ² combines with the nitrogen to which it is attached to form an imino group of formula =CR ^W R ^X , an amidine of formula =C(R ^w )(NR ^y R ^z ), or a guanidine of formula =C(NR ^y R ^z ) ₂ where R ^w , R ^x are independently C1-6 alkyl and R ^y and R ^z are independently selected from hydrogen and C1-6 alkyl; or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 3-15 membered heterocycloalkyl ring or 4-15 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 ; where each R ^a3 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, 4-15 membered heteroaryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , - 0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, and 4-15 membered heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl;

R is selected from the group consisting of Ci-ioalkyl optionally substituted by one or more R ^a , C ₂ -ioalkenyl optionally substituted by one or more R ^a , C _2-6 alkynyl optionally substituted by one or more R ^a , Ce-isaryl optionally substituted by one or more R ^a , C ₆ -isaryl(Ci- e)alkyl optionally substituted by one or more R ^a , C _3-11 cycloalkyl optionally substituted by one or more R ^a , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a , 4-15 membered heterocycloalkyl(Ci- e)alkyl optionally substituted by one or more R ^a , 4-15 membered heteroaryl optionally substituted by one or more R ^a , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a ; where each R ^a is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, Ce-n aryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , NR ^d S(=0) ₂ NR ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, and Ce-n aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, phenyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl;

R ³ is selected from the group consisting of H, C1-6 alkyl, CN, -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -NR ^h R ^j , -NR ⁹ C(=0)R ^f , -NR ^h C(=0)0R ⁹ , -NR ^h C(=0)NR ^h R ^j , - NR ^h S(=0) ₂ R ^f , -NR ^h S(=0) ₂ NR ^h R ^j , -OR ⁹ , -SR ⁹ , -0C(=0)R ^f , -0C(=0)NR ^h R ^j , -0C(=0)0R ⁹ , - S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , -0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -

0S(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j , where said C1-6 alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, phenyl and O-C1-6 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl;

R ⁴ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a4 , C2-ioalkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , Ce-isaryl optionally substituted by one or more R ^a4 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a4 , C3-11 cycloalkyl optionally substituted by one or more R ^a4 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a4 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 4-15 membered heteroaryl optionally substituted by one or more R ^a4 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -OR ⁹ , -SR ⁹ , -0C(=0)R ^f , -0C(=0)NR ^h Ri, -0C(=0)0R ⁹ , - S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , -0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -

0S(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j ; where each R ^a4 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; wherein each R ^b and R ^f are independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, N0 ₂ , C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl; wherein each R ^c and R ⁹ are independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl and Ce-is aryl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl 5-6 membered heteroaryl and C3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl and O-C1-6 alkyl; wherein each R ^d and R ^h are independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; wherein each R ^e and R ^j are independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; or wherein R ^d and R ^e , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; wherein R ^h and R ^j , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; where R ^k is selected from hydrogen, =0, halogen, CN, NH ₂ , NH(Ci-e alkyl), N(Ci- ₆ alkyl) ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; with the provisos that:

(i) when R is methyl, ethyl or butyl then R ³ and R ⁴ cannot both be methyl; and

(ii) when R is optionally substituted phenyl then R ³ and R ⁴ cannot both be -SO ₂ CF ₃ . R

[0048] In one embodiment, R is selected from the group consisting of Ci-ioalkyl optionally substituted by one or more R ^a , C2-ioalkenyl optionally substituted by one or more R ^a , C2- ₆ alkynyl optionally substituted by one or more R ^a , C ₆ -isaryl optionally substituted by one or more R ^a , C ₆ -isaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , C3-11 cycloalkyl optionally substituted by one or more R ^a , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , 4-15 membered heteroaryl optionally substituted by one or more R ^a , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a ;

[0049] In another embodiment, R is selected from the group consisting of Ci- ₆ alkyl optionally substituted by one or more R ^a , C6-i2aryl optionally substituted by one or more R ^a , C3-7cycloalkyl optionally substituted by one or more R ^a , 5-12 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-12 membered heteroaryl optionally substituted by one or more R ^a .

[0050] In another embodiment, R is selected from the group consisting of C6-i2aryl optionally substituted by one or more R ^a , 5-12 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-12 membered heteroaryl optionally substituted by one or more R ^a .

[0051] In another embodiment, R is selected from the group consisting of phenyl optionally substituted by one or more R ^a , 5-10 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-10 membered heteroaryl optionally substituted by one or more R ^a .

[0052] In another embodiment, R is selected from the group consisting of phenyl optionally substituted by one or more R ^a , 5-10 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-10 membered heteroaryl optionally substituted by one or more R ^a .

[0053] In another embodiment, R is selected from the group consisting of phenyl optionally substituted by one or more R ^a , 5-7 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-6 membered heteroaryl optionally substituted by one or more R ^a .

[0054] In one embodiment, R ^a is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, Ce-n aryl, -C(=0)R ^b , -C(=0)OR ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)OR ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said Ci-e alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, and Ce-n aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1- ₆ alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[0055] In one embodiment, R ^a is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , - NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , - 0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[0056] In another embodiment, R ^a is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , -C(=0)NR ^d R ^e , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , - OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , - S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, 0-Ci- ₆ alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[0057] In another embodiment, R ^a is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , -C(=0)NR ^d R ^e , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , - OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -S(=0)NR ^d R ^e and - S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl. [0058] In another embodiment, R ^a is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci-e haloalkoxy, Ci-e alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -NR ^d R ^e , -OR ^c , -SR ^C , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[0059] In another embodiment, R ^a is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[0060] In another embodiment, R ^a is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[0061] In another embodiment, R ^a is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[0062] Suitably, R is selected from the group consisting of phenyl optionally substituted by one or more R ^a , 5-7 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-6 membered heteroaryl optionally substituted by one or more R ^a , wherein R ^a is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, where said C1-6 alkyl and O-C1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

R ¹

[0063] In one embodiment, R ¹ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a1 , C2-ioalkenyl optionally substituted by one or more R ^a1 , C2-6alkynyl optionally substituted by one or more R ^a1 , Ce-isaryl optionally substituted by one or more R ^a1 , C ₆ -isaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , C3-11 cycloalkyl optionally substituted by one or more R ^a1 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a1 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a1 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , 4-15 membered heteroaryl optionally substituted by one or more R ^a1 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b .

[0064] In another embodiment, R ¹ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a1 , C^alkenyl optionally substituted by one or more R ^a1 , C^alkynyl optionally substituted by one or more R ^a1 , C6-i2aryl optionally substituted by one or more R ^a1 , C6-i2aryl(Ci-3)alkyl optionally substituted by one or more R ^a1 , C3-iocycloalkyl optionally substituted by one or more R ^a1 , C3-iocycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a1 , 3-12 membered heterocycloalkyl optionally substituted by one or more R ^a1 , 4-12 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , 4-12 membered heteroaryl optionally substituted by one or more R ^a1 , and 4-12 membered heteroaryl(Ci-3)alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b .

[0065] In another embodiment, R ¹ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a1 , C^alkenyl optionally substituted by one or more R ^a1 , C^alkynyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)OR ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b .

[0066] In another embodiment, R ¹ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)OR ^c , -C(=0)NR ^d R ^e , and - C(0)C(=0)R ^b .

[0067] In another embodiment, R ¹ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , and -C(=0)NR ^d R ^e .

[0068] In another embodiment, R ¹ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a1 , and -C(=0)NR ^d R ^e .

[0069] In another embodiment, R ¹ is hydrogen or Ci- ₆ alkyl optionally substituted by one or more R ^a1 . [0070] In one embodiment, R ^a1 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci-e haloalkoxy, Ci-e alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , - NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , - 0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[0071] In another embodiment, R ^a1 is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , -C(=0)NR ^d R ^e , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , - OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , - S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, 0-Ci- ₆ alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[0072] In another embodiment, R ^a1 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , -C(=0)NR ^d R ^e , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , - OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -S(=0)NR ^d R ^e and - S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[0073] In another embodiment, R ^a1 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -NR ^d R ^e , -OR ^c , -SR ^C , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl. [0074] In another embodiment, R ^a1 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci-e haloalkoxy, Ci-e alkyl, O-C1- ₆ alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, where said Ci-e alkyl, O-Ci-e alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-e haloalkyl, Ci-e haloalkoxy, C _3-6 cycloalkyl, Ci-e alkyl, O-Ci-e alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[0075] In another embodiment, R ^a1 is independently selected from hydroxyl, =0, halogen, CN, C1- ₆ haloalkyl, Ci-e haloalkoxy, Ci-ealkyl, O-Ci-e alkyl, where said Ci-ealkyl and O-Ci-e alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-e haloalkyl, Ci-e haloalkoxy, C _3-6 cycloalkyl, Ci-ealkyl, O-Ci-e alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[0076] In another embodiment, R ^a1 is independently selected from hydroxyl, =0, halogen, CN, C1- ₆ haloalkyl, Ci-e haloalkoxy, Ci-ealkyl, O-C1- ₆ alkyl, where said Ci-ealkyl and O-C1- ₆ alkyl are optionally substituted with one or more groups selected from hydroxyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[0077] In another embodiment, R ^a1 is independently selected from hydroxyl, Ci-e haloalkyl, Ci- 6 haloalkoxy, Ci-e alkyl, O-Ci-e alkyl, where said Ci-e alkyl and O-C1- ₆ alkyl are optionally substituted with one or more groups selected from hydroxyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

R ²

[0078] In one embodiment, R ² is selected from the group consisting of hydrogen, Ci-ealkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , C^alkynyl optionally substituted by one or more R ^a2 , C6-i2aryl optionally substituted by one or more R ^a2 , C6-i2aryl(Ci-3)alkyl optionally substituted by one or more R ^a2 , C3-7cycloalkyl optionally substituted by one or more R ^a2 , C3-7cycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a2 , 3-12 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 4-12 membered heterocycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a2 , 4-12 membered heteroaryl optionally substituted by one or more R ^a2 , and 4-12 membered heteroaryl(Ci-3)alkyl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b .

[0079] In one embodiment, R ² is selected from the group consisting of hydrogen, Ci-ealkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , phenyl optionally substituted by one or more R ^a2 , phenyl(Ci-3)alkyl optionally substituted by one or more R ^a2 , C3-7cycloalkyl optionally substituted by one or more R ^a2 , C3-7cycloalkyl(Ci- 3)alkyl optionally substituted by one or more R ^a2 , 3-12 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 4-12 membered heterocycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a2 , 4-12 membered heteroaryl optionally substituted by one or more R ^a2 , and 4-12 membered heteroaryl(Ci-3)alkyl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b .

[0080] In one embodiment, R ² is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , C^alkynyl optionally substituted by one or more R ^a2 , C ₆ -naryl optionally substituted by one or more R ^a2 , C^cycloalkyl optionally substituted by one or more R ^a2 , 5-12 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 5-12 membered heteroaryl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , and - C(0)C(=0)R ^b .

[0081] In one embodiment, R ² is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , phenyl optionally substituted by one or more R ^a2 , C^cycloalkyl optionally substituted by one or more R ^a2 , 4-7 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 4- 12 membered heteroaryl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)OR ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b .

[0082] In one embodiment, R ² is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , phenyl optionally substituted by one or more R ^a2 , C^cycloalkyl optionally substituted by one or more R ^a2 , 4-7 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 5- 6 membered heteroaryl optionally substituted by one or more R ^a2 , -C(=0)R ^b , and - C(=0)NR ^d R ^e .

[0083] In one embodiment, R ² is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , phenyl optionally substituted by one or more R ^a2 , C^cycloalkyl optionally substituted by one or more R ^a2 , 4-7 membered heterocycloalkyl optionally substituted by one or more R ^a2 , and 5-6 membered heteroaryl optionally substituted by one or more R ^a2 .

[0084] In one embodiment, R ² is hydrogen or Ci- ₆ alkyl optionally substituted by one or more R ^a2 . [0085] In one embodiment, R ^a2 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci-e haloalkoxy, Ci-e alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , - NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , - 0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[0086] In another embodiment, R ^a2 is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , -C(=0)NR ^d R ^e , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , - OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , - S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, 0-Ci- ₆ alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[0087] In another embodiment, R ^a2 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , -C(=0)NR ^d R ^e , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , - OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -S(=0)NR ^d R ^e and - S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[0088] In another embodiment, R ^a2 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -NR ^d R ^e , -OR ^c , -SR ^C , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl. [0089] In another embodiment, R ^a2 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci-e haloalkoxy, Ci-e alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[0090] In another embodiment, R ^a2 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[0091] In another embodiment, R ^a2 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[0092] In another embodiment, R ^a2 is independently selected from hydroxyl, C _1-6 haloalkyl, Ci- ₆ haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

R ¹ and R ²

[0093] In one embodiment, R ¹ is absent and R ² combines with the nitrogen to which it is attached to form an imino group of formula =CR ^W R ^X , an amidine of formula =C(R ^w )(NR ^y R ^z ), or a guanidine of formula =C(NR ^y R ^z )2, where R ^w , R ^x are independently C1-6 alkyl and R ^y and R ^z are independently selected from hydrogen and C1-6 alkyl.

[0094] In another embodiment, R ¹ is absent and R ² combines with the nitrogen to which it is attached to form an amidine of formula =C(R ^w )(NR ^y R ^z ), or a guanidine of formula =C(NR ^y R ^z ) ₂ , where R ^w , R ^x are independently C _1-3 alkyl and R ^y and R ^z are independently selected from hydrogen and C _1-3 alkyl.

[0095] In one embodiment, R ¹ and R ² together with the nitrogen atom to which they are attached form a 3-12 membered heterocycloalkyl ring or 4-12 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

[0096] In one embodiment, R ¹ and R ² together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl ring or 5-12 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

[0097] In one embodiment, R ¹ and R ² together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloalkyl ring or 5-12 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

[0098] In one embodiment, R ¹ and R ² together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloalkyl ring or 5-10 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

[0099] In one embodiment, R ¹ and R ² together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloalkyl ring or 5-6 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

[00100] In one embodiment, R ^a3 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci-e haloalkoxy, Ci-e alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C(=0)R ^b , -C(=0)OR ^c , -C(=0)NR ^d R ^e , - C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)OR ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , - NR ^d S(=0) ₂ NR ^d R ^e , -OR ^c , -SR ^C , -OC(=0)R ^b , -OC(=0)NR ^d R ^e , -OC(=0)OR ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -OS(=0)R ^c , -OS(=0) ₂ R ^c , -OS(=0) ₂ OR ^c , -S(=0)NR ^d R ^e , -OS(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[00101] In another embodiment, R ^a3 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C(=0)R ^b , -C(=0)NR ^d R ^e , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , -OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , - 0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci-e alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1- ₆ alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[00102] In another embodiment, R ^a3 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C(=0)R ^b , -C(=0)NR ^d R ^e , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , -OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , - 0S(=0)R ^c , -S(=0)NR ^d R ^e and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, 0-Ci- ₆ alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00103] In another embodiment, R ^a3 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -NR ^d R ^e , -OR ^c , -SR ^C , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00104] In another embodiment, R ^a3 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00105] In another embodiment, R ^a3 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl. [00106] In another embodiment, R ^a3 is independently selected from hydroxyl, =0, halogen, CN, Ci-e haloalkyl, Ci-e haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, where said C1-6 alkyl and O-C1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[00107] In another embodiment, R ^a3 is independently selected from hydroxyl, =0, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1.6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00108] In one embodiment, R ¹ and R ² together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloalkyl ring or 5-6 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more substituents selected from hydroxyl, =0, C1-6 haloalkyl, Ci-ealkyl, O-C1-6 alkyl, where said C1-6 alkyl is optionally substituted with one or more groups selected from hydroxyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[00109] In one embodiment, R ¹ and R ² are independently selected from hydrogen or Ci-ealkyl optionally substituted by one or more R ^a1 or R ^a2 respectively; or

R ¹ and R ² together with the nitrogen atom to which they are attached, form a 3-15 membered heterocycloalkyl ring or 4-15 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

[00110] In one embodiment, R ¹ and R ² are independently selected from hydrogen or Ci-ealkyl optionally substituted by one or more R ^a1 or R ^a2 respectively; or,

R ¹ and R ² together with the nitrogen atom to which they are attached, form a 4-12 membered heterocycloalkyl ring or 5-12 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

[00111] In one embodiment, R ¹ and R ² are independently selected from hydrogen or Ci-ealkyl optionally substituted by one or more R ^a1 or R ^a2 respectively; or,

R ¹ and R ² together with the nitrogen atom to which they are attached, form a 5-10 membered heterocycloalkyl ring or 5-10 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

[00112] In one embodiment, R ¹ and R ² are independently selected from hydrogen or Ci-3alkyl optionally substituted by one or more R ^a1 or R ^a2 respectively; or,

R ¹ and R ² together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycloalkyl ring or 5-6 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

[00113] In one embodiment, R ¹ is hydrogen and R ² is hydrogen.

R ³

[00114] In one embodiment, R ³ is selected from the group consisting of H, Ci- ₆ alkyl, CN, -C(=0)R ^f , -C(=0)OR ⁹ , -C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -NR ^h R ^j , -NR ⁹ C(=0)R ^f , - NR ^h C(=0)OR ⁹ , -NR ^h C(=0)NR ^h R ^j , -NR ^h S(=0) ₂ R ^f , -NR ^h S(=0) ₂ NR ^h R ^j , -OR ⁹ , -SR ⁹ , - OC(=0)R ^f , -OC(=0)NR ^h R ^j , -OC(=0)OR ⁹ , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -OS(=0)R ⁹ , -0S(=0) ₂ R ⁹ , - 0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -OS(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R, where said Ci- ₆ alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-e haloalkyl, Ci- ₆ haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, and O-C1-6 alkyl.

[00115] In one embodiment, R ³ is selected from the group consisting of H, C1-6 alkyl, CN, -C(=0)R ^f , -C(=0)NR ^h R ^j , -OR ⁹ , -SR ⁹ , -OC(=0)R ^f , -OC(=0)NR ^h R, -OC(=0)OR ⁹ , - S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -OS(=0)R ⁹ , -0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -

OS(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j , where said C1-6 alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl.

[00116] In one embodiment, R ³ is selected from the group consisting of H, C1-6 alkyl, CN, -C(=0)R ^f , -C(=0)NR ^h R ^j , -OR ⁹ , -0C(=0)R ^f , -0C(=0)NR ^h R, -0C(=0)0R ⁹ , where said C1-6 alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl.

[00117] In one embodiment, R ³ is selected from the group consisting of H, C1-6 alkyl, CN, -C(=0)R ^f , -C(=0)0R ⁹ , -C(=0)NR ^h R ^j , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , — S(=0)NR ^h R, and - S(=0) ₂ NR ^h R ^j , where said C1-6 alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-e haloalkyl, Ci-e haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl.

[00118] In one embodiment, R ³ is selected from the group consisting of H, C1-6 alkyl, CN, -C(=0)R ^f and -C(=0)NR ^h R ^j , where said C _1-6 alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl.

[00119] In one embodiment, R ³ is selected from the group consisting of H, C _1-3 alkyl, CN, -C(=0)R ^f and -C(=0)NR ^h R ^j , where said C _1-3 alkyl is optionally substituted with one or more groups selected from hydroxyl, CN, C _1-3 haloalkyl, C _1-3 haloalkoxy, C _3-6 cycloalkyl, and O-C _1-3 alkyl.

R ⁴

[00120] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- _l oalkyl optionally substituted by one or more R ^a4 , C2-ioalkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , Ce-isaryl optionally substituted by one or more R ^a4 , C ₆ -isaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , C3- ₁₁ cycloalkyl optionally substituted by one or more R ^a4 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a4 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 4-15 membered heteroaryl optionally substituted by one or more R ^a4 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -OR ⁹ , -SR ⁹ , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , -0S(=0) ₂ R ⁹ , - 0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -0S(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R.

[00121] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a4 , C _2-6 alkenyl optionally substituted by one or more R ^a4 , C _2-6 alkynyl optionally substituted by one or more R ^a4 , Ce-naryl optionally substituted by one or more R ^a4 , C ₆ -naryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , C3-7cycloalkyl optionally substituted by one or more R ^a4 , C3-7cycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a4 , 5-12 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 5-12 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 5-12 membered heteroaryl optionally substituted by one or more R ^a4 , and 5-12 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -OR ⁹ , -SR ⁹ , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -S(=0)NR ^h R, and -S(=0) ₂ NR ^h R. [00122] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- _l oalkyl optionally substituted by one or more R ^a4 , C2-ioalkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , C6-i2aryl optionally substituted by one or more R ^a4 , C6-i2aryl(Ci-3)alkyl optionally substituted by one or more R ^a4 , C3-7cycloalkyl optionally substituted by one or more R ^a4 , C3-7cycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a4 , 3-12 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 4-12 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 4-12 membered heteroaryl optionally substituted by one or more R ^a4 , and 4-12 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)OR ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -OR ⁹ , -SR ⁹ , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -OS(=0)R ⁹ , -0S(=0) ₂ R ⁹ , - 0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -OS(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h Ri.

[00123] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- _l oalkyl optionally substituted by one or more R ^a4 , C2-ioalkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , C6-i2aryl optionally substituted by one or more R ^a4 , C6-i2aryl(Ci-3)alkyl optionally substituted by one or more R ^a4 , C^cycloalkyl optionally substituted by one or more R ^a4 , C3-7cycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a4 , 3-12 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 4-12 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 4-12 membered heteroaryl optionally substituted by one or more R ^a4 , and 4-12 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)OR ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -OR ⁹ , -SR ⁹ , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -S(=0)NR ^h R ^j , and - S(=0) ₂ NR ^h R ^j .

[00124] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- _l oalkyl optionally substituted by one or more R ^a4 , C2-ioalkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , C6-i2aryl optionally substituted by one or more R ^a4 , C6-i2aryl(Ci-3)alkyl optionally substituted by one or more R ^a4 , C^cycloalkyl optionally substituted by one or more R ^a4 , C3-7cycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a4 , 3-12 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 4-12 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 4-12 membered heteroaryl optionally substituted by one or more R ^a4 , and 4-12 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)OR ⁹ , - C(=0)NR ^h R ^j , -OR ⁹ , -SR ⁹ , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -S(=0)NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j .

[00125] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a4 , C^alkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , phenyl optionally substituted by one or more R ^a4 , phenyl(Ci-3)alkyl optionally substituted by one or more R ^a4 , C3-7cycloalkyl optionally substituted by one or more R ^a4 , C3-7cycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a4 , 5-10 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 5-10 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 5-10 membered heteroaryl optionally substituted by one or more R ^a4 , and 5-10 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)OR ⁹ , - C(=0)NR ^h R ^j , -OR ⁹ , -SR ⁹ , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -S(=0)NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j .

[00126] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a4 , C^alkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , phenyl optionally substituted by one or more R ^a4 , phenyl(Ci-3)alkyl optionally substituted by one or more R ^a4 , 5-10 membered heteroaryl optionally substituted by one or more R ^a4 , and 5-10 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)OR ⁹ , - C(=0)NR ^h R ^j , -OR ⁹ , and -SR ⁹ .

[00127] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a4 , C^alkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , phenyl optionally substituted by one or more R ^a4 , phenyl(Ci-3)alkyl optionally substituted by one or more R ^a4 , 5-10 membered heteroaryl optionally substituted by one or more R ^a4 , and CN, -C(=0)R ^f , - C(=0)OR ⁹ , -C(=0)NR ^h R ^j , -OR ⁹ , and -SR ⁹ .

[00128] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a4 , C^alkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , phenyl optionally substituted by one or more R ^a4 ·, phenyl(Ci-3)alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)OR ⁹ , -C(=0)NR ^h R ^j , -OR ⁹ , and -SR ⁹ .

[00129] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a4 , C _2-6 alkynyl optionally substituted by one or more R ^a4 , phenyl optionally substituted by one or more R ^a4 ·, benzyl optionally substituted by one or more R ^a4 ·, -C(=0)R ^f , -C(=0)OR ⁹ , -C(=0)NR ^h R ^j and -SR ⁹ .

[00130] In one embodiment, R ⁴ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a4 , C _2-6 alkynyl optionally substituted by one or more R ^a4 , phenyl optionally substituted by one or more R ^a4 ·, benzyl optionally substituted by one or more R ^a4 ·, -C(=0)R ^f , -C(=0)0R ⁹ , -C(=0)NR ^h Ri and -SR ⁹ .

[00131] In one embodiment, R ^a4 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci-e haloalkoxy, Ci-e alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , - C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , - NR ^d S(=0) ₂ NR ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[00132] In another embodiment, R ^a4 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C(=0)R ^b , -C(=0)NR ^d R ^e , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , -OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , - 0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C ₁ - ₆ alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00133] In another embodiment, R ^a4 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C(=0)R ^b , -C(=0)NR ^d R ^e , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , -OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , - 0S(=0)R ^c , -S(=0)NR ^d R ^e and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, 0-Ci- ₆ alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00134] In another embodiment, R ^a4 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -NR ^d R ^e , -OR ^c , -SR ^C , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00135] In another embodiment, R ^a4 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00136] In another embodiment, R ^a4 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00137] In another embodiment, R ^a4 is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, where said C1-6 alkyl and O-C1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

[00138] In another embodiment, R ^a4 is independently selected from hydroxyl, =0, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00139] In one embodiment, R ^b and R ^f are independently selected from hydrogen, CN, 3-7 membered heterocycloalkyl, 5-15 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-15 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00140] In another embodiment, R ^b and R ^f are independently selected from hydrogen, CN, 3-7 membered heterocycloalkyl, 5-12 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, O- C _1-6 alkyl, Ce- ₁₂ aryl, C ₆ -i ₂ aryl(Ci- ₃ )alkyl, C ₃ -ncycloalkyl(Ci- ₃ )alkyl, 4-12 membered heterocycloalkyl(Ci- ₃ )alkyl, and 4-12 membered heteroaryl(Ci- ₃ )alkyl, wherein said C _1-6 alkyl, Ce- ₁₂ aryl, 3-7 membered heterocycloalkyl, 5-12 membered heteroaryl, C _3-6 cycloalkyl, C ₆ - i ₂ aryl(Ci- ₃ )alkyl, C ₃ -ncycloalkyl(Ci- ₃ )alkyl, 4-12 membered heterocycloalkyl(Ci- ₃ )alkyl, and 4- 12 membered heteroaryl(Ci- ₃ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , Ci-e haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00141] In another embodiment, R ^b and R ^f are independently selected from hydrogen, 3-7 membered heterocycloalkyl, 5-12 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, Ce- ₁₂ aryl, C ₆ -i ₂ aryl(Ci- ₃ )alkyl, C ₃ -ncycloalkyl(Ci- ₃ )alkyl, 4-12 membered heterocycloalkyl(Ci- ₃ )alkyl, and 4-12 membered heteroaryl(Ci- ₃ )alkyl, wherein said C _1-6 alkyl, Ce- ₁₂ aryl, 3-7 membered heterocycloalkyl, 5-12 membered heteroaryl, C _3-6 cycloalkyl, Ce- i ₂ aryl(Ci- ₃ )alkyl, C ₃ -ncycloalkyl(Ci- ₃ )alkyl, 4-12 membered heterocycloalkyl(Ci- ₃ )alkyl, and 4- 12 membered heteroaryl(Ci- ₃ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , Ci-e haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00142] In another embodiment, R ^b and R ^f are independently selected from hydrogen, C1-6 alkyl, O-C1-6 alkyl, Ce-12 aryl, C6-i2aryl(Ci-3)alkyl, wherein said C1-6 alkyl, Ce-12 aryl, Ce- i ₂ aryl(Ci- ₃ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci- ₆ alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00143] In another embodiment, R ^b and R ^f are independently selected from hydrogen, phenyl, phenyl(Ci- ₃ )alkyl, wherein said phenyl and phenyl(Ci- ₃ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl. [00144] In one embodiment, wherein each R ^c and R ⁹ are independently selected from hydrogen, halogen, CN, Ci-e haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl and Ce-is aryl, wherein said C _1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl 5-6 membered heteroaryl and C _3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl.

[00145] In another embodiment, each R ^c and R ⁹ are independently selected from hydrogen, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl and Ce- ₁₂ aryl, wherein said C _1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl 5-6 membered heteroaryl and C _3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl.

[00146] In another embodiment, each R ^c and R ⁹ are independently selected from hydrogen, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl and phenyl, wherein said C _1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl 5-6 membered heteroaryl and C _3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl.

[00147] In another embodiment, each R ^c and R ⁹ are independently selected from hydrogen, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _1-6 alkyl and phenyl, wherein said C _1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl.

[00148] In one embodiment, R ^d and R ^h are independently selected from hydrogen, CN, C _1-6 haloalkyl, C _3-6 cycloalkyl, and C _1-6 alkyl.

[00149] In another embodiment, R ^d and R ^h are independently selected from hydrogen,

C _3-6 cycloalkyl and C _1-6 alkyl.

[00150] In another embodiment, R ^d and R ^h are independently selected from hydrogen, and C1-3 alkyl. [00151] In one embodiment, R ^e and R ^j are independently selected from hydrogen, CN, Ci- ₆ haloalkyl, 3-7 membered heterocycloalkyl, 5-15 membered heteroaryl, C _3-6 cycloalkyl, Ci- ₆ alkyl, O-C _1-6 alkyl, Ce-is aryl, C ₆ -i ₅ aryl(Ci-e)alkyl, C ₃ -ncycloalkyl(Ci- ₆ )alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C _1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-15 membered heteroaryl, C _3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C ₃ -ncycloalkyl(Ci- ₆ )alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00152] In another embodiment, R ^e and R ^j are independently selected from hydrogen, CN, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-12 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, Ce- ₁₂ aryl, C ₆ -i ₂ aryl(Ci- ₃ )alkyl, C ₃ -ncycloalkyl(Ci- ₃ )alkyl, 4-12 membered heterocycloalkyl(Ci- ₃ )alkyl, and 4-12 membered heteroaryl(Ci- ₃ )alkyl, wherein said C _1-6 alkyl, Ce- ₁₂ aryl, 3-7 membered heterocycloalkyl, 5-12 membered heteroaryl, C _3-6 cycloalkyl, Ce- i ₂ aryl(Ci- ₃ )alkyl, C ₃ -ncycloalkyl(Ci- ₃ )alkyl, 4-12 membered heterocycloalkyl(Ci- ₃ )alkyl, and 4- 12 membered heteroaryl(Ci- ₃ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , Ci-e haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00153] In another embodiment, R ^e and R ^j are independently selected from hydrogen, 3-7 membered heterocycloalkyl, 5-12 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, Ce- ₁₂ aryl, C ₆ -i ₂ aryl(Ci- ₃ )alkyl, C ₃ -ncycloalkyl(Ci- ₃ )alkyl, 4-12 membered heterocycloalkyl(Ci- ₃ )alkyl, and 4-12 membered heteroaryl(Ci- ₃ )alkyl, wherein said C _1-6 alkyl, Ce-^ aryl, 3-7 membered heterocycloalkyl, 5-12 membered heteroaryl, C _3-6 cycloalkyl, C ₆ -i ₂ aryl(Ci- ₃ )alkyl, C ₃ - iicycloalkyl(Ci- ₃ )alkyl, 4-12 membered heterocycloalkyl(Ci- ₃ )alkyl, and 4-12 membered heteroaryl(Ci- ₃ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci- ₆ alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00154] In another embodiment, R ^e and R ^j are independently selected from hydrogen, C _3-6 cycloalkyl, C _1-6 alkyl, Ce-^aryl, C ₆ -i ₂ aryl(Ci- ₃ )alkyl, C ₃ -ncycloalkyl(Ci- ₃ )alkyl, wherein said C _1-6 alkyl, Ce- ₁₂ aryl, C _3-6 cycloalkyl, C ₆ -i ₂ aryl(Ci- ₃ )alkyl, and C ₃ -ncycloalkyl(Ci- ₃ )alkyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , Ci- ₆ haloalkyl, C _3-6 cycloalkyl, C _6-11 aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00155] In another embodiment, R ^e and R ^j are independently selected from hydrogen, C _3-6 cycloalkyl, C _1-6 alkyl, phenyl, pheny(Ci- ₃ )alkyl, C _3-6 cycloalkyl(Ci- ₃ )alkyl, wherein said C _1-6 alkyl, phenyl, C _3-6 cycloalkyl, phenyl(Ci- ₃ )alkyl, and C _3-6 cycloalkyl(Ci- ₃ )alkyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00156] In another embodiment, R ^e and R ^j are independently selected from hydrogen, C _1-3 alkyl, phenyl, and pheny(Ci- ₃ )alkyl, wherein said C _1-3 alkyl, phenyl and phenyl(Ci- ₃ )alkyl, , are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

[00157] In one embodiment, R ^d and R ^e , when attached to the same atom, together with the atom to which they are attached form a 5-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k .

[00158] In one embodiment, R ^h and R ^j , when attached to the same atom, together with the atom to which they are attached form a 5-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k .

[00159] In one embodiment, R ^k is selected from =0, halogen, CN, NH ₂ , NH(Ci-e alkyl), N(Ci- ₆ alkyl) ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5-7 membered heterocycloalkyl, C _1-6 alkyl and O-C1-6 alkyl.

[00160] In another embodiment, R ^k is selected from =0, halogen, CN, NH ₂ , NH(Ci-e alkyl), N(Ci-6alkyl)2, C1-6 haloalkyl, C1-6 alkyl and O-C1-6 alkyl.

[00161] In another embodiment, R ^k is selected from =0, halogen, CN, NH ₂ , NH(CI- ₃ alkyl), N(Ci3alkyl)2, C1-6 haloalkyl, C1-6 alkyl and O-C1-6 alkyl.

[00162] In another embodiment, R ^k is selected from =0, halogen, CN, NH ₂ , NHMe, N(Me)2, C1-3 haloalkyl, C1-3 alkyl and O-C1.3 alkyl. [00163] In one embodiment R’ and R” are independently selected from methyl, ethyl or propyl; preferably methyl or ethyl.

[00164] In one embodiment, there is provided a compound of formula I, ora salt thereof, wherein:

R is selected from the group consisting of C6-i2aryl optionally substituted by one or more R ^a , 5-12 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-12 membered heteroaryl optionally substituted by one or more R ^a ;

R ¹ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , and -C(=0)NR ^d R ^e ;

R ² is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , phenyl optionally substituted by one or more R ^a2 , C3-7cycloalkyl optionally substituted by one or more R ^a2 , 4-7 membered heterocycloalkyl optionally substituted by one or more R ^a2 , and 5-6 membered heteroaryl optionally substituted by one or more R ^a2 ; or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloalkyl ring or 5-6 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 ;

R ³ is selected from the group consisting of H, Ci-e alkyl, CN, -C(=0)R ^f , -C(=0)OR ⁹ , - C(=0)NR ^h R ^j , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , — S(=0)NR ^h Ri, and -S(=0) ₂ NR ^h R ^j , where said Ci- ₆ alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; and

R ⁴ is selected from the group consisting of hydrogen, Ci-ealkyl optionally substituted by one or more R ^a4 , C _2-6 alkynyl optionally substituted by one or more R ^a4 , phenyl optionally substituted by one or more R ^a4 ·, benzyl optionally substituted by one or more R ^a4 ·, -C(=0)R ^f , -C(=0)0R ⁹ , -C(=0)NR ^h R ^j and -SR ⁹ . where R ^a , R ^a1 , R ^a2 , R ^a3 , R ^a4 , R ^b , R ^d , R ^e , R ^f , R ⁹ , R ^h , and R ^j are as defined in any one of the above mentioned embodiments. [00165] Suitably, R ³ is selected from the group consisting of H, C1-3 alkyl, CN, -C(=0)R ^f and -C(=0)NR ^h R ^j , where said C1-3 alkyl is optionally substituted with one or more groups selected from hydroxyl, CN, Ci-3haloalkyl, Ci-3haloalkoxy, C3-6 cycloalkyl, and O-C1-3 alkyl

[00166] In another embodiment, there is provided a compound of formula I, or a salt thereof, wherein:

R is selected from the group consisting of phenyl optionally substituted by one or more R ^a , 5- 7 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-6 membered heteroaryl optionally substituted by one or more R ^a , wherein R ^a is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, where said C1-6 alkyl and O-C1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl;

R ¹ is hydrogen or Ci- ₆ alkyl optionally substituted by one or more R ^a1 ;

R ² is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , phenyl optionally substituted by one or more R ^a2 , C3-7cycloalkyl optionally substituted by one or more R ^a2 , 4-7 membered heterocycloalkyl optionally substituted by one or more R ^a2 , and 5-6 membered heteroaryl optionally substituted by one or more R ^a2 ; or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 3-12 membered heterocycloalkyl ring or 4-12 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 ;

R ³ is selected from the group consisting of H, C _1-3 alkyl, CN, -C(=0)R ^f and -C(=0)NR ^h R ^j , where said C _1-3 alkyl is optionally substituted with one or more groups selected from hydroxyl, CN, C _1-3 haloalkyl, C _1-3 haloalkoxy, C _3-6 cycloalkyl, and O-C _1-3 alkyl; and

R ⁴ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , phenyl optionally substituted by one or more R ^a4 ·, benzyl optionally substituted by one or more R ^a4 ·, -C(=0)R ^f , -C(=0)0R ⁹ , -C(=0)NR ^h R ^j and -SR ⁹ . where R ^a , R ^a1 , R ^a2 , R ^a3 , R ^a4 , R ^f , R ⁹ , R ^h , and R ^j are as defined in any one of the above mentioned embodiments. Process for Preparation of Formula I

[00167] In one aspect the present invention relates to a process for preparing a compound of formula I, or a salt thereof, wherein formula I is defined in any of the foregoing aspects and embodiments.

[00168] A compound of formula I, in one embodiment, is prepared according to Scheme 1 (below):

Scheme 1

[00169] In one aspect, the present invention relates to a process for preparing a compound of formula I, or a salt thereof:

(I),

(i) reacting a compound of formula la:

(la), with a reactant suitable for introducing group R ³ to give a compound of formula lb:

(lb); and/or deprotecting a compound of formula lb to yield a compound of formula lc:

(lc), and/or reacting a compound of formula lc with a reactant suitable for introducing group R ⁴ to give a compound of formula I; and

(ii) optionally preparing a salt of formula I; wherein: P ³ is a nitrogen protecting group of formula -SO2R ⁶ orC(0)R ⁸ , wherein R ⁶ is selected from C1-6 alkyl, Ci- ₆ haloalkyl, -ChhChhSiMes, or a phenyl group optionally substituted with one or more groups selected from NO2 _, halogen and methyl; and wherein R ⁸ is selected from methyl, phenyl, O-f-butyl and O-benzyl (OBn), wherein said phenyl is optionally substituted by NO2, halogen, OMe or CF ₃ ; and

R, R ¹ , R ² , R ³ and R ⁴ are as defined in any one of the foregoing aspects and embodiments of the invention.

[00170] In one embodiment, P ³ is a nitrogen protecting group of formula -SO2R ⁶ .

[00171] In another embodiment, P ³ is a nitrogen protecting group of formula C(0)R ⁸ . For example, P ³ may be the Cbz group (C(O)OBn) or the BOC group (C(O)OfBu).

[00172] In one embodiment, P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-

(Trimethylsilyl)ethanesulfonyl (SES), te/f-Butylsulfonyl (Bus), Cbz, and BOC.

[00173] In one embodiment, P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-

(Trimethylsilyl)ethanesulfonyl (SES), and te/f-Butylsulfonyl (Bus).

[00174] In another embodiment, P ³ is selected from nosyl, tosyl, brosyl and mesyl.

[00175] In another embodiment, P ³ is selected from nosyl and tosyl, suitably nosyl.

[00176] In one embodiment, the reactant suitable for introducing group R ³ is R ³ -X ² wherein X ² is a leaving group. Suitably, X ² is halo, for instance Cl or Br.

[00177] In another embodiment, the reactant suitable for introducing group R ³ is (ii) R ^j - N=C=0, when R ³ is -C(=0)NR ^h Ri, and R ^h is H.

[00178] In another embodiment, the reactant suitable for introducing group R ³ is R ³ - CHO, when R ³ is C1-6 alkyl. Suitably, this reaction is performed in the presence of a reducing agent, such a hydride reducing agent, for instance sodium borohydride (NaBFU), sodium triacetoxyborohydride (NaBH(OAc)3), or sodium cyanoborohydride (NaCNBHs).

[00179] In one embodiment, P ³ is a nosyl group and the deprotection of formula lb to give a compound according to formula lc is performed using a thiolate nucleophile. Suitable thiolate nucleophiles are, for example, thiophenol, thioglycolic acid, Ci-2oalkyl-SH. Removal of the nosyl may be carried out in the presence of a base, such a carbonate or hydroxide base. Non-nucleophilic bases can also be used such as DBU. [00180] In one embodiment, P ³ is nosyl and the deprotection of formula lb to give a compound according to formula lc is performed using Ci2alkyl-SH and DBU. Suitably, in acetonitrile at about 0°C.

[00181] In another embodiment, P ³ is nosyl and the and the deprotection of formula lb to give a compound according to formula lc is performed using a reducing agent, such as sodium amalgam (Na(Hg)), aluminium amalgam, magnesium, samarium(ll) iodide), tin hydrides (tributyltin hydride) and transition metal complexes with reducing agents.

[00182] In another embodiment, P ³ is SES and the deprotection of formula lb to give a compound according to formula lc is performed using a source of fluoride. Suitably, the source of fluoride is selected from TBAF, cesium fluoride, potassium fluoride and HF.

[00183] In another embodiment, P ³ is Bus, tosyl, brosyl and mesyl and the deprotection of formula lb to give a compound according to formula lc is performed using an acid. In one embodiment, the acid is a strong acid. In one embodiment, the acid is selected from TFA, MsOH, TfOH. Suitably, the acid is TFA. In one embodiment, an excess of TFA is used to deprotect formula lb to give a compound of formula lc, suitably in dichloromethane (DCM) at ambient temperature.

[00184] In one embodiment, the reactant suitable for introducing group R ⁴ is selected from:

(i) R ⁴ -B ¹ when R ⁴ is C ₆ -isaryl optionally substituted by one or more R ^a4 or 4-15 membered heteroaryl optionally substituted by one or more R ^a4 , C2-ioalkenyl optionally substituted by one or more R ^a4 and C^alkynyl optionally substituted by one or more R ^a4 , and wherein B ¹ is a boronic acid, a boronic acid ester, a cyclic boronic acid ester, an organotrifluoroborate potassium salt, cyclic trio I bo rate, organoborane, or MIDA boronate;

(ii) X ³ -C(=0)0R ⁹ when R ⁴ is -C(=0)OR ⁹ , wherein X ³ is a leaving group, suitably halo, for instance Cl, Br or I;

(iii) R ⁴ -X ⁴ when R ⁴ is Ci-ioalkyl optionally substituted by one or more R ^a4 , C2-ioalkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , C6-i5aryl optionally substituted by one or more R ^a4 , 4-15 membered heteroaryl optionally substituted by one or more R ^a4 , C ₆ -isaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , C(=0)NR ^h R ^j , -C(=0)R ^f , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -S(=0)NR ^h Ri and -S(=0) ₂ NR ^h Ri and wherein X ⁴ is a leaving group, suitably halo, for instance F, Cl, Br or I;

(iv) TMS-R ⁴ when R ⁴ is CF ₃ or CN. [00185] In one embodiment, the process for preparation of a compound of formula I further comprises preparing a compound of formula la:

(la), comprising reacting a compound of formula (III):

(HI), with a compound of formula (IV):

H-NR ¹ R ² (IV); wherein R, R ¹ , R ² and P ³ are as defined in any of the foregoing aspects and embodiments.

[00186] In one embodiment, the reaction between the compound of formula III and IV is carried out in the presence of hypervalent iodine oxidising agent, suitably a hypervalent iodine (III) reagent.

[00187] In one embodiment, the hypervalent iodine oxidising agent is selected from Dess-Martin Periodinane, hydroxy(tosyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene, 2-iodoxybenzoic acid, iodobenzene dichloride. Suitably, the hypervalent iodine oxidising agent is selected from hydroxy(tosyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene, 2-iodoxybenzoic acid, iodobenzene dichloride. Suitably, the hypervalent iodine oxidising agent is selected from iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene and iodobenzene dichloride. Suitably, the hypervalent iodine oxidising agent is selected from iodosobenzene diacetate, iodosylbenzene and iodobenzene dichloride.

[00188] In another embodiment, the reaction between the compound of formula III and IV is carried out in the presence of iodosobenzene diacetate (Phl(OAc)2).

[00189] In one embodiment, the reaction between the compound of formula III and IV is carried out in the presence of a base, suitably an organic base, for instance, trialkyamines such as triethylamine or A/./V-diisopropylethylamine (DIPEA).

[00190] In one embodiment, the reaction between the compound of formula III and IV is carried out in the presence of iodosobenzene diacetate (Phl(OAc)2) and triethylamine (EtsN).

[00191] In one embodiment, the process for preparation of a compound of formula I further comprises preparing a compound of formula III:

(III), comprising reacting a compound of formula V:

(V), with a compound of formula VI:

P ³ -X ⁵ (VI). wherein P ² is a nitrogen protecting of formula Si(R ⁵ )3 wherein R ⁵ is selected from a Ci- 4 alkyl group or a phenyl group; X ⁵ is a leaving group;

R and P ³ are as defined in any of the foregoing embodiments and aspects of the invention.

[00192] In one embodiment, X ⁵ is halo, suitably Cl, Br or I. In one embodiment, X ⁵ is chloro.

[00193] In one embodiment, P ² is selected from triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS).

[00194] In another embodiment, P ² is selected from triisopropylsilyl (TIPS), butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS). Suitably, P ² is triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS).

[00195] In one embodiment, P ² is selected from triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-(trimethylsilyl)ethanesulfonyl (SES), and tert- butylsulfonyl (Bus), suitably nosyl.

[00196] In another embodiment, P ² is selected from triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-(trimethylsilyl)ethanesulfonyl (SES), and te/f-butylsulfonyl (Bus), suitably nosyl.

[00197] In one embodiment, P ² is TIPS or TBPDS and P ³ is nosyl.

[00198] In one embodiment, the reaction between formula V and VI is conducted in the presence of a source of fluoride. Suitably, the source of fluoride is selected from tetra-n- butylammonium fluoride (TBAF), cesium fluoride, potassium fluoride and HF.

[00199] In one embodiment, P ² is TIPS or TBPDS and the source of fluoride is TBAF.

[00200] In one embodiment, the reaction between formula V and VI is additionally conducted in the presence of a base, suitably an organic base; for instance, trialkylamines such as triethylamine or A/./V-diisopropylethylamine (DIPEA).

[00201] In one embodiment, the reaction between formula V and VI is carried out at ambient temperature. [00202] In one embodiment, the process for preparation of a compound of formula I further comprises preparing a compound of formula V:

(V), comprising reacting a compound of formula VII: with an organometallic reactant compound of formula VIII:

R-M (VIII) wherein P ¹ is a nitrogen protecting group selected from a group of formula Si(R ⁷ )3 wherein R ⁷ is independently selected from C1-4 alkyl and a phenyl group;

M is a metallic moiety; and

R and P ² are as defined in any one of the foregoing aspects or embodiments.

[00203] In one embodiment, the metallic moiety of formula VIII is lithium. In another embodiment, the metallic moiety of formula VIII is MgX ⁶ , wherein X ⁶ is halo, suitably Cl, Br or

I, more suitably Cl or Br.

[00204] In one embodiment, R ⁷ is a C1-4 alkyl group. In another embodiment, R ⁷ is selected from methyl, ethyl or isopropyl. Suitably, each R ⁷ is methyl (i.e. P ¹ is TMS).

[00205] In one embodiment, P ¹ and P ² are not the same protecting group. In one embodiment, the silicon atom of P ¹ is less steri cally hindered than the silicon atom of P ² .

[00206] In one embodiment, P ¹ is TMS or TIPS, suitably TMS.

[00207] In one embodiment, P ¹ is TMS and P ² is TIPS.

[00208] In another embodiment, P ¹ is TMS or TIPS and P ² is TBDPS or TBDMS.

[00209] In another embodiment, P ¹ is TIPS and P ² is TBDPS. [00210] Suitably, the reaction between formula VII and formula VIII is conducted in an ether solvent, for instance THF or diethyl ether.

[00211] In one embodiment, the process for preparation of a compound of formula I further comprises preparing a compound of formula VII: from a compound of formula IX:

[00212] In one embodiment, formula VII is prepared from formula IX by reacting formula IX with P ¹ -X ⁷ and a base, wherein X ⁷ is halo, suitably Cl or Br.

[00213] In one embodiment, when P ¹ is TMS, formula VII is prepared from formula IX by reacting formula IX with LiHMDS and TMSCI.

[00214] In one embodiment, the compounds of formula V and/or the compound of VII is not isolated prior to the following step.

Intermediates and processes for their preparation

[00215] In one aspect of the invention there is provided a compound of formula la, or a salt thereof: wherein R, R ¹ , R ² and P ³ are as defined in any of the afore mentioned aspects or embodiments.

[00216] In one embodiment, P ³ is selected from a tosyl, nosyl, Cbz and BOC group.

In one embodiment, P ³ is a nosyl group. [00217] In another aspect of the invention, there is provided a process for the preparation of a compound of formula la, or a salt thereof:

(la), comprising reacting a compound of formula (III):

(HI), with a compound of formula (IV):

H-NR ¹ R ² (IV); wherein R, R ¹ , R ² and P ³ are as defined in any of the foregoing aspects and embodiments.

[00218] In one embodiment, the reaction between the compound of formula III and IV is carried out in the presence of hypervalent iodine oxidising agent.

[00219] In one embodiment, the hypervalent iodine oxidising agent is selected from Dess-Martin Periodinane, hydroxy(tosyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene, 2-iodoxybenzoicacid, and iodobenzene dichloride. Suitably, the hypervalent iodine oxidising agent is selected from hydroxy(tosyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene, 2-iodoxybenzoicacid, iodobenzene dichloride. Suitably, the hypervalent iodine oxidising agent is selected from iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene and iodobenzene dichloride. Suitably, the hypervalent iodine oxidising agent is selected from iodosobenzene diacetate, iodosylbenzene and iodobenzene dichloride.

[00220] In another embodiment, the reaction between the compound of formula III and IV is carried out in the presence of iodosobenzene diacetate (Phl(OAc)2).

[00221] In one embodiment, the reaction between the compound of formula III and IV is carried out in the presence of a base, suitably an organic base; for instance, trialkylamines, such as triethylamine or A/./V-diisopropylethylamine (DIPEA).

[00222] In one embodiment, the reaction between the compound of formula III and IV is carried out in the presence of iodosobenzene diacetate (Phl(OAc)2) and triethylamine (EtsN).

[00223] In one embodiment, the process for preparation of a compound of formula la further comprises preparing a compound of formula III:

(III), comprising reacting a compound of formula V:

(V), with a compound of formula VI:

P ³ -X ⁵ (VI). wherein P ² is a nitrogen protecting of formula Si(R ⁵ )3 wherein R ⁵ is selected from a Ci- 4 alkyl group or a phenyl group; X ⁵ is a leaving group; and

R and P ³ are as defined in any of the foregoing embodiments and aspects of the invention.

[00224] In one embodiment, X ⁵ is halo, suitably Cl, Br or I. In one embodiment, X ⁵ is chloro.

[00225] In one embodiment, P ² is selected from triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS).

[00226] In another embodiment, P ² is selected from triisopropylsilyl (TIPS), butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS). Suitably, P ² is triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS).

[00227] In one embodiment, P ² is selected from triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-(trimethylsilyl)ethanesulfonyl (SES), and tert- butylsulfonyl (Bus), suitably nosyl.

[00228] In another embodiment, P ² is selected from triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-(trimethylsilyl)ethanesulfonyl (SES), and te/f-butylsulfonyl (Bus), suitanly nosyl.

[00229] In one embodiment, P ² is TIPS or TBPDS and P ³ is nosyl.

[00230] In one embodiment, the reaction between formula V and VI is conducted in the presence of a source of fluoride. Suitably, the source of fluoride is selected from tetra-n- butylammonium fluoride (TBAF), cesium fluoride, potassium fluoride and HF.

[00231] In one embodiment, P ² is TIPS or TBPDS and the source of fluoride is TBAF.

[00232] In one embodiment, the reaction between formula V and VI is additionally conducted in the presence of a base, suitably an organic base; for instance, trialkylamines, such as triethylamine or A/./V-diisopropylethylamine (DIPEA).

[00233] In one embodiment, the reaction between formula V and VI is carried out at ambient temperature. [00234] In one embodiment, the process for preparation of a compound of formula la further comprises preparing a compound of formula V:

(V), comprising reacting a compound of formula VII: with an organometallic reactant compound of formula VIII:

R-M (VIII) wherein P ¹ is a nitrogen protecting group selected from a group of formula Si(R ⁷ )3 wherein R ⁷ is independently selected from C1-4 alkyl and a phenyl group;

M is a metallic moiety; and

R and P ² are as defined in any one of the foregoing aspects or embodiments.

[00235] In one embodiment, the metallic moiety of formula VIII is lithium. In another embodiment, the metallic moiety of formula VIII is MgX ⁶ , wherein X ⁶ is halo, suitably Cl, Br or

I, more suitably Cl or Br.

[00236] In one embodiment, R ⁷ is a C1-4 alkyl group. In another embodiment, R ⁷ is selected from methyl, ethyl or isopropyl. Suitably, each R ⁷ is methyl (i.e. P ¹ is TMS).

[00237] In one embodiment, P ¹ and P ² are not the same protecting group. In one embodiment, the silicon atom of P ¹ is less steri cally hindered than the silicon atom of P ² .

[00238] In one embodiment, P ¹ is TMS or TIPS, suitably TMS.

[00239] In one embodiment, P ¹ is TMS and P ² is TIPS.

[00240] In another embodiment, P ¹ is TMS or TIPS and P ² is TBDPS or TBDMS.

[00241] In another embodiment, P ¹ is TIPS and P ² is TBDPS. [00242] Suitably, the reaction between formula VII and formula VIII is conducted in an ether solvent, for instance THF or diethyl ether.

[00243] In one embodiment, the process for preparation of a compound of formula la further comprises preparing a compound of formula VII: from a compound of formula IX:

[00244] In one embodiment, formula VII is prepared from formula IX by reacting formula IX with P ¹ -X ⁷ and a base, wherein X ⁷ is halo, suitably Cl or Br.

[00245] In one embodiment, when P ¹ is TMS, formula VII is prepared from formula IX by reacting formula IX with LiHMDS and TMSCI.

[00246] In one embodiment, the compounds of formula V and/or the compound of VII is not isolated prior to the following step.

[00247] In another aspect of the invention, there is provided a compound of formula III or a salt thereof:

(III), wherein R and P ³ are as defined in any of the afore-mentioned embodiments.

[00248] In one embodiment, P ³ is selected from a tosyl, nosyl, Cbz and BOC group. In one embodiment, P ³ is a nosyl group.

[00249] In another aspect of the invention, there is provided a process for the preparation of a compound of formula III, or a salt thereof:

(III), comprising reacting a compound of formula V:

(V), with a compound of formula VI:

P ³ -X ⁵ (VI). wherein P ² is a nitrogen protecting of formula Si(R ⁵ )3 wherein R ⁵ is selected from a Ci- 4 alkyl group or a phenyl group;

X ⁵ is a leaving group;

R and P ³ are as defined in any of the foregoing embodiments and aspects of the invention.

[00250] In one embodiment, X ⁵ is halo, suitably Cl, Br or I. In one embodiment, X ⁵ is chloro.

[00251] In one embodiment, P ² is selected from triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS).

[00252] In another embodiment, P ² is selected from triisopropylsilyl (TIPS), butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS). Suitably, P ² is triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS).

[00253] In one embodiment, P ² is selected from triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-(tri ethylsilyl)ethanesulfonyl (SES), and tert- butylsulfonyl (Bus), suitably nosyl.

[00254] In another embodiment, P ² is selected from triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-(trimethylsilyl)ethanesulfonyl (SES), and te/f-butylsulfonyl (Bus), suitanly nosyl.

[00255] In one embodiment, P ² is TIPS or TBPDS and P ³ is nosyl.

[00256] In one embodiment, the reaction between formula V and VI is conducted in the presence of a source of fluoride. Suitably, the source of fluoride is selected from tetra-n- butylammonium fluoride (TBAF), cesium fluoride, potassium fluoride, HF.

[00257] In one embodiment, P ² is TIPS or TBPDS and the source of fluoride is TBAF.

[00258] In one embodiment, the reaction between formula V and VI is additionally conducted in the presence of a base, suitably an organic base, such as triethylamine or N,N- diisopropylethylamine (DIPEA).

[00259] In one embodiment, the reaction between formula V and VI is carried out at ambient temperature.

[00260] In one embodiment, the process for preparation of a compound of formula III further comprises preparing a compound of formula V:

(V), comprising reacting a compound of formula VII: with an organometallic reactant compound of formula VIII:

R-M (VIII) wherein P ¹ is a nitrogen protecting group selected from a group of formula Si(R ⁷ )3 wherein R ⁷ is independently selected from C1-4 alkyl and a phenyl group;

M is a metallic moiety; and

R and P ² are as defined in any one of the foregoing aspects or embodiments.

[00261] In one embodiment, the metallic moiety of formula VIII is lithium. In another embodiment, the metallic moiety of formula VIII is MgX ⁶ , wherein X ⁶ is halo, suitably Cl, Br or I, more suitably Cl or Br.

[00262] In one embodiment, R ⁷ is a C1-4 alkyl group. In another embodiment, R ⁷ is selected from methyl, ethyl or isopropyl. Suitably, each R ⁷ is methyl (i.e. P ¹ is TMS).

[00263] In one embodiment, P ¹ and P ² are not the same protecting group. In one embodiment, the silicon atom of P ¹ is less steri cally hindered than the silicon atom of P ² .

[00264] In one embodiment, P ¹ is TMS or TIPS, suitably TMS.

[00265] In one embodiment, P ¹ is TMS and P ² is TIPS.

[00266] In another embodiment, P ¹ is TMS or TIPS and P ² is TBDPS or TBDMS.

[00267] In another embodiment, P ¹ is TIPS and P ² is TBDPS.

[00268] Suitably, the reaction between formula VII and formula VIII is conducted in an ether solvent, for instance THF or diethyl ether.

[00269] In one embodiment, the process for preparation of a compound of formula III further comprises preparing a compound of formula VII: from a compound of formula IX:

[00270] In one embodiment, formula VII is prepared from formula IX by reacting formula IX with P ¹ -X ⁷ and a base, wherein X ⁷ is halo, suitably Cl or Br.

[00271] In one embodiment, when P ¹ is TMS, formula VII is prepared from formula IX by reacting formula IX with LiHMDS and TMSCI. [00272] In one embodiment, the compounds of formula V and/or the compound of VII is not isolated prior to the following step.

[00273] In another aspect, the present invention relates to a compound of formula V, or a salt thereof:

(V), wherein R and P ² are as defined in any of the foregoing aspects or embodiments.

[00274] In one embodiment, P ² is selected from triisopropylsilyl (TIPS), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS).

[00275] In another embodiment, P ² is selected from triisopropylsilyl (TIPS), butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS). Suitably, P ² is triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS).

[00276] In another aspect of the invention, there is provided a process for the preparation of a compound of formula V, or a salt thereof

(V), comprising reacting a compound of formula VII: with an organometallic reactant compound of formula VIII:

R-M (VIII) wherein P ¹ is a nitrogen protecting group selected from a group of formula Si(R ⁷ )3 wherein R ⁷ is independently selected from C1-4 alkyl and a phenyl group;

M is a metallic moiety; and

R and P ² are as defined in any one of the foregoing aspects or embodiments.

[00277] In one embodiment, the metallic moiety of formula VIII is lithium. In another embodiment, the metallic moiety of formula VIII is MgX ⁶ , wherein X ⁶ is halo, suitably Cl, Br or I, more suitably Cl or Br.

[00278] In one embodiment, R ⁷ is a C1-4 alkyl group. In another embodiment, R ⁷ is selected from methyl, ethyl or isopropyl. Suitably, each R ⁷ is methyl (i.e. P ¹ is TMS).

[00279] In one embodiment, P ¹ and P ² are not the same protecting group. In one embodiment, the silicon atom of P ¹ is less steri cally hindered than the silicon atom of P ² .

[00280] In one embodiment, P ¹ is TMS or TIPS, suitably TMS.

[00281] In one embodiment, P ¹ is TMS and P ² is TIPS.

[00282] In another embodiment, P ¹ is TMS or TIPS and P ² is TBDPS or TBDMS.

[00283] In another embodiment, P ¹ is TIPS and P ² is TBDPS.

[00284] Suitably, the reaction between formula VII and formula VIII is conducted in an ether solvent, for instance THF or diethyl ether.

[00285] In one embodiment, the process for preparation of a compound of formula V further comprises preparing a compound of formula VII: from a compound of formula IX:

[00286] In one embodiment, formula VII is prepared from formula IX by reacting formula IX with P ¹ -X ⁷ and a base, wherein X ⁷ is halo, suitably Cl or Br.

[00287] In one embodiment, when P ¹ is TMS, formula VII is prepared from formula IX by reacting formula IX with LiHMDS and TMSCI. [00288] In one embodiment, the compound of VII is not isolated prior to the following step.

[00289] In another aspect, the present invention provides a compound of formula lb, or a salt thereof:

(lb), wherein R, R ¹ , R ² , R ³ and P ³ are as defined in any of the afore-mentioned aspects or embodiments.

[00290] In one embodiment, P ³ is selected from a tosyl, nosyl, Cbz and BOC group. Suitably, P ³ is nosyl.

[00291] In another aspect, the present invention provides a compound of formula lc, or a salt thereof:

(lc), wherein R, R ¹ , R ² and R ³ are as defined in any of the afore-mentioned aspects or embodiments.

Salts

[00292] The compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts. It should be understood that the terms “salt(s)” and “salt form(s)” used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified. As used herein, industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use. Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.

[00293] Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof. Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.

[00294] In one embodiment, the compounds of Formula I, la, lb or lc are isolated as pharmaceutically acceptable salts.

[00295] A suitable pharmaceutically acceptable 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 or maleic acid. In addition a suitable pharmaceutically acceptable 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 physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[00296] In general, salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. In practice, the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s). Salts of the present application may also be formed via a “salt switch” or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge. One skilled in the art will appreciate that the salts may be prepared and/or isolated using a single method or a combination of methods.

[00297] Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like. Other examples of representative salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.

Tautomers

[00298] Compounds of the Formula I and the various intermediates useful in the preparation thereof may exist in a number of different tautomeric forms and references to compounds of the Formula I and the various intermediates useful in the preparation thereof 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 the general formulae. Examples of tautomeric forms include keto-, enol-, and enolate- forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro. keto enol enolate [00299] For example, in respect of sulfinamidine compounds of the present invention depiction of one tautomeric form should be considered to embrace the other tautomeric forms unless specifically stated to the contrary:

[00300] For example, in respect of sulfondiimidamide compounds of the present invention wherein R ¹ and R ² are hydrogen the depiction of one tautomeric form should be considered to embrace the other tautomeric forms unless specifically stated to the contrary:

Isomers

[00301] 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 centre, 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 centre 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”.

[00302] Certain compounds of Formula I and the various intermediates useful in the preparation thereof, particularly Formulae la, lb and lc, may have one or more asymmetric centres and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, and, in the case of two or more asymmetric centers, single diastereomers and/or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios, unless expressly stated otherwise.

[00303] A person skilled in the art will appreciate that certain compounds, or salts thereof of the present invention, may contain at least one chiral centre, for instance at sulphur. The compounds or salts thereof, may therefore exist in at least two enantiomeric forms. The present invention encompasses racemic mixtures of the compounds, or salts thereof of the present invention as well as enantiomerically enriched and substantially enantiomerically pure isomers. As used herein, a “substantially enantiomerically pure” isomer of a compound comprises less than 5% of other enantiomers of the same compound, more typically less than 2%, and most typically less than 0.5% by weight.

Isotopes

[00304] The compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of the constituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of ¹² C, ¹³ C, and ¹⁴ C; hydrogen atoms may be present in any ratio of ¹ H, ² H, and ³ H; etc. Preferably, the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms.

Numbered Paragraphs

[00305] The invention will now be further described by way of the following numbered paragraphs:

1. A process for preparing a compound of formula I, or a salt thereof:

(I), comprising:

(i) reacting a compound of formula la:

(la), with a reactant suitable for introducing group R ³ to give a compound of formula lb:

(lb); and/or deprotecting a compound of formula lb to yield a compound of formula lc:

(lc), and/or reacting a compound of formula lc with a reactant suitable for introducing group R ⁴ to give a compound of formula I; and

(ii) optionally preparing a salt of formula I; wherein:

P ³ is a nitrogen protecting group of formula -SC> ₂ R ⁶ orC(0)R ⁸ , wherein R ⁶ is selected from C1-6 alkyl, Ci- ₆ haloalkyl, ChhChhSiMes, or a phenyl group optionally substituted with one or more groups selected from NO2 _, halogen and methyl; and wherein R ⁸ is selected from methyl, phenyl, O-f-butyl, and O-benzyl (OBn), wherein said phenyl is optionally substituted by NO2, halogen, OMe or CF3;

R ¹ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a1 , C2-ioalkenyl optionally substituted by one or more R ^a1 , C^alkynyl optionally substituted by one or more R ^a1 , Ce-isaryl optionally substituted by one or more R ^a1 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a1 , C3-11 cycloalkyl optionally substituted by one or more R ^a1 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a1 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a1 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , 4-15 membered heteroaryl optionally substituted by one or more R ^a1 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a1 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl;

R ² is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a2 , C2-ioalkenyl optionally substituted by one or more R ^a2 , C^alkynyl optionally substituted by one or more R ^a2 , Ce-isaryl optionally substituted by one or more R ^a2 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a2 , C3-11 cycloalkyl optionally substituted by one or more R ^a2 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a2 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , 4-15 membered heteroaryl optionally substituted by one or more R ^a2 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a2 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; or

R ¹ is absent and R ² combines with the nitrogen to which it is attached to form an imino group of formula =CR ^W R ^X , an amidine of formula =C(R ^w )(NR ^y R ^z ), or a guanidine of formula =C(NR ^y R ^z ) ₂ where R ^w , R ^x are independently C1-6 alkyl and R ^y and R ^z are independently selected from hydrogen and C1-6 alkyl; or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 3-15 membered heterocycloalkyl ring or 4-15 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 ; where each R ^a3 is independently selected from hydroxyl, =0, halogen, CN, Ci-ehaloalkyl, Ci- ₆ haloalkoxy, Ci-e alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, 4-15 membered heteroaryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , - 0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, and 4-15 membered heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-e haloalkyl, Ci-e haloalkoxy, C3-6 cycloalkyl, Ci-e alkyl, O-Ci-e alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl;

R is selected from the group consisting of Ci-ioalkyl optionally substituted by one or more R ^a , C ₂ -ioalkenyl optionally substituted by one or more R ^a , C _2-6 alkynyl optionally substituted by one or more R ^a , Ce-isaryl optionally substituted by one or more R ^a , Ce-i5aryl(Ci- e)alkyl optionally substituted by one or more R ^a , C _3-11 cycloalkyl optionally substituted by one or more R ^a , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a , 4-15 membered heterocycloalkyl(Ci- e)alkyl optionally substituted by one or more R ^a , 4-15 membered heteroaryl optionally substituted by one or more R ^a , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a ; where each R ^a is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, Ce-n aryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , NR ^d S(=0) ₂ NR ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and Ce-n aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, phenyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl;

R ³ is selected from the group consisting of H, C1-6 alkyl, CN, -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -NR ^h R ^j , -NR ⁹ C(=0)R ^f , -NR ^h C(=0)0R ⁹ , -NR ^h C(=0)NR ^h R ^j , - NR ^h S(=0) ₂ R ^f , -NR ^h S(=0) ₂ NR ^h R ^j , -OR ⁹ , -SR ⁹ , -0C(=0)R ^f , -0C(=0)NR ^h R ^j , -0C(=0)0R ⁹ , - S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , -0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -

0S(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j , where said C1-6 alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-e haloalkyl, Ci-e haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, phenyl and O-C1-6 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl;

R ⁴ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a4 , C ₂ -ioalkenyl optionally substituted by one or more R ^a4 , C _2-6 alkynyl optionally substituted by one or more R ^a4 , Ce-isaryl optionally substituted by one or more R ^a4 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a4 , C _3-11 cycloalkyl optionally substituted by one or more R ^a4 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a4 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 4-15 membered heteroaryl optionally substituted by one or more R ^a4 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -OR ⁹ , -SR ⁹ , -0C(=0)R ^f , -0C(=0)NR ^h R ^j , -0C(=0)0R ⁹ , - S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , -0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -

0S(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j ; where each R ^a4 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; wherein each R ^b and R ^f are independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, N0 ₂ , C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; wherein each R ^c and R ⁹ are independently selected from hydrogen, hydroxyl, halogen, CN, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl and Ce-is aryl, wherein said C _1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl 5-6 membered heteroaryl and C _3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^d and R ^h are independently selected from hydrogen, hydroxyl, halogen, CN, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^e and R ^j are independently selected from hydrogen, hydroxyl, halogen, CN, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; or wherein R ^d and R ^e , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; wherein R ^h and R ^j , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; and where R ^k is selected from hydrogen, =0, halogen, CN, NH ₂ , NH(C _I-6 alkyl), N(Ci- ₆ alkyl) ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl.

2. A process according to any one of the preceding paragraphs wherein P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-(Trimethylsilyl)ethanesulfonyl (SES), and tert-Butylsulfonyl (Bus).

3. A process according to any one of the preceding paragraphs wherein P ³ is selected from nosyl, tosyl, brosyl and mesyl.

4. A process according to any one of the preceding paragraphs wherein P ³ is nosyl or tosyl, suitably nosyl.

5. A process according to any one of the preceding paragraphs wherein the reactant suitable for introducing group R ³ is R ³ -X ² wherein X ² is a leaving group. Suitably, X ² is halo, for instance Cl or Br.

6. A process according to any one of the preceding paragraphs wherein the reactant suitable for introducing group R ³ is (i) R ^j -N=C=0, when R ³ is -C(=0)NR ^h R ^j , and R ^h is H, or (ii) R ³ -CHO, when R ³ is Ci-e alkyl. 7. A process according to any one of the preceding paragraphs, wherein P ³ is a nosyl group and the deprotection of formula lb to give a compound according to formula lc is performed using a thiolate nucleophile. Suitable thiolate nucleophiles are, for example, thiophenol, thioglycolic acid, Ci-2oalkyl-SH.

8. A process according to paragraph 7, wherein the removal of the nosyl is carried out in the presence of a base, such a carbonate or hydroxide base, or a non-nucleophilic base such as DBU.

9. A process according to any one of the preceding paragraphs wherein P ³ is nosyl and the deprotection of formula lb to give a compound according to formula lc is performed using Ci2alkyl-SH and DBU. Suitably, in acetonitrile at about 0°C.

10. A process according to any one paragraphs 1 to 6, wherein P ³ is nosyl and the deprotection of formula lb to give a compound according to formula lc is performed using a reducing agent, such as sodium amalgam (Na(Hg)), aluminium amalgam, magnesium, samarium(ll) iodide), tin hydrides (tributyltin hydride) and transition metal complexes with reducing agents.

11. A process according to any one of paragraphs 1 to 6, wherein P ³ is SES and the deprotection of formula lb to give a compound according to formula lc is performed using a source of fluoride. Suitably, the source of fluoride is selected from TBAF, cesium fluoride, potassium fluoride and HF.

12. A process according to any one of paragraphs 1 to 6, wherein P ³ is Bus, tosyl, brosyl and mesyl and the deprotection of formula lb to give a compound according to formula lc is performed using an acid. Suitably, the acid is selected from TFA, MsOH, TfOH. Suitably, the acid is TFA.

13. A process according to any one of the preceding paragraphs, wherein the reactant suitable for introducing group R ⁴ is selected from:

(i) R ⁴ -B ¹ when R ⁴ is C ₆ -isaryl optionally substituted by one or more R ^a4 or 4-15 membered heteroaryl optionally substituted by one or more R ^a4 , and wherein B ¹ is a boronic acid, a boronic acid ester, a cyclic boronic acid ester, an organotrifluoroborate potassium salt, cyclic triolborate, organoborane, or Ml DA boronate;

(ii) X ³ -C(=0)0R ⁹ when R ⁴ is -C(=0)0R ⁹ , wherein X ³ is a leaving group, suitably halo, for instance Cl, Br or I; (iii) R ⁴ -X ⁴ when R ⁴ is Ci-ioalkyl optionally substituted by one or more R ^a4 , C2-ioalkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , C6-i5aryl optionally substituted by one or more R ^a4 , 4-15 membered heteroaryl optionally substituted by one or more R ^a4 , C ₆ -isaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , C(=0)NR ^h R ^j , and -C(=0)R ^f , and wherein X ⁴ is a leaving group, suitably halo, for instance Cl, Br or I.

(iv) TMS-R ⁴ when R ⁴ is CF ₃ and CN.

14. A process according to any one of the preceding paragraphs wherein, the process further comprises preparing a compound of formula la:

(la), comprising reacting a compound of formula (III):

(III), with a compound of formula (IV):

H-NR ¹ R ² (IV); wherein R, R ¹ , R ² and P ³ are as defined in any one of paragraphs 1 to 4.

15. A process according to paragraph 14, wherein the reaction between the compound of formula III and IV is carried out in the presence of hypervalent iodine oxidising agent. 16. A process according to paragraph 15, wherein the hypervalent iodine oxidising agent is selected from Dess-Martin Periodinane, hydroxy(tosyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene, 2-iodoxybenzoic acid, iodobenzene dichloride.

17. A process according to paragraph 16, wherein the hypervalent iodine oxidising agent is selected from hydroxy(tosyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene, 2-iodoxybenzoic acid, iodobenzene dichloride; suitably selected from iodosobenzene diacetate, iodosylbenzene and iodobenzene dichloride.

18. A process according to paragraph 14, wherein the reaction between the compound of formula III and IV is carried out in the presence of iodosobenzene diacetate (Phl(OAc)2).

19. A process according to any one of paragraphs 14 to 18, wherein the reaction between the compound of formula III and IV is carried out in the presence of a base, suitably an organic base, such as triethylamine or A/./V-diisopropylethylamine (DIPEA).

20. A process according to any one of the preceding paragraphs, wherein the process further comprises preparing a compound of formula III:

(HI), comprising reacting a compound of formula V:

(V), with a compound of formula VI:

P ³ -X ⁵ (VI). wherein P ² is a nitrogen protecting of formula Si(R ⁵ )3 wherein R ⁵ is selected from a Ci- 4 alkyl group or a phenyl group;

X ⁵ is a leaving group; and

R and P ³ are as defined in any one of paragraphs 1 to 4.

21. A process according to paragraph 20, wherein X ⁵ is halo, suitably Cl, Br or I.

22. A process according to paragraph 21 , wherein X ⁵ is chloro.

23. A process according to any one of paragraphs 20 to 22, wherein P ² is selected from triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS).

24. A process according to any one of paragraphs 20 to 23, wherein P ² is selected from triisopropylsilyl (TIPS), butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS). Suitably, P ² is triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS).

25. A process according to any one of paragraphs 20 to 22, wherein P ² is selected from triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2- (trimethylsilyl)ethanesulfonyl (SES), and te/f-butylsulfonyl (Bus), suitably nosyl.

26. A process according to paragraph 25, wherein P ² is selected from triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-(trimethylsilyl)ethanesulfonyl (SES), and te/f-butylsulfonyl (Bus), suitably nosyl.

27. A process according to paragraph 25, wherein P ² is TIPS or TBPDS and P ³ is nosyl.

28. A process according to any one of paragraphs 20 to 27, wherein the reaction between formula V and VI is conducted in the presence of a source of fluoride.

29. A process according to paragraph 28, wherein the source of fluoride is selected from tetra-n-butylammonium fluoride (TBAF), cesium fluoride, potassium fluoride and HF.

30. A process according to paragraph 28 or 29, wherein P ² is TIPS or TBPDS and the source of fluoride is TBAF. 31. A process according to any one of paragraphs 20 to 30, wherein the reaction between formula V and VI is conducted in the presence of a base.

32. A process according to claim 31, wherein the base is an organic base, such as triethylamine or A/./V-diisopropylethylamine (DIPEA).

33. A process according to any one of the preceding paragraphs, wherein the process further comprises preparing a compound of formula V:

(V), comprising reacting a compound of formula VII: with an organometallic reactant compound of formula VIII:

R-M (VIII) wherein P ¹ is a nitrogen protecting group selected from a group of formula Si(R ⁷ )3 wherein R ⁷ is independently selected from C1-4 alkyl and phenyl group;

M is a metallic moiety; and

R and P ² are as defined in any one of claims 1 , 20, 23 and 24.

34. A process according to paragraph 33, wherein the metallic moiety of formula VIII is lithium.

35. A process according to paragraph 33, wherein the metallic moiety of formula VIII is MgX ⁶ , wherein X ⁶ is halo, suitably Cl, Br or I, more suitably Cl or Br.

36. A process according to any one of paragraphs 33 to 35, wherein R ⁷ is selected from methyl, ethyl or isopropyl. Suitably, each R ⁷ is methyl (i.e. P ¹ is TMS).

37. A process according to any one of paragraphs 33 to 36, wherein P ¹ is TMS or TIPS, suitably TMS. 38. A process according to any one of the preceding paragraphs, wherein the process further comprises preparing a compound of formula VII: from a compound of formula IX:

39. A process according to paragraph 38, wherein formula VII is prepared from formula IX by reacting formula IX with P ¹ -X ⁷ and a base, wherein X ⁷ is halo, suitably Cl or Br.

40. A process according to any one of paragraphs 38 and 39, wherein P ¹ is TMS and formula VII is prepared from formula IX by reacting formula IX with LiHMDS and TMSCI.

41. A process according to any one of the preceding paragraphs, wherein the compound of formula V is not isolated prior to the following step.

42. A process according to any one of the preceding paragraphs, wherein the compound of formula VII is not isolated prior to the following step.

43. A process for the preparation of a compound of formula la, or a salt thereof:

(la), comprising reacting a compound of formula (III): (III), with a compound of formula (IV):

H-NR ¹ R ² (IV); wherein:

P ³ is a nitrogen protecting group of formula -SO2R ⁶ orC(0)R ⁸ , wherein R ⁶ is selected from C1-6 alkyl, Ci- ₆ haloalkyl, ChhChhSiMes, or a phenyl group optionally substituted with one or more groups selected from NO2 _, halogen and methyl; and wherein R ⁸ is selected from methyl, phenyl, O-f-butyl, and O-benzyl (OBn), wherein said phenyl is optionally substituted by NO2, halogen, OMe or CF ₃ ;

R ¹ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a1 , C2-ioalkenyl optionally substituted by one or more R ^a1 , C^alkynyl optionally substituted by one or more R ^a1 , Ce-isaryl optionally substituted by one or more R ^a1 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a1 , C3-11 cycloalkyl optionally substituted by one or more R ^a1 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a1 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a1 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , 4-15 membered heteroaryl optionally substituted by one or more R ^a1 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a1 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl;

R ² is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a2 , C2-ioalkenyl optionally substituted by one or more R ^a2 , C^alkynyl optionally substituted by one or more R ^a2 , Ce-isaryl optionally substituted by one or more R ^a2 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a2 , C _3-11 cycloalkyl optionally substituted by one or more R ^a2 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a2 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , 4-15 membered heteroaryl optionally substituted by one or more R ^a2 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a2 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, Ci-e haloalkoxy, C3-6 cycloalkyl, Ci-e alkyl and O-Ci-e alkyl; or

R ¹ is absent and R ² combines with the nitrogen to which it is attached to form an imino group of formula =CR ^W R ^X , an amidine of formula =C(R ^w )(NR ^y R ^z ), or a guanidine of formula =C(NR ^y R ^z ) ₂ where R ^w , R ^x are independently Ci-e alkyl and R ^y and R ^z are independently selected from hydrogen and Ci-e alkyl; or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 3-15 membered heterocycloalkyl ring or 4-15 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 ; where each R ^a3 is independently selected from hydroxyl, =0, halogen, CN, Ci-ehaloalkyl, Ci- ₆ haloalkoxy, Ci-e alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, 4-15 membered heteroaryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , - 0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, and 4-15 membered heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-e haloalkyl, Ci-e haloalkoxy, C3-6 cycloalkyl, Ci-e alkyl, O-Ci-e alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; R is selected from the group consisting of Ci-ioalkyl optionally substituted by one or more R ^a , C2-ioalkenyl optionally substituted by one or more R ^a , C^alkynyl optionally substituted by one or more R ^a , Ce-isaryl optionally substituted by one or more R ^a , C ₆ -isaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , C3-11 cycloalkyl optionally substituted by one or more R ^a , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , 4-15 membered heteroaryl optionally substituted by one or more R ^a , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a ; where each R ^a is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, Ce-n aryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , NR ^d S(=0) ₂ NR ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and Ce-n aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, phenyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^b is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, N0 ₂ , C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; wherein each R ^c is independently selected from hydrogen, hydroxyl, halogen, CN, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl and Ce-isaryl, wherein said Ci-e alkyl, Ce-isaryl, 3-7 membered heterocycloalkyl 5- 6 membered heteroaryl and C3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, Ci- ₆ haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl and O-C1-6 alkyl; wherein each R ^d is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; wherein each R ^e is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; or wherein R ^d and R ^e , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; and where R ^k is selected from hydrogen, =0, halogen, CN, NH ₂ , NH(Ci.e alkyl), N(Ci- ₆ alkyl) ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl.

44. A process according to paragraph 43, wherein the reaction between the compound of formula III and IV is carried out in the presence of hypervalent iodine oxidising agent.

45. A process according to paragraph 44, wherein the hypervalent iodine oxidising agent is selected from Dess-Martin Periodinane, hydroxy(tosyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene, 2-iodoxybenzoic acid, iodobenzene dichloride.

46. A process according to paragraph 45, wherein the hypervalent iodine oxidising agent is selected from hydroxy(tosyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosylbenzene, 2-iodoxybenzoic acid, iodobenzene dichloride; suitably selected from iodosobenzene diacetate, iodosylbenzene and iodobenzene dichloride. 47. A process according to paragraph 43, wherein the reaction between the compound of formula III and IV is carried out in the presence of iodosobenzene diacetate (Phl(OAc)2).

48. A process according to any one of paragraphs 43 to 47, wherein the reaction between the compound of formula III and IV is carried out in the presence of a base, suitably an organic base, such as triethylamine or A/./V-diisopropylethylamine (DIPEA).

49. A process according to any one of paragraphs 43 to 48, wherein the process further comprises preparing a compound of formula III:

(HI), comprising reacting a compound of formula V:

(V), with a compound of formula VI:

P ³ -X ⁵ (VI). wherein P ² is a nitrogen protecting of formula Si(R ⁵ )3 wherein R ⁵ is selected from a Ci- 4 alkyl group or a phenyl group;

X ⁵ is a leaving group; and

R and P ³ are as defined in any one of paragraphs 1 to 4.

50. A process according to paragraph 49, wherein X ⁵ is halo, suitably Cl, Br or I.

51. A process according to paragraph 50, wherein X ⁵ is chloro. 52. A process according to any one of paragraphs 49 to 51 , wherein P ² is selected from triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS).

53. A process according to any one of paragraphs 49 to 52, wherein P ² is selected from triisopropylsilyl (TIPS), butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS). Suitably, P ² is triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS).

54. A process according to any one of paragraphs 49 to 51 , wherein P ² is selected from triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2- (trimethylsilyl)ethanesulfonyl (SES), and te/f-butylsulfonyl (Bus), suitably nosyl.

55. A process according to paragraph 54, wherein P ² is selected from triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-(trimethylsilyl)ethanesulfonyl (SES), and te/f-butylsulfonyl (Bus), suitably nosyl.

56. A process according to paragraph 54, wherein P ² is TIPS or TBPDS and P ³ is nosyl.

57. A process according to any one of paragraphs 49 to 56, wherein the reaction between formula V and VI is conducted in the presence of a source of fluoride.

58. A process according to paragraph 57, wherein the source of fluoride is selected from tetra-n-butylammonium fluoride (TBAF), cesium fluoride, potassium fluoride and HF.

59. A process according to paragraph 57 or 58, wherein P ² is TIPS or TBPDS and the source of fluoride is TBAF.

60. A process according to any one of paragraphs 49 to 59, wherein the reaction between formula V and VI is conducted in the presence of a base.

61. A process according to claim 60, wherein the base is an organic base, such as triethylamine or A/./V-diisopropylethylamine (DIPEA).

62. A process according to any one of paragraphs 43 to 61 , wherein the process further comprises preparing a compound of formula V:

(V), comprising reacting a compound of formula VII: with an organometallic reactant compound of formula VIII:

R-M (VIII) wherein P ¹ is a nitrogen protecting group selected from a group of formula Si(R ⁷ )3 wherein R ⁷ is independently selected from C1-4 alkyl and a phenyl group;

M is a metallic moiety; and

R and P ² are as defined in any one of claims 1 , 20, 23 and 24.

63. A process according to paragraph 62, wherein the metallic moiety of formula VIII is lithium.

64. A process according to paragraph 62, wherein the metallic moiety of formula VIII is MgX ⁶ , wherein X ⁶ is halo, suitably Cl, Br or I, more suitably Cl or Br.

65. A process according to any one of paragraphs 62 to 64, wherein R ⁷ is selected from methyl, ethyl or isopropyl. Suitably, each R ⁷ is methyl (i.e. P ¹ is TMS).

66. A process according to any one of paragraphs 62 to 65, wherein P ¹ is TMS or TIPS, suitably TMS.

67. A process according to any one of paragraphs 43 to 66, wherein the process further comprises preparing a compound of formula VII: from a compound of formula IX: 68. A process according to paragraph 67, wherein formula VII is prepared from formula IX by reacting formula IX with P ¹ -X ⁷ and a base, wherein X ⁷ is halo, suitably Cl or Br.

69. A process according to paragraph 67 or 68, wherein P ¹ is TMS and formula VII is prepared from formula IX by reacting formula IX with LiHMDS and TMSCI.

70. A process according to any one of paragraphs 43 to 69, wherein the compound of formula V is not isolated prior to the following step.

71. A process according to any one of paragraphs 43 to 70, wherein the compound of formula VII is not isolated prior to the following step.

72. A process for the preparation of a compound of formula III:

(HI), comprising reacting a compound of formula V:

(V), with a compound of formula VI:

P ³ -X ⁵ (VI). wherein P ² is a nitrogen protecting of formula Si(R ⁵ )3 wherein R ⁵ is selected from a Ci- 4 alkyl group or a phenyl group; X ⁵ is a leaving group; and

R and P ³ are as defined in any one of paragraphs 1 to 4.

73. A process according to paragraph 72, wherein X ⁵ is halo, suitably Cl, Br or I.

74. A process according to paragraph 73, wherein X ⁵ is chloro.

75. A process according to any one of paragraphs 72 to 74, wherein P ² is selected from triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS).

76. A process according to any one of paragraphs 72 to 75, wherein P ² is selected from triisopropylsilyl (TIPS), butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS). Suitably, P ² is triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS).

77. A process according to any one of paragraphs 72 to 74, wherein P ² is selected from triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and trimethylsilyl (TMS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2- (trimethylsilyl)ethanesulfonyl (SES), and te/f-butylsulfonyl (Bus), suitably nosyl.

78. A process according to paragraph 77, wherein P ² is selected from triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS), and P ³ is selected from nosyl, tosyl, brosyl, mesyl, 2-(trimethylsilyl)ethanesulfonyl (SES), and te/f-butylsulfonyl (Bus), suitably nosyl.

79. A process according to paragraph 78, wherein P ² is TIPS or TBPDS and P ³ is nosyl.

80. A process according to any one of paragraphs 72 to 79, wherein the reaction between formula V and VI is conducted in the presence of a source of fluoride.

81. A process according to paragraph 80, wherein the source of fluoride is selected from tetra-n-butylammonium fluoride (TBAF), cesium fluoride, potassium fluoride and HF.

82. A process according to paragraph 80 or 81, wherein P ² is TIPS or TBPDS and the source of fluoride is TBAF.

83. A process according to any one of paragraphs 72 to 82, wherein the reaction between formula V and VI is conducted in the presence of a base. 84. A process according to claim 83, wherein the base is an organic base, such as triethylamine or A/./V-diisopropylethylamine (DIPEA).

85. A process according to any one of paragraphs 72 to 84, wherein the process further comprises preparing a compound of formula V:

(V), comprising reacting a compound of formula VII: with an organometallic reactant compound of formula VIII:

R-M (VIII) wherein P ¹ is a nitrogen protecting group selected from a group of formula Si(R ⁷ )3 wherein R ⁷ is independently selected from C1-4 alkyl and a phenyl group;

M is a metallic moiety; and

R and P ² are as defined in any one of claims 1 , 20, 23 and 24.

86. A process according to paragraph 85, wherein the metallic moiety of formula VIII is lithium.

87. A process according to paragraph 86, wherein the metallic moiety of formula VIII is MgX ⁶ , wherein X ⁶ is halo, suitably Cl, Br or I, more suitably Cl or Br.

88. A process according to any one of paragraphs 85 to 87, wherein R ⁷ is selected from methyl, ethyl or isopropyl. Suitably, each R ⁷ is methyl (i.e. P ¹ is TMS).

89. A process according to any one of paragraphs 85 to 88, wherein P ¹ is TMS or TIPS, suitably TMS.

90. A process according to any one of paragraphs 72 to 89, wherein the process further comprises preparing a compound of formula VII: from a compound of formula IX:

91. A process according to paragraph 90, wherein formula VII is prepared from formula IX by reacting formula IX with P ¹ -X ⁷ and a base, wherein X ⁷ is halo, suitably Cl or Br.

92. A process according to any one of paragraphs 90 and 91, wherein P ¹ is TMS and formula VII is prepared from formula IX by reacting formula IX with LiHMDS and TMSCI.

93. A process according to any one of paragraphs 72 to 92, wherein the compound of formula V is not isolated prior to the following step.

94. A process according to any one of paragraphs 72 to 93, wherein the compound of formula VII is not isolated prior to the following step.

95. A process for preparing a compound of formula V:

(V), comprising reacting a compound of formula VII: with a compound of formula VIII:

R-M (VIII); wherein P ¹ is a nitrogen protecting group selected from a group of formula Si(R ⁷ )3 wherein R ⁷ is independently selected from C1-4 alkyl and a phenyl group;

M is a metallic moiety; and R and P ² are as defined in any one of claims 1 , 20, 23 and 24.

96. A process according to paragraph 95, wherein the metallic moiety of formula VIII is lithium.

97. A process according to paragraph 95, wherein the metallic moiety of formula VIII is MgX ⁶ , wherein X ⁶ is halo, suitably Cl, Br or I, more suitably Cl or Br.

98. A process according to any one of paragraphs 95 to 97, wherein R ⁷ is selected from methyl, ethyl or isopropyl. Suitably, each R ⁷ is methyl (i.e. P ¹ is TMS).

99. A process according to any one of paragraphs 95 to 98, wherein P ¹ is TMS or TIPS, suitably TMS.

100. A process according to any one of paragraphs 95 to 99, wherein the process further comprises preparing a compound of formula VII: from a compound of formula IX:

101. A process according to paragraph 100, wherein formula VII is prepared from formula IX by reacting formula IX with P ¹ -X ⁷ and a base, wherein X ⁷ is halo, suitably Cl or Br.

102. A process according to paragraph 100 or 101, wherein P ¹ is TMS and formula VII is prepared from formula IX by reacting formula IX with LiHMDS and TMSCI.

103. A process according to any one of paragraphs 95 to 102, wherein the compound of formula VII is not isolated prior to the following step.

104. A compound of formula I, or a salt thereof: (I), wherein,

R ¹ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a1 , C2-ioalkenyl optionally substituted by one or more R ^a1 , C2-6alkynyl optionally substituted by one or more R ^a1 , C ₆ -isaryl optionally substituted by one or more R ^a1 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a1 , C3-11 cycloalkyl optionally substituted by one or more R ^a1 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a1 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a1 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , 4-15 membered heteroaryl optionally substituted by one or more R ^a1 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a1 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl;

R ² is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a2 , C2-ioalkenyl optionally substituted by one or more R ^a2 , C^alkynyl optionally substituted by one or more R ^a2 , Ce-isaryl optionally substituted by one or more R ^a2 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a2 , C3-11 cycloalkyl optionally substituted by one or more R ^a2 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a2 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , 4-15 membered heteroaryl optionally substituted by one or more R ^a2 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a2 is independently selected from hydroxyl, =0, halogen, CN, Ci-ehaloalkyl, Ci. 6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; or

R ¹ is absent and R ² combines with the nitrogen to which it is attached to form an imino group of formula =CR ^W R ^X , an amidine of formula =C(R ^w )(NR ^y R ^z ), or a guanidine of formula =C(NR ^y R ^z ) ₂ where R ^w , R ^x are independently C1-6 alkyl and R ^y and R ^z are independently selected from hydrogen and C1-6 alkyl; or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 3-15 membered heterocycloalkyl ring or 4-15 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 ; where each R ^a3 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, 4-15 membered heteroaryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , - 0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, and 4-15 membered heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl;

R is selected from the group consisting of Ci-ioalkyl optionally substituted by one or more R ^a , C ₂ -ioalkenyl optionally substituted by one or more R ^a , C _2-6 alkynyl optionally substituted by one or more R ^a , Ce-isaryl optionally substituted by one or more R ^a , C ₆ -isaryl(Ci- e)alkyl optionally substituted by one or more R ^a , C3-11 cycloalkyl optionally substituted by one or more R ^a , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a , 4-15 membered heterocycloalkyl(Ci- e)alkyl optionally substituted by one or more R ^a , 4-15 membered heteroaryl optionally substituted by one or more R ^a , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a ; where each R ^a is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, Ce-n aryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , NR ^d S(=0) ₂ NR ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and Ce-n aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, phenyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl;

R ³ is selected from the group consisting of H, C1-6 alkyl, CN, -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -NR ^h R ^j , -NR ⁹ C(=0)R ^f , -NR ^h C(=0)0R ⁹ , -NR ^h C(=0)NR ^h R ^j , - NR ^h S(=0) ₂ R ^f , -NR ^h S(=0) ₂ NR ^h R ^j , -OR ⁹ , -SR ⁹ , -0C(=0)R ^f , -0C(=0)NR ^h R ^j , -0C(=0)0R ⁹ , - S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , -0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -

0S(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j , where said C1-6 alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-e haloalkyl, Ci-e haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, phenyl and O-C1-6 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl;

R ⁴ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a4 , C ₂ -ioalkenyl optionally substituted by one or more R ^a4 , C _2-6 alkynyl optionally substituted by one or more R ^a4 , Ce-isaryl optionally substituted by one or more R ^a4 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a4 , C _3-11 cycloalkyl optionally substituted by one or more R ^a4 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a4 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 4-15 membered heteroaryl optionally substituted by one or more R ^a4 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -OR ⁹ , -SR ⁹ , -0C(=0)R ^f , -0C(=0)NR ^h R ^j , -0C(=0)0R ⁹ , - S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , -0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -

0S(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j ; where each R ^a4 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 e bered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; wherein each R ^b and R ^f are independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, N0 ₂ , C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; wherein each R ^c and R ⁹ are independently selected from hydrogen, hydroxyl, halogen, CN, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl and Ce-is aryl, wherein said C _1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl 5-6 membered heteroaryl and C _3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^d and R ^h are independently selected from hydrogen, hydroxyl, halogen, CN, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^e and R ^j are independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl; or wherein R ^d and R ^e , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; wherein R ^h and R ^j , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; where R ^k is selected from hydrogen, =0, halogen, CN, NH ₂ , NH(CI- ₆ alkyl), N(Ci- ₆ alkyl) ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; with the provisos that:

(i) when R is methyl, ethyl or butyl then R ³ and R ⁴ cannot both be methyl; and

(ii) when R is optionally substituted phenyl then R ³ and R ⁴ cannot both be -SO ₂ CF ₃ . 105. A compound of formula lb or lc:

(lb), (lc), wherein,

R ¹ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a1 , C2-ioalkenyl optionally substituted by one or more R ^a1 , C^alkynyl optionally substituted by one or more R ^a1 , Ce-isaryl optionally substituted by one or more R ^a1 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a1 , C _3-11 cycloalkyl optionally substituted by one or more R ^a1 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a1 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a1 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , 4-15 membered heteroaryl optionally substituted by one or more R ^a1 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a1 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, Ci-e haloalkoxy, C3-6 cycloalkyl, Ci-e alkyl and O-Ci-e alkyl;

R ² is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a2 , C ₂ -ioalkenyl optionally substituted by one or more R ^a2 , C _2-6 alkynyl optionally substituted by one or more R ^a2 , Ce-isaryl optionally substituted by one or more R ^a2 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a2 , C3-11 cycloalkyl optionally substituted by one or more R ^a2 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a2 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , 4-15 membered heteroaryl optionally substituted by one or more R ^a2 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a2 is independently selected from hydroxyl, =0, halogen, CN, Ci-ehaloalkyl, Ci. ₆ haloalkoxy, Ci-e alkyl, O-Ci-e alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-ehaloalkyl, Ci-e haloalkoxy, C3-6 cycloalkyl, Ci-e alkyl and O-Ci-e alkyl; or

R ¹ is absent and R ² combines with the nitrogen to which it is attached to form an imino group of formula =CR ^W R ^X , an amidine of formula =C(R ^w )(NR ^y R ^z ), or a guanidine of formula =C(NR ^y R ^z )2 where R ^w , R ^x are independently Ci-e alkyl and R ^y and R ^z are independently selected from hydrogen and C1-6 alkyl; or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 3-15 membered heterocycloalkyl ring or 4-15 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 ; where each R ^a3 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, 4-15 membered heteroaryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , - 0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, and 4-15 membered heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl;

R is selected from the group consisting of Ci-ioalkyl optionally substituted by one or more R ^a , C ₂ -ioalkenyl optionally substituted by one or more R ^a , C _2-6 alkynyl optionally substituted by one or more R ^a , Ce-isaryl optionally substituted by one or more R ^a , C ₆ -isaryl(Ci- e)alkyl optionally substituted by one or more R ^a , C3-11 cycloalkyl optionally substituted by one or more R ^a , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a , 4-15 membered heterocycloalkyl(Ci- e)alkyl optionally substituted by one or more R ^a , 4-15 membered heteroaryl optionally substituted by one or more R ^a , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a ; where each R ^a is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, Ce-n aryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , NR ^d S(=0) ₂ NR ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, and Ce-n aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, phenyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl;

R ³ is selected from the group consisting of H, C1-6 alkyl, CN, -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -NR ^h R ^j , -NR ⁹ C(=0)R ^f , -NR ^h C(=0)0R ⁹ , -NR ^h C(=0)NR ^h R ^j , - NR ^h S(=0) ₂ R ^f , -NR ^h S(=0) ₂ NR ^h R ^j , -OR ⁹ , -SR ⁹ , -0C(=0)R ^f , -0C(=0)NR ^h R ^j , -0C(=0)0R ⁹ , - S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , -0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -

0S(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j , where said C1-6 alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-e haloalkyl, Ci-e haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, phenyl and O-C1-6 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl;

R ⁴ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a4 , C ₂ -ioalkenyl optionally substituted by one or more R ^a4 , C _2-6 alkynyl optionally substituted by one or more R ^a4 , Ce-isaryl optionally substituted by one or more R ^a4 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a4 , C _3-11 cycloalkyl optionally substituted by one or more R ^a4 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a4 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 4-15 membered heteroaryl optionally substituted by one or more R ^a4 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -C(0)C(=0)R ^f , -OR ⁹ , -SR ⁹ , -0C(=0)R ^f , -0C(=0)NR ^h R ^j , -0C(=0)0R ⁹ , - S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , -0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -

0S(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j ; where each R ^a4 is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, Ci- ₆ haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; wherein each R ^b and R ^f are independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; wherein each R ^c and R ⁹ are independently selected from hydrogen, hydroxyl, halogen, CN, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl and Ce-is aryl, wherein said C _1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl 5-6 membered heteroaryl and C _3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^d and R ^h are independently selected from hydrogen, hydroxyl, halogen, CN, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^e and R ^j are independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; or wherein R ^d and R ^e , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; wherein R ^h and R ^j , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; where R ^k is selected from hydrogen, =0, halogen, CN, NH ₂ , NH(CI- ₆ alkyl), N(Ci- ₆ alkyl) ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1- ₆ alkyl and O-C _1-6 alkyl; and

P ³ is a nitrogen protecting group of formula -SC> ₂ R ⁶ orC(0)R ⁸ , wherein R ⁶ is selected from Ci- ₆ alkyl, C1- ₆ haloalkyl, ChhChhSiMes, or a phenyl group optionally substituted with one or more groups selected from NO2 _, halogen and methyl, and wherein R ⁸ is selected from methyl, phenyl, O-f-butyl, and O-benzyl (OBn), wherein said phenyl is optionally substituted by NO2, halogen, OMe or CF ₃ .

106. A compound of formula la, or a salt thereof: wherein

R ¹ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a1 , C2-ioalkenyl optionally substituted by one or more R ^a1 , C^alkynyl optionally substituted by one or more R ^a1 , Ce-isaryl optionally substituted by one or more R ^a1 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a1 , C3-11 cycloalkyl optionally substituted by one or more R ^a1 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a1 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a1 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , 4-15 membered heteroaryl optionally substituted by one or more R ^a1 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a1 is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, Ci- ₆ haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl;

R ² is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a2 , C ₂ -ioalkenyl optionally substituted by one or more R ^a2 , C _2-6 alkynyl optionally substituted by one or more R ^a2 , Ce-isaryl optionally substituted by one or more R ^a2 , C6-i5aryl(Ci-6)alkyl optionally substituted by one or more R ^a2 , C3-11 cycloalkyl optionally substituted by one or more R ^a2 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a2 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , 4-15 membered heteroaryl optionally substituted by one or more R ^a2 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , - C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b ; where each R ^a2 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- 6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-ehaloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; or

R ¹ is absent and R ² combines with the nitrogen to which it is attached to form an imino group of formula =CR ^W R ^X , an amidine of formula =C(R ^w )(NR ^y R ^z ), or a guanidine of formula =C(NR ^y R ^z ) ₂ where R ^w , R ^x are independently C1-6 alkyl and R ^y and R ^z are independently selected from hydrogen and C1-6 alkyl; or

R ¹ and R ² together with the nitrogen atom to which they are attached form a 3-15 membered heterocycloalkyl ring or 4-15 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 ; where each R ^a3 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, 4-15 membered heteroaryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , - 0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, Ce-n aryl, 3-15 membered heterocycloalkyl, and 4-15 membered heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl;

R is selected from the group consisting of Ci-ioalkyl optionally substituted by one or more R ^a , C ₂ -ioalkenyl optionally substituted by one or more R ^a , C _2-6 alkynyl optionally substituted by one or more R ^a , Ce-isaryl optionally substituted by one or more R ^a , C ₆ -isaryl(Ci- e)alkyl optionally substituted by one or more R ^a , C _3-11 cycloalkyl optionally substituted by one or more R ^a , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a , 4-15 membered heterocycloalkyl(Ci- e)alkyl optionally substituted by one or more R ^a , 4-15 membered heteroaryl optionally substituted by one or more R ^a , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a ; where each R ^a is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, Ce-n aryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , NR ^d S(=0) ₂ NR ^d R ^e , -0R ^C , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, and Ce-n aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, phenyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^b is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said Ci- ₆ alkyl, Ce-15 aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C ₆ - i5aryl(Ci-6)alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; wherein each R ^c is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl and Ce-isaryl, wherein said Ci-e alkyl, Ce-isaryl, 3-7 membered heterocycloalkyl 5- 6 membered heteroaryl and C3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, Ci-e haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl and O-C1-6 alkyl; wherein each R ^d is independently selected from hydrogen, hydroxyl, halogen, CN, Ci-e haloalkyl, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; wherein each R ^e is independently selected from hydrogen, hydroxyl, halogen, CN, Ci-e haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ci-e alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said Ci-e alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- i5aryl(Ci-e)alkyl, C3-ncycloalkyl(Ci-e)alkyl, 4-15 membered heterocycloalkyl(Ci-e)alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, Ci-e haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; or wherein R ^d and R ^e , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; where R ^k is selected from hydrogen, =0, halogen, CN, NH ₂ , NH(Ci-e alkyl), N(Ci- ₆ alkyl) ₂ , Ci-e haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl and O-C _1-6 alkyl; and

P ³ is a nitrogen protecting group of formula -SC> ₂ R ⁶ orC(0)R ⁸ , wherein R ⁶ is selected from C1-6 alkyl, Ci- ₆ haloalkyl, ChhChhSiMes, or a phenyl group optionally substituted with one or more groups selected from NO2 _, halogen and methyl and wherein R ⁸ is selected from methyl, phenyl, O-f-butyl, and O-benzyl (OBn), wherein said phenyl is optionally substituted by NO2, halogen, OMe or CF ₃ .

107. A compound of formula 111 or a salt thereof:

(HI), wherein

R is selected from the group consisting of Ci-ioalkyl optionally substituted by one or more R ^a , C2-ioalkenyl optionally substituted by one or more R ^a , C^alkynyl optionally substituted by one or more R ^a , Ce-isaryl optionally substituted by one or more R ^a , C ₆ -isaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , C _3-11 cycloalkyl optionally substituted by one or more R ^a , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , 4-15 membered heteroaryl optionally substituted by one or more R ^a , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a ; where each R ^a is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, Ce-n aryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , NR ^d S(=0) ₂ NR ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and Ce-n aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, phenyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^b is independently selected from hydrogen, hydroxyl, halogen, CN, Ci-e haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C6-i5aryl(Ci-e)alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C ₆ - i5aryl(Ci-6)alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; wherein each R ^c is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl and Ce-isaryl, wherein said Ci-e alkyl, Ce-isaryl, 3-7 membered heterocycloalkyl 5- 6 membered heteroaryl and C3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, Ci-e haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl and O-C1-6 alkyl; wherein each R ^d is independently selected from hydrogen, hydroxyl, halogen, CN, Ci-e haloalkyl, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; wherein each R ^e is independently selected from hydrogen, hydroxyl, halogen, CN, Ci-e haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ci-e alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said Ci-e alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, Ci-e haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl, O-Ci-e alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; or wherein R ^d and R ^e , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; where R ^k is selected from hydrogen, =0, halogen, CN, NH ₂ , NH(CI- ₆ alkyl), N(Ci- ₆ alkyl) ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; and

P ³ is a nitrogen protecting group of formula -SC> ₂ R ⁶ orC(0)R ⁸ , wherein R ⁶ is selected from C1-6 alkyl, Ci- ₆ haloalkyl, ChhChhSiMes, or a phenyl group optionally substituted with one or more groups selected from NO2 _, halogen and methyl; and wherein R ⁸ is selected from methyl, phenyl, O-f-butyl, and O-benzyl (OBn), wherein said phenyl is optionally substituted by NO2, halogen, OMe or CF3.

108. A compound of formula V, or a salt thereof:

(V), wherein

R is selected from the group consisting of Ci-ioalkyl optionally substituted by one or more R ^a , C2-ioalkenyl optionally substituted by one or more R ^a , C^alkynyl optionally substituted by one or more R ^a , Ce-isaryl optionally substituted by one or more R ^a , C ₆ -isaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , C3-11 cycloalkyl optionally substituted by one or more R ^a , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , 4-15 membered heteroaryl optionally substituted by one or more R ^a , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a ; where each R ^a is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, Ce-n aryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , - NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , NR ^d S(=0) ₂ NR ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl, and Ce-n aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci-e haloalkyl, Ci- ₆ haloalkoxy, C3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, phenyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl, and where said phenyl is optionally substituted hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, Ci- ₆ haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^b is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl; wherein each R ^c is independently selected from hydrogen, hydroxyl, halogen, CN, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl and Ce-isaryl, wherein said Ci-e alkyl, Ce-isaryl, 3-7 membered heterocycloalkyl 5- 6 membered heteroaryl and C _3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, Ci-e haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl and O-C _1-6 alkyl; wherein each R ^d is independently selected from hydrogen, hydroxyl, halogen, CN, Ci-e haloalkyl, C _3-6 cycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; wherein each R ^e is independently selected from hydrogen, hydroxyl, halogen, CN, Ci-e haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ci-e alkyl, O-C1-6 alkyl, Ce-is aryl, C ₆ -isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said Ci-e alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, Ce- isaryl(Ci- ₆ )alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4- 15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, Ci-e haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl, O-Ci-e alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl; or wherein R ^d and R ^e , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k ; where R ^k is selected from hydrogen, =0, halogen, CN, NH ₂ , NH(CI- ₆ alkyl), N(Ci- ₆ alkyl) ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl; and

P ² is a nitrogen protecting group selected from Si(R ⁵ )3 wherein R ⁵ is selected from a C1-4 alkyl group or a phenyl group.

109. A compound or a process according to any one of the preceding paragraphs, wherein R is selected from the group consisting of Ci-ioalkyl optionally substituted by one or more R ^a , C2-ioalkenyl optionally substituted by one or more R ^a , C^alkynyl optionally substituted by one or more R ^a , Ce-isaryl optionally substituted by one or more R ^a , C ₆ -isaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , C3-11 cycloalkyl optionally substituted by one or more R ^a , C3- iicycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a , 4-15 membered heteroaryl optionally substituted by one or more R ^a , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a .

110. A compound or a process according to any one of the preceding paragraphs, wherein R is selected from the group consisting of Ci- ₆ alkyl optionally substituted by one or more R ^a , C6-i2aryl optionally substituted by one or more R ^a , C3-7cycloalkyl optionally substituted by one or more R ^a , 5-12 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5- 12 membered heteroaryl optionally substituted by one or more R ^a .

111. A compound or a process according to any one of the preceding paragraphs, wherein R is selected from the group consisting of C6-i2aryl optionally substituted by one or more R ^a , 5-12 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-12 membered heteroaryl optionally substituted by one or more R ^a .

112. A compound or a process according to any one of the preceding paragraphs, wherein R is selected from the group consisting of phenyl optionally substituted by one or more R ^a , 5- 7 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-6 membered heteroaryl optionally substituted by one or more R ^a . 113. A compound or a process according to any one of the preceding paragraphs, wherein R ^a is independently selected from hydroxyl, =0, halogen, CN, Ci-e haloalkyl, Ci-e haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , - C(=0)NR ^d R ^e , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , -OR ^c , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and - S(=0) ₂ NR ^d R ^e , where said C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

114. A compound or a process according to any one of the preceding paragraphs, wherein R ^a is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

115. A compound or a process according to any one of the preceding paragraphs, wherein R is selected from the group consisting of phenyl optionally substituted by one or more R ^a , 5- 7 membered heterocycloalkyl optionally substituted by one or more R ^a , and 5-6 membered heteroaryl optionally substituted by one or more R ^a , wherein R ^a is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, where said C1-6 alkyl and O-C1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

116. A compound or a process according to any one of the preceding paragraphs, wherein R ¹ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a1 , C ₂ -ioalkenyl optionally substituted by one or more R ^a1 , C _2-6 alkynyl optionally substituted by one or more R ^a1 , Ce-isaryl optionally substituted by one or more R ^a1 , C ₆ -isaryl(Ci- e)alkyl optionally substituted by one or more R ^a1 , C _3-11 cycloalkyl optionally substituted by one or more R ^a1 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a1 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a1 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , 4-15 membered heteroaryl optionally substituted by one or more R ^a1 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , and - C(0)C(=0)R ^b . 117. A compound or a process according to any one of the preceding paragraphs, wherein R ¹ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a1 , C^alkenyl optionally substituted by one or more R ^a1 , C^alkynyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b .

118. A compound or a process according to any one of the preceding paragraphs, wherein R ¹ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a1 , -C(=0)R ^b , and -C(=0)NR ^d R ^e .

119. A compound or a process according to any one of the preceding paragraphs, wherein R ¹ is hydrogen or Ci- ₆ alkyl optionally substituted by one or more R ^a1 .

120. A compound or a process according to any one of the preceding paragraphs, wherein

R ^a1 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , - C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

121. A compound or a process according to any one of the preceding paragraphs, wherein R ^a1 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -NR ^d R ^e , -OR ^c , -SR ^C , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

122. A compound or a process according to any one of the preceding paragraphs, wherein R ^a1 is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, where said C1-6 alkyl and O-C1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl. 123. A compound or a process according to any one of the preceding paragraphs, wherein R ^a1 is independently selected from hydroxyl, Ci-e haloalkyl, Ci-e haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, where said C1-6 alkyl and O-C1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

124. A compound or a process according to any one of the preceding paragraphs, wherein R ² is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , C^alkynyl optionally substituted by one or more R ^a2 , C6-i2aryl optionally substituted by one or more R ^a2 , C6-i2aryl(Ci- 3)alkyl optionally substituted by one or more R ^a2 , C3-7cycloalkyl optionally substituted by one or more R ^a2 , C3-7cycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a2 , 3-12 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 4-12 membered heterocycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a2 , 4-12 membered heteroaryl optionally substituted by one or more R ^a2 , and 4-12 membered heteroaryl(Ci-3)alkyl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , and - C(0)C(=0)R ^b .

125. A compound or a process according to any one of the preceding paragraphs, wherein R ² is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , C^alkynyl optionally substituted by one or more R ^a2 , C ₆ -naryl optionally substituted by one or more R ^a2 , C3- 7cycloalkyl optionally substituted by one or more R ^a2 , 5-12 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 5-12 membered heteroaryl optionally substituted by one or more R ^a2 , -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , and -C(0)C(=0)R ^b .

126. A compound or a process according to any one of the preceding paragraphs, wherein R ² is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a2 , C^alkenyl optionally substituted by one or more R ^a2 , phenyl optionally substituted by one or more R ^a2 , C^cycloalkyl optionally substituted by one or more R ^a2 , 4-7 membered heterocycloalkyl optionally substituted by one or more R ^a2 , 5-6 membered heteroaryl optionally substituted by one or more R ^a2 , -C(=0)R ^b , and -C(=0)NR ^d R ^e .

127. A compound or a process according to any one of the preceding paragraphs, wherein R ² is hydrogen or Ci- ₆ alkyl optionally substituted by one or more R ^a2 .

128. A compound or a process according to any one of the preceding paragraphs, wherein R ^a2 is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , - C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d C(=0)0R ^c , - NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , -0C(=0)R ^b , -

0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -

0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

129. A compound or a process according to any one of the preceding paragraphs, wherein R ^a2 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, -C(=0)R ^b , - C(=0)NR ^d R ^e , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , -0R ^C , -SR ^C , -0C(=0)R ^b , -S(=0) ₂ R ^c , - S(=0)R ^c , -0S(=0)R ^c , -S(=0)NR ^d R ^e and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, 0-Ci- ₆ alkyl, C ₃ - ₆ cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

130. A compound or a process according to any one of the preceding paragraphs, wherein R ^a2 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, where said Ci- ₆ alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

131. A compound or a process according to any one of the preceding paragraphs, wherein R ^a2 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

132. A compound or a process according to any one of the preceding paragraphs, wherein R ^a2 is independently selected from hydroxyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, where said C1-6 alkyl and O-C1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

133. A compound or a process according to any one of the preceding paragraphs, wherein R ¹ is absent and R ² combines with the nitrogen to which it is attached to form an imino group of formula =CR ^W R ^X , an amidine of formula =C(R ^w )(NR ^y R ^z ), or a guanidine of formula =C(NR ^y R ^z )2, where R ^w , R ^x are independently C1-6 alkyl and R ^y and R ^z are independently selected from hydrogen and C1-6 alkyl.

134. A compound or a process according to any one of the preceding paragraphs, wherein R ¹ and R ² together with the nitrogen atom to which they are attached form a 3-12 membered heterocycloalkyl ring or 4-12 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

135. A compound or a process according to any one of the preceding paragraphs, wherein R ¹ and R ² together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloalkyl ring or 5-12 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

136. A compound or a process according to any one of the preceding paragraphs, wherein R ¹ and R ² together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloalkyl ring or 5-6 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

137. A compound or a process according to any one of the preceding paragraphs, wherein R ^a3 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , - NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , - 0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl. 138. A compound or a process according to any one of the preceding paragraphs, wherein R ^a3 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C(=0)R ^b , -C(=0)NR ^d R ^e , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , -OR ^c , -SR ^C , - 0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -S(=0)NR ^d R ^e and -S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

139. A compound or a process according to any one of the preceding paragraphs, wherein R ^a3 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

140. A compound or a process according to any one of the preceding paragraphs, wherein R ^a3 is independently selected from hydroxyl, =0, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, where said C1-6 alkyl and O-C1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

141. A compound or a process according to any one of the preceding paragraphs, wherein R ^a3 is independently selected from hydroxyl, =0, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O- C1-6 alkyl, where said C1-6 alkyl and O-C1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

142. A compound or a process according to any one of the preceding paragraphs, wherein R ¹ and R ² together with the nitrogen atom to which they are attached form a 5-7 membered heterocycloalkyl ring or 5-6 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more substitutents selected from hydroxyl, =0, C1-6 haloalkyl, C1-6 alkyl, O-C1-6 alkyl, where said C1-6 alkyl is optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

143. A compound or a process according to any one of the preceding paragraphs, wherein R ¹ and R ² are independently selected from hydrogen or Ci-3alkyl optionally substituted by one or more R ^a1 or R ^a2 respectively; or,

R ¹ and R ² together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycloalkyl ring or 5-6 membered heteroaryl ring, each independently and optionally containing one or more further heteroatoms selected from O, N, and S and wherein each ring is independently and optionally substituted with one or more R ^a3 .

144. A compound or a process according to any one of the preceding paragraphs, wherein R ³ is selected from the group consisting of H, C1-6 alkyl, CN, -C(=0)R ^f , -C(=0)NR ^h R ^j , -OR ⁹ , -SR ⁹ , -0C(=0)R ^f , -0C(=0)NR ^h R ^j , -0C(=0)0R ⁹ , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , - 0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -0S(=0) ₂ NR ^h Ri, and -S(=0) ₂ NR ^h Ri, where said Ci- ₆ alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl.

145. A compound or a process according to any one of the preceding paragraphs, wherein R ³ is selected from the group consisting of H, C1-6 alkyl, CN, -C(=0)R ^f , -C(=0)0R ⁹ , - C(=0)NR ^h R ^j , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , — S(=0)NR ^h Ri, and -S(=0) ₂ NR ^h Ri, where said Ci- ₆ alkyl is optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- 6 haloalkyl, Ci-6haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl.

146. A compound or a process according to any one of the preceding paragraphs, wherein R ³ is selected from the group consisting of H, C _1-3 alkyl, CN, -C(=0)R ^f and -C(=0)NR ^h R ^j , where said C _1-3 alkyl is optionally substituted with one or more groups selected from hydroxyl, CN, C _1-3 haloalkyl, Ci- ₃ haloalkoxy, C _3-6 cycloalkyl, and O-C _1-3 alkyl.

147. A compound or a process according to any one of the preceding paragraphs, wherein R ⁴ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a4 , C ₂ -ioalkenyl optionally substituted by one or more R ^a4 , C _2-6 alkynyl optionally substituted by one or more R ^a4 , Ce-isaryl optionally substituted by one or more R ^a4 , C ₆ -isaryl(Ci- e)alkyl optionally substituted by one or more R ^a4 , C _3-11 cycloalkyl optionally substituted by one or more R ^a4 , C3-ncycloalkyl(Ci-6)alkyl optionally substituted by one or more R ^a4 , 3-15 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 4-15 membered heteroaryl optionally substituted by one or more R ^a4 , and 4-15 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)0R ⁹ , -C(=0)NR ^h R ^j , - C(0)C(=0)R ^f , -OR ⁹ , -SR ⁹ , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -0S(=0)R ⁹ , -0S(=0) ₂ R ⁹ , -0S(=0) ₂ 0R ⁹ , -S(=0)NR ^h R ^j , -0S(=0) ₂ NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j .

148. A compound or a process according to any one of the preceding paragraphs, wherein R ⁴ is selected from the group consisting of hydrogen, Ci-ioalkyl optionally substituted by one or more R ^a4 , C ₂ -ioalkenyl optionally substituted by one or more R ^a4 , C _2-6 alkynyl optionally substituted by one or more R ^a4 , C ₆ -i ₂ aryl optionally substituted by one or more R ^a4 , C ₆ -i ₂ aryl(Ci- 3)alkyl optionally substituted by one or more R ^a4 , C3-7cycloalkyl optionally substituted by one or more R ^a4 , C3-7cycloalkyl(Ci-3)alkyl optionally substituted by one or more R ^a4 , 3-12 membered heterocycloalkyl optionally substituted by one or more R ^a4 , 4-12 membered heterocycloalkyl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , 4-12 membered heteroaryl optionally substituted by one or more R ^a4 , and 4-12 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)0R ⁹ , -C(=0)NR ^h R ^j , - C(0)C(=0)R ^f , -OR ⁹ , -SR ⁹ , -S(=0) ₂ R ⁹ , -S(=0)R ⁹ , -S(=0)NR ^h R ^j , and -S(=0) ₂ NR ^h R ^j .

149. A compound or a process according to any one of the preceding paragraphs, wherein R ⁴ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a4 , C^alkenyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , phenyl optionally substituted by one or more R ^a4 , phenyl(Ci- 3)alkyl optionally substituted by one or more R ^a4 , 5-10 membered heteroaryl optionally substituted by one or more R ^a4 , and 5-10 membered heteroaryl(Ci- ₆ )alkyl optionally substituted by one or more R ^a4 , CN, -C(=0)R ^f , -C(=0)0R ⁹ , -C(=0)NR ^h Ri, -OR ⁹ , and -SR ⁹ .

150. A compound or a process according to any one of the preceding paragraphs, wherein R ⁴ is selected from the group consisting of hydrogen, Ci- ₆ alkyl optionally substituted by one or more R ^a4 , C^alkynyl optionally substituted by one or more R ^a4 , phenyl optionally substituted by one or more R ^a4 ·, benzyl optionally substituted by one or more R ^a4 ·, -C(=0)R ^f , -C(=0)0R ⁹ , -C(=0)NR ^h R ^j and -SR ⁹ .

151. A compound or a process according to any one of the preceding paragraphs, wherein R ^a4 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, Ci- ₆ haloalkoxy, Ci- ₆ alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C(=0)R ^b , -C(=0)0R ^c , -C(=0)NR ^d R ^e , -C(0)C(=0)R ^b , -NR ^d R ^e , -NR ^d C(=0)R ^b , - NR ^d C(=0)0R ^c , -NR ^d C(=0)NR ^d R ^e , -NR ^d S(=0) ₂ R ^b , -N R ^d S(=0) ₂ N R ^d R ^e , -OR ^c , -SR ^C , - 0C(=0)R ^b , -0C(=0)NR ^d R ^e , -0C(=0)0R ^c , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -0S(=0) ₂ R ^c , -0S(=0) ₂ 0R ^c , -S(=0)NR ^d R ^e , -0S(=0) ₂ NR ^d R ^e , and -S(=0) ₂ NR ^d R ^e , where said Ci- ₆ alkyl, O- C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, Ci- ₆ haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

152. A compound or a process according to any one of the preceding paragraphs, wherein R ^a4 is independently selected from hydroxyl, =0, halogen, CN, Ci- ₆ haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C(=0)R ^b , -C(=0)NR ^d R ^e , -NR ^d R ^e , -NR ^d C(=0)R ^b , -NR ^d S(=0) ₂ R ^b , -0R ^C , -SR ^C , - 0C(=0)R ^b , -S(=0) ₂ R ^c , -S(=0)R ^c , -0S(=0)R ^c , -S(=0)NR ^d R ^e and -S(=0) ₂ NR ^d R ^e , where said C _1-6 alkyl, O-C _1-6 alkyl, C _3-6 cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

153. A compound or a process according to any one of the preceding paragraphs, wherein R ^a4 is independently selected from hydroxyl, =0, halogen, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O-C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =0, CN, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

154. A compound or a process according to any one of the preceding paragraphs, wherein R ^a4 is independently selected from hydroxyl, =0, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, O- C _1-6 alkyl, where said C _1-6 alkyl and O-C _1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

155. A compound or a process according to any one of the preceding paragraphs, wherein R ^b and R ^f are independently selected from hydrogen, CN, 3-7 membered heterocycloalkyl, 5- 15 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, Ce-isaryl, Ce-i5aryl(Ci-6)alkyl, C3-iicycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said Ci-e alkyl, Ce-isaryl, 3-7 membered heterocycloalkyl, 5-15 membered heteroaryl, C3-6 cycloalkyl, Ce-i5aryl(Ci-e)alkyl, C3-ncycloalkyl(Ci-6)alkyl, 4-15 membered heterocycloalkyl (Ci-e)alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, N0 ₂ , Ci-e haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl, O-Ci-e alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl. 156. A compound or a process according to any one of the preceding paragraphs, wherein R ^b and R ^f are independently selected from hydrogen, 3-7 membered heterocycloalkyl, 5-12 membered heteroaryl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl, C6-i2aryl, C6-i2aryl(Ci-3)alkyl, C3- iicycloalkyl(Ci-3)alkyl, 4-12 membered heterocycloalkyl(Ci-3)alkyl, and 4-12 membered heteroaryl(Ci-3)alkyl, wherein said C1-6 alkyl, C6-i2aryl, 3-7 membered heterocycloalkyl, 5-12 membered heteroaryl, C3-6 cycloalkyl, C6-i2aryl(Ci-3)alkyl, C3-ncycloalkyl(Ci-3)alkyl, 4-12 membered heterocycloalkyl (Ci-3)alkyl, and 4-12 membered heteroaryl(Ci-3)alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, Ci- ₆ haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

157. A compound or a process according to any one of the preceding paragraphs, wherein R ^b and R ^f are independently selected from hydrogen, phenyl, phenyl(Ci-3)alkyl, wherein said phenyl and phenyl(Ci-3)alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO2, C1-6 haloalkyl, C3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl, O-C1-6 alkyl, NH2, NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

158. A compound or a process according to any one of the preceding paragraphs, wherein each R ^c and R ⁹ are independently selected from hydrogen, halogen, CN, C1- ₆ haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, C1- ₆ alkyl, O-C1- ₆ alkyl and Ce-isaryl, wherein said Ci-e alkyl, Ce-isaryl, 3-7 membered heterocycloalkyl 5-6 membered heteroaryl and C _3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, Ci-e haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl and O-C1- ₆ alkyl.

159. A compound or a process according to any one of the preceding paragraphs, wherein each R ^c and R ⁹ are independently selected from hydrogen, Ci-e haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, Ci-e alkyl and phenyl, wherein said Ci-e alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, nitro, amino, Ci-e haloalkyl, C3- 6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci-e alkyl and O-C1- ₆ alkyl.

160. A compound or a process according to any one of the preceding paragraphs, wherein R ^d and R ^h are independently selected from hydrogen, CN, Ci-e haloalkyl, C _3-6 cycloalkyl, and C1- ₆ alkyl. 161. A compound or a process according to any one of the preceding paragraphs, wherein R ^d and R ^h are independently selected from hydrogen, and C _1-3 alkyl.

162. A compound or a process according to any one of the preceding paragraphs, wherein R ^e and R ^j are independently selected from hydrogen, CN, C _1-6 haloalkyl, 3-7 membered heterocycloalkyl, 5-15 membered heteroaryl, C _3-6 cycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, Ce-isaryl, C ₆ -i ₅ aryl(Ci- ₆ )alkyl, C ₃ -ncycloalkyl(Ci- ₆ )alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl, wherein said C _1-6 alkyl, Ce-is aryl, 3-7 membered heterocycloalkyl, 5-15 membered heteroaryl, C _3-6 cycloalkyl, C ₆ -isaryl(Ci- ₆ )alkyl, C ₃ - _{1 i} cycloalkyl(Ci- ₆ )alkyl, 4-15 membered heterocycloalkyl(Ci- ₆ )alkyl, and 4-15 membered heteroaryl(Ci- ₆ )alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, Ci- ₆ alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C1-4 alkyl.

163. A compound or a process according to any one of the preceding paragraphs, wherein R ^e and R ^j are independently selected from hydrogen, C _3-6 cycloalkyl, C _1-6 alkyl, C ₆ -i ₂ aryl, C ₆ - ₁₂ ary I (Ci - ₃ )al ky I , C ₃ -ncycloalkyl(Ci- ₃ )alkyl, wherein said C _1-6 alkyl, Ce-^aryl, C _3-6 cycloalkyl, Ce- i ₂ aryl(Ci- ₃ )alkyl, and C ₃ -ncycloalkyl(Ci- ₃ )alkyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

164. A compound or a process according to any one of the preceding paragraphs, wherein R ^e and R ^j are independently selected from hydrogen, C _1-3 alkyl, phenyl, and pheny(Ci- ₃ )alkyl, wherein said C _1-3 alkyl, phenyl and phenyl(Ci- ₃ )alkyl, , are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NO ₂ , C _1-6 haloalkyl, C _3-6 cycloalkyl, Ce-n aryl, 3-7 membered heterocycloalkyl, C _1-6 alkyl, O-C _1-6 alkyl, NH ₂ , NHR’, and NR’R”, where R’ and R” are independently selected from C _1-4 alkyl.

165. A compound or a process according to any one of the preceding paragraphs, wherein R ^d and R ^e , when attached to the same atom, together with the atom to which they are attached form a 5-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k .

166. A compound or a process according to any one of the preceding paragraphs, wherein R ^h and R ^j , when attached to the same atom, together with the atom to which they are attached form a 5-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R ^k .

167. A compound or a process according to any one of the preceding paragraphs, wherein R ^k is selected from =0, halogen, CN, NH ₂ , NH(CI- ₆ alkyl), N(CI- ₆ alkyl)2, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5-7 membered heterocycloalkyl, C _1-6 alkyl and O-C _1-6 alkyl.

168. A compound or a process according to any one of the preceding paragraphs, wherein R ^k is selected from =0, halogen, CN, NH2, NH(Ci-3alkyl), N(Ci ₃ alkyl) ₂ , C1-6 haloalkyl, C1-6 alkyl and O-C _1-6 alkyl.

169. A compound or a process according to any one of the preceding paragraphs, wherein R’ and R” are independently selected from methyl, ethyl or propyl; preferably methyl or ethyl.

170. A compound or a process according to any one of the preceding paragraphs, wherein (i) when R is methyl, ethyl or butyl then R ³ and R ⁴ cannot both be methyl; and (ii) when R is optionally substituted phenyl then R ³ and R ⁴ cannot both be -SO ₂ CF ₃ .

171. A compound according to any one of the preceding paragraphs as a salt, suitably a pharmaceutically acceptable salt.

[00306] 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.

EXAMPLES

[00307] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

[00308] The compounds of the invention may be prepared using synthetic techniques that are known in the art (as illustrated by the examples herein).

[00309] Several methods for the chemical synthesis of the compounds of the present application are described herein. These and/or other well-known methods may be modified and/or adapted in various ways in order to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood as being within the spirit and scope of this application and claims. Accordingly, it should be understood that the methods set forth in the following descriptions, schemes and examples are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure.

General Considerations

[00310] Handling techniques: Reactions were performed under inert nitrogen atmosphere with anhydrous solvent unless otherwise stated. All glassware was oven dried at >100 °C and allowed to cool to room temperature under positive pressure of nitrogen. Reactions were monitored by TLC until deemed complete using aluminium backed silica plates. Plates were visualised under ultraviolet light (254 nm) and/or by staining with KMnCL solution. Cooling of reaction mixtures to 0 °C was achieved using an ice-water bath. Cooling of reaction mixtures to -78 °C was achieved using a dry ice-acetone bath. ‘Room temperature’ refers to an ambient temperature of 21 ± 2 °C.

[00311] Reagents: Reagents were purchased from Sigma-Aldrich Chemical Co. Ltd., Alfa Aesar, Tokyo Chemical Industry UK or Fluorochem Ltd. and were used as supplied. N- Sulfinyl-te/f-octylamine which was prepared by literature method. Anhydrous solvents were purified by filtration through dried alumina columns using the University of Oxford internal solvent drying system (Innovative Technology Inc. PS-400-7) and sparged with nitrogen before use. All inert gases were sourced from the University of Oxford internal supplies and dried through CaCL drying columns. Grignard and organolithium reagents were titrated against salicylaldehyde phenylhydrazone ¹⁰ . Flash column chromatography was carried out using matrix 60 silica gel. ‘Petrol’ refers to the fraction of light petroleum ether boiling in the range 40-60 °C.

[00312] NMR Spectroscopy: ¹ H-NMR spectra were obtained on a Bruker AVIII400 (400 MHz) spectrometer using the residual solvent as an internal standard. ¹³ C-NMR spectra were obtained on a Bruker AVIII400 (101 MHz) using the residual solvent as an internal standard. ¹⁹ F-NMR spectra were obtained on a Bruker AVI 11400 (377 MHz) spectrometer. All reported ¹ H and ¹³ C chemical shifts (¾, be) are referenced to the residual signal of deuterated solvents (CDCh: bpi = 7.26 ppm, be = 77.16 ppm; (CDs)2SO: bpi = 2.50 ppm, be = 39.52 ppm; (CD3)2CO: b _H = 2.05 ppm, be = 206.26 ppm). ¹⁹ F chemical shifts (bp) are referenced externally to CFCI3 (b _F = 0.0 ppm). Chemical shifts (b) are reported in parts per million (ppm) to the nearest 0.01 ppm for ¹ H NMR, and 0.1 ppm for ¹³ C and ¹⁹ F NMR. Coupling constants ( ) are reported in Hertz (Hz). Multiplicities are reported as followings: s (singlet), d (doublet), t (triplet), q (quartet), pent (pentet), m (multiplet), br. (broad signal), app. (apparent). [00313] Mass Spectroscopy: Low resolution ESI mass spectra were recorded on a Waters LCT Premier spectrometer. High resolution mass spectrometry measurements were recorded on a Bruker Daltronics MicroTOF (ESI) spectrometer or on a Micromass LCT (FI) spectrometer by the internal service at Chemistry Research Laboratory, University of Oxford. Samples for mass spectra were prepared as 1 mg/mL solution in MeOH (LRMS, HRMS-ESI) or submitted neat (HRMS-FI).

[00314] IR Spectroscopy: Infrared spectra were recorded as thin films on a Bruker Tensor 27 FT-IR spectrometer.

[00315] Melting point: Melting points were determined using a Stuart Scientific Melting Point Apparatus SMP1.

Synthesis and Characterisation

[00316] Preparation of TIPS-NH ₂ (P1)

NH- (I)

Tips-ci - — - ► TIPS-NH ₂

Et ₂ 0, -78 to °C

[00317] Triisopropylsilyl chloride (13.50 g, 70.0 mmol, 1.00 equiv.) was dissolved in anhydrous diethyl ether (140 ml_) in an oven-dried 500 ml_ round-bottom flask. The reaction mixture was cooled to -78 °C. Anhydrous ammonia was bubbled through this solution for 2 h, resulting in the immediate formation of a white precipitate. The reaction was then warmed to 0 °C and stirred for another 3 h to remove excess ammonia. Filtration over anhydrous Na ₂ S0 ₄ and removal of solvent under reduced pressure afforded TIPS-NH2 as a colourless oil (12.0 g, 69.5 mmol, 99%).

¹ H NMR (400 MHz, C ₆ D ₆ ): <5 (ppm) = 1.05-1.00 (m, 18H), 0.95-0.85 (m, 3H), -0.12 (s, 2H);

¹³ C NMR (101MHz, C ₆ D ₆ ): d (ppm) = 18.4, 12.5;

IR (ATR): v (cm- ¹ ) = 2864, 1546, 1463, 1382, 1245, 1011, 882, 817, 658.

[00318] Preparation of Sulfinylamine (P2)

SOCI ₂ , Et ₃ N

TIPS-NH ₂ Et ₂ Q, 0 °C TIPS ^N V°

[00319] TIPS-NH2 (5.20 g, 30.0 mmol, 1.00 equiv.) was dissolved in anhydrous diethyl ether (600 mL) in an oven-dried 1 L round-bottom flask. The reaction was cooled to 0 °C and anhydrous EΐbN (8.41 mL, 61.8 mmol, 2.06 equiv.) was added. Freshly distilled thionyl chloride (2.25 mL, 30.9 mmol, 1.03 equiv.) was then added dropwise. The reaction was stirred at 0 °C for 1.5 h. Filtration over Na ₂ S0 ₄ (washed with diethyl ether) and removal of solvent under reduced pressure at room temperature afforded TIPS-NSO (P2) as a pale-yellow oil (6.56 g, 30.0 mmol, 100%).

¹ H NMR (400 MHz, C ₆ D ₆ ): <5 (ppm) = 1.19-0.96 (m, 21 H);

¹³ C NMR (101MHz, C ₆ D ₆ ): <5 (ppm) = 18.0, 12.4;

IR (ATR): v (cm ^-1 ) = 2980, 1463, 1385, 1308, 1128, 882, 682, 664.

[00320] General Procedure A - Sulfinamidine Synthesis

[00321] An oven-dried round-bottom flask containing TIPS-NSO (P2) (1.00 equiv.) was sealed and subjected to three N2 evacuation/refill cycles before pre-sparged anhydrous THF (TIPS-NSO cone. 0.5 M) was added. The solution was cooled to -30 °C and then LiHMDS solution (1.0 M in THF, 1.00 equiv.) was added. The reaction was stirred at - 30 °C for 5 min before being warmed to 0 °C and stirred for 10 min at the same temperature. TMSCI (1.00 equiv.) was added. The reaction was stirred at 0 °C for 10 min. Subsequently, the corresponding organometallic reagent (1.20 equiv.) was added. The reaction was stirred at 0 °C for another 10 min before being diluted with EtOAc and quenched with saturated aqueous solution of EDTA. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SC>4 _, filtered and concentrated under reduced pressure. This crude mixture was then dissolved in anhydrous CH2CI2 (TIPS-NSO cone. 0.2 M) and cooled to 0 °C. EΐbN (1.20 equiv.) and an electrophile (1.00 equiv.), such as NsCI shown in the scheme above, were added. The reaction was stirred at 0 °C for 20 min prior to the addition of TBAF solution (1.0 M in THF, 1.10 equiv.) at the same temperature. The reaction was stirred for 10 min. The primary sulfinamidines were isolated following different work-up procedures (Work-up Procedure A1-A3).

[00322] Work-up Procedure A1:

[00323] If addition of TBAF solution to the reaction mixture resulted in the precipitation of a white solid, this white solid was purified by filtration and being washed with a cold mixed solution of EtOAc and Et ₂ 0 (1:2). Sat. aq. NaCI solution was added to the combined filtrates. The aqueous phase was extracted with EtOAc three times. The combined organic layers were then dried over anhydrous Na ₂ S0 _4, filtered and concentrated under reduced pressure. The resulting primary sulfinamidine was then purified by flash column chromatography with the appropriate solvent system, or by recrystallisation.

[00324] Work-up Procedure A2:

[00325] If the addition of TBAF solution to the reaction mixture did not result in the precipitation of a white solid, the reaction was then diluted with EtOAc and quenched with sat. aq. NaCI solution. The aqueous phase was extracted with EtOAc. The combined organic layers were then dried over anhydrous Na ₂ S0 _4, filtered and concentrated under reduced pressure to give an off-white solid. This white solid was purified by filtration and being washed with cold Et ₂ 0 or DCM. The volatiles were removed under reduced pressure from the combined filtrates which were then purified by flash column chromatography with the appropriate solvent system.

[00326] Work-up Procedure A3:

[00327] If the addition of TBAF solution to the reaction mixture did not result in the precipitation of a white solid, the reaction was then diluted with EtOAc and quenched with sat. aq. NaCI solution. The aqueous phase was extracted with EtOAc. The combined organic layers were then dried over anhydrous Na ₂ S0 _4, filtered and concentrated under reduced pressure to give an oil. The primary sulfinamidine was then purified by flash column chromatography with the appropriate solvent system.

[00328] /V-(amino(4-fluorophenyl)-A4-sulfaneylidene)-4-nitrobenzenes ulfonamide

(P3)

[00329] Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 mL, 1.0 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (635 pl_, 5.00 mmol, 1.00 equiv.), 4-fluorophenylmagnesium bromide solution (7.50 mL, 0.80 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 mL), Et ₃ N (836 pL, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.0 M in THF, 5.50 mmol, 1.10 equiv.). [00330] The primary sulfinamidine P3 was isolated and purified according to Work-up Procedure A2. Filtration and flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 3:1 to 1:1) afforded the desired product as a white solid (1.54 g, 4.49 mmol, 90%). mp 145-147 °C (CH ₂ CI ₂ );

Rf0.35 (CH ₂ CI ₂ /ethyl acetate, 3:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.34 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H), 7.83-7.77 (m, 2H), 7.49-7.43 (m, 2H), 7.12 (s, 2H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5 (ppm) = 163.9 (d, = 250.2 Hz), 150.5, 148.8, 134.8 (d, = 2.8 Hz), 129.5 (d, J = 9.4 Hz), 127.3, 124.3, 116.6 (d, J = 22.9 Hz);

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -108.9 (tt, = 8.9, 5.1 Hz);

IR (ATR): v (cm ^-1 ) = 1521, 1487, 1353, 1276, 1230, 1139, 1085, 975, 835, 783, 730;

HRMS (ESF) calcd. for C ₁₂ HnFN ₃ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 344.0170, found: 344.0171.

[00331] yV-(amino(4-chlorophenyl)-A4-sulfaneylidene)-4- nitrobenzenesulfonamide (P4)

[00332] Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 mL, 1.0 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (635 pl_, 5.00 mmol, 1.00 equiv.), 4-chlorophenylmagnesium bromide solution (6.00 mL, 1.00 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 mL), Et ₃ N (836 pL, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.0 M in THF, 5.50 mmol, 1.10 equiv.).

[00333] The primary sulfinamidine P4 was isolated and purified according to Work-up Procedure A2. Filtration and flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 3:1 to 1:1) afforded the desired product as a white solid (1.61 g, 4.48 mmol, 90%). mp 174-176 °C (CH ₂ CI ₂ );

RfO.47 (CH ₂ CI ₂ /ethyl acetate, 2:1); ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.34 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.9 Hz, 2H), 7.75 (d, J= 9.0 Hz, 2H), 7.68 (d, J= 9.0 Hz, 2H), 7.16 (s, 2H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 150.4, 148.8, 137.8, 136.8, 129.5, 128.7, 127.3, 124.3;

IR (ATR): v (cm ^-1 ) = 1520, 1475, 1393, 1350, 1271, 1149, 1080, 968, 832;

HRMS (ESF) calcd. for C ₁₂ HnCIN ₃ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 359.9874, found: 359.9874.

[00334] /V-(amino(2-methylphenyl)-A4-sulfaneylidene)-4- nitrobenzenesulfonamide (P5)

[00335] Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 mL, 1.0 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (635 pl_, 5.00 mmol, 1.00 equiv.), 2-methylphenylmagnesium bromide solution (7.69 mL, 0.78 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 mL), Et ₃ N (836 pL, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.0 M in THF, 5.50 mmol, 1.10 equiv.).

[00336] The primary sulfinamidine P5 was isolated and purified according to Work-up Procedure A2. Filtration and flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 3:1 to 1:1) afforded the desired product as a white solid (1.41 g, 4.16 mmol, 83%). mp 168-170 °C (CH ₂ CI ₂ );

RfO.46 (CH ₂ CI ₂ /ethyl acetate, 2:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.31 (d, J= 8.9 Hz, 2H), 8.05-7.98 (m, 3H), 7.52- 7.41 (m, 2H), 7.34 (ddd, = 7.1 , 1.9, 1.0 Hz, 1H), 6.90 (s, 2H), 2.39 (s, 3H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 150.7, 148.7, 137.6, 135.9, 131.9, 131.3, 127.2, 127.0, 125.0, 124.2, 18.5;

IR (ATR): v (cm ^-1 ) = 1530, 1474, 1382, 1351, 1267, 1152, 1084, 967;

HRMS (ESF) calcd. for C ₁₃ H ₁₄ N ₃ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 340.0425, found: 340.0421. [00337] /V-(amino(2-thienyl)-A4-sulfaneylidene)-4-nitrobenzenesulfon amide (P6)

[00338] Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 ml_, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (635 pl_, 5.00 mmol, 1.00 equiv.), 2-thienylmagnesium bromide solution (6.00 ml_, 1.00 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 ml_), Et ₃ N (836 pl_, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 ml_, 1.0 M in THF, 5.50 mmol, 1.10 equiv.).

[00339] The primary sulfinamidine P6 was isolated and purified according to Work-up Procedure A1. Filtration and flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 3:1 to 1:1) afforded the desired product as a white solid (1.34 g, 4.05 mmol, 81%). mp 162-164 °C (CH ₂ CI ₂ );

Rf0.41 (petrol/ethyl acetate, 1:2);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.35 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.9 Hz, 2H), 7.96 (dd, J= 5.1, 1.4 Hz, 1H), 7.42 (dd, J= 3.8, 1.4 Hz, 1H), 7.38 (s, 2H), 7.21 (dd, J= 5.1, 3.8 Hz, 1H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 150.3, 148.8, 140.2, 133.9, 131.3, 128.8, 127.2, 124.3;

IR (ATR): v (cm ^-1 ) = 1535, 1477, 1431, 1401, 1351, 1294, 1143, 1086, 966, 850, 787, 728, 683;

HRMS (ESF) calcd. for C ₁₀ H ₁₀ N ₃ O ₄ S ₃ ⁺ [M+H] ⁺ : 331.9828, found: 331.9828.

[00340] /V-(amino(6-methoxypyridin-3-yl)-A4-sulfaneylidene)-4- nitrobenzenesulfonamide (P7) [00341] Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 ml_, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (635 pl_, 5.00 mmol, 1.00 equiv.), (6-methoxypyridin-3-yl)lithium solution (6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 mL), Et ₃ N (836 pL, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.0 M in THF, 5.50 mmol, 1.10 equiv.).

[00342] The primary sulfinamidine P7 was isolated and purified according to Work-up Procedure A2. Filtration and flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 2:1 to 1:1) afforded the desired product as a white solid (1.31 g, 3.68 mmol, 74%). mp 158-160 °C (CH ₂ CI ₂ );

RfO.27 (CH ₂ CI ₂ /ethyl acetate, 2:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.44 (dd, J = 2.7, 0.7 Hz, 1H), 8.33 (d, J = 9.0 Hz, 2H), 8.05 (d, J= 9.0 Hz, 2H), 7.98 (dd, J= 8.9, 2.7 Hz, 1H), 7.15 (s, 2H), 7.02 (dd, J= 8.9, 0.7 Hz, 1H), 3.90 (s, 3H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 165.5, 150.5, 148.8, 146.1, 137.6, 128.1, 127.2, 124.3, 111.5, 54.1;

IR (ATR): v (cm ^-1 ) = 1587, 1518, 1475, 1380, 1353, 1280, 1145, 1085, 966, 856, 831, 785, 731, 685;

HRMS (ESF) calcd. for C ₁₂ H ₁₃ N ₄ 0 ₅ S ₂ ⁺ [M+H] ⁺ : 357.0322, found: 357.0323.

[00343] /V-(amino(ferf-butyl)-A4-sulfaneylidene)-4-nitrobenzenesulfo namide (P8)

[00344] Prepared according to General Procedure A using TIPS-NSO (1.31 g, 6.00 mmol, 1.00 equiv.), THF (12.0 mL), LiHMDS solution (6.00 mL, 1.00 M in THF, 6.00 mmol, 1.00 equiv.), TMSCI (761 pL, 6.00 mmol, 1.00 equiv.), te/f-butylmagnesium chloride solution (7.58 mL, 0.95 M in THF, 7.20 mmol, 1.20 equiv.), CH ₂ CI ₂ (30.0 mL), Et ₃ N (1.00 mL, 7.20 mmol, 1.20 equiv.), NsCI (1.33 g, 6.00 mmol, 1.00 equiv.) and TBAF solution (6.60 mL, 1.00 M in THF, 6.60 mmol, 1.10 equiv.). [00345] The primary sulfinamidine P8 was isolated and purified according to Work-up Procedure A1. Filtration and flash column chromatography (C^Ch/ethyl acetate, 3:1 to 1:1) afforded the desired product as a white solid (1.61 g, 5.28 mmol, 88%). mp 174-176 °C (CH2CI2);

RfO.45 (CH ₂ CI ₂ /ethyl acetate, 2:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.32 (d, J = 8.9 Hz, 2H), 7.98 (d, J = 8.9 Hz, 2H), 6.19 (s, 2H), 1.15 (s, 9H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 150.8, 148.5, 127.3, 124.1, 57.0, 22.7;

IR (ATR): v (cm ^-1 ) = 1531, 1350, 1289, 1145, 1084, 972, 853, 733, 683, 624;

HRMS (ESF) calcd. for C ₁₀ H ₁₅ N ₃ O4S2Na ⁺ [M+ Na] ⁺ : 328.0396, found: 328.0397.

[00346] /V-(amino(cyclopentyl)-A4-sulfaneylidene)-4-nitrobenzenesulf onamide (P9)

[00347] Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 ml_, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (635 pL, 5.00 mmol, 1.00 equiv.), cyclopentylmagnesium bromide solution (3.11 ml_, 1.93 M in diethyl ether, 6.00 mmol, 1.20 equiv.), CH2CI2 (25.0 ml_), Et ₃ N (836 mI_, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 ml_, 1.0 M in THF, 5.50 mmol, 1.10 equiv.).

[00348] The primary sulfinamidine P9 was isolated and purified according to Work-up Procedure A3. Flash column chromatography (C^Ch/ethyl acetate, 3:1 to 1:1) afforded the desired product as a white solid (1.11 g, 3.50 mmol, 70%). mp 154-156 °C (CH2CI2);

RfOAO (CH ₂ CI ₂ /ethyl acetate, 1:1); ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.32 (d, J = 8.9 Hz, 2H), 7.98 (d, J = 8.9 Hz, 2H), 6.32 (s, 2H), 3.55 (tt, J= 8.3, 5.7 Hz, 1H), 1.92-1.76 (m, 2H), 1.74-1.60 (m, 2H), 1.60-1.46 (m, 4H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 151.0, 148.5, 127.2, 124.1, 62.0, 27.5, 27.2, 25.0, 24.8;

IR (ATR): v (cm ^-1 ) = 1538, 1382, 1350, 1291, 1143, 1085, 970, 853, 732, 683, 620;

HRMS (ESF) calcd. for C ₁₁ H ₁₅ N ₃ 0 ₄ S ₂ Na ⁺ [M+ Na] ⁺ : 340.0396, found: 340.0397.

[00349] /V-(amino(cyclopropyl)-A4-sulfaneylidene)-4-nitrobenzenesulf onamide

(P10)

[00350] Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 mL, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (635 pL, 5.00 mmol, 1.00 equiv.), cyclopropylmagnesium bromide solution (6.00 mL, 1.00 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 mL), Et ₃ N (836 pL, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.0 M in THF, 5.50 mmol, 1.10 equiv.).

[00351] The primary sulfinamidine P10 was isolated and purified according to Work-up Procedure A2. Filtration and flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 1:1 to 0:1) afforded the desired product as a white solid (1.19 g, 4.12 mmol, 82%). mp 154-156°C (CH ₂ CI ₂ );

Rf0.38 (CH ₂ CI ₂ /ethyl acetate, 1:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.32 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 6.45 (s, 2H), 2.62 (tt, J= 7.8, 4.6 Hz, 1H), 1.12-1.00 (m, 1H), 0.96-0.83 (m, 2H), 0.73-0.61 (m, 1H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 150.9, 148.6, 127.2, 124.2, 29.7, 3.8, 1.8;

IR (ATR): v (cm ^-1 ) = 1526, 1382, 1350, 1284, 1146, 1088, 983, 855, 735, 682, 616; HRMS (ESI ⁺ ) calcd. for C ₉ H ₁₂ N ₃ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 290.0264, found: 290.0266.

[00352] Af-(amino(benzyl)-A4-sulfaneylidene)-4-nitrobenzenesulfonami de (P11 )

[00353] Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 mL, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (635 pL, 5.00 mmol, 1.00 equiv.), benzylmagnesium bromide solution (7.89 mL, 0.76 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 mL), Et ₃ N (836 pL, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.0 M in THF, 5.50 mmol, 1.10 equiv.).

[00354] The primary sulfinamidine P11 was isolated and purified according to Work-up Procedure A1. Filtration and flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 2:1 to 1:2) afforded the desired product as a white solid (1.34 g, 3.95 mmol, 79%). mp 157-159 °C (CH ₂ CI ₂ );

RfO.37 (CH ₂ CI ₂ /ethyl acetate, 1:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.13 (d, J = 8.9 Hz, 2H), 7.68 (d, J = 8.9 Hz, 2H), 7.28-7.21 (m, 5H), 6.55 (s, 2H), 4.43 (d, J= 12.7 Hz, 1H), 4.32 (d, J= 12.6 Hz, 1H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 150.6, 148.3, 130.9, 129.8, 128.4, 128.3, 126.8, 123.9, 57.4;

IR (ATR): v(crrr ¹ ) = 1526, 1381, 1354, 1283, 1139, 1087, 971, 685, 617;

HRMS (ESF) calcd. for C ₁₃ H ₁₄ N ₃ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 340.0420, found: 340.0421.

[00355] /V-(amino-(4-(5-(p-tolyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)-A4- sulfaneylidene)-4-nitrobenzenesulfonamide (P12) [00356] Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 mL, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (635 mI_, 5.00 mmol, 1.00 equiv.), (4-(5-(p-tolyl)-3-(trifluoromethyl)-1/-/- pyrazol-1-yl)phenyl)lithium solution (6.00 mmol, 1.20 equiv.), CH2CI2 (25.0 mL), Et ₃ N (836 pL, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.0 M in THF, 5.50 mmol, 1.10 equiv.).

[00357] The primary sulfinamidine P12 was isolated and purified according to Work-up Procedure A3. Flash column chromatography (C^CL/ethyl acetate, 5:1 to 3:1) afforded the desired product as a white solid (1.64 g, 2.99 mmol, 60%). mp 207-209 °C (CH2CI2);

RfO.54 (CH2Cl2/ethyl acetate, 3:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.34 (d, J = 8.9 Hz, 2H), 8.07 (d, J = 8.9 Hz, 2H), 7.81 (d, J= 8.8 Hz, 2H), 7.58 (d, J= 8.8 Hz, 2H), 7.24-7.15 (m, 7H), 2.31 (s, 3H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 150.4, 148.8, 145.3, 142.4 (q, J= 37.7 Hz), 141.3, 139.1, 138.9, 129.4, 128.8, 128.0, 127.3, 126.4, 125.3, 124.3, 121.3 (q, J= 269.0 Hz), 106.2,

20.8;

19i F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) =-60.9 (s);

IR (ATR): v (cm ^-1 ) = 1527, 1474, 1381, 1351, 1279, 1237, 1141, 1085, 969, 786, 613;

HRMS (ESI ⁺ ) calcd. for CasH^FsNsC^ [M+H] ⁺ : 550.0825, found: 550.0828.

[00358] /V-(amino(vinyl)-A4-sulfaneylidene)-4-nitrobenzenesulfonamid e (P13) [00359] Prepared according to General Procedure A using TIPS-NSO (1.31 g, 6.00 mmol, 1.00 equiv.), THF (12.0 mL), LiHMDS solution (6.00 mL, 1.0 M in THF, 6.00 mmol, 1.00 equiv.), TMSCI (761 pL, 6.00 mmol, 1.00 equiv.), vinylmagnesium bromide solution (8.00 mL, 0.90 M in THF, 7.20 mmol, 1.20 equiv.), CH ₂ CI ₂ (30.0 mL), Et ₃ N (1.00 mL, 7.20 mmol, 1.20 equiv.), NsCI (1.33 g, 6.00 mmol, 1.00 equiv.) and TBAF solution (6.60 mL, 1.0 M in THF, 6.60 mmol, 1.10 equiv.).

[00360] The primary sulfinamidine P13 was isolated and purified according to Work-up Procedure A1. Filtration and flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 2:1 to 1:1) afforded the desired product as a white solid (1.35 g, 4.91 mmol, 82%). mp 174-176 °C (CH ₂ CI ₂ );

R _f 0.36 (CH ₂ CI ₂ /ethyl acetate, 2:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.33 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 6.80-6.65 (m, 3H), 6.03 (d, J= 9.2 Hz, 1H), 5.98 (d, J= 15.9 Hz, 1H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 150.8, 148.7, 136.0, 127.2, 125.0, 124.2;

IR (ATR): v (cm ^-1 ) = 1525, 1351, 1284, 1142, 1084, 971, 855, 734, 623;

HRMS (ESF) calcd. for C ₈ H ₁₀ N ₃ O ₄ S ₂ ⁺ [M+H] ⁺ : 276.0107, found: 276.0109.

[00361] /V-(Amino(4-fluorophenyl)-A ⁴ -sulfaneylidene)-2-(trimethylsilyl)ethane-1- sulfonamide (P50)

Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 ml_, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (0.64 ml_, 5.00 mmol, 1.00 equiv.), 4-fluorophenylmagnesium bromide solution (7.00 ml_, 0.86 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 ml_), Et ₃ N (0.84 mL, 6.00 mmol, 1.20 equiv.), 2-(trimethylsilyl)ethanesulfonyl chloride (1.00 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.00 M in THF, 5.50 mmol, 1.10 equiv.). The primary sulfinamidine P50 was isolated and purified according to Work-up Procedure A3. Flash column chromatography (petrol/ethyl acetate, 1:1 to 1:2) afforded the desired product P50 as a white solid (1.19 g, 3.70 mmol, 74%). mp 126-128 °C;

Rf0.35 (petrol/ethyl acetate, 1:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 7.91-7.86 (m, 2H), 7.51-7.45 (m, 2H), 6.86 (s, 2H), 2.86 (dd, J= 9.5, 8.3 Hz, 2H), 1.01-0.85 (m, 2H), 0.01 (s, 9H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5 (ppm) = 163.8 (d, J= 249.5 Hz), 135.9 (d, J= 2.8 Hz), 129.6 (d, J = 9.2 Hz), 116.4 (d, J = 22.8 Hz), 50.8, 10.6, -19;

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -109.6 (tt, J= 8.6, 5.3 Hz);

IR (ATR): v (cm ^-1 ) = 1589, 1489, 1473, 1462, 1383, 1251, 1155, 1120, 1083, 957, 831;

HRMS (ESF) calcd. for CnH ₂₀ FN ₂ O ₂ S ₂ Si ⁺ [M+H] ⁺ : 323.0714, found: 323.0714.

[00362] yV-(Amino(4-fluorophenyl)-A ⁴ -sulfaneylidene)-4- methylbenzenesulfonamide (P51)

Prepared according to General Procedure A using TIPS-NSO (1.31 g, 6.00 mmol, 1.00 equiv.), THF (12.0 ml_), LiHMDS solution (6.00 ml_, 1.00 M in THF, 6.00 mmol, 1.00 equiv.), TMSCI (0.76 ml_, 6.00 mmol, 1.00 equiv.), 4-fluorophenylmagnesium bromide solution (3.60 ml_, 2.00 M in THF, 7.20 mmol, 1.20 equiv.), CH ₂ CI ₂ (30.0 ml_), Et ₃ N (1.00 mL, 7.20 mmol, 1.20 equiv.), TsCI (1.14 g, 6.00 mmol, 1.00 equiv.) and TBAF solution (6.60 mL, 1.00 M in THF, 6.60 mmol, 1.10 equiv.).

The primary sulfinamidine P51 was isolated and purified according to Work-up Procedure A2. Filtration and flash column chromatography (petrol/ethyl acetate, 1:1 to 1:2) afforded the desired product P51 as a white solid (1.31 g, 4.20 mmol, 70%). mp 158-160°C;

Rf0.47 (petrol/ethyl acetate, 1:2); ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 7.80-7.74 (m, 2H), 7.69 (d, J= 8.2 Hz, 2H), 7.48- 7.41 ( , 2H), 7.30 (d, J= 8.2 Hz, 2H), 6.96 (s, 2H), 2.34 (s, 3H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5 (ppm) = 163.8 (d, = 249.8 Hz), 142.3, 141.0, 135.4 (d, = 2.8 Hz), 129.5 (d, J = 9.4 Hz), 129.2, 125.7, 116.4 (d, J = 23.0 Hz), 20.9;

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -109.4 (tt, J= 8.7, 5.2 Hz);

IR (ATR): v (cm ^-1 ) = 1596, 1487, 1462, 1383, 1252, 1145, 1086, 967, 814;

HRMS (ESI ⁺ ) calcd. for C ₁₃ H ₁₄ FN ₂ 0 ₂ S ₂ ⁺ [M+H] ⁺ : 313.0475, found: 313.0474.

[00363] Benzyl-(amino(4-fluorophenyl)-A ⁴ -sulfaneylidene)carbamate (P52)

Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 ml_, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (0.64 ml_, 5.00 mmol, 1.00 equiv.), 4-fluorophenylmagnesium bromide solution (7.00 ml_, 0.86 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 ml_), Et ₃ N (0.84 mL, 6.00 mmol, 1.20 equiv.), benzyl chloroformate (853 mg, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.00 M in THF, 5.50 mmol, 1.10 equiv.).

The primary sulfinamidine P52 was isolated and purified according to Work-up Procedure A2. Filtration and flash column chromatography (petrol/ethyl acetate, 1:1 to 1:3) afforded the desired product P52 as a white solid (1.07 g, 3.66 mmol, 73%). mp 122-124 °C;

Rf0.42 (petrol/ethyl acetate, 1:2);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 7.90-7.84 (m, 2H), 7.46-7.39 (m, 2H), 7.37-7.26 (m, 5H), 6.50 (s, 2H), 5.06 (d, J= 12.6 Hz, 1H), 5.01 (d, J= 12.6 Hz, 1H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5 (ppm) = 163.6 (d, = 249.1 Hz), 163.4, 138.0, 135.7 (d, = 2.8 Hz), 129.6 (d, J= 9.1 Hz), 128.3, 127.6, 127.5, 116.2 (d, = 22.6 Hz), 66.1;

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -109.8 (tt, J= 8.6, 5.1 Hz); IR (ATR): v (cm ^-1 ) = 1624, 1491, 1461, 1382, 1252, 1156, 1086, 955, 831;

HRMS (ESF) calcd. for C ₁₄ H ₁₄ FN ₂ 0 ₂ S ⁺ [M+H] ⁺ : 293.0755, found: 293.0756.

[00364] /V-(Amino(4-fluorophenyl)-A ⁴ -sulfaneylidene)-4- (trifluoromethyl)benzamide (P53)

Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 ml_, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (0.64 ml_, 5.00 mmol, 1.00 equiv.), 4-fluorophenylmagnesium bromide solution (7.00 ml_, 0.86 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 ml_), Et ₃ N (0.84 mL, 6.00 mmol, 1.20 equiv.), 4-(trifluoromethyl)benzoyl chloride (1.04 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.00 M in THF, 5.50 mmol, 1.10 equiv.).

The primary sulfinamidine P53 was isolated and purified according to Work-up Procedure A1. Filtration and flash column chromatography (petrol/ethyl acetate, 2:1 to 1:1) afforded the desired product P53 as a white solid (1.24 g, 3.76 mmol, 75%). mp 170-172 °C;

Rf0.38 (petrol/ethyl acetate, 2:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.24 (d, J = 7.9 Hz, 2H), 8.03-7.96 (m, 2H), 7.78 (d, J= 7.9 Hz, 2H), 7.51-7.43 (m, 2H), 6.60 (s, 2H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5 (ppm) = 173.3, 163.7 (d, = 249.3 Hz), 140.9, 135.2 (d, J = 2.9 Hz), 130.7 (q, J= 31.6 Hz), 129.7 (d, J= 9.1 Hz), 129.0, 124.9 (q, J= 3.8 Hz), 124.2 (q, J = 272.2 Hz), 116.4 (d, J = 22.9 Hz);

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -61.2 (s), -109.3 (tt, J= 8.7, 5.0 Hz);

IR (ATR): v (cm ^-1 ) = 1597, 1541, 1473, 1383, 1252, 1162, 1070, 955, 829;

HRMS (ESF) calcd. for C ₁₄ HnF ₄ N ₂ OS ⁺ [M+H] ⁺ : 331.0523, found: 331.0524.

[00365] /V-(Amino(4-fluorophenyl)-A ⁴ -sulfaneylidene)acetamide (P54) Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 ml_, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (0.64 ml_, 5.00 mmol, 1.00 equiv.), 4-fluorophenylmagnesium bromide solution (7.00 ml_, 0.86 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 ml_), Et ₃ N (0.84 mL, 6.00 mmol, 1.20 equiv.), Ac ₂ 0 (0.47 mL, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.00 M in THF, 5.50 mmol, 1.10 equiv.).

The primary sulfinamidine P54 was isolated and purified according to Work-up Procedure A1. Filtration and Flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 1:3 to 1:10) afforded the desired product P54 as a white solid (740 mg, 3.70 mmol, 74%). mp 156-158 °C;

Rf0.33 (CH ₂ CI ₂ /ethyl acetate, 1:3);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 7.89-7.83 (m, 2H), 7.45-7.38 (m, 2H), 6.28 (s, 2H), 1.91 (s, 3H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 180.3, 163.5 (d, J = 248.7 Hz), 135.7 (d, J = 2.9 Hz), 129.5 (d, J = 9.1 Hz), 116.2 (d, J = 22.6 Hz), 25.1;

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -109.8 (tt, J= 8.7, 5.3 Hz);

IR (ATR): v (cm ^-1 ) = 1595, 1541, 1490, 1473, 1462, 1382, 1252, 1155, 1073, 956, 836;

HRMS (ESF) calcd. for C ₈ H ₁₀ FN ₂ OS ⁺ [M+H] ⁺ : 201.0492, found: 201.0496.

[00366] /V-(Amino(2-methyl prop-1 -en-1 -yl)-A ⁴ -sulfaneylidene)-4- nitrobenzenesulfonamide (P55)

Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 mL), LiHMDS solution (5.00 mL, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (0.64 mL, 5.00 mmol, 1.00 equiv.), 2-methyl-1-propenylmagnesium bromide solution (13.3 mL, 0.45 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 mL), Et ₃ N (0.84 mL, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.00 M in THF, 5.50 mmol, 1.10 equiv.).

The primary sulfinamidine P55 was isolated and purified according to Work-up Procedure A2. Filtration and flash column chromatography (petrol/ethyl acetate, 1:2 to 1:4) afforded the desired product P55 as a white solid (607 mg, 2.00 mmol, 40%). mp 145-147 °C;

Rf0.42 (petrol/ethyl acetate, 1:4);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.32 (d, J = 8.9 Hz, 2H), 7.97 (d, J = 8.9 Hz, 2H), 6.54 (s, 2H), 6.27-6.21 (m, 1H), 1.82 (d, J= 1.4 Hz, 3H), 1.78 (d, J= 1.2 Hz, 3H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5 (ppm) = 151.1, 148.6, 146.5, 127.1, 125.1, 124.1, 24.3, 19.8;

IR (ATR): v (cm ^-1 ) = 1527, 1349, 1265, 1155, 1086, 982, 784, 688;

HRMS (ESI ⁺ ) calcd. for C ₁₀ H ₁₄ N ₃ O ₄ S ₂ ⁺ [M+H] ⁺ : 304.0420, found: 304.0420.

[00367] /V-(Amino(methyl)-A ⁴ -sulfaneylidene)-4-nitrobenzenesulfonamide (P56)

Prepared according to General Procedure A using TIPS-NSO (2.19 g, 10.00 mmol, 1.00 equiv.), THF (20.0 mL), LiHMDS solution (10.00 mL, 1.00 M in THF, 10.00 mmol, 1.00 equiv.), TMSCI (1.27 mL, 10.00 mmol, 1.00 equiv.), methylmagnesium bromide solution (4.00 mL, 3.00 M in THF, 12.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (50.0 mL), Et ₃ N (1.67 mL, 12.00 mmol, 1.20 equiv.), NsCI (2.22 g, 10.00 mmol, 1.00 equiv.) and TBAF solution (11.00 mL, 1.00 M in THF, 11.00 mmol, 1.10 equiv.).

The primary sulfinamidine P56 was isolated and purified according to Work-up Procedure A1. Filtration afforded the desired product P56 as a white solid (2.10 g, 7.98 mmol, 80%). mp 158-160 °C;

Rf0.33 (ethyl acetate); ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.31 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 6.44 (s, 2H), 2.82 (s, 3H).;

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 151.0, 148.6, 127.2, 124.2, 38.7.;

IR (ATR): v (cm ^-1 ) = 1517, 1381, 1355, 1285, 1141, 1087, 950;

HRMS (ESI ⁺ ) calcd. for C ₇ H ₁₀ N ₃ O ₄ S ₂ ⁺ [M+H] ⁺ : 264.0107, found: 264.0107.

[00368] fV-(Amino(1 -methyl-1 H-indol-5-yl)-A ⁴ -sulfaneylidene)-4- nitrobenzenesulfonamide (P57)

[00369] Preparation of organometallic reagent

(1-Methylindole-5-yl)lithium solution was prepared according to the following procedure. To a solution of 5-bromo-1-methylindole (1.26 g, 6.00 mmol, 1.20 equiv.) in anhydrous THF (12.0 ml_) in an oven-dried 100 ml_ round-bottom flask was added n-butyllithium solution (2.40 ml_, 2.50 M in hexanes, 6.00 mmol, 1.20 equiv.) dropwise at -78 °C under a nitrogen atmosphere. The reaction was stirred at the same temperature for 1 h.

[00370] Preparation of sulfinamidine

Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 ml_, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (0.64 ml_, 5.00 mmol, 1.00 equiv.), (1-methylindole-5-yl)lithium solution (6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 mL), Et ₃ N (0.84 mL, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.00 M in THF, 5.50 mmol, 1.10 equiv.).

The primary sulfinamidine P57 was isolated and purified according to Work-up Procedure A1. Filtration afforded the desired product P57 as a yellow solid (960 mg, 2.54 mmol, 51%). mp 162-164 °C;

RfO.57 (CH ₂ CI ₂ /ethyl acetate, 1:1); ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.32 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.98 (d, J= 2.0 Hz, 1H), 7.63 (d, J= 8.8 Hz, 1H), 7.52-7.42 (m, 2H), 6.91 (s, 2H), 6.59 (dd, J = 3.1, 0.8 Hz, 1 H), 3.83 (s, 3H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 150.9, 148.6, 137.5, 132.1, 128.5, 127.8, 127.2, 124.2, 119.5, 118.8, 110.8, 101.6, 32.8;

IR (ATR): v (crrr ¹ ) = 2160, 2031, 1529, 1348, 1290, 1140, 1084, 974, 732;

HRMS (ESI ⁺ ) calcd. for C ₁₅ H ₁₅ N ₄ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 379.0529, found: 379.0526.

[00371] yV-(Amino(benzofuran-2-yl)-A ⁴ -sulfaneylidene)-4- nitrobenzenesulfonamide (P58)

Preparation of organometallic reagent

2-Lithiobenzofuran solution was prepared according to the following procedure. To a solution of benzofuran (850 mg, 7.20 mmol, 1.20 equiv.) in anhydrous THF (14.4 ml_) in an oven-dried 100 ml_ round-bottom flask was added n-butyllithium solution (2.88 ml_, 2.50 M in hexanes,

7.20 mmol, 1.20 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The reaction was stirred at the same temperature for 1 h.

Preparation of sulfinamidine

Prepared according to General Procedure A using TIPS-NSO (1.31 g, 6.00 mmol, 1.00 equiv.), THF (12.0 ml_), LiHMDS solution (6.00 ml_, 1.00 M in THF, 6.00 mmol, 1.00 equiv.), TMSCI (0.76 mL, 6.00 mmol, 1.00 equiv.), 2-lithiobenzofuran solution (7.20 mmol,

1.20 equiv.), CH ₂ CI ₂ (30.0 mL), Et ₃ N (1.00 mL, 7.20 mmol, 1.20 equiv.), NsCI (1.33 g, 6.00 mmol, 1.00 equiv.) and TBAF solution (6.60 mL, 1.00 M in THF, 6.60 mmol, 1.10 equiv.).

The primary sulfinamidine P58 was isolated and purified according to Work-up Procedure A1. Filtration afforded the desired product P58 as a white solid (2.05 g, 5.62 mmol, 94%). mp 188-190 °C; Rf0.50 (petrol/ethyl acetate, 1:2);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.32 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.9 Hz, 2H), 7.77 (ddd, J= 7.8, 1.3, 0.7 Hz, 1H), 7.66-7.61 (m, 1H), 7.57 (s, 2H), 7.50-7.42 (m, 2H), 7.35 (ddd, = 8.1 , 7.2, 1.0 Hz, 1H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 156.3, 150.1, 149.3, 148.8, 127.3, 127.1, 126.3, 124.23, 124.19, 122.8, 112.0, 111.9;

IR (ATR): v (cm ^-1 ) = 1701, 1529, 1349, 1275, 1137, 1080, 980;

HRMS (ESI ⁺ ) calcd. for C ₁₄ H ₁₂ N ₃ 0 ₅ S ₂ ⁺ [M+H] ⁺ : 366.0213, found: 366.0213.

[00372] /V-(Amino(2,4-dimethoxypyrimidin-5-yl)-A ⁴ -sulfaneylidene)-4- nitrobenzenesulfonamide (P59)

Preparation of Grignard reagent

(2,4-Dimethoxypyrimidin-5-yl)magnesium chloride lithium chloride complex solution was prepared according to the following procedure. To a solution of 5-bromo-2,4- dimethoxypyrimidine (1.31 g, 6.00 mmol, 1.20 equiv.) in anhydrous THF (3.0 ml_) in an oven- dried 50 ml_ round-bottom flask was added /so-propylmagnesium chloride lithium chloride complex solution (Turbo Grignard Reagent, 4.80 ml_, 1.25 M in THF, 6.00 mmol, 1.20 equiv.) dropwise at 0°C under a nitrogen atmosphere. The reaction was stirred at the same temperature for 1 h.

Preparation of sulfinamidine

Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 ml_, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (0.64 ml_, 5.00 mmol, 1.00 equiv.), (2,4-dimethoxypyrimidin-5-yl)magnesium chloride lithium chloride complex solution (6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 ml_), Et ₃ N (0.84 ml_, 6.00 mmol, 1.20 equiv.), NsCI (1.11 g, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 ml_, 1.00 M in THF, 5.50 mmol, 1.10 equiv.). The primary sulfinamidine P59 was isolated and purified according to Work-up Procedure A3. Flash column chromatography (petrol/ethyl acetate, 1 :2 to 1 :4 to 1:10) afforded the desired product P59 as a white solid (1.21 g, 3.13 mmol, 63%). mp 170-172 °C;

Rf0.60 (ethyl acetate);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.72 (s, 1 H), 8.31 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.08 (s, 2H), 3.94 (s, 3H), 3.88 (s, 3H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 166.5, 166.3, 157.5, 150.4, 148.7, 127.2, 124.1, 113.4, 55.5, 54.9;

IR (ATR): v(crrr ¹ ) = 2160, 1740, 1591, 1523, 1470, 1386, 1349, 1279, 1143, 1087, 949, 857, 796;

HRMS (ESI ⁺ ) calcd. for C ₁₂ H ₁₄ N ₅ 0 ₆ S ₂ ⁺ [M+H] ⁺ : 388.0380, found: 388.0379.

[00373] /V-(Amino(4-fluorophenyl)-A ⁴ -sulfaneylidene)cyanamide (P60)

Prepared according to General Procedure A using TIPS-NSO (1.10 g, 5.00 mmol, 1.00 equiv.), THF (10.0 ml_), LiHMDS solution (5.00 ml_, 1.00 M in THF, 5.00 mmol, 1.00 equiv.), TMSCI (0.64 ml_, 5.00 mmol, 1.00 equiv.), 4-fluorophenylmagnesium bromide solution (7.00 ml_, 0.86 M in THF, 6.00 mmol, 1.20 equiv.), CH ₂ CI ₂ (25.0 ml_), Et ₃ N (0.84 mL, 6.00 mmol, 1.20 equiv.), BrCN solution (1.00 mL, 5.0 M in CH ₃ CN, 5.00 mmol, 1.00 equiv.) and TBAF solution (5.50 mL, 1.00 M in THF, 5.50 mmol, 1.10 equiv.).

The primary sulfinamidine P60 was isolated and purified according to Work-up Procedure A3. Flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 1:2 to 0:1) afforded the desired product P60 as a white solid (734 mg, 4.01 mmol, 80%). mp 92-94 °C;

RfO.29 (CH ₂ CI ₂ /ethyl acetate, 2:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 7.90-7.83 (m, 2H), 7.53-7.46 (m, 2H), 7.10 (s, 2H); ¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5 (ppm) = 164.0 (d, J= 250.3 Hz), 134.7 (d, J= 2.8 Hz), 129.7 (d, J = 9.3 Hz), 119.7, 116.6 (d, J = 22.8 Hz);

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -108.7 (tt, J= 8.6, 5.2 Hz);

IR (ATR): v (crrr ¹ ) = 2163, 1588, 1486, 1462, 1383, 1230, 1158, 1085, 1014, 953, 793;

HRMS (ESI ⁺ ) calcd. for C ₇ H ₇ FN ₃ S ⁺ [M+H] ⁺ : 184.0339, found: 184.0342.

[00374] /V-(Amino(4-(5-(p-tolyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)-A ⁴ - sulfaneylidene)-cyanamide (P61)

Preparation of organometallic reagent

(4-(5-(p-Tolyl)-3-(trifluoromethyl)-1/-/-pyrazol-1-yl)phe nyl)lithium solution was prepared according to the following procedure. To a solution of 1-(4-bromophenyl)-5-(p-tolyl)-3- (trifluoromethyl)-1/-/-pyrazole (6.84 g, 18.00 mmol, 1.20 equiv.) in anhydrous THF (36.0 ml_) in an oven-dried 250 ml_ round-bottom flask was added n-butyllithium solution (7.20 ml_, 2.50 M in hexanes, 18.00 mmol, 1.20 equiv.) dropwise at -78 °C under a nitrogen atmosphere. The reaction was stirred at the same temperature for 40 min.

Preparation of sulfinamidine

TIPS-NSO (3.29 g, 15.00 mmol, 1.00 equiv.) was dissolved in anhydrous THF (30.0 ml_) in an oven-dried 250 ml_ round-bottom flask under a nitrogen atmosphere. The mixture was cooled to -30 °C before LiHMDS solution (15.00 ml_, 1.00 M in THF, 15.00 mmol, 1.00 equiv.) was added. After being stirred at - 30 °C for 5 min, the reaction was warmed to 0 °C and stirred for another 5 min. TMSCI (1.90 ml_, 15.00 mmol, 1.00 equiv.) was added and the reaction was stirred at 0 °C for 10 min. Then the reaction solution was added to the (4-(5-(p-tolyl)-3- (trifluoromethyl)-1/-/-pyrazol-1-yl)phenyl)lithium solution (18.00 mmol, 1.20 equiv.) at - 78 °C and stirred at 0 °C for 10 min. The reaction mixture was then diluted with ethyl acetate (150 ml_) and quenched with sat. aq. tetrasodium EDTA solution (300 ml_). The aqueous layer was further extracted with ethyl acetate (2 ^c 80 ml_). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. This crude mixture was then dissolved in anhydrous CH2CI2 (50.0 ml_) in an oven-dried 250 ml_ round-bottom flask and cooled to 0 °C. Then EΐbN (2.51 ml_, 18.00 mmol, 1.20 equiv.) and BrCN solution (3.00 ml_, 5.0 M in CH3CN, 15.00 mmol, 1.00 equiv.) were added. The reaction was stirred atO °C for 20 min prior to the addition of TBAF solution (16.50 ml_, 1.00 M in THF, 16.50 mmol, 1.10 equiv.). The reaction was stirred at 0 °C for another 10 min until completion (judged by TLC). The reaction was then diluted with ethyl acetate (150 ml_) and quenched with sat. aq. NaHCC>3 solution (250 ml_). The aqueous layer was further extracted with ethyl acetate (2 ^c 80 ml_). The combined organic layers were dried over anhydrous Na2SC>4, filtered, concentrated under reduced pressure and purified by flash column chromatography (CFhCh/ethyl acetate, 2:1 to 1:1 to 1:2) to afford sulfinamidine P61 as a pale-yellow oil (5.03 g, 12.93 mmol, 86%).

R _f 0.50 (CFhCh/ethyl acetate, 1:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 7.88 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.23-7.16 (m, 7H), 2.31 (s, 3H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 145.3, 142.3 (q, J= 37.7 Hz), 141.4, 139.1, 138.8, 129.5, 128.8, 128.2, 126.3, 125.4, 121.3 (q, J = 268.6 Hz), 119.7, 106.2, 20.8;

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -60.9 (s);

IR (ATR): v (cm- ¹ ) = 2152, 1496, 1472, 1374, 1236, 1161, 1134, 1097, 975;

HRMS (ESF) calcd. for C ₁₈ H ₁₅ F3N5S ⁺ [M+H] ⁺ : 390.0995, found: 390.0988.

[00375] yV-(amino(4-ethoxy-3-(1 -methyl-7-oxo-3-propyl-6,7-dihydro-1 H- pyrazolo[4,3-c ]pyrimidin-5-yl)phenyl)- A ⁴ -sulfaneylidene)-cyanamide (P62)

Preparation of organometallic reagent

(4-Ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1/-/-pyr azolo[4,3-c(]pyrimidin-5-yl)-phenyl) lithium solution was prepared according to the following procedure. To a solution of 5-(5- Bromo-2-ethoxyphenyl)-1-methyl-3-propyl-1/-/-pyrazolo[4,3-c( ]pyrimidin-7(6H)-one ^{1 1} (3.90 g, 10.00 mmol, 1.00 equiv.) in anhydrous THF (50.0 ml_) in an oven-dried 250 ml_ round-bottom flask was added methyllithium solution (7.50 ml_, 1.60 M in Et2<D, 12.00 mmol, 1.20 equiv.) dropwise at -78 °C under a nitrogen atmosphere. The reaction was stirred at the same temperature for 10 min. Then n-butyllithium solution (6.00 mL, 2.50 M in hexanes, 15.00 mmol, 1.50 equiv.) was added dropwise at -78 °C. The reaction was stirred at the same temperature for 40 min.

Preparation of sulfinamidine

TIPS-NSO (4.38 g, 20.00 mmol, 2.00 equiv.) was dissolved in anhydrous THF (40.0 mL) in an oven-dried 250 mL round-bottom flask and was purged with nitrogen gas. The mixture was cooled to -30 °C before LiHMDS solution (20.00 mL, 1.00 M in THF, 20.00 mmol, 2.00 equiv.) was added. After being stirred at - 30 °C for 5 min, the reaction was warmed to 0 °C and stirred for another 5 min. TMSCI (2.54 mL, 20.00 mmol, 2.00 equiv.) was added and the reaction was stirred at 0 °C for 10 min. Then the reaction solution was added to the (4-ethoxy-3-(1-methyl- 7-oxo-3-propyl-6,7-dihydro-1 /-/-pyrazolo[4,3-c(]pyrimidin-5-yl)-phenyl) lithium solution (10.00 mmol, 1.00 equiv.) at - 78 °C and stirred at 0 °C for 10 min. The reaction mixture was then diluted with ethyl acetate (200 mL) and quenched with sat. aq. tetrasodium EDTA solution (400 mL). The aqueous layer was further extracted with ethyl acetate (2 ^c 100 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. This crude mixture was then dissolved in anhydrous CH2CI2 (50.0 mL) in an oven-dried 250 mL round-bottom flask and cooled to 0 °C. Then EΐbN (2.09 mL, 15.00 mmol, 1.50 equiv.) and BrCN solution (2.40 mL, 5.0 M in CH3CN, 12.00 mmol, 1.20 equiv.) were added. The reaction was stirred at 0 °C for 20 min prior to the addition of TBAF solution (15.00 mL, 1.00 M in THF, 15.00 mmol, 1.50 equiv.) at the same temperature. The reaction was stirred for another 10 min and resulted in the precipitation of a white solid (primary sulfinamidine P62). This white solid was filtered and washed with cold CH ₂ Cl ₂ (30 mL) to give analytically pure product P62. Sat. aq. NaCI solution (200 mL) was added to the combined filtrates. The aqueous phase was extracted with CH2Cl2 (2 ^c 80 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, concentrated under reduced pressure and purified by flash column chromatography. Filtration and flash column chromatography (ethyl acetate/ethanol, 50:1 to 5:1) afforded the desired product P62 as a white solid (2.03 g, 5.09 mmol, 51%). mp 162-164 °C;

R _f 0.50 (ethyl acetate/methanol, 25:1); ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 12.19 (s, 1H), 7.98 (d, J = 2.6 Hz, 1H), 7.88 (dd, J = 8.9, 2.6 Hz, 1H), 7.40 (d, J= 9.0 Hz, 1H), 7.07 (s, 2H), 4.20 (q, J= 7.0 Hz, 2H), 4.16 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 1.79-1.68 (m, 2H), 1.34 (t, J = 6.9 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 159.0, 153.8, 148.4, 145.0, 137.8, 130.6, 129.6, 129.1, 124.4, 123.7, 119.9, 113.7, 64.8, 37.9, 27.1, 21.7, 14.3, 13.8.

IR (ATR): v (cm ^-1 ) = 2154, 2030, 1686, 1463, 1392, 1248, 1152, 1078, 954;

HRMS (ESF) calcd. for C ₁₈ H ₂₂ N ₇ 0 ₂ S ⁺ [M+H] ⁺ : 400.1550, found: 400.1550.

[00376] 5-Bromo-yV-cyanothiophene-2-primary sulfinamidine (P63)

Preparation of LDA reagent

Diisopropylamine (1.35 ml_, 9.60 mmol, 1.20 equiv.) was dissolved in anhydrous THF (4.80 ml_) in an oven-dried 50 ml_ round-bottom flask under a nitrogen atmosphere. The mixture was cooled to -78 °C before n-butyllithium solution (4.27 ml_, 2.25 M in hexane, 9.60 mmol, 1.20 equiv.) was added dropwise. After being stirred at -78 °C for 5 min, the reaction was warmed to 0 °C and stirred for another 20 min.

Preparation of organometallic reagent

(5-Bromothiophen-2-yl)lithium solution was prepared according to the following procedure. 2- bromothiophene (1.56 g, 9.60 mmol, 1.20 equiv.) was dissolved in anhydrous THF (19.2 ml_) in an oven-dried 250 ml_ round-bottom flask under a nitrogen atmosphere. The mixture was cooled to -78 °C before LDA solution (9.60 mmol, 1.20 equiv.) was added dropwise. The reaction was stirred at the same temperature for 30 min.

Preparation of sulfinamidine

TIPS-NSO (1.75 g, 8.00 mmol, 1.00 equiv.) was dissolved in anhydrous THF (16.0 mL) in an oven-dried 100 mL round-bottom flask under a nitrogen atmosphere. The mixture was cooled to -30 °C before LiHMDS solution (8.00 mL, 1.00 M in THF, 8.00 mmol, 1.00 equiv.) was added. After being stirred at - 30 °C for 5 min, the reaction was warmed to 0 °C and stirred for another 5 min. TMSCI (1.02 ml_, 8.00 mmol, 1.00 equiv.) was added and the reaction was stirred at 0 °C for 10 min. Then the reaction solution was added to the (5-bromothiophen-2- yl)lithium solution (9.60 mmol, 1.20 equiv.) at - 78 °C and stirred at 0 °C for 10 min. The reaction mixture was then diluted with ethyl acetate (150 ml_) and quenched with sat. aq. tetrasodium EDTA solution (200 ml_). The aqueous layer was further extracted with ethyl acetate (2 ^c 60 ml_). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. This crude mixture was then dissolved in anhydrous CH2CI2 (40.0 ml_) in an oven-dried 250 ml_ round-bottom flask and cooled to 0 °C. Then EΐbN (1.34 ml_, 9.60 mmol, 1.20 equiv.) and BrCN solution (1.60 ml_, 5.0 M in CH3CN, 8.00 mmol, 1.00 equiv.) were added. The reaction was stirred at 0 °C for 20 min prior to the addition of TBAF solution (8.80 ml_, 1.00 M in THF, 8.80 mmol, 1.10 equiv.). The reaction was stirred at 0 °C for another 10 min until completion (judged by TLC). The reaction was then diluted with ethyl acetate (150 ml_) and quenched with sat. aq. NaHCC>3 solution (250 ml_). The aqueous layer was further extracted with ethyl acetate (2 ^c 80 ml_). The combined organic layers were dried over anhydrous Na2SC>4, filtered, concentrated under reduced pressure to approximately 1/20 ^th of the original volume. At this point, a large amount of solid product (primary sulfinamidine P63) precipitated out of solution, which was then separated by filtration and washed with cold CH2CI2 (30 ml_) to give analytically pure sulfinamidine P63. The filtrate was concentrated under reduced pressure and resulted in the precipitation of a white solid (primary sulfinamidine P63) again, which was then separated by filtration again. Two times of filtration afforded the desired product P63 as a white solid (1.20 g, 4.82 mmol, 60%). mp 114-116 °C;

R _f 0.50 (ethyl acetate);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 7.43 (d, J = 4.1 Hz, 1H), 7.43 (s, 2H), 7.36 (d, J = 4.1 Hz, 1H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 140.5, 132.7, 132.4, 119.3, 118.5;

IR (ATR): v (cm ^-1 ) =2157, 1473, 1383, 1252, 1153, 1073, 955;

HRMS (ESF) calcd. for C ₅ H5 ⁷⁹ BrN ₃ S2 ⁺ [M+H] ⁺ : 249.9103, found: 249.9102; calcd. for C ₅ H5 ⁸¹ BrN ₃ S2 ⁺ [M+H] ⁺ : 251.9081, found: 251.9081.

[00377] General procedure B - Sulfondiimidamide Synthesis [00378] An oven-dried round-bottom flask containing the primary sulfinamidine (1.00 equiv.) and Phl(OAc)2 (phenyl-A ³ -iodanediyl diacetate) (1.50 equiv.) was sealed and subjected to three N2 evacuation/refill cycles before pre-sparged anhydrous toluene (0.1 M- 0.2 M) or DCM (0.1 M) was added. EΐbN (3.00 equiv.) was added to the solution, followed immediately by the addition of amine (1.50 - 3.00 equiv.). The reaction mixture was then stirred at room temperature for the specified time. Once judged complete by TLC, the reaction was diluted with EtOAc and quenched with sat. aq. NaCI solution. The aqueous phase was extracted with EtOAc. The combined organic layers were then dried over anhydrous Na ₂ S0 _4, filtered and concentrated under reduced pressure. The sulfondiimidamide was purified by flash column chromatography with the appropriate solvent system.

[00379] 4-(4-fluoro-/V-(4-nitrosulfonyl)phenylsulfondiimidoyl)morpho line (E1 )

[00380] Following general procedure B, sulfinamidine P3 (686 mg, 2.00 mmol, 1.00 equiv.), Phl(OAc)2 (966 mg, 3.00 mmol, 1.50 equiv.), toluene (20.0 ml_), (836 pl_, 6.00 mmol, 3.00 equiv.) and morpholine (261 mI_, 3.00 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (CFhCh/ethyl acetate, 5:1 to 3:1 ) afforded sulfondiimidamide E1 as a white solid (797 mg, 1.86 mmol, 93%). mp 64-66 °C (CH2CI2);

Rf0.50 (petrol/ethyl acetate, 1:2);

¹ H NMR (400 MHz, CDC ): <5 (ppm) = 8.24 (d, J = 9.0 Hz, 2H), 8.08 (d, J = 9.0 Hz, 2H), 7.98- 7.93 (m, 2H), 7.23-7.17 (m, 2H), 3.72 (t, J= 4.7 Hz, 4H), 3.28 (br. s, 1H), 3.15-3.02 (m, 4H);

¹³ C NMR (101 MHZ, CDCb): d (ppm) = 165.9 (d, J= 257.8 Hz), 149.7, 149.3, 130.4 (d, = 9.5 Hz), 129.3 (d, J= 3.2 Hz), 127.9, 124.1, 116.7 (d, J= 22.9 Hz), 66.2, 46.8;

¹⁹ F NMR (377 MHz, CDCI ₃ ): d (ppm) = -102.9 (tt, J= 8.0, 4.9 Hz);

IR (ATR): v (cm ^-1 ) = 1528, 1351, 1300, 1154, 1089, 1067, 1052, 920;

HRMS (ESF) calcd. for C ₁₆ H ₁₈ FN ₄ 0 ₅ S ₂ ⁺ [M+H] ⁺ : 429.0697, found: 429.0695.

[00381] 4-(4-chloro-/V-(4-nitrosulfonyl)phenylsulfondiimidoyl)morpho line (E2)

[00382] Following general procedure B, sulfinamidine P4 (180 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 24 h. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 5:1 to 3:1 ) afforded sulfondiimidamide E2 as a white solid (138 mg, 0.31 mmol, 62%). mp 150-152 °C (MeCN);

Rf0.50 (CH ₂ CI ₂ /ethyl acetate, 3:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.31 (d, J = 8.9 Hz, 2H), 8.03 (d, J = 8.9 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 5.50 (s, 1H), 3.60-3.49 (m, 4H), 2.97-2.83 (m, 4H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 149.1, 149.0, 138.5, 133.7, 129.5, 129.3, 127.9, 124.1, 65.4, 45.9.

IR (ATR): v (cm ^-1 ) = 1532, 1383, 1260, 1157, 1083, 954, 776, 623;

HRMS (ESI ⁺ ) calcd. for Ci ₆ Hi ₈ CIN ₄ 0 ₅ S ₂ ⁺ [M+H] ⁺ : 445.0402, found: 445.0402.

[00383] 4-(2-methyl-/V-(4-nitrosulfonyl)phenylsulfondiimidoyl)morpho line (E3)

[00384] Following general procedure B, sulfinamidine P5 (170 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc) ₂ (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 2 h. Purification by flash column chromatography (petrol/ethyl acetate, 1:2 to 1:3 ) afforded sulfondiimidamide E3 as a colourless oil (176 mg, 0.42 mmol, 83%).

RfO.54 (CH ₂ CI ₂ /ethyl acetate, 2:1); ¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.16 (d, J= 8.9 Hz, 2H), 7.99 (dd, J= 8.5, 1.4 Hz, 1H), 7.95 (d, J = 8.9 Hz, 2H), 7.47 (td, J = 7.4, 1.4 Hz, 1 H), 7.32-7.26 (m, 2H), 3.74-3.54 (m, 5H), 3.14-3.02 (m, 4H), 2.56 (s, 3H);

¹³ C NMR (101 MHZ, CD ₃ CN): <5 (ppm) = 150.5, 149.9, 139.5, 135.2, 134.6, 134.5, 131.2, 128.7, 127.1, 124.9, 66.6, 45.7, 20.9;

IR (ATR): v (cm ^-1 ) = 1526, 1382, 1350, 1297, 1259, 1151, 1069, 954, 770;

HRMS (ESI ⁺ ) calcd. for C ₁₇ H _2i N ₄ 0 ₅ S ₂ ⁺ [M+H] ⁺ : 425.0948, found: 425.0948.

[00385] 4-/V-(4-nitrosulfonyl)thien-2-ylsulfondiimidoyl)morpholine (E4)

[00386] Following general procedure B, sulfinamidine P6 (165 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (petrol/ethyl acetate, 1:2 to 1 :5 ) afforded sulfondiimidamide E4 as a white solid (180 mg, 0.43 mmol, 87%). mp 146-148 °C (MeCN);

Rf0.44 (petrol/ethyl acetate, 1:3);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.33 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.9 Hz, 2H), 8.01 (dd, = 5.1 , 1.3 Hz, 1H), 7.56 (dd, J = 3.9, 1.3 Hz, 1H), 7.20 (dd, = 5.1 , 3.9 Hz, 1H), 5.54 (s, 1H), 3.62-3.51 (m, 4H), 2.94 (t, J= 4.8 Hz, 4H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 149.2, 149.0, 135.2, 135.0, 133.4, 128.4, 128.0, 124.2, 65.3, 46.2;

IR (ATR): v (cm ^-1 ) = 1531, 1397, 1352, 1321, 1260, 1153, 1069, 955, 915, 700;

HRMS (ESI ⁺ ) calcd. for C ₁₄ H ₁₆ N ₄ 0 ₅ S ₃ Na ⁺ [M+Na] ⁺ : 439.0175, found: 439.0174.

[00387] 4-(6-methoxy(/V-(4-nitrosulfonyl))pyridin-3-ylsulfondiimidoy l)morpholine (E5) [00388] Following general procedure B, sulfinamidine P7 (178 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 2 h. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 3:1 to 1:1 ) afforded sulfondiimidamide E5 as a white solid (196 mg, 0.44 mmol, 89%). mp 152-154 °C (MeCN);

RfO.42 (CH ₂ CI ₂ /ethyl acetate, 2:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.58 (dd, J = 2.7, 0.7 Hz, 1H), 8.31 (d, J = 8.9 Hz, 2H), 8.06-8.01 (m, 3H), 6.98 (dd, J= 8.9, 0.7 Hz, 1H), 5.50 (br. s, 1H), 3.92 (s, 3H), 3.56 (dt, J= 6.4, 3.7 Hz, 4H), 3.00-2.89 (m, 4H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 166.2, 149.1, 149.0, 147.8, 138.5, 128.0, 124.4, 124.1, 111.1, 65.4, 54.3, 45.8;

IR (ATR): v (cm ^-1 ) = 1521, 1474, 1462, 1381, 1255, 1155, 1087, 955;

HRMS (ESI ⁺ ) calcd. for C ₁₆ H ₂ oN ₅ 0 ₆ S ₂ ⁺ [M+H] ⁺ : 442.0850, found: 442.0851.

[00389] 4-(/V-(4-nitrosulfonyl)ferf-butylsulfondiimidoyl)morpholine (E6)

[00390] Following general procedure B, sulfinamidine P8 (153 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc) ₂ (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 5 h. Purification by flash column chromatography (petrol/ethyl acetate, 1:2 to 1:4 ) afforded sulfondiimidamide E6 as a colourless oil (132 mg, 0.34 mmol, 67%).

Rf0.33 (petrol/ethyl acetate, 1:2);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.30 (d, J = 9.0 Hz, 2H), 8.08 (d, J = 9.0 Hz, 2H), 3.73- 3.61 (m, 4H), 3.53-3.41 (m, 4H), 3.25 (s, 1H), 1.32 (s, 9H); ¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 151.1, 150.5, 128.4, 125.0, 67.9, 67.6, 49.8, 24.1; IR (ATR): v (cm ^-1 ) = 1527, 1350, 1295, 1258, 1148, 1089, 1038, 934, 746, 610;

HRMS (ESI ⁺ ) calcd. for C ₁₄ H ₂₂ N ₄ 0 ₅ S ₂ Na ⁺ [M+Na] ⁺ : 413.0924, found: 413.0923.

[00391] 4-(Af-(4-nitrosulfonyl)cyclopentylsulfondiimidoyl)morpholine (E7)

[00392] Following general procedure B, sulfinamidine P9 (159 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 3:2 to 2:3) afforded sulfondiimidamide E7 as a colourless oil (165 mg, 0.41 mmol, 82%).

RfOAO (CH ₂ CI ₂ /ethyl acetate, 1:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.27 (d, J = 9.0 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H), 3.75 (dddd, J = 16.2, 8.6, 7.4, 2.2 Hz, 1 H), 3.55 (dt, J = 11.6, 4.7 Hz, 2H), 3.48 (dt, J = 11.6, 4.7 Hz, 2H), 3.24 (s, 1H), 3.22 (t, J= 4.7 Hz, 4H), 1.92-1.75 (m, 4H), 1.66-1.46 (m, 4H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 151.0, 150.5, 128.5, 125.0, 67.2, 64.2, 47.7, 28.8, 27.9, 26.5, 26.2;

IR (ATR): v (cm ^-1 ) = 1527, 1382, 1350, 1296, 1258, 1149, 1090, 1051, 935;

HRMS (ESI ⁺ ) calcd. for C ₁₅ H ₂₂ N ₄ 0 ₅ S ₂ Na ⁺ [M+Na] ⁺ : 425.0924, found: 425.0924.

[00393] 4-(A-(4-nitrosulfonyl)cyclopropylsulfondiimidoyl)morpholine (E8)

[00394] Following general procedure B, sulfinamidine P10 (145 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc) ₂ (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 24 h. Purification by flash column chromatography (ethyl acetate) afforded sulfondiimidamide E8 as pale-yellow solid (152 mg, 0.41 mmol, 81%). mp 130-132 °C (MeCN);

Rf0.38 (ethyl acetate);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.36 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 4.58 (s, 1 H), 3.56 (ddd, J= 11.6, 6.2, 3.2 Hz, 2H), 3.49 (ddd, J= 11.6, 6.2, 3.2 Hz, 2H), 3.20 (ddd, J= 12.0, 6.2, 3.2 Hz, 2H), 3.13 (ddd, J= 12.0, 6.2, 3.2 Hz, 2H), 2.89-2.81 (m, 1H), 1.06- 0.93 (m, 4H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 149.7, 149.1, 127.9, 124.1, 65.6, 46.2, 29.1, 5.1, 4.7;

IR (ATR): v (cm ^-1 ) = 1524, 1351, 1296, 1148, 1090, 1073, 920, 770, 609;

HRMS (ESP) calcd. for C ₁₃ H ₁₉ N ₄ 0 ₅ S ₂ ⁺ [M+H] ⁺ : 375.0791, found: 375.0792.

[00395] 4-(A-(4-nitrosulfonyl)benzylsulfondiimidoyl)morpholine (E9)

Ns-N ' _W VNH

P f ί - 0

[00396] Following general procedure B, sulfinamidine P11 (170 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc) ₂ (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 pl_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 3:2 to 2:3 ) afforded sulfondiimidamide E9 as a colourless oil (171 mg, 0.40 mmol, 81%). mp 102-104 °C (MeCN);

RfO.44 (CH ₂ CI ₂ /ethyl acetate, 1:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.26 (d, J = 8.9 Hz, 2H), 7.94 (d, J = 8.9 Hz, 2H), 7.44-7.31 (m, 5H), 4.68 (d, J= 13.8 Hz, 1H), 4.61 (d, J= 13.8 Hz, 1H), 4.60 (s, 1H), 3.56 (ddd, J = 11.5, 6.4, 3.0 Hz, 2H), 3.47 (ddd, J = 11.5, 6.4, 3.0 Hz, 2H), 3.23 (ddd, J = 12.4, 6.5, 3.0 Hz, 2H), 3.12 (ddd, J= 12.4, 6.5, 3.0 Hz, 2H); ¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 149.6, 148.9, 131.9, 128.7, 128.1, 128.0, 127.6, 123.9, 65.7, 58.3, 46.2;

IR (ATR): v (cm ^-1 ) = 1528, 1382, 1352, 1292, 1256, 1146, 1060, 746;

HRMS (ESI ⁺ ) calcd. for C ₁₇ H _2i N ₄ 0 ₅ S ₂ ⁺ [M+H] ⁺ : 425.0948, found: 425.0948.

[00397] fV-(4-Nosyl)-1 -morpholino-1 -(4-(5-(p-tolyl)-3-(trifluoromethyl)-1 H-pyrazol-

1-yl)phenyl)-A6-sulfanediimine (E10)

[00398] Following general procedure B, sulfinamidine P12 (275 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 2 h. Purification by flash column chromatography (C^Ch/ethyl acetate, 10:1 to 5:1 ) afforded sulfondiimidamide E10 as a colourless oil (297 mg, 0.47 mmol, 94%).

RfO.43 (CH ₂ CI ₂ /ethyl acetate, 7:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.23 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 8.9 Hz, 2H), 7.89 (d, J= 8.8 Hz, 2H), 7.47 (d, J= 8.8 Hz, 2H), 7.17 (d, J= 8.1 Hz, 2H), 7.12 (d, J= 8.1 Hz, 2H), 6.90 (s, 1 H), 3.70 (s, 1H), 3.55 (ddd, J= 7.5, 5.3, 4.1 Hz, 4H), 2.97 (ddd, J = 6.1, 3.6, 2.2 Hz, 4H), 2.32 (s, 3H);

¹³ C NMR (101 MHz, CD ₃ CN): d (ppm) = 150.7, 150.3, 146.6, 144.2 (q, J = 38.1 Hz), 144.1, 140.8, 134.9, 130.4, 129.9, 129.6, 128.8, 126.7, 126.6, 125.1, 122.4 (q, J = 268.2 Hz), 107.2 (q, J= 1.7 Hz), 66.7, 47.4, 21.3;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -62.8 (s);

IR (ATR): v (cm ^-1 ) = 1529, 1472, 1381, 1237, 1154, 1088, 1069, 969;

HRMS (ESP) calcd. for Cay^eFsNeOsSa ^* [M+H] ⁺ : 635.1353, found: 635.1351. [00399] 1 -(4-(dibenzo[b,/][1 ,4]oxazepin-11 -yl)piperazin-1 -yl)-1 -(4-fluorophenyl)-/V-

(4-nosyl)-A6-sulfanediimine (E11 )

[00400] Following general procedure B, sulfinamidine P3 (172 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and Amoxapine (235 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 2 h. Purification by flash column chromatography (petrol/ethyl acetate, 2:1 to 1:1 ) afforded sulfondiimidamide E11 as a pale-yellow oil (293 mg, 0.45 mmol, 90%).

Rf0.68 (petrol/ethyl acetate, 1:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ CO): <5 (ppm) = 8.31 (d, J = 9.0 Hz, 2H), 8.17 (d, J = 9.0 Hz, 2H), 8.10-8.06 (m, 2H), 7.48 (dd, J= 8.7, 2.6 Hz, 1H), 7.36-7.27 (m, 4H), 7.14-7.05 (m, 3H), 7.00 (ddd, J= 7.8, 6.8, 2.3 Hz, 1H), 4.32 (s, 1H), 3.58 (br. s, 4H), 3.29 (br. s, 4H).

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ CO): <5 (ppm) = 166.2 (d, J= 253.9 Hz), 160.1, 159.0, 152.5, 150.6,

150.4, 140.6, 133.8, 132.3 (d, J = 3.0 Hz), 131.6 (d, J = 9.7 Hz), 130.9, 129.6, 128.9, 127.8,

126.5, 125.6, 125.4, 124.8, 123.8, 121.0, 117.1 (d, J= 23.0 Hz), 47.5, 46.8;

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ CO): <5 (ppm) = -106.2 (tt, J= 8.5, 5.0 Hz);

IR (ATR): v (cm- ¹ ) = 1588, 1528, 1472, 1382, 1241, 1151, 1087, 731;

HRMS (ESF) calcd. for C^H^CIFNeOsS^ [M+H] ⁺ : 655.0995, found: 655.0993.

[00401] 1-(4-(pyrimidin-2-yl)piperazin-1-yl)-1-(4-fluorophenyl)-/V-( 4-nosyl)-A6- sulfanediimine (E12) [00402] Following general procedure B, sulfinamidine P3 (172 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and 2-(piperazin-1-yl)pyrimidine (123 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (petrol/ethyl acetate, 1:1 to 1:3 ) afforded sulfondiimidamide E12 as a colourless oil (233 mg, 0.46 mmol, 92 %).

Rf0.31 (petrol/ethyl acetate, 1:2);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.26 (d, J = 4.8 Hz, 2H), 8.23 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 8.9 Hz, 2H), 7.95-7.91 (m, 2H), 7.27-7.22 (m, 2H), 6.54 (t, J = 4.8 Hz, 1H), 3.78-3.69 (m, 5H), 3.05 (ddd, J = 6.5, 4.1, 2.7 Hz, 4H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 166.5 (d, J = 253.9 Hz), 162.2, 158.8, 150.6, 150.3, 131.7 (d, J= 3.2 Hz), 131.6 (d, J= 9.9 Hz), 128.8, 125.0, 117.3 (d, J= 23.1 Hz), 111.6, 47.0, 43.8;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -106.4 (tt, J= 8.6, 5.0 Hz);

IR (ATR): v (cm ^-1 ) = 1585, 1528, 1488, 1448, 1352, 1303, 1154, 1088, 1049, 950;

HRMS (ESF) calcd. for C ₂ oH _2i FN ₇ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 506.1075, found: 506.1073.

[00403] 1 -(4-(benzo[c/]isothiazol-3-yl)piperazin-1 -yl)-1 -(4-fluorophenyl)-/V-(4- nosyl)-A6-sulfanediimine (E13)

[00404] Following general procedure B, sulfinamidine P3 (172 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and 3-(piperazin-1-yl)benzo[c(]isothiazole (165 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (ChhCh/ethyl acetate, 12:1 to 7:1 ) afforded sulfondiimidamide E13 as a pale-yellow oil (253 mg, 0.45 mmol, 90 %).

RfO.54 (CH ₂ CI ₂ /ethyl acetate, 10:1); ¹ H NMR (400 MHz, (CD ₃ ) ₂ CO): <5 (ppm) = 8.30 (d, J = 8.9 Hz, 2H), 8.18 (d, J = 8.9 Hz, 2H), 8.13-8.08 (m, 2H), 7.98-7.90 (m, 2H), 7.50 (ddd, J= 8.2, 7.0, 1.0 Hz, 1H), 7.40-7.33 (m, 3H), 4.35 (s, 1H), 3.57-3.48 (m, 4H), 3.36 (t, J= 4.9 Hz, 4H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ CO): <5 (ppm) = 166.2 (d, = 253.9 Hz), 163.7, 153.4, 150.5, 150.3,

132.1 (d, J = 3.0 Hz), 131.5 (d, J = 9.7 Hz), 128.8, 128.6, 128.3, 125.0, 124.7, 124.6, 121.4,

117.1 (d, J= 23.0 Hz), 50.0, 46.9;

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ CO): <5 (ppm) = -106.2 (tt, = 9.1, 5.1 Hz).

IR (ATR): v (cm ^-1 ) = 1589, 1528, 1489, 1383, 1350, 1263, 1087, 1056, 891, 731;

HRMS (ESF) calcd. for C ₂₃ H ₂₂ FN ₆ 0 ₄ S ₃ ⁺ [M+H] ⁺ : 561.0843, found: 561.0842.

[00405] 1 -(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-1 -(4-fluorophenyl)-/V-(4- nosyl)-A6-sulfanediimine (E14)

[00406] Following general procedure B, sulfinamidine P3 (172 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (165 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 12:1) afforded sulfondiimidamide E14 as a pale-yellow oil (221 mg, 0.46 mmol, 92 %).

Rf0.60 (CH ₂ CI ₂ /ethyl acetate, 10:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.11 (d, J= 9.0 Hz, 2H), 8.01 (d, J= 9.0 Hz, 2H), 8.00- 7.96 (m, 2H), 7.27-7.21 (m, 2H), 7.05 (d, J= 5.1 Hz, 1H), 6.56 (d, J= 5.1 Hz, 1H), 4.09 (dt, J = 14.9, 1.8 Hz, 1 H), 3.91 (dt, J= 14.9, 1.8 Hz, 1H), 3.85 (s, 1H), 3.68-3.59 (m, 1H), 3.18 (ddd, J= 12.4, 7.4, 5.1 Hz, 1H), 2.81-2.67 (m, 2H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 166.3 (d, J = 253.7 Hz), 150.3, 149.9, 133.6, 132.8 (d, J= 3.0 Hz), 131.5, 131.1 (d, J= 9.7 Hz), 128.7, 125.9, 124.8, 124.7, 117.3 (d, J= 23.0 Hz), 47.4, 45.1, 25.6;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -106.2 (tt, J= 8.6, 5.0 Hz); IR (ATR): v (cm ^-1 ) = 1589, 1526, 1382, 1349, 1299, 1236, 1151, 1088, 1049, 968, 734;

HRMS (ESF) calcd. for C ₁₉ H ₁₈ FN ₄ 0 ₄ S ₃ ⁺ [M+H] ⁺ : 481.0469, found: 481.0467.

[00407] 1 -(1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1 -(4-fluorophenyl)-/V-(4-nosyl)-A6- sulfanediimine (E15)

[00408] Following general procedure B, sulfinamidine P3 (172 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and 1,4-dioxa-8-azaspiro[4.5]decane (107 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 4:1 to 2:1 ) afforded sulfondiimidamide E15 as a pale-yellow solid (203 mg, 0.42 mmol, 84 %). mp 122-124 °C (CH ₂ CI ₂ );

RfO.57 (CH ₂ CI ₂ /ethyl acetate, 2:1);

¹ H NMR (400 MHz, CD ₃ CN): d (ppm) = 8.23 (d, J = 8.9 Hz, 2H), 8.02 (d, J = 8.9 Hz, 2H), 7.96- 7.91 (m, 2H), 7.29-7.22 (m, 2H), 3.82 (s, 4H), 3.63 (s, 1H), 3.13 (t, J= 5.8 Hz, 4H), 1.67-1.56 (m, 4H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 166.3 (d, J = 253.8 Hz), 150.6, 150.3, 132.5 (d, J = 3.0 Hz), 131.3 (d, J= 9.6 Hz), 128.8, 125.0, 117.3 (d, = 23.1 Hz), 106.4, 65.1, 45.7, 35.0;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -106.4 (tt, J= 8.8, 5.0 Hz);

IR (ATR): v (cm ^-1 ) = 1587, 1530, 1471, 1382, 1230, 1153, 1084, 1037, 964;

HRMS (ESF) calcd. for C ₁₉ H ₂₂ FN ₄ 0 ₆ S ₂ ⁺ [M+H] ⁺ : 485.0959, found: 485.0951.

[00409] 1 -(4-cyanopiperidin-1 -yl)-1 -(4-fluorophenyl)-/V-(4-nosyl)-A6- sulfanediimine (E16) [00410] Following general procedure B, sulfinamidine P3 (172 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and piperidine-4-carbonitrile (83 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 10:1 to 4:1 ) afforded sulfondiimidamide E16 as a white solid (171 mg, 0.38 mmol, 76 %). mp 154-156 °C (CH ₂ CI ₂ );

Rf0.50 (CH ₂ CI ₂ /ethyl acetate, 5:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.32 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 8.9 Hz, 2H), 7.95-7.89 (m, 2H), 7.47-7.41 (m, 2H), 5.41 (s, 1H), 3.31-3.17 (m, 2H), 2.93 (tt, J= 8.5, 4.0 Hz, 1 H), 2.88-2.77 (m, 2H), 1.93-1.83 (m, 2H), 1.75-1.58 (m, 2H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 164.7 (d, J= 252.6 Hz), 149.12, 149.10, 132.1 (d, J = 2.8 Hz), 130.5 (d, = 9.8 Hz), 128.0, 124.1, 121.5, 116.4 (d, J= 23.0 Hz), 44.3, 43.7, 27.5, 27.5, 24.4;

IR (ATR): v (cm ^-1 ) = 1526, 1381, 1347, 1294, 1146, 1087, 1055, 952, 836;

HRMS (ESI ⁺ ) calcd. for C^H^FNsCUSa ⁺ [M+H] ⁺ : 452.0857, found: 452.0856.

[00411] /V-((4-fluorophenyl)(imino)(methyl(pyridin-2-ylmethyl)amino) -A6- sulfaneylidene)-4-nitrobenzenesulfonamide (E17)

[00412] Following general procedure B, sulfinamidine P3 (172 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc) ₂ (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and A/-methyl-1-(pyridin-2-yl)methanamine (92 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 2:1 to 2:3 ) afforded sulfondiimidamide E17 as a pale-yellow oil (169 mg, 0.37 mmol, 73 %). Rf0.30 (CH ₂ CI ₂ /ethyl acetate, 1:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ CO): <5 (ppm) = 8.47 (ddd, J = 4.8, 1.8, 1.0 Hz, 1 H), 8.27 (d, J = 8.9 Hz, 2H), 8.16-8.10 (m, 4H), 7.77 (td, J= 7.8, 1.8 Hz, 1H), 7.50 (dt, J= 7.8, 1.0 Hz, 1H), 7.38- 7.32 ( , 2H), 7.27 (ddd, J = 7.8, 4.8, 1.0 Hz, 1 H), 4.71-4.06 (br. s, 1 H), 4.59 (d, J = 15.3 Hz, 1 H), 4.52 (d, J= 15.3 Hz, 1H), 2.74 (s, 3H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ CO): <5 (ppm) = 166.0 (d, J= 253.4 Hz), 156.9, 150.7, 150.2, 150.0, 137.7, 134.2 (d, J = 3.1 Hz), 131.4 (d, J = 9.7 Hz), 128.8, 124.6, 123.5, 123.2, 116.9 (d, J = 23.0 Hz), 56.2, 35.8;

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ CO): <5 (ppm) = -106.8 (tt, J= 8.7, 5.1 Hz);

IR (ATR): v (cm ^-1 ) = 1589, 1526, 1349, 1297, 1233, 1150, 1087, 1048, 730;

HRMS (ESI ⁺ ) calcd. for C^H^FNsCUS^ [M+H] ⁺ : 464.0857, found: 464.0858.

[00413] 1-(pyrrolidin-1-yl)-1-(4-fluorophenyl)-/V-(4-nosyl)-A6-sulfa nediimine (E18)

[00414] Following general procedure B, sulfinamidine P3 (172 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 pl_, 1.50 mmol, 3.00 equiv.) and pyrrolidine (53 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 10:1 to 5:1 ) afforded sulfondiimidamide E18 as a white solid (160 mg, 0.39 mmol, 78 %). mp 124-126 °C (CH ₂ CI ₂ );

Rf0.50 (CH ₂ CI ₂ /ethyl acetate, 9:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.22 (d, J = 9.0 Hz, 2H), 8.00 (d, J = 9.0 Hz, 2H), 7.99- 7.95 (m, 2H), 7.27-7.21 (m, 2H), 3.65 (s, 1H), 3.24-3.17 (m, 2H), 3.16-3.09 (m, 2H), 1.73-1.67 (m, 4H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 166.3 (d, J = 253.4 Hz), 150.6, 150.5, 133.7 (d, J = 3.1 Hz), 131.5 (d, J= 9.7 Hz), 128.8, 124.9, 117.2 (d, J= 23.1 Hz), 49.3, 25.9;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -106.9 (tt, J= 8.7, 5.1 Hz); IR (ATR): v (cm ^-1 ) = 1588, 1521, 1381, 1348, 1293, 1234, 1148, 1083, 954, 849, 616;

HRMS (ESI ⁺ ) calcd. for Ci ₆ Hi ₈ FN ₄ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 413.0748, found: 413.0747.

[00415] /V-((diethylamino)(4-fluorophenyl)(imino)-A6-sulfaneylidene) -4- nitrobenzenesulfonamide (E19)

[00416] Following general procedure B, sulfinamidine P3 (172 mg, 0.50 mmol,

1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (209 mI_, 1.50 mmol, 3.00 equiv.) and diethylamine (55 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 24:1 to 15:1) afforded sulfondiimidamide E19 as a pale-yellow (115 mg, 0.28 mmol, 56 %).

RfOAO (CH ₂ CI ₂ /ethyl acetate, 15:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.20 (d, J = 9.0 Hz, 2H), 7.97 (d, J = 9.0 Hz, 2H), 7.94- 7.89 (m, 2H), 7.23-7.17 (m, 2H), 3.43 (s, 1H), 3.27 (dq, J = 11.8, 7.1 Hz, 4H), 1.05 (t, J= 7.1 Hz, 6H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 166.1 (d, J = 253.1 Hz), 150.53, 150.47, 136.4 (d, J = 3.1 Hz), 131.1 (d, J= 9.6 Hz), 128.7, 124.9, 117.1 (d, J= 23.1 Hz), 43.1, 14.3;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -107.3 (tt, J= 8.6, 5.1 Hz);

IR (ATR): v(crrr ¹ ) = 1589, 1526, 1489, 1382, 1349, 1298, 1235, 1151, 1087, 1045, 1003, 766, 613;

HRMS (ESF) calcd. for C ₁₆ H ₂ oFN ₄ 0 ₄ S ⁺ [M+H] ⁺ : 415.0905, found: 415.0904.

[00417] /V-(Azepan-1-yl(4-fluorophenyl)(imino)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E50) [00418] Following General Procedure B, sulfinamidine P3 (172 mg, 0.50 mmol,

1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (2.5 ml_), Et ₃ N (0.21 mL, 1.50 mmol, 3.00 equiv.) and azepane (150 mg, 1.50 mmol, 3.00 equiv.) were combined at room temperature for 15 min. Purification by flash column chromatography (petrol/ethyl acetate, 2:1 to 2:3) afforded sulfondiimidamide 8ad as a colourless oil (190 mg, 0.43 mmol, 86%).

RfO.50 (petrol/ethyl acetate, 1:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.21 (d, J = 8.9 Hz, 2H), 7.99 (d, J = 8.9 Hz, 2H), 7.93- 7.88 (m, 2H), 7.23-7.17 (m, 2H), 3.53 (s, 1H), 3.35 (ddd, J= 13.8, 7.0, 4.7 Hz, 2H), 3.26 (ddd, J= 13.8, 6.9, 4.5 Hz, 2H), 1.71-1.49 (m, 8H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 166.0 (d, J = 253.1 Hz), 150.7, 150.4, 135.7 (d, J = 3.1 Hz), 130.9 (d, J= 9.8 Hz), 128.7, 124.9, 117.1 (d, J = 23.0 Hz), 49.5, 29.6, 27.1;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) =-107.2 (tt, J= 8.5, 5.1 Hz);

IR (ATR): v (cm ^-1 ) = 1589, 1528, 1489, 1350, 1300, 1235, 1151, 1088, 1046, 1009;

HRMS (ESF) calcd. for C ₁₈ H ₂₂ FN ₄ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 441.1061, found: 441.1054.

[00419] yV-((R)-(4-Fluorophenyl)((S)-2-(methoxymethyl)pyrrolidin-1-y l)(((4- nitrophenyl)sulfonyl)imino)-A ⁶ -sulfaneylidene)acetamide (E51 a)

[00420] V-((S)-(4-Fluorophenyl)((S)-2-(methoxymethyl)pyrrolidin-1-yl )(((4- nitrophenyl)sulfonyl)imino)-A ⁶ -sulfaneylidene)acetamide (E51 b) Step 1

[00421] An oven-dried 25 ml_ round-bottom flask containing primary sulfinamidine P3 (343 mg, 1.00 mmol, 1.00 equiv.) and Phl(OAc)2 (483 mg, 1.50 mmol, 1.50 equiv.) was sealed and subjected to three N2 evacuation/refill cycles before pre-sparged anhydrous toluene (5.0 ml_) was added. EΐbN (0.42 ml_, 3.00 mmol, 3.00 equiv.) was added to the solution, followed immediately by the addition of (S)-(+)-2-(methoxymethyl)pyrrolidine (346 mg, 3.00 mmol, 3.00 equiv.). The reaction mixture was then stirred at room temperature for 30 min until completion (judged by TLC). The crude product was purified by flash column chromatography (CH2Cl2/ethyl acetate, 20:1 to 4:1) without an aqueous work-up to afford a mixture of sulfondiimidamide diastereoisomers as a colourless oil (344 mg, 0.75 mmol, 75%).

Step 2

[00422] This diastereoisomers mixture (344 mg, 0.75 mmol, 1.00 equiv.) was then dissolved in anhydrous CH2CI2 (3.7 ml_). EΐbN (0.42 ml_, 1.50 mmol, 2.00 equiv.) was then added, followed by the addition of AC2O (106 pl_, 1.13 mmol, 1.50 equiv.) and DMAP (18.3 mg, 0.15 mmol, 0.20 equiv.). After being stirred at room temperature for 3h, the reaction mixture was diluted with CH2CI2 (70 ml_) and quenched with sat. aq. NaCI solution (100 ml_). The aqueous phase was separated and extracted with CH2CI2 (2 ^c 30 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 1:1 to 1:2) to afford diastereoisomer E51 a as a colourless oil (174 mg, 0.35 mmol, 35% over two steps) and d/astereo/somer E51b as a colourless oil (173 mg, 0.35 mmol, 35% over two steps). [00423] Diastereoisomer 1 (Sulfur stereochemistry is unknown)

Rf0.59 (petrol/ethyl acetate, 2:3);

¹ H NMR (400 MHz, CDC ): <5 (ppm) = 8.29 (d, J = 8.9 Hz, 2H), 8.14 (d, J = 8.9 Hz, 2H), 8.05- 8.00 (m, 2H), 7.22-7.15 (m, 2H), 4.61 (ddt, J= 8.5, 5.7, 2.8 Hz, 1H), 3.65-3.53 (m, 2H), 3.47 (dd, J = 9.7, 3.0 Hz, 1H), 3.36 (s, 3H), 2.96-2.87 (m, 1H), 2.30-2.16 (m, 1H), 2.13-1.95 (m, 3H), 1.69 (s, 3H); ¹³ C NMR (101 MHZ, CDC ): <5 (ppm) = 176.8, 165.9 (d, J= 258.1 Hz), 149.8, 148.1, 132.6 (d, J = 3.1 Hz), 131.6 (d, J= 9.6 Hz), 128.5, 123.9, 116.8 (d, J = 23.1 Hz), 74.6, 61.3, 59.2, 48.1, 29.0, 26.4, 24.6;

¹⁹ F NMR (377 MHz, CDCb): <5 (ppm) = -102.6 (tt, J= 8.0, 4.9 Hz);

IR (ATR): v (cm ^-1 ) =2360, 2341, 1656, 1530, 1381, 1234, 1162, 1059;

HRMS (ESI ⁺ ) calcd. for C ₂ oH ₂₄ FN ₄ 0 ₆ S ₂ ⁺ [M+H] ⁺ : 499.1116, found: 499.1113;

[a ⁵ : +26.7° (c = 1.0, CHCb).

[00424] Diastereoisomer 2 (Sulfur stereochemistry is unknown)

Rf 0.50 (petrol/ethyl acetate, 2:3);

¹ H NMR (400 MHz, CDCb): d (ppm) = 8.22 (d, J = 8.9 Hz, 2H), 8.04-7.98 (m, 4H), 7.20-7.13 (m, 2H), 4.53-4.43 (m, 1H), 3.48-3.38 (m, 2H), 3.28 (s, 3H), 3.21-3.12 (m, 1H), 2.99 (dtd, J = 10.7, 4.2, 2.3 Hz, 1H), 2.10-1.90 (m, 3H), 1.87-1.78 (s, 4H);

¹³ C NMR (101 MHZ, CDCb): d (ppm) = 177.7, 165.9 (d, J= 258.2 Hz), 149.6, 148.2, 132.7 (d, J = 3.1 Hz), 131.3 (d, J= 9.7 Hz), 128.4, 123.8, 116.8 (d, J = 23.0 Hz), 74.3, 61.3, 59.1, 48.1, 28.5, 26.4, 24.5;

¹⁹ F NMR (377 MHz, CDCb): d (ppm) = -102.4 (tt, J= 8.0, 4.9 Hz);

IR (ATR): v (cm ^-1 ) = 2360, 2341, 1657, 1530, 1382, 1236, 1162, 1086, 955;

HRMS (ESI ⁺ ) calcd. for C ₂ oH ₂₄ FN ₄ 0 ₆ S ₂ ⁺ [M+H] ⁺ : 499.1116, found: 499.1114;

[a ⁵ : +13.1° (c = 1.0, CHCb).

[00425] /V-((4-(2-Chlorodibenzo[b,/][1,4]oxazepin-11-yl)piperazin-1- yl)(4- fluorophenyl)(imino)-A ⁶ -sulfaneylidene)-2-(trimethylsilyl)ethane-1 -sulfonamide (E52) [00426] Following General Procedure B, sulfinamidine P50 (161 mg, 0.50 mmol, I.OO equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (0.21 ml_, 1.50 mmol, 3.00 equiv.) and amoxapine (235 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (petrol/ethyl acetate, 2:1) afforded sulfondiimidamide E52 as a pale-yellow oil (245 mg, 0.39 mmol, 77%).

Rf0.40 (petrol/ethyl acetate, 2:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.08-8.03 (m, 2H), 7.44 (dd, J = 8.7, 2.6 Hz, 1 H), 7.36- 7.30 (m, 2H), 7.28 (d, J = 2.6 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.12-6.97 (m, 4H), 3.60 (s, 1 H), 3.53 (app. s, 4H), 3.17 (app. s, 4H), 3.06-3.01 (m, 2H), 1.06-0.99 (m, 2H), 0.00 (s, 9H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 166.4 (d, J = 253.2 Hz), 160.2, 159.4, 152.6, 140.9, 134.0, 132.9 (d, J = 3.0 Hz), 131.5 (d, J = 9.6 Hz), 131.1, 129.9, 127.7, 126.8, 125.8, 125.5, 123.7, 121.2, 117.2 (d, J= 23.0 Hz), 53.3, 47.7, 47.0, 11.3, -1.9;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -107.0 (tt, J = 8.6, 5.1 Hz);

IR (ATR): v (cm ^-1 ) = 1589, 1471, 1383, 1304, 1250, 1132, 1092, 1008, 833;

HRMS (ESF) calcd. for CaHwCIFNsOsSaSr [M+H] ⁺ : 634.1539, found: 634.1534.

[00427] /V-((4-Fluorophenyl)(imino)(morpholino)-A ⁶ -sulfaneylidene)-4- methylbenzenesulfonamide (E53)

[00428] Following General Procedure B, sulfinamidine P51 (156 mg, 0.50 mmol, I.OO equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (0.21 ml_, 1.50 mmol, 3.00 equiv.) and morpholine (66 pl_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (CH2Cb/ethyl acetate, 2:1) afforded sulfondiimidamide E53 as a colourless oil (185 mg, 0.47 mmol, 93%).

R _f 0.44 (CHaC /ethyl acetate, 2:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 7.94-7.89 (m, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.29-7.22 (m, 4H), 3.62-3.25 (br. s, 1H), 3.54 (ddd, J = 11.8, 5.9, 3.7 Hz, 2H), 3.49 (ddd, J = 11.6, 7.6, 3.6 Hz, 2H), 2.98-2.84 (m, 4H), 2.35 (s, 3H); ¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 166.3 (d, J = 253.2 Hz), 143.7, 142.2, 131.5 (d, J = 9.7 Hz), 131.4 (d, J= 2.9 Hz), 130.2, 127.4, 117.1 (d, = 23.1 Hz), 66.6, 47.4, 21.4;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -106.8 (tt, J = 8.6, 5.2 Hz);

IR (ATR): v (cm ^-1 ) = 1589, 1473, 1462, 1383, 1252, 1151, 1087, 1071, 954;

HRMS (ESI ⁺ ) calcd. for C ₁₇ H _2i FN ₃ 0 ₃ S ₂ ⁺ [M+H] ⁺ : 398.1003, found: 398.0997.

[00429] Benzyl((4-(2-chlorodibenzo[b,/][1,4]oxazepin-11-yl)piperazin -1-yl)(4- fluorophenyl)(imino)-A ⁶ -sulfaneylidene)carbamate (E54)

[00430] Following General Procedure B, sulfinamidine P52 (146 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc) ₂ (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (0.21 ml_, 1.50 mmol, 3.00 equiv.) and amoxapine (235 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (petrol/ethyl acetate, 2:1 to 1:1) afforded sulfondiimidamide E54 as a pale-yellow oil (232mg, 0.38 mmol, 77%).

Rf0.65 (petrol/ethyl acetate, 1:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.05-7.97 (m, 2H), 7.39 (dd, J = 8.6, 2.6 Hz, 1 H), 7.35- 7.24 (m, 7H), 7.21-7.17 (m, 2H), 7.10-6.96 (m, 4H), 5.08 (s, 2H), 3.77-3.28 (br. s, 1H), 3.43 (app. s, 4H), 3.09 (app. s, 4H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 166.1 (d, J = 253.0 Hz), 160.1, 159.4, 159.3, 152.6, 140.8, 138.4, 133.9, 132.0 (d, J= 3.0 Hz), 131.3 (d, J= 9.5 Hz), 131.0, 129.8, 129.4, 128.72, 128.70, 127.7, 126.8, 125.7, 125.4, 123.7, 121.1 , 117.1 (d, J = 22.8 Hz), 67.8, 47.7, 46.7;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -107.1 (tt, J= 8.4, 5.1 Hz);

IR (ATR): v (cm ^-1 ) = 1662, 1588, 1470, 1239, 1102, 1008, 933, 905;

HRMS (ESP) calcd. for C ₃₁ H ₂₈ CIFN ₅ 0 ₃ S ⁺ [M+H] ⁺ : 604.1580, found: 604.1578.

[00431] /V-((4-Fluorophenyl)(imino)(morpholino)-A ⁶ -sulfaneylidene)-4- (trifluoromethyl)benzamide (E55) [00432] Following General Procedure B, sulfinamidine P53 (165 mg, 0.50 mmol, I.OO equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (0.21 ml_, 1.50 mmol, 3.00 equiv.) and morpholine (66 pl_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 4 h. Purification by flash column chromatography (petrol/ethyl acetate, 3:2 to 2:3 to 1:2) afforded sulfondiimidamide E55 as a colourless oil (172 mg, 0.41 mmol, 83%).

Rf0.50 (petrol/ethyl acetate, 2:3);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.28 (dq, J= 8.7, 0.9 Hz, 2H), 8.16-8.11 (m, 2H), 7.73 (d, J= 8.7 Hz, 2H), 7.38-7.30 (m, 2H), 3.76-3.49 (br. s, 1H), 3.65 (t, J= 4.7 Hz, 4H), 3.13-3.00 (m, 4H).

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 172.5, 166.4 (d, J = 252.8 Hz), 141.2, 133.3 (q, J = 32.0 Hz), 131.7 (d, J= 3.0 Hz), 131.5 (d, J= 9.6 Hz), 130.4, 126.0 (q, J= 3.8 Hz), 125.2 (q, J = 271.8 Hz), 117.2 (d, J = 22.9 Hz), 67.0, 47.2;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -63.2 (s), -107.3 (tt, J= 8.6, 5.1 Hz).

IR (ATR): v (cm- ¹ ) = 1620, 1491, 1383, 1312, 1285, 1257, 1129, 1111, 1065, 1015, 921, 828;

HRMS (ESF) calcd. for C ₁₈ H ₁₈ F ₄ N ₃ 0 ₂ S ⁺ [M+H] ⁺ : 416.1050, found: 416.1050.

[00433] /V-((4-(2-Chlorodibenzo[b,/][1,4]oxazepin-11-yl)piperazin-1- yl)(4- fluorophenyl)(imino)-A ⁶ -sulfaneylidene)acetamide (E56)

[00434] Following General Procedure B, sulfinamidine P54 (100 mg, 0.50 mmol, I.OO equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (0.21 ml_, 1.50 mmol, 3.00 equiv.) and amoxapine (235 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 4 h. Purification by flash column chromatography (ChhCh/ethyl acetate, 2:1 to 1:2 ) afforded sulfondiimidamide E56 as a colourless oil (190 mg, 0.37 mmol, 74%).

Rf0.55 (ChhCh/ethyl acetate, 1:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.05-8.00 (m, 2H), 7.43 (dd, J = 8.7, 2.6 Hz, 1 H), 7.33- 7.25 (m, 3H), 7.22 (d, J= 8.7 Hz, 1H), 7.12-6.97 (m, 4H), 3.70-3.35 (br. s, 1H), 3.48 (app. s, 4H), 3.11 (app. s, 4H), 2.04 (s, 3H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 179.9, 166.1 (d, J = 252.3 Hz), 160.2, 159.4, 152.6, 140.9, 133.9, 132.3 (d, J = 3.1 Hz), 131.2 (d, J = 9.5 Hz), 131.1, 129.9, 127.7, 126.8, 125.7, 125.5, 123.7, 121.1, 117.1 (d, J= 23.0 Hz), 47.8, 46.5, 27.1;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -107.7 (tt, J = 8.7, 5.1 Hz);

IR (ATR): v (cm ^-1 ) = 1588, 1558, 1488, 1471, 1363, 1240, 1155, 1101, 934, 833;

HRMS (ESP) calcd. for CasHa^IFNsOaS ^* [M+H] ⁺ : 512.1318, found: 512.1318.

[00435] /V-((4-(2-Chlorodibenzo[b,/][1,4]oxazepin-11-yl)piperazin-1- yl)(imino)(2- methylprop-1 -en-1 -yl)-A ⁶ -sulfaneylidene)-4-nitrobenzenesulfonamide (E57)

[00436] Following General Procedure B, sulfinamidine P55 (152 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), toluene (5.0 ml_), Et ₃ N (0.21 ml_, 1.50 mmol, 3.00 equiv.) and amoxapine (235 mg, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 3 h. Purification by flash column chromatography (petrol/ethyl acetate, 3:2 to 2:3) afforded sulfondiimidamide E57 as a pale-yellow oil (215 mg, 0.35 mmol, 70%).

RfO.55 (petrol/ethyl acetate, 1:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.27 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.9 Hz, 2H), 7.45 (dd, J= 8.7, 2.6 Hz, 1H), 7.33 (d, J= 2.6 Hz, 1H), 7.24 (d, J= 8.7 Hz, 1H), 7.14-6.98 (m, 4H), 5.96 (d, J= 1.4 Hz, 1H), 3.60-3.38 (app. s, 4H), 3.44 (s, 1H), 3.35-3.04 (app. s, 4H), 2.07 (d, J= 1.3 Hz, 3H), 1.86 (d, J= 1.4 Hz, 3H); ¹³ C NMR (101 MHZ, CD ₃ CN): <5 (ppm) = 160.2, 159.4, 159.0, 152.6, 150.8, 150.6, 140.9, 134.0, 131.1, 129.9, 128.9, 127.7, 126.9, 125.8, 125.5, 125.0, 123.7, 121.2, 121.0, 47.6, 46.1, 27.2, 20.2;

IR (ATR): v(crrr ¹ ) =1603, 1587, 1559, 1526, 1471, 1349, 1299, 1151, 1089, 1048, 1010, 932, 855;

HRMS (ESI ⁺ ) calcd. for C ₂₇ H ₂₈ CIN ₆ 0 ₅ S ₂ ⁺ [M+H] ⁺ : 615.1246, found: 615.1241.

[00437] /V-(lmino(methyl)(morpholino)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E58)

[00438] Following General Procedure B, sulfinamidine P56 (132 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc) ₂ (242 mg, 0.75 mmol, 1.50 equiv.), CH ₂ CI ₂ (5.0 mL), Et ₃ N (0.21 mL, 1.50 mmol, 3.00 equiv.) and morpholine (66 pl_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 15 min. Purification by flash column chromatography (ethyl acetate/MeOH, 1:0 to 25:1) afforded sulfondiimidamide E58 as a white solid (138 mg, 0.40 mmol, 79%). mp 112-114 °C;

Rf 0.20 (ethyl acetate);

¹ H NMR (400 MHz, CDCh): <5 (ppm) = 8.27 (d, J = 8.8 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 3.70 (t, J= 4.7 Hz, 4H), 3.29 (dt, J= 11.8, 4.7 Hz, 2H), 3.23 (dt, J= 11.8, 4.7 Hz, 2H), 3.02 (d, J = 1.6 Hz, 3H), 2.92 (s, 1H);

¹³ C NMR (101 MHz, CDCh): <5 (ppm) = 149.6, 149.3, 127.8, 124.1, 66.3, 46.9, 37.9;

IR (ATR): v(crrr ¹ ) = 2361, 1528, 1352, 1296, 1259, 1150, 1110, 1090, 1064, 922;

HRMS (ESI ⁺ ) calcd. for CnH^^OsS^ [M+H] ⁺ : 349.0635, found: 349.0640.

[00439] yV-(lmino(1 -methyl-1 H-indol-5-yl)(morpholino)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E59) [00440] Following General Procedure B, sulfinamidine P57 (189 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc) ₂ (242 mg, 0.75 mmol, 1.50 equiv.), CH ₂ CI ₂ (5.0 ml_), Et ₃ N (0.21 ml_, 1.50 mmol, 3.00 equiv.) and morpholine (66 pl_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 10 min. Purification by flash column chromatography (petrol/ethyl acetate, 1:3 to 1:5) afforded sulfondiimidamide E59 as a yellow oil (201 mg, 0.43 mmol, 87%).

RfO.33 (petrol/ethyl acetate, 1:3);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) =8.12 (dd, J= 2.0, 0.6 Hz, 1H), 8.09 (d, J= 8.9 Hz, 2H), 7.96 (d, J = 8.9 Hz, 2H), 7.64 (dd, J = 8.9, 2.0 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 3.2 Hz, 1 H), 6.56 (dd, J= 3.2, 0.8 Hz, 1H), 3.78 (s, 3H), 3.58-3.47 (m, 5H), 2.97 (ddd, J= 11.9, 5.9, 3.6 Hz, 2H), 2.91 (ddd, J= 11.8, 6.0, 3.5 Hz, 2H);

¹³ C NMR (101 MHZ, CD ₃ CN): <5 (ppm) = 150.5, 150.3, 139.6, 133.3, 128.7, 128.6, 124.8, 124.5, 123.0, 121.0, 110.9, 103.3, 66.7, 47.2, 33.6;

IR (ATR): v (cm ^-1 ) = 1526, 1348, 1297, 1150, 1056, 917, 855;

HRMS (ESI ⁺ ) calcd. for C ₁₉ H ₂₂ N ₅ 0 ₅ S ₂ ⁺ [M+H] ⁺ : 464.1057, found: 464.1057.

[00441] /V-(Benzofuran-2-yl(imino)(morpholino)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E60)

[00442] Following General Procedure B, sulfinamidine P58 (183 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc) ₂ (242 mg, 0.75 mmol, 1.50 equiv.), CH ₂ CI ₂ (5.0 ml_), Et ₃ N (0.21 ml_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 20 min. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 7:1 to 3:1) afforded sulfondiimidamide E60 as a white solid (208 mg, 0.46 mmol, 92%). mp 166-168 °C; Rf 0.56 (CH ₂ CI ₂ /ethyl acetate, 4:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.18 (d, J = 8.9 Hz, 2H), 8.00 (d, J = 8.9 Hz, 2H), 7.79-7.72 (m, 1H), 7.62-7.56 (m, 2H), 7.47 (ddd, J= 8.2, 7.1, 1.3 Hz, 1H), 7.38-7.32 (m, 1H), 5.98 (br. s, 1H), 3.66-3.56 (m, 4H), 3.24 (ddd, J= 12.2, 5.5, 3.8 Hz, 2H), 3.17 (ddd, J= 12.0, 5.7, 3.8 Hz, 2H).

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 155.4, 149.0, 148.3, 146.9, 127.94, 127.91, 125.5, 124.4, 123.9, 123.2, 115.4, 112.1, 65.6, 46.0.

IR (ATR): v (cm ^-1 ) = 1528, 1350, 1303, 1159, 1085, 1069, 1052, 926;

HRMS (ESI ⁺ ) calcd. for C ₁₈ H ₁₉ N ₄ 0 ₆ S ₂ ⁺ [M+H] ⁺ : 451.0741, found: 451.0740.

[00443] /V-((2,4-Dimethoxypyrimidin-5-yl)(imino)(morpholino)-A ⁶ -sulfaneylidene)- 4-nitrobenzenesulfonamide (E61)

[00444] Following General Procedure B, sulfinamidine P59 (194 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc) ₂ (242 mg, 0.75 mmol, 1.50 equiv.), CH ₂ CI ₂ (5.0 ml_), Et ₃ N (0.21 mL, 1.50 mmol, 3.00 equiv.) and morpholine (66 pl_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 15 min. Purification by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 1:3 to 0:1) afforded sulfondiimidamide E61 as a white solid (205 mg, 0.43 mmol, 87%). mp 88-90 °C;

Rf 0.38 (ethyl acetate);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.74 (s, 1 H), 8.21 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 3.96 (s, 3H), 3.95 (s, 3H), 3.63-3.56 (m, 4H), 3.54 (s, 1H), 3.27-3.18 (m, 4H);

¹³ C NMR (101 MHZ, CD ₃ CN): <5 (ppm) = 168.2, 167.8, 163.8, 150.5, 150.1, 128.8, 124.8, 112.9, 67.2, 56.5, 55.6, 46.8;

IR (ATR): v (cm ^-1 ) =1572, 1550, 1529, 1468, 1384, 1350, 1301, 1155, 1109, 1066;

HRMS (ESI ⁺ ) calcd. for C ₁₆ H ₂₁ N ₆ 0 ₇ S ₂ ⁺ [M+H] ⁺ : 473.0908, found: 473.0903. [00445] /V-((Diallylamino)(4-fluorophenyl)(imino)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E62)

[00446] Following General Procedure B, sulfinamidine P3 (343 mg, 1.00 mmol, 1.00 equiv.), Phl(OAc)2 (483 mg, 1.50 mmol, 1.50 equiv.), toluene (5.0 mL), Et ₃ N (0.42 mL, 3.00 mmol, 3.00 equiv.) and diallyl amine (292 mg, 3.00 mmol, 3.00 equiv.) were combined at room temperature for 1 h. Purification by flash column chromatography (petrol/ethyl acetate, 3:1 to 1:1) afforded sulfondiimidamide E62 as a pale-yellow oil (400 mg, 0.91 mmol, 91%).

Rf 0.40 (petrol/ethyl acetate, 2:1);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) =8.21 (d, J= 8.9 Hz, 2H), 8.01-7.93 (m, 4H), 7.24-7.18 (m, 2H), 5.63 (ddt, J= 16.6, 10.1, 6.3 Hz, 2H), 5.23-5.09 (m, 4H), 3.93-3.77 (m, 4H), 3.63 (s, 1H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 166.2 (d, J = 253.5 Hz), 150.6, 150.3, 136.1 (d, J = 3.1 Hz), 133.5, 131.3 (d, J= 9.8 Hz), 128.8, 125.0, 119.9, 117.2 (d, J = 23.0 Hz), 50.5;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) =-106.9 (tt, J= 8.4, 5.1 Hz);

IR (ATR): v (cm ^-1 ) = 1589, 1526, 1491, 1350, 1294, 1233, 1150, 1089, 1007, 744;

HRMS (ESF) calcd. for C ₁₈ H ₂ oFN ₄ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 439.0905, found: 439.0895.

[00447] 4-(4-fluoro-/V-(4-nitrosulfonyl)-/V-cyano- phenylsulfondiimidoyl)morpholine (E20)

[00448] In an oven-dried 250 mL round bottom flask under nitrogen atmosphere, sulfondiimidamide E1 (3.05 g, 7.13 mmol, 1.00 equiv.) was dissolved in anhydrous MeCN (35.7 mL) at room temperature. Et ₃ N (1.99 mL, 14.3 mmol, 2.00 equiv.) was then added, followed by the addition of a BrCN solution (2.14 mL, 5.0 M in MeCN, 10.7 mmol, 2.00 equiv.). After stirring at room temperature for 30 min, the reaction mixture was quenched with sat. aq. NaHCC>3 solution (500 ml_). The product was extracted with ethyl acetate (3 ^c 100 ml_). The combined extracts were dried over anhydrous Na2SC>4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ChhCh/ethyl acetate, 8:1 to 4:1) to afford sulfondiimidamide E20 as a white solid (3.16 g, 6.98 mmol, 98%). mp 50-53 °C (CH2CI2);

Rf0.58 (ChhCh/ethyl acetate, 4:1);

¹ H NMR (400 MHz, CDC ): <5 (ppm) = 8.38 (d, J = 8.9 Hz, 2H), 8.22 (d, J = 8.9 Hz, 2H), 8.05- 8.00 (m, 2H), 7.39-7.33 (m, 2H), 3.82 (t, J= 4.7 Hz, 4H), 3.40 (dt, J= 11.7, 4.6 Hz, 2H), 3.25 (dt, J= 11.7, 4.6 Hz, 2H);

¹³ C NMR (101 MHz, CDCb): <5 (ppm) = 167.1 (d, J = 262.0 Hz), 150.5, 147.3, 131.6 (d, J = 10.1 Hz), 128.7, 127.5 (d, J= 3.3 Hz), 124.6, 118.1 (d, J= 23.1 Hz), 109.3, 65.9, 46.7;

¹⁹ F NMR (377 MHz, CDCI ₃ ): <5 (ppm) = -98.3 (tt, J = 7.8, 4.8 Hz);

IR (ATR): v (cm ^-1 ) = 2360, 2208, 1530, 1350, 1166, 1107, 1084, 930, 846;

HRMS (ESI ⁺ ) calcd. for C ₁₇ H ₁₆ FN ₅ 0 ₅ S ₂ Na ⁺ [M+Na] ⁺ : 476.0469, found: 476.0469.

[00449] 4-(4-fluoro-/V-(cyano)-phenylsulfondiimidoyl)morpholine (E21 )

[00450] In an oven-dried 50 ml_ round bottom flask, sulfondiimidamide E20 (650 g, 1.43 mmol, 1.00 equiv.) was dissolved in anhydrous MeCN (14.3 ml_) at room temperature. Then 1-dodecanethiol (860 pl_, 3.58 mmol, 2.50 equiv.) was added, followed by the addition of DBU (536 mI_, 3.58 mmol, 2.50 equiv.). After stirring at room temperature for 15 mins, the reaction was purified by flash column chromatography (ChhCh/ethyl acetate, 4:1 to 1:1 to 0:1) without concentration to afford sulfondiimidamide E21 as a colourless oil (278 mg, 1.04 mmol, 73%).

[00451] Alternatively, E21 may be prepared following General Procedure B using sulfinamidine P60 (92 mg, 0.50 mmol, 1.00 equiv.), Phl(OAc)2 (242 mg, 0.75 mmol, 1.50 equiv.), CH2CI2 (5.0 ml_), EΐbN (0.21 ml_, 1.50 mmol, 3.00 equiv.) and morpholine (66 mI_, 0.75 mmol, 1.50 equiv.) were combined at room temperature for 10 min. Purification by flash column chromatography (petrol/ethyl acetate, 1:2 to 0:1) afforded sulfondiimidamide E21 as a colourless oil that solidified upon standing to give a white solid (117 mg, 0.44 mmol, 87%). R _f 0.38 (ethyl acetate);

¹ H NMR (400 MHz, CDCI ₃ ): d (ppm) = 8.03-7.98 (m, 2H), 7.30-7.25 (m, 2H), 3.75 (dt, J = 5.0, 3.0 Hz, 4H), 3.12-3.03 (m, 5H);

¹³ C NMR (101 MHz, CDCI ₃ ): d (ppm) = 166.1 (d, J = 258.1 Hz), 130.9 (d, J = 9.5 Hz), 128.6 (d, J = 3.1 Hz), 117.1 (d, = 22.9 Hz), 113.0, 66.2, 46.8;

¹⁹ F NMR (377 MHz, CDCI ₃ ): d (ppm) = -102.5 (tt, J= 8.0, 4.9 Hz);

IR (ATR): v (cm ^-1 ) = 2186, 1588, 1490, 1226, 1109, 924, 839;

HRMS (ESI ⁺ ) calcd. for CnH ₁₄ FN ₄ OS ⁺ [M+H] ⁺ : 269.0867, found: 269.0869.

[00452] 4-(4-fluoro-/V-(4-nitrosulfonyl)-/V-(mesyl)- phenylsulfondiimidoyl)morpholine (E22)

[00453] In an oven-dried 25 mL round bottom flask under nitrogen atmosphere, sulfondiimidamide E1 (190 mg, 0.44 mmol, 1.00 equiv.) was dissolved in anhydrous CH2CI2 (2.2 ml_) at room temperature. EΐbN (92 mI_, 0.66 mmol, 1.50 equiv.) was then added, followed by the addition of MsCI (61 mg, 0.53 mmol, 1.20 equiv.) and DMAP (11 mg, 0.088 mmol, 0.20 equiv.). After stirring at room temperature for 30 min, the reaction mixture was quenched with sat. aq. NaCI solution (100 ml_). The product was extracted with CH2CI2 (3 ^c 50 ml_). The combined extracts were dried over anhydrous Na2SC>4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ChhCh/ethyl acetate, 5:1) to afford sulfondiimidamide E22 as a white solid (181 mg, 0.36 mmol, 81%). mp 56-58 °C (CH2CI2);

R _f O.47 (ChhCh/ethyl acetate, 5:1);

¹ H NMR (400 MHz, CDC ): <5 (ppm) = 8.23 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.9 Hz, 2H), 7.96- 7.91 (m, 2H), 7.24-7.17 (m, 2H), 3.71 (ddd, J = 5.2, 3.9, 1.2 Hz, 4H), 3.25 (dt, J = 12.1, 4.8 Hz, 2H), 3.19 (dt, J= 11.0, 4.3 Hz, 2H), 3.15 (s, 3H);

¹³ C NMR (101 MHZ, CDCb): d (ppm) = 166.5 (d, J= 260.3 Hz), 150.0, 147.6, 131.5 (d, J= 9.9 Hz), 129.5 (d, J= 3.1 Hz), 128.2, 124.1, 117.4 (d, J= 23.1 Hz), 65.9, 46.4, 44.0; 19 F NMR (377 MHz, CDCh): <5 (ppm) = -100.2 (tt, J= 8.2, 4.7 Hz);

IR (ATR): v (cm ^-1 ) = 1530, 1351, 1307, 1169, 1084, 926, 741;

HRMS (ESI ⁺ ) calcd. for C^^oF^OySs ^* [M+H] ⁺ : 507.0473, found: 507.0470.

[00454] 4-(4-fluoro-/V-(mesyl)phenylsulfondiimidoyl)morpholine (E23)

[00455] In an oven-dried 25 ml_ round bottom flask, sulfondiimidamide E22 (152 mg,

0.30 mmol, 1.00 equiv.) was dissolved in anhydrous MeCN (3.0 ml_) at room temperature. Then 1-dodecanethiol (360 pl_, 1.50 mmol, 5.0 equiv.) was added, followed by the addition of DBU (213 mI_, 1.43 mmol, 4.75 equiv.). After stirring at room temperature for 15 mins, the reaction mixture was quenched with sat. aq. NaCI solution (100 ml_). The product was extracted with ethyl acetate (3 ^c 50 ml_). The combined extracts were dried over anhydrous Na2SC>4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/MeOH, 1:0 to 9:1) to afford sulfondiimidamide E23 as a colourless oil (68 mg, 0.21 mmol, 71%).

R _f 0.50 (ethyl acetate/MeOH, 9:1);

¹ H NMR (400 MHz, CDCh): <5 (ppm) = 7.92-7.86 (m, 2H), 7.12-7.06 (m, 2H), 3.58 (ddd, J = 5.8, 3.8, 2.1 Hz, 4H), 3.15 (s, 1H), 3.01-2.94 (m, 2H), 2.94-2.85 (m, 5H);

¹³ C NMR (101 MHz, CDCh): <5 (ppm) = 165.7 (d, J = 257.0 Hz), 130.3 (d, J = 9.4 Hz), 129.9 (d, J = 3.1 Hz), 116.6 (d, J = 22.7 Hz), 66.3, 46.9, 44.6;

¹⁹ F NMR (377 MHz, CDCh): <5 (ppm) = -103.7 (tt, J= 8.0, 5.1 Hz);

IR (ATR): v (cm ^-1 ) = 1590, 1490, 1292, 1137, 1092, 1051, 1009, 913, 725;

HRMS (ESI ⁺ ) calcd. for C ₁₁ H ₁₇ FN ₃ 0 ₃ S ₂ ⁺ [M+H] ⁺ : 322.0690, found: 322.0685.

[00456] yV-((4-Fluorophenyl)(2-oxooxazolidin-3-yl)((4-nitrobenzoyl)i mino)-A ⁶ - sulfaneylidene)-4-nitrobenzenesulfonamide (E24) [00457] In an oven-dried 25 mL round bottom flask under nitrogen atmosphere, sulfondiimidamide E1 (164 mg, 0.38 mmol, 1.00 equiv.) was dissolved in anhydrous CH2CI2 (1.9 mL) at room temperature. EΐbN (80 pL, 0.57 mmol, 1.50 equiv.) was then added, followed by the addition of 4-nitrobenzoyl chloride (78 mg, 0.42 mmol, 1.10 equiv.). After stirring at room temperature for 1 h, the reaction mixture was quenched with sat. aq. NaCI solution (100 mL). The product was extracted with CH2CI2 (3 ^c 50 mL). The combined extracts were dried over anhydrous Na2SC>4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ChhCL/ethyl acetate, 7:1 to 4:1) to afford sulfondiimidamide E24 as a white solid (207 mg, 0.36 mmol, 94%). mp 222-224 °C (CH2CI2);

R _f O.75 (ChhCh/ethyl acetate, 5:1);

¹ H NMR (400 MHz, CDCb): <5 (ppm) = 8.18 (d, J = 9.0 Hz, 2H), 8.14-8.09 (m, 2H), 8.04-7.97 (m, 4H), 7.94 (d, J = 9.0 Hz, 2H), 7.34-7.28 (m, 2H), 3.87-3.81 (m, 4H), 3.63-3.56 (m, 2H), 3.45-3.39 (m, 2H);

¹³ C NMR (101 MHz, CDCb): <5 (ppm) =169.1, 166.5 (d, J = 260.0 Hz), 150.5, 149.8, 147.4, 139.6, 131.6 (d, J = 9.9 Hz), 130.2, 129.8 (d, J = 3.2 Hz), 128.6, 123.9, 123.5, 117.6 (d, J = 23.0 Hz), 66.2, 46.2;

¹⁹ F NMR (377 MHz, CDCI ₃ ): <5 (ppm) = -100.4 (tt, J= 7.7, 4.9 Hz);

IR (ATR): v (cm ^-1 ) = 1525, 1349, 1272, 1107, 1083, 1066, 936, 839, 720;

HRMS (ESI ⁺ ) calcd. for C ₂₃ H _2i FN ₅ 0 ₈ S ₂ ⁺ [M+H] ⁺ : 578.0810, found: 578.0809.

[00458] 4-(4-fluoro-/V-(4-nitrobenzoyl)phenylsulfondiimidoyl)morphol ine (E25) [00459] In an oven-dried 25 ml_ round bottom flask, sulfondiimidamide E24 (202 g, 0.35 mmol, 1.00 equiv.) was dissolved in anhydrous MeCN (3.5 ml_) at room temperature. Then 1-dodecanethiol (420 pl_, 1.75 mmol, 5.00 equiv.) was added, followed by the addition of DBU (248 mI_, 1.66 mmol, 4.75 equiv.). After stirring at room temperature for 30 min, the reaction mixture was quenched with sat. aq. NaCI solution (120 ml_). The product was extracted with ethyl acetate (3 ^c 50 ml_). The combined extracts were dried over anhydrous Na2SC>4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ChhCh/ethyl acetate, 1:1 to 1:2) to afford sulfondiimidamide E25 as a colourless oil (94 mg, 0.24 mmol, 69%).

Rf0.39 (ChhCh/ethyl acetate, 1:2);

¹ H NMR (400 MHz, CDCh): <5 (ppm) = 8.25-8.16 (m, 4H), 8.13-8.08 (m, 2H), 7.27-7.21 (m, 2H), 3.69 (td, J = 4.8, 1.8 Hz, 4H), 3.50 (s, 1H), 3.13 (dt, J = 12.0, 4.8 Hz, 2H), 3.04 (dt, J = 12.0, 4.8 Hz, 2H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ CO): <5 (ppm) = 171.4, 166.2 (d, J = 252.8 Hz), 150.8, 143.3, 132.2(d, J= 1.7 Hz), 131.5 (d, J= 9.5 Hz), 130.9, 124.0, 117.1 (d, J= 23.0 Hz), 66.9, 47.2;

¹⁹ F NMR (377 MHz, CDCh): <5 (ppm) = -104.0 (tt, J= 8.0, 4.0 Hz);

IR (ATR): v (cm ^-1 ) = 1627, 1590, 1522, 1490, 1287, 1258, 1138, 1110, 918, 721;

HRMS (ESI ⁺ ) calcd. for C ₁₇ H ₁₈ FN ₄ 0 ₄ S ⁺ [M+H] ⁺ : 393.1027, found: 393.1024.

[00460] yV-((4-Fluorophenyl)(2-oxooxazolidin-3-yl)(((3,5- bis(trifluoromethyl)phenyl)carbamoyl)imino)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E26) [00461] In an oven-dried 25 mL round bottom flask under nitrogen atmosphere, sulfondiimidamide E1 (255 mg, 0.60 mmol, 1.00 equiv.) was dissolved in anhydrous MeCN (6.0 mL) at room temperature. DBU (134 pL, 0.90 mmol, 1.50 equiv.) was then added, followed by the addition of 3,5-bis(trifluoromethyl)phenyl isocyanate (230 mg, 0.90 mmol, 1.50 equiv.). After stirring at room temperature for 30 min, the reaction mixture was quenched with sat. aq. NaCI solution (120 mL). The product was extracted with ethyl acetate (3 ^c 50 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 1:1 to 2:3) to afford sulfondiimidamide E26 as a white solid (322 mg, 0.47 mmol, 79%). mp 196-198 °C (CH ₂ CI ₂ );

R _f 0.39 (petrol/ethyl acetate, 1:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 10.01 (s, 1H), 8.18-8.13 (m, 2H), 8.08 (br. s, 4H), 7.85 (br. s, 2H), 7.59-7.51 (m, 3H), 3.69 (t, J= 4.6 Hz, 4H), 3.29 (q, J= 4.3 Hz, 4H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5 (ppm) = 165.5 (d, J= 254.9 Hz), 154.2, 148.9, 147.5, 141.2, 131.9 (d, J= 10.1 Hz), 130.7 (q, J= 32.7 Hz), 130.1 (d, J= 2.8 Hz), 128.7, 123.8, 123.2 (q, J = 272.6 Hz), 117.2, 117.1 (d, = 23.2 Hz), 114.7, 65.3, 45.6;

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -62.0 (s), -103.6 (tt, J= 9.0, 5.1 Hz);

IR (ATR): v (cm ^-1 ) =1665, 1533, 1277, 1224, 1161, 1132, 1085, 940;

HRMS (ESI ⁺ ) calcd. for C ₂₅ H ₂ oF ₇ N ₅ 0 ₆ S ₂ Na ⁺ [M+Na] ⁺ : 706.0635, found: 706.0629.

[00462] 4-(4-fluoro-/V-((3,5- bis(trifluoromethyl)phenyl)carbamoyl)phenylsulfondiimidoyl)m orpholine (E27)

[00463] In an oven-dried 25 mL round bottom flask, sulfondiimidamide E26 (180 mg, 0.26 mmol, 1.00 equiv.) was dissolved in anhydrous MeCN (2.6 mL) at room temperature. Then 1-dodecanethiol (316 pL, 1.32 mmol, 5.00 equiv.) was added, followed by the addition of DBU (187 pL, 1.25 mmol, 4.75 equiv.). After stirring at 0 °C for 30 min, the reaction mixture was quenched with sat. aq. NaCI solution (120 ml_). The product was extracted with ethyl acetate (3 ^c 50 ml_). The combined extracts were dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 1:1 to 1:2) to afford sulfondiimidamide E27 as a colorless oil (95 mg, 0.19 mmol, 72%).

R _f 0.50 (petrol/ethyl acetate, 1:2);

¹ H NMR (400 MHz, CDCh): <5 (ppm) = 8.07-8.02 (m, 2H), 7.93 (s, 2H), 7.67 (br. s, 1H), 7.46 (s, 1 H), 7.24-7.18 (m, 2H), 3.71 (t, J = 4.7 Hz, 4H), 3.43 (s, 1H), 3.10 (dt, J = 11.7, 4.7 Hz, 2H), 3.03 (dt, = 11.7, 4.7 Hz, 2H);

¹³ C NMR (101 MHz, CDCh): <5 (ppm) = 165.7 (d, J = 256.6 Hz), 158.2, 141.1, 132.2 (q, J = 33.1 Hz), 130.2 (d, J= 9.3 Hz), 130.0 (d, J= 2.8 Hz), 123.4 (q, J= 272.6 Hz), 118.5, 116.6 (d, J= 22.6 Hz), 115.8, 66.4, 46.6;

¹⁹ F NMR (377 MHz, CDCh): <5 (ppm) = -63.0 (s), -104.3 (s);

IR (ATR): v (cm ^-1 ) = 1638, 1541, 1492, 1474, 1434, 1387, 1277, 1236, 1176, 1129, 924; HRMS (ESI ⁺ ) calcd. for C ₁₉ H ₁₈ F ₇ N ₄ 0 ₂ S ⁺ [M+H] ⁺ : 499.1033, found: 499.1029.

[00464] 4-(4-fluoro-/V-cyano-/V-phenyl-phenylsulfondiimidoyl)morphol ine (E28)

Cu(MeCN) ₄ PF ₆

PhB OH

[00465] Sulfondiimidamide E21 (83 mg, 0.31 mmol, 1.00 equiv.), phenylboronic acid (94 mg, 0.77 mmol, 2.50 equiv.), Cu(MeCN)4PF6 (58 mg, 0.16 mmol, 0.50 equiv.), N- methylpiperidine (277 mg, 2.79 mmol, 9.00 equiv.) were added to an oven-dried 25 ml_ vial and dissolved in anhydrous MeCN (3.1 ml_) under oxygen atmosphere. The reaction was stirred at room temperature for 3 h until completion (TLC). The reaction mixture was quenched with sat. aq. NaCI solution (80 ml_). The product was extracted with ethyl acetate (3 ^c 30 ml_). The combined extracts were dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The crude product was purified by flash column chromatography (CH ₂ CI ₂ /ethyl acetate, 8:1 to 4:1) to afford sulfondiimidamide E28 as a white solid (81 mg, 0.24 mmol, 76%). mp 107-109°C (CH ₂ CI ₂ ); R _f 0.58 (ChhCh/ethyl acetate, 4:1);

¹ H NMR (400 MHz, CDCb): <5 (ppm) = 8.07-8.02 (m, 2H), 7.32-7.22 (m, 6H), 7.07 (tt, J = 7.2, 1.5 Hz, 1 H), 3.68 (ddd, J= 9.2, 5.5, 3.8 Hz, 4H), 3.14 (dt, J = 5.5, 3.7 Hz, 4H);

¹³ C NMR (101 MHz, CDCb): d (ppm) = 166.0 (d, J= 258.1 Hz), 140.6, 131.2 (d, J= 9.6 Hz), 129.5, 128.7 (d, J= 3.3 Hz), 124.1, 123.9, 117.2 (d, J = 22.9 Hz), 112.8, 66.0, 46.8;

¹⁹ F NMR (377 MHz, CDCb): d (ppm) = -102.3 (tt, J= 8.0, 5.0 Hz);

IR (ATR): v (cm ¹ ) = 2980, 2190, 1588, 1487, 1259, 1238, 1110, 927, 843, 759;

HRMS (ESI ⁺ ) calcd. for C ₁₇ H ₁₈ FN ₄ OS ⁺ [M+H] ⁺ : 345.1180, found: 345.1181.

[00466] 4-(4-fluoro-/V-cyano-/V-((trifluoromethyl)thio)- phenylsulfondiimidoyl)morpholine (E29)

[00467] In an oven-dried 10 mL vial under nitrogen atmosphere, sulfondiimidamide E21 (170 mg, 0.63 mmol, 1.00 equiv.) was dissolved in anhydrous MeCN (1.26 mL) at room temperature. NBS (107 mg, 0.60 mmol, 0.95 equiv.) was then added and stirred at room temperature for 30 min, followed by the addition of a solution of AgSCFs (158 mg, 0.76 mmol, 1.20 equiv.) in anhydrous MeCN (1.9 mL). After stirring at room temperature for an additional 30 min, the reaction mixture was purified by flash column chromatography (CH Cb/ethyl acetate, 50:1 to 20:1 to 10:1) to afford sulfondiimidamide E29 as a colourless oil (119 mg, 0.32 mmol, 51%).

R _f 0.57 (CH Cb/ethyl acetate, 10:1);

¹ H NMR (400 MHz, CDCb): d (ppm) = 7.99-7.94 (m, 2H), 7.35-7.29 (m, 2H), 3.76 (ddd, J = 5.3, 3.9, 1.4 Hz, 4H), 3.18 (ddd, J= 8.0, 5.5, 4.4 Hz, 4H);

¹³ C NMR (101 MHz, CDCb): d (ppm) = 166.5 (d, J = 260.3 Hz), 131.5 (d, J = 9.9 Hz), 130.0 (q, J= 312.0 Hz), 127.2 (d, J= 3.2 Hz), 117.7 (d, J= 23.0 Hz), 110.6, 65.9, 46.9;

¹⁹ F NMR (377 MHz, CDCb): d (ppm) = -49.8 (s), -100.1 (tt, J= 7.8, 4.7 Hz);

IR (ATR): v (cm ^-1 ) =2200, 1586, 1490, 1159, 1108, 1085, 1007, 930, 841;. HRMS (ESI ⁺ ) calcd. for C^H^^OSa ^* [M+H] ⁺ : 369.0461, found: 369.0467.

[00468] 4-(4-fluoro-/V-cyano-/V-(phenoxycarbonyl)- phenylsulfondiimidoyl)morpholine (E30)

[00469] In an oven-dried 25 mL round bottom flask under nitrogen atmosphere, sulfondiimidamide E21 (132 mg, 0.49 mmol, 1.00 equiv.) was dissolved in anhydrous CH2CI2 (2.5 ml_) at room temperature. EΐbN (136 mI_, 0.98 mmol, 2.0 equiv.) was then added, followed by the addition of phenyl chloroformate (115 mg, 0.73 mmol, 1.50 equiv.) and DMAP (12 mg, 0.098 mmol, 0.20 equiv.). After stirring at room temperature for 10 mins, the reaction mixture was quenched with sat. aq. NaCI solution (100 ml_). The product was extracted with CH2CI2 (3 x 40 ml_). The combined extracts were dried over anhydrous Na2SC>4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ChhCh/ethyl acetate, 8:1 to 4:1) to afford sulfondiimidamide E30 as a white solid (177 mg, 0.46 mmol, 93%). mp 132-134 °C (CH2CI2);

R _f 0.50 (ChhCh/ethyl acetate, 4:1);

¹ H NMR (400 MHz, CDC ): <5 (ppm) = 8.12-8.07 (m, 2H), 7.38-7.30 (m, 4H), 7.24-7.19 (m, 1 H), 7.18-7.14 (m, 2H), 3.80 (t, J = 4.7 Hz, 4H), 3.39 (dt, J = 12.2, 5.0 Hz, 2H), 3.32 (dt, J = 12.8, 5.0 Hz, 2H);

¹³ C NMR (101 MHZ, CDCb): d (ppm) = 166.5 (d, J= 260.3 Hz), 154.5, 151.1, 131.4 (d, = 9.9 Hz), 129.3, 127.6 (d, J= 3.0 Hz), 125.8, 121.3, 117.6 (d, = 23.1 Hz), 110.4, 65.8, 46.2;

¹⁹ F NMR (377 MHz, CDCI ₃ ): d (ppm) = -99.8 (tt, J = 7.9, 4.7 Hz);

IR (ATR): v (cm- ¹ ) = 2202, 1697, 1588, 1489, 1237, 1184, 1158, 1107, 928, 838, 728;

HRMS (ESI ⁺ ) calcd. for C ₁₈ H ₁₈ FN ₄ 0 ₃ S ⁺ [M+H] ⁺ : 389.1078, found: 389.1078.

[00470] 4-(4-fluoro-/V-cyano-/V-(benzyl)-phenylsulfondiimidoyl)morph oline (E31 ) [00471] Sulfondiimidamide E21 (120 mg, 0.45 mmol, 1.00 equiv.) was added to an oven-dried 25 ml_ round bottom flask under nitrogen atmosphere and dissolved in anhydrous MeCN (4.5 ml_) at room temperature. DBU (202 pl_, 1.35 mmol, 3.00 equiv.) was then added, followed by the addition of BnBr (192 mg, 1.12 mmol, 2.50 equiv.). After stirring at room temperature for 2.5 h, the reaction mixture was quenched with sat. aq. NaCI solution (120 ml_). The product was extracted with ethyl acetate (3 ^c 40 ml_). The combined extracts were dried over anhydrous Na2SC>4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ChhCh/ethyl acetate, 9:1 to 4:1) to afford sulfondiimidamide E31 as a colorless oil (131 mg, 0.37 mmol, 81%).

R _f 0.63 (ChhCh/ethyl acetate, 4:1);

¹ H NMR (400 MHz, CDCh): <5 (ppm) = 8.00-7.95 (m, 2H), 7.46-7.42 (m, 2H), 7.37-7.33 (m, 3H), 7.30-7.24 (m, 2H), 4.56 (d, J = 14.4 Hz, 1H), 4.38 (d, J = 14.4 Hz, 1H), 3.65 (ddd, J = 11.8, 6.3, 3.2 Hz, 2H), 3.57 (ddd, J= 11.8, 6.3, 3.2 Hz, 2H), 3.03 (ddd, J= 11.9, 6.5, 3.2 Hz, 2H), 2.93 (ddd, J= 11.9, 6.5, 3.2 Hz, 2H);

¹³ C NMR (101 MHz, CDCh): <5 (ppm) = 165.8 (d, J= 257.5 Hz), 139.4, 130.8 (d, J= 9.5 Hz), 128.7 (d, J= 3.2 Hz), 128.5, 127.8, 127.2, 116.9 (d, J= 22.7 Hz), 113.3, 65.9, 46.8, 46.3;

¹⁹ F NMR (377 MHz, CDCh): <5 (ppm) = -102.9 (tt, J= 8.0, 4.9 Hz);

IR (ATR): v (cm- ¹ ) = 2187, 1586, 1489, 1185, 1110, 928, 838;

HRMS (ESI ⁺ ) calcd. for C ₁₈ H ₂ oFN ₄ OS ⁺ [M+H] ⁺ : 359.1336, found: 359.1336.

[00472] 4-(4-fluoro-/V-cyano-/V-(prop-2-yn-1 -yl)- phenylsulfondiimidoyl)morpholine (E32)

[00473] Sulfondiimidamide E21 (55.1 mg, 0.20 mmol, 1.00 equiv.) was added to an oven-dried 10 mL vial under nitrogen atmosphere and dissolved in anhydrous MeCN (2.1 ml_) at room temperature. DBU (92 mI_, 0.62 mmol, 3.00 equiv.) was then added, followed by the addition of propargyl bromide solution (76 mg, 80% wt in toluene, 0.51 mmol, 2.50 equiv.). After stirring at room temperature for 16 h, the reaction mixture was quenched with sat. aq. NaCI solution (100 ml_). The product was extracted with ethyl acetate (3 ^c 30 ml_). The combined extracts were dried over anhydrous Na2SC>4 and concentrated in vacuo. The crude product was purified by flash column chromatography (CH2CI2 /ethyl acetate, 10:1 to 4:1) to afford sulfondiimidamide E32 as a white solid (48.5 mg, 0.16 mmol, 77%). mp 128-131 °C (CH2CI2);

RfO.54 (CH ₂ CI ₂ /ethyl acetate, 4:1);

¹ H NMR (400 MHz, CDC ): <5 (ppm) = 7.99-7.94 (m, 2H), 7.30-7.24 (m, 2H), 4.14 (dd, J= 17.4, 2.5 Hz, 1 H), 4.02 (dd, J= 17.4, 2.5 Hz, 1H), 3.78-3.72 (m, 4H), 3.17 (dt, = 11.9, 4.8 Hz, 2H), 3.07 (dt, J = 11.3, 4.2 Hz, 2H), 2.28 (t, J = 2.5 Hz, 1 H);

¹³ C NMR (101 MHz, CDCb): <5 (ppm) = 166.0 (d, J = 257.9 Hz), 131.0 (d, J = 9.6 Hz), 128.4 (d, J = 3.2 Hz), 117.1 (d, J = 22.8 Hz), 112.9, 81.2, 71.5, 66.1, 47.0, 31.8;

¹⁹ F NMR (377 MHz, CDCI ₃ ): d (ppm) = -102.5 (tt, J= 8.0, 4.9 Hz);

IR (ATR): v (cm- ¹ ) = 2190, 1586, 1489, 1260, 1188, 1110, 928;

HRMS (ESI ⁺ ) calcd. for C ₁₄ H ₁₆ FN ₄ OS ⁺ [M+H] ⁺ : 307.1023, found: 307.1021.

[00474] /V-((Benzylimino)(diallylamino)(4-fluorophenyl)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E63)

[00475] To an oven-dried 25 ml_ round-bottom flask under nitrogen atmosphere was added sulfondiimidamide E62 (300 mg, 0.68 mmol, 1.00 equiv.) and anhydrous CH ₃ CN (2.20 ml_) at room temperature. DBU (0.41 ml_, 2.74 mmol, 4.00 equiv.) was then added and the reaction was stirred at room temperature for 5 min, followed by the addition of BnBr (350 mg, 2.05 mmol, 3.00 equiv.). After being stirred at room temperature for 20 h, the reaction was diluted with ethyl acetate (70 ml_) and quenched with sat. aq. NaCI solution (100 ml_). The aqueous phase was separated and extracted with ethyl acetate (2 ^c 50 ml_). The combined organic layers were dried over anhydrous Na2S0 ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 3:1 to 2:1) to afford sulfondiimidamide E63 as a pale-yellow oil (240 mg, 0.45 mmol, 67%).

R _f 0.40 (petrol/ethyl acetate, 4:1); ¹ H NMR (400 MHz, CDCh): <5 (ppm) = 8.06 (d, J = 8.8 Hz, 2H), 8.00-7.96 (m, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.34-7.28 ( , 4H), 7.27-7.21 ( , 1H), 7.16-7.10 ( , 2H), 5.54 (dddd, J = 17.1, 10.2, 7.1, 6.1 Hz, 2H), 5.22-5.11 (m, 4H), 4.20 (d, J= 15.1 Hz, 1H), 4.11 (d, J= 15.1 Hz, 1H), 3.96 (dd, J= 15.6, 6.2 Hz, 2H), 3.76 (dd, J= 15.1, 7.2 Hz, 2H);

¹³ C NMR (101 MHz, CDCh): <5 (ppm) = 165.2 (d, J= 256.6 Hz), 149.3, 149.0, 139.5, 134.5 (d, J= 3.1 Hz), 131.9, 130.8 (d, J= 9.4 Hz), 128.3, 127.9, 127.0, 126.9, 123.6, 120.2, 116.3 (d, J = 22.7 Hz), 49.2, 46.5;

¹⁹ F NMR (377 MHz, CDCh): <5 (ppm) = -104.3 (tt, J= 8.1, 4.9 Hz);

IR (ATR): v (cm ^-1 ) = 1590, 1528, 1489, 1350, 1302, 1154, 1089, 1056, 930;

HRMS (ESI ⁺ ) calcd. for CasHaeF^C^ [M+H] ⁺ : 529.1374, found: 529.1373.

[00476] /V-(Amino(benzylimino)(4-fluorophenyl)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E64)

[00477] Sulfondiimidamide E63 (260 mg, 0.49 mmol, 1.00 equiv.), 1,3- dimethylbarbituric acid (459 mg, 2.94 mmol, 6.00 equiv.), Pd(PPh3)4 (142 mg, 0.12 mmol, 0.25 equiv.) were dissolved in anhydrous, degassed CH2CI2 (2.50 ml_) in an oven-dried 25 ml_ round-bottom flask under a nitrogen atmosphere. After being stirred at 35 °C for 12 h, the reaction mixture was diluted with ethyl acetate (50 ml_) and quenched with 0.2 M aq. Na2CC solution (60 ml_). The aqueous phase was separated and extracted with ethyl acetate (2 x 30 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 3:2 to 2:3) to afford sulfondiimidamide E64 as a pale- yellow solid (132 mg, 0.29 mmol, 60%). mp 122-124 °C;

R _f 0.60 (petrol/ethyl acetate, 1:1); ¹ H NMR (400 MHz, CDCh): <5 (ppm) = 8.19 (d, J = 8.9 Hz, 2H), 8.04-7.99 (m, 2H), 7.98 (d, J = 8.9 Hz, 2H), 7.30-7.25 ( , 3H), 7.18-7.09 ( , 4H), 6.69-1.87 (br. s, 2H), 4.17 (d, J = 14.1 Hz, 1H), 4.04 (d, J= 14.1 Hz, 1H);

¹³ C NMR (101 MHz, CDCh): d (ppm) = 165.6 (d, J= 257.5 Hz), 149.6, 148.9, 135.6, 133.7 (d, J = 3.1 Hz), 130.5 (d, J = 9.5 Hz), 128.9, 128.3, 128.1, 128.0, 124.0, 116.6 (d, J = 22.8 Hz), 46.4;

¹⁹ F NMR (377 MHz, CDCh): d (ppm) = -103.4 (tt, J= 8.0, 5.0 Hz);

IR (ATR): v (cm ^-1 ) = 1589, 1527, 1492, 1350, 1282, 1236, 1151, 1092, 1025, 1009, 967; HRMS (ESI ⁺ ) calcd. for C^H^F^C^ [M+H] ⁺ : 449.0748, found: 449.0744.

[00478] /V-((Diallylamino)(4-fluorophenyl)(methylimino)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E65)

[00479] To an oven-dried 25 ml_ round-bottom flask under nitrogen atmosphere was added sulfondiimidamide E62 (387 mg, 0.88 mmol, 1.00 equiv.) and anhydrous CH ₃ CN (4.40 ml_) at room temperature. DBU (0.40 ml_, 2.64 mmol, 3.00 equiv.) was then added and the reaction was stirred at room temperature for 5 min, followed by the addition of Mel (0.55 ml_,

8.83 mmol, 10.00 equiv.). After being stirred at room temperature for 18 h, the reaction was diluted with ethyl acetate (60 ml_) and quenched with sat. aq. NaCI solution (100 ml_). The aqueous phase was separated and extracted with ethyl acetate (2 ^c 50 ml_). The combined organic layers were dried over anhydrous NaaSCU and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 2:1 to 1:1) to afford sulfondiimidamide E65 as a colourless oil (288 mg, 0.64 mmol, 72%).

R _f 0.48 (petrol/ethyl acetate, 2:1);

¹ H NMR (400 MHz, CDCh): d (ppm) =8.17 (d, J= 8.9 Hz, 2H), 7.95 (d, J= 8.9 Hz, 2H), 7.88-

7.83 (m, 2H), 7.10-7.04 (m, 2H), 5.52 (dddd, J = 17.1, 10.2, 7.0, 6.1 Hz, 2H), 5.18-5.09 (m, 4H), 3.90 (dd, J= 15.5, 6.2 Hz, 2H), 3.74 (dd, J= 15.3, 7.0 Hz, 2H), 2.61 (s, 3H);

¹³ C NMR (101 MHZ, CDCh): d (ppm) = 165.2 (d, = 256.6 Hz), 149.4, 149.3, 134.6 (d, = 3.2 Hz), 132.0, 130.7 (d, J= 9.3 Hz), 128.0, 123.7, 120.1, 116.3 (d, J= 22.7 Hz), 49.0, 29.7; ¹⁹ F NMR (377 MHz, CDCh): <5 (ppm) = -104.6 (tt, J= 8.0, 5.1 Hz);

IR (ATR): v (cm ^-1 ) = 1588, 1528, 1490, 1350, 1301, 1231, 1154, 1089, 1052, 1010;

HRMS (ESI ⁺ ) calcd. for C ₁₉ H ₂₂ FN ₄ 0 ₄ S ₂ ⁺ [M+H] ⁺ : 453.1061, found: 453.1061.

[00480] yV-(Amino(4-fluorophenyl)(methylimino)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E66)

[00481] Sulfondiimidamide E65 (180 mg, 0.40 mmol, 1.00 equiv.), 1,3- dimethylbarbituric acid (374 mg, 2.40 mmol, 6.00 equiv.) and Pd(PPh3)4 (139 mg, 0.12 mmol, 0.30 equiv.) were dissolved in anhydrous, degassed CH2CI2 (2.00 ml_) in an oven-dried 25 ml_ round-bottom flask under a nitrogen atmosphere. After being stirred at 30 °C for 16 h, the reaction mixture was diluted with ethyl acetate (40 ml_) and quenched with 0.2 M aq. Na2CC>3 solution (60 ml_). The aqueous phase was separated and extracted with ethyl acetate (2 x 30 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 1:1 to 1:2) to afford sulfondiimidamide E66 as a pale- yellow solid (79 mg, 0.21 mmol, 53%). mp 116-118 °C;

R _f O.44 (petrol/ethyl acetate, 1:2);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.24 (d, J = 8.8 Hz, 2H), 7.95-7.70 (m, 5H), 7.40- 7.29 (m, 2H), 4.94 (s, 1H), 2.31 (s, 3H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5 (ppm) = 164.3 (d, = 251.6 Hz), 149.3, 148.9, 134.6 (d, J = 3.8 Hz), 130.3 (d, J = 9.7 Hz), 127.8, 123.9, 116.1 (d, J = 22.9 Hz), 26.9;

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -106.9 (s);

IR (ATR): v (cm ^-1 ) = 1588, 1528, 1489, 1350, 1299, 1236, 1154, 1091, 1034, 1009;

HRMS (ESI ⁺ ) calcd. for C HnF^C^ [M+H] ⁺ : 373.0435, found: 373.0433. [00482] /V-((Cyanoimino)(diallylamino)(4-fluorophenyl)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E67)

[00483] To an oven-dried 50 ml_ round-bottom flask under nitrogen atmosphere was added sulfondiimidamide E62 (573 mg, 1.31 mmol, 1.00 equiv.) and anhydrous CH ₃ CN (6.5 ml_) at room temperature. EΐbN (0.37 ml_, 2.65 mmol, 2.00 equiv.) was then added, followed by the addition of BrCN solution (0.39 ml_, 5.0 M in CH ₃ CN, 1.95 mmol, 1.50 equiv.). After being stirred at room temperature for 20 min, the reaction mixture was diluted with ethyl acetate (80 ml_) and quenched with sat. aq. NaHCC>3 solution (100 ml_). The aqueous phase was separated and extracted with ethyl acetate (2 ^c 40 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 2:1 to 1:1) to afford sulfondiimidamide E67 as a colourless oil (598 mg, 1.29 mmol, 99%).

R _f 0.40 (petrol/ethyl acetate, 2:1);

¹ H NMR (400 MHz, CDCI ₃ ): <5 (ppm) = 8.34 (d, J= 8.9 Hz, 2H), 8.18 (d, J= 8.9 Hz, 2H), 8.05- 7.99 (m, 2H), 7.33-7.26 (m, 2H), 5.68 (ddt, J= 16.9, 10.1, 6.7 Hz, 2H), 5.32-5.21 (m, 4H), 4.05 (dd, J= 14.9, 6.5 Hz, 2H), 3.94 (dd, J= 15.3, 6.8 Hz, 2H);

¹³ C NMR (101 MHz, CDCI ₃ ): d (ppm) = 166.7 (d, J = 261.2 Hz), 150.3, 147.5, 131.4 (d, J = 10.0 Hz), 130.8 (d, J= 3.2 Hz), 130.2, 128.5, 124.4, 122.0, 117.7 (d, J = 23.3 Hz), 109.6, 50.2;

¹⁹ F NMR (377 MHz, CDCI ₃ ): d (ppm) = -99.2 (tt, J= 7.8, 4.7 Hz);

IR (ATR): v (cm ^-1 ) = 2206, 1530, 1350, 1216, 1165, 1082, 939, 744;

HRMS (ESI ⁺ ) calcd. for C^H^FNsC^ [M+H] ⁺ : 464.0857, found: 464.0858.

[00484] Sodium /V-(amino(cyanoimino)(4-fluorophenyl)-A ⁶ -sulfaneylidene)-4- nitrobenzenesulfonamide (E68) [00485] Sulfondiimidamide E67 (250 mg, 0.54 mmol, 1.00 equiv.), 1,3- dimethylbarbituric acid (505 mg, 3.24 mmol, 6.00 equiv.) and Pd(PPh3)4 (125 mg, 0.11 mmol, 0.20 equiv.) were dissolved in anhydrous, degassed CH2CI2 (2.70 ml_) in an oven-dried 25 ml_ round-bottom flask a under nitrogen atmosphere. After being stirred at room temperature for 1.5 h, the reaction mixture was diluted with ethyl acetate (40 ml_) and quenched with 0.2 M aq. Na2CC>3 solution (80 ml_). The aqueous phase was separated and extracted with ethyl acetate (2 ^c 40 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate/ethanol, 10:1 to 4:1) to afford sulfondiimidamide salt E68 as a colourless oil (90 mg, 0.22 mmol, 41%).

R _f 0.50 (ethyl acetate/ethanol, 5:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.21 (d, J = 8.9 Hz, 2H), 7.88 (d, J = 8.9 Hz, 2H), 7.87-7.83 (m, 2H), 7.27-7.21 (m, 2H), 3.99 (s, 1H).

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 163.6 (d, J = 249.3 Hz), 150.5, 148.5, 141.2 (d, J = 2.9 Hz), 129.0 (d, J = 9.2 Hz), 127.9, 123.6, 116.3, 115.2 (d, J = 22.6 Hz).

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -109.1 (tt, J= 9.5, 5.4 Hz).

IR (ATR): v (cm- ¹ ) = 2166, 1473, 1383, 1252, 1152, 1056, 1026, 1007, 955.

HRMS (ESI ) calcd. for C HgFNsCUS [M-Na] : 382.0085, found: 382.0082.

[00486] /V-((Diallylamino)(4-fluorophenyl)(((4-nitrophenyl)sulfonyl) imino)-A ⁶ - sulfaneylidene)-4-(trifluoromethyl)benzamide (E69) [00487] To an oven-dried 25 ml_ round-bottom flask under nitrogen atmosphere was added sulfondiimidamide E62 (285 mg, 0.65 mmol, 1.00 equiv.) and anhydrous CH2CI2 (3.3 ml_) at room temperature. EΐbN (0.18 ml_, 1.29 mmol, 2.00 equiv.) was then added, followed by the addition of 4-(trifluoromethyl)benzoyl chloride (204 mg, 0.98 mmol, 1.50 equiv.). After being stirred at room temperature for 3 h, the reaction mixture was diluted with CH2CI2 (60 ml_) and quenched with sat. aq. NaCI solution (100 ml_). The aqueous phase was separated and extracted with CH2CI2 (2 ^c 40 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 3:1 to 2:1) to afford sulfondiimidamide E69 as a white solid (335 mg, 0.55 mmol, 84%). mp 138-140 °C;

Rf0.41 (petrol/ethyl acetate, 3:1);

¹ H NMR (400 MHz, CDC ): <5 (ppm) = 8.12-8.06 (m, 2H), 7.97 (d, J = 8.9 Hz, 2H), 7.91 (d, J = 8.9 Hz, 2H), 7.83 (d, J= 8.1 Hz, 2H), 7.57 (d, J= 8.1 Hz, 2H), 7.30-7.22 (m, 2H), 5.82 (ddt, J = 16.5, 9.9, 6.6 Hz, 2H), 5.31-5.22 (m, 4H), 4.16 (dd, J = 15.6, 6.6 Hz, 2H), 4.05 (dd, J = 15.6, 6.6 Hz, 2H);

¹³ C NMR (101 MHz, CDCb): d (ppm) = 169.6, 166.2 (d, J = 259.2 Hz), 149.5, 147.5, 137.6, 134.3 (q, J= 32.7 Hz), 132.3 (d, J= 3.1 Hz), 131.6, 131.5 (d, J= 9.7 Hz), 129.4, 128.6, 125.2 (q, J = 3.7 Hz), 123.74, 123.68 (q, = 272.6 Hz), 120.9, 117.3 (d, = 23.1 Hz), 50.6;

¹⁹ F NMR (377 MHz, CDCI ₃ ): d (ppm) = -63.1 (s), -101.4 (tt, J= 8.0, 4.9 Hz);

IR (ATR): v(crrr ¹ ) = 2981, 2888, 1633, 1586, 1528, 1382, 1277, 1249, 1164, 1126, 1065, 949;

HRMS (ESI ⁺ ) calcd. for C ₂₆ H ₂₃ F ₄ N ₄ 0 ₅ S ₂ ⁺ [M+H] ⁺ : 611.1041, found: 611.1039.

[00488] Sodium /V-(Amino(4-fluorophenyl)(((4-nitrophenyl)sulfonyl)imino)-A ⁶ - sulfaneylidene)-4-(trifluoromethyl)benzamide (E70) [00489] Sulfondiimidamide E69 (230 mg, 0.38 mmol, 1.00 equiv.), 1,3- dimethylbarbituric acid (356 mg, 2.28 mmol, 6.00 equiv.) and Pd(PPh3)4 (88 mg, 0.076 mmol, 0.20 equiv.) were dissolved in anhydrous, degassed CH2CI2 (1.90 ml_) in an oven-dried 25 ml_ round-bottom flask under a nitrogen atmosphere. After being stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate (50 ml_) and quenched with 0.2 M aq. Na2CC>3 solution (60 ml_). The aqueous phase was separated and extracted with ethyl acetate (2 x 40 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure to approximately 1/10 ^th of the original volume. At this point, a large amount of solid product precipitated out of solution, which was then separated by filtration and washed with cold CH2CI2 (10 ml_) to afford sulfondiimidamide salt E70 as a white solid (131 mg, 0.24 mmol, 62%). mp 218-220 °C;

R _f 0.40 (ethyl acetate);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.10 (d, J= 8.8 Hz, 2H), 8.04-7.98 (m, 2H), 7.91 (d, J= 8.8 Hz, 2H), 7.83 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.1 Hz, 2H), 7.29-7.22 (m, 2H), 3.60 (s, 1H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5(ppm) = 169.1, 163.4 (d, = 248.5 Hz), 151.3, 148.1, 141.58, 141.57 (d, J= 3.5 Hz), 130.4 (q, J= 31.5 Hz), 129.4 (d, J= 9.1 Hz), 128.8, 128.1, 124.4 (q, J = 3.6 Hz), 124.2 (q, J = 272.6 Hz), 123.3, 114.8 (d, J = 22.5 Hz);

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -61.2 (s), -110.0 (tt, J = 8.9, 5.4 Hz);

IR (ATR): v(crrr ¹ ) = 2981, 2888, 1531, 1462, 1382, 1318, 1251, 1149, 1088, 1068, 1015, 955, 858;

HRMS (ESI ) calcd. for C20H13F4N4O5S2- [M-Na] : 529.0269, found: 529.0259.

[00490] 4-Bromo-/V-((diallylamino)(4-fluorophenyl)(((4- nitrophenyl)sulfonyl)imino)-A ⁶ -sulfaneylidene)benzenesulfonamide (E71) [00491] To an oven-dried 25 ml_ round-bottom flask under nitrogen atmosphere was dissolved sulfondiimidamide E62 (300 mg, 0.68 mmol, 1.00 equiv.) in anhydrous CH2CI2 (3.4 ml_) at room temperature. EΐbN (0.19 ml_, 1.36 mmol, 2.00 equiv.) was then added, followed by the addition of benzenesulfonyl chloride (180 mg, 1.02 mmol, 1.50 equiv.) and DMAP (17 mg, 0.14 mmol, 0.20 equiv.). After being stirred at room temperature for 16 h, the reaction mixture was diluted with CH2CI2 (60 ml_) and quenched with sat. aq. NaCI solution (100 ml_). The aqueous phase was separated and extracted with CH2CI2 (2 ^c 50 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 2:1 to 1:1) to afford sulfondiimidamide E71 as a pale-yellow oil (390 mg, 0.67 mmol, 99%).

RfO.39 (petrol/ethyl acetate, 2:1);

¹ H NMR (400 MHz, CDC ): <5 (ppm) = 8.19 (d, J= 8.9 Hz, 2H), 8.00 (d, J= 8.9 Hz, 2H), 7.81- 7.74 (m, 2H), 7.57-7.51 (m, 2H), 7.47-7.41 (m, 1H), 7.34-7.27 (m, 2H), 7.10-7.04 (m, 2H), 5.72 (ddt, J= 17.0, 10.3, 6.7 Hz, 2H), 5.26-5.14 (m, 4H), 4.05 (dd, J= 15.4, 6.7 Hz, 2H), 3.95 (dd, J= 15.4, 6.9 Hz, 2H);

¹³ C NMR (101 MHz, CDCb): <5 (ppm) = 166.1(d, J = 259.7 Hz), 149.7, 147.5, 141.9, 132.5, 131.8 (d, J = 9.9 Hz), 131.0, 130.7 (d, J = 3.2 Hz), 128.6, 128.3, 126.3, 123.8, 121.3, 116.8 (d, J = 23.1 Hz), 50.5;

¹⁹ F NMR (377 MHz, CDCI ₃ ): <5 (ppm) = -100.7 (tt, J= 8.0, 5.0 Hz);

IR (ATR): v (cm ^-1 ) = 1589, 1529, 1489, 1350, 1327, 1308, 1167, 1068;

HRMS (ESI ⁺ ) calcd. for C ₂₄ H ₂₄ FN ₄ 0 ₆ S ₃ ⁺ [M+H] ⁺ : 579.0837, found: 579.0830.

[00492] Sodium /V-(Amino(((4-bromophenyl)sulfonyl)imino)(4-fluorophenyl)-A ⁶ - sulfaneylidene)-4-nitrobenzenesulfonamide (E72)

[00493] Sulfondiimidamide E71 (355 mg, 0.61 mmol, 1.00 equiv.), 1,3- dimethylbarbituric acid (571 mg, 3.66 mmol, 6.00 equiv.), Pd(PPh3)4 (141 mg, 0.12 mmol, 0.20 equiv.) were dissolved in anhydrous, degassed CH2CI2 (3.00 ml_) in an oven-dried 25 ml_ round-bottom flask under a nitrogen atmosphere. After being stirred at room temperature for 3 h, the reaction mixture was diluted with ethyl acetate (50 ml_) and quenched with 0.2 M aq. Na2CC>3 solution (60 ml_). The aqueous phase was separated and extracted with ethyl acetate (3 x 40 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate/ethanol, 1:0 to 20:1 to 10:1) to afford sulfondiimidamide salt E72 as a pale-yellow oil (160 mg, 0.31 mmol, 50%).

R _f 0.50 (ethyl acetate/ethanol, 10:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 8.16 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.79-7.74 (m, 2H), 7.57-7.53 (m, 2H), 7.43-7.38 (m, 1H), 7.35-7.29 (m, 2H), 7.16-7.10 (m, 2H), 3.56 (s, 1H);

¹³ C NMR (101 MHZ, (CD ₃ ) ₂ SO): <5 (ppm) = 163.3 (d, J= 248.8 Hz), 151.0, 148.2, 145.0, 141.4 (d, J= 2.7 Hz), 130.6, 129.2 (d, J= 9.3 Hz), 128.0, 127.9, 126.1, 123.3, 114.7 (d, J= 22.5 Hz);

¹⁹ F NMR (377 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = -109.8 (tt, J= 9.2, 5.4 Hz);

IR (ATR): v (cm ^-1 ) = 1588, 1528, 1491, 1350, 1283, 1149, 1087, 1029, 1008, 996;

HRMS (ESI ⁺ ) calcd. For C ₁₈ H ₁₄ FN ₄ 0 ₆ S ₃ - [M-Na] : 497.0065, found: 497.0064.

[00494] /V/V-Diallyl-yV-cyano^-iS-ip-toly -S-itrifluoromethy -l H-pyrazol-1 - yl)benzenesulfondiimidamide (E73)

[00495] An oven-dried 100 ml_ round-bottom flask containing primary sulfinamidine P61 (105 mg, 0.27 mmol, 1.00 equiv.) and Phl(OAc)2 (130 mg, 0.40 mmol, 1.50 equiv.) was sealed and subjected to three N2 evacuation/refill cycles before anhydrous toluene (1.35 ml_) was added. Et ₃ N (113 pl_, 0.81 mmol, 3.00 equiv.) was added to the solution, followed immediately by the addition of diallyl amine (130 mg, 1.34 mmol, 5.00 equiv.). After being stirred at room temperature for 40 min, the reaction mixture was diluted with ethyl acetate (30 ml_) and quenched with sat. aq. NaCI solution (50 ml_). The aqueous layer was further extracted with ethyl acetate (2 ^c 30 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 2:1 to 1:1) to afford sulfondiimidamide E73 as a pale- yellow oil (106 mg, 0.22 mmol, 81%).

R _f 0.40 (petrol/ethyl acetate, 3:2);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.03 (d, J= 8.9 Hz, 2H), 7.52 (d, J= 8.9 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.93 (s, 1H), 5.65 (ddt, J = 16.6, 10.2, 6.3 Hz, 2H), 5.28-5.12 (m, 4H), 3.94 (ddt, J = 15.0, 6.1, 1.7 Hz, 2H), 3.87 (ddt, J = 15.9, 6.4, 1.7 Hz, 2H), 3.82 (s, 1 H), 2.35 (s, 3H);

¹³ C NMR (101 MHz, CD ₃ CN): <5 (ppm) = 146.7, 144.2 (q, J = 37.8 Hz), 144.1, 140.9, 139.2, 133.2, 130.4, 129.9, 129.5, 127.1, 126.7, 122.5 (q, J = 268.2 Hz), 120.1, 114.0, 107.1, 50.7, 21.3;

¹⁹ F NMR (377 MHz, CD ₃ CN): <5 (ppm) = -62.9 (s);

IR (ATR): v (cm- ¹ ) = 2188, 1495, 1471, 1373, 1235, 1160, 1133, 1097, 974, 808;

HRMS (ESI ⁺ ) calcd. for C ₂ 4H ₂ 4F ₃ N ₆ S ⁺ [M+H] ⁺ : 485.1730, found: 485.1729.

[00496] fV-((4-Ethoxy-3-(1 -methyl-7-oxo-3-propyl-6,7-dihydro-1 H-pyrazolo[4,3- c ]pyrimidin-5-yl)phenyl)(imino)(4-methylpiperazin-1-yl)-A ⁶ -sulfaneylidene)cyanamide

(E74)

[00497] An oven-dried 25 ml_ round-bottom flask containing primary sulfinamidine P62 (399 mg, 1.00 mmol, 1.00 equiv.) and Phl(OAc)2 (644 mg, 2.00 mmol, 2.00 equiv.) was sealed and subjected to three N ₂ evacuation/refill cycles before pre-sparged anhydrous CH ₃ CN (5.0 ml_) was added. DBU (0.30 ml_, 2.0 mmol, 2.00 equiv.) was added to the solution, followed immediately by the addition of /V-methyl piperazine (401 mg, 4.00 mmol, 4.00 equiv.). After being stirred at room temperature for 30 min (judged by TLC), the reaction mixture was diluted with ethyl acetate (60 ml_) and quenched with sat. aq. NaCI solution (100 ml_). The aqueous layer was further extracted with ethyl acetate (2 ^c 50 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate/ethanol, 4:1 to 1:1 to 1:4 to 1:100 with 2% Et ₃ N) to afford sulfondiimidamide E74 as a pale-yellow oil (306 mg, 0.62 mmol, 62%).

R _f 0.18 (ethyl acetate/ethanol, 1:5);

¹ H NMR (400 MHz, CD ₃ CN): <5 (ppm) = 8.57 (d, J = 2.6 Hz, 1 H), 7.96 (dd, J = 8.9, 2.6 Hz, 1 H), 7.81-4.34 (br. s, 2H), 7.26 (d, J= 9.0 Hz, 1H), 4.26 (q, J= 6.9 Hz, 2H), 4.08 (s, 3H), 3.07 (app. s, 4H), 2.78 (t, J= 7.4 Hz, 2H), 2.37 (app. s, 4H), 2.14 (s, 3H), 1.85-1.66 (m, 2H), 1.45 (t, J = 6.9 Hz, 3H), 0.94 (t, J= 7.3 Hz, 3H);

¹³ C NMR (101 MHZ, CD ₃ CN): <5 (ppm) = 161.4, 154.3, 148.0, 146.8, 138.9, 132.8, 131.5, 127.0, 125.4, 122.9, 114.8, 114.3, 67.1, 54.8, 47.4, 45.7, 38.6, 28.4, 22.8, 14.8, 14.4;

IR (ATR): v(crrr ¹ ) = 2187, 1689, 1596, 1489, 1467, 1394, 1277, 1219, 1128, 1028, 908, 726;

HRMS (ESI ⁺ ) calcd. for C ₂₃ H ₃₂ N ₉ 0 ₂ S ⁺ [M+H] ⁺ : 498.2394, found: 498.2388.

[00498] yV,yV-DiaMyl-yV-5-bromothiophene-2-sulfondiimidamide (E75)

[00499] An oven-dried 100 ml_ round-bottom flask containing primary sulfinamidine E74

(747 mg, 3.00 mmol, 1.00 equiv.) and Phl(OAc)2 (1.45 g, 4.50 mmol, 1.50 equiv.) was sealed and subjected to three N ₂ evacuation/refill cycles before anhydrous toluene (15.0 ml_) was added. Et ₃ N (1.25 ml_, 9.00 mmol, 3.00 equiv.) was added to the solution, followed immediately by the addition of diallylamine (1.46 g, 15.00 mmol, 5.00 equiv.). After being stirred at room temperature for 30 min, the crude product was purified by flash column chromatography (petrol/ethyl acetate, 2:1 to 1:1) to afford sulfondiimidamide E75 as a pale- yellow oil (830 mg, 2.41 mmol, 80%).

R _f 0.25 (petrol/ethyl acetate, 2:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 7.65 (d, J = 4.1 Hz, 1H), 7.42 (d, J = 4.2 Hz, 1H), 5.91 (s, 1H), 5.70 (ddt, J= 16.6, 10.1, 6.2 Hz, 2H), 5.29-5.16 (m, 4H), 3.96 (dd, J = 15.6, 6.1 Hz, 2H), 3.83 (dd, J= 15.5, 6.4 Hz, 2H); ¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 139.9, 133.4, 132.3, 132.1, 120.6, 119.5, 112.9, 49.9;

IR (ATR): v (crrr ¹ ) = 2361, 2341, 2188, 1660, 1642, 1399, 1222, 1174, 968, 931;

HRMS (ESI ⁺ ) calcd. for C ₁₁ H ₁₄ ⁷⁹ BrN ₄ S ₂ ⁺ [M+H] ⁺ : 344.9838, found: 344.9837; calcd. for CnHi ₄ ⁸¹ BrN ₄ S ₂ ⁺ [M+H] ⁺ : 346.9816, found: 346.9813.

[00500] /V-((5-Bromothiophen-2-yl)(cyanoimino)(diallylamino)-A ⁶ -sulfaneylidene)- 2,4-dichlorobenzamide (E76)

[00501] To an oven-dried 50 L round-bottom flask was added sulfondiimidamide E75 (820 mg, 2.38 mmol, 1.00 equiv.) and anhydrous CH ₂ CI ₂ (12.0 mL) at room temperature. Et ₃ N (0.66 mL, 4.73 mmol, 2.00 equiv.) was then added, followed by the addition of 2,4- dichlorobenzoyl chloride (748 mg, 3.57 mmol, 1.50 equiv.) and DMAP (58.2 mg, 0.48 mmol, 0.20 equiv.). After being stirred at room temperature for 15 min, the reaction mixture was diluted with CH ₂ CI ₂ (60 mL) and quenched with sat. aq. NaCI solution (150 mL). The aqueous layer was further extracted with CH ₂ CI ₂ (2 ^c 50 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (petrol/ethyl acetate, 2:1 to 1:1) to afford sulfondiimidamide E76 as a colourless oil (1.22 g, 2.36 mmol, 99%)

R _f 0.59 (petrol/ethyl acetate, 1:1);

¹ H NMR (400 MHz, CDCI ₃ ): <5 (ppm) = 7.89 (d, J = 8.4 Hz, 1 H), 7.62 (d, J = 4.2 Hz, 1 H), 7.43 (d, J= 2.1 Hz, 1 H), 7.28 (dd, J= 8.4, 2.0 Hz, 1H), 7.20 (d, J= 4.2 Hz, 1H), 5.79 (ddt, J= 16.8, 10.2, 6.6 Hz, 2H), 5.35-5.24 (m, 4H), 4.12 (dd, J = 14.7, 6.4 Hz, 2H), 3.98 (dd, J = 15.4, 6.8 Hz, 2H);

¹³ C NMR (101 MHz, CDCI ₃ ): <5 (ppm) = 170.2, 137.9, 135.4, 134.9, 134.2, 132.9, 132.7, 132.1, 130.9, 130.7, 127.1, 125.3, 121.6, 110.6, 50.3.

IR (ATR): v(crrr ¹ ) = 2361, 2202, 1660, 1652, 1582, 1394, 1282, 1241, 1139, 1102, 1054, 885, 858; HRMS (ESI ⁺ ) calcd. for Ci ₈ Hi5 ⁷⁹ BrCl2N ₄ OS2 ⁺ [M+H] ⁺ : 516.9320, found: 516.9323; calcd. for Ci ₈ Hi5 ⁸¹ BrCI ₂ N ₄ OS ₂ ⁺ [M+H] ⁺ : 518.9296, found: 518.9296.

[00502] Sodium /V-(Amino(5-bromothiophen-2-yl)(cyanoimino)-A ⁶ - sulfaneylidene)-2,4-dichlorobenzamide (E77)

[00503] Sulfondiimidamide E76 (530 mg, 1.03 mmol, 1.00 equiv.), 1,3- dimethylbarbituric acid (964 mg, 6.18 mmol, 6.00 equiv.) and Pd(PPh3)4 (237 mg, 0.21 mmol, 0.20 equiv.) were dissolved in anhydrous, degassed CH2CI2 (5.50 ml_) in an oven-dried 25 ml_ round-bottom flask under a nitrogen atmosphere. After being stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate (60 ml_) and quenched with 0.2 M aq. Na2CC>3 solution (100 ml_). The aqueous layer was further extracted with ethyl acetate (2 x 40 ml_). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate/ethanol, 1:0 to 4:1) to afford sulfondiimidamide salt E77 as a colourless oil (284 mg, 0.62 mmol, 60%)

R _f 0.50 (ethyl acetate/ethanol, 4:1);

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 7.65 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.44-7.38 (m, 2H), 7.22 (d, J= 4.0 Hz, 1H), 4.07 (s, 1H);

¹³ C NMR (101 MHz, (CD ₃ ) ₂ SO): <5 (ppm) = 171.1, 149.0, 137.2, 134.0, 131.8, 131.5, 130.4, 130.3, 129.4, 126.9, 116.7, 116.4;

IR (ATR): v (cm ^-1 ) =2361, 2185, 1584, 1472, 1381, 1330, 1251, 1156, 1053, 967;

HRMS (ESI ⁺ ) calcd. for C^He^BrCh^OS [M-Na] : 434.8549, found: 434.8547; calcd. for CI ₂ H ₆ ⁸¹ BrCI ₂ N ₄ OS2 [M-Na] : 436.8524, found: 436.8520. [00504] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).

[00505] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in anyway.

[00506] The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise paragraphed. No language in the specification should be construed as indicating any non-paragraphed element as essential to the practice of the invention.

[00507] The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.

[00508] This invention includes all modifications and equivalents of the subject matter recited in the paragraphs appended hereto as permitted by applicable law.

REFERENCES

1) (a) Scott, K. A.; Njardarson, J. T. Analysis of US FDA-Approved Drugs Containing Sulfur Atoms. Top Curr. Chem. (Cham) 2018, 376, 5. (b) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Sulfur Containing Scaffolds in Drugs: Synthesis and Application in Medicinal Chemistry. Curr. Top. Med. Chem. 2016, 16, 1200-1216.

(2) Reggelin, M.; Zur, C. Sulfoximines: Structures, Properties and Synthetic Applications. Synthesis 2000, 2000, 1-64.

(3) Nandi, G. C.; Arvidsson, P. I. Sulfonimidamides: Synthesis and Applications in Preparative Organic Chemistry. Adv. Synth. Catal. 2018, 360, 2976-3001.

(4) Sehgelmeble, F.; Janson, J.; Ray, C.; Rosqvist, S.; Gustavsson, S.; Nilsson, L. I.; Minidis, A.; Holenz, J.; Rotticci, D.; Lundkvist, J.; Arvidsson, P. I. Sulfonimidamides as Sulfonamides Bioisosteres: Rational Evaluation through Synthetic, in Vitro, and in Vivo Studies with y- Secretase Inhibitors. ChemMedChem 2012, 7, 396-399.

(5) Frings, M.; Bolm, C.; Blum, A.; Gnamm, C. Sulfoximines from a Medicinal Chemist’s Perspective: Physicochemical and in vitro Parameters Relevant for Drug Discovery. Eur. J. Med. Chem. 2017, 126, 225-245.

(6) (a) Lucking, U. Sulfoximines: A Neglected Opportunity in Medicinal Chemistry. Angew. Chem., Int. Ed. 2013, 52, 9399-9408. (b) Chinthakindi, P. K.; Naicker, T.; Thota, N.; Govender, T.; Kruger, H. G.; Arvidsson, P. I. Sulfonimidamides in Medicinal and Agricultural Chemistry. Angew. Chem., Int. Ed. 2017, 56, 4100-4109.

(7) (a) Verbelen, B.; Siemes, E.; Ehnbom, A.; Rauber, C.; Rissanen, K.; Woll, D. Bolm, C. From One PotNH-Sulfoximidations of Thiophene Derivatives to Dithienylethene-Type Photoswitches. Org. Lett. 2019, 21, 4293-4297. (b) Chaabouni, S.; Lohier, J. F.; Barthelemy, A. L.; Glachet, T.; Anselmi, E.; Dagousset, G.; Diter, P.; Pegot, B.; Magnier, E.; Reboul, V. One-Pot Synthesis of Aryl- and Alkyl S-Perfluoroalkylated NH-Sulfoximines from Sulfides. Chem. Eur. J. 2018, 24, 17006-17010. (c) Tota, A.; Zenzola, M.; Chawner, S. J.; St John- Campbell, S.; Carlucci, C.; Romanazzi, G.; Degennaro, L.; Bull, J. A.; Luisi, R. Synthesis of NH-sulfoximines from sulfides by chemoselective one-pot N- and O-transfers. Chem. Commun. 2017, 53, 348-351. (d) Lohier, J.-F.; Glachet, T.; Marzag, H.; Gaumont, A.C.; Reboul, V. Mechanistic Investigation of the NH-sulfoximination of sulfide. Evidence for l 6- sulfanenitrile intermediates. Chem. Commun2017, 53, 2064-2067. (e) Bizet, V.; Hendriks, C. M. M.; Bolm, C. Sulfur imidations: access to sulfimides and sulfoximines. Chem. Soc. Rev. 2015, 44, 3378-3390.

(8) (a) Yu, H.; Li, Z.; Bolm, C. lron(ll)-Catalyzed Direct Synthesis of NH Sulfoximines from Sulfoxides. Angew. Chem., Int. Ed. 2018, 57, 324-327. (b) Zenzola, M.; Doran, R.; Degennaro, L.; Luisi, R.; Bull, J. A. Transfer of Electrophilic NH Using Convenient Sources of Ammonia: Direct Synthesis of NH Sulfoximines from Sulfoxides. Angew. Chem., Int. Ed. 2016, 55, 7203- 7207. (c) Okamura, H.; Bolm, C. Rhodium-Catalyzed Imination of Sulfoxides and Sulfides: Efficient Preparation of N-Unsubstituted Sulfoximines and Sulfilimines. Org. Lett. 2004, 6, 1305-1307.

(9) Briggs, E. L.; Tota, A.; Colella, M.; Degennaro, L.; Luisi, R.; Bull, J. A. Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy-amino-A6-sulfanenitrile Intermediate. Angew. Chem., Int. Ed. 2019, 58, 14303-14310.

(10) Krasovskiy, A.; Knochel, P. Synthesis, 2006, 5, 8

(11) Shavnya, A., Coffey, S. B., Smith, A. C. & Mascitti, V. Palladium-catalyzed sulfination of aryl and heteroaryl halides: direct access to sulfones and sulfonamides. Org. Lett. 15, 6226- 6229. doi: 10.1021/ol403072r (2013).